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Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
In what year do payments to subcontactors count, for tax purposes? For example if I don't make the payment until after Jan 1 but the money was earned the previous year, which tax year does that count for?
I'm pretty sure the answer is obvious but just in case.
share|improve this question
1 Answer
up vote 2 down vote accepted
First you need to understand that each country has its own tax laws which vary.
In the United States companies have a choice of using either the cash or accrual basis of accounting. Under the cash basis the revenue counts in the tax year that the payment was actually received (or paid in the case of the company making the payment).
Under the accrual system, the revenue (or cost) is recognized in the year the work was done. Payment could have occurred either before (pre-payment) or after the work.
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2024-06-03T21:29:47.544Z | 2013-05-18T05:49:05.000Z | 4cbynrhh2jb4brvoadpxrbfy2c2cuv6y | {
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} | cccc_CC-MAIN-2013-20 | Apache w/ PHP and MySQL Support (MIPSel)
From NAS-Central Buffalo - The Linkstation Wiki
Revision as of 08:23, 13 July 2006 by <IP_ADDRESS> (Talk)
Jump to: navigation, search
Originally by Nick and edited by ...
BurnHard, frontalot, Cathedrow & Ralf from linkstationwiki.org
Installing Apache w/ PHP and MySQL Support.
Contents
Opening Comments
Apache, along with PHP and MySQL, is very straight forward to install on a stock LinkStation 2 with the OpenLink firmware installed. If you have experience with building these packages, or compiling in general, it is a snap. If you have little or no experience in such matter, just follow the guide -- everything is reversible.
If you have not already done so, visit the Openlink section and follow the instructions for installing the telnet enabled firmware. You will also need to download and install the [MIPSel Tools] before continuing.
A Remark on "--prefix"
The prefix argument, which you will see in every section below, allows you to install Unix packages to alternate locations. This is very important is the case of the LinkStation since all three packages take over 75 megs to install. You will not be able to install these packages to your root partition and doing so would be very bad.
I chose to create an "opt" directory under "/mnt/hda" to install each of these packages too, using a separate directory for each. This was done to keep the packages separated and easy to manage in the future. You may, of course, alter your install locations in any way but, if you are new to this, I suggest following my example.
It's also a good idea to create a directory to download stuff when using wget, lets use /mnt/hda/misc
MySQL
Begin with MySQL. If you do not wish to compile MySQL support into your system, please skip to the next section.
cd /mnt/hda/misc
• Download the latest recommended release of MySQL from http://www.mysql.com (4.1.13, at the time of this writing).
wget http://www.mirrorservice.org/sites/ftp.mysql.com/Downloads/MySQL-4.1/mysql-4.1.20.tar.gz
tar -zxvf mysql-xxx' (replacing xxx with your MySQL version number)
cd mysql-xxx' (replacing xxx with your MySQL version number)
groupadd mysql
(Not sure if this is necessary, just following instructions from dev.mysql.com)
• [Ralf] without this MySQL will try to run as root, but you need several special settings for this - better stick to the extra mysql user
useradd -g mysql mysql
./configure --prefix=/mnt/hda/opt/mysql --with-readline
make
make install
cp support-files/my-medium.cnf /etc/my.cnf
• [Ralf] there are more sample configuration files which you can try, e.g. my-small.cfg. Read the beginning of the files for a description
cd /mnt/hda/opt/mysql
bin/mysql_install_db --user=mysql
creates databases
chown -R root .
chown -R mysql var
chgrp -R mysql .
[Ralf] MySQL 5 seems to require the following extra actions:
• Create a MySQL password file:
libexec/mysqlmanager --passwd --user mysql >> /etc/mysqlmanager.passwd
• At the following prompt enter
mysql
You should now have a fully functioning version of MySQL on your LinkStation. Now we can set up the server to start like any other service.
Go back to where you have build MySQL (also see above):
/mnt/hda/misc/mysql-xxx
cp support-files/mysql.server /etc/init.d
chmod 755 /etc/init.d/mysql.server
You can now start your MySQL daemon as follows:
/etc/init.d/mysql.server start
PLEASE REMEMBER TO SET A PASSWORD FOR THE MySQL root USER ! To do so, start the server, then issue the following commands:
/mnt/hda/opt/mysql/bin/mysqladmin -u root password 'new-password'
/mnt/hda/opt/mysql/bin/mysqladmin -u root -h 'servername' password 'new-password'
Start up and shutdown at boot
ln -s /etc/init.d/mysql.server /etc/rc.d/rc2.d/S99mysql.server
ln -s /etc/init.d/mysql.server /etc/rc.d/rc6.d/K92mysql.server
ln -s /etc/init.d/mysql.server /etc/rc.d/rc0.d/K92mysql.server
Important Memory Usage Note: MySQL takes just under 25% of the LinkStation's total available memory when running. This should be taken into serious consideration if you choose to install MySQL support with your web server.
• TODO: Need to get the server running automatically at boot.
[Ralf] Here is how to start MySQL 5 automatically at boot. I guess it works quite similar with MySQL 4.X.
cd /etc/rc.d
ln -s ../init.d/mysql.server rc2.d/S99mysql
ln -s ../init.d/mysql.server rc2.d/K99mysql
Apache 1.3.xx
Apache itself is the next install. If you are not planning on installing PHP, you may ignore the "--enable-module=so" attribute below.
I decided to install Apache 1.3 because that is what my web host uses. Installing Apache 2 would be very similar and the following instructions can be easily adapted by reading the INSTALL document in the Apache 2 tarball.
Download the latest version of Apache 1.3 from http://www.apache.org (1.3.33, at the time of this writing).
wget http://apache.rmplc.co.uk/httpd/apache_1.3.36.tar.gz
tar -zxvf apache-xxx' (replacing xxx with your Apache version number)
cd apache-xxx' (replacing xxx with your Apache version number)
./configure --prefix=/mnt/hda/opt/apache --enable-module=so
make
make install
You will, at the very least, need to change your port to 81 (or some other port).
vi /mnt/hda/opt/apache/conf/httpd.conf
Search for '80' -- change it to '81' (or some other port).
I also suggest changing the root directory to the files to "/mnt/hda/share/www" so you can have easy access to them over the Samba share. Search for 'DocumentRoot' and change the first reference (roughly line 288) to the above path. Search again and you will find another reference to change (around line 313).
Finally, start the server.
/mnt/hda/opt/apache/bin/apachectl start
Copy that start up script to /etc/init.d and include in startup shutdown
cp /mnt/hda/opt/apache/bin/apachectl /etc/init.d
ln -s /etc/init.d/apachectl /etc/rc.d/rc2.d/S99apachectl
ln -s /etc/init.d/apachectl /etc/rc.d/rc6.d/K92apachectl
ln -s /etc/init.d/apachectl /etc/rc.d/rc0.d/K92apachectl
• TODO: Flush out the config file editing instructions.
PHP
Last we will set up PHP. I decided to install the latest version of PHP4 because, again, this is what my web host uses. You may decide to install PHP5, which would requires only 1 slightly different step below.
Pay special attention to the 'configure' (step 6) command below. If you installed the above packages to an alternate location you will need to update the paths in the proper attribute.
1. Download the latest version of PHP4 from http://www.php.net (4.4.0, at the time of this writing).
2. Copy the archive to your LinkStation as you would any other file, into your share folder.
3. Log into your LinkStation and 'cd /mnt/hda/share'
4. Execute 'tar -zxvf php-xxx' (replacing xxx with your PHP version number)
5. Execute 'cd php-xxx' (replacing xxx with your PHP version number)
6. ./configure --prefix=/mnt/hda/opt/php4 --with-mysql=/mnt/hda/opt/mysql --with-apxs=/mnt/hda/opt/apache/bin/apxs --with-config-file-path=/mnt/hda/opt/php4/lib
7. make
8. make install
Copy over the default config file. If you altered the "--with-config-file-path" attribute, in step 6, you will need to change the below command to copy to the appropriate path.
• cp php.ini-dist /mnt/hda/opt/php4/lib
Open up '/mnt/hda/opt/apache/conf/httpd.conf' and verify that the following line is included:
• LoadModule php4_module libexec/libphp4.so (for PHP4)
• LoadModule php4_module libexec/libphp5.so (for PHP5)
If it is not, add it. Also add the following two lines just below the LoadModule command:
1. AddType application/x-httpd-php .php .phtml
2. AddType application/x-httpd-php-source .phps
Restart Apache and PHP should now be working.
• TODO: More information on configuration of PHP
• TODO: Information on adding additional modules to PHP
Personal tools | v0 |
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} | cccc_CC-MAIN-2013-20 | How to modify an initrd
From NAS-Central Buffalo - The Linkstation Wiki
Revision as of 16:33, 17 December 2008 by Themel (Talk | contribs)
Jump to: navigation, search
This pages describes how to modify the initrds aka ramdisks of the linkstations/terastations/kuroboxes.
ppc-based boxes
BEWARE: this info is for the original firmimg.bins which were burned to flash. If you flash uboot as a replacement for the stock bootloader you can place the initrd + kernel also to /boot/ instead.
the kernel and the initrd both are inside the firmimg.bin-files which are inside the firmware-update-packages.
so we need to extract both from the firmimg.bin first. some smart japanese guys wrote a tool called firmimgtool.
sourcecode:
http://downloads.nas-central.org/ALL_LS_KB_PPC/DevelopmentTools/Flash/Utilities/firmimgtool.c
here you have all the tools you need compiled for ppc:
http://downloads.nas-central.org/ALL_LS_KB_PPC/DevelopmentTools/Flash/Utilities/flash_dev_tools_ppc.tar.gz
Usage: ./firmimgtool [-icmkr] <firmimg_filename>
-i : show firmimg_file information
-c : cut out from firmimg_file
-m : merge into firmimg_file
-k <filename> : kernel image filename
-r <filename> : ramdisk image filename
-f <filename> : copy headers from file
-h : show this help message
Now we extract kernel.gz and the initrd.gz:
./firmimgtool -c -k kernel.gz -r initrd.gz firmimg.bin
afterwards you should have a kernel.gz and a initrd.gz in the same folder.
unpack initrd.gz
gunzip initrd.gz
and loop mount it
mkdir INITRD
mount -o loop initrd INITRD
now you can change everything you want by changing it in the folder INITRD....if you unmount it all changes are saved.
After applying the changes you need to reassemble the firmimg.bin... this works that way:
umount INITRD
gzip initrd
./firmimgtool -m -k kernel.gz -r initrd.gz firmimg.bin -f firmimg.bin.103
and voila, the new firmimg.bin is ready for flashing.
mipsel-based
the firmimg.bin is encrypted unfortunately. LNI knows how to do this, but he hasn`t published this.
arm9-based boxes
All these boxes feature UBoot as the stock bootloader. The uboot bootloader loads initrd.buffalo from /dev/sda1.
The initrd.buffalo is named initrd.img in the firmware-update-packages. initrd.img is (like the hddrootfs) a password protected zip-file.
just unzip it and supply the right password.
unzip initrd.img
Archive: initrd.img
[initrd.img] initrd.buffalo password:
try one of these (source of passwords)
1NIf_2yUOlRDpYZUVNqboRpMBoZwT4PzoUvOPUp6l
aAhvlM1Yp7_2VSm6BhgkmTOrCN1JyE0C5Q6cB3oBB
YvSInIQopeipx66t_DCdfEvfP47qeVPhNhAuSYmA4
IeY8omJwGlGkIbJm2FH_MV4fLsXE8ieu0gNYwE6Ty
for the LS Pro it is YvSInIQopeipx66t_DCdfEvfP47qeVPhNhAuSYmA4 for example.
the initrd.buffalo still is not the real initrd....as it is booted from uboot is has a 64 byte long header. We use dd to get rid of the header, unzip the resulting image.gz and loop-mount the file
dd if=initrd.buffalo of=initrd.gz ibs=64 skip=1
gunzip initrd.gz
mkdir INITRD
mount -t ext2 -o loop initrd INITRD
there we are...in the folder INITRD you now have loop-mounted the initrd...make your changes as you want.
after making your changes do do this to get the initrd in a bootable condition again:
umount INITRD
rmdir INITRD
mv initrd.buffalo initrd.stock [backup just in case]
gzip initrd
mkimage -A arm -O linux -T ramdisk -C gzip -a 0x0 -e 0x0 -n initrd -d initrd.gz initrd.buffalo
Personal tools | v0 |
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} | cccc_CC-MAIN-2013-20 | Australian Collection
Info
Search:
Photo by Ivan Kozik
The Australian Collection primarily features trees and shrubs native to Australia. Tall eucalyptus trees, with their distinctive aromatic leaves, dominate the north bank of the creek. With more than 50 species of this native Australian genus, the trees vary from tall and erect specimens to broadly-spreading small trees. Throughout the collection, their characteristic camphor-like fragrance fills the air. A fine collection of bottlebrush, Callistemon, and honey-myrtles, Melaleuca, lines the path near the old bridge. Across the creek, new plantings of showy Australian flowering plants complement older plantings that feature plants from various regions in the world with a Mediterranean climate.
Photo by Mia Ingolia
Photo by Mia Ingolia Photo by Mia Ingolia A gift by Arley Firch Photo by Mia Ingolia Photo by Mia Ingolia Some of the trees from the Australian Collection
This is a Wiki Spot wiki. Wiki Spot is a 501(c)3 non-profit organization that helps communities collaborate via wikis. | v0 |
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} | cccc_CC-MAIN-2013-20 | GlobalVoices in Learn more »
Brazilian Family Loses Home to the World Cup
This post also available in:
Español · Río de Janeiro: Elisângela llegó a tiempo para ver caer su casa
Français · Rio de Janeiro: Elisângela est arrivée à temps pour voir sa maison détruite.
Malagasy · Fianakaviana Breziliana Very Trano Noho Ny Fiadiana Ny Ho Tompondakan'ny Baolina Kitra
繁體中文 · 因世界盃而流離失所的巴西家庭
简体中文 · 因世界杯而流离失所的巴西家庭
Português · Rio de Janeiro: Elisângela chegou a tempo de ver sua casa cair
This article, by Andrea Dip, is a part of Agência Pública's special #CopaPública [pt] coverage, and was originally published on June 26, 2012, with the title Elisângela Got Home Just in Time to See it Being Torn Down: Watch the Minidoc [pt]
Elisângela wasn't home when authorities arrived without warning to tear down her house on Pavão-Pavãozinho hill in Rio de Janeiro.
Her 17-year-old daughter answered the door and was told that the property was going to be destroyed at that very moment. Panicking, the girl called her mother:
Tem vários homens da Prefeitura aqui na porta; eles estão dizendo que vão derrubar a nossa casa.
There are many men here from the city at the door; they're saying they are going to tear down our house.
Elisângela ran back home, tried to reason with the men, ask for some time to find another home, but it was no use. In a few hours, all that was left was debris. This happened in early 2011. To this day, Elisângela has not been compensated nor relocated. Her daughter had to go live with her grandmother, while Elisângela still searches for a new home.
Elisângela gazes at the site of her destroyed home. Photo: Agência Pública / Credits: Henrique Zizo
The minidocumentary “We Are the Legacy: the Story of Elisângela” (“O Legado Somos Nós: A História de Elisângela”) is the first in a series of video portraits being produced by the human rights organization Witness, which partnered with the Rio People's World Cup and Olympics Committee (Comitê Popular Rio Copa e Olimpíadas), in an attempt to tell the stories of those affected by forced evictions in Rio de Janeiro, directly or indirectly connected to the 2014 World Cup and the 2016 Olympics. Priscila Neri, from Witness, explains that the idea is to give an alternative to the official narrative, which claims that everything is being done in compliance with the law and through constant dialogue with the communities.
Elisângela at Pavão Pavãozinho. Photo: Agência Pública / Credits: Henrique Zizo
In Elisângela's particular case, the justification provided at the time of the eviction was that her home was in a risk area in Pavão-Pavãozinho, but only some houses were destroyed and, according to the Rio People's World Cup and Olympics Committee, the city hasn't even removed the debris yet. The hill is located between two of Rio's most sought-after neighborhoods: Ipanema and Copacabana.
According to the dossier [pt] published by the Rio People's World Cup and Olympics Committee, the city intends to use the argument of geotechnical or structural risk to evict more than 300 families from the Pavão-Pavãozinho community:
Até o momento a Prefeitura não apresentou o laudo que comprove o risco e nem discutiu com a comunidade a possibilidade de realização de obras para garantir a segurança dos moradores.
Up until now the city hasn't presented any technical report that backs up the risk claim nor has it discussed with the community the possibility of carrying out infrastructural work to ensure the residents’ safety.
Still according to the Rio People's World Cup and Olympics Committee, engineers that have written technical reports about areas like the Pavão-Pavãozinho have pointed out that doing construction work to restrain or strengthen the slope, in order to eliminate the risk of slippage, would cost even less than relocating the families that live in the area.
Watch the minidoc:
The blog #CopaPública [pt] is a citizen journalism initiative that reports how the Brazilian population is being affected by – and mobilizing against – preparations for the 2014 World Cup.
World regions
Countries
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} | cccc_CC-MAIN-2013-20 | For the half-year to 30 June 2013, the IPKat's regular team is supplemented by contributions from guest bloggers Stefano Barazza, Matthias Lamping and Jeff John Roberts.
Two of our regular Kats are currently on blogging sabbaticals. They are Birgit Clark and Catherine Lee.
Friday, 17 August 2012
Taking it personally: patents, medicines and genetic markers
Purr-sonalised medicine
The IPKat is all in favour of medicine which, he thinks, can come in really handy -- even when you're unwell. He was therefore fascinated to learn of a recent discussion in Europe of a topic which has already exercised some of the finest minds of his American colleagues: the patenting of inventions relating to personalised medicine. Having heard about this from katfriend Suleman Ali (Holly IP), he is pleased to say that the latter was willingly persuaded to write a short note on the topic for the benefit of readers of this weblog. Here it is:
"Is the EPO changing Its stance on personalised medicine inventions?
Case law is an important means by which we know what is patentable at the European Patent Office (EPO). However, sometimes the EPO’s view of what is patentable in an area changes before the case law does. This can sometimes be detected when Examiners start raising objections they would not have previously done. Clearly, applicants need to know about such changes as soon as possible so that they can revise their filing strategies and re-evaluate their expectations of the claims they are likely obtain. Meetings between the EPO and the epi (the professional institute for EPO attorneys) are very useful forums for obtaining ‘inside information’ about the EPO’s thinking which is not yet apparent from the case law. The June 2012 issue of epi Information provides a report of such a meeting held on 10 November 2011 between the EPO and the biotech committee of the epi. Discussion item 8 is reported as follows:
‘8. Inventions in the area of pharmacogenomics
This concerns cases which are based on a genetic marker to treat a disease, for example methylation profiles. It can involve a new patient group defined by an SNP. The EPO said that often the claims can lack novelty, as one patient will have inevitably been treated with the SNP, even if the art does not explicitly say so.’
The EPO’s comments seem to indicate that it is about to change the way it assesses novelty when looking at medical use claims that refer to treatment of a specific patient group.
To give a little technical background to the EPO’s comments, an SNP is a form of genetic marker which varies between individuals. The idea behind the relatively new field of pharmacogenomics is that, if you know which SNP variants a patient possesses, you can personalise the drugs given to a patient in accordance with his genetic makeup. It is now recognised that the genetic makeup of an individual can be very influential as to whether he responds to a drug, and so one application of pharmacogenomics is to only give those drugs to patients who will respond to them.
Personalised medicines can also be based on non-genetic biomarkers, such as the level of virus the individual has.
Personalised medicines offer the potential to use drugs much more effectively. That is clearly of benefit to patients, but should also help to reduce costs in times when many governments feel increasingly dismayed at the yearly increases needed to health budgets. The sector most likely to benefit in the short time is cancer therapy where most of the work in identifying biomarkers is focussed. However, biomarkers are increasingly being sought for many other diseases.
Presently, suitable biomarkers for personalised medicine are proving difficult to find. So it seems that the sector is going to require a lot of investment -- but in investors in biotech do like to see that strong patent protection is available in the relevant sector.
Personalised medicines, and in fact diagnostics in general, has been thrown into uncertainty in the US after the Supreme Court’s decision in Mayo v Prometheus [on which see earlier Katposts here and here] which found that a claim referring to steps that determined the level of a drug in a patient was directed to a law of nature and was thus not patentable. It would be unfortunate for personalised medicines to be dealt a further blow by the EPO, making the test for novelty stricter in this area.
Claims for personalised medicine inventions can have many different forms, but typically they are along the following lines:
Substance X for use in a method of treating condition Y in an individual with biomarker Z’.
There is an argument here that perhaps applicants only deserve claims to the method of selecting the individual (by detection of the biomarker), and not to treatment of the individual. However there is a lot more money in therapy, with figures being quoted of 6% versus 94% for the money to be made in selection versus therapy. Since personalised medicine results in therapy being more effective, there is an argument that the applicant deserves claims to the therapy step.
The crux of the present issue is whether limiting a medical use claim by specifying that the individual has biomarker Z will confer novelty where the prior art is silent about patients having biomarker Z, but where patients with biomarker Z will inevitably have been treated, i.e. does limiting a medical use claim to a patient group that overlaps with, or is within, the prior art patient group, make the claim novel?
The earliest case to tackle the issue seems to have been T233/96 which gave a strict two-part test for novelty requiring the patient groups to be non-overlapping and for there to be a functional relationship between the biomarker and the therapy, i.e. the patient group could not be an arbitrary group. However, subsequent case law has not followed the test. In T1399/04 the Board cited T233/96, but took a different view, generously allowing claims which covered more than 50% of a prior art patient group. Decisions T836/01 and T1642/06 also allowed claims where patient groups overlapped with the prior art.
Based on the comments at the EPO/epi meeting and from the experiences of attorneys I know who are handling European patent applications in this area, it seems that EPO is taking a stricter view of the issue, and is probably looking for a test case to change the case law. If the EPO decides on a test which is based on the concept of a patient with the relevant biomarker ‘inevitably’ having been treated, presumably this is a prior use test, in which case it would be burdensome for applicants to locate evidence on what actually happened. However if the test is similar to that used in T233/96, i.e. requiring that patient groups do not overlap, then it will have the effect of severely curtailing patent protection for personalised medicines because most drugs are initially given to everyone with the condition.
I hope that the EPO will be wise enough to recognise that making the test for novelty stricter for medical use claims limited by patient group will have a substantial impact on the patent protection that can be obtained in the area of personalised medicines, at a time when this very promising sector needs all the support it can get".
Thanks, Suleman, for this most instructive piece, says the IPKat. Merpel is fascinated by this for quite another reason, though. It reflects a growing trend towards what might be termed "mass personalisation". We have it in branding and marketing, where the use of sophisticated software in reading your emails and online purchases enables a personalised dose of advertising to be specifically targeted at the individual. It also exists in the design and fashion sector, where a combination of interactive software and manufacturing improvements produces the result that a purchaser of, say, sports shoes, can determine the style, size, colour and bolt-on features that characterise it, rather than going into some random shop and putting a tentative foot into a sample shoe that might previously have been tried by someone with sweaty socks and fungal growths between the toes ...
Your own personalised medicine here and here [not for the squeamish]
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Monday, 27 April 2009
Malicious falsehood case
The IPKat has read with interest Ajinomoto Sweeteners Europe v Asda, a malicious falsehood case.
Ajinomoto is the manufacturer of the artificial sweetener, aspartame. The supermarket, Asda, commenced a campaign which was designed to ensure that, by the end of 2007, none of its 9,000 own-label food and soft-drinks products would contain any artificial colours or flavours or any hydrogenated fat or flavour enhancers. The catch-phrase used was 'NO HIDDEN NASTIES'. One of the statements used in conjunction with the catch-phrase was "No artificial colours or flavours and no aspartame" and "We promise that all good for you products are always low or lower in fat and won't ever contain any hydrogenated fat, artificial flavours, artificial colours or aspartame."
Ajinomoto alleged that the natural and ordinary meaning of the words on the packaging is that aspartame is an especially harmful or unhealthy, or potentially harmful or unhealthy, sweetener and is one which consumers concerned for their own health and that of their families would do well to avoid, either altogether or in the quantities likely to be found in soft drinks and other food products.
In the recent decision, Sir Charles Gray had to decide whether to grant Ajimoto's request for a trial of the preliminary issue "as to the statement(s) of fact contained in or conveyed by the words complained of in paragraphs 4 and 8 of the Particulars of Claim". The alternative would be to hold a single trial incorporating (i) the meaning of the statement; (ii) whether the statement was false and (iii) whether the statement was malicious.
The judge held that in the interests of saving costs, it was right for the preliminary issue to be tried first. If Ajimoto's contention that the meaning of Asda's statements were that aspartame was harmful was rejected then there would be no issue as to falsity, and malice would not be relevant. The judge accepted that the issue of meaning was essentially a "slam dunk" point. Separating the issue of meaning out into a preliminary trial was commonly used in defamation actions and would work here. However, the judge did suggest that the approach might be considered an abuse if it was used as a tactic to 'slice up' the action into three separate trials of meaning, falsity and malice.
The IPKat is all in favour of efficiency and saving costs (except when it comes to kitty treats) and thinks that this looks like a sensible decison.
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} | cccc_CC-MAIN-2013-20 | Talk:20.109(F12) Pre-Proposal: Engineering Viral Magnetic Nanoparticles for Magnetic Hyperthermic Cancer Therapy
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This is a brainstorming page.
You are very welcome to write any crazy / non-crazy / inventive / conventional / knowledgeable ideas or information you may have about our project.
Some key words: Magnetic Nanoparticles (MNP), Viruses, Magnetic Hyperthermia, Bioengineering
Contents
What is Magnetic Hyperthermia?
Definition
How it works?
Under an alternating magnetic field, MNP releases heat due to relaxation of magnetic moments (hysteresis). This can cause an increase in temperature to the range of 41C to 47C. Since tumor cells are more heat sensitive than normal cells, they will be killed by this thermal dissipation.
Here is an interesting tidbit from a paper I was reading: "In addition to the expected tumor cell death, hyperthermia treatment has also induced unexpected biological responses, such as tumor-specific immune responses as a result of heat-shock protein expression. These results suggest that hyperthermia is able to kill not only local tumors exposed to heat treatment, but also tumors at distant sites, including metastatic cancer cells." (Kobayashi)
Current Research
• Clinical trials in prostate cancer
• Shows promising results when coupled with irradiation on breast cancer (mouse)
Current Limitations (This information will help us shape and define the problem.)
(1) To achieve the necessary rise in temperature with minimal dose of MNP.
In other words, this means:
• High specific loss power / specific absorption rate (SLP) of the MNP.
• why is higher applied dosage bad? > leads to unnecessary heat dissipation
(2) Lack of knowledge about the metabolism, clearance, and toxicity of MNP.
Biomedical potentials of MNP
• Could be used as early detection for the following using MRI:
• Inflammation
• Cancer
• Diabetes
• Atherosclerosis
• Drug Delivery
• Cellular labeling and tissue targeting
• Purifying and separating cells and DNAs
• Hyperthermia
• Transfection by magnetic nanoparticles
• Tissue repair
• Magnetic resonance imaging (MRI)
Types of Relevant Viruses
1. Tobacco Mosaic Virus (TMV)
• 18nmx300nm, helical
• Can withstand high temperatures up to 50C for 30mins (conventional hyperthermia involves heating up to 50C from an external source
• Safe for human consumption
• Mann group has active research on it
• 2130 molecules of coat protein
2. M13 Bacteriophage
• 6.6nmx880nm, helical (Length is too long - pose an issue in targeting cells)
• Lots of research done by the Belcher group, including attaching MNPs to M13 for imaging purposes
• We are familiar with the system
3. Cowpea chlorotic mottle virus (CCMV)
• 26nm, icosahedral
4. Cowpea mosaic virus (CPMV)
• 27nm, icosahedral
5. Brome mosaic virus (BMV)
• 28nm, icosahedral
6. Turnip yellow mosaic virus (TYMV)
• 30nm, icosahedral
Current Work in Viral MNP Attachment
Attachment of MNPs to M13 phage for in vivo imaging of prostate cancer
What we propose to do
See flowchart sketch.
Specific Aims
1. Identifying / Screening for appropriate virus vehicles and tumor-specific anchoring sequencse
2. Developing / Engineering viral MNPs
3. in vivo testing for efficacy of engineered vMNPs in mouse tumor cells.
We will start with using ferritin (Fe3O4) as the MNP.
Steps Stage 1: Virus Hunt
We need to investigate how the selected virus (likely one of the following: TMV, M13, CCMV, CPMV, BMV or TPMV) interacts with mammalian cells in vivo.
Stage 2: Screening for MNP binding site on virus
We will start by using Fe3O4 as our MNP of interest. With this, a protein coat screen of the selected virus for a protein coat that can bind with our MNP is necessary.
Stage 3: Screening for tumor-specific sequence binding site on virus
We need to do a protein coat or RNA screen of the virus for a region that can bind with a tumor-specific peptide sequence. If necessary, we might need to screen tumors for unique short sequences on their cell surfaces.
Stage 4: Virus engineering
We can now engineer wild-type viruses using specific protein coats or RNA regions isolated in Stage 2 and 3 to produce the viral MNP of interest.
Stage 5: in vivo testing
Perform an in vivo experiment by injecting the engineered viral MNPs into the circulatory system of mice that have developed tumors. By subjecting these mice to an alternating magnetic field under standard hyperthermia conditions and measuring the change in tumor size, we will be able to quantify the efficacy of using viral MNPs in magnetic hyperthermia.
Future directions:
• Experimenting with double layer MNP to increase response
• Target other cancerous cells
• Experiment with other types of viruses
Quantitative Goals (We can quantify with IC50 value)
• Currently, with the aid of 10Gy radiation, the hyperthermia treatment successfully accumulated less than 0.3mg Fe/g tissue. Dosage: 0.2mg Fe per gram of mouse. Say mouse is 25g, so 5mg total dosage injected. so 1% efficiency with the aid of radiation. (MNP sizes used: 70nm and 120nm; murine flank breast tumors were 150mm3)
Calculations:
From http://manalis-lab.mit.edu/publications/grover%20PNAS%202011.pdf, we estimated that a typical cell has an average density of 1.1g/mL. Since the murine flank breast tumors were 150mm3, and 0.25mg Fe/g of tumor was detected in the tumors, we can calculate that only a total of 0.0495mg of Fe is accumulated in the tumors. This gives a % efficacy of 1%.
• South Korean experiment: 75ug of MNPs were injected.
• From Belcher lab's paper, what is the % efficacy of using M13?
Potential Issues
• "The actual rotations of the nanoparticles are disordered because the microviscosity of the local environment in cancer cells is not constant, and effective elasticity depends on the binding conditions between nanoparticles and membranes."
but this is actually present because when treatment is done with individual MNPs, one side of the MNP is always bound to the targeted cell, so direction is never constant!
Future Directions
Useful Resources
1. Gupta AK, Naregalkar RR, Vaidya VD, and Gupta M. Recent advances on surface engineering of magnetic iron oxide nanoparticles and their biomedical applications. Future Medicine. 2007. 2(1), 23-39.
2. Bakoglidis KD, Simeonidis K, Sakellari D, G. Stefanou, and Angelakeris M. Size-Dependent Mechanisms in AC Magnetic Hyperthermia Response of Iron-Oxide Nanoparticles. IEEE Transactions on Magnetics. 2012. 48:1320-1323.
3. Great layman's way of explaining magnetic hyperthermia http://trialx.com/curetalk/2012/11/cancer-treatment-multifunctional-magnetic-nanoparticles-for-molecular-imaging-and-hyperthermia/
4. A.J. Giustini, A.A. Petryk, S.M. Cassim, J.A. Tate, I. Baker, P.J. Hoopes. Magnetic nanoparticle hyperthermia in cancer treatment. Nano LIFE 2010; 01: 17.
5. D. Ghosh, Y. Lee, S. Thomas, A. G. Kohli, D. S. Yun, A. M. Belcher, K. A. Kelly. M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer. Nat. Nanotechnol. 2012; 7 (10): 677–82.
6. Add more references as deem appropriate
Feedback
11/29 from Professor Angela Belcher:
1. Look at Nature Nano Belcher lab paper
2. Need to do very good characterization of materials using TEM, elemental analysis, etc.
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There can be no forced inspiration. Stojanovic, Dejan
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Dejan Stojanoviæ was born in Pec, Kosovo (the former Yugoslavia), in 1959. Although a lawyer by education, he has never practiced law and instead became a journalist. He is a poet, essayist, philosopher, and businessman and published six critically acclaimed books of poetry in Serbia: "Circling," "The Sun Watches the Sun," "The Sign and Its Children," "The Shape," "The Creator," and "Dance of Time." In 1986, as a young writer, he was recognized among 200 writers at the Bor (former Yugoslavia) Literary Festival. He also received the prestigious "Rastko Petrovic" Award from the Society of Serbian Writers for his book of interviews with major European and American artists and writers. In addition to poetry and prose, he has worked as a correspondent for the Serbian weekly magazine "Pogledi" ("Views"). His book of interviews from 1990 to 1992 in Europe and America, entitled Conversations, included interviews with several major American writers, including Nobel Laureate Saul Bellow, Charles Simic, and Steve Tesic. He has been living in Chicago since 1990.
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Founder, Earth Treasury, an NGO to link schools around the world for education and business. See Plans and Essays.
NEW PROJECT: Replacing Textbooks XOs and other netbooks cost much less than printed textbooks, so as soon as we replace enough of the textbooks with Open Education Resources, we can explain that OLPC + Sugar delivers better education while saving money. Mokurai has received permission to set up a server for this purpose at Sugar Labs, and is also raising funds to support it.
CrowdRise Fundraiser donations
Mokurai volunteers at OLPC and Sugar Labs as a volunteer coordinator, localization administrator (Khmer and Kreyòl), and general knoker (an especially Yiddish know-all, the kind who did math homework in pen), based on
• his training as a mathematician, classroom teacher, amateur musician and linguist, philosopher, and Buddhist priest
• plus his lifetime of encyclopedic reading, many years in high-tech market research and technical writing, and work in Unicode and Free Software.
Contents
Vision
End Poverty at a Profit all around by educating children to collaborate and not be helpless.
Quotes
• Epictetus - "Only the educated are free."
• Aristotle - "All men by nature desire to know. An indication of this is the delight we take in our senses."
More quotes
Mission
The mission is whatever planning, funding, research, development, and deployment is needed to make that happen, with a focus on Management by Exception in order to keep on top of what is needed in changing circumstances and make sure that nothing gets missed that we must have.
Sugar Labs has the Sugar software as its main focus, but needs to work with others on the rest of the mission. We should raise substantial funding to support these substantive projects, up to the point at which they can become self-sustaining, in the manner of the Grameen Group of companies.
These are the principal elements of the mission today. More will appear.
• Extend the OLPC and Sugar Labs work with evidence-based education research, curriculum development, and the redesign of textbooks, taking maximum advantage of software on the XO, and of the best research that we can find or carry out on how children learn, and what is of greatest value for them to learn.
• Engineer appropriate solutions for electricity and Internet connections in even the poorest and most remote villages in every target environment, in collaboration with university Schools of Engineering, Engineers Without Borders, and others, in order to maximize the usefulness of XOs to children everywhere.
• Work with microfinance organizations to place these electricity and Internet solutions along with XOs. The intention is to jump-start local economies by selling modest amounts of surplus power and bandwidth, and thereby raise the money to pay off the original loans and make further investments.
• Create an R&D consortium to further all of these goals and whatever else turns out to be necessary. We know that issues of economics, governance, social attitudes, and sustainability are important. What do we need to know, and how can we come to know it? What can we learn from the children themselves, and from teachers, parents, and others?
• Tap into Barack Obama's plans to increase global development aid by $25 billion annually, including a $2 billion Global Education Fund; into the UN Millennium Development Goals program; Make Poverty History; and all of the other initiatives that share our vision, even if they don't know it yet.
• Save as many languages and cultures as possible from extinction by teaching the children how to record them.
• Link children, schools, and communities together around the world in a safe manner for collaborative development.
• Teach children how to create sustainable international businesses together using their new knowledge and skills.
Current Projects and Partners
OLPC and Sugar Labs, of course, within the scope of their own missions to provide hardware, software, content, and teacher training materials. In each case, the intention is to expand to a comprehensive, integrated program including infrastructure, education, community development, and economic opportunity. Volunteers, donors, and partners welcome.
By country
• Ghana
• Nana's House (school and orphanage), computers, Internet, and accessories for students and teachers
• Winneba Linux Users Group, Linux+Sugar Installfests
• Catch IT Young youth computer training
• University of Education, Winneba, research, curriculum, teaching materials, localization
• OneVillage Foundation Ghana, Winneba wireless broadband project
• Nigeria
• Fantsuam Foundation microfinance project and Cisco Network Academy
• Kenya
• Asante Foundation Maasai schools and cultural preservation
• Uganda
• Bunabumali Good Shepherd Orphanage and School, computers, accessories, electricity, Internet
• Mt. Elgon coffee growers co-operative equipment and training
• School programs and the rest
• Tanzania
• Mt. Kilimanjaro coffee growers co-operative equipment and training
• School programs and the rest
Components
• Interactive digital textbooks, with Lots of partners.
• Free computers for schools, two per pupil: one at school, one at home. Possibly Computers4Africa
• Flash drives for carrying software and work, so that students can use them on any computer
• Electricity generation and storage, Engineers Without Borders
• Broadband Internet, OVF Ghana
• Microfinance, Fantsuam Foundation
• Economic opportunity, education program to be developed at EduForge, social entrepreneurial investors welcome.
Analysis
The following is as much a prediction as a set of goals. Much of this will happen regardless of us. We can make those parts happen sooner, and more effectively. The other parts have to do with the new ideas that we are discovering and shaping together, particularly integrated development that includes the economy, the social structure of society, and spiritual growth. The only project that I know of that currently does this is the Sarvodaya Shramadana Movement in Sri Lanka, which I commend to your study and, if possible, participation.
Preliminary
For several years I have been seeing a gradual coming together of many strands in development toward the possibility of an integrated strategy that can be replicated worldwide. After the initial stage, it should all become self-sustaining in the manner of the Grameen Bank, Grameen Phone, and the like, and thus independent of the usual sources of non-profit funding. Here are the leading strands.
• ICT4D, including newly powerful mobile phones, computers, and Internet at prices that make sense in even the poorest and most remote villages, given the promise of economic growth to enable paying back costs.
• One Laptop Per Child, for many reasons, including a rethinking of curricula, textbook content, and publishing models. Scarcity of information is no longer the limiting factor in education. Electronic publications still take effort and time to write, but the reproduction cost on the Internet is nearly nil. Governments will soon realize that they don't have to buy textbooks. They can contract for writing textbooks and other materials with the proviso that the government, or we should say the public, owns the copyright. We can take advantage of Free Software and Open Access publishing throughout this process, and of a century of discoveries in how children really learn. Currently XOs are $198 each, with $75 versions promised for 2010. GiveOneGetOne is to start up again in November.
• WiMax and other broadband technologies that can provide Internet to whole countries (90-95% coverage) for $10 per person installed.
• Fiber optic cables for every country in Africa. There is one installed on the West Coast, two being laid on the East Coast, and four more promised. Rwanda and the other dozen landlocked countries in Africa are making deals with their neighbors for overland links. Some regions in Central Asia may take a little longer.
• New satellite launches that promise both to break the current cartel pricing in Africa, and to link Africa directly to South America, the Middle East, and Asia, not just by multihop through Europe.
• African banks that are now in a position to start creating a continent-wide network and to roll out electronic banking.
• Global GIS initiatives dealing with mapping critical poverty issues: environment, water, agriculture, climate, health, and much more.
• More than 100,000 of the million and more NGOs of the world now connected with each other through Wiser Earth.
• Barack Obama's plan to double US Foreign Aid, and redirect it to much more efficient methods (toward helping the poor, not just subsidizing US agriculture, manufacturing, and consulting). This includes a $2 billion annual Global Education Fund.
• The microfinance movement's casting about for the next big challenge. I predict village electricity and Internet along with school computers, and I am working on alliances toward that end.
Sugar Labs has taken over software development for the OLPC XO. Walter Bender of Sugar Labs is putting together a research consortium to tackle problems in education, and I am assisting in recruiting, and in problem definition. My program is not of the usual kind, where we know what subjects we mean to tackle.
My version of the mission is: Whatever turns out to be needed. My self-appointed task is to find the holes in current programs, and fill them, first with my own efforts and second by recruiting others to do the work, research further solutions, and plan where we might go next. Among the critical tasks are village electricity and Internet, redesigning curricula and textbooks, and bringing all of this together into target communities with microfinance, with a flexible, integrated business plan for whole societies to advance societal infrastructure (education, health, clean water, and other essentials), and the private sector (sole proprietorships, sustainable international companies, producer and consumer co-operatives), and shared values.
It is no longer practical to impose the illusion of shared values on a society. They must grow out of the situation. The report on OLPC's early effects in Ethiopia gives a glimpse into where we are going. Within a few months, in a highly traditional society that has valued teaching politeness and obedience over subject matter in schools, and where asking questions of a teacher was considered insulting, the XO and its software have opened up a new, collaborative relationship between teachers and students. This is in no small part attributable to the collaborative nature of the XO's Sugar and other software. Access to the information riches of the Internet is another important factor. See Academic Papers on the OLPC Wiki for this and other recent reports.
There is more, but that will do to begin with.
General Consequences
• We are looking at the possibility of ending poverty as we know it within a generation, except in the most repressive countries (Burma and North Korea are the most likely, but a few others might possibly regress).
• We are doing this by means that promise far freer markets, with
• Market access for all, at least for electronic markets, including easy entry and exit
• General availability of essential economic information, including the price of almost anything right up to the moment
• General availability of production technologies, except where embargoes linger (Cuba, Burma, Syria, Iran, North Korea and a few others)
In short, these and a few other points add up to the closest approximation to the economic ideal of Perfect Competition ever seen, worldwide. We can confidently predict the largest explosion of productivity and prosperity ever seen, and at some point the end of the continual search for ever-more-benighted denizens of ever-poorer countries to ship jobs off to. The existence of wage differentials between countries is conclusive proof that their market relations are not free.
• A complete communications network, in which every person will have the means to connect with any other person who answers the phone.
• Directories and social network sites that enable everybody to find the right people to do business with and make alliances with for any economic, social, spiritual, or political purpose.
• We can confidently predict an explosive growth of civil society organizations worldwide, among other things.
AKA
• Edward Mokurai Cherlin/Czerwin
• גרשון בן יסעף
• Эдуард Георгеевич Черлын
• 장영구/張永久
• 法雲默雷/धर्ममेघशब्दगर्ज
Contact
Background
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East Norway
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Scandinavia : Norway : East Norway
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East Norway (actually southeast) is the region surrounding the capital Oslo, where the largest number of people live.
[edit] Regions
[edit] Cities
[edit] Other destinations
[edit] Understand
[edit] Talk
[edit] Get in
[edit] Get around
Oslo totally dominates this region. Oslo and its airport at Gardermoen is the transport hub for East Norway. Roads and railway lines has Oslo as their focal points. All railway lines, including the airport express train, terminate at Oslo Central Station ("Oslo S"). Main roads E6, E18, E16 and Road 4 meet at or near Oslo S. Regional as well as long distance buses depart from the bus station next door to Oslo S. Oslo Subway (T-banen) has a main station underground next to the train station.
[edit] By plane
• Fagernes Airport (Leirin - operated by DOT), (10 minutes from Fagernes), [1]. edit The local airport with daily connections to Oslo (30 minutes)
[edit] By bus
[edit][add listing] See
[edit] Itineraries
[edit][add listing] Do
[edit][add listing] Eat
[edit][add listing] Drink
[edit] Stay safe
[edit] Get out
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Difference between revisions of "Meran"
From Wikitravel
Burgraviate : Meran
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(added listing Bar Rossini)
(added listing Sketch Clublounge)
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*<drink name="Café Forum" alt="" address="Via Leonardo da Vinci 11 (Postgasse)" directions="" phone="" url="" hours="" price="" lat="" long="">A fine Cocktails and Wine Bar.</drink>
*<drink name="Café Forum" alt="" address="Via Leonardo da Vinci 11 (Postgasse)" directions="" phone="" url="" hours="" price="" lat="" long="">A fine Cocktails and Wine Bar.</drink>
*<drink name="Bar Rossini" alt="" address="Corso della libertà 19" directions="" phone="" url="www.rossini-bar.it" hours="" price="" lat="" long=""></drink>
*<drink name="Bar Rossini" alt="" address="Corso della libertà 19" directions="" phone="" url="www.rossini-bar.it" hours="" price="" lat="" long=""></drink>
+
*<drink name="Sketch Clublounge" alt="" address="Passegiata lungo Passirio 40" directions="" phone="" url="www.sketch.bz" hours="" price="" lat="" long=""></drink>
Revision as of 19:16, 26 February 2009
Meran (Italian: Merano) [1] is the second largest town in South Tyrol with a population of about 35,000 (63,000 including the metropolitan area). A slight majority (51.5%) of the population is German-speaking, while the others are Italian-speaking. It's an old spa town with very charming promenades and interesting highlights.
Contents
Get in
Meran is located outside of the Brenner line and whether you want to reach the town by plane, by train, by bus or by car you have likely to reach before Bolzano and from this point Meran. Meran is located 33 km (20 miles) north-west from Bolzano.
By plane
The Airport Bolzano Dolomites is nearest airport, which is located in Bolzano.
Getting to/from the airport
Many hotels offer a transfer from Bolzano airport, especially if you book through a travel agency (in this case you probably have the possibility to have a transfer from other major airports). In the airport you will find some rent-a-car agencies. http://www.taxidriver-tirol.at/
By train
In order to get in Meran by train you have to arrive in Bolzano first and from here you can take the train to Meran (every 30 minutes). When you buy the ticket at the departure station you can have the ticket from Bolzano to Meran included, saying that your destination is Meran. The Meran Central Rail Station is closed to the town centre.
By bus
Some German, Austrian and Swiss travel agencies offer direct bus connection to Meran. Normally international bus lines stop in Bolzano and from here you can take the bus Bolzano-Meran (bus line 201) at the Bolzano Bus Station or other stops inside Bolzano (like Dominikanerplatz). Buses are run by SASA [2], which uses the same orange buses you can find inside cities, and SAD's [3], with grey-coloured buses (they operate on the same line). There is a departure every hour. A fare from Bolzano to Merano costs EUR 4 (only 2.61 with value card).
By car
You have to exit at Bolzano South on motorway A22 and taking the modern freeway. In Meran there are three exits: Sinich/Meran Süd, Meran Zentrum and Algund (freeway end). If you are coming from Landeck in Austria or Engadin, Switzerland, you can follow the signs along the road. <IP_ADDRESS> 15:49, 28 October 2008 (EDT)
Get around
The best way in order to discover Meran is by foot, but it's covered by an excellent public transport system, which is composed by buses and a chair lift to the village of Tirol.
By Bus
In Meran there are 9 bus lines (generally 6 am - 9 pm) run by SASA [4] and 1 of this have also a night service (9 pm - 1 am). Buses pass frequently (every 15-25 minutes). Buses run always on time.
Stamp your ticket at the start of its first use (there are green - on new buses yellow - stamping machines). You have to buy another ticket if you stop and you catch a bus after 45 minutes after the printing (only with single trip ticket or spent value card). Payment is by the honor system and inspectors check for valid tickets. If you don't have one, it's an instant EUR 25 fine (plus the fare you were supposed to have paid). All timetables and bus maps you can find free in the tourist offices or in the bus station.
Chair lift
Meran is connected with the village of Tirol - located on a hill above the town - by a chair lift, which is in service between April and November.
By Taxi
Taxis are only on call available. Meran's taxi service is powered by Radio Taxi 24h24 calling 0473 21 20 13.
By bike
Meran has a good bike trail system - but not so developed as in Bolzano, though - but around the town it's excellent. Maps are available in tourist offices and online [5].
Rentals are available in the following places:
• Rail Station
• Spa Building
• Tennis Centre
The service is available from April until mid of October (M-Sa 9AM-7PM) and it's free. You only have to pay a EUR 5 bail - which is returned if the bike has not been damaged.
By car
The public transportation or your own feet should be enough in order to travel inside Meran. Finding a parking in the town centre can be complicated.
In winter (from November to March) the whole city is forbidden for the EURO 0 cars in order to prevent from air pollution. In cases of high concentration of polluted substances the streets are forbidden also for EURO 1 cars.
See
Museums, Galleries, and Memorials
• Touriseum - South Tyrol Museum of Tourism with Botanical Garden [6] - admission €9.80 (students/handicapped people €7.50, over 65 €8.50, after 6PM €5.00, children up to 6 years free) It's a very interesting highlight. The Museum hosted at Trauttmansdorff Castle reports the long history of tourist tradition in South Tyrol. The ticket includes the visit to the well-kept and quite wide Botanical Garden. The Museum is open only from the first half of March to the first half of September, considering that the Botanical Garden is closed during the cold season.
• City Museum - admission €2.00 (reduced €1.50) It's located in a former hotel, it shows interesting archaeological and historical founds.
• Princely Castle Museum - admission €2.00 (reduced €1.50) de, it Building from the 15th century located in the old town with an interesting exhibition for lovers of medieval history.
• Jewish Museum - free entry. The small museum located at the only South Tyrol's Synogogue reports the history and documentation about the Jewish community in South Tyrol.
• Women's Museum Evelyn Ortner - [7] - free entry. Unique museum about women specialized in culture of women's everyday life.
• Meran Art - City Gallery - [8] - free entry. Exhibitions of contemporary art, literature and architecture and other interesting features.
• Monument of Empress Elisabeth - is a statue situated at the Summer Promenade's entrance, which was modeled with white marble after Sissi's assasination in Geneva in 1898. The Empress of Austria visited Meran four times - the last time being one year before her death. After WWII the statue was replaced and the head re-modeled. It shows an interesting parallel with the Monument of Walther von der Vogelweide in Bolzano.
Churches
• Main Parish Church Gothic bulding with Baroque features in the old town built in different periods between 1302 and the 18th century. Its bell tower is one of the highest in South Tyrol (83 metres) and it shows 7 clocks.
• Holy Spirit's Church Gothic building built between the 14th and 15th century beyond the Passer river. A building built by Fascist Italy in rationalist style hides the church, because the Gothic style was considered to be a symbol of the German-speaking countries.
• Holy Mary's Church Located in the district of Untermais it's an interesting Romanic building built in the 12th century.
Buy
Eat
• Restaurant Kallmünz, Piazza Rena 12.
• Restaurant Sissi - Andrea Fenoglio, Via G. Galilei 44, [9].
Drink
• Café Forum, Via Leonardo da Vinci 11 (Postgasse). A fine Cocktails and Wine Bar.
• Bar Rossini, Corso della libertà 19, [10].
• Sketch Clublounge, Passegiata lungo Passirio 40, [11].
Sleep
• Hotel Palace Merano - Espace Henri Chenot, Via Cavour 2, [12].
• Hotel Aurora, Passegiata lungo Passirio 38, [13].
Contact
Get out
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Valparaíso
From Wikitravel
Chile : Central Chile : Valparaíso
Revision as of 12:32, 26 January 2013 by <IP_ADDRESS> (Talk)
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For other places with the same name, see Valparaíso (disambiguation).
Valparaíso is a city of around 300,000 on the Pacific coast of Central Chile. Frequently referred to as simply Valpo, it is located approximately 120km west of the capital, Santiago de Chile. The city is widely known for its bohemian culture, brightly colored houses, and beautiful seaside views.
View from downtown Valparaiso (Chile) to one of the hills.
Valparaiso (Chile), focusing on one of the escalators (Ascensores) connecting the harbour area to the hills.
Understand
• The city's main economic activities are shipping, petroleum refining, and tourism.
• Valparaiso was designated a UNESCO World Heritage Site in 2003.
• Visiting Valparaiso has less to do with touring specific sites than it is about roaming the chaotic, hilly streets, and taking in the views and ambiance. There is also an active nightlife and a constantly changing variety of artistic events.
Get in
By plane
Valparaiso does not have its own airport. The closest airport with commercial service is Arturo Merino Benitez International Airport (SCL) in Santiago, 115km from Valparaiso, which offers extensive domestic and international service.
To to get to Valparaíso from Santiago's airport, you will catch a bus heading to Pajaritos outside of the airport terminal. This will drop you off at the North side of "Pajaritos" a bus/subway station on the outskirts of Santiago, cross to the South side of the Subway station to get to the Bus Platform. From here, buses leave frequently for Valparaiso and other destinations; you may also take the subway into downtown Santiago. It is generally not necessary to have a bus ticket before arriving at Pajaritos.
Alternately, there are many transfer service companies at the airport, a van for max 8 people is around 85.000CLP.
Also, there are many rent-a-car companies at the airport. By car from the airport to Valparaíso is only 1 hour.
By train
The Metro Valparaíso or Merval runs between Valparaiso and Viña del Mar, as well as surrounding communities.[1] It runs from 6.00am to 11.30pm, and is new, clean and fast. Adult fares range from Ch$204 to Ch$1080 depending on the time of day and the distance travelled, but value cards of a minimum of Ch$1200 must be used; single tickets are not sold.
By car
While Valparaiso itself can be a bit of a difficult city in which to drive, the area's highway system is generally of good quality. Note that there are often tolls on highways.
By bus
Buses from a wide variety of destinations within Chile have scheduled service to Valparaiso, in addition to service to the Argentine city of Mendoza. The bus terminal is located close to the National Congress building.
Approximate bus travel times to/from Valparaiso:
• 1.5 hours: Santiago de Chile (many times every hour)
• 7 hours: La Serena (every other hour)
• 12 hours: Mendoza, Argentina (the road may be closed in winter due to bad weather)
Local buses also ply between Viña del Mar and Valparaiso, taking about 15 minutes each way. Fares range from Ch$350 to Ch$380.
By boat
Some cruise ships dock in Valparaiso, mostly as part of a long South American itinerary. Also possible is a Freighter Cruise from Mexico, taking two weeks and making several stops along the way.
Get around
The city micros are run by Transporte Metropolitano Valparaíso.[2] Exact routes and fares can be found under "Empresas" on the website, and single journeys cost about Ch$250 for local routes and Ch$300 for routes running between El Plan and the hills.
Colectivos are taxis painted in black with yellow roofs that run fixed routes, and are a very common mode of transport between (and within) Valparaiso, Viña del Mar, and other surrounding areas. The cost of the trip, while more expensive than the bus or metro, depends upon the distance being traveled following a system of zones. There are also regular taxis that do custom rides, but they are less common and more expensive. This type of taxis often congregate in the area around the Plaza Anibal Pinto.
The recently completed light-rail system, Metro Valparaíso or Merval, runs along the coast. It starts at Valparaiso's port and heads into Viña del Mar and other more rural locales. The metro provides quick access to major places of interest, and is only slightly more expensive than taking public buses. Adult fares range from Ch$204 to Ch$1080 depending on the time of day and the distance travelled, but value cards of a minimum of Ch$1200 must be used; single tickets are not sold.
Ascensores, funiculars, ply between El Plan, or the coastal strip, with the cerros, or hillside communitiies. They are for the most part old and creaky, but generally reliable. The fare may sometimes differ between going up and going down, but cost about Ch$300 each way. The ascensors are a unique mode of transportation in Valparaiso, and offer gorgeous views of the cityscape, port, and the Pacific Ocean.
See
• Cerros Alegre and Concepción
• Plaza Echaurren – Serrano Street
• Cerro Bellavista: residential area & artistic hill with colorful murals
• Museo a cielo abierto: 20 murals spread out over cerro Bellavista
• Ascensor & cerro Polanco: unique vertical funicular on Polanco hill with plenty of nice paintings
• Cerro Cordillera
• Banking area - Prat Street
• Paseo 21 de Mayo (Cerro Artilleria)
• La Matriz Church and surroundings
• Ascensores (inclines)
• La Sebastiana, one of three homes of poet Pablo Neruda (cerro Bellavista)
• Ex Cárcel, a former jail turned cultural center and concert venue
• Museo Naval y Maritimo (Naval and Maritime Museum), Paseo 21 de Mayo 45, at top of Ascensor Artillería, 56 32 2437651, [3]. Tuesday to Sunday, 10.00am to 6.00pm. This museum is dedicated to military naval exploits and battles, and puts a large focus on the Chilean victory against Peru and Bolivia in the War of the Pacific.
Do
Going to Valparaiso and not going on the ascensores (inclines) is like going to Venice and not taking a ride on a Gondola, only that the ascensores cost as little as 100 Chilean Pesos (around 20 US cents). They are also of practical use as they help many local people get to the higher parts of town, saving them from having to walk otherwise long and steep pedestrian routes.
During the last week in the year, Valparaiso holds an annual carnival that everyone should experience at least once in their lives. Each year the festival centers around a different country, from which performers and artists are invited to come and represent their culture and their work in theater, music, and the performance arts. Most activities are free and are held outdoors. The celebration culminates with a New Year firework display that within five of the most beautiful in the planet. Oops, but get ready in time because the city's population triples on those dates. I recommend visiting the Mirador del Cerro Artillery, panoramic view of the city of Vina del Mar, Reñaca, Con Con and more ... It reaches through the "lift" Artillery, in operation since 1893 (ask for Customs plaza area), its current value is 250 Chilean pesos, on the first floor is the Mirador "Walk May 21," (delivered to the community in the year 1911) in which impossible not to enjoy the restaurant "Calaufquen", typical dishes of fresh seafood, with a fair value. We are here with a Craft Fair in which they can buy from winter clothing (ponchos, Ruan, scarves, socks, gloves, wool hats), souvenir of the most varied models and prices, up figures and jewelry from lapis lazuli (blue stone semi-precious which is only in Chile and Afghanistan), by price and quality of the stone, I recommend the last local. Also visit the Naval Museum "(500 Chilean pesos) whose income is in the midst of the Paseo.
• The German Pirate (myvalparaiso.cl), [4]. Amazing tour by a German man who's lived in Valparaiso for years. He seems to know everything and everyone about the place. He speaks Spanish, English and German. Discounts for groups. You're unlikely to find a more immersive tour of Valparaiso.
Learn
The universities of Valparaiso are:
• 'University Federico Santamaria' [5]
• 'University of Valparaiso' [6]
• 'University of Playa Ancha' [7]
• 'Pontifical Catholic University of Valparaiso'[8]
Many international students study at the Catholic University and the University of Valparaiso.
Work
Buy
Valparaiso, to its charm, is not a city of malls and department stores. While several large grocery stores are present, most other shopping is done in smaller, non-chain stores tucked in along crowded city streets, or with street vendors; larger chain stores (and more upscale goods) are more commonly found in nearby Viña del Mar. A large shopping center, however, is found on the eastern end of Avenida Brasil.
Eat
The most traditional food in Valparaiso is the Chorrillana, a heaping mound of french fries topped with steak, onion, and eggs. You can eat this in the traditional restaurant J Cruz. Fresh seafood is readily available in many small restaurants around the city, especially around the muelle (wharf) areas, and is considered a must for any seafood lover. Neighboring Viña del Mar features a much larger (and more expensive) variety of international cuisines, including Thai, Mexican, and Argentine.
There are also some restaurants which specialize in different seafood dishes near Mercado Puerto, which is near the last metro station. The more the customers dining inside the restaurants, the better the dishes you'll be likely to get.
Bakeries are located on nearly every block, and produce quite delicious breads that can be had warm and right out of the oven at almost any time throughout the day. They are best enjoyed smothered with palta, which are grown en masse in Chile (palta is the Chilean word for avocado, known in most other Spanish-speaking countries as aguacate). In addition to the many types of bread, another widely available snack to keep you settled as you walk the streets are empanadas, a flaky pastry, almost like a croissant, filled with meat or cheese.
Budget
On the second floor of the Mercado Cardonal (cnr Ave Brasil and Uruguay) there are a few excellent, cheap and midrange restaurants serving lunch.
• Chile - Suecia, Calle Bellavista (Just off the square). Open even on Sundays. Good sandwiches, hot dogs and set menus at $2500.
• El Valenciano, Avenida Colon 3110, +56 32 225 1619. Delicious chicken, good sandwiches and good value meals.
• Estación Cielo Amierto, Ferrari 68 (Cerro Bellavista). A cute cafe on the Cerro Bellavista which has juices, smoothies, and sandwiches.
• Los Portenos II, (at the corner of Valdivia and Cochrane), 225 19 15. Delicious seafood dishes and many local people choose this restaurant at weekends.
• Cafe del Poeta, Plaza Anibal Pinto (Opposite the statue of A. Pinto). Good place for a sweat treat. Try the truffa de chocolate.
Mid-range
• Bijoux (Bijoux Restobar), Abtao 561-A, Cerro Concepcion, 56 9 9548 2321 (). Beautiful little Restaurant in the heart of Cerro Concepciòn. Instead of a menu card, the chef and owner comes to you and according to the daily market specialities and your wishes he creates an individual menu just for you.The food is always fresh, delicious and offers an unique experience in Chile. cl$7900.
• Le Filou Montpellier Almte Montt 382. Great French-run restaurant in Cerro Concepciòn.
• Epif Calle Dr. Grossi 268, Cerro Alegre. Tastey vegetarian food and drinks at reasonable prices. Cozy cafe environment with great music and service.
• Delicatessen Emporio, Urriola 383, C. Concepcion (Head north (and up) from the Armada main buiding - two blocks), +56-32-2339373, [9]. Beautiful food in a small, romantic setting. Carpaccio with oysters was exquisite, Garbanzo soup was flavorful (read: spicey), fresh and probably the best I've ever had. 7,500 for a full lunch.
• La Concepción Papudo 541, Cerro Concepción.[10] Voted best restaurant in Valparaiso in many magazines and on TripAdvisor. They serve everything from daily fresh fish to classic Chilean dishes with a modern presentation.[11]
Splurge
Cafe Turri Paseo Gervasoni (by the ascensor conception) great views and good food
Drink
On weekends, the time to go out for a drink (Chilean people call it "salir de carrete") starts no earlier than midnight, though somewhat earlier during the week. The pubs and clubs close at 5 AM on weekends, and 4 AM on weekdays.
Drinking alcohol in the streets is not allowed and 18 years is the minimum age for drinking alcohol, though enforcement of these rules is somewhat lax. If you are under 18, you may not be allowed entry into some pubs.
Chile is a major wine-producing country, and bottles of fairly tasty wines can be had for slightly more than US$1.
Nightlife
• La Torre - offers inexpensive drinks, and is frequented by university students
• Balmaceda
• Barcelona
• La Piedra Feliz - a more expensive and touristy club that often features salsa dancing, mosty for the older crowds
• Club El Cielo
• Club Stockolmo
• Club El Huevo - one of the largest dance clubs in Valparaiso which usually features a young crowd [12]
• Bar La Playa
• Mascara - caters to an artsy and gay/lesbian crowd
Many clubs and bars are also found in Viña del Mar. Public transportation and taxis continue to run throughout the night, making it entirely feasible to have accommodations in one city while going out for the night in the other.
Coffee
• Puro Cafe, Calle Edwards, 301, Valparaiso, + 56 9 96380239. One of the very few places in Chile to have real espresso, not instant coffee. The cafe has beautiful and comfortable furniture, making probably the best place in Valparaiso for coffee.
Sleep
Budget
• Hostel Casa Verde Limón [13] Cumming 198, (56) (32) 2121699, nice living room where you can meet people, very helpful staff, dorms from $5500
• Hostal Pilcomayo, Pilcomayo #491 (Cerro Concepción),<PHONE_NUMBER> ([email protected]). Basic rooms, very friendly atmosphere. The large living rooms makes it a good meeting place. Free internet.Dorm room 6000 per person.www.hostalpilcomayo.cl
• Angel Hostal [14] Cumming 160 Cerro Carcel, (56)(32) 2126940. Dorm room 7000 per person. Double room 8000 per person, matrimonial and single beds. Good breakfast, decent rooms, friendly helpful staff, good place to meet people, free internet and some tickets to nightlife bohemian experience.
• Hostal Girasoles [15] Almirante Montt 167, (56)(32) 2331024. Dorm room 8000 per person. Double room 15000 per person with breakfast, WiFi. They have sinlges as well. Clean rooms and bathroom and a central location close to Plaza Anibal Pinto. From the bus terminal you can catch a colectivo towards Anibal Pinto for 200 pesos, Almirante Montt is one of the streets off the plaza uphill.
Mid-range
• APARTMENTS: Valparaiso Experience, Pasaje Santa Margarita, Cerro BELLAVISTA, Valparaíso, Chile (Strategic central location on residential and artistic hill Bellavista, boasting great views over The Pacific ocean and coastline), (+56 9) 88308764, [16]. Valparaiso Experience offers fuly furnished ocean view apartments on residential cerro (hill) Bellavista. A remodeled building from 1904 with 3 apartments: Queen Mary Duplex - 4 bedrooms/2 bathrooms/large living-kitchen and 2 deck terraces with panoramic views - sleeps max. 8, Pablo Neruda Apartment - 3 bedrooms/1 bathroom/living/kitchen/patio sleeps 5-6, Bellavista Cottage - 2 bedrooms/1 bathroom/kitchen-living/garden with deck terrace and a couple of generous peach trees. A new building on the same central location with 4 luxury ECCO duplex apartments, each provided with solar panels/double glazing windows/central heating/2 bedrooms/2 bathrooms/full kitchen/bright living/ample deck terraces with panoramic ocean views.
• The Mirador Bed and Breakfast, 251 Levarte, [17]. A very comfortable hospedaje in the Playa Ancha sector of the city, with several rooms, small apartments, and a balcony with a great view of the city and port. Internet and Wi-Fi. A nice kitchen to use. Parking. Marisol, the owner, is wonderful and very helpful.
• The Yellow House, Capitán Muñoz Gamero 91, Cerro Artillería, Valparaíso, Chile (The Yellow House is easily reached by using the Ascensor Artilleria, on foot, by public transport or by car.), (56) 32 2339435, [18]. The Yellow House has 7 comfortable guest rooms. Most rooms as well as the homes two galleries, living and dining areas offer wonderful views of the port and harbour and on a clear day extend as far as the AndesMountains separating Chile and Argentina. The Yellow House also has a book exchange, WiFi, cable TV and a selection of board games. The house was built in the late 1800s and has been fully restored. The "Ocean View" room, as the name indicates, has the best view and is really worth it.
• Residencia en El Cerro, Pasaje Pierre Lotti 51, Conceptione, Valparaíso, Chile (Pierre Lotti 51 is easily reached by using the Ascensor Concepcion.). For absolute quietness, except for the creaking floors, try Residencia en El Cerro, Pasaje Pierre Lotti 51. Next door at 43 there is also accommodation. This Hostal is on an alley where no traffic get and the gardens add a little attractive colour. A twin room costs 30,000 a night. Breakfast is just OK with coffee/tea, bread, butter and jam. The place is in its original 1880`s decor - maybe. Wi-fi, TV.
Stay safe
In the context of Chile being a relatively safe country, Valparaiso is amongst its more dangerous locales, like many harbour cities around the world. Mainly, watch out for pickpockets, for instance avoid hanging your purse or bag in the back of your chair when seated, because it may get stolen. Violent crime is very uncommon, but normal precautionary measures should be taken; while in the street, do not display expensive jewelry. The port area (called "Puerto") is generally considered to be dangerous even during the day.
Contact
Cope
• There is a laundry in the mall of Hotel Prat. 5kg $3700.
Consulates
Get out
• Viña del Mar - The beachtown Viña del Mar is only ten minutes by train from Valparaíso, and slightly longer by bus. If you take bus 612 from Plaza Echaurren you will get a full tour of the Valpo hills, and you can jump off at La Sebastiana.
• The idyllic village Quintay is 45 minutes to the south by car. Take a colectivo from Calle 12 de Feberero, behind the bus terminal, 'they leave as soon as they fill up. $1400.
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2024-06-03T21:29:47.544Z | 2013-05-18T07:14:03.000Z | 2dtqn37n5kbxa4hx6ovvq755esstwhoi | {
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: Well, whaddaya know. The rubric problem was on my end after all. You can get your rubrics here. And please, send me your ideas for additional rubrics. Eight is not enough.
I'm gradually going through all the Crummy articles and changing them from evil Microsoft-created files into friendly Linux files. I'm taking the opportunity to do some minor updates and change links. Eventually all the Crummy links will work. Help me out by sending me dead links.
If you have to send me mail on Saturday, send it to<EMAIL_ADDRESS>The UCLA mailserver is going down for maintenance on that day, and I won't be able to get mail from<EMAIL_ADDRESS>until Sunday [Sunday Sunday!] or Monday.
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Unless otherwise noted, all content licensed by Leonard Richardson
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} | cccc_CC-MAIN-2013-20 | advanced search
Category: Educational Resources > Environmental Ethics > Religion and the Environment
BodyEarthSelf
BodyEarthSelf contains vital information for self-improvement, better health, environmental awareness, and simplifying your life. The information is designed to provide hope, positive thinking, and encouragement for a better, more environmentally prosperous life.
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Contact Person: D.A. Colvin
E-Mail<EMAIL_ADDRESS>Website: http://www.bodyearthself.com
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Information about simpler living living free of chemicals with natural substitutions and effective viable suggestions and ideas to help you maintain your body/mind/spirit and increase your environmental awareness.
It is my hope that through my writing and my special compassionate colorful words people will glean hope, positivity, love, faith, and higher awareness. Plato's theory was correct. Everyone has a different perspective and outlook on the world and life and the glass is either half full or half empty, depending on how you perceive it. The one true genuine way to succeed in life and the world and achieve happiness is through compassion, passion, love, kindness, generosity, and most of all truth.
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2024-06-03T21:29:47.544Z | 2013-05-18T06:19:23.000Z | 7znwo52zx7azisow6ank3w5gawq5idbl | {
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} | cccc_CC-MAIN-2013-20 | advanced search
Category: Organizations > Wildlife > Biodiversity
Walden Woods Project
Dedicated to preserving endangered sites within the Walden Woods ecosystem (Concord-Lincoln, Mass.) and educating the public on the importance of land preservation.
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Henry David Thoreau (1817-1862), the author of WALDEN, "Civil Disobedience," and other famous writings, is justly regarded as the founder of the environmental movement in America. Thoreau lived in the Walden Woods during his famous sojourn at Walden Pond, and the Walden Woods was the living laboratory where Thoreau developed his seminal ideas on forest succession and the dispersion of seeds. The mission of the Walden Woods Project is to ensure that the integrity of this important ecosystem remains intact, even in the face of onslaughts from well-financed developers and officials who seem not to understand the cultural and ecological significance of this treasured landscape. In collaborating with the Thoreau Society on the Thoreau Institute, which is located in the midst of Walden Woods and less than half a mile from Walden Pond, the Walden Woods Project disseminates Thoreau's ideas to the public and supports research that clarifies and adds to Thoreau's many and varied legacies.
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2024-06-03T21:29:47.544Z | 2013-05-18T07:22:05.000Z | oklyrsyuflym7r37xwhozre6hfprvwbs | {
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} | cccc_CC-MAIN-2013-20 | Fast internet
Newbie Member
4Jun2011,02:31 #1
Can I bond multiple internet servies together to get better speed?
Go4Expert Founder
4Jun2011,09:47 #2
What type of services?
Mentor
4Jun2011,16:39 #3
Ask them.
Banned
19Apr2013,17:58 #4
No its not possible if you want to get a high speed on internet so you only take one plan just like a unlimited plan in this you will get a high speed. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:09:39.000Z | 3ar5o7trp7nkywmj64g6bj3tzxtsy4mv | {
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} | cccc_CC-MAIN-2013-20 | [50]
“Do not let the exhortations of the Assyrian trouble you in the least, Chrysantas,” Cyrus answered; “for no speech of admonition can be so fine that it will all at once make those who hear it good men if they are not good already; it would surely not make archers good if they had not had previous practice in shooting; neither could it make lancers good, nor horsemen; it cannot even make men able to endure bodily labour, unless they have been trained to it before.”
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2024-06-03T21:29:47.544Z | 2013-05-18T07:26:01.000Z | j4rfmgztzould6potl2t7oicomwj4frt | {
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Watchers
Children
BirthDeath
1.
2.
aft. 1819
3.
aft. 1799
4.
5.
Robert Spring was a gardener who lived in the environs of Aberdeen, Scotland. What is known of him at this point is only what can be gathered from the christening records of his five children. His first two children were christened in the Kincardineshire parish of Banchory-Ternan (about 20 miles WSW of Aberdeen, along the Dee River), and his latter three children were christened in the Aberdeenshire parish of Udny (about 15 miles NNW of Aberdeen), suggesting that the family moved circa 1763. The christening records of the time typically only named the father, although the christening record of Mary names both a father and a mother. It is only a presumption that Mary's mother, Margaret Mearns, was the mother of all of the children, though it is also possible that the move from Banchory to Udny coincided with a second wife for Robert, and that the atypical nomination of a mother on the christening of Robert's first child in Udny was meant to indicate a different wife/mother than for his previous children.
Disambiguation
One might question whether the Robert Spring in Banchory was the same Robert Spring in Udny. However, the connection is supported by the configuration of children, who are themselves shown to be siblings. It can be shown that the Christian Spring who married Archibald Farquharson of Finzean had a brother Robert, a sister Isobel who married Robert Sherrat, and a sister Mary. Isobel and Mary both followed Christian to Finzean. In Christian's will, she identifies her brother Robert as well as the children of her sister Isobel. Only by viewing Robert Spring of Banchory and Robert Spring of Udny as one and the same can we find a family in the approximate right place and time with siblings Christian, Robert, Isobel, and Mary. Moreover, the regular and non-overlapping sequence of christening years in the two parishes would support them being the same Robert. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T05:32:43.000Z | xenenf6o7tjyztm6j7o4p7lk7i4exsmf | {
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Mary Elizabeth "Betty" Taylor
b.20 APR 1824 Jefferson CO., KY
d.26 JUL 1909 Winchester, VA
m. 21 JUN 1810
1. Ann Margaret Mackall Taylor1811 - 1875
2. Sarah Knox Taylor1814 - 1835
3. Octavia Pannill Taylor1816 - 1820
4. Margaret Smith Taylor1819 - 1820
5. Mary Elizabeth "Betty" Taylor1824 - 1909
6. Richard Taylor1826 - 1879
Facts and Events
Name Mary Elizabeth "Betty" Taylor
Gender Female
Birth? 20 APR 1824 Jefferson CO., KY
Death? 26 JUL 1909 Winchester, VA
the text in this section is copied from an article in Wikipedia
Mary Elizabeth Taylor Bliss, born Mary Elizabeth Taylor (April 20, 1824 – July 25, 1909), was the youngest of the five daughters of President Zachary Taylor (1849-1850) and Margaret Mackall Smith Taylor.
In 1848, after her father was elected president, Mary Elizabeth married William Wallace Smith Bliss, an army officer who had served with her father. Taylor appointed William Bliss as Presidential Secretary. At the age of 22, Mary Elizabeth Bliss served as First Lady during her father's presidency, as her mother declined the social role.
Her father, mother and husband all died by 1853. Mary Elizabeth Bliss remarried five years later and had a long life.
This page uses content from the English Wikipedia. The original content was at Mary Elizabeth Bliss. The list of authors can be seen in the page history. As with WeRelate, the content of Wikipedia is available under the Creative Commons Attribution/Share-Alike License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:34:12.000Z | kcm4jndo4lysnjqacpiu773ciszoig53 | {
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Watchers
NameGraettinger
TypeCity
Coordinates43.238°N 94.751°W
Located inPalo Alto, Iowa, United States
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Graettinger is a city in Palo Alto County, Iowa, United States. The population was 844 at the 2010 census.
Research Tips
This page uses content from the English Wikipedia. The original content was at Graettinger, Iowa. The list of authors can be seen in the page history. As with WeRelate, the content of Wikipedia is available under the Creative Commons Attribution/Share-Alike License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T07:25:50.000Z | jbpy225lghf7gcy5jspsfxav22mj7juy | {
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Answers OnStartups is a question and answer site for entrepreneurs looking to start or run a new business. It's 100% free, no registration required.
Say I have a company called Business, and I've been operating under the domain name greatbusiness.com for 2 years. The "tm" symbol is on our logo and elsewhere on our website.
Then someone else comes along and registers greatbusiness.co and files for trademark "Great Business" at the USPTO and was approved. His company name is Great Business Inc.
What are my options at this point to get the trademark back? I want to file for a trademark.
share|improve this question
1 Answer
up vote 1 down vote accepted
Your options will cost money. What you can do depends on how much money you have to fight this and how important the mark is to you.
Your likelihood of success depends on the following factors among others:
• How similar your business is to his. If you sell software and he sells toothbrushes, then you might not have a case.
• How prominent your business is. If you have a lot of sales and sell to most states in the U.S. that helps your case. If you have a primarily local business and low sales, then that makes it a lot harder.
• How distinctive the word is. If it is a word in the dictionary, then you are less likely to succeed. If it is a made-up word, then you have a better chance.
Your options are (in increasing order of cost):
1. Negotiate with the other party. You could do this on your own, but having a lawyer will bring the other party to the table.
2. Oppose the trademark in the USPTO. You would have been better off doing this before the other party got the trademark, but you can still do it. You will need a lawyer to do this, and the initial stages are not so expensive. Are you willing to spend $10,000 on this?
3. File a lawsuit.
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2024-06-03T21:29:47.544Z | 2013-05-18T05:29:19.000Z | rnva5htrdszkkodtk3zipoh6e7kmynku | {
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} | cccc_CC-MAIN-2013-20 | Bullying: Risk Factors Becoming ‘Bullies’
Kasetchai Laeheem, Metta Kuning, Nittaya McNeil
Abstract
The primary purpose of this study was to analyze the internal consistency and construct validity of a classification of bullying outcomes, and to investigate the risk factors associated with bullying behaviour at Pattani primary schools, southern Thailand. A cross-sectional study was conducted with a sample of 1,440 students. Factor analysis, descriptive statistics, Pearson’s chi-squared test, and logistic regression were used for data analysis. The results showed that 20.9% of students in Pattani primary schools reported having bullied others. A four factors structure of bullying was clearly shown; serious, general physical, psychological-maligning parent and psychological-maligning student. Witnessing parental physical abuse was clearly the most strongly associated determinants, and much more strongly linked to bullying others than was the group who had never witnessed parental physical abuse (OR 7.60, 95% CI 5.60-10.31). The students who preferred action cartoons were more often bullies than were those who preferred comedy cartoons (OR 2.87, 95% CI 1.91-430).
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2024-06-03T21:29:47.544Z | 2013-05-18T08:09:36.000Z | sbn75qjvhi4t3wgfg32pkeknd6wrnu5n | {
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} | cccc_CC-MAIN-2013-20 | GlobalVoices in Learn more »
Iran's Supreme Leader Behind Enemy Lines with New Facebook Page
This post also available in:
Français · Iran : Le Guide Suprême "derrière les lignes ennemies" avec une nouvelle page Facebook
Español · Líder supremo iraní tras las líneas enemigas con nueva página de Facebook
So Facebook is Halal all of a sudden?
by Peyman Majidzadeh Excerpted from a longer post originally published on Arseh Sevom.
Amid all the discussions about launching a halal or national Internet in Iran, Ayatollah Khamenei, the Supreme Leader, took everybody by surprise with a new Facebook page launched on December 13, 2012. We are talking about the same Facebook, which for most Iranian citizens to access requires special software or a Virtual Private Network to bypass the country’s strict filtering! The news became official on December 15 when Mr. Khamenei’s Twitter account, believed to be run by his office, promoted the page by posting a link to it. According to The Guardian, Khamenei's official website has not yet confirmed the existence of the page, but the conservative news site Baztab reported that the account was run by his office.
In defense of Mr. Khamenei, Mehr News [fa] criticized Western news outlets for their reporting, stating:
“A simple search shows over a hundred accounts and similar pages attributed to Ayatollah Khamenei on Facebook.”
What Mehr fails to mention is that only one of these pages has been promoted through Khamenei’s Twitter account.
In addition to the recent Facebook account, Mr. Khamenei has a Twitter account and uses Instagram. On the flip side he has been very vocal about his opposition to social networks, reports Small Media [en].
Ayatollah Khamenei’s Facebook debut has generated heated debates in the Iranian online community. The ayatollah seems to have attracted over 20,000 “likes” so far. Unsurprisingly, the censorship apparatus seems to be on guard here too, as critical comments are being removed and many have been quickly blocked by the page’s admin. Masih Alinejad, an exiled journalist, posted on her Facebook page [fa]:
“The virtual guardianship of Khamenei on Facebook: If Mr. Khamenei or his office has officially joined Facebook, this implies that he has made up his mind to fight the ‘enemy’ behind the enemy’s line.”
She continues her post by publishing her own comments on the ayatollah’s page which were removed in the blink of an eye:
“If this is your official page, your majesty, you undoubtedly realized that there is no leader of a country nowadays who has never done an interview with a journalist throughout his leadership period. So please inbox me your telephone number so that I can bother you for an interview over the phone.”
Some have encouraged people to report this page as spam and ask Facebook to block the page. The have also created a new page called “No to Ayatollah Khamenei” and urged him to leave Facebook. They state that free access to information and the internet is everybody’s right, not one exclusive to the leader.
The blog Evolution-Adam [fa] posted a photoshopped screenshot of the page portraying Bashar Assad, Putin, Ayatollah Mesbah, [former] Judge Mortazavi, Seyed Hassan Nasrollah, Shariatmadari, and Kim Jong-un in the Facebook friends list of Khamenei.
Altered screenshot from the blog Evolution-Adam
In a blog entry titled “It is a crime for ordinary people, but it is permitted for him”, the author wrote [fa]:
“Ayatollah Khamenei has recently launched his own Facebook page while Facebook is blocked in Iran and the use of anti-filters is a crime!… What kind of a law is it when breaking it is easy for the authorities but ordinary people are jailed, lashed, or end up like Sattar Beheshti [a blogger who was killed] if they don't respect it.”
Former vice president Mohammad Ali Abtahi takes a different view. In his blog [fa] he writes:
“I believe this debut requires the attention of Internet policy makers and telecom organization officials. The most important thing here is to lift the filters on the page so that everybody can have access to it. Connecting to the highest-ranking official of the country for those inside by using circumvention is considered disrespectful to the people and to the Supreme Leader himself.”
On the page itself, many have commented only to have their comments swiftly removed by the page admin.
“When Bashar Assad falls, you will be next,” read a post which quickly disappeared. Another post with a similar fate read, “Which VPN do you use?”
Plenty of posts could also be seen urging the ayatollah to release political prisoners, grant freedom of expression and assembly, and allow free and fair elections. On the other hand, there are many comments praising Ayatollah Khamenei, which are not removed.
Despite the fact that the page has been widely publicized and commented on, so far there has been neither confirmation nor denial from Ayatollah Khamenei’s office of its authenticity. Confirmation from his office would highlight the double standards of the regime when it comes to social media. Meanwhile, Facebook is all about interaction and engagement, not just removing comments and blocking users. It is not clear how long the supreme leader will be able to maintain a similar no-comments approach.
Only time will tell.
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2024-06-03T21:29:47.544Z | 2013-05-18T06:33:08.000Z | 2dgkaweuje3qizvvalwefuporf6whmhh | {
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} | cccc_CC-MAIN-2013-20 | SIMULATION OF SORTING SEDIMENTATION IN THE CHANNEL OF HUANGHUA HARBOR BY USING 3D MULTI-SIZED SEDIMENT TRANSPORT MODEL OF EFDC
Qinghe Zhang, Feng Tan, Tao Han, Xiaoyuan Wang, Zhiqiang Hou, Hua Yang
Abstract
Huanghua Harbor, located in the south-west coast of Bohai Bay, China, has frequently encountered severe channel siltation with sorting sedimentation along the channel during storm events since its construction. For prediction of channel siltation, a 3D numerical model of multi-fraction sediment transport based on the coupling of modified EFDC model and SWAN model is developed to investigate the sediment transport. It is shown from simulated results that the sorted sedimentation in the channel was well simulated in storm events, and the high sediment concentration near sea bed for silty coast during storm process can also be basically reflected by the model.
Keywords
EFDC model; SWAN model; Sorting Sedimentation; multi-fraction sediment; sediment concentration
References
Booij, N.C., R.C. Ris, and L.H. Holthuijsen. 1999. A third-generation wave model for coastal regions: 1. Model description and validation, Journal of Geophysical Research, 104, 7649-7666.http://dx.doi.org/10.1029/98JC02622
Hamrick, J.M. 1992. A three-dimensional environmental fluid dynamics computer code: theoretical and computational aspects, Special Report, VIMS, Virginia, 317pp.
Han H.S., S.S. Li, and Q. Zhao. 2006. Experiment study of vertical distribution of suspended concentration for silt under breaking wave condition. Journal of Sediment Research, (6), 30-36. (in Chinese).
Mellor G.L., and T. Yamada. 1982. Development of a turbulence closure model for geophysical fluid problems, Reviews of Geophysics and Space Physics, 20, 851-875. http://dx.doi.org/10.1029/RG020i004p00851
van Rijn L.C., M. W. C. Nieuwjaar, T. van der Kaay, E. Nap and A. van Kampen. 1993. Transport of fine sands by currents and waves. Journal of Waterway, Port, Coastal and Ocean Engineering119(2),123-133. http://dx.doi.org/10.1061/(ASCE)0733-950X(1993)119:2(123)
van Rijn L.C. 2007. Unified View of Sediment Transport by Currents and Waves. II: Suspended Transport, Journal of Hydraulic Engineering, 133, 668-689. http://dx.doi.org/10.1061/(ASCE)0733-9429(2007)133:6(668)
Xu H.M., and Y.L. Feng. 1998. Study on sediment transport in Huanghua Port project, Journal of Sediment Research, (1), 20-29. (in Chinese).
Yan B. 2008. Study of Sediment Transport and Channel Siltation on Silty Coast, Ph.D. thesis, Tianjin University (in Chinese).
Yan X.X. 2005. The sediment composition and distribution in nearshore zones of Huanghua Port, Journal of Waterway and Harbor, 26, 144-148. (in Chinese).
Zhang Q.H., F.L. Hou, B. Xia, J.F. Zhang, and H. Yan. 2006. Two dimensional numerical simulation of siltation in outer channel of Huanghua Harbor, China Harbor Engineering, 5, 6-9. (in Chinese)
Zhang Q.H., C.X. Wang, and H. Yang. 2004. The characteristics and affects of seabed surface sediment of Huanghua port, China Harbour Engineering, 4, 14-17. (in Chinese)
Zhao Q. 2006. Fine sediment transport in storm event-the Huanghua experience, Proceedings of 30thInternational Conference on Coastal Engineering. ASCE, 2956-2968.
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Why not add this quote to your bookmarks?
...his pale and haggard face, and gloomy bearing, had so far influenced the remark, that Edward was, for the moment, at a loss to answer him.
'Tut, tut,' said Mr Haredale, ''twas not very difficult to read a thought so natural. But you are mistaken nevertheless. I have had my share of sorrows--more than the common lot, perhaps, but I have borne them ill. I have broken where I should have bent; and have mused and brooded, when my spirit should have mixed with all God's great creation.
The men who learn endurance, are they who call the whole world, brother. I have turned FROM the world, and I pay the penalty.'
Edward would have interposed, but he went on without giving him time.
'It is too late to evade it now. I sometimes think, that if I had to live my life once more, I might amend this fault--not so much, I discover when I search my mind, for the love of what is right, as for my own sake. But even when I make these better resolutions, I instinctively recoil from the idea of suffering again what I have undergone; and in this...
Dickens, Charles
This quote is about endurance · Search on Google Books to find all references and sources for this quotation.
A bit about Dickens, Charles ...
Charles John Huffam Dickens FRSA (7 February 1812 - 9 June 1870), pen-name "Boz", was an English novelist. During his career Dickens achieved massive worldwide popularity, winning acclaim for his rich storytelling and memorable characters. Considered one of the English language's greatest writers, he was the foremost novelist of the Victorian era as well as a vigorous social campaigner.
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} | cccc_CC-MAIN-2013-20 | Apologetics Press
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Apologetics Press is a site that focuses on Christian apologetics. The site's editors compile topics related to Christianity, throw out the ones that don't agree with them, and makes the ones that do look trustworthy.
Apologetics Press seems to be written from a fundamentalist point of view, as they hold that there are no biblical contradictions. The site seems to enjoy archiving debates in which atheists have lost. They think this will make them more respectable because rhetoric is better than evidence. Who needs empirical evidence and consistent observation when you can just play on the audience's ignorance and persuade them that there is a magic man who'll take them to heaven if they believe in him?
Contents
[edit] Purpose
The logo of Apologetics press.
Apologetic Press's purpose is to make the scripture of their Oh So Holy and Truthful Divine Graceful All-Loving Merciful Christian God seem scientifically accurate. The site has stated what its authors believe, and then tries to bend logic and evidence to fit their faith.
[edit] Effect
Christian apologists will sometimes use Apologetics Press to damage what credibility they originally had.[more detail please] The site can be a useful tool to examine various apologist oxymorons, such as "Reason and Revelation." The site has a sleek design, having recently been revamped. Despite this, it still contains obvious bias and reversal of scientific method, the site is also a good place where one can practice one's knowledge of logical fallacies. The site's most popular ones are: the false dichotomy, non sequitur, argument from design, argument from authority and the typical straw man.
[edit] See also:
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} | cccc_CC-MAIN-2013-20 | But not in a good way... the pitiful results betray the fact that a solid majority of Americans have absolutely no idea what's going on in this country.
80% of the voting public doesn't have a clue
and got less than half right!
This goes some ways towards explaining how a shady post-turtle like Barack Obama found his way into the Oval Office- and how the public can continue to be so easily manipulated by the thoroughly-discredited MSM hacks that endeavor to prop him up.
And there are no trick questions here - just a very simple test to see if you are current on your information. It's only a dozen questions... but NO Googling during the test, kids~
I just took it and got two wrong, I'll admit... but that's still good-enough to put me in the 94%tile, what does that tell you about the American voter today...
Click here:
Pew Research Center | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:50:17.000Z | czadjtbarayyuahzsybmu5p7px57kpxh | {
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} | cccc_CC-MAIN-2013-20 | Kirby's Dream Land
From StrategyWiki, the video game walkthrough and strategy guide wiki
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This page is a stub. Help us expand it, and you get a cookie.
Kirby's Dream Land
Developer(s) HAL Laboratory
Publisher(s) Nintendo
Distributor(s) 3DS Virtual Console
Release date(s)
Game Boy
Nintendo 3DS
Genre(s) Platform
System(s) Game Boy, Nintendo 3DS
Mode(s) Single player
Rating(s)
ESRB: Kids to Adults
Series Kirby
Neoseeker Related Pages
Kirby's Dream Land, known as Hoshi no Kābī (星のカービィ? lit. "Kirby of the Stars") in Japan, is a 1992 third party developed platform game developed by HAL Laboratory and published by Nintendo for the Game Boy handheld video game console. It was first released in Japan, and was later released in North America. It is both the first video game in the Kirby series and the debut of the Kirby character. Kirby's Dream Land was designed by Masahiro Sakurai, at HAL Laboratory who intended for Kirby's Dream Land to be a simple game that could be played by beginning gamers. As the inaugural Kirby title, Kirby's Dream Land created many conventions that would appear in later games in the series, including Kirby's basic moves. However, Kirby's trademark "copy" ability would not appear until Kirby's Adventure, released less than one year later. Kirby's Dream Land was re-released for the 3DS's Virtual Console service. It is also one of the games included in Kirby's Dream Collection, which was released to celebrate Kirby's 20th anniversary.
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Mount Isa
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Mount Isa [1] is a mining city in the north-west of the Australian state of Queensland, situated some 900 km west of Townsville and some 1900 km north-west of the capital Brisbane. Population 22,000. Geology is the key drawcard to Mount Isa, best represented in the World Heritage Riversleigh Fossil Field located near the city (250 km! - "near" for Queensland....).
Mount Isa Mines at dusk
[edit] Understand
Mount Isa is the birthplace of two Australian sporting greats: Greg Norman (golf) and Pat Rafter (tennis).
Mount Isa City municipality covers an area of over 43,310 square kilometres, making it geographically the second largest city in the world to Kalgoorlie-Boulder, Western Australia.
[edit] Get in
[edit] By train
Mount Isa is served by The Inlander passenger train [2] which travels overnight between Townsville (via Charters Towers) twice weekly (977 km). The air-conditioned train offers twinette, roomette, triple bunk and coach accommodation, and has a club car for movies and food.
[edit] Get around
[edit][add listing] See
The Mount Isa Rotary Rodeo [3] is the biggest and richest event Rodeo Event in the Southern Hemisphere. During Rodeo Week, Mount Isa's population swells almost three-fold with travelers coming from all over Australia and overseas to witness the thrills, the excitement, the raw power and courage that is rodeo. It's where city meets country, east meets west, man meets beast. With a packed program of rodeo events - saddle bronc riding, bareback bronc riding, bull riding, rope & tie, steer wrestling and team roping, wild horse racing, ladies barrel racing and ladies breakaway roping. Every year it all seems to get bigger better and more fun!
Outback at Isa - Hard Times Mines Mount Isa
• Riversleigh Fossils Centre, ph: +61 (0)7 4749 1555 or 1300 659 660<EMAIL_ADDRESS>, fax: +61 (0)7 4743 6296,)[4] Conveniently displaying the results of excavation at the World Heritage site
[edit][add listing] Do
Hard Times Mine tour [5] Experience the history of Mount Isa's long and illustrious mining history in this purpose built mine. Guided by current and former miners from the Mount Isa mines, machinery demonstrations, old stories and hands on experience can all be experienced in a real underground environment. An amazing and unforgettable experience for locals and tourists alike.
[edit][add listing] Buy
[edit][add listing] Eat
Mount Isa, for a city of its size, is a considerable dining experience for the hearty traveller and local. Selections such as Indian, Italian, Chinese, German and French are all represented, either in the CBD or on the major roads. As well as this, all the major fast-food giants such as McDonalds, KFC, Eagle Boys, Red Rooster, Pizza Hut and Subway all have outlets in the Copper City.
• Abyssinia Cafe Restaurant [6], 103 Marian Sreet. ph: 07 4743 3328. The Abyssinia Cafe is a Licensed Restaurant serving traditional Ethiopean Cuisine as well as standard Australian meals and Indian food. For the last 20 years, Almaz Taye (Leila) Cashmore has owned and operated the cafe building up a broad reputation for excellent food. The Cafe has been featured on SBS for Ethipoean Cuisine
• The Isa Hotel] [7], 11 Miles Street. ph: 07 4749 8888. The Isa Hotel hosts the very popular Rodeo Bar & Grill. The ample menu focuses on the beef and barramundi found in the region while providing many alternative dishes to suit almost everybody. Bookings are recommended from Friday and Saturday nights.
[edit][add listing] Drink
Drinking aplenty in the Isa. The Irish Club [8], Buffs Club [9], The Overlander Hotel, The Isa and the Red Earth Hotel [10] and many others are make up the great selection of watering holes in the city. Many outlets have meals, happy hours and special promotions going all the time.
[edit][add listing] Sleep
Mount Isa offers a range of accommodation options to suit everyone's budget.
[edit] Budget
• Travellers Haven Backpacker Hostel [11], 75 Spence Street, ph: +61 (0)7 4743 0313. A relaxed, family-run hostel only 10 minutes walk from the city centre. The Haven offers free pick-up and drop-off from the bus and train station, cooking and laundry facilities, air conditioning, swimming pool, internet and off-street parking. Dorms from $25.
[edit] Mid-range
• Cityside Accommodation [12], 20 Fourth Avenue, Parkside. ph: (07) 4749 0007. Comfortable and quiet self-contained rooms to accommodate any traveler type. Located only minutes from cbd and within walking distance of Aquatic Centre. Clean outdoor shared areas - garden and BBQ. Friendly staff and strong sense of community among residents and guests.
• Townview Motel in Mount Isa [13], 103 Marian St. ph: +61 7 4743 3328. 4-star accommodation with 24 rooms that include Budget, Standard and 2 Bedroom Spa Suites. Most rooms include cooking facilities. There is also a 3 bedroom house for longer stays. The Abyssinia Cafe Restaurant is on site which serves traditional Ethiopean Cuisine as well as standard Australian meals and Indian food.
[edit] Get out
The roads into and out of Mount Isa are generally of good quality and passable for all vehicles. Care should be taken if travelling during the wet season as many of these roads can become flooded and impassable. Never try to cross covered causeways even if no signage or barricades are erected at the site. Purpose built signs are placed along the Barkly Highway to Townsville to indicate what roads are passable during flood times. Alternatively, asking locals of possible road conditions can give surprising accuracy.
• Flights can be booked with Airnorth, Qantas, Rex and Skytrans to various locations around the Queensland and Northern Territory (depending on carrier)
• Train services are run twice per week to Townsville and other towns along the Barkly Highway with the Inlander
• Bus services between Mount Isa and surrounding areas are run by Greyhound Australia [14]
General Distances
This is a usable article. It has information for getting in as well as some complete entries for restaurants and hotels. An adventurous person could use this article, but please plunge forward and help it grow!
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} | cccc_CC-MAIN-2013-20 | Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
1307.6 - Tasmanian State and Regional Indicators, Jun 2009
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 29/07/2009
Page tools: Print Page Print All RSS Search this Product
EDUCATION
SCHOOLS
In August 2008, there were 277 schools in Tasmania, of which 210 (75.8%) were government schools and 67 (24.2%) were non-government schools. There were 169 (61.0%) primary only schools, 46 (16.6%) secondary only schools, 56 (20.2%) combined primary/secondary schools and 6 (2.2%) special schools.
The number of schools in a particular year can be affected by structural change in the composition of schooling rather than necessarily a change in the number of sites delivering full-time school education. That stated, over the ten-year period 1998-2008, the numbers and proportions of primary only and secondary only schools have remained steady. In 1998, there were 176 primary only schools in Tasmania representing 64.0% of all schools (not including special schools) and 47 secondary only schools (17.1%).
SCHOOLS(a), Tasmania
SCHOOL STUDENTS
In August 2008, there were 81,591 full-time school students in Tasmania. From 1998 to 2008, the number of full-time students attending government schools fell by 7.5% (from 62,978 to 58,280), while the number attending non-government schools increased by 10.3% (from 21,138 to 23,311).
In August 2008, 54.9% of all full-time school students in Tasmania were attending primary schools (44,770); 45.1% were attending secondary schools (36,821).
In August 2008, apart from the Northern Territory (NT), Tasmania had the lowest proportion of full-time students attending non-government schools (28.6%). By contrast, the state or territory with the highest proportion was the Australian Capital Territory with 42.5%.
PROPORTION OF NON-GOVERNMENT FULL-TIME STUDENTS, Tasmania
There were 1,546 part-time school students in Tasmania in August 2008, a significant decrease (42.8%) on the numbers in 1998 (2,701). There were 5,017 indigenous full-time school students, a significant increase (22.1%) on the numbers in 1998 (4,108).
HIGHER EDUCATION STUDENTS
In 2007, there were 19,531 higher education students in Tasmania. Of these, 53.7% were female, 73.4% were undertaking a bachelor degree and 17.6% were undertaking postgraduate study. The most popular field of education study by Tasmanian higher education students in 2006 was 'society and culture' (22.3% of all students) followed by 'management and commerce' (18.8%).
PROPORTION OF HIGHER EDUCATION STUDENTS, Tasmania
AGE PARTICIPATION RATES
The school age participation rate indicates the proportion of the resident population who are at school. Occasionally, a participation rate can exceed 100%, mainly due to the enrolment of students in schools who are not residents of that state. The age participation rates for full-time Tasmanian school students in August 2008 were 99.8% for 14 year olds, 99.7% for 15 year olds, 86.3% for 16 year olds and 60.6% for 17 year olds.
Tasmania's participation rate for 17 year olds exceeded that of Western Australia (41.4%), the NT (5.2%) and Queensland (47.1%).
APPARENT RETENTION RATES
The apparent retention rate is the number of school students in a designated level/year of education expressed as a percentage of their respective cohort group. To calculate the apparent retention rate of full-time secondary school students in Tasmania, the total of full-time students in Year 12 in August 2008 is divided by the number of full-time students that were in Year 7 in 2003. The resultant figure is converted to a percentage. Care should be taken in interpreting apparent retention rates as the method of calculation does not take into account a range of factors. Please refer to paragraphs 20 and 22 of the explanatory notes in Schools, Australia, 2008 (ABS cat no. 4221.0).
In August 2008, the apparent retention rate of full-time Tasmanian students from Year 7/8 to Year 12 was 64.8%, compared to 62.1% in 1998. The apparent retention rate for females in 2008 was 71.1% and for males 58.9%.
In recent years, apparent retention rates for students in non-government schools have exceeded those for students in government schools. In August 2008, the apparent retention rate of full-time Tasmanian students from Year 10 to Year 12 was 71.8% for those in non-government schools, compared to 61.8% for those in government schools.
APPARENT RETENTION RATES, Year 10 to Year 12, Tasmania
STUDENTS ACHIEVING BENCHMARK
In March 1997, all state, territory and commonwealth education ministers agreed on the national goal: that every child leaving primary school should be numerate and able to read, write and spell at an appropriate level. The Ministerial Council for Education, Early Childhood Development and Youth Affairs (MCEECDYA) publishes national reports which include the results of testing conducted to identify the achievement of students in each of Years 3, 5, 7 and 9 as measured against national benchmarks for reading, writing and numeracy.
In general, the results for Tasmania for 2008 show that the large majority of Years 3, 5, 7 and 9 students are achieving at the benchmark level or better in reading, writing and numeracy. The highest percentage results for Tasmania were gained by Year 3 students for writing and numeracy where this cohort saw a respective 97.1% and 96.7% of students achieving at the benchmark level or better; the lowest percentage results were gained by Year 9 for writing (84.1%) and Year 5 for reading (89.7%).
Across all categories and years except one, Tasmanian female school students achieved better benchmark results than equivalent male school students. The one exception was for Year 9 numeracy where 92.6% of males achieved the benchmark or better compared to 92.0% for females.
PERCENTAGE OF STUDENTS ACHIEVING BENCHMARK IN READING, Tasmania, 2008
PERCENTAGE OF STUDENTS ACHIEVING BENCHMARK IN WRITING, Tasmania, 2008
PERCENTAGE OF STUDENTS ACHIEVING BENCHMARK IN NUMERACY, Tasmania, 2008
SCHOOL TEACHERS
There were 6,973 teaching staff in Tasmania in August 2008. Of these, 4,921 were female and 2,052 were male.
There were 5,816 full-time equivalent (FTE) teaching staff in Tasmania in August 2008. Of these, 4,122 were at government schools and 1,694 were at non-government schools; 2,976 were at secondary schools and 2,840 were at primary schools; and 3,952 were female and 1,864 were male.
PROPORTION OF FULL-TIME EQUIVALENT TEACHING STAFF, Tasmania
The proportion of Tasmanian FTE female teaching staff has continued to rise, albeit slowly, since 1998. Conversely, the proportion of male staff has fallen. In August 2008, 67.9% of all Tasmanian FTE teachers were female; this compared to 65.2% in 1998. In August 2008, 32.1% of all Tasmanian FTE teachers were male; this compared to 34.8% in 1998.
Tasmanian primary schools have significantly more female teachers than male teachers. In August 2008, 80.0% of all FTE teachers in primary schools were female compared to 56.5% in secondary schools. The comparable figures in 1998 were 78.8% and 52.2% respectively.
Overall, in August 2008, the average number of FTE Tasmanian primary school students per FTE teacher was 15.8. In government primary schools the average was 15.5; in non-government primary schools it was 16.5. The equivalent figures for secondary schools were 12.7 students, with an average of 13.0 in government secondary schools and 11.9 in non-government secondary schools.
SOURCES
Ministerial Council for Education, Early Childhood Development and Youth Affairs (MCEECDYA)
Schools, Australia (ABS cat no. 4221.0)
Further information can also be found on the Education and Training Statistics Theme Page of the ABS website.
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Detection and mapping of mtDNA SNPs in Atlantic salmon using high throughput DNA sequencing
Olafur Fridjonsson1*, Kristinn Olafsson1, Scott Tompsett2, Snaedis Bjornsdottir1, Sonia Consuegra2, David Knox4, Carlos G de Leaniz3, Steinunn Magnusdottir1, Gudbjorg Olafsdottir1, Eric Verspoor4 and Sigridur Hjorleifsdottir1
Author Affiliations
1 Matís, Vínlandsleið 12, 113 Reykjavík, Iceland
2 Institute of Biological Sciences, University of Wales, Aberystwyth, UK
3 Department of Pure & Applied Ecology, Swansea University, Swansea SA2 8PP, UK
4 Freshwater Laboratory, Marine Scotland, Pitlochry, Scotland PH16 5LB, UK
For all author emails, please log on.
BMC Genomics 2011, 12:179 doi:10.1186/1471-2164-12-179
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2164/12/179
Received:21 October 2010
Accepted:7 April 2011
Published:7 April 2011
© 2011 Fridjonsson et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Approximately half of the mitochondrial genome inherent within 546 individual Atlantic salmon (Salmo salar) derived from across the species' North Atlantic range, was selectively amplified with a novel combination of standard PCR and pyro-sequencing in a single run using 454 Titanium FLX technology (Roche, 454 Life Sciences). A unique combination of barcoded primers and a partitioned sequencing plate was employed to designate each sequence read to its original sample. The sequence reads were aligned according to the S. salar mitochondrial reference sequence (NC_001960.1), with the objective of identifying single nucleotide polymorphisms (SNPs). They were validated if they met with the following three stringent criteria: (i) sequence reads were produced from both DNA strands; (ii) SNPs were confirmed in a minimum of 90% of replicate sequence reads; and (iii) SNPs occurred in more than one individual.
Results
Pyrosequencing generated a total of 179,826,884 bp of data, and 10,765 of the total 10,920 S. salar sequences (98.6%) were assigned back to their original samples. The approach taken resulted in a total of 216 SNPs and 2 indels, which were validated and mapped onto the S. salar mitochondrial genome, including 107 SNPs and one indel not previously reported. An average of 27.3 sequence reads with a standard deviation of 11.7 supported each SNP per individual.
Conclusion
The study generated a mitochondrial SNP panel from a large sample group across a broad geographical area, reducing the potential for ascertainment bias, which has hampered previous studies. The SNPs identified here validate those identified in previous studies, and also contribute additional potentially informative loci for the future study of phylogeography and evolution in the Atlantic salmon. The overall success experienced with this novel application of HT sequencing of targeted regions suggests that the same approach could be successfully applied for SNP mining in other species.
Background
Single nucleotide polymorphisms (SNPs), representing single base differences between individuals, are a common form of genome variation [1]. Once identified, SNPs have the potential to be used as genotyping markers for population assignment or in phylogeographic analysis, and are rapidly becoming the marker of choice within this field of study [2]. The emergence of high-throughput (HT) sequencing technologies provides an unparalleled opportunity for the cost-effective sequencing of targeted genomic regions for SNP identification. HT sequencing has been applied for SNP discovery in humans [3,4], animals [5], plants [6,7] and bacteria [8] - in species where reference genomes exist. In organisms lacking a sequenced reference genome, SNPs have also been mined from the random sequencing of either expressed sequence tags (ESTs) [9,10] or reduced representation libraries [11-13]. However, with an available reference sequence, specific genetic regions of interest can be amplified using PCR prior to HT sequencing. The sequence reads of about 400 bp obtained using the Titanium GS FLX chemistry (Roche, 454 Life Sciences) make the 454 sequencing platform particularly suitable for sequencing PCR generated amplicons. This approach involves the emulsion based amplification of individual PCR products and simultaneous, parallel pyrosequencing of DNA strands [14].
Mitochondrial DNA (mtDNA) has been widely used in studies of phylogenetics, molecular ecology and phylogeography in a range of organisms, including the Atlantic salmon based on RFLP or sequences from using Sanger technology [15-17]. As SNPs represent the main form of polymorphism observed in the mtDNA, recent research has been focused upon the identification of a geographically informative mitochondrial SNP panel suitable for high-throughput genotyping (e.g. mtSNP mini-sequencing) [18].
Traditional Sanger-based sequencing methods are relatively expensive and time-consuming, restricting the number of individuals and gene regions that can be sequenced, given the funding available for most studies. Consequently, often a relatively few individuals from restricted geographical areas have been sequenced in order to obtain SNP panels. The SNPs have been subsequently used to screen larger samples from a broader geographical range [1], which has led to low power in resolving lineages and their relationships. It has also raised potentially serious concerns associated with ascertainment bias, such as the situation whereby inferences are significantly conditioned by the gene region screened or the populations used to identify the polymorphisms. The latter could potentially lead to a biased interpretation of the extent to which individuals and populations are related.
HT sequencing technologies offer the potential to overcome these limitations by allowing the rapid and economic sequencing of large genome regions. However, most applications of HT technology to-date have been designed to sequence a large number of fragments from relatively few individuals. In this study, a novel approach was developed by combining the traditional PCR amplification of known gene regions with 454 Titanium FLX (Roche, 454 Life Sciences) sequencing. This approach allowed the sequencing of extensive regions of the mtDNA genome within a broad sample group both quickly and in accordance with a limited budget. The method was tested on the Atlantic salmon (Salmo salar) - a fish extensively surveyed using both nuclear [19] and mitochondrial DNA markers, including a mtDNA SNP variation [19-22], and for which 152 nuclear SNPs and 125 mtDNA SNPs [20,22,23] have already been reported. Here, 546 samples from 48 locations throughout the species' geographical range were screened for 7215 bp, encompassing approximately 43% of the mtDNA genome in order to minimize the degree of ascertainment bias relative to previous comparable studies.
Results
PCR Amplification
546 S. salar samples derived from across the species' North Atlantic range were included in this study (Figure 1). In addition, 12 brown trout and 18 Arctic charr samples were included in the sequencing setup as a part of another study. The samples were divided into 16 groups, each composed of 36 samples (see Additional file 1, Table S1). Ten regions of the S. salar mitochondrial genome covering the D-loop region and nine coding genes (ND1, ND2, COXI, COXII, ATP6, ND3, ND4, ND5, CYTB) were selected for the SNP detection (Table 1), taking into account those regions previously shown to have high levels of polymorphism by studies of EST libraries and genome sequencing [19,20,22]. Some of the target regions were divided into 2-3 amplicons of about 400 bp, which is the average sequence length obtained with the FLX Titanium chemistry (Table 1). Thus, each sample was subjected to a total of 20 PCR reactions. For each of the 16 sample groups, 720 PCR reactions were carried out separately (Figure 2). Single PCR products of the expected sizes were obtained from the majority of the 11,520 reactions performed. Only 127 PCR reactions (1.1%) with S. salar DNA yielded low quantities of amplified products, despite optimization. Geographic bias was not pronounced; although the amplification of approximately half of the samples from two rivers produced low yields. This could be attributed to limited or low quality DNA isolated from the corresponding samples (data not shown).
Figure 1. A map showing the sampling locations. See also Additional file 1, Table S1: Sampling sites, the number of samples and the division into groups.
Additional file 1. Table S1: Sampling locations. The file shows the sampling locations and the number of individuals per location as well as grouping of samples
Format: DOCX Size: 19KB Download file
Table 1. Target regions used in this study and the number of validated SNPs
Figure 2. The experimental setup. In order to sequence 20 mitochondrial amplicons from 576 samples of Atlantic salmon, brown trout and Arctic charr, in a single run, the isolated DNA was divided into 16 groups, each containing 36 samples. The mitochondrial fragments were amplified from each group in a matrix of PCR reactions, using barcoded primers (MIDs) (A). 20 matrices of PCR reactions, one for each mitochondrion fragment, were carried out (B). Up to 720 amplicons from each group were pooled together in near equimolar concentrations. The 16 pools created were used to generate single stranded fragment DNA templates for the FLX sequencing. 16 amplified sst libraries, consisting of DNA fragments on beads, were loaded onto a PicoTiterPlate equipped with a sixteen-lane gasket where each library was assigned one lane (C). Based on the combination of MIDs on both sites of the amplicons within each group (library), individual sequencing reads were assigned to the corresponding samples.
Pyrosequencing and Amplicon Analysis
The PCR products for each group were pooled for sequencing in near equimolar concentrations and the sequencing was carried out as described in Materials and Methods. The pyrosequencing yielded a total of 179,826,884 filter passed base pairs. An average of 11,546,081 bp (±1,612,536 SD) was obtained from each of the 16 regions on the picotiter plate, excluding one that yielded 6,635,668 bp. The majority of sequence reads were between 400-420 bp, corresponding to the size of the amplicons (see Additional file 2, Figure S1 and Table S2, on the distribution of read length). Each PCR product contained multiplex identifying sequences [MIDs], designed by Roche (454 Life Sciences), at both ends, which enabled the identification of the corresponding sample within a group (Figure 2). Hence, to correctly assign a PCR product to a sample, its entire sequence was required, including both MIDs. The GS Amplicon Variant Analyzer software from Roche, 454 Life Sciences was used to align and assign the sequence reads. The sequences obtained were assigned to 10,765 of the 10,920 S. salar products targeted by PCR (98.6%). The number of sequence reads (sequence coverage) supporting a SNP per individual was on average 27.3 with a standard deviation of 11.74. The yield of sequenced S. salar amplicons was generally high, with less than 1.5% of samples missing on average. The exception to this observation was amplicon 18 (Table 1), where no sequences were obtained for 62 of 546 S. salar samples (12%).
Additional file 2. Figure S1: Distribution of read length Table S2: Read length statistics of the FLX sequencing run. The file contains a graph showing the number of reads vs. read length and a table indicating the read length statistics of the FLX sequencing run.
Format: DOCX Size: 26KB Download file
SNP Analysis
The GS Amplicon Variant Analyzer software identified a total of 1714 variants following alignment of the raw sequence data. Applying the first stringency filter, requiring sequence reads from both DNA strands, reduced this number to 904. After rejecting variants resulting from potential sequencing errors, including under-reads of homopolymer regions, and single base insertions, the variants were confined to those confirmed in at least 90% of replicate sequence reads. Subsequently, 242 variants remained. Thereof, 24 variants were rejected since they occurred in only one individual. Consequently, the alignment analysis and filtering yielded a total of 218 variants, consisting of 216 SNPs and 2 indels. Maps of the S. salar mitochondrial genome, indicating the regions selected for the SNP analysis and the accepted SNPs for each region are shown in Figure 3 and 4, respectively. (See also Table 1, and Additional file 3, Table S3, for further details on 454 read statistics). The greatest number of SNPs was observed in the ND4 gene region (38), whilst the lowest number (10) was observed in the ND3 gene. When considered as a proportion of the length of each region, the D-loop had the highest density of SNPs (0.55 SNPs bp-1) whilst the COX2 region gene yielded the least (0.021 SNPs bp-1). Of the variants observed, 196 are transitions while 20 are transversions, and nearly half of the latter is located in the D-Loop region (Table 1). In three cases (D-Loop: bp973; ND1: bp3989 and CYT-B: bp16421) both a transition and transversion were observed at the same locus in different samples. Indels were only observed within the D-Loop region, with a two bp insertion (CT) at bp 963 and a two bp deletion at bp 967. When compared to previous studies of smaller [20] and more geographically constrained discovery panels [15,19,22-24], 109 of the SNPs and one of the indels had been reported, while 107 new SNPs and one indel were identified in this study (Figure 4). When this data is considered according to populations, 0.5% of SNPs were found in all geographic locations, whilst 13.1% existed in only one. Additionally, a further 56.3% were found in less than 10 populations, whilst 13.1% were found in more than 50% of populations.
Figure 3. A map of the Salmo salar mitochondrial genome. The regions selected for sequence analysis in this study are shown.
Figure 4. Maps of the accepted SNPs obtained in this study, shown for each region. New SNPs are shown red.
Additional file 3. Table S3: mtDNA SNPs validated in this study. The file shows the validated SNPs, their location according to S. salar mitochondrial DNA reference sequence (NC_001960.1); the number of individuals supporting the SNP; and the sequence coverage per individual.
Format: DOCX Size: 50KB Download file
Discussion
Next generation sequencing technology, such as 454 sequencing, is rapidly expanding the possibility for SNP mining by genome sequencing within a reasonable budget. However, the technology to-date has generally been restricted to the sequencing of large regions of the genome using relatively few samples [12,13]. In this work, a large SNP ascertainment panel was obtained at a relatively low cost by amplifying multiple regions of a mitochondrial genome in numerous samples and their subsequent sequencing using the 454 technology. The resultant SNP panel provides the least likelihood of ascertainment bias [25], with a discovery panel of 546 samples from 48 locations across the North Atlantic range of S. salar, making this the most informative and geographically comprehensive SNP panel for the species to-date (Figure 1).
The cost of sequencing using the 454 platform was minimized by carefully designing the experiment to require only a single pyrosequencing run, whilst obtaining sufficient sequence reads in both directions to yield a robust result, essentially minimizing false positives and avoid missing true polymorphisms from each ~400 bp read. The most challenging aspect faced was the need to ensure that each individual amplicon of a given type could be traced to the original sample. This was achieved using a sequencing plate with a 16-region gasket, and a set of 5' MID primer sequences. To decrease the primer cost (and ultimately the overall cost), the necessary adaptor sequences for the 454 sequencing were ligated to the PCR products instead of including them in the primer sequences; this may have also reduced complications in the PCR reactions due to the shorter 5' non-complementary primer sequences. Thus, sequencing libraries were prepared for the 16 PCR pools using the GS FLX Titanium General Library Preparation protocol for shotgun sequencing, instead of using amplicon sequencing (Roche, 454 Life Sciences). Furthermore, a Taq-comparable polymerase was used for generating the PCR pools of 11,520 reactions, instead of using an expensive high fidelity polymerase. The lack of proof-reading activity during the PCR might have increased the error rate in the sequence data, although the numerous specimens used here as well as the sequence coverage obtained should adequately compensate for this. Furthermore, variations observed in a single individual were not accepted as SNPs in accordance with the set criteria. Even if legitimate SNPs were necessarily discarded in this manner, their low frequency suggests that any information that was lost was probably minimal. Given that there is no geographical or population association, it can be assumed that this would not compromise the informative essence of the overall SNP suite, at least from the perspective of the studies of biodiversity and phylogeography. Considering the high coverage obtained in this experiment, the application of a high fidelity polymerase could enable the reliable SNP detection for simultaneous processing of even greater sample numbers than in the current study. Thus, if the budget is not restricting, the processing capacity of the method can be further increased by applying a high fidelity polymerase to generate the amplicons, at the cost of sequence coverage.
The sequence yield in this experiment was approximately 179 million bp, which is within the range of 160-320 million bp expected for Titanium 454 sequencing, using a 16-region gasket (Roche, 454 Life Sciences). However, for an undetermined reason, the sequence yield ranged from 6,635,668 to 13,135,520 filter-passed base pairs between different regions of the sequencing plate. Also, the sequence yield for amplicon 18 was relatively low in comparison to that of the other amplicons. This could be due to a bias in the sample pooling. Nevertheless, the distribution of sequences was relatively similar over the sample range, resulting in an average coverage of 27.3 (±11.7) sequence reads per SNP per individual. The sequencing setup described here also included 30 brown trout and Arctic charr samples. The data sets obtained for these samples were not included in this analysis, and they will be the subject of future studies. Nevertheless, they are mentioned here since they were a part of the original experimental setup of 576 individuals divided into 16 groups, each with 36 individuals. The total number of base pairs that were to be sequenced in this study (including the brown trout and Arctic charr samples) was 4,115,840 bp (number of sequenced bases for 576 individuals). The total sequence data obtained consisted of 179.826.884 bp, so 39-fold coverage would therefore be expected. However, a substantial part of the sequence reads were not assigned to any sample and were consequently excluded from the analysis. The anticipated reason behind this is accounted to short sequence reads missing a MID from either end. Fusing MID sequences to only one end of an amplicon should reduce this problem and increase the number of analysed sequence reads. This practice, however, reduces the number of samples, which can be analysed simultaneously, although with the emergence of new MID sequences validated for 454 sequencing, more samples with only one MID could be assigned.
Although the existence of MIDs on both ends of a sequence read was requisite in order to assign it to the corresponding individual, some global and consensi alignments (made with the GS Amplicon Variant Analyzer) included partial sequences. This was the result of default stringency levels causing parts of some sequences with low quality bases to be discarded. The trimming was however performed following the alignment of the sequence reads. Hence, as the design of the MIDs allows for (corrects) two sequencing errors, these partial sequences could still be assigned to the corresponding individual prior to the trimming.
As expected for high-throughput sequencing methods, which produce high amounts of reads, numerous deviations from the reference sequence were observed in the raw data. The stringent criteria applied here for the SNP validation rejected the great majority of these variants. However, the filtering may also have eliminated legitimate SNPs. Such variants could be identified by a modest reduction in the stringency levels and verified by Sanger sequencing. Following the validation, about 3.0% of the bases screened exhibited sequence variance and the final number of variants, 218 (including two indels), is nearly double the number of mtDNA SNPs previously reported. The new SNPs are predominantly transitions although the number of transversions is relatively high in the non-coding D-loop region (Table 1). Similar transition/transversion ratios were observed in other studies on the genetic variability of the S. salar mitochondrion [19,20,22]. The 107 new SNPs and a new indel identified in this study are indicated in Figure 4 in red letters. Although the average number of sequence reads supporting the new SNPs per individual is similar to that of those reported, the number of individuals harbouring the new SNPs is generally lower (see Additional file 3, Table S3). This is due to the numerous samples and the great geographical range analyzed here, which consequently allowed the detection of new rare variants. The greater the number of amplicons and individuals screened, the more likely it is that an accurate picture of the extent and nature of SNP variation will be revealed, and that a suite of SNP markers for population genetic studies can be compiled. The challenge remains to determine the optimal balance between the number of amplicons (i.e. proportion of mtDNA genome screened), the number of populations (i.e. representativeness of species as a whole) and the number of individuals per population for studies of matrilineal variation in the target species, Atlantic salmon. This will only be achieved by a detailed analysis of the within and among population variation and a consideration of the robustness of its evolutionary and phylogeographic implications. It should, however, provide a basis for robust inferences concerning the general levels of genetic diversity in the species and broad scale, deep phylogenetic structuring. Given, though, that the geographical sampling is extensive rather than intensive, and that sample sizes per population are limited, the ability to resolve any finer scale, shallower evolutionary structuring on the regional level will be diminished. To achieve the latter, a more focused and intensive search, based on sequencing of the entire mtDNA genome from more individuals would be of greater use since a higher proportion of regionally or population restricted or low frequency polymorphisms could be detected.
The analysis of within and among population distribution of variation is currently underway and can be expected to yield considerable insights into the phylogeography and matrilineal evolution of the Atlantic salmon. Analysis of the linkage of variation and its spatial distribution should also assist in the identification of a subset of the overall SNP suite that can be genetically typed more cost-effectively using PCR-based SNP assays. The SNP subset could then be investigated within samples from a wider geographical range and in archival material, in order to establish a more accurate assessment of the mixed stock assignment and population evolutionary hypotheses extracted from the current data set. Additionally, the markers that were identified in the study will likely prove highly useful as genetic tags for use in the assessment of the extent of population processes such as female mediated gene flow, as well as for tracking individual family groups in experimental studies.
Conclusion
A novel approach that combines targeted PCR amplification and a single HT sequencing run proved successful in screening numerous targeted genomic regions in a large number of individuals. This technique presents a valuable tool for the identification of SNPs for population studies in other species, and also minimizes the risks of ascertainment bias associated with previous approaches that screened either confined regions of the genome or only several individuals from few populations.
Methods
Samples and DNA Extraction
Atlantic salmon samples (N = 546) were collected from 48 locations throughout the North Atlantic range of the species using electro-fishing. Additionally, 12 brown trout (Salmo trutta) and 18 Arctic charr (Salvelinus alpinus) samples were included in the sequencing run as a part of the experimental setup shown in Figure 2. Table S1 submitted as Additional file 1 lists the sampling sites, the number of samples, and their subdivision into 16 groups. DNA was isolated from fin-clip tissue samples using the DNeasy Blood & Tissue Kit (Qiagen) and standard protocols, and DNA concentrations were measured with a NanoDrop ND1000 spectrophotometer. The concentrations of stock DNA eluted were 9-484 ng/μl and diluted to 2-10 ng/μl for subsequent PCR reactions.
Primer Design
Ten regions of the S. salar mitochondrial genome (DLOOPB, ND1, ND2, COXI, COXII, ATP6, ND3, ND4, ND5, CYTB) were selected for SNP detection (Table 1). Seven of the ten selected gene regions were amplified in two or three fragments of approximately 400 bps, resulting in a total of 20 amplicons covering 7,215 bps excluding the primer binding sites (Table 1). Primers were designed according to the reference sequence (16.7 kb) of the S. salar mitochondrion (NC_001960.1) (see Additional File 4, Table S4). Barcodes or multiplex identifying sequences (MIDs) of 10 bp were added to the 5' end of each primer, providing a unique means of identification for every sample in a single sequence group. The MIDs used (Figure 2), were those designed by Roche, 454 Life Sciences for automated software identification of samples following sequencing and allow up to 2 sequencing errors in the MID region before a read is misidentified. To minimize the number of MID tagged primers required, samples were divided into 16 groups, each composed of 36 individuals (see Additional File 1, Table S1, for subdivision of samples). Six forward MID-primers (numbered 1-6) and six reverse MID-primers (numbered 7-12) were synthesized (Sigma Aldrich) for each of the 20 amplicons. As a consequence of using a combination of 6 forward and 6 reverse MID tagged primers, the same MIDs could be re-used by conducting the PCR and sequencing of each of the 16 groups separately (See primer matrix, Figure 2). Critically, this minimized the cost associated with the use of multiple MID tagged primers.
Additional file 4. Table S4: The primer set for the 20 amplicons used in this study. The file shows the designation and the sequence of the primers used, as well as the primer binding sites on the mitochondrial DNA according to the reference sequence (NC_001960.1).
Format: DOCX Size: 16KB Download file
PCR Setup
In order to simultaneously amplify 20 traceable mitochondrial fragments from 576 samples in a single run, PCR reactions for each group of 36 samples were conducted separately, resulting in a total of 11,520 PCR reactions across all 16 groups. PCR was performed in 20 μl reactions containing 0.5 mM betaine (Sigma Aldrich), 50 μM dNTP mix, 1 × reaction buffer and 1 U Teg polymerase (Matís production, Taq comparable polymerase), 0.5 μM each primer (synthesized by Sigma Aldrich) and 2-3 μl DNA (2-10 ng/μl). Initial denaturation was at 94°C for 2 minutes followed by 31-33 cycles of 94°C for 60 seconds, 53°C for 45 seconds and 72°C for 90 seconds, and then a final extension of 5 minutes at 72°C. The relative amount of PCR products was estimated using gel electrophoresis and ethidium bromide staining. Subsequently, products from each group were pooled in near equimolar concentrations resulting in 16 pools of up to 720 amplicons.
Construction of single stranded DNA libraries
The DNA pools (3 μg) were electrophoresed on 1% agarose gels and a band of approximately 400 bp was purified from each pool using the QIAquick Gel Extraction Kit (Qiagen). These were subsequently examined using Bioanalyzer 2100 and a DNA 7500 LabChip (Agilent Technologies). Observed traces were correlative for all 16 sample groups, with an average fragment length of 425 bp. Both ends of the DNA fragments were repaired, phosphorylated and ligated to adaptor oligonucleotides A and B. The DNA fragments carrying the 5'-biotin of adaptor B were immobilized onto magnetic streptavidin coated beads. Single stranded template DNAs carrying adaptor A at the 5'-end and adaptor B at the 3'-end were then purified by alkaline denaturation. Reagents, enzymes and oligonucleotides for the single-stranded DNA (sst DNA) library construction were supplied with the GS FLX Titanium General Library Preparation Kit (Roche, 454 Life Sciences). The integrity and concentrations of the sst libraries were estimated using the Bioanalyzer and the RNA 6000 LabChip and Quant-iT Ribogreen DNA Assay Kit (Invitrogen), respectively.
454 pyrosequencing and assembly
Shotgun sequencing of the 16 sst DNA libraries was carried out using the GS FLX Titanium reagents as described by the manufacturer (Roche, 454 Life Sciences). Purified DNA fragments were hybridised onto DNA capture beads and the 16 sst DNA libraries were separately amplified by emulsion PCR. Beads containing amplified DNA were deposited onto a 75 × 75 mm Titanium PicoTiterPlate equipped with a sixteen-region gasket. Those corresponding to each of the 16 original DNA pools (20 amplicons from 36 individuals) were assigned one region and then the pyrosequencing was performed in a single run. The sequence data generated from each region, corresponding to each of the 16 groups, was assembled separately using the GS Amplicon Variant Analyzer software (Roche, 454 Life Sciences) with default stringency settings. Sequence reads were sorted according to the sequence and the combination of the MIDs, and the sequence reads from an individual for each amplicon were aligned with the S. salar reference sequence (NC_001960.1).
SNP analysis and mapping
Candidate SNPs were identified and checked against the global and consensus alignments of the corresponding sequence using the GS Amplicon Variant Analyzer software (Roche, 454 Life Sciences). Variants resulting from potential sequencing errors, including under-reads of homopolymer regions, and single base insertions (carry-forward events) were rejected [26]. Homopolymer under-reads and carry-forward events were observed in the misalignment of underlying consensi, by confirming support in both forward and reverse reads and, where necessary, the observation of underlying flowgrams. SNPs were accepted as valid only if they met the following criteria: (i) Sequence reads with variants were produced from both DNA strands. (ii) Those with >90% support from sequencing reads should have a total of more than 10 supporting reads in both read directions, or in cases of less than 10 supporting reads that the SNP in question should also be present in other samples with higher support. (iii) The final list of SNPs rejected those only found in one sample as these readings could be considered uninformative and possibly arose as a result of a PCR or sequencing error. To determine the sequence coverage for each SNP per individual, only sequence reads comprising the consensus sequence, truly supporting the SNP were taken into account, excluding those reads that did not show the variance (e.g. due to a sequencing error or truncation).
Availability
The SNPs identified and evaluated in this study have been deposited in the National Center of Biotechnology (NCBI) SNP database (dbSNP) under submitter handle MATIS. The accession numbers are: NCBI_ss 295476608 - 295476815.
Authors' contributions
The study was conceived and coordinated by SH and EV and set up by OF, ST and EV. DK, CGL and EV were responsible for the DNA collections. SM, SB, and GO organized and performed the PCR and the sequencing work. OF and SM prepared the sequence alignments and ST and KO did the SNP validations and variant analysis. OF, EV, SB, KO, ST, CGL and SC wrote the manuscript. All participants of this study read and approved the final draft.
Acknowledgements
This work is part of the EU SALSEA MERGE project (No. 212529, FP7-ENV-2007-1) and was sponsored by EU funding in association with internal fundings from Matis and Marine Scotland. Their support is gratefully acknowledged. We thank Vidar Wennevik for providing samples from Norwegian populations for the work. Most of the remaining samples used were drawn largely from archival material collected over the last two decades for other purposes, by numerous individuals. Their contribution to making the study possible is also acknowledged.
References
1. Brookes AJ: The essence of SNPs.
Gene 1999, 234(2):177-186. PubMed Abstract | Publisher Full Text
2. Papachristou C, Lin S: Microsatellites versus Single-Nucleotide Polymorphisms in confidence interval estimation of disease loci.
Genet Epidemiol 2006, 30(1):3-17. PubMed Abstract | Publisher Full Text
3. Bordoni R, Bonnal R, Rizzi E, Carrera P, Benedetti S, Cremonesi L, Stenirri S, Colombo A, Montrasio C, Bonalumi S, et al.: Evaluation of human gene variant detection in amplicon pools by the GS-FLX parallel Pyrosequencer.
BMC Genomics 2008, 9:464. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
4. Ingman M, Gyllensten U: SNP frequency estimation using massively parallel sequencing of pooled DNA.
Eur J Hum Genet 2009, 17(3):383-386. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
5. Van Tassell CP, Smith TP, Matukumalli LK, Taylor JF, Schnabel RD, Lawley CT, Haudenschild CD, Moore SS, Warren WC, Sonstegard TS: SNP discovery and allele frequency estimation by deep sequencing of reduced representation libraries.
Nat Methods 2008, 5(3):247-252. PubMed Abstract | Publisher Full Text
6. Bundock PC, Eliott FG, Ablett G, Benson AD, Casu RE, Aitken KS, Henry RJ: Targeted single nucleotide polymorphism (SNP) discovery in a highly polyploid plant species using 454 sequencing.
Plant Biotechnol J 2009, 7(4):347-354. PubMed Abstract | Publisher Full Text
7. Kulheim C, Yeoh SH, Maintz J, Foley WJ, Moran GF: Comparative SNP diversity among four Eucalyptus species for genes from secondary metabolite biosynthetic pathways.
BMC Genomics 2009, 10:452. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
8. Holt KE, Parkhill J, Mazzoni CJ, Roumagnac P, Weill FX, Goodhead I, Rance R, Baker S, Maskell DJ, Wain J, et al.: High-throughput sequencing provides insights into genome variation and evolution in Salmonella typhi.
Nat Genet 2008, 40(8):987-993. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
9. Deleu W, Esteras C, Roig C, Gonzalez-To M, Fernandez-Silva I, Gonzalez-Ibeas D, Blanca J, Aranda MA, Arus P, Nuez F, et al.: A set of EST-SNPs for map saturation and cultivar identification in melon.
BMC Plant Biol 2009, 9:90. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
10. Wang S, Sha Z, Sonstegard TS, Liu H, Xu P, Somridhivej B, Peatman E, Kucuktas H, Liu Z: Quality assessment parameters for EST-derived SNPs from catfish.
BMC Genomics 2008, 9:450. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
11. Sanchez CC, Smith TP, Wiedmann RT, Vallejo RL, Salem M, Yao J, Rexroad CE: Single nucleotide polymorphism discovery in rainbow trout by deep sequencing of a reduced representation library.
BMC Genomics 2009, 10:559. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
12. Wiedmann RT, Smith TP, Nonneman DJ: SNP discovery in swine by reduced representation and high throughput pyrosequencing.
BMC Genet 2008, 9:81. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
13. Kerstens HHD, Crooijmans R, Veenendaal A, Dibbits BW, Chin-A-Woeng TFC, den Dunnen JT, Groenen MAM: Large scale single nucleotide polymorphism discovery in unsequenced genomes using second generation high throughput sequencing technology: applied to turkey.
BMC Genomics 2009, 10:11. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
14. Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen YJ, Chen Z, et al.: Genome sequencing in microfabricated high-density picolitre reactors.
Nature 2005, 437(7057):376-380. PubMed Abstract | PubMed Central Full Text
15. Nilsson J, Gross R, Asplund T, Dove O, Jansson H, Kelloniemi J, Kohlmann K, Loytynoja A, Nielsen EE, Paaver T, et al.: Matrilinear phylogeography of Atlantic salmon (Salmo salar L.) in Europe and postglacial colonization of the Baltic Sea area.
Mol Ecol 2001, 10(1):89-102. PubMed Abstract | Publisher Full Text
16. Consuegra S, Garcia de Leaniz C, Serdio A, Gonzalez Morales M, Straus LG, Knox D, Verspoor E: Mitochondrial DNA variation in Pleistocene and modern Atlantic salmon from the Iberian glacial refugium.
Mol Ecol 2002, 11(10):2037-2048. PubMed Abstract | Publisher Full Text
17. Verspoor E, O'Sullivan M, Arnold AL, Knox D, Amiro PG: Restricted matrilineal gene flow and regional differentiation among Atlantic salmon (Salmo salar L.) populations within the Bay of Fundy, eastern Canada.
Heredity 2002, 89(6):465-472. PubMed Abstract | Publisher Full Text
18. Mosquera-Miguel A, Alvarez-Iglesias V, Cerezo M, Lareu MV, Carracedo A, Salas A: Testing the performance of mtSNP minisequencing in forensic samples.
Forensic Sci Int Genet 2009, 3(4):261-264. PubMed Abstract | Publisher Full Text
19. King TL, Verspoor E, Spidle AP, Gross R, Phillips RB, Koljonen ML, Sanchez J, Morrison CL: Biodiversity and population structure. Oxford: Blackwell Publishing Ltd; 2007.
20. So MSY: Evolution of mitochondrial DNA in the genus Salmo. In Ph.D Thesis. Vancouver, Canada: Simon Fraser University; 2006.
21. Carr SM, Marshall D, Duggan AT, Flynn SMC, Johnstone KA, Pope AM, Wilkerson CD: Phylogeographic genomics of mitochondrial DNA: Highly-resolved patterns of intraspecific evolution and a multi-species, microarray-based DNA sequencing strategy for biodiversity studies.
Comparative Biochemistry and Physiology 2008, 3:1-11. PubMed Abstract | Publisher Full Text
22. Karlsson S, Moen T, Hindar K: An extended panel of single nucleotide polymorphisms in Atlantic salmon (Salmo salar L.) mitochondrial DNA.
Conservation Genetics 2009., 11(2):
23. Ciborowski KL, Consuegra S, Garcia de Leaniz C, Wang J, Beaumont MA, Jordan WC: Stocking may increase mitochondrial DNA diversity but fails to halt the decline of endangered Atlantic salmon populations.
Conservation Genetics 2007, 8:1355-1367. Publisher Full Text
24. Verspoor E, O'Sullivan M, Arnold A, Knox D, Curry A, Lacroix G, Amiro P: The Nature and Distribution of Genetic Variation at the Mitochondrial Nd1 Gene of the Atlantic Salmon (Salmo salar L.) Within and Among Rivers Associated With The Bay Of Fundy and the Southern Uplands of Nova Scotia.
FRS Research Services Internal Report 2006.
25. Luikart G, England P, Tallmon D, Jordan S, Taberlet P: The power and promise of population genomics: from genotyping to genome typing.
Nature Reviews Genetics 2003, 4:981-994. PubMed Abstract | Publisher Full Text
26. Huse SM, Dethlefsen L, Huber JA, Mark Welch D, Relman DA, Sogin ML: Exploring microbial diversity and taxonomy using SSU rRNA hypervariable tag sequencing.
PLoS Genet 2008, 4(11):e1000255. PubMed Abstract | Publisher Full Text | PubMed Central Full Text | v0 |
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} | cccc_CC-MAIN-2013-20 | Research article
Inequities in skilled attendance at birth in Namibia: A decomposition analysis
Eyob Zere1*, Doyin Oluwole1, Joses M Kirigia2, Chris N Mwikisa2 and Thomas Mbeeli3
Author Affiliations
1 Africa's Health in 2010, Academy for Educational Development, 1825 Connecticut Avenue, Washington, DC 20009, USA
2 World Health Organization, Regional Office for Africa, Brazzaville, Congo, Africa
3 Ministry of Health and Social Services, Windhoek, Namibia, Africa
For all author emails, please log on.
BMC Pregnancy and Childbirth 2011, 11:34 doi:10.1186/1471-2393-11-34
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2393/11/34
Received:13 December 2010
Accepted:14 May 2011
Published:14 May 2011
© 2011 Zere et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
The fifth Millennium Development Goal (MDG5) aims at improving maternal health. Globally, the maternal mortality ratio (MMR) declined from 400 to 260 per 100000 live births between 1990 and 2008. During the same period, MMR in sub-Saharan Africa decreased from 870 to 640. The decreased in MMR has been attributed to increase in the proportion of deliveries attended by skilled health personnel. Global improvements maternal health and health service provision indicators mask inequalities both between and within countries. In Namibia, there are significant inequities in births attended by skilled providers that favour those that are economically better off. The objective of this study was to identify the drivers of wealth-related inequalities in child delivery by skilled health providers.
Methods
Namibia Demographic and Health Survey data of 2006-07 are analysed for the causes of inequities in skilled birth attendance using a decomposable health concentration index and the framework of the Commission on Social Determinants of Health.
Results
About 80.3% of the deliveries were attended by skilled health providers. Skilled birth attendance in the richest quintile is about 70% more than that of the poorest quintile. The rate of skilled attendance among educated women is almost twice that of women with no education. Furthermore, women in urban areas access the services of trained birth attendant 30% more than those in rural areas. Use of skilled birth attendants is over 90% in Erongo, Hardap, Karas and Khomas Regions, while the lowest (about 60-70%) is seen in Kavango, Kunene and Ohangwena. The concentration curve and concentration index show statistically significant wealth-related inequalities in delivery by skilled providers that are to the advantage of women from economically better off households (C = 0.0979; P < 0.001).
Delivery by skilled health provider by various maternal and household characteristics was 21 percentage points higher in urban than rural areas; 39 percentage points higher among those in richest wealth quintile than the poorest; 47 percentage points higher among mothers with higher level of education than those with no education; 5 percentage points higher among female headed households than those headed by men; 20 percentage points higher among people with health insurance cover than those without; and 31 percentage points higher in Karas region than Kavango region.
Conclusion
Inequalities in wealth and education of the mother are seen to be the main drivers of inequities in the percentage of births attended by skilled health personnel. This clearly implies that addressing inequalities in access to child delivery services should not be confined to the health system and that a concerted multi-sectoral action is needed in line with the principles of the Primary health Care.
Background
There is increasing evidence on the existence of pervasive inequalities in health and health care that are related to socio-economic position as may be measured by household income/expenditure/wealth, occupation, gender, area of residence etc. both between and within countries [1,2]. The existing evidence unequivocally reveals that morbidity and mortality are more prevalent at the lower end of the socio-economic ladder. In contrast, access to health services is concentrated among those at the upper end of the socio-economic spectrum.
The overwhelming evidence on socio-economic inequalities in health and health care has led to renewed interest globally and nationally to understand the causes of health sector inequalities and develop appropriate policy responses [3].
The differential in maternal health indicators is perhaps the largest differential in health status between rich and poor countries [4,5]. In Sub-Saharan Africa, the adjusted maternal mortality ratio in 2008 was 640 per 100,000 live births, as compared to 14 per 100,000 in the developed regions. Similarly, while the life time risk of maternal death is 1 in 31 in Sub-Saharan Africa, the corresponding figure in the developed regions of the world is 1 in 4,300 [6].
In the period 2000-2008, about 96% of child deliveries were attended by skilled health personnel in the European Region of the World Health Organization. However, despite global improvement in the proportion of women delivered by skilled health workers, the situation in Africa has not changed [7]. In the African Region only 47% of births were attended by skilled health personnel. The situation in Namibia is much better compared to this average - about 81% of births attended by skilled health personnel.
Data from low and middle-income countries also show significant within country gradients in health outcomes and utilization of health services. In the poorest 20% of the population, an infant is more than twice as likely to die before the age of 1 year and an under-five child is more than three times as likely to be stunted (short-for-age) compared to children from the 20% economically better-off households [8].
At the dawn of the current Millennium, World Leaders agreed to reduce maternal mortality by 75% in 2015 compared to its 1990 levels. One of the indicators for MDG 5 is the proportion of deliveries attended by trained health providers, which include doctors, nurses or midwives. Delivery by trained providers is necessary to reduce maternal mortality and is easy to monitor regularly and at reasonably short intervals compared to maternal mortality.
Global improvements mask inequalities both between and within countries. In Namibia, there are significant inequities in births attended by skilled providers that favour those that are economically better off [9]. Identifying the determinants of inequities in health and health care is essential to designing equitable interventions [10].
In line with the conceptual framework of the WHO Commission on Social Determinants of Health, access to delivery services by skilled health providers is shaped by political, social and economic forces. It then follows that addressing inequities requires a concerted multi-sectoral action, which is also in line with the Principles of Primary Health Care. The objective of this study was to identify the drivers of wealth-related inequalities in child delivery by skilled health providers using a decomposable health concentration index and the framework of the Commission on Social Determinants of Health (CSDH).
Brief country profile
Namibia is a country in the South Western part of Africa covering a land area of 824,000 square kilometers. According to the 2001 population and housing census, the population was about 1.8 million with an inter-censal growth rate of 2.6% per annum [11]. The country is divided into 13 Administrative Regions, which also correspond to the health regions.
Namibia is an upper middle income country [12] and one of those with the highest income inequality in the world [13]. Table 1 below depicts data on selected health and development indicators [13-16].
Table 1. Namibia: selected health and development indicators
As can be seen from Table 1, although the country is better off than many countries in sub-Saharan Africa in terms of resources for health and development, there is a significant amount of inequity and inefficiency. The potential loss in human development due to inequalities in each of the dimensions of the HDI (life expectancy at birth, gross national income per capita and schooling) amounts to about 44%. The HDI falls to a level which is less than that of countries classified as low human development (HDI = 0.393) [13]. Furthermore, the GNP per capita rank minus the HDI rank was -14 indicating inefficiency in translating resources into welfare, i.e. the country did not achieve the level of human development that could potentially have been achieved given its resources.
Antenatal care from a skilled provider (at least one visit) was about 95%. However, the proportion of pregnant women who received four or more antenatal care visits was only about 70%. The maternal mortality ratio of 449 per 100,000 live births in 2006/07 is a significant increase from the 1992 level, which was 225 per 100,000 live births. Apart from the direct and indirect causes of maternal mortality; limited access to emergency obstetric care and lack of transport and communication facilities also contribute to maternal mortality.
To reverse the increasing trend of maternal mortality and consequently accelerate the progress towards the achievement of the 5th Millennium Development Goal (MDG 5) of reducing the maternal mortality ratio by three-quarters between 1990 and 2015, the Government has embarked on a number of initiatives, including development and implementation of a Roadmap for Accelerating the Reduction of Maternal and Neonatal morbidity and mortality.
Methods
Measuring inequalities
In measuring equity in a health outcome or access to health interventions, the following are required:
- indicator of the health intervention of interest (delivery by skilled health providers)
- a variable (stratifier) capturing socio-economic status against which the distribution is to be assessed (wealth); and
- a measure of socio-economic inequality to quantify the degree of inequity in the indicator variable of interest.
A concentration index (C) is used to measure wealth-related inequalities in the observed use of delivery services by skilled health providers. The concentration index of a health care variable y (utilization of delivery services by trained health providers) can be defined using the concentration curve that links the cumulative proportion of individuals ranked by wealth to the corresponding cumulative proportion of y (use of delivery services by trained health providers). The concentration curve plots shares of the health care variable (y) against quantiles of the measure of socio-economic status (asset-based wealth index) [17].
The concentration index is defined as twice the area between the concentration curve and the line of equality and assumes values between -1 and +1. A negative value of the concentration index denotes inequity in skilled care at birth that is to the advantage of the lower wealth quintiles implying that women of lower socio-economic status are delivered by skilled health providers more than their counterparts who are wealthier. In this case the concentration curve lies above the line of equality. On the other hand, a positive concentration index implies inequality in the use of delivery services by skilled providers that favours women who are wealthier (the concentration curve lies below the line of equality). When the value of the concentration index is zero, there are no wealth related inequalities in the use of delivery services by skilled providers. The concentration curve overlaps with the 45-degree line.
From individual level data, the concentration index can be computed using the following formula [18]:
(1)
Where
hi is the health variable of interest (delivery by skilled health providers);
μ is the mean of hi;
Ri is the fractional rank of individual i in the distribution of socio-economic position; and
(; i = 1 for the poorest and i = n for the richest).
Decomposing the concentration index
Wagstaff et al. [19] demonstrated that the concentration index of a health variable is additively decomposable to the concentration indices of the determinants of that health variable. In other words, the concentration index of the health variable of interest can be expressed as the sum of the contributions of the various determinants of that variable, together with unexplained residual component.
In decomposing the concentration index of delivery by skilled providers, the following steps are pursued:
1. Regressing the health variable against its determinants:
(2)
Where: yi = 1 if the delivery was conducted by a skilled health provider;
xk: a set of exogenous determinants of delivery by trained health provider;
βk: coefficient of determinant xk; and
εi: random error term.
The dependent variable (delivery by skilled health personnel) is a binary variable with values of 1 (delivered by skilled provider) and 0 (otherwise). The linear probability model (LPM) in Equation 2 above has been used in order to satisfy the linearity assumption of the decomposition analysis, although the estimates are inefficient and the probability of delivery by skilled health providers may not fall within the conventional values of 0 ≤ p ≤ 1 and has heteroskedastic errors [20]. However, the estimated probabilities from the LPM model have been constrained within the conventional values and a comparison with a probit model has not shown significant variations between the coefficients of the LPM and the marginal (or average) effects of the probit regression derived using the dprobit Stata command [17]. Furthermore, to adjust for heteroskedasticity, the predicted values from the regression model have been saved and used as weights to run weighted least squares (WLS) using the "aweight" option in Stata [21]
2. Calculating concentration indices for the health variable and for its determinants (and generalized concentration index of the error term):
For any linearly additive regression model of the health variable of interest (yi) such as Equation 2 above, the concentration index for y, can be written as:
(3)
Where:
Cy: concentration index of skilled care at birth (i.e. concentration index of yi);
: mean value of determinant xk;
μ: mean of the outcome variable yi - that is the mean of deliveries by skilled health providers
ck: concentration index of determinant xk
GCε: residual component that captures wealth-related inequality in skilled care at birth that is not accounted for by systematic variation in determinants across wealth groups.
The term in parenthesis in Equation 3 above expresses the impact of each determinant on the probability of delivery by skilled health providers. In other words, it denotes the elasticity (ηk) of the outcome variable (delivery by skilled health providers) with respect to the determinant xk evaluated at the mean value of yi (delivery by skilled health providers). The concentration index of delivery by skilled health providers is thus a weighted sum of the inequality in each of its determinants, with the weights equal to the elasticities of the determinants:
(4)
The social determinants of health framework
Report of the WHO Commission on the Social Determinants of Health revitalized the need for sustained and concerted efforts to achieve health equity through action on the social determinants of health. The Commission's social determinants framework takes a holistic view of inequities in health and health care within and between countries. Inequities in health/healthcare are caused by the unequal distribution of power, income, goods and services nationally and internationally (Figure 1) [22].
Figure 1. Commission on Social Determinants of health conceptual framework.
The social determinants of health are the circumstances in which people are born, grow up, live, work and age, and the systems put in place to deal with illness. These circumstances are in turn influenced by a wider set of forces: economics, social policies and politics [22].
The social determinants framework suggests that interventions to address health inequities have to be geared towards:
1. The circumstances of daily living, which include: differential exposure to health risks in early life, the social and physical environments and work associated with social stratification; and health care responses.
2. Structural drivers including the nature and degree of social stratification; biases, norms and values within society; global and national economic and social policy; and processes of governance at all levels.
As observed in Figure 1, the health system is an important social determinant of health influenced by and influencing the other social determinants. However, the health system is not the only social determinant of health. The effect of the each of the factors in Figure 1 in the genesis and perpetuation of health/health care inequities may vary from one country to another. It is therefore important to try to identify the effect of the various social determinants of health on health outcomes and access to health care in order to design evidence-based interventions and policy instruments.
Data and Variables
Data from the Namibia Demographic and Health Survey 2006-07 was used for this study. The data is available on the MEASURE DHS website for registered users.
In the linear probability model of the determinants of delivery by skilled health providers and the decomposition analysis the following variables have been used:
1. Dependent variable: delivery by skilled health providers, which takes a value of 1 if the delivery has been attended by skilled health providers and a value of zero otherwise.
2. Independent variables:
• Region;
• Place of residence - urban/rural;
• Wealth as computed from the asset indices;
• Education of mother in years of schooling completed
• Head of household - a dummy where female household assumes a value of one; and
• Insurance coverage - a dummy with a value of one if the woman has insurance coverage.
In NDHS 2006-07, a representative two-stage probability sample of 10,000 households was selected. The first stage consisted of selection of 500 primary sampling units (PSUs) from a sampling frame of 3,750 PSUs with probability proportional to size; the size being the number of households in the 2001 Population Census. The second stage involved the systematic selection of 20 households in each PSU [14].
The demographic and health surveys do not contain data on household income or consumption expenditure. Instead wealth index is used as a proxy. The wealth index is based on household ownership of consumer goods (such as radio, television); dwelling characteristics; type of drinking water source; toilet facilities and other characteristics related to the household's socio-economic status. The asset indices are constructed using the method of principal component analysis (PCA) [14]. Studies have shown a close relationship between asset ownership and consumption expenditure in developing countries [23] and that household asset is a good indicator of the long-run economic status of households [24]
Data analysis
Data was analyzed using STATA 10 statistical software and MS Excel.
Results
Descriptive statistics
About 80.3% of the deliveries were attended by skilled health providers. A breakdown by various maternal and household characteristics is provided in Table 2.
Table 2. Delivery by skilled health provider by various maternal and household characteristics
Delivery by skilled health providers is observed to differ by the various characteristics provided in Table 2. Most pronounced differences are seen by the household wealth status and mother's level of education. Skilled birth attendance in the richest quintile is about 70% more than that of the poorest quintile. The rate of skilled attendance among educated women is almost twice that of women with no education. Furthermore, women in urban areas access the services of trained birth attendant 30% more than those in rural areas.
Use of skilled birth attendants is over 90% in Erongo, Hardap, Karas and Khomas Regions, while the lowest (about 60-70%) is seen in Kavango, Kunene and Ohangwena. Parturient women in Erongo, Hardap, Karas and Khomas utilize the services of skilled attendants by more than 40% compared to those in Kavango. In six out of the thirteen regions, use of skilled delivery is less than the national average of 81%.
The concentration curve (Figure 2) and concentration index show statistically significant wealth-related inequalities in delivery by skilled providers that are to the advantage of women from economically better off households (C = 0.0979; P = < 0.001). The concentration curve in Figure 2 lies below the main diagonal indicating that economically better off women are skilled birth attendants more than those who are economically worse off.
Figure 2. Concentration curve: delivery by skilled health providers.
Decomposition analysis
The decomposition analysis clarifies how each determinant of delivery by skilled providers contributes to the total wealth-related inequality in delivery by skilled health providers [25]. As can be observed from formula 4 (), the contribution of each determinant depends on: (i) its impact on delivery by skilled health providers (elasticity); and (ii) how unequally distributed over wealth the determinant is (its concentration index). The results of the decomposition analysis are depicted in Table 3.
Table 3. Results of the decomposition analysis
The concentration indices of Erongo, Hardap, Karas, Khomas have a high pro-wealthy concentration index (P < 0.001) implying that most of the relatively wealthy people inhabit this regions. In contrast, most of the relatively less wealthy people live in Ohangwena, Omusati and Oshikoto regions (P < 0.001). The concentration indices for urban residence, education of mother, and insurance coverage have a statistically significant positive value indicating that they are more prevalent among the relatively wealthier segment of the population. On the other hand, female household heads are seen more among those that are less wealthy.
It is also observed that the three regions (Kavango, Kunene and Ohangwena) with the lowest rates of skilled birth attendance are mainly inhabited by the poor, as demonstrated by the negative concentration indices.
As discussed above, the contribution of each of the determinants to the total concentration index of delivery by skilled health providers depends on the impact of the determinant and its concentration index. A determinant that has a high impact but with no wealth-related gradient will have less contribution to the overall concentration index as opposed to one that with a high impact and high wealth-related inequality.
Figure 3 presents a summary of the contribution of the determinants to the overall concentration index of the variable, delivery by skilled health providers.
Figure 3. Contribution of the determinants to the concentration index of delivery by skilled health providers.
It is clearly observed that most of the inequality in delivery by skilled health providers that is to the advantage of the wealthier segment of the population is explained by inequalities in income, education and urban residence. The variables: region, insurance coverage and female-headed household seem to have inequality reducing effect, although not substantial.
Discussion
To the best of our knowledge this is the first study of its kind in Namibia. An attempt is made to identify the drivers of wealth-related inequalities in child delivery by skilled health providers using a decomposable health concentration index and the framework of the Commission on Social Determinants of Health. Addressing inequities in health and health care requires action on the social determinants of health [1]. Design of appropriate evidence-based policy responses entails identification of those social determinants of health and health care that significantly influence inequities.
The findings of this study highlight the significant role that social determinants play in access to child delivery services by trained providers. Health systems are a social determinant of health that influence and are influenced by the other social determinants. Inequalities in wealth and education of the mother are seen to be the main drivers of inequities in the health system variable - delivery by trained health providers. This brings to the fore that addressing inequalities in access to child delivery services should not be confined to the health system and that a concerted multi-sectoral action is needed in line with the principles of the Primary Health Care [26].
In Namibia, inequality in wealth is found to be one of the major contributors of inequity in access to child delivery by trained providers. The country is one of those with the highest income inequality in the world. It is therefore imperative to address this unacceptably high level of income inequality, in order to improve inequities in access to delivery services by trained health providers. There has been a debate on the relationship between income inequality and health; findings and conclusions have been far from consistent [27]. However, income inequality is one of the markers of the unequal distribution of goods and services [22] including health-enhancing ones. Addressing inequities in delivery care by skilled attendants is essential for achieving MDG targets for maternal health [28]. Hence, addressing wealth inequalities contributes to improving equity in delivery by skilled attendants and consequently to achievement of the MDG related to improving maternal health. It is, however, important to note that redressing wealth inequalities alone can not be an effective intervention to inequities in access to maternity care in the absence of interventions that also tackle the other social determinants such as education [27].
The link between education of the mother and use of delivery services by trained health providers is well established [29]. Influences of maternal education can be observed in two ways: (i) education can improve the ability of individuals to produce health (without relying on health services) by influencing their life style; and (ii) increasing the use of health care services through improved knowledge, attitude and practice [30]. A study in Thailand using data from Multiple Indicator Cluster Survey (MICS) found that education of the mother is the major determinant of inequities in delivery by skilled health workers [31]. Our study indicates that inequality in maternal level of education is the major driver of inequities in delivery by trained health providers. Hence, bridging inequalities in the maternal levels of education is an important undertaking to narrow inequities in the use of delivery services by skilled health providers.
The other determinant of inequities in delivery by skilled providers is distribution according to residential location. It has been observed that there is a very high positive concentration index in urban residence implying that there is a high concentration of the economically better off segment of society in urban areas. It may be difficult in the current study to identify the mechanisms by which inequalities in urban residence influence inequities in delivery by skilled attendants. It may partly be explained by supply-side factors, where there is commonly a differential access to services favoring urban areas (urban-bias). There may also be a high concentration of the economically better off and the better educated in urban areas, which may contribute to the influence of inequalities of urban location to inequities in delivery by skilled attendants. It is thus important to carefully understand the mechanisms of influence and take appropriate equity-enhancing measures accordingly.
The social determinants of health such as education, income and place of residence are closely linked to access, experiences and benefits from health care, which is itself a social determinant of health [32]. The findings of this study are in line with this assertion of the WHO Commission on Social Determinants of Health. Therefore, addressing inequities in the use of delivery services by skilled health providers requires tackling these social determinants of health systems through a concerted multi-sectoral action. The four sets of Primary Health Care reforms that include: (i) the universal coverage reforms; (ii) service delivery reforms; (iii) public policy reforms; and (iv) leadership reforms [33] are very relevant here in bridging the observed inequities in the use of delivery services by skilled health providers and consequently contribute to the achievement of the MDG 5 targets.
Conclusions
Most of the inequality in births attended by skilled health personnel, which is skewed towards the wealthier segment of the population, is explained by inequalities in income, education and urban residence. The region, insurance coverage and female-headed household variables seem to have inequality reducing effect, although not substantial.
Therefore, the fact that inequalities in wealth and education of the mother are the main drivers of inequities in the percentage of births attended by skilled health personnel implies that policy interventions for addressing inequalities in access to child delivery services should be multi-sectoral in line with the principles of the Primary health Care.
List of abbreviations
C: Concentration index; CSDH: WHO Commission on Social Determinants of Health; DHS: Demographic and Health Survey; HDI: Human Development Index (HDI); LPM: Linear probability model; MDGs: Millennium Development Goals; MMR: Maternal mortality ratio; MICS: Multiple Indicator Cluster Survey; PHC: Primary health care
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
EZ conceived the research, performed the analysis and drafted the manuscript. DO, TM, CNM and JMK contributed to the drafting of and review of the manuscript. All authors read and approved the final manuscript.
Acknowledgements
The authors would like to thank all the teams that conducted the Namibia Demographic and Health Survey. The manuscript contains the analysis and views of the authors only and does not represent the decisions or stated policies of the institutions that they work for.
References
1. Marmot M: Social determinants of health inequalities.
The Lancet 2005, 365:1099-1104.
2. Marmot M, Commission on Social Determinants of Health: Achieving health equity: from root causes to fair outcomes.
The Lancet 2007, 370:1153-63. Publisher Full Text
3. Yazbeck AS: Attacking inequality in the health sector: a synthesis of evidence and tools. Washington, DC: World Bank; 2009.
4. United Nations: The Millennium Development Goals Report 2009. New York; 2009.
5. Kruk ME, Prescott MR, Galea S: Equity of Skilled Birth Attendant Utilization in Developing Countries: Financing and Policy Determinants.
American Journal of Public Health 2008, 98(1):142-147. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
6. WHO, UNICEF, UNFPA, World Bank: Trends in maternal mortality: 1990-2008. Geneva: World Health Organization; 2010.
7. World Health Organization: World Health Statistics 2010. Geneva; 2010.
8. Gwatkin D, Rutstein S, Johnson K, Suliman E, Wagstaff A, Amouzou A: Socio-economic differences in health, nutrition and population. Washington, DC: World Bank; 2007.
9. Zere E, Tumusiime P, Walker O, Kirigia J, Mwikisa C, Mbeeli T: Inequities in utilization of maternal health interventions: implications for progress towards MDG 5 targets.
International Journal for Equity in Health 2010, 9:16. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
10. Yiengprugsawan V, Lim LLY, Carmichael GA, Seubsman SA, Sleigh AC: Tracking and decomposing health and disease inequality in Thailand.
Ann Epidemiol 2009, 19:800-807. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
11. National Planning Commission: 2001 population and housing census. Windhoek; 2003.
12. World Bank: World Development Report 2010: Development and climate change. Washington DC; 2009.
13. United Nations Development Programme: Human Development Report 2010: The real wealth of nations - pathways to human development. New York; 2010.
14. Ministry of Health and Social Services, Macro International Inc: Namibia Demographic and Health Survey 2006-07. Windhoek, Namibia and Calverton, USA; 2008.
15. World Health Organization: World Health Statistics 2009. Geneva; 2009.
16. Ministry of Health and Social Services, Health Systems 20/20: Namibia National Health Accounts 2001/02-2006/07. Windhoek, Namibia and Bethesda, MD, USA; 2008.
17. O'Donnell O, van Doorslaer E, Wagstaff E, Lindelow M: Analyzing health equity using household survey data. Washington DC: World Bank; 2008.
18. Kakwani N, Wagstaff A, van Doorslaer E: Socio-economic inequalities in health: measurement, computation and statistical inference.
Journal of Econometrics 1997, 77(1):87-103. Publisher Full Text
19. Wagstaff A, van Doorslaer E, Watanabe N: On decomposing the causes of health sector inequalities with an application to malnutrition inequalities in Vietnam.
Journal of Econometrics 2003, 112(1):219-227.
20. Hosseinpoor AR, Van Doorslaer E, Speybroeck N, Naghavi M, Mohammad K, Majdzadeh R, Delavar B, Jamshidi H, Vega : Decomposing socioeconomic inequality in infant mortality in Iran.
International Journal of Epidemiology 2006, 35:1211-1219. PubMed Abstract | Publisher Full Text
21. Jones A: Applied econometrics for health economists. United Kingdom: Radcliffe Publishing Ltd; 2007.
22. World Health Organization: Closing the gap in a generation: health equity through action on the social determinants of health. Final report of the Commission on Social Determinants of health. Geneva; 2008.
23. Filmer D, Pritchett L: Estimating wealth effects without expenditure data - or tears: An application to educational enrolments in States of India. Washington DC: The World Bank; 1989.
24. Houweling TA, Kunst AE, Mackenbach JP: Measuring health inequality in developing countries: does the choice of the indicator of economic status matter?
International Journal for Equity in Health 2003, 2:8. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
25. Van Doorslaer E, Koolman X: Estimating the differences in income-related health inequalities across European countries.
Health Economics 2004, 13:609-628. PubMed Abstract | Publisher Full Text
26. World Health Organization: Ouagadougou Declaration on primary Health Care and Health Systems in Africa: Achieving better health for Africa in the new millennium. Brazzaville: WHO Regional Office for Africa; 2008.
27. Starfield B, Birn AE: Income redistribution is not enough: income inequality, social welfare programs, and achieving equity in health.
J Epidemiol Community Health 2007, 61:1038-1041. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
28. Houweling TAJ, Ronsmans C, Campbel OMR, Kunst AE: Huge poor-rich inequalities in maternity care: An international comparative study of maternity and child care in developing countries.
Bulletin of the World Health Organization 2007, 85(10):745-754. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
29. Ahmed S, Creanga AA, Gillespie DG, Tsui AO: Economic status, education and empowerment: implications for maternal health service utilization in developing countries.
PLoS ONE 2010, 5(6):e11190. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
30. Ensor T, Cooper S: Overcoming barriers to health service access: influencing the demand side.
Health Policy and Planning 2004, 19(2):69-79. PubMed Abstract | Publisher Full Text
31. Limwattananon S, Tangcharoensathienb V, Prakongsaib P: Equity in maternal and child health in Thailand.
Bulletin of the World Health Organization 2010, 88:420-427. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
32. Marmot M, Friel S, Bell R, Houweling TAJ, Taylor S, Commission on Social Determinants of Health: Closing the gap in a generation: health equity through action on the social determinants of health.
The Lancet 2008, 372:1661-69. Publisher Full Text
33. World Health Organization: The world health report 2008: primary health care now more than ever. Geneva; 2008.
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Poster presentation
Design of novel semisynethetic metalloenzyme from thermolysin
Mohd BA Rahman1*, Ahmad H Jaafar1, Mahiran Basri1, Raja NZRA Rahman2, Abu B Salleh2 and Habibah A Wahab3
Author Affiliations
1 Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
2 Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
3 Laborotary of Biocrystallography and Bioinformatic Structure, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
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BMC Systems Biology 2007, 1(Suppl 1):P68 doi:10.1186/1752-0509-1-S1-P68
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1752-0509/1/S1/P68
Published:8 May 2007
© 2007 Rahman et al; licensee BioMed Central Ltd.
Background
Initial applications of biocatalysis involved the used of naturally occurring enzyme. With new challenges in green chemical reaction, biocatalyst that shed the light is metalloenzyme, which function as enzyme and contain metal that are tightly attached and always isolated with the protein [1]. In recent years, enzyme engineering has proven to be an invaluable tool for elucidating biocatalytic mechanisms as well as producing enzymes for industrial purposes. Approaches developed for in vivo chemical modification and in silico computational methods promise to increase the scope and have already been used successfully to alter existing protein so that they have better stability and functionality [2]. This task might be good to address in designing a new biocatalyst with improved properties.
Methods
The AutoDock programme 3.05 was employed in order to identify the binding conformations of the ligands and the metal ions and to perform docking using Lamarckian Genetic Algorithm (LGA) [3]. The coordinate of thermolysin-substrate free structure coded as 1KEI was taken from Brookhaven Protein Data Bank (PDB).
Results
The predicted KEI-ligand complexes with the lowest final docked energy for PSE and PHN were -6.71 kcal/mol at pocket 45 and -6.60 kcal/mol at pocket 47, respectively. Non-covalent interactions of hydrogen bond and hydrophobic interaction between protein and ligands established the final conformation. Analysis on finding the most favorable metal ions to dock onto each complex found that Mg2+ was docked onto KEI-PSE45 complex with final docked energy of -1.09 kcal/mol and performed four interactions with the PSE ligand. Meanwhile, Ca2+ represented the best metal ions to dock to the KEI-PHN47 complex with final docked energy of -4.12 kcal/mol and performed three interactions with the nearby residues.
Conclusion
An important branch of novel protein design is through engineering and design of new metal-binding sites into native proteins. By employing in silico approach of molecular docking, screening of putative ligand for possible interactions may enhance the discovery of novel semisynthetic enzyme and lead to a new protein function. Finally, the framework which was introduced for the experiment may be a competent method for screening potential metal ions in this in vivo route.
References
1. Davies RR, Kuang H, Qi D, Mazhary A, Mayaan E, Distefeno MD: Artificial Metalloenzymes Based on Protein Cavities: Exploring the Effect of Altering the Metal Ligand Attachment Position by Site Directed Mutagenesis.
Bioorg Med Chem Lett 1999, 9:79-84. PubMed Abstract | Publisher Full Text
2. Abdul Rahman MB, Misran A, Abdul Wahab H, Abdul Rahman RNZ, Salleh AB, Basri M: Screening and Docking of Chemical Ligands onto Pocket Cavities of Protease for Designing a Biocatalyst.
Biocatal Biotransform 2005, 23:211-216. Publisher Full Text
3. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ: Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function.
J Comput Chem 1998, 19:1639-1662. Publisher Full Text | v0 |
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Proceedings
Comparison of linear mixed model analysis and genealogy-based haplotype clustering with a Bayesian approach for association mapping in a pedigreed population
Golam R Dashab1,2, Naveen K Kadri1*, Mohammad M Shariati1,2 and Goutam Sahana1*
Author Affiliations
1 Department of Molecular Biology and Genetics, Faculty of Science and Technology, Aarhus University, DK-8830 Tjele, Denmark
2 Department of Animal Science, Ferdowsi University of Mashhad, 91775 Mashhad, Iran
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BMC Proceedings 2012, 6(Suppl 2):S4 doi:10.1186/1753-6561-6-S2-S4
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Published:21 May 2012
© 2012 Dashab et al.; licensee BioMed Central Ltd.
Abstract
Background
Despite many success stories of genome wide association studies (GWAS), challenges exist in QTL detection especially in datasets with many levels of relatedness. In this study we compared four methods of GWA on a dataset simulated for the 15th QTL-MAS workshop. The four methods were 1) Mixed model analysis (MMA), 2) Random haplotype model (RHM), 3) Genealogy-based mixed model (GENMIX), and 4) Bayesian variable selection (BVS). The data consisted of phenotypes of 2000 animals from 20 sire families and were genotyped with 9990 SNPs on five chromosomes.
Results
Out of the eight simulated QTL, these four methods MMA, RHM, GENMIX and BVS identified 6, 6, 8 and 7 QTL respectively and 4 QTL were common across the methods. GENMIX had the highest power to detect QTL however it also produced 4 false positives. BVS was the second best method in terms of power, detecting all QTL except the one on chromosome 5 with epistatic interaction. Two spurious associations were obtained across methods. Though all the methods considered the full pedigree in the analyses, it was not sufficient to avoid all the spurious associations arising due to family structure.
Conclusions
Using several methods with divergent approaches for GWAS can be useful in gaining confidence on the QTL identified. In our comparison, GENMIX was found to be the best method in terms of power but it needs appropriate correction for multiple testing to avoid the false positives. This study shows that the issues of multiple testing and the relatedness among study samples need special attention in GWAS.
Background
Despite many successes, genome-wide association studies (GWAS) still present major challenges. This is particularly true for samples drawn from a population with multiple levels of relatedness, such as population structure and/or familial relatedness. The efficiency of a GWAS method to detect a quantitative trait locus (QTL) depends on several factors, for example, the genetic architecture, allele frequency and heritability of the QTL, and the linkage disequilibrium with the marker. The population structure and relatedness of the samples may result in spurious associations. We applied a range of GWAS methods to map quantitative trait loci (QTL) in the simulated dataset provided by the 15th QTL-MAS workshop [1] and compared their efficiency in QTL detection with respected to this particular dataset.
We compared four different methods of GWAS, 1) Mixed model analysis (MMA); 2) Random haplotype model (RHM); 3) Genealogy-based mixed model (GENMIX) and 4) Bayesian variable selection method (BVS). The mixed model approach [2] utilizes the full relationship matrix and is the method of choice when the samples are drawn from a complex pedigreed population. The haplotype-based association methods using mixed models are generally regarded as more powerful than methods based on single markers [3,4] since they fully exploit LD information from multiple markers. On the other hand, genealogy based clustering of haplotypes in GENMIX not only consider the local LD but also takes the history of the origin of these haplotypes [5]. Contrary to the above three methods which analyze single markers or a few markers at a time, Bayesian variable selection [6] simultaneously fits multiple marker effects and avoids the problem of multiple testing. Therefore, it is useful to compare such Bayesian methods with more standard frequentist approaches where a single or a few SNPs are fitted at a time. The above-mentioned methods were compared for power, precision of location estimate, and type I error rate.
Methods
The simulated population consisted of 20 sire families, each sire was mated to 10 dams and each full-sib family had 15 progeny. The phenotype was available for 10 progeny per full-sib family i.e. a total of 2000 individuals. There were five chromosomes each with 1998 SNPs at equal distance of 0.05 cM. The four GWAS method used for association mapping are described below.
Mixed model analysis (MMA)
The association between each SNP and the phenotype was assessed by a linear mixed model analysis [2], using DMU software [7]. The model was as follows:
Where y is the vector of 2,000 phenotypes, 1 is a vector of 1s of length 2,000, μ is the general mean, g is the additive effect of the SNP and X is a vector with genotypic indicators (0, 1, or 2) associating records to the marker effect, u is the random polygenic effect with the normal distribution , where A is the additive relationship matrix and is the polygenic variance. Z is an incidence matrix relating phenotypes to the corresponding random polygenic effect, and e is a vector of random environmental deviates with the normal distribution , where is the error variance and I is the identity matrix. Testing was done using a Wald test against a null hypothesis of H0:gi=0. The significance threshold was determined using a Bonferroni correction for the number of markers tested to obtain an experiment-wise P-value of 0.05.
Random haplotype model (RHM)
The SNP genotype data were phased using software FastPhase [8].The haplotypes were 4 SNP long and they were tested for association sliding windows from SNP to SNP. The model for testing the association of the haplotypes at position j and the phenotype can be clarified in scalar form as follows:
Where yi is the phenotype of animal i, μ is the population mean, ui is the random polygenic effect, and are the random effects of the maternal and paternal haplotypes carried by individual i, and ei is the random residual effect as defined for MMA. The other random effect q was assumed to be normally distributed with mean zero and variances (assuming equal variance for paternal and maternal haplotypes). The significance of the haplotype substitution effect was assessed with a likelihood ratio test comparing the RHM model with a null-model containing mean, polygenic effect and random error terms but no haplotype effects. Analysis was performed using the DMU software package [7]. Significant threshold was fixed at genome wide 5% level after Bonferroni correction and the mid-point of significant haplotypes were considered as the putative QTL positions.
Genealogy based mixed-model (GENMIX)
The efficiency of GENMIX for association mapping was described by Sahana et al. [5]. In contrast to regular genome-wide association studies where phenotypic differences are either associated with single markers or with groups of markers organized in to haplo-groups in a non-stratified fashion, here phenotypes were associated using a hierarchical approach. Both grouping of markers into haplo-groups and clustering of observed haplotypes was done based on local genealogies [9]. This method identifies the widest possible region surrounding a marker that allows construction of a genealogy forming a bifurcating tree without either recurrent mutation or recombination, in other words it satisfies the four-gamete condition of Hudson and Kaplan [10]. Each bifurcation in the binary tree corresponds to one bi-allelic marker. Splitting the tree at the top generates two clusters of haplotypes. Splitting the tree at any other node generates three clusters: one above the split point and two corresponding to the two branches below. For the analyses presented in this paper we split the tree at the top (one set of two clusters), the second level (two sets of three clusters) and at the third level (four sets of three clusters). Successively each clustering of haplotypes was included as a random effect in the model for analysis:
where yi is the phenotype of individual i, μ is the population mean, ui is as described above in the MMA; and are two haplotype effects of individual i, where h1i and h2i can take values 11, 12, 13, 22, 23, and 33 and , is the haplotype variance, and ei is a random residual as defined for MMA. The local genealogies were constructed using the software Blossoc (http://www.daimi.au.dk/~mailund/Blossoc/ webcite) and variance component analysis was carried out using the software DMU [7]. The significance of the SNP association was tested using likelihood ratio test and the significant threshold was fixed at genome-wide 5% level after Bonferroni correction for multiple testing for the total number of markers.
Bayesian variable selection (BVS)
The method is based on specifying a mixture distribution for SNP effects while all SNP are fitted simultaneously in the model [6]. It was assumed that most markers had very small effects on the trait (98% of SNP in this analysis) and only few markers (2%) had large effects. The allocation of each SNP to either of these two distributions is done using an indicator variable in Gibbs sampling. The averaged mixture indicator estimates a posterior probability for that SNP to come from the distribution with large effects, which is interpreted as the probability for presence of an associated marker or QTL. The analysis was performed using BAYZ software [11] and the variances of the two mixture components were estimated. The SNP with posterior probability of the mixture indicator higher than 0.10; that corresponds to a Bayes factor of 5.5 were reported as QTL. In cases where adjacent markers showed a decreasing or increasing posterior probability of association due to linkage disequilibrium, only the SNP with highest probability was reported as QTL.
Results
The results of our analysis from four methods are summarised in Table 1 and graphically represented in Figure 1. A QTL was considered as identified if the putative location was within 10 cM of the true simulated location of the QTL. Out of the 8 simulated QTL, these four methods, MMA, RHM, GENMIX and BVS identified 6, 6, 8 and 7 QTL, respectively. Four QTL regions, one on chromosome 1 and 5 and two on chromosome 3, were identified by all the four methods. The numbers of false positives for these methods were 2, 6, 4 and 2 respectively (Table 1).
Table 1. Positions (cM) of identified QTL with the four methods
Figure 1. Comparison of the positions of the simulated and detected QTL by four methods. The positions of the detected QTL are given chromosome-wise for the four methods. The correct identifications are given in red diamonds and the false positives are given in gray circles.
The effects of the QTL localised by MMA are given in table 2. The QTL with the biggest effect, explaining 10.2% of the variation in the phenotype was localised on chromosome 1 at 3.55 cM region. The 6 QTL detected by MMA together explained 18.4% of the phenotypic variance.
Table 2. QTL effects estimated by single marker analysis based on linear mixed model; fitting all the detected QTL simultaneously
Precision of the methods was assessed by the average of absolute differences between the positions of the simulated and the detected QTL, whenever it was identified. The QTL with the biggest effect on chromosome 1 was detected with high precision (on average ± 0.3 cM from the simulated QTL) and the epistatic QTL on chromosome 5 was detected with least precision (on an average 8 cM from the simulated QTL). In general the MMA identified the QTL with higher precision.
Discussion
In our study we used additive models without considering the genetic architecture of the simulated QTL; however the methods performed well in localising the true simulated QTL. Out of the four methods employed, GENMIX performed comparatively better in QTL detection. It detected all the 8 simulated QTL and 6 were mapped accurately within a 2 cM region of the QTL region. However, it also identified 4 false positives (FP). The number of tests carried out in GENMIX was approximately 7 times the number of markers and we used Bonferroni multiple testing correction for the number of total marker but not for the total number of tests (i.e. ~7 times the number of markers) which could have resulted in increased number of false positives. Besides the number of haplotypes in a lineage goes down as we moved down the tree [5] which can give numerical instability. Out of these four FPs in GENMIX, two (on chromosome 4 and 5) were identified by other methods at the same location (Figure 1). Divergent approaches of GWAS picking up the same FP could be due to insufficient correction for family structure. A likely explanation is that some SNPs in these two regions were positively correlated (in linkage disequilibrium) with the QTL because of linkage (within family). It is thus not straightforward to distinguish true associations from spurious, regardless of the correction for the pedigree structure. This underlines the importance of replication study before a follow-up study can be taken up for identifying causal mutation underlying a QTL.
BVS was the second best method in terms of power to identify QTL and it had less FP compared to GENMIX. It detected all the simulated QTL except the one on chromosome 5 with epistatic interactions. BVS fits all the SNPs simultaneously and given that the first epistatic QTL was fitted in the model, there was a little chance for the second one to be significant in the model. In other words, the first QTL explains most of the variation induced by both QTL because of their dependency. Especially, this can happen if the epistasis is of additive by additive nature, where most of the epistatic variance is converted to additive [12]. In order to confirm this, we ran the MMA for all SNP on chromosome 5 where the first epistatic QTL was already in the model. As a result, the second epistatic QTL was not detected (results not shown).
The MMA identified six QTL. The two linked QTL on chromosome 2 were both identified by MMA but only the first one (the most significant) was reported in the workshop as the second QTL was not significant when fitted along with first one in the model. On the other hand RHM detected both of them but the first QTL was mapped 10 cM downstream the true QTL.
The highest significant SNP for the multi-allelic QTL on chromosome 1 (largest QTL) in MMA was 0.7 cM away from the true position, while the other methods mapped it closer to its position. No individual SNP (bi-allelic) can be in perfect LD with this QTL (multi-allelic) which might have resulted in poor precision for this QTL in MMA.
The imprinted QTL on chromosome 4 was only detected by GENMIX and BVS. The power of detection of the QTL will decrease if the model does not reflect the true genetic architecture of the QTL. However, GENMIX and BVS methods were sensitive enough to identify the imprinted QTL, though both of them model its effect as additive.
Sahana et al. [13] observed very high false positives when haplotypes were considered as fixed effects in the model. Because the frequency of some haplotypes can be very low, this could result in low accuracy of estimates and result in false positive when haplotypes are fitted as fixed effect. We expected this problem can be taken care by fitting haplotypes as random where the effects of the low frequent haplotypes will be regressed towards zero. However, RHM still had very high false positive rate.
Conclusions
Using several methods in analysing GWA can be useful in gaining confidence on the QTL identified. Though, genealogy-based mixed model can be a powerful approach for GWAS, appropriate multiple testing correction is necessary to avoid false positives. Our study also shows that correction for pedigree relationship is not always enough to avoid spurious association arising due to family structure.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All the authors have contributed in planning the study, analyses of data and writing the article.
Acknowledgements
NKK and GS were supported by a grant No. 3405-10-0137, funded jointly by the Danish Ministry of Food, Agriculture and Fisheries, The Milk Levy Fund, Viking Genetics, and Nordic Cattle Genetic Evaluation. GRD acknowledges financial support by The Ministry of Science, Research and Technology of Iran.
This article has been published as part of BMC Proceedings Volume 6 Supplement 2, 2012: Proceedings of the 15th European workshop on QTL mapping and marker assisted selection (QTL-MAS). The full contents of the supplement are available online at http://www.biomedcentral.com/bmcproc/supplements/6/S2.
References
1. [https://colloque.inra.fr/qtlmas] webcite
2. Yu J, Pressoir G, Briggs WH, Bi IV, Yamasaki M, Doebley JF, McMullen MD, Gaut BS, Nielsen DM, Holland JB: A unified mixed-model method for association mapping that accounts for multiple levels of relatedness.
Nature genetics 2005, 38:203-208. PubMed Abstract | Publisher Full Text
3. Akey J, Jin L, Xiong M: Haplotypes vs single marker linkage disequilibrium tests: what do we gain?
European Journal of Human Genetics 2001, 9:291-300. PubMed Abstract | Publisher Full Text
4. Morris RW, Kaplan NL: On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles.
Genetic epidemiology 2002, 23:221-233. PubMed Abstract | Publisher Full Text
5. Sahana G, Mailund T, Lund M, Guldbrandtsen B: A New Powerful Method for Genome-wide Association Mapping Using Local Genealogies in a Mixed Model.
Local Genealogies in a Linear Mixed Model for Genome-Wide Association Mapping in Complex Pedigreed Populations. PLoS ONE 2011, 11(6):e27061.
6. George EI, McCulloch RE: Variable selection via Gibbs sampling.
Journal of the American Statistical Association 1993, 88:881-889. Publisher Full Text
7. Madsen P, Jensen J: DMU-A user's guide, A package for analyzing multivariate mixed models. [http://www.dmu.agrsci.dk/dmuv6_guide.5.0.pdf] webcite
Version 6, DJF, Foulum, Denmark 2011. Release 5
8. Scheet P, Stephens M: A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase.
The American Journal of Human Genetics 2006, 78:629-644. Publisher Full Text
9. Mailund T, Besenbacher S, Schierup MH: Whole genome association mapping by incompatibilities and local perfect phylogenies.
BMC bioinformatics 2006, 7:454. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
10. Hudson RR, Kaplan NL: Statistical properties of the number of recombination events in the history of a sample of DNA sequences.
Genetics 1985, 111:147. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
11. Janss L: BAYZ Manual version 2.02.
Janss Biostatistics, Leiden, Netherlands 2011.
12. Hill WG, Goddard ME, Visscher PM: Data and theory point to mainly additive genetic variance for complex traits.
PLoS Genetics 2008, 4:e1000008. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
13. Sahana G, Guldbrandtsen B, Janss L, Lund MS: Comparison of association mapping methods in a complex pedigreed population.
Genetic epidemiology 2010, 34:455-462. PubMed Abstract | Publisher Full Text | v0 |
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PanARMENIAN.Net - Anonymous hackers have published more than 1.7 GB of data allegedly stolen from Azerbaijan’s Special State Protection Service (dmx.gov.az).
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Partner news
Employers and job seekers: how to find each other
Arpine Grigoryan։ each job seeker should understand why to apply for this “x” job in this “x” company but not for “y” job in “y” company. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:33:31.000Z | axslkipcth5upxhgyslvkwbrfe3h4xtd | {
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} | cccc_CC-MAIN-2013-20 | 116 reputation
bio website
location Corona, CA
age
visits member for 6 months
seen May 1 at 15:06
stats profile views 4
I am a student on a F1 Visa in the US and would like to learn about finance in the US to lead a better life.
Being a non US Citizen and on a student Visa, I am unauthorized to work off campus, and so I am restricted to work upto 20 hours a week on a hourly wage and have no fixed monthly income.
This user has no revisions | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T05:49:44.000Z | 2ycuq6dxqu5j3m2rvdaoqigq6n7rm4l3 | {
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} | cccc_CC-MAIN-2013-20 | Southern California Hot Spot Hits 812 Degrees, Baffles Experts
rating: 0+x
Summary
August 6, 2008: In Ventura Coutry, just north of Los Angeles, California, a mysterious "hot spot" appeared that caused the ground to reach a temperature of over 800 degrees Fahrenheit on August 1st, 2008. The exact cause is unknown, though some geologists suspect that natural gases might have caused a fire deep underground, which in turn caused the high surface temperature.
Source
Game and Story Use
• It might have been caused by some large entity of fire living below California which is slowly moving towards the surface.
• In a fantasy campaign with a stereotypical "Underdark", this might be a local temperature hazard that doesn't have anything to do with streams of lava.
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:19:37.000Z | ao3mqise7co3k73fijspij3tyxug7yvk | {
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} | cccc_CC-MAIN-2013-20 | BaSTA (1.2)
A package for estimating age-specific survival from incomplete capture-recapture/recovery data.
http://cran.r-project.org/web/packages/BaSTA
This package estimates survival and mortality with covariates from capture-recapture/recovery data in a Bayesian framework when many individuals are of unknown age. It includes tools for data checking, model diagnostics and outputs such as life-tables and plots.
Maintainer: Fernando Colchero
Author(s): Fernando Colchero, Owen Jones, Maren Rebke
License: GPL
Uses: msm, snowfall
Released about 1 year ago. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:01:30.000Z | rzi532lvr25vprdl537s43qr4t6wyzc6 | {
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"warc_url": "http://crantastic.org/packages/fdrtool"
} | cccc_CC-MAIN-2013-20 | fdrtool (1.2.10)
0 users
Estimation of (Local) False Discovery Rates and Higher Criticism.
http://strimmerlab.org/software/fdrtool/
http://cran.r-project.org/web/packages/fdrtool
This package allows to estimate both tail area-based false discovery rates (Fdr) as well as local false discovery rates (fdr) for a variety of null models (p-values, z-scores, correlation coefficients, t-scores). The proportion of null values and the parameters of the null distribution are adaptively estimated from the data. In addition, the package contains functions for non-parametric density estimation (Grenander estimator), for monotone regression (isotonic regression and antitonic regression with weights), for computing the greatest convex minorant (GCM) and the least concave majorant (LCM), for the half-normal and correlation distributions, and for computing empirical higher criticism (HC) scores and the corresponding decision threshold.
Maintainer: Korbinian Strimmer
Author(s): Bernd Klaus and Korbinian Strimmer.
License: GPL (>= 3)
Uses: Does not use any package
Reverse depends: GeneCycle, GeneNet, sda, st
Reverse suggests: frontier, MALDIquant, mutoss, qgraph
Released 10 months ago.
6 previous versions
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Visit fdrtool on R Graphical Manual. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:57:07.000Z | dzyfzhkit24jngfu3me6f3fff53qhied | {
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} | cccc_CC-MAIN-2013-20 | Error!
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Test Driven Development with the ASP.NET MVC framework - screencast
0
kicks
Test Driven Development with the ASP.NET MVC framework - screencast (Unpublished)
A while ago, KatrienDG asked me to do some screencasts on the ASP.NET MVC framework for the MSDN Chopsticks page. I've been working on 2 screencasts: an introductory talk to the ASP.NET MVC framework and a Test Driven Development story. Feel free to leave some comments! This video explains you how to develop ASP.NET MVC web applications using 2 different approaches: regular development and test-driven development.
Kicked By:
Drop Kicked By: | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:56:07.000Z | mxkukdob6hmymt3x76gplu7malh5jvw4 | {
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"url": "globalvoicesonline.org/-/world/caribbean/anguilla/",
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"warc_url": "http://globalvoicesonline.org/-/world/caribbean/anguilla/"
} | cccc_CC-MAIN-2013-20 | GlobalVoices in Learn more »
Anguilla
Country archive · 13 posts
Latest stories about Anguilla
3 November 2008
Caribbean: Region Scores Big in Stanford 20/20 Cricket
U.S. billionaire Allen Stanford is trying to remake the face of cricket. His latest "big idea" is a 20/20 contest in which the winning team walks away with US$20 million (that's US$1 million per man) and the loser gets...well, nothing. It all happened this past weekend and West Indian bloggers put in their two cents' worth...
27 January 2008
Brazil: Countdown to Carnival
There is a popular belief that in Brazil the year only starts after Carnival. Be this an exaggeration or not, there is not much else being talked about on the country's blogosphere: everyone is dusting off their costumes, getting into the mood and counting down the days for the biggest street party on Earth. Here's a round up of bloggers expectations in Rio de Janeiro, Bahia, Pernambuco, and the lesser known carnival in Minas Gerais.
30 May 2007
One Caribbean; Many Identities…
Calypsonian Lord Nelson once sang, “all ah we is one family”. Optimists in the Caribbean may well agree with these words, but the reality is that if you were to describe Caribbean states as a family, you would have to call it a complex unit - and one in which there is much sibling rivalry. Trinidadian blogger Karel Mc Intosh discusses the intricate subject of Caribbean unity with Jamaicans Geoffrey Philp and Francis Wade and Guyanese blogger Media Critic.
25 April 2007
Caribbean: Farewell to a cricketing legend
In the early ’90s, the West Indies' dominance of the international cricket scene entered its long decline. There were fewer victories to celebrate, fewer exceptional demonstrations of the brilliance to which West Indian fans had become so accustomed. And when there were bright spots, they often came courtesy of one man: Brian Charles Lara. Lara played his last ever international cricket match in Barbados on April 21, 2007, in front of thousands of fans and visitors. The Caribbean blogosphere pays tribute to the man some consider the greatest cricketer of all time.
18 June 2006
Haiti: Telecom Wars
Digicel billboard, Martinique. By blogger Greg at InternetRapide.com. Jamaica-based Caribbean telecom giant Digicel has a presence in over a dozen countries in the region. Digicel officially launched operations on the...
6 June 2006
Global Voices, Caribbean Accents: report on Caribbean blogging roundtable
THE CARIBBEAN STUDIES ASSOCIATION (CSA), one of the major assemblies of scholars of the history, culture, and society of the Caribbean region, held its annual conference in Port of Spain,...
22 May 2006
Montserrat volcano watch and West Indies cricket
A woman looks at the rear window of her car, broken by a flying rock from the nearby Soufriere Hills Volcano, Montserrat, on Saturday. Photo from the Trinidad Express website...
28 April 2006
West Indian literature online
One of the crucial elements in the rapid development of the literature of the Anglophone Caribbean in the 1940s and 50s was a weekly radio programme called Caribbean Voices, broadcast...
17 April 2006
Village cricket match, Caribbean-style
Easter Sunday cricket match — Howsen Village, Trinidad. From caribbeanfreephoto At this time of year, thoughts in the English-speaking Caribbean turn to the game of cricket. Travel around any of...
9 April 2006
Guilt-Free Food Blogs Review
#1: From Japan, I was just really very hungry Milking the soy bean, part 1: learn how to make soy milk with no special equipment. Milking the soy bean, part...
World regions
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2024-06-03T21:29:47.544Z | 2013-05-18T06:02:42.000Z | lxyrrk6cxwqssjuyxcxphsxesrrhxp5g | {
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An unofficial blog that watches Google's attempts to move your operating system online.
Send your tips to<EMAIL_ADDRESS>
April 13, 2011
Google Calendar's Favicon Changes Every Day
When Google Calendar changed the favicon, many people wondered why it only shows 31. "Does it mean that starting today, every day will be the 31st ? Serously, favicon should be changed everyday to match the date," suggested a Google Calendar user.
Google listened to the feedback and the favicon will now change every day. "When you look at the Google Calendar icon at the top of your browser window, it will no longer always display 31 but will instead change to reflect the current day of the month. Today's date is now always a short glance away."
Google Calendar is the first Google service that has a dynamic favicon, but you can change Gmail's favicon to show the number of unread messages.
| v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:31:20.000Z | aoyg7bzsx3olwmlmm53php6zb64bwrx6 | {
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} | cccc_CC-MAIN-2013-20 | 23 November 2007
Openness: Purity of Essence
I wrote a piece for Linux Journal recently warning that Microsoft was beginning to hijack the meaning of the phrase "open source". But the problem is much bigger than this: the other opens face similar pressures, as Peter Murray-Rust notes.
In some ways it's even more serious for fledgling movements like open access and open data: there, the real meaning has barely been established, and so defending it is harder than for open source, which has had a well-defined definition for some time. Given the importance of labels, this is a matter that needs to be addressed with some urgency before "open access" and "open data" become little more than bland marketing terms.
| v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:03:59.000Z | yt67gvchx3goqytrpyqa22e4qnyw5d2a | {
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} | cccc_CC-MAIN-2013-20 | David Lowry
From OpenWetWare
Revision as of 22:00, 8 August 2012 by Lowry (Talk | contribs)
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The University of Texas at Austin: USDA Postdoctoral Fellow, 2010-2012
Duke University: PhD, 2004-2010
The University of California, Berkeley: BS, 1997-2001
Research Interests
Phenotypic diversity of Switchgrass, Panicum virgatum
Field experiment with Mimulus guttatus
The genetics of adaptation and speciation
Adaptation is the most fundamental way that the environment can mold the diverse phenotypes of organisms. Adaptations can also lead to the formation of reproductive isolating barriers, which are the building blocks of new species. I am very interested in understanding the genetic underpinnings of reproductive isolation at various stages in the speciation process.
Understanding adaptation is also crucial to predicting how organisms will respond to future global change and will help inform management decisions as well as guide future agricultural breeding.
Landscape evolutionary genomics
One of the core goals of my research program is to understand how the natural landscape molds the genomes of organisms through adaptation. To that end, I am using a combination of genetic mapping and genome sequencing approaches to identify genes involved with adaptation to the heterogeneity of the natural landscape. During my dissertation, I focused on how adaptive alleles in Mimulus guttatus are spread across the landscape and what phenotypic effects they have in different environments across western North America. Currently, I am developing Panicum grasses as a model system to understand adaptation along a longitudinal soil moisture cline across Southwestern United States and a latitudinal temperature cline across the Great Plains. Our lab recently received funding from the Department of Energy to develop Panicum hallii as a model system for local adaptation and bioenergy research.
The role of the genome structure in phenotypic evolution
Whether or not a gene will be involved in adaptation and phenotypic evolution is dependent on the position of that gene in the genome. Differential rates of recombination and selection across the genome can have a large impact on patterns of standing genetic variation, which is raw source of evolution. I am currently using multi-genome data sets in Arabidopsis thaliana to understand how genome structure impacts phenotypic evolution.
Field experiment with Panicum hallii
Using evolutionary biology to improve bioenergy crops
Civilization is built on a foundation of domesticated grasses. Without those grasses (corn, wheat, rice, oats, barley, sorghum) there would be no ballet and human beings would never of landed on the moon. Plant breeders have quietly worked in the shadows to increase the yield of crops and in turn maintain our modern world.
Now, there may actually be potential to domesticate a new set of grass species to use to help combat the growing energy problem. My research is focused understanding the factors involved in local adaptation in the bioenergy crop switchgrass (Panicum virgatum). Loci involved in local adaptation are likely to be of high value to crop breeders interested in improving drought, heat, cold, herbivore, and disease tolerance.
Publications
Cover photo for PLoS Biology
Lowry, D. B., C. T. Purmal, T. E. Juenger. A population genetic transect of Panicum hallii (Poaceae). In review
Wright, K. M., D. Lloyd, D. B. Lowry, M. R. Macnair, J. H. Willis. Indirect evolution of hybrid lethality due to linkage with selected locus in Mimulus guttatus. In review
Lowry D. B., R. Hopkins. (2012) “Speciation and Natural Selection.” Invited book chapter in The Princeton Guide to Evolution, edited by Jonathan Losos. Princeton, NJ: Princeton University Press. In press
Lowry D. B. (2012) Local adaptation in The model plant. New Phytologist. 194: 888-890.
Lowry D. B. (2012) Ecotypes and the controversy over stages in the formation of new species. Biological Journal of the Linnean Society. 106: 241-257.
Lowry, D. B., C. T. Purmal, E. Meyer, T. E. Juenger. (2012) Microsatellite markers for the native Texas perennial grass, Panicum hallii (Poaceae). American Journal of Botany Primer Notes & Protocols. 99: e114-e116
Lowry, D. B., C. S. Sheng, Z. Zhu, T. E. Juenger, B. Lahner, D. E. Salt, J. H. Willis. (2012) Mapping of ionomic traits in Mimulus guttatus reveals Mo and Cd QTLs that colocalize with MOT1 homologues. PLoS One 7: e30730.
Lowry D. B., C. S. Sheng,, J. R. Lasky, J.H. Willis. (2012) Five anthocyanin polymorphisms are associated with an R2R3-MYB cluster in Mimulus guttatus. American Journal of Botany 99:82-91
Lowry, D.B., J. H. Willis. (2010) A widespread chromosomal inversion polymorphism contributes to a major life-history transition, local adaptation, and reproductive isolation. PLoS Biology 8: e1000500
Hall M. C., D. B. Lowry, J. H. Willis. (2010). Hall M. C., D. B. Lowry, J. H. Willis. (2010) Is local adaptation in Mimulus guttatus caused by trade-offs at individual loci? Molecular Ecology. 19: 2739-2753
Lowry, D. B. (2010) Landscape evolutionary genomics. Biology Letters. 6: 502-504
Wu, C. A., D. B. Lowry, L. I. Nutter, J. H. Willis. (2010) Natural variation for drought response in the Mimulus guttatus species complex. Oecologia 162: 23-33
Lowry, D. B., M. C. Hall, D. E. Salt, J. H. Willis. (2009). Genetic and physiological basis of adaptive salt tolerance divergence between coastal and inland Mimulus guttatus. New Phytologist 183: 776-788
Lowry, D. B., J. L. Modliszewski, K. M. Wright, C. A. Wu, J. H. Willis. (2008). The strength and genetic basis of reproductive isolating barriers in flowering plants. Philosophical Transactions of the Royal Society B 363: 3009-3021
Lowry, D. B., R. C. Rockwood, J. H. Willis. (2008). Ecological reproductive isolation of coast and inland races of Mimulus guttatus. Evolution 62: 2196-2214
Wu, C. A., D. B. Lowry, A. M. Cooley, K. M. Wright, Y. W. Lee, and J. H. Willis. (2008). Mimulus is an emerging model system for the integration of ecological and genomic studies. Heredity 100: 220-230.
Important Things
• Contact Info: You can contact me at<EMAIL_ADDRESS>Personal tools | v0 |
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The first thing to do in life is to do with purpose what one purposes to do. Casals, Pablo
This quote is about purpose · Search on Google Books to find all references and sources for this quotation.
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Pau Carlos Salvador Casals i Defill (December 29, 1876 October 22, 1973), commonly known as Pablo Casals, was a virtuoso Catalan cello player (and later conductor). He made many recordings throughout his career, of solo, chamber, and orchestral music, also as conductor, but Casals is best remembered for the recording of Bach's Cello Suites he made from 1936 to 1939.
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2024-06-03T21:29:47.544Z | 2013-05-18T05:25:19.000Z | xmkla523cmcuim3azncohuflxpxppqby | {
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} | cccc_CC-MAIN-2013-20 | Bandwagon argument
From RationalWiki
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Hop on, it'll be loads of fun
A "bandwagon" argument says that because "everyone is doing it (or thinking it or saying it), you also should".[1]
Contents
[edit] Form
The logical argument here is:
• Everyone (the majority) is doing it.
• The majority is always right.
• If I do it, I will be in the majority, and therefore right.
The argument is problematic because unfortunately, the premise "the majority is always right" may not be true. In a manner similar to the Matthew effect[wp], something that gains attention (legitimately or otherwise) will attract more interest. This interest generates more interest, like an internet meme circulating around internet forums, and before you know it everyone is on the bandwagon shouting "yee haw!!" While this is merely just how information tends to propagate, the bandwagon argument truly becomes fallacious when people use it as an excuse to say that an issue is important or that the circulating opinion must be correct.
[edit] Examples
Jumping on the bandwagon is the seizing of current events or taking on board of recent popular opinion, by politicians or political parties in order to attract popular support.
In the UK the tabloid press (red tops) are sometimes accused of 'rabble rousing' (e.g. paedophilia hysteria), leading to much public debate and political posturing. Politicians are forced to take a position on such events and the opposition, of whatever party, 'jumps on the bandwagon' by condemning the Government's record and their legislative plans. An recent example was widespread flooding in South-West England caused by heavy rain and the political reaction to it; the opposition parties made great capital of the state of flood defences, the preparedness and financing of the emergency services and building of homes and businesses on flood plains.
It should be noted that it is not necessary for the facts to get in the way of a good argument, the bandwagon has its own momentum and will carry its passengers whether true or not.
Sometimes, when events are due to external causes, both political sides will jump onto the same bandwagon and each will accuse the other of doing so (e.g. Terrorism).
[edit] See also
[edit] Footnotes
1. Glenn, Cheryl; Loretta Gray. Hodges' Harbrace Handbook. 16th ed. Thomson: Boston, 2007: p. 479.
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2024-06-03T21:29:47.544Z | 2013-05-18T08:11:45.000Z | bsdi7edgtgd5g5nlkyiqmxr2ipxgt2tb | {
"content_type": "text/html",
"provenance": "dolma-cccc-filtered-0000.json.gz:51",
"uncompressed_offset": 289164454,
"url": "wikitravel.org/en/Anxi",
"warc_date": "2013-11-22T14:55:02.000Z",
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"warc_url": "http://wikitravel.org/en/Anxi"
} | cccc_CC-MAIN-2013-20 | Help Wikitravel grow by contributing to an article! Learn how.
Anxi
From Wikitravel
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Anxi (安溪; Ānxī) is a small city near Quanzhou in Fujian.
[edit] Get in
[edit] Get around
[edit][add listing] See
Qingshui rock is a scenic spot.
[edit][add listing] Do
[edit][add listing] Buy
The Anxi area produces a famous oolong tea, Tieguanyin (铁观音). Guan Yin is a Goddess of Mercy' "tie" means "iron". It was Anxi tea that was thrown overboard by colonists protesting British taxes at the Boston Tea Party.
[edit][add listing] Eat
[edit][add listing] Drink
[edit][add listing] Sleep
[edit] Get out
This article is an outline and needs more content. It has a template, but there is not enough information present. Please plunge forward and help it grow!
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Nairobi
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Nairobi is the capital of Kenya and the largest city in the country.
Contents
[edit] Understand
Nairobi has a population of three million plus. Situated on the Nairobi River, the city is not only the largest and fastest growing city in Kenya, but one of the largest in Africa.
[edit] History
The word Nairobi derives from a water hole known in Maasai (an Eastern Nilotic language) as Enkare Nyirobi, which means "cool waters." Nairobi, which was a swamp area, was founded in 1899 and was first a railway camp for the Uganda Railway. The city became Kenya’s capital, which was Mombasa initially, and it also became the capital of the British East Africa Protectorate in 1905. With the spread of plagues in the early 1900s, the town was burnt down and had to be rebuilt. Having a railroad system in the system helped it to have drastic growth, becoming the second largest city in Kenya behind Mombasa.
The city of Nairobi also grew due to administration and tourism businesses (mostly big game hunting). The British, who were one of Kenya’s colonizers, set up shop in Nairobi, leading to the creation of big hotels primarily for the British hunters. Also, Nairobi has an East Indian community from those who are the descendents of original colonial railway laborers and merchants.
[edit] Get in
Citizens from most countries will have to obtain a visa upon arrival. Currently, this costs US$50 for a single-entry visa and $100 for a multiple-entry visa (Euros, British Pounds and Swiss Francs are accepted as well). However, some countries require a visa before arrival, and some don't require one at all.
For more information, see the Kenya article. If you are only traveling through the country via a connecting flight and will not leave the secure area of the airport you will not need a visa.
The yellow fever vaccination is no longer required if you're coming from EU, Asia or North America. However, a vaccination certificate might be required if you're coming from a country where yellow flu is endemic.
[edit] By plane
Regular flights to Nairobi are operated by Air France,Air Kenya, British Airways, Egypt Air, Etihad Airways, Fly Emirates, Kenya Airways, KLM, Lufthansa, Qatar Airways, Swiss International Airlines, Turkish Airlines, and Virgin Atlantic. Kenya Airways is the national airline and travels throughout Europe, Africa, and the Asia-Pacific region. Nairobi’s main airport is JKIA Jomo Kenyatta International Airport (IATA: NBO), 15 kilometers (9 mi) southeast from the center of the city.
If taking a taxi from JKIA, use a reputable taxi; many are waiting outside to give you conveyance, and the cost should be very near 1,500KSh to the city center; Westlands or such places more west or north will be more. When taking a taxi to your accommodation, avoid being talked into taking their recommendation for accommodation, although this is very at your own risk. There is also Wilson Airport, 11 km (7 mi) south from the city's center, for domestic flights. Lighter, Cessna-type aircrafts can be seen there. The military/government airport is in Eastleigh district (pron: "East-Lee"), a very large residential area of housing in the east/north-east of Nairobi, but the government airport is fenced around and does not handle civilian traffic. From the center, you can take Bus #34 for 50KSH, to the international airport, from the front of the Ambassador Hotel.
[edit] By train
The city is also accessible by train, with daily arrivals and departures at the Nairobi Railway station. The trains go east to Mombasa and west to Kisumu. There are 3 classes: First, Second and General. First and Second are sleepers. First have 2 seats in a cabin, Second have 4. In Second Class genders are separated unless you purchase the entire compartment of 4 seats. First-class includes bedding, breakfast, and dinner all-inclusive for around $50; Second is $35 all-inclusive. Both can be purchased without bedding or food. Tickets have to be booked through the office on Station Road in south-central Nairobi, or online.
[edit] By bus
Kenya’s bus system is mostly reliable. There are many bus companies that have routes going to and from the country’s different cities, including Nairobi, the center of the bus network.
[edit] By matatu
Matatus (14-18 seater minibuses) and shuttles (6-seater cars) are convenient, inexpensive (and often the only) modes of public transport connecting Nairobi to towns and tourist destinations in the Rift Valley and Central Highlands such as Naivasha, Nyeri, Nanyuki, Isiolo, and Thika. Matatus can be obtained from the River Road area.
Exercise extreme caution in this area: petty theft is a major concern, and valuables such as mobile phones and wallets should not be prominently displayed here, particularly after dark and even while in the matatu (see safety section below). The best method of connecting to a matatu is to arrange for a taxi to drop you off and pick you up directly at the location of the matatu that you are boarding or alighting from. If you're boarding a matatu from Nairobi, tell the taxi driver your destination and they will drop you off at the correct location. If you are being picked up, then tell the taxi driver the location you're coming from as well as the matatu company that you are using (your ticket should have the operator's name). It is best to arrange for a taxi from the hotel you're staying at. Matatu prices can cost anything from 200 KSh (matatu to Naivasha) to 450 Ksh (shuttle to Nanyuki). The price is dependent on the distance of travel.
[edit] By boat
Entry into Nairobi by boat is of course not possible, however, one could certainly arrive in Kenya by boat via Mombasa or Lamu, and proceeding by road, air, or rail to Nairobi. Immigration should be processed at the port facility.
[edit] Get around
Be careful getting around Nairobi. Traffic is very bad like any other major city, but if you use common sense and a local or guide, you should be able to get where you want.
Car Hire And Rental
Car hire and rental options are available. You can hire cars with a driver(chauffeur-driven) or on self-drive basis. Nairobi car hire companies offer salons, 4x4, and safari cars.
Carefully read the rental contract to check for rules on insurance liabilities in case of accident or theft of the vehicle.
Nairobi Car Hire [1] offers good services for 4x4 and other categories of cars.
Central car hire [2] is a reliable, trustworthy, and helpful rental company based in Nairobi. Two-wheel drive and four-wheel drive vehicles are available and are well-maintained.
[edit] By taxi
Taxis are not very cheap, but will make city life easier and safer, at least at night. Always set and agree on prices before the trip, and pay afterwards. You can find taxis parked around hotels and tourist areas. The taxis tend to be marked with a yellow line on each side. Your best bet is to ask a local or at your hotel.
[edit] By bus (matatu)
A matatu (public minibuses/commuter buses) is typically used for traveling between downtown Nairobi and the suburbs. Matatus vary in size, between the van sized 14 seat Matatus and the larger 50-seat buses. While generally safe, you should be aware that matatus are involved in a high number of accidents every year. Matatus are often overcrowded, with more people than seatbelts and therefore can be dangerous if involved in accidents. Because there are no licensing requirements, matatus are often poorly driven, with drivers passing on curbs, speeding, or passing in oncoming lanes while cars are oncoming.
On each bus is a conductor who will hang out of the matatu and call out a price (usually between 10ksh and 40ksh) and location the matatu is driving. Recently, the government has decided to ban the 14-seat matatus inside Nairobi, effective January 2011 in hopes of reducing traffic and accidents in town (which is actually not in effect since 2011-2013, that is until now). The best choice is probably the Double M Commuter Buses or the City Hoppa bus service and of late, the revived Kenya Bus Service. Beware of traffic jams on the large motorways, not only in the rush hours.
[edit] By foot
Walking around Nairobi is fairly easy since the city is small and places are easy to get to. However, there are some areas within the city where tourists should not go; minimise walking around at night. Thugs are rampant in many areas.
[edit] By road
Car hire from the airport is possible, and fairly painless with prices in line with other African countries. In the recent past, Nairobi had a severe car-jacking problem, but because of increased police check-points, it has become marginally safer. Travelling during the day reduces your chances of getting car-jacked, as most car-jackings occur after dark.
[edit][add listing] See
Nairobi is known as the safari capital of Africa, however the city has still managed to keep up with modernization. Unlike other cities, Nairobi is surrounded by 113 km² (70 mi²) of plains, cliffs and forest that makes up the city’s Nairobi National Park. The city is filled with many things to do during the day and the night. Tourists can have their pick from numerous safaris (wildlife, cultural, sport, adventure, scenic and specialist), ecotourism tours, restaurants, culture, shopping and entertainment. While in Nairobi, tourists can also engage in numerous sports from golf, rugby, athletics, polo, horse-racing, cricket and football (soccer).
• Nairobi National Park, just outside Nairobi. This is home to large herds of Zebra, Wildebeest, Buffalo, Giraffe, Lion, Cheetah, Hippo, Rhino and even birdlife (over 400 species). Here you can also go on the Nairobi Safari Walk, an educational centre to make people aware of wildlife and habitat conservation. Also in the park is the Nairobi Animal Orphanage.
• Sheldrick Elephant Orphanage, close to the Nairobi National Park. This Orphanage takes in elephant calves and rhinos from all over Kenya which were orphaned by poaching. Showing is only once per day from 11am-12pm (admission 500Ksh) and gives you a great opportunity to interact directly with baby elephants.
• Giraffe Centre, in Lang'ata right outside of Nairobi. The Centre breeds the endangered Rothschild Giraffe and has conservation/education programmes for Kenyan children. It also has many warthogs.
• Mamba Village. Typically the 3rd stop for most tourists after the Elephant Orphanage and Giraffe Center, this pleasant park is home to ostriches and crocodiles. Surprisingly quite interesting as you get the chance to interact directly with crocodiles and even hold a baby, with very knowledgable employees serving as guides.
• Lake Naivasha. About 1.5hrs outside of central Nairobi, this area is a haven away from the chaos of the city where many 3rd and 4th generation British colonialists continue to reside. Crescent Island [3] is a particularly nice place to visit, even if you have already done a safari. Unique because it gives you the opportunity to walk around the grounds literally alongside giraffes, zebras, wildebeest, impalas, etc.
• Ol Donyo Sabuk National Park, 65 km from Nairobi, is centred around a 2,146-m (7,141 ft) mountain. This is a mountain forest and plain land, with a large population of Buffalo. It also serves as a refuge for Colobus monkeys, bushbuck, duiker, leopard, and a large variety of bird species.
• 14 Falls, a waterfall at Thika.
• Kenyatta International Conference Center (K.I.C.C), (Central District), [4]. The best place to get that far ranging view over the sprawling, congested metropolis that is Nairobi. You can go up to the saucer-shaped top of the conference centre's round viewing tower and depending on smog and fog, you might be able to see as far as the slums and the national park. 400KSH / 200KSH reduced. edit
• US Embassy Memorial Site, (Central District), [5]. In 1998 a blast rocked downtown Nairobi. A truck had exploded next to the US Embassy building, reducing it to rubble and killing 212 people some on staff, most bystanders. On the same day, August 7, the US embassy in Dar Es Salaam, Tanzania, was also subject to a similar terrorist attack. 21 people have been charged with the crime, including Osama Bin Laden. The former embassy site today contains a memorial that can be visited. edit
• Tana River, is an hour's drive from the city. White water rafting throughout cataracts, which leads to the 14 falls can be done here. The rafting trip also includes a full BBQ lunch.
• Nairobi National Museum, [6]. 8:30AM-5:30PM. Where visitors can learn about Nairobi, its history and culture. The museum celebrated 100 years in 2010. edit
• National Railway Museum, visitors can learn more about the history of Kenya’s railroads and the Kenya/Uganda railway. It also houses, some of the engines and rolling stock from the country’s colonial period.
• Nairobi Gallery, P.O.Box 40658-00100, +25420216566. This is a museum housing only special exhibits, so the featured artwork is always changing. edit
• Karen Blixen Museum, P.O Box 40658-00100, +254208002139 (). is based on the Karen Blixen’s book "Out of Africa". Her house is now the home of the museum. It is on the outskirts of Nairobi and a taxi or bus can get you to the museum. edit
• Bomas of Kenya, portrays Kenya’s culture. Visitors can see exhibits of traditional Kenyan homes, artifacts, dances, music, and song.
• Uhuru Gardens, built in remembrance of the struggle for independence, which Kenya was granted in 1963. The monument is a 24-m (79 ft) high triumphal column supporting a pair of clasped hands and the dove of peace, high over a statue of freedom fighter raising the flag. The monument is surround by fountains and lush-landscaped gardens.
• Westlands by night, Visit the bustling and hip Westlands district, which has turned into the new nightlife center of Nairobi. Many restaurants and bars line the busy Woodvale Grove and Mpaka Road. A visit to 'Tree house' club is a must if you are looking for a spacious one and crowd outnumbered with expats, rather than the otherwise congested natives dominated ones. Traffic can become hectic, well into the early hours. Security is generally tight and the action spills out from packed clubs into the street.
• Jamia Mosque, (Central District), [7]. While Jamia Mosque is tucked away in between other buildings their are striking views to be glimpsed of its intricate structure from many different angles. Easily the most impressive religious structure in the capital, the interior is off-limits to non believers edit
[edit][add listing] Do
• Safari in central Nairobi park.
• Try the many excellent restaurants in Nairobi.
• Go dancing and be a part of Nairobi's excellent nightlife
• Go ice skating at Panari
• Visit Village Market and Sherlocks with your friends
• Go to Maasai market and buy keepsakes for yourself and friends: On Saturday it is at Nairobi High Court parking lot, Village Market on Friday, The Junction on Thursday, Capital Centre on Wednesday. Prepare to haggle and as a guide, pay about half to two thirds of the asking price.
• Do something different: visit Kibera, the slums of Nairobi. Guided walks are arranged by Kiberatours.
• Go-Down Arts Centre, (South of Center), +254 (0)20 555770, [8]. A former warehouse turned arts centre - this has also happened in Nairobi and this spot allows you to get a glimpse of what contemporary Kenyan artists are up to, including exhibitions, performances and discussions. edit
• Kazuri Beads shop - Started in 1977 the workshop of beads is adjacent to Karen Blixen's Museum. Was started by an English women to provide sustainable income to the poor Kenyan women. Has beautiful jewelry created of clay brought from the areas surrounding Mt. Kenya.
• Visit Oloo’s Children Center (OCC) in Kibera: Lend a hand at the volunteer operated school, take a tour of Kibera, and have a cup of tea with the OCC Founder. The founder of the school lives in Kibera and works to provide children in need with education and meals.<PHONE_NUMBER>
[edit][add listing] Buy
There are quite a number of networked banking machines in major shopping areas of Nairobi as well as the arrivals area of the airport. A Barlays ATM can be found near Gate 9 within the security area, easily accessible when arriving, and another one on the left side immediately after leaving the security area. Most transactions are cash only, so it is best to have enough cash on hand to pay for purchases and transport. Major banks such as Barclays, Kenya Commercial Bank, and Standard Bank give better exchange rates than any of the FOREX bureaus. Independent machines such as Pesa-point have lower cash limits and may have a higher fee. For example, in 2007, Barclays did not charge any additional fee for a cash withdrawal but gave a lower exchange rate than Kenya Commercial Bank. KCB charges a CDN$5 fee for a withdrawal with a maximum of 40,000/= per day.
Cash is dispensed in units of 1000/=. Note: Many smaller businesses do not have much change, so be sure to have a good selection of smaller notes before going shopping for curios.
Forex Bureaus are located in many parts of the city where tourists are common. They will exchange cash of different currencies, and may also accept a personal cheque for Kenyan cash. Rates are not bad, but will be worse than a banking machine will offer. Be aware that many exchange bureaus and hotels will NOT accept or exchange American currency printed before 2000. When the exchange bureaus do accept pre-2000 notes, they typically offer substantially lower exchange rates than for curreny printed after 2000. Exchange rates are also typically lower for small denomination currency than for $100 and $50 bills.
Credit Cards Many specialty stores accept international credit cards, however they normally tell you up front that they will charge you bank fees, typically 5% of the purchase. The Nakumat and Uchumi supermarket chains would accept credit cards without a surcharge.
This may also be a good place to repeat the warning about safety: Pickpockets are rampant in Nairobi and have been known to keep an eye on people getting cash from a machine. It is best to carry cash in a hidden pouch rather than a wallet. Men: do not carry your wallet in your back pocket, and women: do not carry your purse to your side or behind you, particularly in busy locations.
The four primary supermarkets in Nairobi are Tusky's, Uchumi, Naivas and Nakumatt. For goods beyond supermarket fare, try Yaya Centre on Argwings Kodhek Road in the Kilimani area, The Junction on Ngong Road, or the Sarit Centre and Nakumatt Westgate which are both located in the Westlands suburb.
The Sarit Centre will be recognizable to any Western traveller as a shopping mall, with an Uchumi supermarket inside. Clothing, shipping, and Internet are all available here. In addition, there is a small movie theater. Other malls in Nairobi include Yaya Centre near Hurlingham and The Mall in Westlands.
Nakumatt Westgate is a just finished competitor to Sarit Centre. It is a large building with many spaces for stores to move in to (they have yet to move in at the time of this writing, however the building is still unfinished). Currently, the primary occupant is the Nakumatt itself, which has modeled itself to emulate a Super Wal-Mart type experience. Any taxi driver will know these two shopping centers by name, so getting there is not a problem.
An additional smaller supermarket, catering more to expatriates, is in ABC Plaza, along Waiyaki Way. Chandarana supermarket carries a wide variety of imported goods, Zucchini greengrocer is a highly dependable spot for clean and varied veggies, and Gilani's is a well stocked western style butchery.
For local curios and souvenirs, the most easily accessible and tourist-friendly is the Maasai Market, held on Fridays at the Village Market, an upscale, open concept shopping center near the United Nations and American Embassy complexes. Bargaining is necessary, and one should probably not spend more than 1000KSh on one item, except in extraordinary circumstances. The Masai Market is also held on Thursdays at the parking lot of the Junction Shopping Center and Tuesdays at the parking lot of the Westgate shopping center. Bargain hard, and do not let that deter you from speaking with many of the friendly shopkeepers who are apt to offer gifts with no other incentives.
For slightly better prices, visit the Tuesday market in town, just down from the Norfolk hotel. This market is less secure, but is larger and offers more variety and opportunity for bargaining.
Another Nakumatt is located at Nakumatt Junction, past Lavington towards the Ngong Racecourse (Horse Flat-Racing takes place 3 Sundays a month, and is a great way to spend an afternoon). The Nakumatt Junction shopping complex features a few more boutiques - one of note being Zebu, a store highlighting local Designer Annabelle Thom's leather bags and more, where you will find higher quality and higher prices for beautiful designs.
Biashara Street, located downtown, is the spot for textiles. Make sure you pick up at least one kikoi or kikoy (a traditional wrap for Swahili men, predominantly at the coast). Haria's Stamp Shop (been around for more than 70 years!) (www.hariastamp.com) has one of the best selections of kikoy as well as other african fabrics and souvenirs.
[edit][add listing] Eat
[edit] Budget
Roast House in the city centre facing the matatu station on Tom Mboya Rd. Regular local prices with more selection, excellent food, friendly service. Very busy at lunchtime.
Habesha near Ya Ya center- great Ethipian food for around 5-6 USD
[edit] Mid-range
Nairobi has a fantastic array of mid-range eateries.
Open House [9] is an excellent Indian restaurant nearby Westlands area of Nairobi. With such a high predominance of Indians in the country, this is one of the best places to get authentic cuisine in an upscale environment at a reasonable price. Do not miss the ginger chicken wings - very unique!
Mesob is an authentic Ethiopian restaurant located at the China Centre on Ngong Road near the Chinese embassy. Meals cost around Ksh 500 and the food is excellent.
Java House, with quite a few locations, including The Junction, ABC Place, and close to the United Nations, features a western coffee house menu, from bagels to burritos, with excellent coffees and milkshakes, and a full breakfast menu. 500KSh-750 for a complete meal. Another popular coffeehouse is Dormans
Trattoria is an Italian restaurant. Do not expect anything decent when it comes to the mains (all around 700KSh). However, there is a fabulous and extensive dessert menu, including crepes, tiramisu, souffle, and a coffee granita with fresh cream (250KSh-500).
Motherland, is an authentic Ethiopian restaurant with great and affordable food (typical of Ethiopian restaurants in Nairobi!).
Havana Bar, Woodvale Grove, Westlands. Popular bar and restaurant with a laid-back Latin theme. Renowned for their sizzling Fajitas, steaks and seafood dishes. Reasonably priced. The kitchen is open daily from noon til late. [10] Tel:<PHONE_NUMBER>
Village Market Food Court, Has an array of different ethnic cuisines, including Thai, Italian, Chinese and German, as well as a Mongolian Barbeque. Good prices as well. Venture further into Village Market to find a good Japanese restaurant as well, though with slightly steeper prices. There are also food courts at other malls in the city.
Nairobi has a wide range of Indian restaurants that speaks to the significant South Asian community in Kenya. The city also offers other restaurants specializing in different European and Asian cuisine.
Common fast food restaurants include Steers, Debonairs, Wimpy, Galito's, local favourite, Kenchic among others.
In addition, there are several local restaurants that cater to local cuisine like sukuma wiki (green spinach-like vegetable, 'Kale' in English), ugali (corn bread, ground maize flour and made to a tasty white bread/porridge form), nyama choma (lit: meat roast), chapati, and other specialties.
[edit] Splurge
The Carnivore, located just outside the city, close to the Uhuru Gardens, is a luxury restaurant famous for its meats. In 2006, the restaurant was listed as one of the top 50 restaurants in the world. Once seated, different masai grilled meats will be carried around on sticks and carved to your plate at request. Very expensive by Kenyan standards, beware of additional taxes and catering levys. Reservations might be a good idea, ask at your hotel.
Furusato, located in Westlands, has fantastic Japanese food. For a price.
The Rusty Nail, in Karen, has been super in the past, but mediocre of late. No reason not to give it another chance.
The Lord Errol, past Village Market and into Runda, is said to have very good food, and is popular with the expat crowd.
"Moonflower," on State House hill at the Palacina hotel, is a very upscale bistro / fusion / grill restaurant in a lovely outdoor setting. Fantastic food.
"Pango Brasserie" at the Fairview Hotel features upscale french and continental dishes. Dinner begins in an underground stone wine cellar where the chef will send out complimentary tasters while you sip a bottle of wine of your choice.
"Alan Bobbe's Bistro" is a venerable, legendary restaurant now located on Rhapta Road (near St. Marys School). Founded in 1962, the restaurant features French haute cuisine at about a third of what you would pay in Paris!
[edit][add listing] Drink
• Club Soundd, junction of Kaunda and Wabera St, +254 722 571 382
• Gipsy:, Opp,Barclays,Bank Westland, Box 40322, Nairobi, Tel:<PHONE_NUMBER>,4440836, Mob: 0733 730529<EMAIL_ADDRESS> • Klub House 1 (K1):, is located along Ojijo Road in Parklands, Box 33003 - 00600 Nairobi, Tel: +254 20 374 9870, Fax: 254 20 374 7099, Mob:+254 733 77 22 33<EMAIL_ADDRESS>[11]
• Klub House 2 (K2):, Baricho Road, Industrial Area is home to K2 Klubhouse
• Choices:, Majestic House, Moi Avenue, Box 53319, Nairobi, Tel: +254 20 550 629, Mob: +254 722 521, Email<EMAIL_ADDRESS>Leobag Investment Ltd, Baricho Road
• Chillers:, Anniv Towers
• Black Diamond:, many expats and travelers and has a cover band that plays very good music.
• Havana: Its an expats favorite on Thursdays nights. The live band on Saturdays attracts a good cosmopolitan crowd. Bar snacks available throughout the night.[12] Tel:<PHONE_NUMBER>
• Apple Bees: (Strip club) located downtown and recently opened a branch in Parklands, next to the local Police Station.
• Annie Oakley's:Next to Milimani Backpackers, has pool tables, a descent menu, and a big screen with cable TV. another expats favorite hangout.
• Cockpit: Langata Road opposite Uchumi Langata Hyper, not just popular with Wilson Airport pilots
• Barrels: Stripclub. Watch out for police raids
• Red Tape:, Westlands, Mpaka Road, Bishan Plaza, e-mail<EMAIL_ADDRESS> • Florida 2000 (F2):, Located at Commerce House, Moi Avenue. [13]
• New Florida Clubs (F1):, The New Florida, locally known as Madhouse or Madi, is in the heart of Nairobi on Koinange Street.
• Pango (F3):, Commerce House, 1st Floor, P.O.Box 55381 - 00200 Nairobi, Tel:+254-20-229036/217269<EMAIL_ADDRESS>The Latest addition to the Florida Group
• Double Inn: Also out in Karen, they show rugby/cricket games and it's always full of expats and white Kenyans. The place to get hammered.
• Seven Seafood & Grill, ABC Place (ABC Place Waiyaki Way),<PHONE_NUMBER>, [14]. 24. Amazing seafood and spectacular decor a must visit 2000. edit
• Klub Zinc Thika (Zinc Club Thika), Kenyatta Hwy (Opp. Total Filling Station Thika), +254202621500, [15]. We pride ourselves as masters of all tastes and genres of music and also the ability to cut across generations as music is 'Food for All'. The music ranges widely from the latest to the golden oldies and in styles such as Rock, Rhumba, Reggae, R n B, Hip Hop, Lingala and Salsa to mention but a few. Patrons are also encouraged to place their requests and dedications to the DJs. The atmosphere is further enhanced by the latest disco lights and effects. edit
• Shooters & Dips Cocktail Lounge, 4372-00506 (Panari Sky Centre,Mombasa Road opp Simba Colt Offices,5km from JKIA), +254 787 637948 OR 254 725 694 000/1/2, [16]. 5PM. Chill out, relax and unwind at the dazzling Shooters & Dips where the decor transports you to an international surrounding. Listen to handpicked music by the DJ and let yourself go to the rhythm. The bar also offers a varied food menu along with a long list of signature cocktails, fine wines and liquors. Shooters and Dips is the perfect place to meet friends, meet new people and experience Nairobi's nightlife right in the safety of the hotel. 250/=. edit
• Mercury Lounge ABC, ABC Place (Off Waiyaki Way),<PHONE_NUMBER>, [17]. 4pm. Mercury ABC, ABC Place (Off Waiyaki Way), ☎<PHONE_NUMBER>. checkin: 4:00pm. Mercury ABC is an upscale modern cocktail and tapas bar. Open from 4pm to late. Recently put under new management, Mercury is definitely the place to be seen, with a delicious tapas and bitings menu, and the best cocktails and high end spirits array in Nairobi.All major imported and local wine and beers are available chilled to perfection. A popular hangout for expats, well to do locals and local business leaders. A must for any Nairobi traveller. Shooters and cocktails range from $3 to $6 with shooters and high end globally popular wines and spirits from $6-$15. All major credit cards accepted. Ample parking and good security make this one of Nairobi's more popular spots. edit
• Mercury Irish Pub (The Last Drop), Junction Mall (Corner of Ngong Road and Kingara Rds),<PHONE_NUMBER>, [18]. 11:00am. Mercury Pub at the new Junction Mall is the latest and most authentic Irish Pub in Nairobi. The most recent addition to the Mercury Group, the pub specializes in the best steaks in town, a wide range of cocktails, local and imported beers, high end spirits and shooters and a superb wine list. Furnished in beautiful woodwork, leather seating, and with images of colonial Nairobi, it is located in the secure Junction Mall which has ample parking, good security and central location. Doubles up as a popular sports bar on the weekends with multiple screens. A popular expat hangout. A great balcony from which one can sip a cocktail while watching life pass by. Food prices from$10-$15, and all major credit cards are accepted. edit
[edit][add listing] Sleep
• Upper Hill Campsite and Backpackers, Hospital Road – Upper Hill (off Hospital Road, on a cul de sac), +254 (0)20 2500218, [19]. Provides a range of budget accommodation. Bringing your own tent is the cheapest way. If you are two people, try to go for a big hire tent which is the better deal than a dorm 500 - 3500 KSh. (S 01 17.161,E36 46.387) edit
[edit] Budget
The area around the main bus station has a ton of budget hotels and you can save on a taxi.
• Terminal Hotel, Moktar Dadah Street opposite Nakumatt, [20]. Spacious rooms with faded simple, decor are on offer here. And at very reasonable prices. Like any place in the city centre it can get loud - but then you are in a prime location just opposite from the Nakumatt shopping centre. If you store you luggage there - consider that you will only get your luggage at the aggreed date because the hotel cleark does not have the key to the "safe room". from 2000KSH (single) / 2300 Double, 2600 Tripple. edit
• Diani Beach Villas Cottages, Diani Beach Rd, P.O. Box 63692 - 00619 (It is about 7 mins drive to the Ukunda airstip, and 10mins drive to Leisure Golf Club), +254-714-100-026, [21]. All rooms are equipped with kitchen, cable television, private toilet and bath. Some of its facilities and services are parking, swimming pool, garden, cleaning service, tours and travel services. Rates start at 89.00 USD. edit
• Wildebeest Camp, 151 Mokoyeti Road West, Langata, [22]. You can get a bed in a dorm here or camp (they provide the tent and bedding) for Ksh 1000 per night per person. They also have larger permanent tents and rooms available at a higher price. The place is clean, secure and popular with backpackers. from 1000 KSh per person for dorm and camping (tent provided). edit
• Hotel Downtown, Moktar Dadah Street opposite Nakumatt, [23]. checkout: 10AM. In the same league as the Terminal hotel next door or the Parkside across the road, the Downtown hotel has clean rooms and is as the name says: downtown - with all its advantages (shopping centre nearby, etc.) and disadvantages: noise. Note that leaving valuables and especially credit cards in the safe at the front desk for safekeeping is not a good idea. from 1900KSh for singles. edit
• International Guest House, UpperHill, Matumbato Road (Next to Don Bosco Church, 10 min walk from Kenyatta National Hospital), +254<PHONE_NUMBER>, [24]. With 30 years in the tourism business, owner Tom J. Kamau is happy to custom arrange any additional travel or safari needs. Located on a quite street in Upperhill, this family owned and operated guest house is conveniently located just a few minutes from downtown. Airport pickup and transportation is available for a small fee. Single rooms available from from 600KSh-2000. edit
• Milimani Backpackers & Safari Centre, PO Box 21005 - 00500, [25]. A little further out of the downtown core, about 15 minutes walk down a major, safe road, is Milimani Backpackers which has moved from Milimani Road. It has internet (for 300 ks/day), cable TV, WI-FI, hot showers, 24hr self-service bar, popular restaurant, fireplace, and a parking area. They offer dorms, doubles, singles, twins, camping space, permanent tents, and cabins. Milimani also offers good-value safaris and other trips from 1000KSh for dorms. edit
[edit] Mid-range
• Olive Gardens Hotel, Argwings Kodhek Rd, Hurlingham (Opposite Nairobi Womens Hospital) (30-min drive from the Jomo Kenyatta International Airport.), +254 20 2737854, 2727777, [26]. Olive Gardens Hotel has 62 rooms. edit
• Ole-Sereni Hotel (Sarovar Hotels & Resorts), Mombasa Rd (5 km from Jomo Kenyatta international airport off Mombasa Rd opposite Zain offices), +254 20 390 1000 (), [27]. checkin: noon; checkout: noon. Wildlife resort overlooking the Nairobi National Game Park. (-1.326888,36.845956) edit
• Country Lodge, [28]. On upper hill, the Country Lodge is aimed at the budget business traveler. Probably the best deal in town.
• Fairview Inn, [29]. Also on upper hill, the Fairview is a lovely old historic hotel, with beautiful grounds and several restaurants. It is quiet at night, a real respite from the city. Rates are relatively low, compared to many of the other hotels listed here. They also rent apartments.
• Holiday Inn Nairobi. Built in the 1940s as the Mayfair Court Hotel, this historic hotel has retained its charm even as it has joined the Holiday Inn family.
• InterContinental Hotel. Located only 5 minutes from the city center and 15 min from the airport with views of the city.
• Nairobi Hilton. Part of the Hilton family of hotels and located near the city center.
• Nairobi Safari Club. Kenya's only all-suite hotel.
• Panafric Hotel. Located in the city centre and only 20 minutes from the airport.
• Karen Blixen Cottages. Located in the suburb of Karen, 32 km (20 mi) from downtown, the cottages offer a unique change from the normal hotel fare.
• Nairobi Serena Hotel. Found in the middle of Nairobi's Central Park this hotel offers great convenience as well as a quiet place to stay.
• Norfolk Hotel. Opened on Christmas Day over 100 years ago, this hotel that has served many special guests is located only 30 min from the airport, and a short distance from the shopping district.
• Safari Park Hotel. Started as a retreat for British Army officers more than 50 years ago, this hotel is only 15 min from downtown.
• The Stanley Hotel. This over 100 year old hotel has recently be renovated back to its days of Victorian perfection. Lcoated in the city's shopping and business district.
• Windsor Golf and Country Club. Located 15 min from the city center, 45 min from the airport. Features a 18 hole golf course on site.
[edit] Splurge
• The King Post [[30]. Rhapta Road, Westlands, Nairobi. The King Post brings about a unique architectural synthesis between the East African coast and the lands across the Indian Ocean. it reflects the social and cultural interaction between the regions over more than 2000 years.Accommodation is in 1, 2 or 3 bedroom apartments available on daily basis and long-term.The apartments are secluded but not isolated from the hustle and bustle of the city centre and the main roads being sorrounded by peace, tranquility and security.
• Giraffe Manor. The converted home of the founders of the African Fund for Endangered Wildlife, located a few kilometres from the city center, sitting on 57 ha (140 a) of land. The giraffes can be fed at the front door or even from the second floor bedroom window!
• Ngong House [[31]. 30-min drive from the city center and airport, the Ngong House is on a land that was originally part of a vast coffee estate. Located on the grounds are five traditional looking, yet elegantly decorated tree houses.
[edit] Stay safe
Nairobi has a reputation for thievery. Beware of snatch and grab, con artists, or groups of people following you. Scams are elaborate and can involve up to 10 or more people working together. The best advice for a tourist is to stay in the city centre, know where you are at all times, and pretend you know where you're going (even if you don't). If you find yourself in an unfamiliar area your best bet is to find a taxi (although you will probably pay dearly if the driver suspects a panicked westerner!). Don't carry large quantities of money or passports on the street, and assume that anyone trying to engage you is up to no good or trying to sell you something. In recent years, crime has significantly reduced, though one should still be wary. If one stays smart and plays safe, without going around much after dark, Nairobi is a safe place to stay. Most locals are honest people who will happily help you if you approach them.
Kenyans are proud people and there is not a lot of begging like you find in some other countries. Some opportunistic people will hang around shopping centres and beg, but they will generally accept a simple 'sorry' and leave you alone if you do not give. Many of these 'beggars' are middle class kids or adults who have realised they can profit from exploiting foreigners, and should not be encouraged. If you are ever lucky enough to visit a slum as a local (not on some perverse tourist safari) you will discover the poorest of the poor do not even beg.
Outside of tourist and expat communities, young children will become excited at the sight of foreigners. If you are fair-skinned, children may run towards you to try to shake your hand, or yell "mzungu" (white person) or "how are you?". Older kids are more reserved, and you should be wary of kids who are older than 9 or 10 who are trying to distract or get close to you.
Slums should be avoided by tourists as you will attract a lot of attention which can quickly turn into a dangerous situation.
Apart from the inner city centre, Nairobi dies out at night. Streets are mostly empty. Do not walk alone after nightfall. Always use taxis. The areas north and east of River Road should be avoided, especially if you're not a local!
Biashara Street is a safe shopping street due to the presence of 10-15 Maasai guards. A place to avoid as a tourist is the City Market; you could end up paying a much higher price than on Biashara Street.
If you are in a matatu and moving slowly through traffic, particularly after dark, you should keep your window closed if your valuables are in reach to prevent people snatching them from the outside (there are thieves who walk through traffic looking for such opportunities). Mobile phones and wallets should be securely kept and not displayed prominently during calls or cash transactions in the River Road area, particularly after dark.
Eastleigh (known as 'little Mogadishu') is an area near the city centre that is decaying due to years of neglect by the government (including the police). It is predominantly populated by Somalian migrants and refugees, and most Kenyans will not go there for fear of their safety. Tourists would be wise to avoid it day and night.
There have been several grenade attacks in the city for which Al-Shabaab have claimed responsibility. These are likely to be ongoing while the Kenyan army has a presence in Somalia. They are random and often fatal, and one should be weary and report any suspicious behaviour.
[edit] Stay healthy
It is recommended that before tourists come to Nairobi, that they should be vaccinated well in advance (6 weeks) of their trip. The most common recommended vaccines for people traveling to Africa are Tetanus, Diphtheria, Polio, Typhoid, Hepatitis A, Hepatitis B, Yellow Fever, Rabies and Meningitis.
[edit] Food and beverages
Be careful with the food that you eat outside the more upscale establishments. Before eating, make sure that the food is freshly and thoroughly cooked and served hot. Also avoid seafood,apart from the upmarket restaurants and hotels, and make sure that your fruits and vegetables have been properly sterilized in clean water. The safest fruits to eat are bananas and papayas. Do not drink tap water or brush your teeth with it. Only use bottled or canned drinks (especially popular brands). Also, do not use ice as it may also be contaminated water, and remember that alcohol does not sterilize a drink. The general rule of thumb is, the more high end an establishment is, the greater the safety of the food and drink within.
[edit] Insects
In Africa you are going to be exposed to yellow fever, dengue fever, other viral diseases, sleeping sickness, filariasis and malaria, although none of these diseases are a concern in Nairobi itself. When insects are biting you should cover up and wear long-sleeved shirts and trousers, socks and pyjamas especially when night falls. It is best to use an insect repellent that contains DEET on your exposed skin and clothing. As for mosquito nets, it is best to use a permethrin-impregnated net along with an insecticide such a pyrethrum coils or an electric mosquito killer during the night. And remember to spray your hotel room every evening.
[edit] Heat & Sun
Make sure to drink plenty of fluids (not coffee, alcohol or strong tea) to avoid dehydration. The average temperature is around 25 C (maximum might reach 30 C) throughout the year. Try to avoid plenty of physical exertion and try to stay in the shade and keep cool as much as possible. Increase the amount of salt intake in your food and water. Also, apply a lot of high factor sunscreen, avoid direct sunlight, and try to wear a hat and shady clothing.
[edit] Contact
There are very many internet cafés around Nairobi, but connection speeds and computers are not always super fast, but still you will manage to open your email, probably even use a webcam or watch YouTube. Prices are usually at ranges from 0.5KSh/minute to 1KSh/minute, usually with a minimum fee of 5-20KSh. The more expensive internet cafés are rarely better and the best ones charge 1KSh/minute with discounts for using the internet for longer. Most of the good cafés are found in Norwich Union which has quite a number just opposite Hilton Hotel next to Nandos while the expensive ones are found in malls in Westlands. Although it may be more appropriate for tourists to use the ones in Westlands since they are usually less crowded and are more exclusive but not necessarily faster or better in terms of equipment.
Free wireless internet is available at Java House restaurants and Doorman's coffee shops in the city and malls. Some bars like Havana in Westlands also offer free wifi. The internet cafe in Sarit Centre also has wireless internet available at a good speed and a reasonable price.
Mobile Phones are ubiquitous in Kenya with fairly good coverage from all providers (Safaricom, Orange and Airtel) that extends to most populated parts of the country. Safaricom has the best national coverage especially if you are using 3G data. The phone system is GSM 900 and 3G 2100 (Asian and European standard). Phones and SIM cards are available at many locations throughout Nairobi and the country including at the airport. Phone prices are very competitive and priced for average income Kenyans. A basic phone may be obtained new from an independent dealer for ~2000/=. A vast majority of people use pre-paid phones with scratch-card top-ups available at a huge number of merchants across the country. All phones are sold "unlocked" for use on any network. Much business is conducted via mobile phone, so possession of one for even a relatively short stay in the country can be beneficial. Rates are extremely affordable with in-country calls at around 3/= per minute. Overseas calls cost around 5/= per minute to the United States (~USD$0.06/minute) and 3/= per minute to India (~INR 1.80, USD 0.04) on the Airtel network.
3G data service is available in most coverage areas on Safaricom and is of a fairly high standard. The other networks have 3G in major population areas and EDGE/GPRS everywhere else. If you have a smart phone you should buy a data pack (200mb, 500mb or 1.5gb) or your credit will go down very fast!
[edit] Cope
Smoking is against the law out on the streets in the city center (the downtown grid area with numerous skyscrapers). There are certain smoking zones, and outside of the city center it becomes much easier to find locations where it is acceptable. However, a general rule would be to not smoke along the side of any roads or streets with pedestrians and/or vehicles. Be observant and take your cues from other smokers - if there are no smokers or cigarette butts on the ground, it is likely a non-smoking location.
[edit] Embassies & High Commissions
• Australia, Riverside Drive (400 meters off Chiromo Road), +254 20 4277100 (fax: +254 20 4277139), [32]. edit
• Djibouti, Mama Ngina St, +254 20 2122859 (fax: +254 20 313120), [35]. edit
• Indonesia, Menengai Road, Upper Hill P.O.Box 48868 Nairobi, (+254) (20) 714-196 to 198 (, fax: +254 20 713-475), [38]. edit
• Japan, Mara Rd, Upper Hill, +254 20 2898000 (fax: +254 20 2898220), [40]. edit
• Republic of Korea, 15F Anniversary Towers, University Way, +254 20 2220000. edit
• Spain, CBA Building, 3rd floor, Mara & Ragati Road, Upper Hill, +254 20 2720222 (, fax: +254 20 2720226). edit
• United States of America, UN Avenue, +254 20 363-6000 (fax: +254 20 363-3410), [44]. edit
[edit] Get out
Lake Naivasha is worth at least a day's visit and has enough to keep you occupied for two or three days. Lakeshore country clubs are a good place for lunch. You can take a boat ride on the lake to see hippos, go for a walk among zebra and giraffes on Crescent Island, ride thoroughbred horses among zebra, giraffes and wildebeest at the Sanctuary Farm, and ride bicycles among wildlife and dramatic scenery at Hell's Gate National Park.
Further afield, Nakuru National Park deservedly warrants a 1-night stay for a late-afternoon and early-morning game drive.
This is a usable article. It has information for getting in as well as some complete entries for restaurants and hotels. An adventurous person could use this article, but please plunge forward and help it grow!
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} | cccc_CC-MAIN-2013-20 | Australian Bureau of Statistics
Celebrating the International Year of Statistics 2013
ABS Home > Statistics > By Release Date
1301.0 - Year Book Australia, 2002
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 25/01/2002
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UNDERSTANDING AGRICULTURAL EXPORTS DATA
INTRODUCTION
The Australian Bureau of Statistics has had a long history of producing international trade statistics. These are used by economic analysts and policy advisers to monitor, evaluate and forecast developments in Australia's external trade and the general level of economic wellbeing. However, measuring the importance of this trade has, for the agricultural industry, become increasingly difficult and complex as the economy develops.
In relation to agricultural production and exports this article illustrates how different classifications, methodologies and assumptions can be used with the same body of data to provide quite different outcomes, depending on the perspective from which users wish to view the data, and the purpose of the analysis. Like most economic statistics, agricultural export and production data are based on underlying assumptions relating to industry and commodity classification, as well as market and business functions. In addition, the methodology used in collecting export data from customs records introduces its own set of limitations.
The article seeks to provide an understanding of the most appropriate methods available for comparing agricultural production with exports. The year selected for the comparison is 1997-98; however, due to fluctuations in agricultural production, overseas market access, availability of stocks etc., any comparison undertaken on the basis of a single year needs to be treated with caution.
Background
Since settlement a proportion of Australia's agricultural output has been exported. Initially, measuring the importance of agricultural exports was relatively straightforward as most of the exports were in raw form, and could be easily identified and compared with agricultural production. However, as the Australian economy developed, proportionally more agricultural output was exported in a processed or manufactured form, such as processed meat products, wine and woollen products.
In situations where agricultural production is directly exported as a raw or unprocessed product one can compare production quantities or values with export quantities or values for individual commodities, although in comparing values one needs to take account of the differences between the valuation basis for production ('farm gate') and that for exports ('free on board' (f.o.b.)). Difficulties arise, however, for those agricultural commodities which have undergone some manufacturing process and are indirectly exported as part of the manufactured product. For example, how might analysts compare the value of grape production with the value of a transformed agricultural product such as wine?
Making legitimate comparisons between production and trade is further complicated by the variety of trade data available. ABS merchandise trade data can be manipulated and grouped in a number of ways by both the ABS and external clients, depending on the use being made of the data.
Agricultural export statistics
The ways in which agricultural export data can be presented include:
• a commodity based approach
• an industry based approach
• a balance of payments approach
• an input-output approach
• an embedded commodities approach
These approaches are discussed below.
Commodity based data
For exports, the ABS uses the Australian Harmonised Export Commodity Classification (AHECC). The details and descriptions of the statistical codes of the AHECC are identified in the Australian Harmonised Export Commodity Classification (1233.0).
Commodity-based trade data are useful for monitoring changes in levels of trade over time. For example, for a particular commodity, or group of commodities, monthly or yearly data can be compared to provide an accurate picture of changes in the levels of those commodities exported. However, commodity based trade data alone should not be used to measure the complete proportion of agricultural output which is exported. This measure offers no method of calculating the agricultural component in exported processed goods.
S4.1 VALUE OF SELECTED AGRICULTURAL COMMODITIES PRODUCED AND EXPORTED - 1997-98
Commodity
Agricultural production (a)
$ '000
Unprocessed exports (b)
$ '000
Wool
2,753,936
(c)2,276,797
Cattle
(d)4,138,239
(e)352,348
Sheep
(d)1,066,217
(e)200,159
Pigs
(d)709,806
(e)1,065
Grapes
998,197
(f)82,438
Apples
272,720
37,961
Wheat
3,801,497
3,629,554
Canola
329,847
256,216
Potatoes
493,149
9,984
Oats
223,269
30,305
Sugar cane
1,247,744
(g)3
Milk
2,816,977
(h)67,451
(a) Agricultural production is Gross Value of Agricultural Commodities Produced (GVACP), and is the value measured at the metropolitan market in each State or Territory. It is not the 'farm gate' value of production.
(b) Exports are valued on a free on board (f.o.b.) basis which includes the value of distribution and other costs incurred between the farm and the point of export.
(c) Exports of greasy wool, not carded or combed.
(d) The value of livestock at slaughtering and other disposals (including net exports of live animals).
(e) Exports of live animals. Does not include the export of carcasses and cuts of beef ($2,700m), mutton/lamb ($653m) and pig meat ($51.7m),because these commodities are considered to be manufactured products.
(f) Does not include the export of wine ($874m) because wine is considered to be a manufactured product.
(g) Contains $3,000 of exported sugar cane. Does not include the export of raw sugar ($1,159m) because raw sugar is considered to be a manufactured product.
(h) Milk contains some non-agricultural value added as a result of the pasteurisation process undertaken prior to the sale of milk.
Source: Agriculture, Australia (7113.0).
In analysing table S4.1, the following points should be noted:
• Many commodities (e.g. wool) can draw on stocks accumulated in previous years, which can distort yearly comparisons of exports and production.
• Unprocessed commodities only are shown. Any embedded agricultural output contained in processed goods, such as meat, sugar, canned fruit, processed wool, woollen products, wine etc. are not included. In other words, the table shows only direct exports of agricultural commodities.
• Different valuation bases are used for measuring production and exports. Value of production is the gross value received by the farmer at the market place, which in general is the metropolitan market in each State and Territory. Exports are valued at the point of export (f.o.b.), and therefore include any distributional and marketing costs incurred up until the point of export.
Industry based data
Export data are also available on an 'Industry of origin' basis. The Australian and New Zealand Standard Industrial Classification (ANZSIC) is the standard classification used by the ABS for the presentation and analysis of industry statistics. It provides a framework for classifying businesses to industries according to the predominant activities undertaken by a business.
The classification is used in international merchandise trade statistics to provide an indication only of the industry which is determined to have produced the goods which are exported or imported. This is undertaken by allocating AHECC items to the ANZSIC industry which is considered to have ultimately produced the commodity. Any agricultural commodity that has undergone any form of processing is, under the ANZSIC classification system, coded to the manufacturing industry.
Therefore while raw cows' milk production is classified to the Agricultural ANZSIC Class 0130 'Dairy cattle farming', the sale of pasteurised liquid whole milk would be classified to the Manufacturing ANZSIC Class 2121 'Milk and cream processing'.
In addition, any exported items that have confidentiality restrictions on the publication of value details are not classified to their industry of origin, but are instead included in the category 'Other industries'. In 1997-98, no exported commodity items that would be allocated to agriculture under the 'Industry of origin' classification had confidentiality restrictions, but this is not always the case.
Table S4.2 shows data for exports emanating from agriculture on an 'Industry of origin' basis, and data for production from agricultural holdings classified to those ANZSIC industries. The production data shown for each Agricultural class relate to the total value of agricultural production from holdings that are primarily involved in the activity to which the class relates. For example a holding that is primarily involved in vegetable farming would be classified to the ANZSIC Class 0113, 'Vegetable growing'. The value of production data for that holding which is attributed to Class 0113 includes the value of all agricultural commodities produced by that holding, which may include commodities such as livestock, fruit and other non-vegetable crops. However, the export data for that holding would be classified on an 'Industry of origin' basis and any non-vegetable commodities exported from that holding would be classified to a different ANZSIC class.
S4.2 VALUE OF AGRICULTURAL COMMODITIES PRODUCED AND EXPORTED, by Industry - 1997-98(a)
ANZSIC
industry class
Description
Agricultural production(b)
$ '000
Exports (c)
$ '000
0111Plant nurseries
506,866
5,624
0112Cut flower and flower seed growing
150,830
24,325
0113Vegetable growing
1,803,250
244,149
0114Grape growing
917,041
82,438
0115Apple and pear growing
448,910
62,267
0116Stone fruit growing
154,176
24,479
0117Kiwifruit growing
5,135
2,892
0119Fruit growing n.e.c.
1,030,860
203,301
0121Grain growing
4,845,010
4,556,510
0122Grain-sheep and grain-beef cattle farming
4,069,771
-
0123Sheep-beef cattle farming
1,168,076
-
0124Sheep farming
1,663,012
2,476,956
0125Beef cattle farming
2,576,120
352,348
0130Dairy cattle
3,472,001
-
0141Poultry farming (Meat)
1,045,567
1,156
0142Poultry farming (Eggs)
386,942
2,524
0151Pig farming
662,170
1,065
0152Horse farming (d)
19,646
63,813
0153Deer farming (d)
810
-
0159Livestock farming n.e.c.
61,204
34,215
0161Sugar cane growing
1,273,127
3
0162Cotton growing
1,420,464
(e)-
0169Crop and plant growing n.e.c.
330,960
93,770
Total
28,011,946
8,231,835
(a) The value of production of a business is classified to an industry based on the predominant activity of that business. Export data are classified to the most likely industry to have produced the commodity.
(b) Agricultural production is the Gross Value of Agricultural Commodities Produced (GVACP), and is the value measured at the metropolitan market in each State or Territory.
(c) Exports are valued on a free on board (f.o.b.) basis which includes the value of distribution and other costs incurred between the farm and the point of export.
(d) The sale of horses and deer is out of scope for VACP. The values of Class 0152 and Class 0153 come from valuing crops and other livestock sales for holdings allocated to the respective industries.
(e) The export of cotton lint is not classified to subdivision 01 Agriculture, but to subdivision 02 Services to Agriculture, Hunting and Trapping, Class 0211 'Cotton Ginning'.
Source: ABS data available on request, Value of Agricultural Production, 1997-98; International Merchandise Trade, 1997-98.
Table S4.2 suffers from the same limitations as the data in table S4.1, in that a run-down of stocks can influence export levels and only direct agricultural exports are included. It is important to realise that the production and export data in tables S4.1 and S4.2 are derived from the same source, but that table S4.2 is classified on the basis of industry rather than commodity.
Balance of payments exports data
The balance of payments (BOP) exports data are based on international trade statistics, adjusted where necessary for timing, coverage, classification and valuation in order to meet the change of ownership conventions and classification requirements contained in the international statistical standards for BOP statistics. For example, wool exported to stockpile abroad before being sold will be excluded from the BOP when shipped, but included when sold. The ABS publication Balance of Payments and International Investment Position, Australia, Concepts, Sources and Methods 1998 (5331.0) provides a detailed description of balance of payments methods.
The broadest level commodity breakdown for general merchandise goods credits (exports) shown in BOP is 'Rural' and 'Non-rural', followed by more detailed commodity dissections within those groupings. Allocation to these groupings is largely in terms of Section(s) or Division(s) of the Standard International Trade Classification (SITC). This commodity breakdown was adopted by the ABS in the early 1960s in response to user demand.
S4.3 RURAL MERCHANDISE EXPORTS, Balance of Payments Basis(a) - 1997-98
Description
$m
Rural goods(b) -
- Meat and meat preparations
3,731
- Cereal grains and cereal preparations
5,094
- Wool and sheepskins
4,020
- Other rural
9,285
Total
22,130
(a) Exports are valued on a free on board (f.o.b.) basis which includes the value of distribution and other costs incurred between the farm and the point of export.
(b) For confidentiality reasons, excludes sugar, sugar preparations and honey.
Source: International Trade in Goods and Services, Australia (5368.0).
The category 'rural goods' is broad, and attempts to provide an indication of those exports most closely associated with the agriculture, forestry and fishing industries. For example, while meat and meat preparations, cereal preparations, canned fruit salad and timber boards are all classified as 'rural goods', beverages (including wine) are excluded. Non-rural exports, therefore, can include agricultural production embedded in other products. Because of this, and because of different valuation bases, BOP and production data cannot be directly compared.
Input-output based data
Input-output tables show the flows of inputs into and outputs from each industry for a country's entire production system for a given period. In doing this, input-output tables identify which goods and services are produced by each industry and how they are used (for example goods and services used in the production of more goods and services, or goods and services consumed by final consumers). The tables are based on the principle that the value of the output of each industry can be expressed as the sum of the values of all inputs to that industry, including any profits made. All exports data used in input-output analysis undergo some transformation, including conversion from an f.o.b. basis to a basis of 'basic prices' (for agriculture, basic prices are those received at the 'farm gate'). This has the effect of removing transport and distribution margins, and product taxes, from the export values so that the values are consistent with those received by producers. Similarly, agricultural output is also valued at basic prices in input-output tables.
Input-output tables are produced using the Input-Output Industry Classification (IOIC) and the Input-Output Product Classification (IOPC). These classifications have been specifically developed for the compilation and the application of Australian Input-Output tables. Additional information on input-output tables can be found in Australian National Accounts: Input-Output Tables (5209.0)
Value of exports from an industry
Input-output tables provide a means of tracing flows of goods and services step by step through the production process, and this information can be used to calculate the contribution made by various industries to the final value of a commodity. It is therefore possible to derive the value of the output from the agricultural industry which is embedded in products produced by other industries, and therefore to derive the value of agricultural output contained in exports of these products. This is illustrated in table S4.4.
S4.4 INPUT-OUTPUT APPROACH: VALUE(a) of AGRICULTURAL OUTPUT PRODUCED AND EXPORTED, By Industry - 1997-98
IOIC Industry Class
Australian production(b)
$m
Direct exports from the agricultural industry
$m
Share of production
%
Agricultural output embedded in indirect
exports (c)
$m
Share of
production
%
Total exports of agricultural
output
$m
Share of
production
%
0101 Sheep
3,708
1,395
37.6
888
23.9
2,283
61.6
0102 Grains
6,267
4,043
64.5
1,305
20.8
5,348
85.3
0103 Beef Cattle
3,783
312
8.3
1,906
50.4
2,218
58.6
0104 Dairy cattle
3,002
0
0
1,025
34.1
1,025
34.1
0105 Pigs
601
1
0.1
267
44.4
268
44.6
0106 Poultry
1,484
2
0.1
428
28.8
430
29.0
0107 Other agriculture
9,738
857
8.8
2,051
21.1
2,908
29.9
01 Total agriculture
(d)28,583
6,610
23.1
7,871
27.5
(d)14,481
50.7
(a) All values are at basic prices (i.e. farm gate) which remove distribution costs, including commodity taxes, associated with sale or export of the product.
(b) Includes the value of livestock used for breeding purposes. Also includes an estimate of the value of production by private households for own consumption.
(c) Estimated using total requirements coefficients contained in 1994-95 input-output tables.
(d) Derived by summing the components.
Source: ABS data available on request, Input-Output Section.
Table S4.4 shows that $7.9b of agricultural output is exported indirectly through the export of processed products. For example, much food, which is a basic output of agriculture, requires some processing before being exported. From table S4.4 it can be seen that indirect exports from the beef cattle industry ($1.9b) are more than direct exports ($312b). On the other hand, direct exports of grains ($4.0b) are more than indirect exports from the grains industry ($1.3b).
From table S4.4 it can be established, using the input-output approach, that the total value of agricultural production exported directly or indirectly in 1997-98 was $14.5b. It is important to realise that a number of factors, such as run-down of stocks, weather conditions and changes in the availability of export markets, mean that this is a short period on which to make long term judgements on the overall level of agricultural output exported.
In addition, certain basic assumptions apply when analysing both direct and indirect exports estimates calculated using the input-output approach. These are:
• Commodities exported from a particular industry consist of the same quality and content as those sold on the domestic market. It follows that, if the proportion of agricultural output embedded in an exported processed food product is significantly different to the average for that product, any estimate of the value of agricultural output exported will be deficient to that extent.
• Export prices are similar to domestic prices for the output of a particular industry. It follows that, if prices paid for output which is indirectly exported are significantly higher than domestic prices, the value of output exported indirectly would be underestimated.
Proportion of industry output exported
Estimating the proportion of total agricultural output which is exported adds further complexities.
The simplest approach would be to use the value of production shown in table S4.4 as the denominator. Doing so provides an estimate of approximately 51% for 1997-98. This estimate has been calculated without making any adjustments for agricultural output that is subsequently consumed within the agricultural industry. If such adjustments are made, a similar estimate is derived because, using the input-output approach, the reduction in the value of agricultural output is almost exactly offset by a proportional reduction in the value of indirect exports. However, for certain analyses it may be appropriate to deduct from the estimate of value of production the value of livestock produced for breeding purposes (on the basis that this production is not available for sale until the livestock is slaughtered) and the value of commodities produced for own account consumption (on the basis that this production is not available to the market). If both of these adjustments are made, the proportion of agricultural output that is exported under the input-output approach rises to about 56%.
Embedded commodities approach
This approach estimates the volumes of agricultural commodities contained in indirect exports using factors which calculate the percentage of raw product contained in various processed goods. These volumes are then added to the volumes of direct exports of agricultural commodities. The value of exports for any commodity is derived by multiplying the gross unit value received by farmers for that commodity by the volume of product exported.
When this method is used, production estimates need to be adjusted to remove production used within the agriculture industry, in order to derive the denominator necessary to calculate the proportion of agricultural output that is exported. The denominator can also be adjusted to take account of the value of livestock produced for breeding purposes and commodities produced for own-account consumption. Using this approach, the Australian Bureau of Agricultural and Resource Economics (ABARE), has estimated that the proportion of agricultural output exported in 1997-98 was approximately 65%.
Conclusion
Analysis of data about the exports of agricultural commodities requires an understanding of the concepts, classifications and methodology.
This article illustrates that the value of agricultural output finally exported is very much influenced by the value of agricultural output included in processed exports. For example, table S4.4 shows that, using the input-output approach, the percentage of output exported from the beef cattle industry increases from 8% (direct exports), to 58% (direct and indirect). Equally importantly, this article shows that the assumptions used in defining agricultural output and exports, and the methodologies used to derive these estimates, can also affect results, and users need a basic understanding of these methodologies in order to interpret the data effectively.
Given the variety of methodologies used to estimate exports and production, and the assumptions required to use these methodologies, any estimate of the proportion of agricultural output which is exported will only be an approximation, and should not be interpreted as an exact result. Finally, while this article presents some illustrative estimates in respect of 1997-98, agricultural production and exports of agricultural commodities can vary from year to year, and users are cautioned about making firm conclusions based on only one year's data.
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4618.0 - Water Use on Australian Farms, 2007-08 Quality Declaration
Previous ISSUE Released at 11:30 AM (CANBERRA TIME) 26/05/2009
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PASTURES AND CROPS IRRIGATED
Australia
Australian irrigating agricultural businesses applied 18% less irrigation water to agricultural land in 2007-08 than the previous year. The area irrigated nationally decreased 4% to 1,851 thousand hectares.
The rice industry showed the effects of dry conditions and limited irrigation water with only 23 rice producers using 27 gigalitres of irrigation water, a drop of 89%. This drop in application of irrigation water follows the 81% reduction in 2006-07.
Cotton growers faced similar conditions in 2007-08 and applied 309 gigalitres of irrigation water to 58 thousand hectares. This was in comparison to the 868 gigalitres used for irrigation and 134 thousand hectares irrigated in 2006-07.
State/Territory
While in 2006-07 cotton growers were the primary users of irrigation water in New South Wales, accounting for 26% of irrigation water use, in 2007-08 the major irrigators were irrigating other cereals for grain or seed, using 34% of all irrigation water applied. The area of cotton crop irrigated in New South Wales fell 62 thousand hectares (63%).
The volume of water applied to grapevines nationally dropped from 639 gigalitres in 2006-07 to 517 gigalitres in 2007-08. Victoria accounted for over half of this reduction, with water used on grapevines declining to 153 gigalitres. Pasture, cereal and other crops for grazing used the majority of Victoria's irrigation water (50%), irrigating 221 thousand hectares at an application rate of 3.0ML/ha.
Whilst reporting a downturn in area under crop, sugar cane producers continued to be the largest irrigator in Queensland, using 45% of the state's irrigation water at an application rate of 4.5ML/ha. Queensland saw a large increase in irrigation of other cereals for grain or seed (327 gigalitres).
In 2007-08, pasture, cereal and other crops used for grazing was the major use of irrigation water in South Australia, Western Australia and Tasmania, accounting for 32%, 35% and 62% of irrigation water applied in each state respectively.
Grapevines were the second largest irrigation water consumers in South Australia (23%) in 2007-08. The second largest irrigators in Western Australia were fruit tree, nut tree, plantation or berry fruit producers, irrigating 67% of the area of these crops, at an application rate of 4.7ML/ha. In Tasmania, 44 gigalitres of water was applied to vegetables for human consumption or seed, the second largest irrigated agricultural area in the state at 14 thousand hectares.
Irrigation of fruit trees, nut trees, plantation fruit or berries in the Northern Territory continued to decline from 13 gigalitres in 2006-07, to 7 gigalitres in 2007-08.
Murray-Darling Basin
The area of agricultural land irrigated in the Murray-Darling Basin continued to decrease in 2007-08, to 958 thousand hectares, with 30% less irrigation water being applied than in 2006-07. These drops follow the declines of 2006-07 where the area irrigated fell 33%, and the volume of irrigation water applied fell 40%.
In contrast, irrigation water use outside the Murray-Darling Basin decreased much less in both years, down 1% between 2006-07 and 2007-08, following on from a decline of 6% between 2005-06 and 2006-07.
All of Australia's rice producers were located in the Murray-Darling Basin in 2007-08, and the impact of limited irrigation water was seen at the national level. Similarly, 92% of Australia's cotton growers are located in the region, irrigating 81 thousand hectares (60%) less land than in 2006-07.
In 2007-08, other cereals for grain or seed accounted for the highest proportion of irrigation water in the region (26%) followed by pasture, cereal and other crops for grazing (21%) and grapevines (14%).
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1301.0 - Year Book Australia, 2008
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Contents >> Mining
MINING
Mining broadly relates to the extraction of minerals occurring naturally as solids such as coal and ores, liquids such as crude petroleum, or gases such as natural gas. Activities carried out at or near mine sites as an integral part of mining operations, such as dressing or beneficiation of ores or other minerals, are included. Natural gas absorption and purifying plants are also included. However, the first stage processing of minerals and mineral extracts, while closely related to the mining industry, is included as part of the manufacturing industry.
Australia continues to rank as one of the world's leading mining nations with substantial identified resources of major minerals and fuel close to the surface. In 2006 it had the world's largest economic demonstrated resources of brown coal, lead, mineral sands (rutile and zircon), nickel, tantalum, uranium and zinc.
Australia was the largest producer of bauxite, mineral sands (ilmenite, rutile and zircon) and tantalum in 2006. It was also one of the largest producers of uranium, iron ore, lead, zinc and nickel.
The contribution of the mining industry to Australia's gross domestic product remained around 4-5% over the period 1996-97 to 2004-05 but increased to 7% in 2005-06. The mining industry is Australia's second largest export earner (after manufacturing), accounting for 37% of the total value of exports in 2006-07, principally from the metal ore and coal mining industries.
This chapter concludes with the article Sustaining the mineral resources industry - overcoming the tyranny of depth.
This section contains the following subsection :
Mineral, oil and gas resources
Expenditure on mineral and petroleum exploration
Mining industry
Production and trade of minerals
Profile of major minerals, oil and gas
Mining Bibliography
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} | cccc_CC-MAIN-2013-20 | Database
ProMEX: a mass spectral reference database for proteins and protein phosphorylation sites
Jan Hummel1, Michaela Niemann1, Stefanie Wienkoop1, Waltraud Schulze1, Dirk Steinhauser1, Joachim Selbig2, Dirk Walther1 and Wolfram Weckwerth1,2*
Author Affiliations
1 Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14424 Potsdam, Germany
2 University of Potsdam, Institute of Biochemistry and Biology, c/o MPI-MP, Am Mühlenberg 1, 14424 Potsdam, Germany
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BMC Bioinformatics 2007, 8:216 doi:10.1186/1471-2105-8-216
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2105/8/216
Received:30 January 2007
Accepted:23 June 2007
Published:23 June 2007
© 2007 Hummel et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
In the last decade, techniques were established for the large scale genome-wide analysis of proteins, RNA, and metabolites, and database solutions have been developed to manage the generated data sets. The Golm Metabolome Database for metabolite data (GMD) represents one such effort to make these data broadly available and to interconnect the different molecular levels of a biological system [1]. As data interpretation in the light of already existing data becomes increasingly important, these initiatives are an essential part of current and future systems biology.
Results
A mass spectral library consisting of experimentally derived tryptic peptide product ion spectra was generated based on liquid chromatography coupled to ion trap mass spectrometry (LC-IT-MS). Protein samples derived from Arabidopsis thaliana, Chlamydomonas reinhardii, Medicago truncatula, and Sinorhizobium meliloti were analysed. With currently 4,557 manually validated spectra associated with 4,226 unique peptides from 1,367 proteins, the database serves as a continuously growing reference data set and can be used for protein identification and quantification in uncharacterized biological samples. For peptide identification, several algorithms were implemented based on a recently published study for peptide mass fingerprinting [2] and tested for false positive and negative rates. An algorithm which considers intensity distribution for match correlation scores was found to yield best results. For proof of concept, an LC-IT-MS analysis of a tryptic leaf protein digest was converted to mzData format and searched against the mass spectral library. The utility of the mass spectral library was also tested for the identification of phosphorylated tryptic peptides. We included in vivo phosphorylation sites of Arabidopsis thaliana proteins and the identification performance was found to be improved compared to genome-based search algorithms. Protein identification by ProMEX is linked to other levels of biological organization such as metabolite, pathway, and transcript data. The database is further connected to annotation and classification services via BioMoby.
Conclusion
The ProMEX protein/peptide database represents a mass spectral reference library with the capability of matching unknown samples for protein identification. The database allows text searches based on metadata such as experimental information of the samples, mass spectrometric instrument parameters or unique protein identifier like AGI codes. ProMEX integrates proteomics data with other levels of molecular organization including metabolite, pathway, and transcript information and may thus become a useful resource for plant systems biology studies. The ProMEX mass spectral library is available at http://promex.mpimp-golm.mpg.de/ webcite.
Background
Large-scale protein analysis is closely linked to mass spectrometric techniques. Peptide fragmentation in an ion trap mass spectrometer (IT-MS) is one of the most used approaches for protein identification in complex samples [3]. One such technique, referred to as "shotgun proteomics", can be exploited for rapid screening and – in combination with further fractionation – comprehensive qualitative protein identification in complex samples [4,5]. Proteins are extracted from tissues and analysed after separation on gel electrophoresis or directly via tryptic digestion. Thousands or tens of thousands of peptide mass spectra are generated in a typical analysis. For high throughput identification, these mass spectra can be matched against theoretical amino acid sequences derived from the annotated or predicted proteome of an organism. However, in many of the available algorithms, only the appearance of specific mass fragments in a CID-MS, but not their intensity distribution is considered specifically, because it can not easily be predicted from the amino acid sequence of peptides alone. Therefore, the approach of establishing a mass spectral reference library as used routinely in metabolic and metabolite profiling by gas chromatography coupled to mass spectrometry appears promising [6-8]. We investigate here the utility of a mass spectral reference library by implementing a database consisting of 4,557 manually validated tryptic peptide product ion spectra of divers plant proteins generated by LC-IT-MS and mass fragment intensity correlation search for protein identification.
Construction and content
Creation of the mass spectral library
A library of 4,557 manually validated peptide/phosphopeptide product ion spectra from approximately 330,000 collision-induced dissociation (CID) fragment spectra analysed in various LC-MS/MS analyses from recent studies was generated [4,5,9-12]. These CID spectra were annotated with Sequest and Mascot using the filter and search criteria as described in these studies [4,5,9-12]. In addition to the filtering, the resulting spectra were further validated manually using the SILVER web application [13].
ProMEX database system
ProMEX was designed as a web-based service in a Linux/Apache environment using Perl-CGI for HTML page generation. A Microsoft SQL Server 2005® was utilised as the relational database backend for storing the library spectra as well as the query spectra uploaded by the user. Algorithms for comparing spectra to identify matching hits were implemented using the Common Language Runtime (CLR) .Net framework using the C# programming language. Library mass spectra as well as user-uploaded query spectra are saved using a User-defined Data Type (UDT) in the database permitting us to calculate the score values directly within the database by using standard T-SQL to access the spectra. Using indices to select matching library spectra according to a given precursor ion mass and a charge state of a user-submitted product ion spectra and taking advantage of the server's memory management system, we achieved high performance and efficient memory usage.
Because of the server's limitation of the UDT size to 8,000 Bytes, it was necessary to limit the product ion spectra to maximally 1,000 fragment peaks each (1,000 peaks with 4 Byte m/z and 4 Byte intensity each). Upon evaluating the intensity distribution (Figure 1), we assessed the dependence of the identification process on the level of noise removal; i.e. peaks with very low intensity. Applying the receiver operating characteristic (ROC) analysis, peptide identification accuracy was observed to be robust with regard to noise filtering and a level of 2% relative peak intensity was chosen as a conservative threshold for noise removal (Figure 2).
Figure 1. Peak intensity distribution from product ion spectra. 70% of all fragment peaks have a relative intensity less or equal 0.02. The peak on the right hand side originates from the prior scaling of all spectra to a maximum peak intensity of 1.
Figure 2. Assessment of the effect of noise removal on the identification performance illustrated by the receiver operating characteristic (ROC). The identification rate is robust against different levels of peak noise filters up to 10%. We decided to use a conservative noise removal level of 2%. Recall (true positives) reflects the number of correctly identified peptides based on SEQUEST search, whereas 1 specificity corresponds to all ProMEX peptide identifications which did not match to the SEQUEST identifications. As a comparison, results from using the Euclidean distance are also included which proved to be inferior to the dot product.
As described in [2], the performance of peak-list comparison is influenced by several factors, most importantly by the choice of the distance measurement itself. Here, we found a modified dot product [7] distance measure
to perform best on the mass spectra used in this study where x and y denote the two spectra to be compared, are the mass-charge ratios and are the normalised intensity values of the i-th peak in the spectrum x, likewise for spectrum y and index k. A and B are the total number of peaks in the spectra x and y, respectively. The term
is a windowed, linear weighting factor accounting for the match accuracy with regard to mass-charge ratio difference of fragment peaks xi and yk where a corresponds to the fragment ion mass tolerance specified by the user. The same strategy was applied in a recent mass spectral match algorithm [2]. Because all peaks are normalised to
where I refers to the raw intensities of a given spectrum with l peaks including only those peaks above the noise threshold discussed above, D is always within the range of (0, 1) with values closer to zero indicating better matches between two spectra. The dot product distance is calculated looping through both MS/MS spectra x and y under comparison sorted in ascending order according to their m/z ratios and using a reference pointing to the next fragment peak for a potential fragment match for each peak list. In case the mass difference between those referenced peaks is less than or equal to the fragment ion mass tolerance a, both referenced peaks are used in Eq. 1 with their respective intensities. Otherwise a zero-intensity peak is "matched" to that referenced peak. In the first case, both peak reference pointers are incremented simultaneously, whereas only the index pointing to the peak with the smaller m/z ratio is incremented in the latter case. We iterate that loop until all peaks are checked off.
To balance flexible process parameterisation and performance of mass spectra identification, we limited the user interface to a subset of parameters (Figure 3):
Figure 3. Screenshot of the ProMEX user interface. Input can be inserted into the textbox or uploaded as file using the file selection dialog.
Precursor ion mass tolerance defines a window for considering two distinct MS/MS spectra coming from the same parent ion;
Fragment ion mass tolerance defines a window for considering two ion peaks from different peak lists as identical;
Threshold defines a threshold value to ignore mass spectra hits above this score value; i.e. spectra are not considered as matching.
ProMEX is able to handle uploads of merged MS/MS text files (dta or mgf) [14] or mzData http://psidev.sourceforge.net/ms/ webcite standard http://psidev.sourceforge.net/ms/xml/mzdata/mzdata.xsd webcite. User-uploaded data are verified and parsed using Perl, and the spectra submitted as queries to the database. Spectra contained in the library are sorted according to their matching score ignoring hits above a given score threshold value. The hit list of identified proteins is further augmented by information contained in the database including peptide annotations, information regarding the biological experiment, instrument settings as well as links to online resources of the National Center for Biotechnology Information (NCBI), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Comprehensive Systems-Biology Database (CSB.DB) (Figure 4).
Figure 4. Screenshot of the result page showing four identified peptides associated with the candidate hit protein At1g13440 which was tagged in the sample by 8 submitted fragment spectra. For visual inspection of the spectra match, a north-south-plot of the library versus query spectra is shown below.
Considering widespread use of the BioMOBY http://www.biomoby.org/ webcite environment in web-based bioinformatics and as a common framework for biological resources, we implemented a service getTrypticPeptideSequenceByAGI that returns a list of experimentally measured tryptic peptides for Arabidopsis genes identified by their Arabidopsis Genome Initiative (AGI) code.
To obtain maximal performance and limit temporary disk space usage, all uploaded spectra, results, and session information will be deleted within 24 hours after transmittal. Using current standard hardware equipment, a typical ProMEX analysis of a 196 MB merged dta file with >30,000 MS/MS spectra is completed within approximately 13 minutes.
Utility and Discussion
Mass spectral library and experimental metainformation
A library containing 4,557 measured peptide MS/MS spectra from 1,367 distinct proteins represented by 4,226 peptides including the corresponding experimental information was created. In case of replicated fragment spectra contained in the database – a small fraction of all spectra, only the best matching spectrum is returned. In addition to existing algorithms which use mass spectral library searches such as GPM X!Hunter http://www.thegpm.org webcite or SpectraST [6], we attempted to link the identification process to experimental metainformation and quantification. The latter is facilitated by the possibility to upload complete LC-MS runs in mzData format and to search them against the database. The result of peptide/protein identifications is accompanied by a semiquantitative measure called spectral count giving the possibility to estimate the relative abundance of proteins in the sample [4,15] (see also below). Furthermore, we optimised the database search to allow analyses of large file sizes (up to 200 Mbyte and more, see below) which to our knowledge is not yet implemented in other databases. The peptide spectra presently stored in the database were mainly derived from Arabidopsis thaliana, Medicago truncatula, Chlamydomonas reinhardii and Sinorhizobium meliloti, acquired in 18 experiments through fragmentation with LCQ, LTQ or Orbitrap mass spectrometers [5,9,10,12].
ProMEX mass spectral library search of unknown samples
For the analysis of protein identification efficiency of ProMEX, LC/MS analyses were processed by both ProMEX and SEQUEST http://fields.scripps.edu/sequest/ webcite. The disadvantage of ProMEX may lie in the use of an inherently incomplete dataset compared to a genomic database. On the other hand, a mass spectral library consisting of experimentally observed and validated spectra as implemented in ProMEX can be expected to provide clear advantages over genome-based prediction of mass spectra [6].
To set a suitable default cutoff threshold for the search algorithm implemented in ProMEX, two different distance measures – the dot product and Euclidean distance – were compared by searching mzData files of LC-MS analyses against the ProMEX mass spectral library. The results were compared to the SEQUEST result file ("true positives"). Figure 2 illustrates the gain of correct predictions by the dot product in comparison to the Euclidean distance. Because of the better performance, the dot product distance was chosen and the default threshold value was set to 0.5. In Figure 5, the resulting peptide identification output was examined for the number of false hits against true positive peptide hits (list of peptides identified by SEQUEST) as a function of threshold score for the dot product distance. Using the default threshold, the false peptide detection rate was found to be less than 1%, while the number of false negatives reached a level of 25% in our dataset.
Figure 5. Comparison of peptide identification rate as a function of match score. True positive identifications are all matches found by SEQUEST and ProMEX. False positives are defined as residual peptide identifications by ProMEX which did not match to the SEQUEST hits. The default threshold value for ProMEX was set to 0.5 according to this diagram.
For 86 proteins, the list of protein identifications was identical in both systems. From subsequent searches, it became clear that the specificity for peptide identification increases with ProMEX because fragment intensity distributions in product ion spectra are taken into account as an additional parameter.
Very importantly, spectra which are not assigned by SEQUEST or MASCOT can easily be included in the ProMEX mass spectral library as unknowns. This allows recognizing these spectra again in new analyses which is not possible by using algorithms based on genome-derived theoretical mass spectra. Another potential advantage of a mass spectral reference database lies in the identification of phosphorylated peptides which usually give very ambiguous results in genome-based database searches [11,16]. For proof of concept, we included CID-MS of synthetic phosphopeptides in the ProMEX reference database which were based on in vivo and in vitro protein phosphorylation sites detected in Arabidopsis thaliana samples [11,17-19]. Subsequently, we were able to identify these phosphopeptides in a set of different plant samples. Several of these peptides were not identified reproducibly with genome-based search algorithms like SEQUEST.
Protein quantification using ProMEX
ProMEX provides a quantitative estimate for the abundance of a protein/peptide in the sample. In case a complete LC/MS run is uploaded in mzData-format the ProMEX result table has an entry for each protein/peptide how often it was identified. This measure is similar to spectral count (SC) [4,15] and has been shown to be a valuable parameter for semi-quantitative mass spectrometry analysis.
Identifying bottlenecks and limits
Setting the threshold too high or uploading LC/MS runs with large numbers of mass spectra results in computation times proportional to the number of submitted spectra in parallel to an overwhelming number of matches which is difficult to handle using a web server and HTMLformatted output. It may also appear that implementing such a tool with high computational demands as a web-based service may not be the best choice and client-site applications may be more suitable. On the other hand, this approach requires only a web browser to be accessible for the research community, thereby facilitating access to large amounts of available reference data. Some of the shortcomings could be addressed by utilizing a computer cluster and parallelising the task of scoring or by limiting the allowed file upload size. However, data file sizes will likely increase in the future. Therefore, restricting to file size may not be a viable option. Another option might be to implement a Microsoft Windows binary for a local computer utilization.
The ProMEX library will be extended by the ongoing proteomic analyses. Considering quality assurance reasons, an automated upload facility is not yet intended. However, linking ProMEX to other databases with similar background in plant proteomics research as well as databases such as peptide atlas http://www.peptideatlas.org/ webcite is an ongoing project and greatly appreciated by the authors. Further, other groups are encouraged to submit their data directly to the ProMEX database curators for inclusion. In the future we aim to apply further quality algorithms to improve the library based on spectral replicate analyses.
Interconnecting different molecular levels through databases – a systems biology approach
As described earlier, ProMEX provides also metainformation for every mass spectrum, thereby allowing the user to trace back the experimental origin of the protein appearance. Additionally, the protein identification is linked to transcript and metabolite data via CSB.DB and the Metabolome database (GMD) [1,20]. Gene expression databases such as AtGenExpress can be directly searched with AGI codes of identified proteins looking for correlations with other genes. Metabolite data together with experimental data and reaction pathways are linked automatically via the AGI code of the identified protein. By accessing this interconnected information network data interpretation becomes more convenient. Even more important is that due to the unbiased nature of such large-scale data sets the immediate understanding is complicated. Therefore data storage in a useful way is in our experience indispensable to allow subsequent interpretation in the light of new biochemical knowledge. Thus, the data have to be made available for the community to revalidate, reconfirm or explore new information. These linked databases are probably one of the most important challenges for systems biology in the future.
Conclusion
Here we present the plant proteomics reference database ProMEX. The database consists of tryptic peptide/phosphopeptide fragmentation mass spectra and has the potential to include all different kinds of mass spectra as demonstrated with phosphorylation site mass spectra. Search algorithms are implemented which allow the identification of proteins/peptides based on mass spectral library matching. In case complete LC/MS runs are uploaded as mzData formats it is possible to obtain semiquantitative information in form of the cumulative sum of spectra per peptide and protein. The database allows text searches based on metadata like experimental information of the samples, mass spectrometric instrument parameters or unique protein identifier like AGI codes. ProMEX integrates proteomics data with other levels of molecular organization by linking the peptide-identification to metabolite, pathway, and transcript databases. Based on these capabilities we will exploit the search function of the database in future and extend the approach to metabolite spectra.
Availability and requirements
Project name: ProMEX
Project home page: http://promex.mpimp-golm.mpg.de/ webcite
Operating system(s): Available as web-based service, accessible via any web-browser
License: The service is freely available.
The BioMOBY web service getTrypticPeptideSequenceByAGI is listed in mobycentral under the creator bioinformatics.mpimpgolm.mpg.de.
The content of the peptide and experiment tables will be made available upon request either as mdf file for a Microsoft SQL Server Express database (freely downloadable) or as comma separated value (csv) file.
Authors' contributions
JH implemented the database and the search algorithms, and wrote parts of the manuscript. SW tested the service, validated the results and wrote parts of the manuscript. MN selected the mass spectra, assisted to set up the database and wrote parts of the manuscript. DS was involved in the design of the project. JS and DW supervised the project and wrote parts of the manuscript. WW conceived and initiated a mass spectral reference library for the investigation of experimental mass fragment intensity distributions and compound identification, designed the study, and wrote parts of the manuscript.
Acknowledgements
Jan Hummel is grateful to Björn Usadel and Dirk Haase for technical support regarding BioMOBY, and Witold E. Wolski for assistance with mass spectra comparisons. Finally, we want to thank the four anonymous reviewers for their kind and constructive help with this manuscript.
References
1. Kopka J, Schauer N, Krueger S, Birkemeyer C, Usadel B, Bergmuller E, Dormann P, Weckwerth W, Gibon Y, Stitt M, Willmitzer L, Fernie AR, Steinhauser D<EMAIL_ADDRESS>the Golm Metabolome Database.
Bioinformatics 2005, 21(8):1635-1638. PubMed Abstract | Publisher Full Text
2. Wolski W, Lalowski M, Martus P, Herwig R, Giavalisco P, Gobom J, Sickmann A, Lehrach H, Reinert K: Transformation and other factors of the peptide mass spectrometry pairwise peak-list comparison process.
BMC Bioinformatics 2005, 6(1):285. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
3. Washburn MP, Wolters D, Yates JR: Large-scale analysis of the yeast proteome by multidimensional protein identification technology.
Nat Biotechnol 2001, 19(3):242-247. PubMed Abstract | Publisher Full Text
4. Wienkoop S, Larrainzar E, Niemann M, Gonzalez E, Lehmann U, Weckwerth W: Stable isotope-free quantitative shotgun proteomics combined with sample pattern recognition for rapid diagnostics - a case study in Medicago truncatula nodules.
Journal of Separation Science 2006, 29:2793-2801. PubMed Abstract | Publisher Full Text
5. Wienkoop S, Glinski M, Tanaka N, Tolstikov V, Fiehn O, Weckwerth W: Linking protein fractionation with multidimensional monolithic RP peptide chromatography/mass spectrometry enhances protein identification from complex mixtures even in the presence of abundant proteins.
Rapid Communications of Mass Spectrometry 2004, 18:643-650. Publisher Full Text
6. Lam H, Deutsch EW, Eddes JS, Eng JK, King N, Stein SE, Aebersold R: Development and validation of a spectral library searching method for peptide identification from MS/MS.
Proteomics 2007, 7(5):655-667. PubMed Abstract | Publisher Full Text
7. Stein SE, Scott DR: Optimization and Testing of Mass-Spectral Library Search Algorithms for Compound Identification.
J Am Soc Mass Spectr 1994, 5(9):859-866. Publisher Full Text
8. Stein SE: An integrated method for spectrum extraction and compound identification from gas chromatography/mass spectrometry data.
J Am Soc Mass Spectr 1999, 10(8):770-781. Publisher Full Text
9. Weckwerth W, Wenzel K, Fiehn O: Process for the integrated extraction identification, and quantification of metabolites, proteins and RNA to reveal their co-regulation in biochemical networks.
Proteomics 2004, 4(1):78-83. PubMed Abstract | Publisher Full Text
10. Morgenthal K, Wienkoop S, Scholz M, Selbig J, Weckwerth W: Correlative GC-TOF-MS based metabolite profiling and LC-MS based protein profiling reveal time-related systemic regulation of metabolite-protein networks and improve pattern recognition for multiple biomarker selection.
Metabolomics 2005, 1(2):109-121. Publisher Full Text
11. Wolschin F, Weckwerth W: Combining metal oxide affinity chromatography (MOAC) and selective mass spectrometry for robust identification of in vivo protein phosphorylation sites.
Plant methods [electronic resource] 2005, 1(1):9. BioMed Central Full Text
12. Wienkoop S, Zoeller D, Ebert B, Simon-Rosin U, Fisahn J, Glinski M, Weckwerth W: Cell-specific protein profiling in Arabidopsis thaliana trichomes: identification of trichome-located proteins involved in sulfur metabolism and detoxification.
Phytochemistry 2004, 65(11):1641-1649. PubMed Abstract | Publisher Full Text
13. Elias JE, Gibbons FD, King OD, Roth FP, Gygi SP: Intensity-based protein identification by machine learning from a library of tandem mass spectra.
Nat Biotechnol 2004, 22(2):214-219. PubMed Abstract | Publisher Full Text
14. Eng JK, Mccormack AL, Yates JR: An Approach to Correlate Tandem Mass-Spectral Data of Peptides with Amino-Acid-Sequences in a Protein Database.
J Am Soc Mass Spectr 1994, 5(11):976-989. Publisher Full Text
15. Liu H, Sadygov RG, Yates JR 3rd: A model for random sampling and estimation of relative protein abundance in shotgun proteomics.
Anal Chem 2004, 76(14):4193-4201. PubMed Abstract | Publisher Full Text
16. Wolschin F, Weckwerth W: Methionine oxidation in peptides-a source for false positive phosphopeptide identification in neutral loss driven MS(3).
Rapid Commun Mass Spectrom 2006, 20(16):2516-2518. PubMed Abstract | Publisher Full Text
17. Wolschin F, Lehmann U, Glinski M, Weckwerth W: An integrated strategy for identification and relative quantification of site-specific protein phosphorylation using liquid chromatography coupled to MS2/MS3.
Rapid Commun Mass Spectrom 2005, 19(24):3626-3632. PubMed Abstract | Publisher Full Text
18. Glinski M, Romeis T, Witte CP, Wienkoop S, Weckwerth W: Stable isotope labeling of phosphopeptides for multiparallel kinase target analysis and identification of phosphorylation sites.
Rapid Commun Mass Spectrom 2003, 17(14):1579-1584. PubMed Abstract | Publisher Full Text
19. Glinski M, Weckwerth W: Differential multisite phosphorylation of the trehalose-6-phosphate synthase gene family in Arabidopsis thaliana - A mass spectrometry-based process for multiparallel peptide library phosphorylation analysis.
Mol Cell Proteomics 2005, 4(10):1614-1625. PubMed Abstract | Publisher Full Text
20. Steinhauser D, Usadel B, Luedemann A, Thimm O, Kopka J: CSB.DB: a comprehensive systems-biology database.
Bioinformatics 2004, 20(18):3647-3651. PubMed Abstract | Publisher Full Text | v0 |
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} | cccc_CC-MAIN-2013-20 | Research article
Preclinical students’ experiences in early clerkships after skills training partly offered in primary health care centers: a qualitative study from Indonesia
Doni Widyandana1*, Gerard Majoor2 and Albert Scherpbier2
Author Affiliations
1 Skills Laboratory and Department of Medical Education, Faculty of Medicine, Gadjah Mada University, Farmako Street no 1, Sekip Utara, Jogjakarta, 55281, Indonesia
2 Institute for Education, Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 60, 6229ER, Maastricht, The Netherlands
For all author emails, please log on.
BMC Medical Education 2012, 12:35 doi:10.1186/1472-6920-12-35
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6920/12/35
Received:7 July 2011
Accepted:13 April 2012
Published:28 May 2012
© 2012 Widyandana et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Students may encounter difficulties when they have to apply clinical skills trained in their pre-clinical studies in clerkships. Early clinical exposure in the pre-clinical phase has been recommended to reduce these transition problems. The aim of this study is to explore differences in students' experiences during the first clerkships between students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by early clinical experiences (ECE).
Methods
Thirty pre-clinical students trained clinical skills exclusively in a skills laboratory; 30 peers received part of their skills training in PHC centers. Within half a year after commencing their clerkships all 60 students shared their experiences in focus group discussions (FGDs). Verbatim transcripts of FGDs were analyzed using Atlas-Ti software.
Results
Clerkship students who had participated in ECE in PHC centers felt better prepared to perform their clinical skills during the first clerkships than peers who had only practiced in a skills laboratory. ECE in PHC centers impacted positively in particular on students’ confidence, clinical reasoning, and interpersonal communication.
Conclusion
In the Indonesian setting ECE in PHC centers reduce difficulties commonly encountered by medical students in the first clerkships.
Keywords:
Clinical skills training; Early clinical experiences; Clerkships
Background
Medical institutions across the world have installed clinical skills laboratories to train students’ clinical skills [1]. Skills laboratory are used to train pre-clinical, clinical, and post graduate students, however in this study we will focus on skills training for pre-clinical students. In skills laboratories, pre-clinical students practice their clinical skills with peers, manikins and simulated patients. Skills laboratories provide a safe environment for practice and learning processes therein can be well structured [2].
However, recent studies have indicated that pre-clinical students entering their clerkships may encounter difficulties when they have to apply clinical skills learned, especially in patient contacts [3-5]. For example, students feel anxious when they have to perform diagnostic or therapeutic procedures with patients because they fear to harm patients [6].
To mitigate transition problems as described above, Dornan et al. [7] recommended inclusion of early clinical experiences (ECE) in the curriculum for pre-clinical students. ECE are supposed to improve preparation of pre-clinical students for their clinical rotations by immersing them in the reality of the clinical environment, by facilitating application of knowledge to clinical practice, and by improving students’ motivation for learning.
In principle ECE can be offered in any clinical setting, including facilities for primary, secondary and tertiary health care. With respect to primary health care (PHC) some studies have shown the relative advantage of PHC centers to provide opportunities for “hands on” practice by pre-clinical students, availability of general practitioners (GPs) to supervise the students, and with respect to the scope of PHC, which next to patient care also includes community health education [8,9]. We have shown the advantages of PHC for practical training of pre-clinical students, compared with secondary and tertiary hospital settings in the Indonesian context [10]. Furthermore, we demonstrated that pre-clinical students who were trained in PHC centers felt better prepared for entering their clerkships. [11]. For this study, the same students involved in the previous one were interviewed for this study after they had entered the clinical phase of their studies.
This study was undertaken to explore the effect of ECE in PHC on students’ performance in their first clinical clerkships. To this aim, we compared experiences of students exclusively trained in a skills laboratory and peers for whom part of their skills training was substituted by ECE in PHC centers.
Materials and Methods
This study was conducted with 60 pre-clinical students who were randomly sampled based on student numbers from a full class of 197 fourth year students of the Faculty of Medicine at Gadjah Mada University (FM-GMU) in Jogjakarta, Indonesia. These students were in the last semester of their pre-clinical studies since the medical curriculum of FM-GMU has a pre-clinical phase of 3.5 years (and a clinical phase of 1.5 years).
All 60 students sampled attended the regular clinical skills training program conducted in the skills laboratory. In duos or trios, 30 of these students were offered in addition an 11-day clinical skills training program in PHC centers (PHC-trained: PT). In the PHC centers PT students were supervised by GP’s who had been trained to become aware of the standard procedures for clinical skills as taught in FM-GMU’s skills laboratory. For their training, GP’s were invited to the skills laboratory to be introduced to the skills training program for pre-clinical students, to attend demonstrations of some skills trainings to instruct them how to train students on certain clinical skills.
In Indonesia, each sub-district has at least one PHC center (called Puskesmas). For example in 2000 in Jogjakarta a sub-district encompassed on average 35,278 people [12]. Each center hosts one or some doctors and paramedics, the latter including nurses, midwives, and pharmacists who may be involved in the teaching of pre-clinical students. The characteristics and the availability of PHC centers in the proximity of any medical school in Indonesia have led us to elect PHC centers to arrange for ECE for pre-clinical students, particularly to prepare these students for their clinical rotations [13]. Eleven PHC centers around Yogyakarta city were involved in this study. Each centre hosted groups of five or six students for 11 days dispersed over a five-week period. PT students were assigned to provide health services, patient management, and health promotion in communities. The other 30 students received for the same time span additional clinical skills training in the skills laboratory, facilitated by senior students trained to act as skills laboratory assistants (not PHC-trained: NPT). Those senior students had received intensive training from staff to assure that training given by them would be equal to that provide by skills laboratory teachers [14,15]. In tha additional program NPT students practiced (“doctor-to-patient”) communication, physical examination, procedural, and clinical reasoning skills in the laboratory with manikins, their peers and simulated patients.
After conclusion of their pre-clinical program students commenced their clinical rotations in the teaching hospital. Six months after commencing their clinical clerkships 30 PT and 30 NPT students were randomly invited to participate in Focus Group Discussions (FGDs). By that time, each student had completed three or four clerkships (out of the total of 14 clinical departments). During those periods, the students have opportunity to interact with real patients in particular clinical departments in the hospital, such as internal medicine, ENT, surgery, etc. Those students were randomly assigned to three focus groups of ten NPT or PT students, respectively.
FGDs were facilitated by the first author and a research assistant. Discussions were structured by the following questions: 1) What is your opinion about pre-clinical training in the skills laboratory as preparation for your clerkships?; 2) What difficulties did you encounter in your first clerkships?; 3) What is your opinion about ECE in PHC centers?; and 4) What is your impression of the performance of students in the other group, compared with the performance of your own group?”. Each focus group convened twice and each session continued until no more new items emerged.
FGDs were audiotaped and transcribed verbatim by a research assistant. Transcripts were analyzed using ‘inductive content analysis’ by three persons: the first author, a senior clinical supervisor from the teaching hospital, and a research assistant. The first author briefed his co-analyzers about the objective of the study and how to perform open coding using Atlas-Ti version 6. Each coder worked independently to analyze the texts and assigned codes in accord with the main categories (i.e., the four questions asked) and tried to distinguish sub-categories therein [16,17]. To finalize the coding process, a meeting was held with the three coders to discuss their results until consensus was reached. A written summary of the outcomes was distributed among all FGD participants for checking its validity and to solicit comments. Two research assistants met with groups of students and sent e-mails to those not attending to solicit their comments on the summary of the outcomes of the FGDs [18]. The design of this study was approved by the ethical committee of FM-GMU.
Results
All 60 students attended at least one of the FGD sessions. Each small group had two FGD sessions; the number of participants in each FGD sessions varied between six to twelve.
In the coding process 1,433 issues were identified in the 12 FGD transcripts. During the meeting of the coders consensus was reached that ten sub-categories could be identified, based on the issues most frequently emerging in each main category. In reporting on the outcomes of the FGDs the focus will be on issues mentioned eight times more frequently in either NPT or PT groups to condense presentation of the data in Table 1. Of course all issues mentioned were recorded and the most striking ones will be presented in the text.
Table 1. Issues referred to eight times more frequently in FGDs with NPT and PT students
In the checking process with FGD participants only minor comments were made with respect to weaknesses of training in the skills laboratory and expectations to practice in PHC centers during the pre-clinical studies. Those comments have been integrated in the final outcome of the FGDs.
Pre-clinical training in skills laboratory
NPT students more often made positive remarks about their preparation for interpersonal communication skills and had more suggestions for improvement of the skills training program than PT students. On the other hand, PT students more frequently recognized differences between standards for skills as taught in skills laboratory and the way those skills were performed in clinical practice. Both NPT and PT students frequently advised to include ECE in the pre-clinical curriculum.
“…the [ECE] program is good, because it improves students’ clinical performance [in early clerkship] … all [pre-clinical] students should have it from the beginning… (NPT/1/1)
Difficulties met in first clerkships
In this main category large differences emerged in the number of difficulties mentioned by NPT students as compared with PT students. NPT students brought up 202 different problems whereas PT students mentioned only 52. Difficulties to perform clinical skills were mentioned 74 times by NPT students versus 14 times by PT students. Difficulties mentioned by NPT students related to communication skills, including difficulties with interpersonal communication (e.g. greeting, showing empathy), taking an anamnesis, and understanding the local dialect. NPT students had also encountered more difficulties than PT students with physical examination (e.g., in ophthalmology and neurology) and recognizing pathological signs in patients (e.g., wheezing sounds, liver enlargement, and cardiac murmurs). Both NPT and PT students frequently mentioned that different guidelines given by distinct clinical supervisors negatively impacted on their performance in physical examination. With therapeutic skills NPT students had suffered most from differences between manikins and patients, e.g. with insertion of intravenous lines, minor surgery, tracheal intubation, urethral catheterization, and assisting at a delivery. More often than PT students NPT students mentioned to be afraid to harm the patient.
“…when we insert an intravenous catheter or perform minor surgery on a manikin, they [the manikins] are not screaming, but pediatric patients are always screaming from the beginning (…) Performing wound suturing on a patient feels really different, [real] skin is much more stretchy…” (NPT/3/1)
Beyond difficulties with the application of clinical skills, NPT more frequently than PT students referred to difficulties in adapting to the clerkship environment, cooperation with other health workers, and with clinical reasoning. NPT students also more often than PT students mentioned low confidence, confusion, and anxiety in front of patients. NPT students shared that they first needed to watch a clinical procedure before performing it themselves.
“…Yes, indeed, because we [PT students] had earlier [clinical] experiences, we are confident and courageous if the supervisors give us opportunities to perform clinical procedures on patients, like inserting an intravenous infusion, venapuncture, minor surgery, delivering a baby, etc. … It is different with our [NPT] colleagues who prefer to observe prior to performing…” (PT/3/1)
Both NPT and PT students frequently stated that insufficient supervision had been a problem in their first clerkships.
Students’ opinions on ECE for pre-clinical students
Based on their personal experiences, PT students commented extensively on their attachment in PHC centers. Based on their observations also students in NPT groups shared opinions on ECE. The main advantages of ECE identified by many PT students was the opportunity to practice clinical skills in a real health care setting. ECE made PT students aware of differences between the skills laboratory and a clinical environment. ECE had positively impacted on PT students’ motivation for learning, on their confidence, clinical reasoning, and interpersonal communication. (…) On the first day [of that clerkship] we [NPT students] observed our [PT] peers [performing that skill] and practiced with them. Then in the second day the supervisor would also allow us [NPT students] to perform that skill…” (NPT/1/2)
Both NPT and PT students recognized that the effectiveness of ECE depends on the quality of supervision in the PHC centers. In particular NPT students were worried that the range of clinical procedures which could be practiced in PHC centers would be too limited.
“…opportunities to observe various clinical procedures are more available in the Sardjito [teaching] Hospital than in Puskesmas [PHC centers]…” (PT/2/1)
In addition, NPT students recognized the advanced functioning of their PT peers in the first clerkships.
“…the way my peer [PT] student Tasya interacted with patients differed strongly from my [NPT student] performance … she looked ready [for practice] and knew what should she do with the patient… and I was not.” (NPT/1/1)
Discussion
This study shows that students who participated in ECE in PHC centers had less difficulties than NPT students with the transition from the pre-clinical phase of their studies to the clerkships. In the setting of Indonesia PHC centers proved to be suitable to offer ECE to medical students.
PT students and NPT students spent the same time on clinical skills training but in different contexts. PT students had the opportunity to interact with real patients in PHC centres. We assume this context to be more challenging for them than for NPT students who expanded their training in the skills laboratory setting. Even though the NPT group cannot be regarded as a true ‘control group’, we feel the advantages of ECE as experienced by the PT students clearly demonstrate the advantage of inclusion of such activities in the pre-clinical medical curriculum.
ECE impacted in particular on students’ confidence, clinical reasoning abilities and interpersonal communication skills. With respect to confidence, PT as well as NPT students (based on experience and observation of peers, respectively) frequently felt ECE had or would boost their confidence. As far as the NPT students are concerned this may be explained by their anxiety and lack of confidence when in their first clerkships they were confronted with patients. Apparently PT students had passed this stage in the PHC centers, where possibly close supervision by GP’s had supported them in overcoming this barrier.
Expectations with respect to improving clinical reasoning through ECE were far more frequently voiced by NPT students than by PT students. Perhaps expectations were set too high in the NPT students who had not participated in ECE, or the NPT students were highly impressed by the progress PT students had made with respect to clinical reasoning during ECE, often demonstrated by their ability to appropriately perform an anamnesis and to arrive at a diagnosis.
Opinions of students with respect to interpersonal communication yielded the most convincing data in support of ECE. NPT students mentioned frequently to feel they had been adequately prepared for interpersonal communication by training in the skills laboratory, but apparently this perception was challenged in practice because PT students expressed this opinion less frequently than their NPT peers. On the other hand, when PT students had entered the clerkships ECE had apparently erased their difficulties with interpersonal communication, whereas understandably those difficulties persisted in NPT students. This explanation is corroborated by the high frequency by which PT students advocated ECE for practicing interpersonal communication skills.
The reduction of difficulties encountered by PT students in their first clerkships as compared to those encountered by their NPT peers resulted in frequent recommendation by students from both groups to include ECE in the pre-clinical curriculum. It is remarkable that NPT students did not mention the advantage of having clinical experiences in the pre-clinical curriculum, although in the first clerkships they had been impressed by the advanced functioning of their PT peers. Perhaps their failure to see this advantage reflects the doubt whether attachments to PHC centers can adequately prepare them to perform advanced clinical procedures.
The data gathered from the students confirm the shortcomings of clinical skills training in the skills laboratory to prepare students for the clinical phase of their studies as also observed by others [2,19,20]. Perhaps offering more sessions with simulated patients and patients manifesting certain pathological conditions (e.g. liver enlargement, heart murmurs), if possible situated in a hospital environment might compensate for some of the shortcomings of skills laboratory training as experienced by NPT students (and thus also by regular students) [21]. Furthermore, involving clinical supervisors in the hospital in trainings with (simulated) patients may assist in further adjustment of clinical procedures as taught in the skills laboratory and as performed in practice. On the other hand, ECE seems more efficient to improve preparation of pre-clinical students for their clinical rotations than considerable expansion of the skills laboratory training program. This may be particularly important in developing countries where budget restrictions call for the selection of the most cost-efficient solutions [11].
Insufficient supervision experienced in the clerkships by both NPT and PT students may have elicited their joint comment that also effectiveness of ECE in PHC relies on the quality of supervision. Also for this pilot experiment FM-GMU skills laboratory staff extensively informed supervisors-to-be in PHC centers about the pre-clinical students’ level of competency and their derived learning needs, and about standards for execution clinical procedures as taught in the skills laboratory [22,23]. Unfortunately in many developing countries (including Indonesia), PHC centers may be severely understaffed [11,24]. Therefore, in the selection of PHC centers for ECE availability of adequate numbers of supervising staff must be carefully considered, because medical students need close supervision particularly in their first encounters with patients [25].
In the Indonesian setting PHC centers proved to be suitable to offer ECE for pre-clinical students. Although more advanced equipment and procedures may not avail in PHC centers, this setting was apparently ‘clinical’ enough to satisfactorily prepare pre-clinical students for functioning in the hospital setting. Training in PHC centers also fits in with the policy of the Indonesian government which requires that every medical graduate must serve for at least half a year in PHC. Furthermore, ECE in PHC centers may motivate some students to opt for a future career in PHC [7].
A limitation of this study is that the assessment of the effectiveness of ECE in PHC centers was only based on student opinions. By involving students representing two different groups (i.e., PT and NPT) and by comparing their mutual opinions we aimed to improve the validity of these subjective data. Furthermore, we have taken the paucity of significant comments by FGD participants on the summary of the FGD sessions as support for the validity of the analyzing process as applied.
In a future study we intend to involve objective assessment tools to compare the clinical performance of NPT and PT students during their first clerkships. A suitable approach in this respect could be assessment by direct observation using the Mini-Clinical Evaluation Exercise (Mini-CEX) [25].
Conclusion
In the setting of a developing country, an 11-day ECE program in PHC centers was demonstrated to significantly reduce difficulties as commonly encountered by pre-clinical students in their first clinical clerkships.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
DW contributed to the conceptual and practical design of the study, collected data, analyzed and interpreted the data, and wrote the first draft of the manuscript. GM and AS contributed to the conceptual design of the study and reviewed and edited the manuscript. All authors approved the final version of the manuscript.
Author's Information
DW is a staff member in the Skills Laboratory and Department of Medical Education, Faculty of Medicine, Gadjah Mada University, Jogjakarta, Indonesia. He is a PhD student in Maastricht University, The Netherlands.
GM is an Associate Professor based in the Institute for Education, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
AS is Professor and Dean of the Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
Acknowledgements
The authors are indebted to Dr. Bambang Djarwoto and Ms. Bina Muntafia Dewintari for providing assisting with analyzing FGD transcripts. We gratefully acknowledge the contributions of student assistants. Our studies were facilitated by the Department of Medical Education at FM-GMU and financially supported by a Dutch NPT project.
References
1. Lynagh M, Burton R, Fisher RS: A systematic review of medical skills laboratory training: where to from here?
Med Educ 2007, 41:879-887. PubMed Abstract | Publisher Full Text
2. Van Dalen J, Bartholomeus P, Kerkhofs E, Lulofs R, van Thiel J, Rethans JJ, Scherpbier AJJA, van der Vleuten CPM: Teaching and assessing communication skills in Maastricht: the first twenty years.
Med Teach 2001, 23(3):245-251. PubMed Abstract | Publisher Full Text
3. Radcliffe C, Lester H: Perceived stress during undergraduate medical training: a qualitative study.
Med Educ 2003, 37:32-38. PubMed Abstract | Publisher Full Text
4. Prince KJAH, Boshuizen HPA, van der Vleuten CPM, Scherpbier AJJA: Students opinions about their preparation for clinical practice.
Med Educ 2005, 39:704-712. PubMed Abstract | Publisher Full Text
5. Godefrooij MJ, Diemers AD, Scherpbier AJJA: Students' perceptions about the transition to the clinical phase of a medical curriculum with preclinical patient contacts; a focus group study.
BMC Med Educ 2010, 10(28):1-9. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
6. Sarikaya O, Civaner M, Kalaca S: The anxieties of medical students related to clinical training.
J Clin Pract 2006, 60:1414-1418. Publisher Full Text
7. Dornan T, Littlewood S, Margolis SA, Scherpbier A, Spencer J, Ypinazar V: How can experience in clinical and community settings contribute to early medical education? A BEME systematic review.
Med Teach 2006, 28(1):3-18. PubMed Abstract | Publisher Full Text
8. Johnston BT, Boohan M: Basic clinical skills: don't leave teaching to the teaching hospitals.
Med Educ 2000, 34:692-699. PubMed Abstract | Publisher Full Text
9. Kristina TN, Majoor GD, Van der Vleuten CPM: A survey validation of generic objectives for community-based education in undergraduate medical training.
Educ Health 2006, 19(2):189-206. Publisher Full Text
10. Widyandana D, Majoor GD, Scherpbier AJJA: Comparison of three clinical environments for pre-clinical clinical skills training.
Medical Teacher Online 2011, 1-5.
http://dx.doi.org/10.3109/0142159X.2011.558141 webcite)
11. Widyandana D, Majoor GD, Scherpbier AJJA: Effects of partial substitution of pre-clinical skills training by attachments to primary health care centers: An experimental study.
Med Teach 2011, 33(6):e313-e337. PubMed Abstract | Publisher Full Text
12. Pemerintah Kota Yogyakarta [http://www.jogjakota.go.id/index/extra.detail/22 webcite]
13. Shields LE, Hartati LE: Primary care in Indonesia.
J Child Health Care 2006, 10(1):4-8. PubMed Abstract | Publisher Full Text
14. Toolsgard MG, Gustafsson A, Rasmussen MB, Hoiby P, Muller CG, Ringsted C: Student teachers can be good as associate professors in teaching clinical skills.
Med Teach 2007, 29(6):553-557. PubMed Abstract | Publisher Full Text
15. Weirich P, Celebi N, Schrauth M, Moltner A, Lammerding-Koppel M, Nikendei C: Peer-assisted versus faculty staff-led skills laboratory training: a randomized controlled trial.
Med Educ 2009, 43(2):113-120. PubMed Abstract | Publisher Full Text
16. Elo S, Kyngäs H: The qualitative content analysis process.
J Adv Nurs 2008, 62:107-115. PubMed Abstract | Publisher Full Text
17. Anderson G, Arsenault N: Fundamentals of Educational Research. 2nd edition. London: Falmer Press; 1998:200-209.
18. Fraenkel JR, Wallen NE: How to Design and Evaluate Research in Education. 8th edition. New York: McGraw-Hill; 2009:485-494.
19. Al-Jishi E, Khalek NA, Hamdy HM: Students' perceptions of the effectiveness of a professional skills program in preparation for clerkship training.
Educ Health 2009, 22:1-7.
20. Kerr JR, Dowie A, Dowell J, Dewar G, Dent JA, Ramsay J, Benvie S, Bracher L, Jackson C: Twelve tips for developing and maintaining a simulated patient bank.
Med Teach 2005, 27(1):4-9. PubMed Abstract | Publisher Full Text
21. Stark P, Fortune F: Teaching clinical skills in developing countries: Are clinical skills centres the answer?
Educ Health 2003, 16:298-306. Publisher Full Text
22. Yeates PJA, Stewart J, Barton JR: What can we expect of clinical teachers? Establishing consensus on applicable skills, attitudes and practices.
Med Educ 2008, 42:134-142. PubMed Abstract | Publisher Full Text
23. Barber SL, Gertler PJ, Harimurti P: The contribution of human resources for health to the quality of care in Indonesia.
Health Aff 2007, 26:367-379. Publisher Full Text
24. Smith B: From simulation to reality - breaking down the barriers.
Clin Teach 2006, 3:112-117. Publisher Full Text
25. Norcini J, Burch V: Workplace-based assessment as an educational tool: AMEE Guide No. 31.
Med Teach 2007, 29:855-871. PubMed Abstract | Publisher Full Text
Pre-publication history
The pre-publication history for this paper can be accessed here:
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} | cccc_CC-MAIN-2013-20 | THE BEST OF DADA POKEY !!!
Dada Pokey provides grist for the Pokey hilarity mill, but, as with all things dada, does not distinguish between that which is truly funny or weird in human eyes, and that which is merely random. "The Best of Dada Pokey" is in no means a contradiction in terms or an imposition on the random nature of Dada Pokey; rather it is a celebration of the human spirit. Or something. You know, there are probably classes I could take where I would get credit for this.
HERE IT IS, WENCH!
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Note: This post was originally written on August 16, 2012 in response to the announcement of Rockman Xover. It was updated on October 13 with a slightly more general tone to reflect new developments since then. It is still focused on Mega Man as I still feel it best epitomizes everything wrong with Capcom today.
When I read the post on Destructoid about a new game called Rockman Xover, I got a pretty good laugh. I laughed because I totally saw it coming and a lot of people are upset that the all-important silver anniversary of Mega Man is going to be celebrated with what looks to be a trashy cell phone game. I'm usually not one to judge on early appearances, but there's precedent for this one not looking like it's going to be a barn burner, and even the venerable Tony Ponce agrees. I've gone on record multiple times playing devil's advocate for issues like this. This time, I see a solution. Hear me out, because it's not going to be easy.
A lot of commenters on that post and the original source they cited are understandably farty over this announcement, claiming that Mega Man Legends 3 and Mega Man Universe were canned to make room for this and the infamous Mega Man X port on iOS, among other travesties, like they always do when a Mega Man thing is announced that isn't a new game. I think they're wrong, because Capcom made the right call pulling the plug on those projects when their hearts weren't in it. They know that a whole new game is too much for them to handle, so they don't do it. I'd rather have nothing at all if the developers would not have been proud of the result had they continued. For that reason, I tend to side with the developer when a game gets cancelled and I still do in these cases. I know what it's like to abort a project I invested a lot of time and effort into and how much it sucks, so I sympathize with the developer any time they announce a big cancellation. (Update: It's been suggested to me that their hearts actually were in it and it was cancelled because the executives wanted it dead, not the actual coders. If that's true, it doesn't change the points I'm about to make.)
It makes me churn a little when I see people not caring about the quality of a cancelled game because they just want to play it. They're the ones who enable Capcom to make sequels that do not need to be. But I'm getting off point. This isn't about sequels, it's about what led to this pitiful milestone release. This has been a long time coming, because for all the wrongdoing Capcom has been pulling the last few years, they got off relatively scot-free, if not a little worse for wear in reviews. Now that the big name developers and directors have bailed, maybe this is all they're capable of doing with Mega Man anymore. Predictably, early impressions for Rockman Xover are not looking good. Despite this, for the last few years, Capcom has gotten the idea that they can act with impunity because
1. The people who are boycotting or otherwise taking a stand against them aren't doing it right
2. There aren't enough people doing so
3. Sales figures are still counterbalancing any boycotting efforts
This is what happens when people don't properly punish a company that acts out of line. To this day, Capcom is getting money it should not be getting. Now everyone pays the price. By not completely starving Capcom of all profit, they are doing whatever they please and you all swallow it up (or so it seems to them anyway). When I say "you", I mean the gaming community as a whole, because the minority that knows what's what is being drowned out by the people who only talk in dollar signs. For all the people who complain, a few months later, Capcom announces some kind of remake or sequel of a series everyone used to like just to appease to the people calling them out. A shadow of their lofty greatness as opposed to the genuine article will restore their image, just like they did with Jojo's Bizarre Adventure and Darkstalkers and Marvel vs. Capcom recently, and no one learns a thing. Capcom will profit with this title (because Mega Man is still a big name franchise and "social RPGs" almost always make money) and the change that desperately needs to happen never will, because gamers are too short-sighted and selfish to effect any real change in the industry. If you don't like this, then buckle up because I'm going to tell you how to cause that change. And you have a lot of work to do.
I've observed something during this console generation which applies to every major gaming company that missteps more than a few times. No matter what happens, Capcom has enough diehard fans and casual fans who don't know any better to survive the worst beatings that those in the know have to offer. I recall the Wii version of Okami as a particular sticking point with the community at the time over failure to properly credit those involved in that port and even those who worked on the original game. Gamers took offense and a number of them vowed to boycott Capcom for their flagrant disrespect for the hard work of the individuals who worked on this game, but in the end, nothing happened. Okami on the Wii sold well enough and everyone forgot about it by the time the sequels came out. (Funny how Capcom's scramble to fix the infamous cover watermark was viewed as a token of respect before word of this got out.)
Earlier this year, there was a case regarding Dragon's Dogma where a junior developer was nearly driven to suicide, and people still bought the game even after the story broke. Whatever horrid working conditions caused that case live on because there's no incentive to change it -- that is, poor sales as a result of people boycotting Capcom out of principle, just like they didn't with Okami. Granted, this has more to do with Japanese business culture than Capcom and is on the same level as the people who refuse to shop at Walmart. I bet it happens all the time and this is a case that managed to make headlines. But since Capcom was outed for it, why not make an example of them?
After those missed opportunities to make a change, the failing I'm seeing is that gamers are saying Capcom should pay, but no one is doing anything to make them. People tell me that Capcom learned their lesson with Ultimate Marvel vs. Capcom 3 and Street Fighter X Tekken in regard to mishandling gamers' trust with their money (free 2013 update to the latter notwithstanding), and they also tell me I'm silly for thinking Capcom needs even more punishment. Yeah, Capcom has learned its lesson, which is why they're still going at it with these half-hearted cash grabs and suboptimal working conditions. Isn't that right, Yoshinori Ono? How is anyone going to learn anything with that kind of attitude?
Actions speak louder than words, and for years I've been seeing a whole lot of words and barely any action. Forgive the hypocrisy on my part, but I can't do it alone. You can't do it. One person cannot do it. Nor can a hundred. Nor can a thousand. Nor can a hundred thousand, no matter how strong they all think they are as a group. VGChartz shows that Capcom-published games routinely push millions of copies, even the "bad" ones like Resident Evil 6 that still broke the one million barrier. That's how many people we need to do it. Capcom is big, and we need to be bigger. Gamers need to all stand up at once and give them the biggest middle finger a Japanese gaming company has ever seen for any change to happen, because we've been taking it in the rear for far too long.
Unfortunately, with the way the industry is set up now, no one can communicate to the most important game companies and tell them off directly, never mind foreign companies. Community websites and Facebook pages are only for advertising, not for feedback. Yeah, bad feedback on social media has pressed Capcom to say they are reconsidering how they'll handle DLC in the future, but that's just more words.
(Update about Resident Evil 6: I don't want to have to bring up the fact that it has on-disc DLC because development on it started long before Capcom made the claim that they'll rethink that policy. I don't care that the DLC is free; this should never have happened in the first place.
Speaking of words, petitions mean squat. They imply support for a cause other than the surgical extraction of everything wrong with a company, which in Capcom's case is probably no longer feasible. Let me digress here for a moment: Suppose a petition does work. We get one game, maybe a handful, the signers wanted. Then what? Does the company change in any meaningful way as a result of listening to the fans? Are more games in their vein promised immediately regardless of sales and the company's current direction just because the fans made their voices known when they should not have needed to in the first place? Or do the fans wait and write up another petition for the next game they decide is worth more than the company decides it's worth? Given how long the petition process takes, I just don't think it's worth the effort and I'd rather see that effort bettering the industry rather than racing toward short-term gains.
That tangent aside, we need unprecedented backlash to make Capcom turn over a new leaf, because like everyone else, I desperately want this bad Capcom to go away forever and a good Capcom, or even the old Capcom that did cool things in the last console generation and before, to appear in its place. But Exy, you're being too hard on them! Why kill the whole company off? Capcom still does good stuff once in a while. I know. Capcom was very good just a few years ago. I know this because of the lengths they went to to spread Tatsunoko vs. Capcom: Ultimate All-Stars around the planet. No one saw it coming, and Capcom did everything they could to make it work, and it totally did. They fixed the original up and even threw in new characters just because. They listened, even though it wasn't the most anticipated game of its season, and now few people play it anymore. (I believe it's due to poor timing, but I'm told that it was because it was on the one console most of the target audience didn't have, but that's for another article.) I can't emphasize enough just how much of a miracle Ultimate All-Stars is, and I feel it's been wasted. Who knows how long it'll be before we see such a defiance of region boundaries again?
Then something happened and Capcom got greedy. I don't know what that something was or how long it took, but here we are. Whatever trace of good is left in the current Capcom is being overshadowed far too heavily by the bad. The way the industry is set up, we can't help them differentiate. If we buy only what we want and not what we don't want, we will get more of the good. "Voting with your wallet," as gamers like to say, regardless of how fundamentally broken that concept is. (Gotta write that rant sometime.) Unfortunately, too many people buy everything regardless if it's good or bad. Since the undiscerning gamers who make up a majority of the paying customer base aren't being reached, this ideal has no chance of success. The people who don't know any better are voting with their wallets as well, and their votes outnumber yours. I don't care about what the reports say about games held up by DLC and/or gems, games farmed out to subpar contractors, and ill-advised cell phone remakes not selling well. That they're being developed at all means something is wrong higher up. Kenji Inafune and Shinji Mikami and now Seth Killian all jumped ship just before and even during this all went down, and people still held hope. That's all gone now.
Speaking of regions, I need to go back to something that's very personal to me: Voting with your wallet. Sure, it works fine for the usual domestic competitions of highly-rated games versus not-so-highly rated mediocrity, but how do you vote for a game that's not even in the ballot? But first, how do democracies work? Correct me if I'm wrong, but a big part of it is being able to vote out the people who run a state badly and then vote in good people, yes? When was the last time that happened with a game company? Does anyone even know what the names of those Capcom executives are? Are they as bad as Bobby Kotick or even worse? Let's ignore the fact that we non-Japanese gamers shouldn't even have any votes in a Japanese ballot, so to speak, or even the fact that I have yet to suggest giving this article to the Japanese since they matter more to Japanese companies like I usually do. The only thing that ousts bad executives is major scandal, and below-average sales is not an example of it. Super bad sales, sure, but there needs to be a string of those, or something really, really bad. I'm talking Virtual Boy bad. You're not going to be able to just vote the problematic executives out, the people who actually make development decisions--not with your wallet, not with Facebook petitions, and certainly not with your internet posts. If there is actually a way to vote executives out, by all means go do it right now. But get all the shareholders to vote with you while you're at it.
I'm assuming the reader of this article is not a Capcom shareholder, so to go back to my previous point, the next best thing is to coordinate a number of people comparable to Capcom's VGChartz numbers to make a difference. The best example I can think of that many gamers working together to remove a problematic individual from gaming is Jack Thompson, and he's never even worked for a gaming company! Countless people contributed to his demise, exposing his misinformed attitudes on gaming, wearing away at his reputation and possibly his mental state, and culminating in disbarment. Why can't we use that synergy to fix a gaming company? Probably because unlike Jack Thompson, gaming companies can distract gamers from their cause with a game. It works every single time, as the biggest American game companies can attest. But that's a whole different battle.
There's hope, however, assuming the problems with Capcom are really all about the money as opposed to any respect for the Mega Man name. A comment on the Destructoid post from Tubatic gave me an idea:
"I propose a year long Game Jam in which people make tons of Mega Man sidescrollers. It's the only way to revive and reclaim it, I think. Capcom just isn't going there."
To which I replied, why not go all the way? Not only do we stand up all together and tell Capcom off, we should blatantly tread all over their copyright and sell such games en masse to send the message that people are willing to pay for them, even if they don't come from Capcom. Capcom doesn't get to see a cent of that money for something that belongs to them. (They don't care about it, right? Is that what you're trying to say, Exy?) Gamers think they vote with their wallets, so I further propose that those people who are still deluded into thinking that gaming is a democracy vote for write-in candidates. Disgruntled fans with talent and a drive to see this franchise retake its place in the top game series of all time should steal the franchise and hold it for ransom. Then we'll see just how much Capcom cares about Mega Man. The fans would essentially be detaining Mega Man against his will, but better for fans to do that than Capcom.
This will only work if:
1. A lot of developers participate in selling Mega Man "tributes" for profit
2. None of those developers give any proceeds to Capcom for any reason, be it respect, hope for a new good game, or anything else
3. A balance between such projects made out of spite to Capcom and out of tough love to them is made
4. At least one of them sells big and the developer openly brags about all the money he's making from a Mega Man fan product
That last point is the most important. A handful of the best Mega Man fan works needs to make bank and have everyone know it. After seeing Rockman 4 Minus Infinity, I have faith in the indie and hacker communities to make games good enough for this to work. As an even more compelling proof of concept, fans decided to make a playable mock-up of Rockman Xover in Flash based on currently available media and assets just to spite Capcom. This is exactly what I envisioned: People taking the fight straight to Capcom and not to the online forums where anything of consequence rarely occurs.
It's like what the old Japanese proverb says--and I'm paraphrasing here so correct me if I'm off--if a whole lot of people all illegally cross the street, none of them can get in trouble because there's too many of them. The same mindset needs to be applied to this Game Jam idea to have any effect. It will end in either a lot of lawsuits, a lot of buyouts, or desperation on Capcom's part, but if it's construed as a mass rebellion, it's my best idea to get Capcom to panic and rethink their strategy. Some people suggest that Capcom should sell the rights to Mega Man to a company that cares more about it. If they take Mega Man games to the heights seen in the best ROM hacks and fan games, then I would be for it. But the problem of Capcom being Capcom would still exist. It would be a half-fix: Mega Man gets a chance at redemption, while Capcom just has one less franchise to work with. I would rather all of it be fixed at once.
Mega Man needs to be taken by force if it's to get any better. Of course, this is a horrible idea--mostly because Capcom always has their other departments to make up the slack, not just because it's stupidly illegal--but Capcom is clearly hurting for cash whether they actually need it or not, so let's hit them where it counts. The title of this post is about fixing Capcom, but I really think we need to tear them down. There are just too many issues with this Capcom to expect a few fixes to make everything right. If this Capcom falls, the shock will be felt throughout the entire industry, like when Sega stopped making consoles. Again, Capcom is big, but we are bigger.
The best legal way to do this, of course, is to boycott. Let me tell you how. Three steps.
A lot of customers have claimed over the years on news posts that they are through with Capcom for some mistake they made. To me, this means cutting off all financial support completely. It's simple, really. If they get any money, they win. They interpret that statement as meaning that their current strategy is profitable, so there's no incentive to change. What you need to do is say no. No more appeasements. No more second chances. No buying anything of theirs on Virtual Console or whatever. No buying incremental upgrades for fighting games just to stay competitive. Nothing. This step is the easiest, but it is by no means easy or even the most important, as I'll explain below.
The next step is the most overlooked: Don't just stop buying anything Mega Man or anything Capcom, make sure everyone else stops too. Urge random civilians everywhere, in game shops, online, at gaming meetups, not to support Capcom. Educate them. Maybe we'll get a fraction of the millions of people needed to change Capcom this way. It's our best chance. I would predict a great many of them won't listen or won't help, but if you really want Capcom to change, you won't let that slow you down. This is what I took issue with most with Operation Rainfall. Their primary goal wasn't about convincing the gaming community at large that there needs to be significant change to the localization process, but rather about getting three games that appeal to JRPG and Wii owners. Now that they have them, they're resting on their laurels. And now people are questioning if the effort was worth it. Like I said in my spiel about petitions above, they should be focusing their efforts on fixing the industry, ideally from the inside out, not begging to it. Don't make their mistake -- Remember, this isn't about Mega Man, it's about the industry. Get everyone you can to join your cause. Why should we still have to expect mediocrity at this point? How can any of you get excited for Ace Attorney 5 when we're missing an entire game of investigating? Maybe it wasn't that great, but on principle we still should have seen a glimpse of it anyway.
Now here's the hardest--and most important--part: Stand strong and don't buy anything from Capcom, no matter how good the games are. It sounds like I'm repeating myself at this point, but this is where a great majority of boycotts fail: The boycotters let themselves be won over by announcements of new games. A lot of would-be boycotters don't seem to understand that getting excited for a new release is the opposite of a boycott. Even if tongue-in-cheek, that mentality is pushing us two steps back for every step forward. Then the whole process starts anew. Enough is enough. Say you're going to boycott Capcom, then stick to your guns. Resist the temptation to give them a dime. Give that money to talented fans instead, just as long as that money doesn't end up in Capcom's bank account. This isn't a vote, it's a protest.
When a boycott is done right, it hurts the executives and the other people poisoning the company from within, but it also hurts the programmers, it hurts the artists, it hurts the musicians, and most of all, it hurts you. It's sad and unfair to the hard-working employees and maybe even to you, the Capcom fan or ex-fan, but it's the only way -- after all, this is what boycotts do. There's going to be a lot of collateral damage, but it's that or allow Capcom to destroy themselves. This Capcom needs to know the suffering everyone involved had to put up with for years. Think about what they've gotten away with, all the people they hurt, all the disappointments and the times they cheated you, because they are not. Show no mercy, for they have none. If they announce a new game, hurt them by not caring. When the new game is released, hurt them by stifling week one sales. When DLC is announced, hurt them by not buying it. Every time this happens, hurt them again and again. Once they're on their knees begging for another chance, hurt them more. Hurt them because you love them. If you really care about Mega Man, then hurt Capcom for all the times they hurt Mega Man. If you love Street Fighter or Resident Evil or Devil May Cry or what have you, hurt them for what they did to those series. Hurt them for every old Capcom series you love that has not been given a chance this generation. If you care about Capcom, hurt them for all the times they hurt their customers and their employees. Hurt them nonstop until their bad influences are completely driven out, and then we can rebuild with whatever's left. Hopefully, the affected programmers and artists and musicians will take Kenji Inafune and Shinji Mikami's lead and find better companies that are more than willing to take them in, and then they can hurt Capcom as well. For all I know, maybe that's what a lot of them want. If you're a Capcom employee or ex-employee and you're reading this, I'm sorry if it made you feel bad. Most likely, this isn't your fault. But I'm not one for third chances.
If it sounds like I'm saying Capcom is beyond hope, notice how I've been using the term "this Capcom" throughout this post. I believe this Capcom has been corrupted from the one I grew up with, the old one I mentioned earlier. I don't like this Capcom and it pains me to see Capcom fans supporting them. This Capcom is not Capcom. This Capcom is the enemy. This Capcom did not give the world Mega Man X, Street Fighter IV, Resident Evil 4, or Mega Man Legends. Instead, this Capcom gave us Mega Man X on iOS, Street Fighter X Tekken, Resident Evil: The Mercenaries 3D, and now Rockman Xover. This Capcom would never have given us Ultimate All-Stars. The only thing that will stop it is a mercy killing, not just a mild prolonged sting.
If Capcom dies tomorrow, then we can start talking recovery tomorrow. Clearly, no one at Capcom is listening now. If alarmingly low sales is what they need to reconsider anything they're doing, then so be it. Something is seriously wrong with Capcom and it's not going away without a fight. We can only claim victory once the people who made Capcom what it is now leave Capcom forever, or ideally, retire from the game industry forever. Once they're gone, only then will Capcom be able to find new direction, pick up the pieces, and win any fans back for good. It will be a slow, grueling process, but it can happen. It can happen when everyone in the world wants it to happen. I want it to happen. Let's make it happen. And if you don't want to shoulder that responsibility, don't interfere with the people who want this Capcom to perish.
[Original artwork by Darka22]
But of course, none of this is going to work. I'm just as ineffectual at getting millions of people around the world to listen as the best games writers are, and that's to say nothing of speaking to Japanese gamers, even if some of them do agree already that this game is the beginning of the end. And for that, I am truly sorry. I'm sorry for wasting your time with bitter rambling and dangerous ideas. I'm just as naive as everyone else involved. I've asked too many questions and the few answers I gave are not very encouraging, but I felt they had to be said. I don't know if any of this has a chance of reaching out to the people who can fix Capcom or can get enough people to get the process started. All I know is this: Capcom used to be good. Now they are not. I refuse to accept that this Capcom is Capcom. They are an evil that must be slain by any means necessary. Boycotting is so hip these days, but no one knows how to do it anymore. Until they learn, everything is for naught.
All things considered, this is probably not the last straw for the fraction of the fanbase that can make this plan go, which is truly tragic since this means that this sad story will only continue. But once you've decided that enough is enough, this article will be here for you. I've said it too many times already, but things will get worse before they get better, and they need to. If you don't think so, if you want to show me that not everyone has to suffer to make things right, if you want to be the change, then prove me wrong. I beg you. But at the end of the day, the real question is this: What is it going to take for gamers to snap and take an actual stand? How much lower can Capcom go? What will Capcom at its most pathetic look like? Are they really getting close to hitting rock bottom? I don't want to think about the answers to these questions. I want them solved before we ever get there. But then again, I am naive.
Note 1: For the record, I just want to say that I'm not the sort who cares very much for milestones and anniversaries. They're great when a game released on an anniversary happens to be very good because we humans like assigning sentimental importance to nice, round numbers, but the pressure to not miss anniversaries for frankly unimportant things is like a big arbitrary deadline. I bet Nintendo did nothing for Metroid's big one this year because they didn't have anything good to offer in time. Better that than, say, Other M part 2.
Note 2: I don't want to suggest that you bomb Amazon and Metacritic reviews with unfairly low scores for legitimately good games because I think that's extremely petty and unproductive, but if that actually hurts them, don't let me stop you.
The past few months have seen a PR fiasco unlike any other. A throng of fans banding under the name Operation Rainfall have decided that they want a select three games because Nintendo has not delivered on their word to bring it over sooner. Their efforts have brought out the absolute worst in irrational fans with a scant few trying to keep them in check. Despite that, it's never going to work. I've been sitting on this post for some time since I heard about Operation Rainfall, but now that Nintendo of Europe is lording it over us poor, poor American gamers, it's a perfect time to get it off my chest. While the majority sees this as a group of concerned gamers trying to reach out to a company, I see it as a subset of Western gamers waging war on a subset of Eastern gamers. And frankly, it won't end well for either side.
The illusion of democracy
This movement and others like it operate under the assumption that the relationship between gamers and companies is democratic. In an ideal world, that would indeed be how the business worked. Gamers speak, game makers listen. That's how it's supposed to go. Instead, neither is happening: Gamers are screaming and game makers are turning a deaf ear. As you will see on any of Nintendo's social network profiles, the vast majority of gamers affected by this don't see a business opportunity, but rather an enemy. Nintendo is the devil for not giving them what they ask for. Not allowing them to give them their money, as a lot of them like to put it. There has been a breakdown in communication and the only way to solve it is to write letters and compare them to Justin Bieber.
There are, unfortunately for them, two fallacies with this thinking. The first is that the hardcore fans that comprise these movements don't realize is they are not the majority they think they are. Nintendo's fanbase is composed largely of the dreaded casuals who aren't aware of the pressing issues that sites like this report on so heavily. With Nintendo, much of their customer base is unaware of the problems plaguing their hardware and software. (I have plenty of grievances against them myself, but that's for another post.) The hardest part for them to accept is that even though they're the most aware of what makes the gaming industry work, they are the minority of the total number of gamers. To put it in perspective, Operation Rainfall has 2860 followers on Twitter and 8522 people on their Facebook page as of this writing. Nintendo of America has 133730 followers and 296621 on their Facebook page. If Operation Rainfall is to be taken seriously by the people who matter, they need to expand and fast. They need to compete directly against Nintendo for the market share that the latter adores so much. They need to convince the casuals that outnumber them. If the true majority speaks out, I guarantee you that Nintendo will actually listen. A PSA isn't going to cut it. Some nobody with a webcam and the gall to wave cash in front of it isn't going to change any minds at Nintendo. Despite what anyone says, Nintendo's number one demographic is still younger gamers and their parents. This is no way to get anything done in this industry.
In the case of decidedly hardcore companies like Activision and Ubisoft, petitions against things like bad DRM work because it actually is a majority of their customers making those outrages. Companies like Capcom, Valve, and Atlus, which are famed for their attention toward their respective fanbases, are in fact comprised almost exclusively of the hardcores that populate sites like this. (In Capcom's case, it's arguable, but that's for another post.) They're fully aware of any backlash and do whatever they can to fix it whenever they're in the mood to. And yet, they don't always do what we ask them for one reason or another. Worse yet, they are the exception, not the rule. They only exist for hardcores, who, as I've said before, are the minority in this climate of phone games and casual throwaway titles. Make no mistake, I have nothing against petitions for bad business decisions like abusive DRM. In this case, this is a decision that has a lot more to do with freedom. It has to do with demographics, which leads me to my next point.
Excel-2011 goes political
The second problem is that these fans are the most selfish, ungrateful, myopic, inconsiderate gamers on the planet. I see right through the purpose of these supposed grassroots movements. They don't care about Nintendo's future or allowing them to take their money. They just want three games they think they deserve just because they're loyal customers. You would think such loyal fans would do anything to meet their favorite company halfway. Sadly, all they can think to do when there's a misunderstanding is shout and spit and cry. While Operation Rainfall puts up an air of pretentiousness to distance themselves from the babies, the people that make up the rest of the operation do not hesitate to threaten to violate Nintendo's intellectual property rights if their demands aren't met. What you probably don't know is that the organizers behind the operation are no better than their constituents. They're just as selfish, except they let others revel in their delusions. Their stated goal is to convince Nintendo of America to bring notable titles to the worldwide markets. Who is anyone to decide what titles are "notable"? They see something that looks cool to them and sit around waiting for the big announcement that they can play too. When it doesn't come, rather than accept that Nintendo decided it wasn't a risk worth taking, they declare war. This isn't the first time it's happened, and yet Operation Rainfall has thousands of supporters even from people who don't need it. They have successfully manipulated thousands of people into putting aside their rationality. They won't stop until the entire world knows that they are starting a revolution.
What all of these fan movements fail to do is consider the other side of the equation, what their enemy thinks about them. Running a business is a very difficult thing. Running an international business is even harder. Do you honestly believe Nintendo of America would announce that they would publish some Japanese games and then turn back on their word after seeing the support for it? Do you really think they're trying to spite you? There could very well be some bigger force at work that's conspiring against them to not release it right away that doesn't exist in Europe. It could be plain old incompetence or it could be some legitimate issue that they can't disclose. Even after acknowledging the outcry and turning the other cheek on Facebook and their mailboxes, Nintendo will not hear the end of it. They're the real victim here, not the gamers who feel betrayed. Here's the key: Nintendo did not betray you. They did not ever "join" you in the first place. No matter how hardcore you are, you're just another customer who can't give more than $50 at a time for a single title. Which is worth more? A dollar from a hardcore supporting Operation Rainfail, or a dollar from a casual gamer who has never played an RPG in his life? Whether they think badly of Nintendo or not, a dollar is a dollar. That's all that matters.
Gamers want nothing more than to be heard by the game companies. They want to be pampered and given what they want, when they want it. Social media has so far not gotten us anywhere close to that ideal. If the game industry is to ideally be a democracy, we are heading the wrong way fast. Petitions should not be the norm as Operation Moonfall is looking to be. In a real democracy, interest groups are often ignored or ridiculed if their motives aren't in line with common sentiments. Here, they get unanimous support if they aren't 100% insane. We have "operations" that fashion themselves after subversive groups looking to effect change from the ground up by any means necessary. This isn't a compliment; that they think this is the only way to get things done is a very sad thing. I am frankly afraid that Operation Rainfall has gotten as far as it has. Should it succeed, it will set a very bad precedent. It will show that the minority of hardcore gamers get what they want, regardless of whether it is in the best interest of the companies they fight so hard. More importantly, it will show that being irrational and naive to the larger workings of an international corporation really is the way to get products. They think that just offering money is the solution. They honestly believe it's that simple. Sadly, it costs money to earn money. Nintendo of America has decided that it's not worth the financial risk that localizing these relatively unknown games requires. They have determined that their customer base neither needs nor wants this game, simply because the part of it that matters hasn't made a stance on it. It's fortunate that Nintendo of Europe didn't think so, but I'll get to that later. Nintendo of America claims it will track sales of Monado in Europe, but when was the last time that correlated to potential American sales?
Something to think about
I've talked a lot about the Western demographic, so here's a question about the other side to mix it up: When was the last time a group of Japanese gamers clamored for the release of a Western game in Japan? How is it that Japanese gamers are content with what they have and we Westerners bicker amongst ourselves over whether we deserve any of what they have? Is it really right for Japanese companies to listen to their customers who are right there next to them and mistreat the Americans just because their American branch isn't doing their job?
An aside: Region locking
A lot of people hate region locking, and with good reason, not least of which is that the successors of systems that did not feature it now enforce it with an iron fist. The real reason for its continued existence evades many gamers who, as I've said, are selfish. They don't consider the economic or political justifications for region locking, notwithstanding the taking away of freedom from one generation to the next. They just see it as another weapon pointed at them to keep them from enjoying something that wasn't made for them. Sure, those reasons may not be good ones. DRM is a complicated affair under the hood, whereas region locks are a single line of code (so to speak) in software that can be set on and off at the publisher's whim, as proven by the handful of region-free releases on the Xbox 360 and the region-unlocking solutions effected by hackers. If that's the case, why keep them? Why not just erase them and let the money flow in from all over the world? Why keep fighting the hackers who will eventually get their way in order to get less money? Heck, why not go all out and make every single game be released internationally at the same time?
Off the top of my head, I can think of two reasons. I don't claim to know a thing about economics, but I would think that keeping domestic income in its own region rather than allowing it to cross borders and be subject to conversion fees is better for all involved, not least of which is a regional branch of a Japanese company. The second is that keeping regional releases in markets made for them ensures that nobody is accidentally sold the wrong regional version of a game. It can happen, especially on the internet. Differences in culture and social mores are far too vast to risk violating by releasing games internationally without any consideration. You may not mind or even actually know the original language, but, as mentioned, you're the minority. Nintendo is not willing to take that risk on you. Region locking is one step toward ensuring that people in a given region don't see what they don't need to see. It may not be the best solution, but no one has proposed an alternative. I would like to point out that I hate region locking as much as anyone, but I can at least respect why they're there.
On the issue of importing, there are those who also pledge that they will buy an import version of the games. Unfortunately for them, this is equally futile, as import markups benefit only import dealers. It may help your conscious, but when has moral fiber ever made any money? The money also goes to foreign developers, and even then it's a fraction of what you paid; not a cent goes to the people who actually need to see that money. They're willing to accept a foreign product rather than canvass for support for something that they don't have to jump through hoops to get. Should we be willing to subject ourselves to breaking the law just to play a video game? Yes, the import numbers can be a powerful figure, especially when a company decides to take a risk by making their game region-free. But Western stores generally don't market region-free games from overseas despite it being playable on Western systems. So the customers who want them still have to go through the extra trouble of paying extra for a game they will have no trouble playing just because it's not made for their market. Why do you suppose this is? Why, in an age where everyone is aware of every culture in the world, do game companies still have to worry about regions? Do you think game companies like how they have to go through the trouble of making multiple versions of the same game for different languages even when it may not be necessary? Why does Nintendo and Microsoft have to put up with anti-region locking sentiment? (Sony region-locks too, but they do it in a way that happens to keep them out of this debate.) Do you really think they're the ones you should be fighting about this? I believe there is a much bigger force that is conspiring to keep region locking in place, but no one can see them. No one wants to look at the big picture, so they continue to attack the people doing the region-locking instead of the people making them do the region-locking. I can go on, but this is a post for people being immature about three specific games, not a general practice.
How to get your way
As far as money goes, in order to effect any real change, we have to communicate to the decision makers. As you might have guessed, they only speak in terms of income, not social media trends or fan voices because history has shown that they don't always correlate to income. Your first instinct is to "vote with your wallet." Therefore, there are three ways to "vote": Buy, don't buy, or pirate. Two of these options gets you what you want. Two of them leave the company worse off. One of them does neither. It's impossible to count sales that were not made. The only numbers that can be calculated are legitimate copies and illegitimate copies. In a real democracy, constituents can pick and choose which issues they want to voice their opinions on. In a commercial industry, you're either all for or all against a company. That is the real problem with these movements. Not buying is the obvious choice, but there aren't enough people for that option to make an appreciable mark on sales records. It's a self-defeating strategy.
But let's assume that's not the case. The only way to speak out to Nintendo is to, as some members of this site put it, "not reward bad behavior." Fully cutting off your support to Nintendo, financially or otherwise, is the only real way to speak to the people holding the money, and therefore power, in the company. You have to show them that if you don't get what you want, you will give your money to someone else who will. It's been said before, but this is how real boycotts work. If you still support them by buying other Nintendo-published products, you accomplish absolutely nothing. Flinging complaints, slurs, and slander over their social media gates also does nothing for you, since bad PR hasn't stopped Nintendo from making any decisions in the past. They've made good and bad decisions in the past, and a large majority of them had nothing to do with what you had to say, only what you wanted to pay for.
This is enough for the more sensible people, but I want to challenge them to go one further. Speak out to the people who really matter. Take it to the Japanese branches. Learn Japanese and play the games the way they were meant to be played. With some exceptions, Japanese gamers matter more to Japanese companies than gamers from other regions. They turn to them first for input on their design decisions and wonder later why the prospective American customers hate the changes. They're generally better about it now, but there is still a massive barrier that no one is willing to overcome. Those who do are still only the exception. They aren't setting an example. There aren't more than a handful of Cave Co., Ltd.s in the world in 2011. I'm going to leave it to you to figure out why.
A hint that's lost on you
As a technically concerned gamer, I have one other solution for the guys who think petitioning an old-fashioned company is going to work, and it's one that goes back at least a decade. Mother 3 is a game that, despite much demand from overseas, has never been considered for release even by Nintendo of Europe. As ruthless as the Mother fan community can be, they knew that after years of crying about it, that wouldn't get their holy grail to them any sooner. What did they do? They took it into their own hands. They made a frankly marvelous translation patch and released it into the wild for all to enjoy, and they did it without shedding a single drop of blood.
Fatal Frame IV is the same story. It was supposed to be released in Europe, but a fallout between Nintendo and Tecmo had those plans fall through. Did the Fatal Frame community start a minor firestorm over that? God, no. They made a translation patch of their own and went out of their way to ensure it would only work with legal copies and any kind of Wii, modified or not. Countless other games that fans in America and Europe think they want were translated by other fans who were willing to cross legal boundaries to bring back a treasure.
This is, in my opinion, the right way to get what you want. Nintendo failed two sizable communities but didn't get any harsh PR for it. Those communities knew that Nintendo doesn't care about them or their money, so they didn't care for what they thought either. They supported themselves and even made sure that money went to Nintendo anyway for trying. I personally think that last part doesn't help matters any, but at least they aren't greedy about their work. Heck, even Pokémon Black and White got translation patches for the Japanese ROMs well before the English versions were released, and they didn't even have to. It's illegal, but they didn't want to wait, so they didn't.
So where are the translation patches for Xenoblade Chronicles, Pandora's Tower, and The Last Story? Why did no one even attempt to beat Nintendo to the punch for their sake? Why did the community resort to throwing tantrums? Why is Operation Rainfall not taking a stronger anti-piracy stance when so many of its supporters are pledging to do exactly that? Because the periphery for Mistwalker's fanbase is selfish. They don't want to find a champion that will get them what they want despite Nintendo. They think that only official action will do it. They don't want to show Nintendo that it could be done. They expect that saying they'll buy an English version will do it rather than show them that they will support an actual thing. They aren't giving their support to an alternative group of workers. They are supporting only a group of dreamers. Granted, as a technically concerned gamer, I am confident that someone will come up with a region unlocker homebrew that will run European copies of Monado in a similar fashion to Fatal Frame IV within hours of its release, but again, it won't help Nintendo of America one bit. It certainly won't help Operation Rainfall, who have stated that not only do they hate homebrew, their goal is an NTSC release, not a PAL release. They cannot be happy that Europe is getting something we still don't have just because they don't have it too.
Why Operation Rainfall must not succeed
The only way to speak to the decision makers is to realize that business is all or nothing. Failing that, invent an alternative and support that. I would personally have you learn Japanese and never worry about a company deciding to bring a game or three you want in a package that's convenient for you. But all of that is too much work for you, isn't it? You can't just change all of your ways and think of the other side for a change, can you? You want to continue this war until Nintendo gets it. You don't want to back down now. Europe gets one nice thing for once in their entire miserable gaming history and rather than be happy about it, you're consumed with jealousy. You want more. You want to be equal. America built its history on complaining that things aren't right and you don't want to turn back on that legacy. I'm afraid that's not how life works. That's not how this industry works. You're either for or against Nintendo in this case, and a large number of the combatants are lukewarm. They want very badly for Nintendo to deliver, but they will still support them until they do. What kind of movement is this, again? I find it hard to believe so much is at stake when not nearly enough people are taking this movement seriously enough to realize this.
Even if Operation Rainfall goes absolutely perfectly and follows the above plan by holding their support to Nintendo hostage until their demands are met, they're still only a small fraction of Nintendo's customers. If you feel offended that I'm insinuating that you are one of the irrational people who shout before they think, I would like to remind you that you are the minority. The vast majority of people being heard are the ones typing in all caps why Nintendo sucks and that they're going to pirate and be proud of it, neener neener. There is nothing that can be done for them. Sadly, they're the ones representing your movement, not Operation Rainfall. They're the ones on the front lines disregarding Operation Rainfall's tiny notice to not pirate. They're the ones calling Nintendo the enemy. They're the ones who make it on the news. If Operation Rainfall succeeds, these fans are the ones who are going to take the credit. I shudder to think that they'll take the credit for making Nintendo do something they were going to do in the first place but weren't able to at the time the fans wanted. It won't be a victory for mistreated fans. It will be a victory for greedy fans.
YOUR FAULT
We've gotten to the point where when one promise is broken, dreams are shattered. It makes so much sense for Nintendo to publish three little games, and yet they don't. We have to resort to full-scale campaigns just to get something that we obviously should have gotten years ago or even games that we shouldn't get due to real quality concerns by the developers. This is some democracy we gamers have built. Countless people are proudly proclaiming that they are going to pirate without regard for the consequences. They claim that Nintendo forced them to turn to crime just so they can play some games. This is obviously not true; no one has forced you to do anything. But no one listens, and the war rages on. So who is to blame for this? Who allowed the state of gaming to get to the point where we have to petition in the first place? Who is the real enemy here?
Everyone. Everyone in the world, without exception. I blame Mistwalker for acknowledging the international support and starting this whole mess. I blame Nintendo of Japan for not being built to handle this kind of feedback. I blame Nintendo of America for that Facebook post that fanned the flames to record highs. I blame Destructoid and all other sites like this for encouraging the poor behavior on the part of the fans. I blame the fans for not knowing better. I blame Nintendo's shareholders for not sharing the fans' opinions on this matter. I blame whoever thought region locks were a good idea, and I'm 100% positive that they aren't involved in video games. I blame fan translators for taking away incentive to learn the original language. But most importantly, I blame myself for not noticing any of this sooner. The problems that led to this are far too advanced to do anything about them now. Despite what I or anyone else who thinks as I do say, there will still be unstoppable crowds of complainers at Nintendo's door and there will still be petitions organized by idealists who still don't get it. They never will. They're too set in their greedy ways to sympathize with Nintendo's problems, instead content with savaging them for falling off their pedestal. They're all fighting the wrong fight and nothing can be done to set them on the right track. Somewhere along the line, things got out of hand and nobody did a thing about it. It's simply too little too late.
Therefore, my message to you, the reader, is this: Give it up. Just stop. You do not matter as much as you think. Nintendo will survive despite you. They don't care about you, so you should not care about them. Be thankful that we got anything at all from Japan while they fear us mighty Westerners so much. I would say that you should either get supporters from a demographic that matters or do Nintendo's job for them since they obviously won't, but that's not going to happen. Not on a site like this, where not even my older brother, who is much more hardcore than me, dare tread. It's a lost cause. Just let it go. Let these titles stay in Japan, where they belong. Just cut your losses and be happy for someone else for a change. You'll live longer if you do. If we were truly meant to get these games, we will. We don't need to petition. We need to be adults. And if you still can't accept that message, these fellows said it much better than I ever could.
Welcome to the minority.
La-Mulana is one of the few upcoming games I'm looking forward to. Fortunately, I discovered just in time that the developers were holding a Ustream of their panel at the Tokyo Game Show, which I was able to capture and put on YouTube. Regrettably, I was not able to save the chat, which brought up a few points I didn't record.
Highlights:
Hell Temple is DLC. No price or release date has been set at this time.
The bosses shown are drastically updated.
Mantras are accessible from the pause screen.
Many more traps in previously safe areas.
Release date is targeted for this year.
Some people actually asked me if I ever got my copies of Sakura Wars 1-4 to run. After discussing it with a professional, we concluded that my Dreamcast had somehow lost the ability to execute signed code, meaning I had to get another. Luckily, a local used game store had a bunch of Dreamcast stuff at very reasonable prices. A few solder points and burned discs later and I'm now in the possession of a Japanese Dreamcast with a black swirl in its boot-up splash, two controllers, a giant box with 10 discs I can actually play now and some of my favorites from back in the day: NBA Showtime, Power Stone 2 and Ready 2 Rumble (only the demo of which I actually played in the past). However, that soldering turned out to be completely pointless since I still need a boot disc to run imports for more than ten minutes. What's all that about? I could change its region back to American, but I'm not going through all of that unscrewing again any time soon, especially since now I sometimes have to close the disc door twice to get the drive to spin. Anyway, to justify this blog I guess I'll write up some (re-)impressions.
Sakura Wars isn't an entirely new experience for me. My Social Link training is coming into play here, but I'm less than an hour in and already I'm beginning to see why people appreciate it. In Persona 3 and other dating sim-like games, I'm inclined to do the engineer thing and carefully consider every option given when I'm presented with a branch instead of answering impulsively like I think I should. Here, I don't get that opportunity. If you haven't been following the news of the English release, when you encounter a dialogue option, you get only a few seconds (3-10) to think about what you say. You're always on your toes and always under pressure because the more important ones take you by surprise. The LIPS system as it's known is quite flexible, as demonstrated very early on: in one event, I found myself at the door of the dressing room looking for one of the performers of a play about to open. I was given a single choice: open the door. I did the gentlemanly thing and waited out the 10 seconds until it went away and was rewarded for it. I can't wait to see what combat is like, but to play it I need to have my laptop next to my television because I'm not printing out 100 pages and flipping through them like a madman. I recently had to change out the power strip to one with only six plugs instead of seven and my laptop battery will last for all of three seconds (literally), so until I come up with a workaround for all of that, it will have to wait just a little longer. Time will tell if this was worth the effort.
For whatever reason, NBA Showtime, or as I've always known it, NBA on NBC, was always my favorite sports game. There's nothing remarkable about it: it's your standard 2-on-2 basketball game with a character editor. It's no different now. I think what captivated me a decade ago was its commercial tie-in. I thought the idea of playing something based on a non-fictional television show was the coolest thing. The inclusion of all of the NBC markings and voices ("This is the NBA on NBC") strengthened that impression. It just seemed so authentic and real back in the day despite the fact that my older brother always played an emaciated horse man nicknamed "Phat". I remember one time my little sister tried playing it. She held the controller upside-down and managed to score a 3-point shot. How broken is that?
Power Stone 2 is just as chaotic as I remember, even on single-player. I still find it a little hard to believe that it actually came out in the arcades because it feels much more at home on a console. I hear that there's a PSP compilation that combines this and the first game out now, but I have yet to come across it. All I know about the first game is that the players get five lifebars instead of just one.
I can't believe that someone at Midway thought that a single first-person camera for a two-player game would be a good idea. Ready 2 Rumble becomes a very interesting experience when only one of you can actually see your fighter. It might be one of the few second-person games in existence. Also, don't try maximizing the time and round count to the regulation setting of 12 three-minute rounds because odds are you won't make it to the second round if you don't fully remember how to play. I've heard nothing but bad things about the Wii remake and I'm guessing that's because this is just Fight Night for Morons with one analog stick and a single memorable character: Afro Thunder.
Maybe one day I'll do the right thing and pick up a proper copy of Seaman on eBay. After that maybe I could find some shmups and get a PS-to-Dreamcast adapter so I can use my stick on it. Also, would anyone be interested in taking that clock off my hands?
I have no idea what to do with any of this. Playing them is certainly out of the question and I don't have any safe place to store them. No clue what the lanyard is for, by the way.
Dreamcast is retro, right?
I wanted to just post this in the forum, but since I've posted a blog about Card Sagas Wars preview videos in the past, I figured I should follow with another. This video shows that more of the cards in the frankly impressive gallery than previously thought will be in the game. In particular, the Green Series cards, none of which have gallery entries yet, are demonstrated as strikers that can be triggered after sustaining damage. This mechanic finally explains what the letters on the cards refer to: they indicate the strength of supporting attacks by that card. Earlier updates explain that combos and special attacks are done by inputting very simple button commands, making it more like a party fighter and less traditional. I don't think MUGEN has ever been implemented this way. Its release cannot come soon enough.
The last five seconds of the video are golden. Also, I call dibs on Soma Cruz. | v0 |
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From eLinux.org
Revision as of 16:50, 3 July 2007 by Wmat (Talk | contribs)
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Here are some links to information and projects related to Linux system size.
Contents
Documentation on reducing kernel size
There is a draft of a comprehensive document on the subject of measuring and reducing the size of the Linux kernel following page:
Kernel Size Tuning Guide
Technologies for decreasing system size
The Linux-tiny patchset
• see the Linux Tiny page. There is a project to characterize the sub-patches in the Linux-tiny patchset, in order to prioritize them for porting to non-x86 architectures.
• see Linux Tiny Test Project
Compiler options for reducing kernel size
An LWN article talks about three gcc options to shrink the kernel.
Shrinking the Kernel with GCC
The first option is -Os which is already in the tiny kernel patch.
The second option is new in gcc 3.4, -funit-at-a-time. This apparently makes gcc do a much better job of inlining and dead code removal. It reduces the size of both text and data. It depends on another inlining patch that I think is in the tiny kernel patch (maybe same idea but different details).
The third option, -mregparm=3, seems to be x86 specific, it instructs the compiler to use registers for the first three function arguments. by John Rigby
SquashFS file system
For read-only data, it is useful to utilize a compressed file system. The following are used heavily in embedded systems:
• Cramfs - [should put some information or link here]
• SquashFS - see the Squash Fs page
Use of a smaller libc
• uClibc - small footprint but complete C library
• klibc - very small library for use in init ram filesystems
• dietlibc - another library to produce very small statically compiled executables.
• Subset Libc Specification - CELF is researching the possibility of creating a subset libc specification
Kernel XIP
By executing the kernel in-place from flash, it is possible to save RAM space.
Application XIP
By executing applications in-place from flash, it is possible to save RAM space.
• see ApplicationXIP
Data Read In Place (DRIP)
This is a technique for keeping data in flash, until it is written to, and then making a RAM page for it.
Size measurement tools and techniques
How to measure the kernel image size
• to see the size of the major kernel sections (code and data):
size vmlinux */built-in.o
[tbird@crest ebony]$ size vmlinux */built-in.o
text data bss dec hex filename
2921377 369712<PHONE_NUMBER>085 343f55 vmlinux
764472 35692 22768 822932 c8e94 drivers/built-in.o
918344 22364 36824 977532 eea7c fs/built-in.o
18260 1868 1604 21732 54e4 init/built-in.o
39960 864 224 41048 a058 ipc/built-in.o
257292 14656 34516 306464 4ad20 kernel/built-in.o
34728 156 2280 37164 912c lib/built-in.o
182312 2704 736 185752 2d598 mm/built-in.o
620864 20820 26676 668360 a32c8 net/built-in.o
1912 0 0 1912 778 security/built-in.o
133 0 0 133 85 usr/built-in.o
• to see the size of the largest kernel symbols:
• nm --size -r vmlinux
[tbird@crest ebony]$ nm --size -r vmlinux | head -10
00008000 b read_buffers
00004000 b __log_buf
00003100 B ide_hwifs
000024f8 T jffs2_garbage_collect_pass
00002418 T journal_commit_transaction
00002400 b futex_queues
000021a8 t jedec_probe_chip
00002000 b write_buf
00002000 D init_thread_union
00001e6c t tcp_ack
How to measure the memory usage at runtime
See Runtime Memory Measurement for a description of ways to measure runtime memory usage in Linux.
Also, see Accurate Memory Measurement for a description of techniques (and patches) which can be used to measure the runtime memory more accurately.
Linux size increase from 2.4 to 2.6
Linux increased in size by between 10% and 30% from version 2.4 to 2.6. This incremental growth in kernel size has been a big concern by forum members.
Please see the Szwg Linux26Data page for supporting data.
GCC Code-Size Benchmarking
CSiBE is a code size benchmark for the GCC compiler. The primary purpose of CSiBE is to monitor the size of the code generated by GCC. In addition, compilation time and code performance measurements are also provided.
CSiBE
Case Studies
• Motorola reduction of system size (presumably for cell phones) using 2.4 Linux: see Mot Size Reduction.ppt
Other Tidbits on System Size
Memory leak detection for the kernel
Catalin Marinas of ARM has been recently (as of 2.6.17?) been posting a memory leak detector for the Linux kernel. It may get mainlined in the future. Here's a link to the LKML discussions around it: http://lkml.org/lkml/2006/6/11/39
How System Size may affect performance
It has long been theorized that reducing system size could provide a performance benefit because it could reduce cache misses. There does not appear to be hard data to support this theory on Linux, but this has been discussed on the kernel mailing list.
See this post by Linus Torvalds | v0 |
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Rate This Article
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Great barracuda
Species:
Great barracuda
Great barracuda. Photo by Bob Klemow, Florida Museum of Natural History.
This article has been reviewed by the following Topic Editor: C Michael Hogan
The Great barracuda (Sphyraena barracuda) is a large predatory fish in the Family Sphraenidae that is found worldwide in tropical waters.
Great barracuda. © 2004-08 Florent Charpin
Scientific Classification
Kingdom: Animalia (Animals)
Phylum:--- Chordata
Class:------ Osteichthyes (Bony Fishes)
Order:-------- Perciformes
Family:-------- Sphraenidae (Damselfishes)
Genus:----------Sphyraena
Species:--------- Sphyraena barracuda (Edwards, 1771)
Physical Description
Great barracudas are long (0.45 to 2.00 meters) silvery fish, with large scales, and may grow to 50 kilograms in body mass. The species pointed head ends in a large mouth that contains two rows of knife-like teeth. The lower jaw projects beyond the upper jaw, which feature is helpful in biting.
They are a grayish brown above and silvery below, which color combination is quite universal throughout the geographic range. They often have dark ink-like spots that are arranged in no particular pattern on their sides. The young have dark crossbars on their backs and blotches on their sides. The young also have a soft dorsal fin, with anal and caudal fins manifesting as blackish. Males and females are superficially indistinguishable to humans.
Distribution
Distribution of the Great barracuda. Florida Museum of Natural History.
This species is almost always found in warm seas. In the Indo-Pacific they are found in the Red Sea, and from the east coast of Africa to Hawaii and the Marquesan and Tuamoto Islands. In the Western Atlantic they are occur from Massachusetts (USA) and Bermuda throughout the Caribbean Sea to Brazil. In the Eastern Atlantic they occur in Sierra Leone, Côte d'Ivoire, Togo, Nigeria, Senegal, Mauritania, St. Paul's Rocks, and São Tomé Island.
Habitat
Adult Great barracudas live in and around the edges of coral reefs at depths ranging from one to 100 meters, most commonly between three and 30 meters. They tend to avoid brackish water unless they are getting ready to spawn. Juveniles occur among mangroves, estuaries and shallow sheltered inner reef areas. When adults attain a large enough stature to protect themselves, they move out into the open ocean and then to the margins of the coral reefs.
Feeding Behavior
Great barracuda chiefly consume fish, but they also feed on cephalopods and shrimp. Their large teeth are quite useful for capturing fish prey. They have a large gape which allows them to feed on extremely large fish by chopping them in half. They devour what they can catch using their combination of a sit-in-wait and active predator style. Their narrow head-on profile and silvery color reduces their visibility to prey. They feed on both bottom-dwelling species as well as species of the higher water column. They rely on their acute vision to locate prey. Great barracudas may herd schools of fish into shallow water and guard them until their previous meal has been digested, and they are hungry again.
Behavior
S.barracuda is usually a solitary fish in its adult phase, especially at night. Juveniles and adults may form groups during the day, sometimes containing hundreds, or even thousands, of individuals.
Great barracudas are inquisitive and may follow divers or snorkelers. However, attacks by barracudas on humans are very rare, and may most often occur when the fish attempt to take food from spear fishers .
Reproduction
It is still unclear about the timing and location of spawning of the Great barracuda. In fact, great barracudas appear to show different spawning patterns in different areas of the world. They typically spawn in shallow waters such as estuaries. Great barracuda do not care for their fertilized eggs, which drift out into the ocean, and after hatching the larvae enter the planktonic stage. The larvae settle in shallow areas on the margins of clear-water estuaries. When the larvae reach about 30 centimeters they move to open waters and eventually they move out of the estuaries completely when they reach about half a meter in length. They reach sexual maturity at 60 centimeters and may live for about 14 years.
Associations
As juveniles, these fish compete for food supplies with needlefishes and small snapper. This competition consists of killifishes, herrings, sardines, gobies, silversides, anchovies small mullets, and lizardfishes to name a few. As the fish get older and bigger, they may compete with larger fish like mackerel, or even dolphins, depending on their habitat
The Great barracuda may be parasitized by fish, such as remoras or pilotfish, that attach to their bodies and use them as a source of propulsion.
Conservation Status
The Great barracuda is not listed as a threatened or endangered species.
Further Reading
Citation
Mark McGinley (Lead Author);C Michael Hogan (Topic Editor) "Great barracuda". In: Encyclopedia of Earth. Eds. Cutler J. Cleveland (Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment). [First published in the Encyclopedia of Earth October 23, 2009; Last revised Date November 19, 2012; Retrieved May 18, 2013 <http://www.eoearth.org/articles/view/153116/Mauritania/Mauritania/?topic=49540>
The Author
Mark McGinley is an Associate Professor in the Honors College and Department of Biological Sciences at Texas Tech University. He has conducted research in the evolutionary, behavioral, and community ecology of animals and plants. Dr. McGinley’s recent scholarly interests focus on educating the general public about scientific (particularly environmental) issues. He is currently working closely with students in an interdisciplinary degree program, Natural History and Humanities, which combine ... (Full Bio) | v0 |
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} | cccc_CC-MAIN-2013-20 | DCOM & related technologies
This is an article on DCOM & related technologies in Engineering Concepts.
The Component Object Model (COM) is a softwarearchitecture that allows applications to be built frombinary software components. COM is the underlyingarchitecture that forms the foundation forhigher-level software services, like those provided byOLE. OLE services span various aspects of commonlyneeded system functionality, including compounddocuments, custom controls, interapplicationscripting, data transfer, and other software interactions.
In information technology, a compound document is anorganized collection of user interfaces that form asingle integrated perceptual environment. A compounddocument includes a data structure that containsdifferent data types, such as text, audio files, andmotion video files. A compound document is also anapplication environment containing program objectsthat can be interlinked and interacted with by a user.
Compound documents can be formed of information partsthat originate from different sources and that areassembled on the fly. Microsoft's Internet Explorerdesktop uses the compound document concept.Microsoft's Object Linking and Embedding is aframework for assembling and managing compounddocuments. OpenDoc is an alternative standard.Component Object Model (COM) is Microsoft's frameworkfor developing and supporting program componentobjects. In object-oriented programming anddistributed object technology, a component is areusable program building block that can be combinedwith other components in the same or other computersin a distributed network to form an application.
Examples of a component include:�
• a single button in agraphical user interface
• a small interest calculator
• an interface to a database manager
Components can bedeployed on different servers in a network andcommunicate with each other for needed services. Acomponent runs within a context called a container.Examples of containers include pages on a Web site,Web browsers, and word processors.
It is aimed at providing similar capabilities to thosedefined in the Common Object Request BrokerArchitecture (COBRA), a framework for theinteroperation of distributed objects in a networkthat is supported by other major companies in thecomputer industry. Whereas Microsoft's Object Linkingand Embedding provides services for the compounddocument that users see on their display, COM providesthe underlying services of interface negotiation, lifecycle management (determining when an object can beremoved from a system), licensing, and event services(putting one object into service as the result of anevent that has happened to another object).
The reason for the broad use of COM technologies issimple: for a tremendously wide range of problems, COMallows the creation of better software.Using COM, objects (or classes) and their methods andassociated data are compiled into binary executablemodules, that are, in fact, files with a dynamic linklibrary (DLL) or EXE file name suffix. A module cancontain more than one class.COM allows components of an application to be split upamong different, computers. Because of COM local andremote transparency the client access a component without the knowledge or concern of where the component isrunningHere are some of the facts about COM today:
• COM is in use on well over 150 million systemsworldwide.
• COM consists of a well-defined, mature, stable, andfreely available specification, as well as a referenceimplementation, which has been widely tested andadopted worldwide as a de-facto standard.
• COM provides the richest set of existing servicesfor applications today, as well as the largest set ofdevelopment tools available from a wide variety ofvendors.
• COM supports the only currently viable componentmarketplace. The market for third-party componentsbased on COM has been estimated at US$670 milliondollars in 1998, with a projected 65 percent compoundannual growth rate, growing to approximately US$3billion dollars by 2001. (Source: Giga InformationGroup)
• COM supports thousands of available applications,including all of today's highest volume applications.Major system vendors such as Hewlett Packard, DigitalEquipment Corporation, Siemens-Nixdorf, and SiliconGraphics have announced plans to ship COM on UNIX andother operating systems within the year, with morevendor commitments on the way.
• COM is supported by the largest number ofdevelopment tools available for any component orobject model on the market.
COM includes COM+, Distributed Component Object Model (DCOM), and ActiveX interfaces and programming tools.The Component Object Model (COM) and its relatedCOM-based technologies of DCOM, COM+, MTS and ActiveX�comprise the most widely-used component software modelin the world.
ActiveX:
ActiveX is the name Microsoft has given to a set of"strategic" object-oriented programming technologiesand tools. The main technology is the Component ObjectModel (COM). Used in a network with a directory andadditional support, COM becomes the DistributedComponent Object Model (DCOM). The main thing that youcreate when writing a program to run in the ActiveXenvironment is a component, a self-sufficient programthat can be run anywhere in your ActiveX network(currently a network consisting of Windows andMacintosh systems). This component is known as anActiveX control. ActiveX is Microsoft's answer to theJava technology from Sun Microsystems. An ActiveXcontrol is roughly equivalent to a Java applet.If you have a Windows operating system on yourpersonal computer, you may notice a number of Windowsfiles with the "OCX" file name suffix. OCX stands for"Object Linking and Embedding control." Object Linkingand Embedding (OLE) was Microsoft's program technologyfor supporting compound documents such as the Windowsdesktop. The Component Object Model now takes in OLEas part of a larger concept. Microsoft now uses theterm "ActiveX control" instead of "OCX" for thecomponent object.
One of the main advantages of a component is that itcan be re-used by many applications (referred to ascomponent containers). A COM component object (ActiveXcontrol) can be created using one of several languagesor development tools, including C++ and Visual Basic,or PowerBuilder, or with scripting tools such asVBScript.
Currently, ActiveX controls run in Windows95/98/NT/2000 and in Macintosh. Microsoft plans tosupport ActiveX controls for UNIX.
DCOM:
DCOM (Distributed Component Object Model) is a set ofMicrosoft concepts and program interfaces in whichclient program objects can request services fromserver program objects on other computers in anetwork. DCOM is based on the Component Object Model(COM), which provides a set of interfaces allowingclients and servers to communicate within the samecomputer (that is running Windows 95 or a laterversion).
For example, you can create a page for a Web site thatcontains a script or program that can be processed(before being sent to a requesting user) not on theWeb site server but on another, more specializedserver in the network. Using DCOM interfaces, the Webserver site program (now acting as a client object)can forward a Remote Procedure Call (RPC) to thespecialized server object, which provides thenecessary processing and returns the result to the Webserver site. It passes the result on to the Web pageviewer.
DCOM can also work on a network within an enterpriseor on other networks besides the public Internet. Ituses TCP/IP and Hypertext Transfer Protocol. DCOMcomes as part of the Windows operating systems. DCOMis or soon will be available on all major UNIXplatforms and on IBM's large server products. DCOMreplaces OLE Remote Automation.
DCOM is generally equivalent to the Common ObjectRequest Broker Architecture (COBRA) in terms ofproviding a set of distributed services. DCOM isMicrosoft's approach to a network-wide environment forprogram and data objects. COBRA is sponsored by therest of the information technology industry under theauspices of the Object Management Group (OMGDCOM is simply "COM with a longer wire"-a low-levelextension of the Component Object Model, the coreobject technology within Microsoft� ActiveX�.
Majordevelopment tools vendors-including Microsoft,Borland, Powersoft/Sybase, Symantec, ORACLE, IBM, andMicro Focus-already sell software development toolsthat produce ActiveX components. These tools and theapplications they produce automatically support DCOM,providing the broadest possible industry support.Additionally, over 1,000 existing commercial softwarecomponents that will work with DCOM are alreadyavailable for use by developers.�
COM+:
COM+ is an extension of Component Object Model (COM),Microsoft's strategic building block approach fordeveloping application programs. COM+ is both anobject-oriented programming architecture and a set of operating system services. It adds to COM a new set ofsystem services for application components while theyare running, such as notifying them of significantevents or ensuring they are authorized to run. COM+ isintended to provide a model that makes it relativelyeasy to create business applications that work wellwith the Microsoft Transaction Server (MTS) in a Windows NT or subsequent system. It is viewed asMicrosoft's answer to the Sun Microsystems-IBM-Oracle approach known as Enterprise JavaBeans (EJB).
Among the services provided by COM+ are:
• An event registry that allows components to publishthe possibility of an event and other components tosubscribe to be notified when the event takes place.For example, when a sales transaction is completed, itcould trigger an event that would allow other programsto be notified for subsequent processing.
• The interception of designated system requests forthe purpose of ensuring security.
• The queues of asynchronously received requests for aservice.
A "component" is a building block program that isself-describing. This means that it can be run with amix of other components and each will be able tounderstand the capabilities and characteristics of theother components. Practically, this means that a newapplication can be built by reusing components alreadyknown to exist and without having to compile theapplication. It also makes it relatively easy todistribute different components of an applicationamong different computers in a network. Microsoft'sDistributed Component Object Model (DCOM) addsinterfaces to do this.
In addition to its self-description, a componentconsists of one or more classes that describe objectsand the methods or actions that can be performed on anobject. A class (or coclass in COM+ terminology) hasproperties described in an interface (or cointerface).The class and its interface are language-neutral.Associated with the class are one or more methods andfields that are implemented in a specific languagesuch as C++ or Java or a visual programmingenvironment. When you instantiate a class, you createan object (something real that can be executed in thecomputer). Sometimes the term "class" is also used forthe instantiated object (which can be confusing).
MTS:
Microsoft� Transaction Server (MTS) is the transactionservice in the Windows NT� operating system. Firstavailable in 1996, MTS is now in use at manyorganizations. Enterprise JavaBeans (EJB) is aspecification for a Java-based transaction service.
Created by a group of companies led by SunMicrosystems Inc., the initial specification for EJBwas released in spring 1998. Both MicrosoftTransaction Server and Enterprise JavaBeans target thecreation of component-based, transaction-orientedapplications. This paper provides a comparison ofthese two technologies. More specifically, the paperanalyzes the similarities and differences between theways the two component models handle objects,transaction support, controlling complexity,portability, interoperability, language choice andadministration.
Put simply, a transaction can be thought of as a setof events that are committed or rolled back as aunit-either all of the events happen, or none of themdo. For example, transferring $100 from your savingsaccount to your checking account requires bothsubtracting the money from your savings account andadding it to your checking account. To achieve aconsistent result, either both operations should occuror neither one should. Transaction-orientedapplications like this are very common, and so manyvendors provide software that makes writingtransactional applications easier. And becausetransactional applications often need to handlehundreds or thousands of clients (i.e., users atworkstations), services that make it easier to buildscalable applications are commonly built into productsthat support transactions.
Both Microsoft Transaction Server and EnterpriseJavaBeans support transactional applications andprovide services for scalability. Because the twotechnologies attempt to solve many of the sameproblems, they have much in common. The easiest way toillustrate their similarities is to describe the basicarchitecture and terminology of each MTS is based on the Component Object Model (COM), andan MTS application is implemented as one or morecomponents.
Ambitious contributor
24Jul2007,20:46 #2
Can I ask you about the way writting article as your ? | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T07:11:40.000Z | dnd2rce4qt3bje57x3ukf3i75h23xymp | {
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} | cccc_CC-MAIN-2013-20 | 10 years of Bt cotton: false hype and failed promises
Ten years after Bt cotton first made its appearance in India, the Coalition for GM-free India has released this special report and demands an immediate halt to the policy of promoting Bt cotton.
In summary, the story of Bt cotton is clearly that of false hype and failed promises. Bt cotton has failed to meet its promise in terms of sustained yield gains, pest protection and reduction in pesticide usage. It is time for the government, scientists and policy-makers to reject the hype around Bt cotton, and focus on sustainable solutions and pro-farmer measures to achieve production, environmental safety and farmers’ welfare that are long-lasting.
See Also
Feature: Water starved village caught in Bt debate.
Feature: Cleaning the cotton stain.
Feature: Ministry bats for GM crops.
Report: A decade of Bt cotton.
Report: Socio-economic and farm level impact of Bt cotton.
Report: Adoption and impact of Bt cotton in India, 2002 to 2010.
Report: Bt cotton in India.
Report: Bt cotton in India - a profile.
Report: Bt cotton and farmer suicides..
Attachment(s): | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T05:18:48.000Z | 4ar2mdelzqvhm4wfeemyymbnsdrsbnab | {
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} | cccc_CC-MAIN-2013-20 | Captcha help
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Personal tools | v0 |
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} | cccc_CC-MAIN-2013-20 | Open World Forum (OWF'12)
Open World Forum
October 11-13, 2012
Paris
For the fifth year running we, at OW2, are organizing the Community Summit at the Open World Forum (October 11-13, Paris). This year, free and open source software communities practitioners will debate on the changes brought by the emergence of cloud computing to the roles and functioning of free and open source software communities.
Today's cloud computing software innovation is mostly open source. Open source innovation leads in all compartments of the cloud computing stack: virtualization, VM management, security, file systems, monitoring, big data, broker, etc. A fertile terrain for free and open source software communities.
However, as we all know, what customers get with cloud computing is a service, not software. With cloud computing, software is hosted and vendors do not distribute it. Since the code is no longer circulating, improvements to the software are no longer shared.
Is cloud computing changing the fate of open source software communities? Open source software community members are the primary implementors of the software, they create value directly for the end user. With cloud computing, the value creators are the hosting companies; they mediate the software value creation process and they have the ability to generate new kind of proprietary lock-in, foe example at the data level.
Whereas IT freedom used to be broadly defined in terms of software accessibility, in the age of cloud computing it must now be defined in terms of service accessibility and data freedom. How do we define free service? Is open data the new open source? Is cloud computing a paradigm shift that makes open source claims irrelevant? What does “open” and “free” mean in the age of cloud computing? What new challenges are posed to free and open source software communities?
On the following day, Friday, October 12, from 10am to 6pm, CompatibleOne is organizing a full track dedicated to open cloud and open standards. Click here for link to the CompatibleOne track details
Tentative Program
- Cedric Thomas, OW2 CEO
- Ralph Mueller, Director, Eclipse Foundation
- Leslie Hawthorn, Red Hat
- Dave Neary, Red Hat
- Lars Kurth, Xen
- Simon Phipps, Open Source Initiative
- Ross Turk, Vice President of Community for Inktank
- Michael Meeks, SUSE
See more about the Community Summit and the progam here.
Practical information for the Open World Forum Community Summit:
October 11, 2012, 1:30am to 5:30pm
EUROSITES, Room: Brussels
George V 28, Avenue George V, 75008 Paris
Save the dates and attend OWF'12.
Community Summit details and abstracts: (to be completed progressively)
Speaker: Lars Kurt, Xen, Citrix.
Title: Cloud Computing and the Xen Community
Abstract: The Xen Hypervisor open source project was founded in 2003 as a direct result of Cambridge Universities XenoServer research project that defined Cloud Computing as we know it today. In 2006 Amazon Web Services built their business on top of Xen, followed by Slicehost and many other cloud and hosting providers. In other words: the Xen project provided the technology that enabled many multi-million dollar businesses to thrive. However, until recently cloud and service providers have not been active members of the Xen community. This talk will look at characteristics of the Xen community, its evolution over time, consider licensing and related topics. We will also look at incentives to engage service providers and help them become more active members of your open source community.
Biography
Speaker: Michael Meeks
Title: LibreOffice: turning vinegar into wine
Abstract: Come and hear the story of how the development community around LibreOffice was created from the ashes of the OpenOffice.org project. Hear some of the lessons we learned from both projects, and the ways we use to ensure that corporations play a constructive role with an interest in a diverse developer community. Hear a detailed rational for our release process, and how it helps to reduce problems around conflicting goals. Hear about our progress to date, see some community diversity metrics we track, and more. Finally enjoy a gratuitous plug for our new features and functionality.
Biography:
Michael is a Christian and enthusiastic believer in Free software. He very much enjoys working for SUSE where as the Linux Desktop Architect he tries to understand and nudge the direction of our Linux investment. He has appreciated working on various pieces of infrastructure and applications over the years: from GNOME office, through component technologies, to Evolution, Accessibility, MeeGo, and latterly LibreOffice much of the time. Prior to this he worked for Quantel gaining expertise in both hardware and software for real time on-line AV editing systems.
Speaker: Ross Turk
Title: The Dangers of Apathetic Abstraction
Abstract: What began as a vague shape on a diagram (indicating something so incomprehensibly vast the diagrammer decided against trying to draw it) has changed everything. Yesterday, the network was out of your control and too complicated to understand; now your entire operation is. But one thing hasn't changed: you probably don't care how most of it works, just that it continues to. Every day, scores of excited entrepreneurs build new companies on cloud infrastructure without a second thought. Every day, established companies relinquish their data centers. The reason is clear: it's far easier to build something amazing when you can stop paying attention to what makes large portions of it work. Abstraction is not having to worry how underlying technology functions; apathetic abstraction is not caring. This session will discuss how to avoid the danger of relying on something you don't control and don't understand.
Biography:
Ross Turk is Vice President of Community for Inktank, responsible for building a strategic relationship with users, contributors, and the open source community. Ross brings more than 15 years of experience creating software, managing complex IT systems, and helping companies understand and serve developers. Before joining Inktank, Ross managed developer communities for Talend, Alcatel-Lucent and SourceForge.net, the world’s largest open source community. In the more distant past, Ross ran the engineering team for SourceForge and provided architectural leadership.
Speaker: Leslie Hawthorn, Red Hat
Title: Compromise and Collaboration: Engaging FOSS Contributors in the Age of Cloud Computing
Abstract: As FOSS communities look to bring on new contributors, we're faced with a fundamental challenge - our new would-be users, contributors and advocates are largely operating in a world of non-free software. While the fact that most folks are using proprietary software - and that FOSS advocates would prefer they use FOSS - is nothing new, the rise of cloud computing puts a different spin on the problem. The ease of use promised by software as a service applications, the ubiquity and popularity of non-free social networks and the great increase in non-free real-time communications tools presents us with a more difficult use case: how do we convince folks of the value of FOSS when they expect things to "just work" and want to "hang out" where their friends are? In this talk, Leslie Hawthorn will explore the tensions between effectively engaging our audience of would-be converts to FOSS while maintaining the values of software freedom. Specifically, she will explore the activist roots of the free software movement and how these activist principles can be channelled to effectively amplify the value of FOSS amongst users of cloud services and other non-free tools. Last but not least, she will discuss some libre tools that can be used in our community outreach activities, allowing us to effectively engage with our audience's user experience expectations while preserving software freedom in our discourse.
Biography:
An internationally known community manager, speaker and author, Leslie Hawthorn has over 10 years experience in high tech project management, marketing and public relations. In March 2012 she joined Red Hat, Inc., where she is responsible for Community Action & Impact on the company’s Open Source and Standards team. Prior to Red Hat, she served as Outreach Manager at Oregon State University’s Open Source Lab and as a Program Manager for Google’s Open Source Team, where she managed the Google Summer of Code Program, created the contest now known as Google Code In and launched the company’s Open Source Developer Blog.
Speaker: Dave Neary, Red Hat
Title: Do Androids Dream of Electric Sheep? Cultivating Empathy in Increasingly Disconnected Communities
Abstract: With the advent of communities which are distributed around the world, and increasingly with the professionalisation of Open Source development, we have seen the human bonds between participants in Open Source projects weaken. As projects grow, and we hit the limits of Dunbar's Numbers, newcomers have a higher bar to clear to become part of the group, and our sense of belonging decreases.
Project leaders have tried many approaches to mitigate the effect, but more and more our tools insulate us from human contact and turn collaboration problems into co-operation problems.
What can we do to ensure that our community members keep in mind that behind every user name is a person, that the sum of our interactions defines us as a community? In short, what can we do to encourage empathy in contributors
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Watchers
NameLewistown
Alt namesPoketytownsource: USGS, GNIS Digital Gazetteer (1994) GNIS42014316
TypeBorough
Coordinates40.583°N 77.567°W
Located inMifflin, Pennsylvania, United States
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Lewistown is a borough in and the county seat of Mifflin County, Pennsylvania, United States. It is the principal city of the Lewistown, Pennsylvania Metropolitan Statistical Area which encompasses all of Mifflin County. It lies along the Juniata River, northwest of Harrisburg. The number of people living in the borough in 1900 was 4,451; in 1910, 8,166; in 1940, 13,017; and in 2000, 8,998. The population was 8,338 at the 2010 census. It is the principal borough of the Lewistown Micropolitan Statistical Area. Of the four communities in the United States named "Lewistown", this borough is the largest.
Contents
History
the text in this section is copied from an article in Wikipedia
Early history
The borough was incorporated in 1795 and was named for William "Bill" Lewis, a Quaker and a member of the legislature, who was responsible for the designation of the borough, which was then known as the Village of Ohesson, as the county seat of Mifflin County.
During the late 19th century Mifflin County became the crossroads of the Commonwealth. Located near the geographic center of the state, the area became a hub for traffic moving in every direction.
Early roads crisscrossed the region, but it was the eventual construction of the Pennsylvania Canal and the railroads that followed that truly positioned Mifflin County as an economic force in the state.
Lewistown, as the major city in Mifflin County, saw its economy expand dramatically as entrepreneurs launched companies to construct canal boats or build inns offering lodging for travelers and workers.
At its zenith, Mifflin County was one of the busiest centers for cargo and passenger traffic in the United States. But with the demise of the canal system, Mifflin County eventually lost its place as a major transportation hub.
American Civil War
On April 16, 1861, Lewistown sent its Logan Guards, a militia group originally formed in 1858, to Washington, D.C. for its defense. They were one of only five companies, all recruited in Pennsylvania, to share the honor of being the first U.S. troops sent to the capital. Monument Square, situated at the intersection of Main and Market Streets in Lewistown, serves as a memorial to these men.
Tropical Storm Agnes
Lewistown lost its role as a major transportation hub, but still boasted a strong industrial economy until the early 1970s when the county's industries began a slow decline. A ruinous natural event in June 1972 would cripple the local economy and Lewistown has never recovered.
One June 19, Agnes made initial landfall along the Florida Panhandle as a weak Category 1 Hurricane. Agnes then proceeded through Georgia, South Carolina and North Carolina before she moved back over the Atlantic off the North Carolina coast on June 21.
After regaining strength over the Atlantic, she made landfall again over southeastern New York on June 22 and moved westward in an arc over southern New York into north-central Pennsylvania. She became nearly stationary over Pennsylvania by morning of June 23, but was soon absorbed by a low-pressure system that slowly drifted northeastward from Pennsylvania into New York.
Rainfall from storm over the Mid-Atlantic region ranged from 2-3 inches in the extreme upper basins of the Potomac and North Branch Susquehanna Rivers to near Shamokin, Pennsylvania, in the Main Stem Susquehanna River basin. An average of 6-10 inches of rain fell over the Mid-Atlantic region. The soil, already well watered by spring rains, could not absorb so much water so quickly.
While flooding from the Juniata River was somewhat controlled due to a dam at Raystown Lake, west of Lewistown, the county experienced extensive flooding from the river and major streams which resulted in the permanent closure of many businesses along the river. Most notably, the flood submerged much of the American Viscose Plant, then a division of FMC Corporation. The facility, located on the banks of the Juniata River across from Lewistown proper, manufactured rayon fiber (primarily for rayon-belted automobile tires), polyester and Avistrap.
FMC was one of two major employers in the area at the time, the other being the Standard Steel Works. The "Viscose" plant was only marginally profitable before the storm and the cost to reopen was prohibitive. (Ironically, the demand for rayon fabric for trendy clothing shot upward only a few years later.) Rayon production, and with it, thousands of good-paying jobs, moved to another FMC plant in Front Royal, Virginia. The Lewistown polyester plant reopened, but it rehired only a fraction of the previous workforce. The site eventually became the Mifflin County Industrial Plaza and a variety of businesses have come and gone since then.
Present day
While Lewistown did receive the prestigious All-American City award in 1973 for its rebuilding process following the disaster, many of the blue collar workforce left the area to head south, along with the companies which chose not to rebuild in Lewistown.
Lewistown is home to the Pennsylvania State Fire School, which is the only such facility in the state. Firefighting in Lewistown is very important, as volunteer firefighters have strong allegiance to the multiple independent fire companies in the borough to which they devote their time.
Today, Lewistown is still looking to rebuild, but is now overshadowed by nearby State College. Due to the growth of Penn State and the construction of a new highway system, Lewistown is now struggling to avoid becoming the last rest stop for travelers coming from the east on their way to State College.
The Embassy Theatre, McCoy House, Mifflin County Courthouse, Montgomery Ward Building, and Wollner Building are listed on the National Register of Historic Places.
Research Tips
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O'Reilly's Radar: Remix Patterns
Tim O'Reilly delivers O'Reilly's Radar (click to enlarge)
Tim's keynote was on patterns for remixing. Patterns consist of three parts: an issue, a prescription, and examples. Here are some of Tim's patterns (I missed much of it):
Issue: A successful open source project consists of "small pieces, loosely joined."
Therefore: Architect your software or service so as to be used easily as a component of a larger system: keep it modular, document your interfaces and use a license that doesn't hinder the recombinations.
Example: missed it
Issue: There is great benefit to sharing your development efforts with users
Therefore: release early and often. Set up mechanisms for user feedback, bug reports and so on.
Issue: On today's web you no longer need to build or own all the components of your application.
Example: isbn.nu
Therefore: don't lock away the interfaces to your ecommerce application.
Issue: When devices and program are connected to the Internet, applications are no longer software artifacts, they're on-going services.
Therefore: don't package up new features into monolithic releases, rather, fold them in on a regular basis. Let your users into the process. Engage your users as real-time testers and instrument such that you know how new features are faring. Operate as if you're in perpetual beta.
Examples: Google, Flickr, del.icio.us, Safari U.
Issue: The key to competitive advantage in networked applications is the extent to which users augment your data with their own.
Therefore: Architect for participation beyond design and development.
Example: Amazon using its user's intelligence to create new value. Adding user data to their own.
Issue: Only a small percentage of user will go to the trouble of explicitly adding value.
Therefore: make participation the default, aggregating user data as a side-effect of their using your application.
Example: Flickr's defaults for sharing is for "everyone." The default for annotation is "open."
Issue: Many of the limiting factors from the physical world are absent on the Internet.
Therefore: Use the power of the computer to monetize niches formerly too small to be commercial.
Example: Google Ad Sense.
Issue: The PC is no longer the only access point for networked applications.
Therefore: Design your application from the get-go to integrate services and share data on multiple devices.
Example: iSync.
Issue: Social networking are a by-product of social application like email, instant messaging, photo sharing, and book buying.
Therefore: Architect your application to capture and share the social fabric underlying you application (rather than artificially constructing another.
Example: The ETech Attention Stream (which is displayed on a flat panel in the lobby).
Issue: As demonstrated by container shipping, IP packages, and HTML pages, a standard content-agnostic packet is the most effective way to ship for good and data.
Therefore: Understand the optimum "packet size" for your application domain and devise products that fit it.
Example: Books don't fit on a Web page. O'Reilly Make and the new Cookbook series are examples of repackaging content in an effort to more closely match the right "packet size."
Issue: When content is digital, it lends itself to being broken down and remixed.
Therefore: Create your business model so that it make money from the atomic units of your products.
Example: Safari U.
Although they're not patterns, Tim also mentions AJAX and Ruby on Rails. | v0 |
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We sell software online. Our international trial to purchase ratio is abysmal compared to US domestic. I'm trying to determine why? Some possible answers:
• Higher piracy overseas
• PayPal and PO are only purchase options
What other possibilities am I missing?
What can I do to help my int'l customer purchase my product?
NOTE: We sell a B2B product for US$399.
share|improve this question
11 Answers
International vs US Domestic markets are fundamentally of different magnitude.
Not sure who your target audience is and whether they face the same issues your Software addresses.
The following may be some reaons:
1. Target Audience : Are they facing same issues you are trying to solve?
2. Visibility : Do you have some kind of advertisement/marketing in other Countries?
3. Price Point : Does it take local market information ?
4. Localization : !
5. Local partners : In many cases local partners will help to identify market opportunities
Good luck.
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Probably it will be best that you reach out to those international users and ask them the same question. Give them incentives to participate in your survey.
My guesses would be:
• They don't see value for money.
• Its too expensive for them.
• Not enough payment options.
Piracy should not be an issue cuz it looks like your products targets enterprises and software houses.
share|improve this answer
What language is your software and documentation written in? If you haven't localized then it is clear that you really are trying to cherry-pick as opposed to getting involved in the lives of your customers.
Don't market by U.S. vs. world but by English vs. other languages.
share|improve this answer
Paypal has a poor international reputation as a payment scheme. I'd wager that at least some of your problem is associated with the fact that it's hard to pay you. Investigate more locally adopted payment forms, and seriously consider accepting bare credit card payments. Many corporate purchasers don't want to mess with a PO, but aren't authorized to sign up for a company paypal account.
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This may sound trivial but do you give the option to view the price equivalent for different currencies? This would at least establish you as something to be used internationally and not just within the US.
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The first thing you need to do is to break you sales into domestic and international. The world's a big place and different things will work for different places.
So start by analyzing your western European sales. The British are probably the best candidates to start with since there are almost no language issues. How are you sales there?
Also, you don't mention the source of your sales. Could it be that many of your sales in the US are word of mouth, and you need to generate that in other parts of the world too? Are you using Google ads?
Yes, there are large parts of the world where the ratio is going to be much lower than in the US, including India and China, though you can do well in India, since yours is a business tool.
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I think rather than guess it would be best if you gave them some kind of offer to tell you why they're leaving. Say I'll give you a $10 certificate to whatever in return for 5 minutes of your time.
If you follow a systematic process, you'll find out pretty quick. Good luck.
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Back when I sold software development tools in the mid-late 1990s we reckoned on 50% US, 50% "international" sales as a rough benchmark for an established product in an established market.
If you're new you will need to establish credibility outside the US before you'll see acceptable sales. In particular:
• You must have a full trial version that is unrestricted. $399 is a lot of money for someone (even a company) to ante up for software that can't be tested. Screencams etc. won't be enough, it needs to be the full version.
• Investigate whether you can create a lower band price point with reduced features.
• Get some buzz around the product on well respected blogs. Consider SO advertising: according to traffic India is the #2 destination for SO users.
• Don't worry about piracy too much, especially for a B2B product. Things like dongles, copy protection and whathaveyou really just get in the way. For B2B at that price point I'd consider a simple serial number and a call-home on startup.
• Make sure that you don't have latent cultural assumptions in your product or supporting material. For instance, most people outside the US (and Japan) have no clue about baseball, so samples that do e.g. baseball scoring will be completely incomprehensible.
• On uninstallation, consider opening a browser window to a page that has a simple text box asking why the user uninstalled the software. There's no need for an incentive.
Hope this helps, best of luck
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A concrete example: our main product is made in EU and we have 50% sales in EU, 30% USA, 20% rest of the world. We sell only through paypal and bank transfers. Paypal is not a concern for selling in EU. We just offer the double currency pay buttons. Our site, forum and documentation is only in English - otherwise maintenance would be costly - and hardly anyone complains. Sales are good.
Your product seems linked to administrering Windows servers; consider that in the EU the penetration of Linux servers is probably higher than in the USA. Maybe you should do a version for Linux servers and windows clients?
share|improve this answer
Perhaps you could offer a bounty hunter for everyone that wants to translate your software to other languages (for example Spain and France are very nationalist countries and they would prefer the software translated).
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International markets vary wildly. Some countries are very price sensitive, while others demand features. You have to tailor your marketing for each one.
-Price. Your $399 piece of software might sell well in first world countries like the US, but in developing economies like India, you probably have thousands of customers looking for something $99 to free due to the difference in market rates there.
-Payment. Even in the age of technology, payment through internet or electronic transfer is difficult. Each country has a different system of banking that can cause numerous issues. This forces customers and vendors to go through third party services adding an additional layer of cost. Very undesirable.
-Support. Customers still like to be able to pick up a phone and reach you when they are having difficulties getting your gadget to work. Problem is, your 2pm might be 2am for an international customer. Unless you have 24 hours international support, they might look closer to home.
-Awareness. Sure adwords and google work well for getting customers to your site, but not all countries have high internet connectivity. In some places printed media still rules. Find ways of getting an ad into a local publication or newspaper.
The best way to solve many of these problems is to start a channel sales program. Search for and develop relationships with overseas vendors who do business in these overseas markets. Work out contracts with them for pricing tailored to their location. They will be able to handle all the marketing and support a lot better than you in their own area. Just make sure they know the product inside and out.
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I have a decade experience in software developement and specially web related applications. As a geek, I have a nice contacts but I do not see any of my contact turning into a perspective client. Recently I got an offer to incubate a small consulting firm inside another bigger firm. My firm will work in a specific niche. Say Mobile development consulting.
As of now I do not have any client and am dependent upon the various lead generation tools available on web.
My question is, I have heard bigger consulting firms do subcontracting, is there any specific process of becoming a subcontractors. And is this the right path to get into consulting business when we have bigger giants ruling.
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2 Answers
up vote 0 down vote accepted
+50
Seems like you dont have any expeirence in sales. If you start consulting co you would need to do sales. Get yourself comfortable with that.
I think for consulting most important is to start building relationships. Try doing first projects really, really free and make sure people are happy about your results. Then start asking for recommendations. Then you can start slowly increasing the price.
Hope it helps Mark
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Being a subcontractor just means you're not the prime contractor, nothing more nothing less - so no, there's nothing special about it. That said, some very large contracts require that a percent of the contract be subcontracted to disadvantaged business enterprises. On the other end of the spectrum, some contracts forbid subcontractors.
As for getting subcontracts, just find the people who have the primes, find out who writes the proposals, management the projects, handles outsources, etc. -- and make contact in a meaningful way to them; really depends on your pitch, meaning you're able to do something they can't, are a disadvantaged business enterprise, etc.
Honestly most bizdev on subcontracts comes down to building relationships, but professionally speaking, this is one of many great books on doing business development as a consultant, "Rain Making: The Professional's Guide to Attracting New Clients".
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Libya: Obama Speaks, Tweeps Heckle
This post also available in:
Malagasy · Libya: Niteny i Obama, antso tao amin'ny Tweeps
Español · Libia: Obama habla, los tuiteros le reprochan
This post is part of our special coverage Libya Uprising 2011.
United States President Barack Obama broke his silence on Libya in a speech at the White House on Wednesday, but his words did little to satisfy the listening masses on Twitter who for the most heckled the president in tweets throughout the speech.
Without mentioning Libyan leader Colonel Muammar Gaddafi by name, Obama condemned the violence unleashed on Libyans since anti-government protests began on the night of February 16 (#Feb17) and offered condolences for those killed.
Obama said that Secretary of State Hillary Clinton would soon be meeting with the Human Rights Council in Geneva, and offered the following condemnation:
The suffering and bloodshed is outrageous, and it is unacceptable. So are threats and orders to shoot peaceful protesters and further punish the people of Libya. These actions violate international norms and every standard of common decency. This violence must stop.
The United States also strongly supports the universal rights of the Libyan people. That includes the rights of peaceful assembly, free speech and the ability of the Libyan people to determine their own destiny. These are human rights. They are not negotiable.
Below, is a selection of tweets made during Obama's speech.
@mafouad: Obama condemns use of Violence n Libya adding “The entire world is watching”. Isnt the “watching” piece that got us where we freekin are!
@Abdulla_AlAthba: Obama offered nothing to Libya, he is just selling nice words in silly way, and insulted us #Libya #Gaddafi #Obama #SecClinton #Tripoli
@Kim_AE: Is it a coincidence that Obama waited to condemn the violence in Libya till the UN did so on Tuesday? http://tinyurl.com/4tjxat9
@JacksonDiehl: Gaddafi was surely worried about US military intervention–instead, Obama announces a meeting of the UN Human Rights Council #Libya
@PressSecret: After 9 days of silence, commenting on Libya Obama fails to condemn or mention genocidal Gaddafi by name. Strange. || #Obama #Gaddafi #Libya
@MassimoBianchi1: I am tired to see obama speech he need to take actions in LIBYA RIGHT NOW!
@bangkolo88: It is a nice thing that Obama has finally involve in the crises in Libya. But we wish he was clearer on his plan of action.
@ranty_man: Obama finally comes out with a statement on Libya now that the outcome looks certiain
@tristamsparks: hey #Obama the world has been watching #Libya for 8 days. #hardlydecisive
@EmyDib: @seedsown the thing in times like these how soon is soon enough!? #Feb17 #Libya #Egypt #Obama #Algeria
@obamafoodorama: #Obama took no questions after he made his statement on #Libya. #Clinton made no statement.
@alienmedia: #Bahrain & #Yemen were NOT in Obama's speech on #Libya. Urged for peaceful transition to democracy in #Tunis & #Egypt. http://bit.ly/gAf2L6
@Algerian_Dude: President Obama didn't say suffering and bloodshed in #Gaza is “outrageous & unacceptable” #Libya
@Pkatt: @aldamario Lets see what Obama does… YOU? #p2 #tcot #ocra #teaparty
@MagButter: One common thing between #Obama & #Gaddafi: Both speeches are useless! #Libya #Feb17
@klaus_eduard: #Obama basically said US won't irritate #Gaddafi until US citizens are out. Should have been out long time ago. Will he ever act? #Libya
@StephenMullen: Dear Obama, Gaddafi is respecting the rights of Libyans. It's a dictatorship, they have none. That what the protests are about.
@AliTweel: so, Obama has no deal with Libya, but Gaddafi says this revolution is all made by “the west” as he described! who is right and who is wrong?
@RuwaydaMustafah: #Obama didn't mention #Gaddafi by name, why? #Libya
@aishes: Maybe Obama refusing to mention #Gaddafi was his way of delegitimizing him? I'm still trying to glean something substantial from his speech.
@TheGaryRuppert: Gaddafi mentioned murdering protesters 17 times in his speech. But Obama thinks they can go to Geneva and have a peace summit? #tcot #p2
@Abdulla_AlAthba: @PhoenixRising4O I'm not after Mr. Obama speech, I wanted free fly-zone in #Libya right away, to make sure #Gaddafi wont bomb his ppl.
@Jim_Gardner: #Obama speech on #Libya didn't mention #Gaddafi by name. Not once. Is he trying to safeguard Americans living in Libya? Could be.
@Afterseven: If Gaddafi's not careful, Obama could write him a very sternly worded letter of rebuke. Framed of course, with an accompanying iPod
@shablibi: To be fair I think that @obama's statement was smart, he distant himself from #Gaddafi and talked simply about #Libya therefore no cause
@RamsayShort: Obama talks crap.He has not mentioned the word Gaddafi once.He is buying time, ignoring the reality.His nation supported Gaddafi.A joker.
@mattklewis: Obama must show leadership. Should call on Gaddafi to immediately step down. Should work with UN to set up a no-fly zone to protect citizens
@Doylech: Obama has finally decided to say something re #gaddafi. Several thousand lives too late #libya
@bengalbabydaddy: But suffering elsewhere is okay. @foxnews: #BreakingNews: Obama Calls Suffering and Bloodshed in Libya ‘Outrageous’ and ‘Unacceptable’
This post is part of our special coverage Libya Uprising 2011.
World regions
Countries
Languages | v0 |
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} | cccc_CC-MAIN-2013-20 | A GUIDE TO THE DESIGN OP AIR BUBBLERS FOR MELTING ICE
Simon Ince
Abstract
The use of air bubblers for maintaining ice-free areas in lakes and in the sea has been reported abundantly in the technical literature. This author (1962) reported his observations on two air bubbler installations in the Canadian Arctic to the Eighth International Conference on Coastal Engineering. The results of these investigations were, at that time, still inconclusive. Today, some of the mystery is resolved and it is the author's opinion that the existence of a heat reserve is the answer to the problem. Based on this premise, an attempt is made here to develop some guide lines for the proper utilization of this thermal reserve.
Keywords
air bubbles; melting of ice; ice deterrance
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:33:00.000Z | igkntmne4rqn3nuo5hh3ltwovjmnlb6u | {
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} | cccc_CC-MAIN-2013-20 | FIELD MEASUREMENTS AND NUMERICAL MODELING OF HARBOR OSCILLATIONS DURING STORM WAVES
W.M. Jeong, J.W. Chae, W.S. Park, K.T. Jung
Abstract
A series of simultaneous field measurements for long and short-period waves under storm and calm wave conditions were made to understand harbor resonances in a partially enclosed harbor. During storm condition the frequency spectra show peaks of considerable magnitude around the wave period of 1 ~ 5 minutes, which are bounded long waves and their harmonics. They are strongly related with storm waves but longer period (free long) waves are not in the harbor. Numerical tests were also carried out by using the hybrid element model including entrance separation losses in a simple rectangular harbor to validate the model for a mostly constricted entrance case. Further the model was used to simulate the long period oscillation in Muko harbor. Comparisons were made between field data and numerical results to discuss the effect of storm waves on the long period oscillations. Tests demonstrate the effect of input parameters on model results and proper choice of them are stressed.
Keywords
field measurement; numerical model; harbor; harbor oscillation; storm waves
Full Text: PDF
This work is licensed under a Creative Commons Attribution 3.0 License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T05:55:54.000Z | bqqggon2nkqabtyt7wzajomh5odkd2i6 | {
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} | cccc_CC-MAIN-2013-20 | Thursday, March 23, 2006
Majority Rules is Democracy But so Is Dissent Democratic
If you go here, you can find the entire decision but for a short survey, here is okay.
The story? The Chief Justice of the US Supreme Court was in the minority on a question of constitutional validity of a search. What was at issue was the justification the judges used to alter the law, something similar here in Israel in terms of sociall norms, etc.
Excerpts:-
Writing for the majority, Justice David H. Souter said the search was unreasonable, given the vocal objection of the husband, Scott Randolph. True, Justice Souter said, the court had long permitted one party to give consent to a search of shared premises under what is known as the "co-occupant consent rule." But he said that rule should be limited to the context in which it was first applied, the absence of the person who later objected.
The presence of the objecting person changed everything, Justice Souter said, noting that it defied "widely shared social expectations" for someone to come to the door of a dwelling and to cross the threshold at one occupant's invitation if another objected.
"Without some very good reason, no sensible person would go inside under those conditions," he said.
"We have, after all, lived our whole national history with an understanding of the ancient adage that a man's home is his castle," Justice Souter said. "Disputed permission is thus no match for this central value of the Fourth Amendment."
The dissenters, in addition to Chief Justice Roberts, were Justices Antonin Scalia and Clarence Thomas. In his opinion, the chief justice took aim at the majority's description of social custom, as well as its reliance on that description to reshape "a great deal of established Fourth Amendment law."
Every lower federal court to have considered the issue, as well as most state courts, had concluded that one party's consent was sufficient. The Georgia Supreme Court, in its 2004 decision that the justices affirmed, was in the minority, ruling in this case that the evidence of Mr. Randolph's cocaine use was inadmissible.
"The fact is that a wide variety of differing social situations can readily be imagined, giving rise to quite different social expectations," Chief Justice Roberts said. For example, he continued, "a guest who came to celebrate an occupant's birthday, or one who had traveled some distance for a particular reason, might not readily turn away simply because of a roommate's objection."
Noting that "the possible scenarios are limitless," he said, "Such shifting expectations are not a promising foundation on which to ground a constitutional rule, particularly because the majority has no support for its basic assumption — that an invited guest encountering two disagreeing co-occupants would flee — beyond a hunch about how people would typically act in an atypical situation."
The majority missed the point, the chief justice said; the fact is that someone choosing to share space has also, already, chosen to share privacy.
"Our common social expectations may well be that the other person will not, in turn, share what we have shared with them with another — including the police," he said, "but that is the risk we take in sharing."
In a concluding paragraph of his dissent, he said: "The majority reminds us, in high tones, that a man's home is his castle, but even under the majority's rule, it is not his castle if he happens to be absent, asleep in the keep or otherwise engaged when the constable arrives at the gate. Then it is his co-owner's castle."
In Israel, I can't recall the judges voting that way. In fact, they usually kowtow to Professor Aharon Barak's activism and liberalism.
| v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T05:43:09.000Z | q2kmio7btrkg556h4ymm67fefplua66f | {
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} | cccc_CC-MAIN-2013-20 | Quotes by Unknown, Source
We don't have a biography. Please consult wikipedia.
"It was once said that love is giving someone the ability to destroy you, but trusting them not to."
Unknown, Source on love
3 fans of this quote
"If you look to the lives of others, you’ll always find yourself lacking. Look instead at what you have, and be grateful."
Unknown, Source on (kingdom of heaven)
But wait... There are more: prev 41, 42, 43, 44, 45, 46
Take a look at recent activity on QB!
Search Quotations Book | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:50:38.000Z | nenuqfcvvi4l6yxm2mr3wfiz2o7z7kan | {
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} | cccc_CC-MAIN-2013-20 | Viva Mars Vegas
From The Infosphere, the Futurama Wiki
Jump to: navigation, search
Season 7 episode
Broadcast season 9 episode
Viva Mars Vegas
Zoidberg handing money to some Martians.
No.126
Production number7ACV12
Broadcast numberS09E11
Written byJosh Weinstein
Directed byFrank Marino
Title captionMade By Hand (and Tentacle)
First air date22 August, 2012
Title referenceThe 1964 Elvis Presley film Viva Las Vegas
Opening cartoonFuturama - "Reincarnation" (2011)
Additional
Commentary
(Transcript)
Transcript
Pictures
Season 7
1. The Bots and the Bees
2. A Farewell to Arms
3. Decision 3012
4. The Thief of Baghead
5. Zapp Dingbat
6. The Butterjunk Effect
7. The Six Million Dollar Mon
8. Fun on a Bun
9. Free Will Hunting
10. Near-Death Wish
11. 31st Century Fox
12. Viva Mars Vegas
13. Naturama
14. Forty Percent Leadbelly
15. 2-D Blacktop
16. T.: The Terrestrial
17. Fry and Leela's Big Fling
18. The Inhuman Torch
19. Saturday Morning Fun Pit
20. Calculon 2.0
21. Assie Come Home
22. Leela and the Genestalk
23. Game of Tones
24. Murder on the Planet Express
25. Stench and Stenchibility
26. Meanwhile
← Season 6
"Viva Mars Vegas" is the one hundred and twenty-sixth episode of Futurama, the twelfth of the seventh production season and the ninth broadcast season. The Planet Express crew stages a casino heist to recover stolen property from the Robot Mafia.
Contents
[edit] Plot
[edit] Act I: "Category Five Sucker Now Arriving."
The Robot Mafia steals some money from a delivery company. Meanwhile, the crew decides to go to a casino in Mars Vegas. Zoidberg is excited to go, but Amy tells him not to come because of his poor money managing skills. Dejected, he goes back to his dumpster. Meanwhile, the Robot Mafia is being chased by the police, so they decide to dump their money in Zoidberg's dumpster, where Zoidberg takes it. Zoidberg goes to Mars Vegas, and after a few risky bets, he loses all of the money. When he gets back to the dumpster, he finds it occupied by the Robot Mafia wanting their money back.
[edit] Act II: "Mr. Wong, we have a mafia proposal for you. Your casino...give it to us."
After Zoidberg tells them that he lost all of the money to the casino, they try to kill them, but Zoidberg escapes by triggering his ink defense, which covers him in ink. He goes to the Planet Express building, where Professor Farnsworth accidentally uses a ink remover to make all the ink on Zoidberg invisible. This makes Zoidberg invisible as well, and then the Robot Mafia break into the PE bulding and look for Zoidberg. Because Zoidberg is invisible, he cannot be found by them. The mafia decide to get their money back by taking over the casino. In the process, they take away all of Leo and Inez Wong's property, including their mansion, which reduces them to living in the area they set aside for their employees. However, Amy comes up with a plan to get the money back, with a little help from Zoidberg.
[edit] Act III: "He STINKS like the inside of a Tauntaun."
Using a smelly shrimp cart to hide Zoidberg's stench, the crew goes upstairs to the area with the safe. Leela, Amy, and Fry, who are pushing the cart, pretend to have a broken wheel so that they have a reason to stay up there, while Professor Farnsworth, Hermes, and Bender distract Donbot to keep him from closing the safe door prematurely. Meanwhile, Zoidberg gets into the safe and eats all of the money, except a few bills he coughs up, making it just as invisible as he is. He also eats a black box. However, after eating all of this, he becomes too heavy to move, so the Professor, Hermes, and Farnsworth have to carry him out until they can get him on the shrimp cart. They had intended to escape through the roof, but Zoidberg's weight made the elevator fall to the first floor, forcing them to escape through the main lobby. Zoidberg starts coughing up money as they go. Despite this, they almost make it to the exit, until a blind guard, Blind Joe catches them. He tries to force them to give him the money, but Amy tries to make a deal with him. Because the guard is a Native Martian, he doesn't like making deals with the Wong Family. Amy says that this is because he doesn't know about the original deal, which only gave the Wong family the right to occupy the land for 100 years before they gave the land back to the Native Martians. Because of this, the Native Martians own the casino, and they kick the Robot Mafia out. Fortunately for the Wong family, the Native Martians give back the Wong's mansion and their other casino. Professor Farnsworth tells Zoidberg that he'll become visible again as soon as he takes a bath, and he goes with Amy to the other casino.
[edit] Production
On 29 February 2012, CGEF revealed the episode's title, its writer to be Josh Weinstein and its director to be Frank Marino.[1][2] On 10 July, MSN TV updated their Futurama episode guide, revealing the episode's plot and air date.[3] The same day, Zap2it released a TV listing of Futurama which showed the same information about the episode, with slight variation from the plot published by MSN.[4]
On 12 July, following the broadcast of the episode "Zapp Dingbat", the public were given the opportunity to participate in a live chat with the Futurama cast and crew. Several clips of "Viva Mars Vegas" during the live stream.[5]
[edit] Additional information
[edit] Continuity
[edit] Allusions
• The episode's title is a reference to the 1964 Elvis Presley film Viva Las Vegas.
• The song played through the montage of Zoidberg spending his cash and sung by Zoidberg himself at the end of the episode is a parody of the song Big Spender from 1966 musical Sweet Charity.
• The Binks Armored Express truck at the beginning of the episode is a reference to the Star Wars character Jar Jar Binks from Episode I: The Phantom Menace, and the Brink's armored trucks. The truck is also piloted by two aliens that bear a striking resemblance to the Gungans, Jar Jar's species, and they also speak like him.
• The Donbot refers to the stolen money as "De Niros", a play on "denaros" and Robert De Niro whom the Donbot is based upon. Of De Niro's various films is Casino which involves mob connections in Vegas.
• The Professor says "Dude, where's my ship?", in reference to the 2000 stoner comedy film Dude, Where's My Car?
• The ball that the croupier uses in the roulette game flaps its "wings" and flies around the roulette wheel, making it very similar to a Golden Snitch from Harry Potter. It does not behave this way during the final spin that results in Zoidberg losing, though.
• The plot of an orchestrated casino heist has been the subject of many films including Ocean's Eleven.
• The deal made by Sir Reginald Wong with the Native Martians was supposed to last as long as the deal the deal the British made with the Chinese to gain control of Hong Kong.
• Wong Island is a parody of the Las Vegas hotel and casino Treasure Island. Its name may also be a reference to New York's Long Island.
[edit] Trivia
The opening caption of the live recreation of the opening sequence.
• When the vault scans the Donbot's finger, it identifies him as Don "Smith".
• The title sequence for this episode is a live-action recreation, which was also used to promote the new season through ads on Comedy Central. It is also the second major alternate one-off title sequence since Into the Wild Green Yonder.
• Zoidberg reads a newspaper called "The Daily Bum Blanket".
• This is the second episode (in production order) of season 7 to be aired out of order, as the broadcast order of both this episode and "31st Century Fox" were swapped.
• It is confirmed in the commentaries that this swap was requested by Comedy Central as they wanted to advertise Patrick Stewart being in the season finale (which they subsequently did not).
• The Professor says that he is a young internet billionaire, in reference to Mark Zuckerberg, who created Facebook whilst at University.
• Arriving at the parking lot of the casino, Planet Express Ship crushes what appears to be Mars Curiosity rover, although it appears larger than the real life robot compared to the size of the ship.
[edit] Quotes
Zoidberg: Look out, penny slots, I've got a system! It's to put all my money in you! [He laughs to himself.]
Zoidberg: [He sighs then puts his claws together and begins to pray.] God, it's Zoidberg.
Joey Mousepad: [He bangs on the door.] It's no use, Zoidberg! We're like 85% sure you're in there!
Professor: My God! He was so saturated with ink that his entire body structure was polarized!
Zoidberg: You mean I'm invisible?
Professor: No, no, no, not in any sense of the word. But essentially, yes, entirely.
[As Zoidberg risks the $8 million on a single game of roulette.]
Amy: Zoidberg, what are you doing?
Zoidberg: I don't know. I think it's called "roulette".
[edit] Goofs
• Native martians are seen here, but they all left Mars in "Where the Buggalo Roam".
• That doesn't mean some few would not return possibly out of a sense of attachment to their ancestral lands.
• Zoidberg spends a lot of money before he gets to the table, so he couldn't have had eight million left. Because of this, he shouldn't have been able to buy eight chips, each worth a million dollars.
• At the beginning of the episode Donbot said "It's over eight million bucks". So Zoidberg could only spend the "over" part.
• If the Wongs had two casinos, then why not just go there when the mafia take their first casino and their house? Furthermore, if this is New Mars Vegas as in Into the Wild Green Yonder, wouldn't the Wong family have many business holdings over the entire planet?
• It might have been possible that most of the building were damage during the Farewell to arms' incident with only those two casino being operational at the time.
• None of the mafia, or the native martians seemed to question, why the old shrimp carriers, and all those people turned up (the crew in disguise) in the money counting room, despite the fact its supposed to be the most secure area.
• This may have been done intentionally as a joke.
• The deal between the native martians and the Wongs here is different to the deal mentioned in "Where the Buggalo Roam".
• The deal only involved paying for the land, there was no mention of whether Sir Reginald was purchasing or leasing it. Thus his compassionate intentions to give back the land must have been a lost detail that only Amy was familiar with.
• Amy also might have told Blind Joe something that he'd want to hear to make him side with her family.
• Zoidberg doesn't eat the two 100 dollar bills that fall out of his mouth.
• The ink on Zoidberg's mouth is wiped off, exposing it. When Amy escorts Zoidberg to Wong Island, the ink on Zoidberg's mouth has returned, as the pink of his skin would have been able to see from the back of him.
• It's possible that it doesn't show because the ink on the back of his head covers it, which would be why we can't see inside of him.
• The Professor says that the ink will wash off when Zoidberg takes a bath. But in the bath scene, the ink doesn't wash off.
• As a robot, Bender doesn't possess a scent, so how could Blind Joe smell, he was stealing money?
• Bender would have a strong scent of alcohol and tobacco.
• In Godfellas the Professor notes that Bender does have an odor, however mild.
• Why didn't the ink come off on the money or Amy when Zoidberg touched them?
• The ink would have dried by then.
• When Zoidberg places his third bet on 34 red, he pushes all the chips away to his left onto 34 on the roulette board, but while the wheel is spinning the chips are right in front of him again. His sardinie has also filled back up after he loses, although it could be a refilling glass like the ones seen in "That Darn Katz!".
• Zoidberg's eyes weren't covered with ink, neither was the inside of his mouth. So, while he is invisible, you should have been able to see his eyes and see his tongue when he speaks.
[edit] Appearances
[edit] Characters
(In alphabetic order)
[edit] Places
(In alphabetic order)
[edit] References
1. ^ Episode Guide: 7 ACV. (CGEF.) 29 February 2012. Retrieved on 29 February 2012.
2. ^ "Just Fan" (29 February 2012). "Futurama: Futurama News (pre-season 7)". (PEEL.) Retrieved on 29 February 2012.
3. ^ Futurama - Episode Guide. (MSN TV.) Retrieved on 12 July 2012.
4. ^ Futurama : Viva Mars Vegas; Naturama. (Zap2It.) Retrieved on 10 July 2013.
5. ^ "Tastes Like Fry" (12 July 2012). "Newsarama! (Futurama News Thread)" (page 1). (PEEL.) Retrieved on 13 July 2012.
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2024-06-03T21:29:47.544Z | 2013-05-18T05:57:06.000Z | agdg2mkelqopqey6wsdlvrszbvuxxkze | {
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} | cccc_CC-MAIN-2013-20 | Research article
Mucin 1 (MUC1) is a novel partner for MAL2 in breast carcinoma cells
Susan Fanayan1, Mona Shehata1,2, Annelies P Agterof1,3, Michael A McGuckin4, Miguel A Alonso5 and Jennifer A Byrne1,2*
Author Affiliations
1 Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, 2145 NSW, Australia
2 The University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia
3 Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
4 Epithelial Cancer and Mucosal Biology Laboratory, Mater Medical Research Institute, Mater Health Services, South Brisbane 4101 Qld, Australia
5 Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid and Consejo Superior de Investigaciones Científicas, Cantoblanco, 28049-Madrid, Spain
For all author emails, please log on.
BMC Cell Biology 2009, 10:7 doi:10.1186/1471-2121-10-7
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2121/10/7
Received:21 August 2008
Accepted:28 January 2009
Published:28 January 2009
© 2009 Fanayan et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
The MAL2 gene, encoding a four-transmembrane protein of the MAL family, is amplified and overexpressed in breast and other cancers, yet the significance of this is unknown. MAL-like proteins have trafficking functions, but their molecular roles are largely obscure, partly due to a lack of known binding partners.
Methods
Yeast two-hybrid screening of a breast carcinoma cDNA expression library was performed using a full-length MAL2 bait, and subsequent deletion mapping experiments were performed. MAL2 interactions were confirmed by co-immunoprecipitation analyses and confocal microscopy was employed to compare protein sub-cellular distributions. Sucrose density gradient centrifugation of membranes extracted in cold Triton X-100 was employed to compare protein distributions between Triton X-100-soluble and -insoluble fractions.
Results
The tumor-associated protein mucin 1 (MUC1) was identified as a potential MAL2 partner, with MAL2/MUC1 interactions being confirmed in myc-tagged MAL2-expressing MCF-10A cells using co-immunoprecipitation assays. Deletion mapping experiments demonstrated a requirement for the first MAL2 transmembrane domain for MUC1 binding, whereas the MAL2 N-terminal domain was required to bind D52-like proteins. Confocal microscopy identified cytoplasmic co-localisation of MUC1 and MAL2 in breast cell lines, and centrifugation of cell lysates to equilibrium in sucrose density gradients demonstrated that MAL2 and MUC1 proteins were co-distributed between Triton X-100-soluble and -insoluble fractions. However co-immunoprecipitation analyses detected MAL2/MUC1 interactions in Triton X-100-soluble fractions only. Myc-MAL2 expression in MCF-10A cells was associated with both increased MUC1 detection within Triton X-100-soluble and -insoluble fractions, and increased MUC1 detection at the cell surface.
Conclusion
These results identify MUC1 as a novel MAL2 partner, and suggest a role for MAL2 in regulating MUC1 expression and/or localisation.
Background
Human MAL2, a 19 kDa protein with four transmembrane (TM) domains [1,2] is a member of the MAL protein family. The founding member MAL [3] resides in lipid rafts [4,5] and is required in apical vesicle transport [6-9]. The MAL family also includes less characterised members, including BENE, which is also a raft-associated integral membrane protein [10], plasmolipin, a 20 kDa proteolipid expressed in compact myelin and epithelial cells [11] and chemokine-like factor superfamily 8 (CKLFSF8), a novel regulator of EGF-induced signalling [12]. MAL2 was identified as a partner for tumor protein D52-like proteins through yeast two-hybrid (Y2H) expression screening of a human breast carcinoma library [1]. The MAL2 protein is now known to be expressed in many epithelial cell types, as well as peripheral neurons, mast cells and dendritic cells [13]. In HepG2 hepatoma cells, MAL2 resides exclusively within lipid rafts, and represents an essential component for indirect basolateral-to-apical transcytosis [2], where it shows a highly dynamic subcellular localisation [14]. MAL2 has also been reported to be distributed in both lipid raft and non-raft fractions in primary thyrocytes [15] and PC-3 prostate carcinoma cells [16], predicting additional, uncharacterised cellular functions for MAL2 outside lipid rafts.
The initial identification of MAL2 suggested its overexpression in breast cancer [1], which is supported by the MAL2 gene being found at chromosome 8q24, which is frequently gained in breast and other cancers [17]. Several studies have now identified MAL2 amplification and/or overexpression in breast cancer [18-22]. Overexpression of MAL2 has also been reported in other cancers, including primary ovarian carcinoma [23,24] and ascites [25], and pancreatic carcinoma [26], where MAL2 has since been employed as a discriminator of pancreatic carcinoma versus chronic pancreatitis [27]. Expression profiling has also indicated MAL2 overexpression in malignant pleural mesothelioma of the epithelial type [28], and in head and neck squamous cell carcinoma [29]. Immunohistochemical analyses first revealed differential MAL2 expression in renal carcinomas [15], with this being recently confirmed in chromophobe renal cell carcinoma versus oncocytoma [30].
Despite numerous reports of MAL2 overexpression in breast cancer, little is known about how increased MAL2 expression may provide an advantage to cancer cells. While MAL2 cellular localisation and function have been explored in previous studies [2,14,15], the only known MAL2 partners are members of the D52-like protein family [1]. Interactions between MAL2 and both D52 and D53 have since been identified in a large scale Y2H analysis [31], which supports further use of the Y2H system to analyse MAL2 function. We therefore carried out a Y2H screening of a breast carcinoma cDNA expression library [1,32] to identify novel MAL2 binding partners. One protein thus identified was mucin 1 (MUC1), a transmembrane protein expressed on the apical surface of epithelial cells [33] and overexpressed in multiple cancers [34], in part through MUC1 gene amplification [35]. Like other mucins, MUC1 protects and lubricates normal glandular epithelia, whereas MUC1 overexpression in cancer alters many cellular properties, including intercellular adhesion and immune recognition [33,34]. As MUC1 therefore represented a candidate MAL2 partner of particular interest, subsequent experiments were performed to confirm MAL2/MUC1 interactions, and examine their significance in breast epithelial and cancer cells. As we will describe, this work identifies a MAL2 as a cytoplasmic MUC1 partner which binds MUC1 in non-lipid raft fractions, and may regulate MUC1 expression and/or subcellular distribution.
Methods
Plasmid constructs
Bait proteins for use in the Y2H system were expressed from the pAS2-1 vector (Clontech, Mountain View, California, USA), and prey proteins were expressed from the pACT2 (Clontech) or pAD-GAL4 (Stratagene, La Jolla, CA, USA) vectors. The pAS2-1MAL2 bait construct was obtained by subcloning an EcoRI-XhoI fragment, representing the entire MAL2 cDNA insert, into the EcoRI and SalI sites of pAS2-1 vector. For the pAS2-1MAL and pACT2MAL constructs, a MAL cDNA insert was amplified by PCR amplification to introduce a 5' NcoI site, and a 3' XhoI site downstream of the stop codon, which was then subcloned into the corresponding or compatible sites in pAS2-1 and pACT2. Constructs including truncated versions of the MAL2 coding region were amplified by the polymerase chain reaction (PCR) using specific primers (Table 1). For the pAS2-1MAL2ΔN and pACT2 MAL2ΔN constructs, primers introduced a 5' NcoI site, and a 3' XhoI site downstream of the stop codon. For the pAS2-1MAL2ΔNTM1, pAS2-1MAL2ΔNTM12, pAS2-1MAL2ΔNTM123 and pAS2-1MAL2ΔNTM1234 constructs, primers introduced a 5' EcoRI site, and a 3' XhoI site downstream of the stop codon. All subcloned constructs were verified by DNA sequencing, with PCR-generated inserts being fully sequenced on one DNA strand. The pCR3.1/Myc-MAL2 expression construct has been previously described [2]. All constructs encoding D52-like fusion proteins, and the human breast carcinoma cDNA library constructed in the HybriZAP vector (Stratagene) have been previously described [1,32].
Table 1. Deleted MAL2 yeast two-hybrid constructs, primer sequences and MAL2 regions deleted
Yeast two-hybrid system and screening
Yeast cultures of the Saccharomyces cerevisiae Hf7c strain were grown at 30°C in standard liquid or solid media, based upon either rich YPD media (2% bacto-peptone, 1% yeast extract, 2% dextrose), or minimal SD medium (0.67% yeast nitrogen base without amino acids, 2% dextrose, with appropriate amino acid supplements) for expression library screening and direct interaction testing. For cDNA library expression screening, bait (pAS2-1MAL2) and human breast carcinoma pAD-GAL4 library plasmids were transfected simultaneously into Hf7c cells. Subsequent screening and the recovery of plasmid DNA from yeast cells were carried out as described [32]. For the direct testing of interactions, paired baits (pAS2-1 constructs) and preys (pACT2 or pAD-GAL4 constructs) were transfected into Hf7c cells as described [32]. Interactions between baits and preys were assessed by qualitatively determining HIS3 reporter gene activity [1].
Antibodies
The BC2 (an anti-MUC1 VNTR epitope mouse IgG1 monoclonal) and FITC-BC2 antibodies have been previously described [36]. Rabbit polyclonal c-Myc (A-14) and CAV1 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and BD Biosciences (BD Biosciences, San Jose, CA, USA), respectively. Affinity-purified D52 rabbit polyclonal antibody has been described previously [37]. Peroxidase-conjugated donkey anti-rabbit and anti-mouse, FITC-conjugated donkey anti-mouse and CY3-conjugated donkey anti-rabbit secondary antibodies were purchased from Jackson ImmunoResearch, Inc (West Grove, PA, USA).
Preparation and affinity purification of polyclonal MAL2 antisera
For the production of sheep antisera, one sheep was injected subcutaneously with 2 mg coupled MAL2 C165-P176 peptide antigen on 2 occasions, spaced by 3 weeks. For the production of rabbit antisera, two rabbits were injected subcutaneously with 0.5 mg coupled N13-V24 and C165-P176 MAL2 peptide antigens on 2 occasions, spaced by 2 weeks. Antisera were affinity-purified using relevant MAL2 peptides as previously described [37].
Human breast cell lines
The MDA-MB-435 (a kind gift from Dr Janet Price, MD Anderson Cancer Centre, Houston, TX), MDA-MB-453, SK-BR-3 and MCF-7 breast cancer cells were cultured as described in the American Type Culture Collection Catalogue. MCF-10A cells are described in the American Type Culture Collection Catalogue and were cultured as described [38].
Derivation of stably-transfected cell lines
The Myc-tagged MAL2 expression construct was stably transfected into MCF-10A cells. Cells were seeded at approximately 60% confluence in 100 mm dishes and transfected 18 h later with 20 μg plasmid DNA using LipofectAMINE 2000 Reagent (Life Technologies, Inc., Gaithersburg, MD, USA), according to the manufacturer's instructions. After 24 h, G418 was added to a concentration of 1 mg/ml. Media were replenished every 2–3 days and a G418-resistant mixed population was selected 14 days post-transfection. MDA-MB-435 and MDA-MB-453 breast cancer cells were transfected by electroporation with a MUC1 cDNA containing 22 VNTR repeats in the pcDNA3 vector (Invitrogen) or the vector alone. Stable G418 resistant clones were isolated and MUC1 expression determined by flow cytometry.
Preparation of total protein extracts and Western blot analyses
Cells were harvested in cold PBS, pelleted and washed twice in cold PBS. Total cell protein extracts were prepared by resuspending the pellet in SDS extraction buffer (125 mM Tris-HCl pH 6.8, 3% SDS, 5% 2-mercaptoethanol, 1 mM PMSF, and protease inhibitors [Roche, Basel, Switzerland]), which were then briefly sonicated. Samples were resolved using SDS-PAGE on 12.5% polyacrylamide gels, and electrotransferred to nitrocellulose filters (Millipore, Billerica, MA, USA). Protein loading was analysed using Ponceau S staining, and filters were blocked overnight at 4°C in 5% skim milk powder in TBS. Membranes were washed twice with TBS and incubated with either affinity-purified rabbit polyclonal MAL2 antisera (1/100), affinity-purified rabbit polyclonal D52 antisera (1/100), BC2 (1/100) or CAV1 antibody (1/2000) in 0.1% Tween 20 in TBS, for 2 h. Membranes were washed 3 times in 0.1% Tween 20 in TBS, and then incubated with horseradish peroxidase-conjugated donkey anti-rabbit or donkey anti-mouse secondary antibody (Jackson ImmunoResearch, Inc) (1/5000) for 2 h. Blots were washed 4 times with 0.1% Tween 20 in TBS, followed by 2 washes in TBS and antigen-antibody complexes were visualised by Western lightning chemiluminescent reagent (Perkin Elmer, Waltham, Massachusetts, USA).
Co-immunoprecipitation analyses
MCF-10A cells were grown to 80% confluence in 100 mm dishes and washed with cold PBS. For each co-immunoprecipitation, proteins were extracted by scraping cells from 6 dishes into 0.15 ml lysis buffer per dish. For co-immunoprecipitation of MAL2 and D52 proteins, 10 mM Tris with 1 mg/ml Saponin (Sigma-Aldrich, St. Louis, MO, USA) was employed as a lysis buffer [39]. For co-immunoprecipitation of MAL2 and MUC1 proteins, SDS lysis buffer (125 mM Tris-HCl pH 6.8, 3% SDS, 5% 2-mercaptoethanol, 1 mM PMSF, and protease inhibitors (Roche) was employed. Protein A-Sepharose beads (Sigma-Aldrich) plus rabbit MAL2 antisera (1/50), either alone or with 1 μg/ml synthetic peptides N13-V24 and C165-P176, or protein G-agarose beads (Sigma-Aldrich) plus BC2 (1/50) were added to cell lysates and incubated on a rotary mixer at 4°C for 16 h. Beads were washed 4 times with 1 ml lysis buffer, followed by a final wash with PBS. Eluted proteins (15 μl) were separated using SDS-PAGE on 12.5% polyacrylamide gels and electrotransferred to nitrocellulose filters (Millipore) for Western blot analyses, as above.
Immunofluorescent labelling of breast cell lines
Cell lines were cultured to near confluence, and harvested by trypsinisation. Cells were diluted 3- to 10-fold and cultured overnight on glass coverslips. For immunofluorescent staining, cells were washed twice with PBS, and fixed in 4% paraformaldehyde supplemented with 0.1% saponin for 20 min at RT. Cells were washed twice with PBS, and incubated at RT for 2 h with affinity-purified rabbit MAL2 (1/50), D52 (1/100) antisera or mouse BC2-FITC (40 μg/ml), in 0.1% bovine serum albumin (BSA) in PBS. Primary antibody was omitted in control incubations. Cells were washed twice with PBS and incubated with a CY3-conjugated donkey anti-rabbit secondary antibody (1/500) (Jackson ImmunoResearch) in 0.1% BSA in PBS, for 1 h in the dark. Cells were washed again and DNA was counterstained with 10 nM DAPI (Sigma-Aldrich). Following 2 washes in PBS, cells were mounted in DAPCO (Sigma-Aldrich) prepared according to the manufacturer's instructions. Images were taken using a TCS SP2 Laser Scanning Confocal microscope (Leica Technologies, Wetzlar, Germany), using a 63× oil-immersion objective and a 4× zoom factor.
Membrane fractionation analyses
Triton X-100 soluble and insoluble fractions were prepared essentially as described [40]. Cells grown in 4 × 100 mm dishes were treated with 20 mM methyl β-cyclodextrin (MβCD) at 37°C for 30 min. Cells were then rinsed with PBS and lysed for 20 min in 1 ml 25 mM Tris-HCl pH 7.5, 150 mM NaCl, 5 mM EDTA, 1% Triton X-100 at 4°C. The lysate was brought to 40% sucrose in a final volume of 4 ml, placed at the bottom of a 12 ml tube, and then layered with 6 ml 30% sucrose followed by 2 ml 5% sucrose, made in the same buffer without Triton X-100. Gradients were centrifuged for 22 h at 36,000 rpm at 4°C in a Beckman SW41 rotor. Fractions of 1 ml were harvested from the top of the tube and aliquots were subjected to Western blot analyses.
Results
Yeast two-hybrid screening identifies MUC1 as a putative MAL2 partner
To identify MAL2 partners expressed in breast cancer tissue, a Y2H screen of a breast carcinoma cDNA expression library [1,32] was performed with a full-length MAL2 bait. Screening 5,000,000 cfu in Hf7c cells identified 72 Hf7c colonies that remained His+ on restreaking on solid SD/-Leu-Trp-His media. Sequencing the corresponding cDNA inserts identified 6 novel candidate MAL2 binding partners, of which MUC1 was most frequently isolated. DNA sequencing indicated that all 7 MUC1 prey constructs [preys #1–#7] encoded N-terminally truncated MUC1 proteins, which commonly included the SEA module, the TM domain and the cytoplasmic tail (Figure 1a). Testing whether MUC1 (prey#1, Figure 1a) could reproducibly bind MAL2 and/or the related protein MAL showed that MUC1 could bind both MAL2 and MAL baits in the Y2H system (Figure 1b). In contrast, D52-like baits bound MAL2 prey as previously reported [1], but not MAL (Figure 1b). Since MAL and MAL2 sequences differ in their N-terminal regions [1] and a full-length MAL2 prey was originally isolated using a D54 bait [1], the MAL2 N-terminal domain (M1-T34) was hypothesised to represent the interaction interface with D52-like proteins. Deleting this region abolished interactions with all D52-like proteins tested, but did not affect interactions with MUC1 (Figure 1b), suggesting that MUC1 and D52-like proteins bind discrete regions of MAL2.
Figure 1. (a) Schematic diagram of MUC1 preys (prey#1-prey#7) isolated during Y2H screen. All prey proteins were predicted to include the SEA module, the transmembrane domain (TM) and the cytoplasmic tail (CT). The length of the extracellular tandem repeat is not shown to scale in full-length MUC1. (b) Deleting the MAL2 N-terminus does not affect its binding to MUC1 but abrogates its interaction with D52-like proteins. Interactions were tested between MAL, MAL2 or MAL2ΔN, and MUC1 (prey#1) or D52-like proteins in Hf7c cells using the Y2H system. (-) indicates no detectable growth of co-transformants on triple drop-out plates after 6–8 days at 30°C, (++) indicates growth after 3–4 days and (+++) indicates growth after 1–2 days. Identical results were obtained for all 3 D52-like baits, which were grouped together in a single column. Results shown are representative of those obtained in 3 independent experiments.
Derivation of polyclonal antisera which specifically recognise MAL2 protein
To confirm MAL2/MUC1 interactions in other systems, MAL2 antisera were generated in two species. Polyclonal antisera were generated in sheep and targeted the MAL2 C-terminus (C165-P176). An N-terminal MAL2 peptide (N13-V24) [2] as well as the C-terminus (C165-P176) were also targeted for polyclonal antibody production in rabbit [1]. Both peptide sequences are poorly conserved in other MAL-like proteins [1]. Rabbit MAL2 antisera were employed in Western blot analyses of total protein extracts from a panel of human breast carcinoma cell lines, as well as MCF-10A breast epithelial cells. A MAL2 species of the predicted molecular weight of 19 kDa was detected in extracts from MDA-MB-435 and MDA-MB-453 cell lines stably transfected with a MUC1 expression vector (M) or the corresponding vector (V), and from MCF-10A, SK-BR-3 and MCF-7 cells. This is in agreement with previous detection of the 19 kDa MAL2 species in other cell types [2,13]. Higher molecular weight MAL2 species were also detected (Figure 2), and are likely to represent glycosylated MAL2 forms [1,2,15].
Figure 2. MAL2 antisera detect glycosylated and non-glycosylated MAL2 forms in human breast cell lines, as indicated above the top panel. Total protein extracts were subjected to Western blot analysis using rabbit MAL2, D52 and MUC1 antisera, as indicated to the left of each panel. Sizes of detected proteins are indicated at the right. Results shown are representative of at least 3 independent experiments.
Co-immunoprecipitation of MUC1 and MAL2 from MCF-10A/Myc-MAL2 cells
Co-immunoprecipitation analyses were used to confirm interactions between MAL2 and MUC1 proteins in MCF-10A breast epithelial cells, stably-transfected with a Myc-tagged MAL2 construct (MCF-10A/Myc-MAL2 cells). Protein extracts were immunoprecipitated with either MUC1, c-Myc or MAL2 antisera, the latter in the absence or presence of MAL2 peptides. Immunoprecipitated proteins were then subjected to Western blot analyses with MUC1, MAL2, c-Myc and D52 antisera. These analyses demonstrated that MUC1 monoclonal antibody immunoprecipitated MUC1 and co-immunoprecipitated MAL2, as demonstrated by both MAL2 and c-Myc antisera, and that c-Myc and MAL2 antisera immunoprecipitated MAL2 and co-immunoprecipitated MUC1 (Figure 3). Interactions between MUC1 and MAL2 proteins were also reproducibly demonstrated in MCF-7 cells and MUC1-transfected MDA-MB-435 cells (data not shown). As expected, D52 co-immunoprecipitated with MAL2 and c-Myc antisera, and interestingly with MUC1 as well (Figure 3), suggesting that MUC1 and D52 may form a multi-molecular complex with MAL2. Inclusion of MAL2 peptide abolished immunoprecipitation of MAL2 and co-immunoprecipitation of both MUC1 and D52 (Figure 3).
Figure 3. Co-immunoprecipitation analyses verifying interactions between MAL2 and MUC1. Total cell lysate from MCF-10A/Myc-MAL2 cells was immunoprecipitated with MUC1, c-Myc, or rabbit MAL2 antisera, either alone or with MAL2 peptides, as indicated above the top panel. Total cell lysate and immunoprecipitates were separated by SDS-PAGE and subjected to Western blot analyses with antisera against MUC1, MAL2, c-Myc and D52, as indicated at the left. Sizes of detected proteins are indicated at the right. Results shown are representative of at least 3 independent experiments.
Mapping the MAL2 region required for MUC1 binding
The differential binding of D52-like proteins and MUC1 to MAL2ΔN and MAL (Figure 1b) suggested that D52 and MUC1 bind different MAL2 domains. To map the MUC1 binding domain in MAL2, additional N-terminal MAL2 deletion mutants were constructed, to serially delete the four MAL2 TM domains (Figure 4a). The TM domains were specifically targeted as the MUC1 TM domain was encoded by all prey constructs isolated (Figure 1a). Interactions were detected between MUC1 prey and MAL2ΔN bait, but not MAL2 bait additionally lacking the first TM domain (MAL2ΔNTM1). Another putative MAL2 partner identified through Y2H screening showed detectable interactions with MAL2ΔNTM1, indicating that the lack of MUC1 binding to MAL2ΔNTM1 was not artifactual (S. Fanayan, unpublished results). These analyses therefore indicate that the first MAL2 TM domain (Y35-S56) is required for MUC1 binding (Figure 4b). Similar deletion mapping experiments involving MUC1 indicated that the minimal MAL2 binding region was contained within the shortest MUC1 prey (prey #7) identified through yeast two-hybrid screening (Figure 1a) (S. Fanayan, unpublished results).
Figure 4. (a) Schematic representation of N-terminally-deleted MAL2 proteins (defined in Table 1) employed in Y2H analyses. (b) Results of testing interactions between full-length and deleted MAL2 bait proteins and MUC1 (prey#1) prey protein in Hf7c cells using the Y2H system. (-) indicates no detectable growth of co-transformants on triple drop-out plates after 6–8 days incubation at 30°C while (++) indicates growth after 3–4 days. Results shown are representative of those obtained in 3 independent experiments.
MAL2 and MUC1 co-localise in the cytoplasm of breast carcinoma cells
The intracellular localisation of MAL2 in breast cancer cells was determined using indirect immunofluorescence and confocal microscopy, and compared with that of MUC1. As shown in Figure 5, SK-BR-3 and MUC1-overexpressing MDA-MB-435(M) cells showed punctate distributions of MAL2 and MUC1 throughout the cell cytoplasm, with partial co-localisation. In MCF-7 and MDA-MB-453(M) cells, MAL2 was similarly detected throughout the cytoplasm, while MUC1 was concentrated towards the cell periphery, and showed only partial co-localisation with MAL2. These results indicate that MAL2 and MUC1 co-localise within the cytoplasm, regardless of the predominant site of MUC1 localisation. Furthermore, MUC1 overexpression in MDA-MB-435 and MDA-MB-453 cells did not alter MAL2 distribution in these cells (Figure 5).
Figure 5. MAL2 and MUC1 co-localise in the cytoplasm of breast carcinoma cell lines. Indirect immunofluorescent analyses were carried out using the cell lines indicated to the left of each row, and MUC1 and sheep MAL2 antisera. MUC1 antibody was identified as green color using a FITC-conjugated secondary antibody (left column) and MAL2 antisera was identified as red color using a Cy3-conjugated secondary antibody (middle column). Overlap between MUC1 and MAL2 proteins is shown as yellow in merged images (right column). Results shown represent those obtained from 3–4 independent experiments.
MAL2 and MUC1 are present in lipid raft fractions in human breast carcinoma cells
MAL2 has consistently been found in lipid raft-containing membrane fractions in hepatoma HepG2 cells [2,14] as well as in human thyroid epithelial cells [15]. We therefore examined the distribution of MAL2 and MUC1 in Triton X-100-soluble and -insoluble fractions from breast carcinoma cell lines. Following centrifugation to equilibrium in sucrose density gradients, the distributions of MAL2 and MUC1 was compared in fractions 2–4, which include Triton X-100-insoluble lipid rafts, and fractions 8–12, which include Triton X-100-soluble cytoplasmic proteins and cell membranes. The distribution of the MAL2 partner D52 was also determined, and compared with that of caveolin-1 (CAV1), a known lipid raft protein [16]. MUC1 was detected in both Triton X-100-soluble and -insoluble fractions when endogenously expressed in SK-BR-3 cells (Figure 6a) and exogenously expressed in MDA-MB-435(M) (Figure 6c) and MDA-MB-453(M) cells (Figure 6e), with MUC1 being predominantly detected in lipid raft fractions in MDA-MB-453(M) cells (Figure 6e). In MDA-MB-435(V) (Figure 6b) and MDA-MB-453(V) cells (Figure 6d), MUC1 was weakly detected in soluble fractions only. MAL2 was detected in both soluble and insoluble fractions in all cell lines examined (Figure 6). The D52 protein was predominantly detected in soluble fractions but weakly detected in insoluble fractions in most cell lines (Figure 6a, b–e). As expected, CAV1 was exclusively detected in lipid raft fractions (Figure 6a and data not shown).
Figure 6. Distribution of MUC1, MAL2 and D52 in membrane fractions from breast cancer cell lines. (a) SK-BR-3, (b) MDA-MB-435(V) (c) MDA-MB-435(M) (d) MDA-MB-453(V) and (e) MDA-MB-453(M) cells were extracted with 1% Triton X-100 at 4°C, and subjected to centrifugation to equilibrium in sucrose density gradients. Twelve 1 ml fractions (Fr, shown above each top panel) were collected from the top of the gradient and 15 μl aliquots from each were subjected to SDS-PAGE and Western blot analysis with antibodies against MUC1, MAL2 and D52, as indicated to the left of each panel. SK-BR-3 fractions (a) were also immunoblotted with CAV1 antibody. In all panels, vertical lines between fractions 8 and 9 distinguish samples loaded on different gels. Sizes of detected proteins are indicated at the right. Results shown represent those obtained from 2–3 independent experiments.
The effect of cholesterol depletion on MUC1 and MAL2 distributions was examined by treating SK-BR-3 and MDA-MB-435(M) cell lines with MβCD. In SK-BR-3 cells, MβCD treatment rendered MUC1, MAL2 and CAV1 virtually undetectable in fractions 2–4 (Figure 7). The apparent disappearance of CAV1 from SK-BR-3 fractions after MβCD treatment is consistent with CAV1 expression being reported as undetectable in whole SK-BR-3 cell extracts [41,42]. In MDA-MB-435(M) cells, MβCD treatment reduced MUC1, MAL2 and CAV1 detection in the same fractions, which was accompanied by increased detection in Triton X-100-soluble fractions (Figure 7), further supporting co-distribution of MUC1 and MAL2 within lipid rafts. We then carried out (co)-immunoprecipitations of MUC1 and MAL2 from pooled soluble and insoluble membrane fractions from MCF-10A/Myc-MAL2 cells. Both MAL2 and MUC1 were detected in insoluble fractions (Figure 8a), yet MAL2 antisera co-immunoprecipitated MUC1 from pooled soluble fractions only (Figure 8b). The ability of MAL2 antisera to co-immunoprecipitate MUC1 from fractions 5–8 despite low MUC1 concentrations supports an association between MAL2 and MUC1 in Triton X-100 soluble fractions.
Figure 7. Effect of MβCD treatment on MUC1 and MAL2 distribution in lipid raft fractions. SK-BR-3 and MDA-MB-435(M) cells were treated (+Mβ), or not (-Mβ), with 20 mM MβCD, extracted with 1% Triton X-100 at 4°C, and subjected to sucrose gradient centrifugation. Twelve fractions of 1 ml (Fr, as shown above each top panel) were collected and 15 μl aliquots were subjected to SDS-PAGE and Western blot analysis with antibodies to MUC1, MAL2 or CAV1, as indicated at the left, with sizes of detected proteins indicated at the right. In all panels, vertical lines between fractions 8 and 9 distinguish samples loaded on different gels. In fractions 2–4, MUC1, MAL2 and CAV1 were not detected in SK-BR-3 cells, or were significantly reduced in MDA-MB-435 [M] cells following MβCD treatment. Results shown represent those obtained from 3 independent experiments.
Figure 8. Co-immunoprecipitation analyses to detect MAL2/MUC1 interactions in Triton X-100-soluble versus-insoluble fractions. MCF-10A/Myc-MAL2 cells were extracted with 1% Triton X-100 at 4°C, and subjected to sucrose gradient centrifugation. Antisera employed in Western blot analyses are shown at the left, and sizes of detected proteins are shown at the right. (a) Fractions (Fr, as shown above the top panel) of 1 ml were collected, and aliquots from each were subjected to SDS-PAGE and Western blot analysis with MUC1 and MAL2 antisera. Vertical lines between fractions 8 and 9 distinguish samples loaded on different gels. (b) Pooled fractions (fractions 1–4, which include lipid rafts, fractions 5–8 and fractions 9–12) were immunoprecipitated with MUC1 or MAL2 antisera either alone or with MAL2 peptides (+Pep), as shown at the top of the panel. Immunoprecipitates were separated by SDS-PAGE and subjected to Western blot analysis with MUC1 monoclonal antibody. Results shown represent those obtained from 3 independent experiments.
Increased MAL2 expression leads to increased cell surface expression of MUC1
Interactions between MUC1 and MAL2, together with previous data showing MAL2 involvement in basolateral-to-apical transport [2] suggested a role for MAL2 in localising MUC1 to the cell surface. The effect of ectopic Myc-MAL2 expression on MUC1 subcellular localisation was therefore compared in parental and MCF-10A/Myc-MAL2 cells. As shown in Figure 9a, MCF-10A/Myc-MAL2 cells showed a dramatically elongated morphology relative to the parental cell line, which did not reflect a change in differentiation status, as assessed using neuronal and epithelial-mesenchymal transition markers (data not shown). Increased detection of glycosylated MAL2 in both raft and non-raft fractions from MCF-10A/Myc-MAL2 cells was also accompanied by increased MUC1 detection across all membrane fractions (Figure 9c). Comparing the sub-cellular localisations of these proteins using confocal microscopy revealed an accumulation of MUC1 at the periphery of MCF-10A/Myc-MAL2 cells compared with parental cells, which incompletely co-localised with MAL2 (Figure 9b). Taken together, these data show that ectopic Myc-MAL2 expression in MCF-10A/Myc-MAL2 cells expands the plasma membrane domain, and increases MUC1 detection at the cell periphery.
Figure 9. Effect of ectopic Myc-MAL2 expression on MCF-10A cell morphology and intracellular localisation of MUC1. (a) MCF-10A and MCF-10A/Myc-MAL2 cells were grown in culture and their morphologies compared by light microscopy (X100 magnification). (b) MCF-10A and MCF-10A/Myc-MAL2 cells were co-stained for MUC1 (left panel) and MAL2 (middle panel). Overlap between the MUC1 and MAL2 proteins are shown in merged images (right panel). Images shown are single horizontal x-y sections. (c) MCF-10A and MCF-10A/Myc-MAL2 cells were extracted with 1% Triton X-100 at 4°C, and centrifuged to equilibrium in sucrose density gradients. Twelve fractions of 1 ml were collected (Fr, as shown above each top panel), and aliquots were subjected to SDS-PAGE and Western blot analysis with MUC1, MAL2 or CAV1 antisera, as indicated at the left, with sizes of detected proteins indicated at the right. Vertical lines between fractions 8 and 9 distinguish samples loaded on different gels. Results shown represent those obtained from 3 independent experiments.
Discussion
MAL2 was first identified through its expression in breast carcinoma and interactions with D52-like proteins within the Y2H system [1]. We therefore undertook a Y2H screen to identify MAL2 binding partners expressed in human breast cancer tissue, which identified a number of novel putative binding proteins, including MUC1. MUC1 represented a candidate partner of particular interest, given the fact that it is overexpressed in cancer types where MAL2 overexpression has also been reported, and as MUC1 overexpression contributes to cancer progression through a number of mechanisms [43,44]. Interactions between human MUC1 and MAL2 proteins are also broadly consistent with the previously reported interactions between the yeast signalling mucin Msb2 and the tetraspanin protein Sho1 [45]. Subsequent results collectively identify MAL2 as a novel cytoplasmic MUC1 partner, and a possible regulator of MUC1 expression and/or subcellular distribution. It is striking to note that MAL2, a chromosome 8q24 amplification target, has now been shown to bind MUC1 and D52, both of which are amplified and/or overexpressed in breast and other cancers [21,22,34,35,46] strongly suggesting that these proteins have co-operating functions in cancer cells.
While a recent study by Kinlough et al. [47] indicated that palmitoylation is the dominant feature modulating MUC1 recycling to the plasma membrane, the mechanisms by which MUC1 is targeted and maintained at the plasma membrane are not fully understood. Since ectopic Myc-MAL2 expression in MCF-10A cells was associated with increased MUC1 detection at the cell periphery in the present study, MAL2 may play a direct or indirect role in MUC1 targeting. Interestingly, MAL2 incompletely co-localised with peripheral MUC1 in MCF-10A/Myc-MAL2 cells, which supports previous findings that altering MAL2 expression can alter cargo accumulation distant to the predominant site of MAL2 expression [2,14]. However, ectopic Myc-MAL2 expression also produced an apparent expansion of cell surface domains in MCF-10A cells, which may also contribute to increased MUC1 detection at the cell periphery. Similar observations have been made in a previous study where MAL overexpression altered the morphology of MDCK cells, by seemingly expanding apical cell surface domains through increased apical delivery [6]. Finally, we also noted that ectopic MAL2 expression produced an increase in MUC1 detection across Triton X-100-soluble and -insoluble protein fractions in MCF-10A/Myc-MAL2 cells, indicating that Myc-MAL2 may positively regulate MUC1 expression. This may also lead to increased peripheral MUC1 detection. While it remains to be determined whether MAL2 can alter MUC1 distribution in other cell types, the broad expression of MAL2 within epithelia [13] is consistent with MAL2 contributing to MUC1 targetting under physiological conditions. It will also be of interest to examine whether MAL2 can similarly regulate MUC1 secretion.
If MAL2 similarly regulates MUC1 expression and/or distribution in cancer cells, increased MAL2 levels could alter cancer cell biology in several ways. Increased MUC1 localisation at the cell surface could reduce intercellular adhesion and promote invasiveness [44], and increased MAL2 expression would thus be expected to have adverse significance in cancer cells. Accordingly, MAL2 has been included within a gene signature of poor prognosis in breast cancer [48], and MAL2 overexpression was associated with resistance to doxorubicin therapy in breast cancer patients [49]. MAL2 overexpression might also reduce cytoplasmic MUC1 accumulation, which has been indicated to be an adverse finding in breast and ovarian carcinomas [50-52], tumor types which also overexpress MAL2 [20,24,25]. Interestingly, suppression of MUC1 expression in a pancreatic cancer cell line reduced these cells' metastatic potential, and was accompanied by reduced MAL2 levels [53]. Further direct analyses are therefore required to determine whether MAL2 and MUC1 levels are positively correlated in cancer types commonly expressing these proteins, and whether MAL2 expression is significantly associated with cell surface expression of MUC1 in cancer cells.
The present study also provides the first report that MUC1 localises within lipid raft fractions in breast carcinoma cells, and raises the possibility that some of MUC1's signalling functions [43,44] may occur within lipid rafts. Previous studies reported that MUC1 in T-lymphocyte cell lines was insoluble in cold Triton X-100 and associated with low density membrane fractions [54,55], yet Kinlough et al. [47] showed MUC1 from MDCK cells was fully soluble in Triton X-100. The reported differences in MUC1 solubility may be due to cell specific differences in membrane composition and their selectivity for detergents, as reported by Schuck et al. [56], or alternatively MUC1 may not reside in lipid rafts in all cell types. We demonstrated associations between MUC1 and MAL2 in Triton X-100 soluble fractions, in agreement with MUC1 and MAL2 being predominantly detected in non-raft fractions in all cell lines analysed, which was also noted for the MAL2 partner D52. While we were unable to determine whether MAL2 and MUC1 associate within lipid rafts, our results indicate that MAL2 associates with MUC1 and potentially other proteins outside lipid raft membrane microdomains, as indicated for other tetraspanins [57], and highlights the fact that MAL2 may have independent functions within and outside lipid rafts.
Our analysis of MAL2 partners has also indicated that MAL2 may represent a multifunctional transmembrane adaptor protein, capable of binding more than one partner simultaneously. We noted that both MAL2 and D52 co-immunoprecipitated with MUC1 in the present study, despite the fact that direct interactions between MUC1 and D52 were not detected in the Y2H system. Independent interaction domains for MAL2/MUC1 and MAL2/D52 binding were also indicated by the MAL2 N-terminal domain being required to bind D52-like proteins, yet the first TM domain was required for binding MUC1. Correspondingly, D52-like proteins did not bind MAL, whose N-terminal sequence is poorly conserved with respect to that of MAL2 [1], yet MUC1 bound both MAL and MAL2 in the Y2H system. These results therefore predict shared and isoform-specific functions for MAL-like proteins, through shared and discrete binding partners.
Conclusion
This study has identified MAL2 as a novel cytoplasmic MUC1 partner and a potential regulator of MUC1 subcellular distribution. MAL2/MUC1 interactions were detected in Triton X-100-soluble membrane fractions, indicating that MAL2 has specific functions within non-raft membrane compartments in breast cancer cells. Since MAL2 is known to be amplified and overexpressed in breast and other cancers, it is striking that MAL2 has now been shown to bind two proteins, MUC1 and D52, which are also amplified and/or overexpressed. Based on these results, and a previous study highlighting the co-amplification of MAL2 and D52 genes in breast cancer [21], it will be interesting to examine whether MAL2 and MUC1 are commonly amplified and overexpressed in breast cancer, and whether MAL2 expression is significantly associated with cell surface expression of MUC1.
Abbreviations
TM: transmembrane; EGF: epidermal growth factor; CKLFSF8: chemokine-like factor superfamily8; Y2H: yeast two-hybrid; cfu: colony forming unit; MAL: Mal T-cell differentiation protein; MUC1: mucin 1; CAV1: caveolin-1; PCR: polymerase chain reaction; BSA: bovine serum albumin; MβCD: methyl β-cyclodextrin.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
SF contributed to the Y2H screening and analyses, carried out all other experiments, and drafted the manuscript. MS assisted with Y2H screening, and MS and APA contributed to subsequent Y2H analyses. MAM and MAA provided essential reagents for the analysis of MUC1 and MAL2, respectively, and participated in the design of the study. JAB conceived the study, conducted the Y2H screen, participated in study design and co-ordination, and helped to draft the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We wish to thank Professor Peter Gunning (CHW) for his ongoing support, and Ms Roumayne Schepers (CHW, UU) for excellent technical assistance. This work was supported by a National Health and Medical Research Council of Australia Peter Doherty Fellowship (to SF), a Cancer Institute NSW Fellow (to JAB), funding from the Dr. Saal van Zwanenberg Foundation and the KWF Kankerbestrijding (to APA), donations to the Oncology Department of the Children's Hospital at Westmead, and the Oncology Children's Foundation. MAA is the recipient of grants BFU2006-01925 and GEN2003-20662-C07-02 from the Spanish Ministry of Education and Science.
References
1. Wilson SH, Bailey AM, Nourse CR, Mattei MG, Byrne JA: Identification of MAL2, a novel member of the mal proteolipid family, through interactions with TPD52-like proteins in the yeast two-hybrid system.
Genomics 2001, 76:81-88. PubMed Abstract | Publisher Full Text
2. de Marco MC, Martín-Belmonte F, Kremer L, Albar JP, Correas I, Vaerman JP, Marazuela M, Byrne JA, Alonso MA: MAL2, a novel raft protein of the MAL family, is an essential component of the machinery for transcytosis in hepatoma HepG2 cells.
J Cell Biol 2002, 159:37-44. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
3. Alonso MA, Weissman SM: cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation.
Proc Natl Acad Sci USA 1987, 84:1997-2001. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
4. Zacchetti D, Peranen J, Murata M, Fiedler K, Simons K: VIP17/MAL, a proteolipid in apical transport vesicles.
FEBS Lett 1995, 377:465-469. PubMed Abstract | Publisher Full Text
5. Millan J, Puertollano R, Fan L, Rancano C, Alonso MA: The MAL proteolipid is a component of the detergent-insoluble membrane subdomains of human T-lymphocytes.
Biochem J 1997, 321:247-252. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
6. Cheong KH, Zacchetti D, Schneeberger EE, Simons K: VIP17/MAL, a lipid raft associated protein, is involved in apical transport in MDCK cells.
Proc Natl Acad Sci USA 1999, 96:6241-6248. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
7. Puertollano R, Martin-Belmonte F, Millan J, de Marco MC, Albar JP, Kremer L, Alonso MA: The MAL proteolipid is necessary for normal apical transport and accurate sorting of the influenza virus hemagglutinin in Madin-Darby canine kidney cells.
J Cell Biol 1999, 145:141-151. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
8. Martin-Belmonte F, Puertollano R, Millan J, Alonso MA: The MAL proteolipid is necessary for the overall apical delivery of membrane proteins in the polarized epithelial Madin-Darby canine kidney and fischer rat thyroid cell lines.
Mol Biol Cell 2000, 11:2033-2045. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
9. Martin-Belmonte F, Arvan P, Alonso MA: MAL mediates apical transport of secretory proteins in polarized epithelial Madin-Darby canine kidney cells.
J Biol Chem 2001, 276:49337-49342. PubMed Abstract | Publisher Full Text
10. de Marco MC, Kremer L, Albar JP, Martinez-Menarguez JA, Ballesta J, Garcia-Lopez MA, Marazuela M, Puertollano R, Alonso MA: BENE, a novel raft-associated protein of the MAL proteolipid family, interacts with Caveolin-1 in human endothelial-like ECV304 cells.
J Biol Chem 2001, 276:23009-23017. PubMed Abstract | Publisher Full Text
11. Bosse F, Hasse B, Pippirs U, Greiner-Petter R, Muller H-W: Proteolipid plasmolipin: localization in polarized cells, regulated expression and lipid raft association in CNS and PNS myelin.
J Neurochem 2003, 86:508-518. PubMed Abstract | Publisher Full Text
12. Jin C, Ding P, Wang Y, Ma D: Regulation of EGF receptor signaling by the MARVEL domain-containing protein CKLFSF8.
FEBS Lett 2005, 579:6375-6382. PubMed Abstract | Publisher Full Text
13. Marazuela M, Acevedo A, García-López MA, Adrados M, de Marco MC, Alonso MA: Expression of MAL2, an integral protein component of the machinery of basolateral to-apical transcytosis, in human epithelia.
J Histochem Cytochem 2004, 52:243-252. PubMed Abstract | Publisher Full Text
14. de Marco MC, Puertollano M, Martinez-Menarguez JA, Alonso MA: Dynamics of MAL2 during glycosylphosphatidylinositol-anchored protein transcytotic transport to the apical surface of hepatoma HepG2 cells.
Traffic 2006, 7:61-73. PubMed Abstract | Publisher Full Text
15. Marazuela M, Martín-Belmonte F, García-López MA, Aranda JF, de Marco MC, Alonso MA: Expression and distribution of MAL2, an essential element of the machinery for basolateral-to apical transcytosis in human thyroid epithelial cells.
Endocrinology 2004, 145(2):1011-1016. PubMed Abstract | Publisher Full Text
16. Llorente A, de Marco MC, Alonso MA: Caveolin-1 and MAL are located on prostasomes secreted by the prostate cancer PC-3 cell line.
J Cell Sci 2004, 117:5343-5351. PubMed Abstract | Publisher Full Text
17. Myllykangas S, Himberg J, Bohling T, Nagy B, Hollmen J, Knuutila S: DNA copy number amplification profiling of human neoplasms.
Oncogene 2006, 25:7324-7332. PubMed Abstract | Publisher Full Text
18. Nupponen NN, Isola J, Visakorpi T: Mapping the amplification of EIF3S3 in breast and prostate cancer.
Genes Chromosomes Cancer 2000, 28:203-210. PubMed Abstract | Publisher Full Text
19. Chung CH, Bernard PS, Perou CM: Molecular portraits and the family tree of cancer.
Nat Genet 2002, 32(Suppl):533-540. PubMed Abstract | Publisher Full Text
20. Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PF, Tibshirani R, Botstein D, Borresen-Dale AL, Brown PO: Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors.
Proc Natl Acad Sci USA 2002, 99:12963-12968. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
21. Paik S, Kim C-K, Song Y-K, Kim W-S: Technology insight: Application of molecular techniques to formalin-fixed paraffin-embedded tissues from breast cancer.
Nat Clin Pract Oncol 2005, 2(5):246-254. PubMed Abstract | Publisher Full Text
22. Shehata M, Bièche I, Boutros R, Weidenhofer J, Fanayan S, Spalding L, Zeps N, Byth K, Bright RK, Lidereau R, Byrne JA: Non-redundant functions for tumor protein D52-like proteins support specific targeting of TPD52.
Clin Cancer Res 2008, 14:5050-60. PubMed Abstract | Publisher Full Text
23. Shridhar V, Lee J, Pandita A, Itturia S, Avula R, Staub J, Morrissey M, Calhoun E, Sen A, Kalli K, Keeney G, Roche P, Cliby W, Lu K, Schmandt R, Mills GB, Bast RC Jr, James CD, Couch FJ, Hartmann LC, Lillie J, Smith DI: Genetic analysis of early versus late-stage ovarian tumors.
Cancer Res 2001, 61:5895-5904. PubMed Abstract | Publisher Full Text
24. Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, Heinzelmann M, Kalish LH, Bali A, Kench JG, Edwards LS, Bergh PM, Hacker NF, Sutherland RL, O'Brien PM: A distinct molecular profile associated with mucinous epithelial ovarian cancer.
Clin Cancer Res 2004, 10:4427-36. PubMed Abstract | Publisher Full Text
25. Schaner ME, Davidson B, Skrede M, Reich R, Flørenes VA, Risberg B, Berner A, Goldberg I, Givant-Horwitz V, Tropè CG, Kristensen GB, Nesland JM, Børresen-Dale AL: Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients.
Mol Cancer 2005, 4:26. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
26. Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M: Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays.
Am J Pathol 2003, 162:1151-1162. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
27. Chen Y, Zheng B, Robbins DH, Lewin DN, Mikhitarian K, Graham A, Rumpp L, Glenn T, Gillanders WE, Cole DJ, Lu X, Hoffman BJ, Mitas M: Accurate discrimination of pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration.
Int J Cancer 2007, 120:1511-1517. PubMed Abstract | Publisher Full Text
28. Hoang CD, D'Cunha J, Kratzke MG, Casmey CE, Frizelle SP, Maddaus MA, Kratzke RA: Gene expression profiling identifies matriptase overexpression in malignant mesothelioma.
Chest 2004, 125:1843-1852. PubMed Abstract | Publisher Full Text
29. Dasgupta S, Tripathi PK, Qin H, Bhattacharya-Chatterjee M, Valentino J, Chatterjee SK: Identification of molecular targets for immunotherapy of patients with head and neck squamous cell carcinoma.
Oral Oncol 2006, 42:306-316. PubMed Abstract | Publisher Full Text
30. Rohan S, Tu JJ, Kao J, Mukherjee P, Campagne F, Zhou XK, Hyjek F, Alonso MA, Chen YT: Gene expression profiling separates chromophobe renal cell carcinoma from oncocytoma and identifies vesicular transport and cell junction proteins as differentially expressed genes.
Clin Cancer Res 2006, 12:6937-6945. PubMed Abstract | Publisher Full Text
31. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M: Towards a proteome-scale map of the human protein-protein interaction network.
Nature 2005, 437:1173-1178. PubMed Abstract | Publisher Full Text
32. Byrne JA, Nourse CR, Basset P, Gunning P: Identification of homo- and heteromeric interactions between members of the breast carcinoma-associated D52 protein family using the yeast two-hybrid system.
Oncogene 1998, 16:873-881. PubMed Abstract | Publisher Full Text
33. Taylor-Papadimitriou J, Burchell JM, Plunkett T, Graham R, Correa I, Miles D, Smith M: MUC1 and the immunobiology of cancer.
J Mammary Gland Biol Neoplasia 2002, 7:209-21. PubMed Abstract | Publisher Full Text
34. Vlad AM, Kettel JC, Alajez NM, Carlos CA, Finn OJ: MUC1 immunobiology: from discovery to clinical applications.
Adv Immunol 2004, 82:249-93. PubMed Abstract | Publisher Full Text
35. Bièche I, Lidereau R: A gene dosage effect is responsible for high overexpression of the MUC1 gene observed in human breast tumors.
Cancer Genet Cytogenet 1997, 98:75-80. PubMed Abstract | Publisher Full Text
36. Wykes M, MacDonald KP, Tran M, Quin RJ, Xing PX, Gendler SJ, Hart DN, McGuckin MA: MUC1 epithelial mucin (CD227) is expressed by activated dendritic cells.
J Leukoc Biol 2002, 72:692-701. PubMed Abstract | Publisher Full Text
37. Balleine R, Schoenberg Fejzo M, Sathasivam P, Basset P, Clarke C, Byrne JA: The hD52 (TPD52) gene is a candidate target gene for events resulting in increased 8q21 copy number in human breast carcinoma.
Genes Chromosomes Cancer 2000, 29:48-57. PubMed Abstract | Publisher Full Text
38. Debnath J, Muthuswamy SK, Brugge JS: Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.
Methods 2003, 30:256-268. PubMed Abstract | Publisher Full Text
39. Boutros R, Bailey AM, Wilson SH, Byrne JA: Alternative splicing as a mechanism for regulating 14-3-3 binding: interactions between hD53 (TPD52L1) and 14-3-3 proteins.
J Mol Biol 2003, 332:675-687. PubMed Abstract | Publisher Full Text
40. Brown DA, Rose JK: Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface.
Cell 1992, 68:533-544. PubMed Abstract | Publisher Full Text
41. Xie Z, Zeng X, Waldman T, Glazer RI: Transformation of mammary epithelial cells by 3-phosphoinositide-dependent protein kinase-1 activates beta-catenin and c-Myc, and down-regulates caveolin-1.
Cancer Res 2003, 63:5370-5375. PubMed Abstract | Publisher Full Text
42. Ostapkowicz A, Inai K, Smith L, Kreda S, Spychala J: Lipid rafts remodeling in estrogen receptor-negative breast cancer is reversed by histone deacetylase inhibitor.
Mol Cancer Ther 2006, 5:238-245. PubMed Abstract | Publisher Full Text
43. Gendler SJ: MUC1, the renaissance molecule.
J Mammary Gland Biol Neoplasia 2001, 6:339-353. PubMed Abstract | Publisher Full Text
44. Hollingsworth MA, Swanson BJ: Mucins in cancer: protection and control of the cell surface.
Nat Rev Cancer 2004, 4(1):45-60. PubMed Abstract | Publisher Full Text
45. Cullen PJ, Sabbagh W Jr, Graham E, Irick MM, van Olden EK, Neal C, Delrow J, Bardwell L, Sprague GF Jr: A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth pathway in yeast.
Genes Dev 2004, 18:1695-1708. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
46. Boutros R, Fanayan S, Shehata M, Byrne JA: The tumor protein D52 family: many pieces, many puzzles.
Biochem Biophys Res Commun 2004, 325:1115-1121. PubMed Abstract | Publisher Full Text
47. Kinlough CL, McMahan RJ, Poland PA, Bruns JB, Harkleroad KL, Stremple RJ, Kashlan OB, Weixel KM, Weisz OA, Hughey RP: Recycling of MUC1 is dependent on its palmitoylation.
J Biol Chem 2006, 281:12112-12122. PubMed Abstract | Publisher Full Text
48. Adler AS, Lin M, Horlings M, Nuyten DS, Vijver MJ, Chang HY: Genetic regulators of large-scale transcriptional signatures in cancer.
Nat Genet 2006, 38:421-430. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
49.
Clin Cancer Res 2005, 11:7434-7443. PubMed Abstract | Publisher Full Text
50. McGuckin MA, Walsh MD, Hohn BG, Ward BG, Wright RG: Prognostic significance of MUC1 epithelial mucin expression in breast cancer.
Hum Pathol 1995, 26:432-439. PubMed Abstract
51. Dong Y, Walsh MD, Cummings MC, Wright RG, Khoo SK, Parsons PG, McGuckin MA: Expression of MUC1 and MUC2 mucins in epithelial ovarian tumours.
J Pathol 1997, 183:311-317. PubMed Abstract | Publisher Full Text
52. Rahn JJ, Dabbagh L, Pasdar M, Hugh JC: The importance of MUC1 cellular localization in patients with breast carcinoma: an immunohistologic study of 71 patients and review of the literature.
Cancer 2001, 91:1973-1982. PubMed Abstract | Publisher Full Text
53. Tsutsumida H, Swanson BJ, Singh PK, Caffrey TC, Kitajima S, Goto M, Yonezawa S, Hollingsworth MA: RNA interference suppression of MUC1 reduces the growth rate and metastatic phenotype of human pancreatic cancer cells.
Clin Cancer Res 2006, 12:2976-2987. PubMed Abstract | Publisher Full Text
54. Handa K, Jacobs F, Longgenecker BM, Hakomori S: Association of MUC1 and PSGL-1 with low-density microdomain in T-lymphocytes: A preliminary note.
Biochem Biophys Res Commun 2001, 285:788-794. PubMed Abstract | Publisher Full Text
55. Mukherjee P, Tinder TL, Basu GD, Gendler SJ: MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lyphoma cells and normal T cells.
J Leukoc Biol 2004, 77:90-9. PubMed Abstract | Publisher Full Text
56. Schuck S, Honsho M, Ekroos K, Shevchenko A, Simons K: Resistance of cell membranes to different detergents.
Proc Natl Acad Sci USA 2003, 100:5795-5800. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
57. Yang X, Claas C, Kraeft S-K, Chen LB, Wang Z, Kreidberg JA, Hemler ME: Palmitoylation of tetraspanin proteins: modulation of CD151 lateral interactions, subcellular distribution and integrin-dependent cell morphology.
Mol Biol Cell 2002, 13:767-781. PubMed Abstract | Publisher Full Text | PubMed Central Full Text | v0 |
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} | cccc_CC-MAIN-2013-20 | Study protocol
Prevalence of peripheral arterial disease in patients at non-high cardiovascular risk. Rationale and design of the PANDORA study
Claudio Cimminiello1*, Claudio Borghi2, Serge Kownator3, Jean C Wautrecht4, Christos P Carvounis5, Stefanus E Kranendonk6, Beat Kindler7, Mario Mangrella8 and the PANDORA Study Investigators
Author Affiliations
1 Department of Medicine, via Cesare Battisti 23, Vimercate Hospital, Vimercate (MI), 20059, Italy
2 Internal Medicine Unit, University Hospital Sant'Orsola-Malpighi, Bologna, Italy
3 Clinique Ambroise Paré, Cardiology Department, Thionville, France
4 Department of Vascular Diseases, Hôpital Erasme, Brussels, Belgium
5 Internal Medicine Department, Blue Cross Hospital, Athens, Greece
6 TweeSteden Hospital, Dr Deelenlaan 5, 5042 AD Tilburg, The Netherlands
7 General Practitioner, Dufourstrasse 77, 8008 Zurich, Switzerland
8 R&D Department, AstraZeneca SpA, Milan, Italy
For all author emails, please log on.
BMC Cardiovascular Disorders 2010, 10:35 doi:10.1186/1471-2261-10-35
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2261/10/35
Received:19 April 2010
Accepted:5 August 2010
Published:5 August 2010
© 2010 Cimminiello et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Lower extremity peripheral arterial disease (PAD) is a marker of widespread atherosclerosis. Individuals with PAD, most of whom do not show typical PAD symptoms ('asymptomatic' patients), are at increased risk of cardiovascular ischaemic events. American College of Cardiology/American Heart Association guidelines recommend that individuals with asymptomatic lower extremity PAD should be identified by measurement of ankle-brachial index (ABI). However, despite its associated risk, PAD remains under-recognised by clinicians and the general population and office-based ABI detection is still poorly-known and under-used in clinical practice. The Prevalence of peripheral Arterial disease in patients with a non-high cardiovascular disease risk, with No overt vascular Diseases nOR diAbetes mellitus (PANDORA) study has a primary aim of assessing the prevalence of lower extremity PAD through ABI measurement, in patients at non-high cardiovascular risk, with no overt cardiovascular diseases (including symptomatic PAD), or diabetes mellitus. Secondary objectives include documenting the prevalence and treatment of cardiovascular risk factors and the characteristics of both patients and physicians as possible determinants for PAD under-diagnosis.
Methods/Design
PANDORA is a non-interventional, cross-sectional, pan-European study. It includes approximately 1,000 primary care participating sites, across six European countries (Belgium, France, Greece, Italy, The Netherlands, Switzerland). Investigator and patient questionnaires will be used to collect both right and left ABI values at rest, presence of cardiovascular disease risk factors, current pharmacological treatment, and determinants for PAD under-diagnosis.
Discussion
The PANDORA study will provide important data to estimate the prevalence of asymptomatic PAD in a population otherwise classified at low or intermediate risk on the basis of current risk scores in a primary care setting.
Trial registration number
Clinical Trials.gov Identifier: NCT00689377.
Background
Lower extremity peripheral arterial disease (PAD) is considered to be a marker of widespread atherosclerosis. In patients without overt cardiovascular disease (CVD), the presence of PAD predicts approximately a 30% risk of myocardial infarction, ischaemic stroke, and vascular death over 5 years. Patients with PAD show a 2- to 6-fold increase in death from cardiovascular causes and a greater risk of limb amputation than those without PAD. Individuals with PAD also experience higher 1-year rates of cardiovascular death (2.5%) and major cardiovascular events (21.1%) caused by an increase in atherothrombotic events, compared with patients with coronary artery disease (1.9% and 15.2%, respectively) or with any cerebrovascular disease (2.1% and 14.5%, respectively) [1-7].
Despite its association with severe health risk, PAD remains under-recognised by clinicians and the general population [8,9]. This may be due to the fact that the majority of individuals with lower extremity PAD do not experience recognisable ischaemic symptoms in the limb and are considered 'asymptomatic'. Nevertheless, these individuals share the unfavourable cardiovascular prognosis of symptomatic patients, as they show a risk profile comparable to that of patients with symptomatic lower extremity PAD or with coronary heart disease (CHD) [1,2,10,11]. Patients diagnosed with PAD, including those with asymptomatic PAD, should be treated to reach the recommended therapeutic goals, including low-density lipoprotein cholesterol (LDL-C) target levels <2.6 mmol/L (100 mg/dL) [12], which are similar to those recommended for high risk patients, i.e. those with CHD or CHD risk equivalents - although more challenging than that recommended for individuals at moderate CVD risk, i.e. 3.3 mmol/L (130 mg/dL) [2,12,13].
Ankle-brachial index (ABI) value ≤0.90 is the recognised cut-off for diagnosis of PAD. According to a few observational studies, pathological ABI values are frequently observed among elderly patients (aged 70+ years or 50-69 years but with a history of cigarette smoking) who are otherwise not classified as high risk [1,2]. Indeed, the prevalence of a pathological ABI still remains substantially unknown among patients classified at intermediate or low risk according to the current risk scores. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend screening for both symptomatic and asymptomatic PAD, by physical examination and/or ABI measurement, in order to identify patients with asymptomatic lower limb PAD and to offer appropriate therapeutic interventions that diminish risk of myocardial infarction, stroke, and death.
Hence, the Prevalence of peripheral Arterial disease in patients with a non-high CVD risk, with No overt vascular Diseases nOR diAbetes mellitus (PANDORA) study was designed to provide updated information on the prevalence of PAD, in the context of traditional risk factor assessment, and insight on clinical characteristics as possible determinants for PAD under-diagnosis.
Methods/Design
PANDORA is a non-interventional, cross-sectional, pan-European study of patients with a non-high CVD risk, defined as having at least two CVD risk factors according to National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) guidelines, with no overt CVDs or diabetes mellitus. Patients with definite symptoms of PAD will be also excluded (ClinicalTrials.gov Identifier: NCT00689377).
Approximately 1,000 sites will participate in the study in six European countries (Belgium, France, Greece, Italy, The Netherlands, Switzerland). Study objectives and selection criteria are listed in Table 1. Since the majority of individuals with a CVD risk factor score of 0 or 1 have a low 10-year risk, i.e. below 10%, these patients are excluded from the study population [13]. Study variables, as listed in Table 2, are collected in the Subject Record Form. Data are captured electronically in most participating countries.
Table 1. Study objectives and selection criteria
Table 2. Data captured in the Patient Record Form (PRF)
Prior to the inclusion of the first patient, investigators are requested to complete an Investigator Questionnaire regarding their personal experience and perception of the management of CVD risk, and attitude towards CVD diagnosis, guidelines and goals. The study will collect data on knowledge and behaviour in CVD diagnosis and management, quantity of CVD cases experienced, and attitudinal statements about guidelines and goals.
Patients recruited will be asked to complete a Patient Questionnaire which aims to collect data on awareness of CVD risk factors, knowledge and awareness of PAD, CVD risk perception and treatment, frequency of medical appointments.
The study conforms to the ethical principles outlined in the Declaration of Helsinki and is consistent with ICH/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
ABI measurement
Each investigator receives theoretical and practical training on the ABI measurement technique according to ACC/AHA guidelines for the management of patients with PAD [1,2]. Right and left ABI measurement is performed at rest by measuring the systolic blood pressure from both brachial arteries and from both the dorsalis pedis and posterior tibial arteries after the patient has been at rest in the supine position for 10 minutes. Measurements are taken with blood pressure cuffs that are appropriately sized to the patient's lower calf (immediately above the ankle). The hand-held Doppler ultrasonography instrument Elite 100R, Nicolet Vascular Inc. (Golden, Colorado, USA), with an 8 MHz vascular probe, is used to measure systolic pressures and ABI. The Elite 100R vascular Doppler device was chosen since it has been used in major published studies on PAD detection [1,14]. The 8 MHz probe is preferred over the 5 MHz probe, due to its higher sensitivity and reliability in detecting both superficial and deep arteries.
For ABI calculations, the higher of the two brachial artery systolic pressures, and the higher of the dorsalis pedis and posterior tibial pressures in each ankle, are selected. The right and left ABI values are separately calculated by dividing the higher of the two ankle systolic pressures in that leg by the higher brachial artery systolic pressure. Calculated ABI values are recorded to two decimal places. Each patient is considered to have PAD if ABI in either leg is 0.90 or less [1,2,15].
Statistical analysis
The statistical analyses will be descriptive in nature. Data will be presented as mean ± standard deviation or median with minimum and maximum. Summary data will be presented from all available data. Categorical data will be described by the number and percentage of patients in each category. Missing observations will be presented in tables as a separate category. The calculation of proportions will not include the missing category.
The primary objective of this survey is to determine the proportion of patients with pathological ABI, according to ACC/AHA guidelines for the management of patients with PAD. The overall sample size calculations were based on a confidence interval approach to ensure that the estimates will have adequate precision. A reasonable requirement on the precision is that the incidence should be determined within ± 1%, i.e. the length of the two-sided 99% confidence should not exceed 1 percentage value in each direction from the estimated value. Based on these calculations and expecting a 15% prevalence of individuals with pathological ABI in the selected population [14], the minimum sample size considered sufficient to meet the objectives of this protocol is 8,454 patients. However, to account for potential drop-outs, the survey plans to enrol 9,000 patients. Such sample size also ensures that the proportion reporting on the primary endpoint can be estimated with sufficient precision, on a 'by-country' basis, to represent the country-based heterogeneity of this population.
Results and discussion
PAD, especially in the asymptomatic stage is common, and its prompt screening and treatment can reduce cardiovascular risk [2].
Although PAD shares the same risk factors of other CVDs and the guidelines recommend the same preventive treatments and therapeutic targets, there is low awareness of PAD (26% for PAD, compared with 74% for stroke, and 67% for coronary artery disease and heart failure, respectively) [8]. There appears to be greater awareness even of a rare disease such as Lou Gehrig's disease (36%), or conditions such as multiple sclerosis (42%) and cystic fibrosis (29%) [12].
The detection of asymptomatic people with an ABI ≤0.90 allows for the identification of a subgroup at higher cardiovascular risk than can be determined based on the usual CVD risk assessment. Diagnosis of asymptomatic PAD in such a population assigns these individuals to the 'secondary prevention risk level' [12].
ABI measurement is now accepted as a simple and reliable vascular test to assess leg perfusion. ABI testing is appropriate in populations targeted from the epidemiological database to be at risk for PAD. Among patients with no history of CVD or diabetes, ABI measurement is recommended in certain categories appearing to be at moderate CVD risk, including individuals at higher-risk ages, and with risk factors typically associated with PAD, such as cigarette smoking [2]. Quite recently, Cacoub et al. assessed the prevalence of PAD in a population of patients with two or more cardiovascular risk factors [16]. Diehm et al. provided data on the prevalence of PAD in a large population of unselected individuals aged ≥65 years from the primary care setting [17]. However, data on the prevalence of asymptomatic PAD in a large population otherwise classified at low or intermediate risk are lacking.
Office-based detection of ABI is the most cost-effective tool for lower extremity PAD detection and provides objective data both for the diagnosis in epidemiological surveys and in-office practice, and monitoring of efficacy of therapeutic interventions [2,18,19].
ACC/AHA guidelines state that the initial responsibility for the detection of lower extremity PAD should be with primary-care providers, because such providers are best positioned to determine an at-risk population and to initiate educational, lifestyle, and cardiovascular risk reduction therapies [2].
Conclusions
Low awareness of PAD and scarce familiarity with the ABI technique seems to greatly undermine the diagnosis of asymptomatic PAD patients, who are at comparable risk to patients with CHD and should be appropriately treated. Unfortunately, most asymptomatic patients do not receive a diagnosis of PAD prior to the occurrence of a morbid or fatal ischaemic disease or event [1,2]. This is particularly true for individuals with asymptomatic PAD otherwise classified at low or intermediate risk on the basis of current risk scores. Information on the prevalence of asymptomatic PAD in such a setting is lacking. Improving PAD awareness among clinicians and the public is crucial for effective CVD prevention, early detection and integrated treatment. The PANDORA study will provide important pan-European data to estimate the prevalence of asymptomatic PAD in people with a non-high CVD risk in a primary care setting, by using the ABI technique, a risk-free gold-standard diagnostic test for PAD. This study may provide additional insights on identifying an at-risk segment of population that may benefit from appropriate preventive therapy.
Abbreviations
ABI: ankle-brachial index; ATC: anatomical therapeutic chemical; CHD: coronary heart disease; CVD: cardiovascular disease; HDL: high-density lipoprotein; LDL: low-density lipoprotein; PAD: peripheral arterial disease; PANDORA: Prevalence of peripheral Arterial disease in patients with a non-high CVD risk, with No overt vascular Diseases nOR diAbetes mellitus; PCI: percutaneous coronary intervention.
Competing interests
CC has no financial or non-financial competing interests. He has acted as a speaker and chairman at scientific meetings sponsored by AstraZeneca, Sanofi-Aventis and Bristol-Myers Squibb.
CB has acted as a consultant or speaker on occasions for Recordati, AstraZeneca, Merck, MSD, Novartis, Boehringer Ingelheim, Takeda, and Schering-Plough, and has received research funding from Boehringer Ingelheim, Sanofi-Aventis, Takeda, Italian Society of Hypertension, and the Regional Drug Agency. He holds shares in Abbott and Bristol-Myers Squibb and has received honoraria as a speaker in international and national meetings. He does not have any conflict of interest relating to the present activity.
SK has been a consultant or speaker for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Daichi-Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and Solvay.
JCW has no financial or non-financial competing interests.
CPC has received honoraria from Mount Sinai Medical Center and has received research grants as National Coordinator of five Phase IV local studies. He has received grants and acted as a consultant for AstraZeneca.
SEK has acted as occasional speaker and has received honoraria as National Coordinator of the PANDORA study, and as consultant on PAD Advisory Board
BK has participated as investigator in an AstraZeneca sponsored clinical trial and has received honoraria
MM is an employee of AstraZeneca.
Authors' contributions
CC participated in the study design, evaluated the statistical analysis, and drafted the manuscript. CB participated in the study design, evaluated the statistical analysis, and drafted the manuscript. SK participated in the study design and drafted the manuscript. JCW participated in the study design and drafted the manuscript. CPC participated in the study design and drafted the manuscript. SEK participated in the study design and drafted the manuscript. BK drafted, read and approved the final manuscript. MM participated in the study design, evaluated the statistical analysis, and drafted the manuscript. All authors read and approved the final manuscript.
Acknowledgements
This study is sponsored by AstraZeneca.
The authors would like to thank Catherine Bryant (QXV Communications, Macclesfield, UK) for her editorial assistance in the manuscript preparation that was funded by AstraZeneca and thank Dr Milena Fioravanti and Dr Barbara Merati (AstraZeneca SpA) for assistance with manuscript preparation and review.
References
1. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR: Peripheral arterial disease detection, awareness, and treatment in primary care.
JAMA 2001, 286:1317-1324. PubMed Abstract | Publisher Full Text
2. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B: ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
J Am Coll Cardiol 2006, 47:1239-1312. PubMed Abstract | Publisher Full Text
3. Sans S, Kesteloot H, Kromhout D, on behalf of the Task Force: The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe.
Eur Heart J 1997, 18:1231-1248.
4. British Heart Foundation:
European Cardiovascular Disease Statistics. London. 2005.
5. Murabito JM, D'Agostino RB, Silbershatz H, Wilson WF: Intermittent claudication. A risk profile from The Framingham Heart Study.
Circulation 1997, 96:44-49. PubMed Abstract | Publisher Full Text
6. Treat-Jacobson D, Halverson SL, Ratchford A, Regensteiner JG, Lindquist R, Hirsch AT: A patient-derived perspective of health-related quality of life with peripheral arterial disease.
J Nursing Scholarsh 2002, 34:55-60. Publisher Full Text
7. Steg PG, Bhatt DL, Wilson PWF, D'Agostino R Sr, Ohman EM, Röther J, Liau CS, Hirsch AT, Mas JL, Ikeda Y, Pencina MJ, Goto S, REACH Registry Investigators: One-year cardiovascular event rates in outpatients with atherothrombosis.
JAMA 2007, 297:1197-1206. PubMed Abstract | Publisher Full Text
8. Hirsch AT, Murphy TP, Lovell MB, Twillman G, Treat-Jacobson D, Harwood EM, Mohler ER, Creager MA, Hobson RW, Robertson RM, Howard WJ, Schroeder P, Criqui MH, Peripheral Arterial Disease Coalition: Gaps in public knowledge of peripheral arterial disease the first national PAD public awareness survey.
Circulation 2007, 116:2086-2094. PubMed Abstract | Publisher Full Text
9. Tzou WS, Mohler ER III: Peripheral arterial disease: diagnosis and medical management.
Hosp Physician 2006, 42:17-25.
10. Hooi JD, Stoffers HE, Kester AD, Rinkens PE, Kaiser V, van Ree JW, Knottnerus JA: Risk factors and cardiovascular diseases associated with asymptomatic peripheral arterial occlusive disease. The Limburg PAOD Study. Peripheral arterial occlusive disease.
Scand J Prim Health Care 1998, 16:177-182. PubMed Abstract | Publisher Full Text
11. Hooi JD, Kester AD, Stoffers HE, Overdijk MM, van Ree JW, Knottnerus JA: Incidence of and risk factors for asymptomatic peripheral arterial occlusive disease: a longitudinal study.
Am J Epidemiol 2001, 153:666-672. PubMed Abstract | Publisher Full Text
12. National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation and, treatment of high blood cholesterol in adults (Adult Treatment Panel III): Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and, treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report.
Circulation 2002, 106:3143-3121. PubMed Abstract | Publisher Full Text
13. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
Circulation 2004, 110:227-239. PubMed Abstract | Publisher Full Text
14. Fowkes FGR, Low LP, Tuta S, Kozak J, AGATHA Investigators: Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study.
Eur Heart J 2006, 27:1861-1867. PubMed Abstract | Publisher Full Text
15. Hiatt WR: Medical treatment of peripheral arterial disease and claudication.
New Engl J Med 2001, 344:1608-1621. PubMed Abstract | Publisher Full Text
16. Cacoub P, Cambou JP, Kownator S, Belliard JP, Beregi JP, Branchereau A, Carpentier P, Léger P, Luizy F, Maïza D, Mihci E, Herrmann MA, Priollet P: Prevalence of peripheral arterial disease in high-risk patients using ankle-brachial index in general practice: a cross-sectional study.
Int J Clin Pract 2009, 63:63-70. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
17. Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, Haberl RL, Allenberg JR, Dasch B, Trampisch HJ: Association of low ankle brachial index with high mortality in primary care.
Eur Heart J 2006, 27:1743-1749. PubMed Abstract | Publisher Full Text
18. Kannel WB: The demographics of claudication and the aging of the American population.
Vasc Med 1996, 1:60-64. PubMed Abstract
19. Greenland P, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, Crouse JR, Friedman L, Fuster V, Herrington DM, Kuller LH, Ridker PM, Roberts WC, Stanford W, Stone N, Swan HJ, Taubert KA, Wexler L: Prevention Conference V. Beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III.
Circulation 2000, 101:e16-e22. PubMed Abstract | Publisher Full Text
Pre-publication history
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Climate Adaptation of Rice
Food security:
Climate Adaptation of Rice
Rice grown with and without endophytes. Source: USGS; Credit: R. Rodriguez.
This article has been reviewed by the following Topic Editor: Sidney Draggan Ph.D.
Climate Adaptation of Rice
Symbiogenics: A New Strategy for Reducing Climate Impacts on Plants
Rice–which provides nearly half the daily calories for the world’s population–could become adapted to climate change and some catastrophic events by colonizing its seeds or plants with the spores of tiny naturally occurring fungi. In an effort to explore ways to increase the adaptability of rice to climatic scourges such as tsunamis and tidal surges that have already led to rice shortages, USGS researchers and their colleagues colonized two commercial varieties of rice with the spores of fungi that exist naturally within native coastal (salt-tolerant) and geothermal (heat-tolerant) plants.
The rice plants thrived, achieving notable increased tolerance to cold, salt and drought, even though the rice varieties they tested were not naturally adapted to these stressors. Conferring heat tolerance to rice is the next step for the research team since rice production decreases by 10 percent for every temperature increase of 1-degree centigrade during the rice-growing season.
"This is an exciting breakthrough," Rusty Rodriguez, Ph.D. said. "The ability of these fungi to colonize and confer stress tolerance, as well as increased seed yields and root systems in rice–a genetically unrelated plant species from the native plants from which the fungi were isolated—suggests that the fungi may be useful in adapting plants to drought, salt and temperature stressors predicted to worsen in future years due to climate change."
In fact, said Rodriguez, using these tiny fungi–called endophytes–is one of the only real strategies available for mitigating the effects of climate change on plants in natural and agricultural ecosystems. "We have named this emerging area of research symbiogenics for symbiosis-altered gene expression. The DNA of the rice plant itself, however, is not changed. Instead, we are re-creating what normally happens in nature. And with rice yields projected to decrease by 15 percent in developing countries by 2050, such strategies are needed."
The way it works is this. All plants seem to have symbiotic endophytes—microscopic fungi or bacteria—living in them that do not cause disease in the plant. The kind of endophytes that Rodriguez and his colleagues examined are all mutualistic, meaning the plant and the fungi have a close and positive relationship that bestows benefits on both partners: stress tolerance for the plant, nutrients and a lack of competition for the fungus.
The scientists took fungal endophytes from dunegrass, a species exposed to seawater and therefore salt-tolerant, and colonized the rice plants and seeds with its fungal spores, which germinated and infiltrated the plant’s tissue. The results were dramatic: the endophytes reduced water consumption of the plant by up to one half, and increased its growth, the number of seeds it produced, and how much it weighed by as much as 50 percent.
"Conventional thinking was that the dunegrass is salt tolerant because of genetic adaptations that occurred over time (the process of Darwinian evolution), but we found that when we removed the fungus from dunegrass, the plants were no longer salt tolerant," Rodriguez said. "This means that plants in natural habitats may not be adapting themselves genetically to the stress, but instead are establishing a beneficial partnership with a fungus that makes them more salt tolerant."
During the last 40 years of climate change, the authors pointed out, the minimum air temperature in rice-growing season has increased in China and the Philippines, resulting in a substantial decrease in rice yields there, decreases predicted to continue. "Collectively, these events, along with an increasing world population, have contributed to shortages and increased prices of rice, exacerbating hunger and famine issues globally."
The authors emphasized that even though it may be possible to compensate for some of the effects of climate change by incorporating, say, earlier-producing varieties of rice into agricultural practices, the adaptive capabilities of rice will be what ultimately determines how severely climate change affects the annual yield of rice.
The research, Increased Fitness of Rice Plants to Abiotic Stress via Habitat Adapted Symbiosis: A Strategy for Mitigating Impacts of Climate Change, was published in PLoS One, and is available online.
Released: 7/13/2011 12:37:41 PM
Contact Information:
U.S. Department of the Interior, U.S. Geological Survey
Office of Communication
119 National Center
Reston, VA 20192
Rusty Rodriguez
Phone:<PHONE_NUMBER>
Catherine Puckett
Phone:<PHONE_NUMBER>
Citation
U.S. Geological Survey (Content Source);Sidney Draggan Ph.D. (Topic Editor) "Climate Adaptation of Rice". In: Encyclopedia of Earth. Eds. Cutler J. Cleveland (Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment). [First published in the Encyclopedia of Earth July 14, 2011; Last revised Date June 5, 2012; Retrieved May 18, 2013 <http://www.eoearth.org/article/Climate_Adaptation_of_Rice?topic=54424> | v0 |
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International Journal of Alzheimer's Disease
Volume 2012 (2012), Article ID 674142, 4 pages
doi:10.1155/2012/674142
Review Article
Shilajit: A Natural Phytocomplex with Potential Procognitive Activity
Laboratory of Cellular and Molecular Neurosciences, International Center for Biomedicine (ICC) and University of Chile, Millennium Building, Las Encinas 3370, Ñuñoa, 780023 Santiago, Chile
Received 22 August 2011; Accepted 17 December 2011
Academic Editor: Yoram Barak
Copyright © 2012 Carlos Carrasco-Gallardo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Shilajit is a natural substance found mainly in the Himalayas, formed for centuries by the gradual decomposition of certain plants by the action of microorganisms. It is a potent and very safe dietary supplement, restoring the energetic balance and potentially able to prevent several diseases. Recent investigations point to an interesting medical application toward the control of cognitive disorders associated with aging, and cognitive stimulation. Thus, fulvic acid, the main active principle, blocks tau self-aggregation, opening an avenue toward the study of Alzheimer's therapy. In essence, this is a nutraceutical product of demonstrated benefits for human health. Considering the expected impact of shilajit usage in the medical field, especially in the neurological sciences, more investigations at the basic biological level as well as clinical trials are necessary, in order to understand how organic molecules of shilajit and particularly fulvic acid, one of the active principles, and oligoelements act at both the molecular and cellular levels and in the whole organism.
1. Introduction
Shilajit also known in the north of India as salajit, shilajatu, mimie, or mummiyo is a blackish-brown powder or an exudate from high mountain rocks, especially in the Himalayans mountains between India and Nepal, although it has been also found in Russia, Tibet, Afghanistan, and now in the north of Chile, named as Andean Shilajit [1]. Shilajit has been known and used for centuries by the Ayurvedic medicine, as a rejuvenator and as antiaging compound. There are two important characteristics of a rasayana compound in the ancient Indian Ayurvedic medicine: that is, to increase physical strength and to promote human health [2]. The health benefits of shilajit have been shown to differ from region to region, depending on the place from which it was extracted [3, 4].
2. Origins of Shilajit
Considering its unique composition as a phytocomplex, very rich in fulvic acid, researchers hypothesize that Shilajit is produced by the decomposition of plant material from species such as Euphorbia royleana and Trifolium repens [4, 5]. This decomposition seems to occur through centuries, and on this basis, shilajit is considered a millenary product of nature. However, further studies have identified that several other plant organisms may generate shilajit, such as molds as Barbula, Fissidens, Minium, and Thuidium and other species like Asterella, Dumortiera, Marchantia, Pellia, Plagiochasma, and Stephenrencella-Anthoceros [4].
3. Molecular Composition of Shilajit
Shilajit is composed mainly of humic substances, including fulvic acid, that account for around 60% to 80% of the total nutraceutical compound plus some oligoelements including selenium of antiaging properties [6, 7] (Figure 1). The humic substances are the results of degradation of organic matter, mainly vegetal substances, which is the result of the action of many microorganisms. Components are divided operationally in humins, humic acid, and fulvic acids according to their solubility in water at different pH levels. Humins are not soluble in water under any pH condition. Humic acid is soluble in water under alkaline conditions and has a molecular weight of 5–10 kDa. Fulvic acid is soluble in water under different pH conditions, and because of its low molecular weight (around 2 kDa), it is well absorbed in the intestinal tract and eliminated within hours from the body [8, 9]. It is likely that the curative properties attributable to shilajit are provided by the significant levels of fulvic acids that shilajit contains, considering that fulvic acid is known by its strong antioxidant actions [9] and likely has systemic effects as complement activator [10]. Recent studies on the composition of Andean Shilajit in Chile have evidenced an ORAC index between 50 and 500 Trolox units/g of material, which is substantially higher than Noni and blueberries (Quinteros et al., unpublished data). In this context, shilajit seems to be a powerful antioxidant phytocomplex.
Figure 1: Shilajit, its main components, and potential uses based on properties of fulvic acid. This phytocomplex known as shilajit is mainly composed of humic substances. One of them, fulvic acid, is known by its properties such as antioxidant, anti-inflammatory, and memory enhancer. Novel investigations indicate that fulvic acid is an antiaggregation factor of tau protein in vitro [1], which projects fulvic acid as a potential anti-Alzheimer’s disease molecule.
Other molecules present in shilajit preparations are eldagic acid, some fatty acids, resins, latex, gums, albumins, triterpenes, sterols, aromatic carboxylic acids, 3,4-benzocoumarins, amino acids, polyphenols, and phenolic lipids [3, 6, 11]. Certainly its molecular composition varies from region to region. Newer investigations based on high-performance size exclusion chromatography (HP-SEC) show that shilajit contains specific molecular species of polysaccharides and lignins [10]. As humic components, humins, humic acids, and fulvic acids are found in all shilajit preparations, being the last one, fulvic acids, the biologically active compound, along with dibenzo--pyrones, which acts as carrier of other substances [3].
4. Traditional Uses of Shilajit
Shilajit is an important, known component of the ayurvedic medicine given its characteristics as a rasayana. In this context, health benefits such as an increase in longevity, rejuvenating, and arresting aging roles have been attributed to it [3]. Traditionally, shilajit is consumed by people from Nepal and the North of India, and children usually take it with milk in their breakfast. The Sherpas claim to have shilajit as part of their diet; they constitute a population of strong men with very high levels of a healthy longevity. Our laboratory has found evidence on the high activity of the Andean form of shilajit in improving cognitive disorders and as a stimulant of cognitive activity in humans [1] (Table 1).
Table 1: Morphometric study of primary cultured rat hippocampal cells exposed to Shilajit and the Brain Up-10 formulae that contain Shilajit plus complex B vitamins (Vit B6, B9, and B12).
Considering the actions of fulvic acid in preventing tau self-aggregation into pathological filaments, this compound appears to be of interest for prevention of Alzheimer’s disease [1]. Other common traditional uses include its action in genitourinary disorders, jaundice, digestive disorders, enlarged spleen, epilepsy, nervous disorders, chronic bronchitis, and anemia [2]. Shilajit has been also useful for the treatment of kidney stones, edema, and hemorrhoids, as an internal antiseptic, and to reduce anorexia. Also, it has been claimed in India to be used as yogavaha [12, 13], that is, as synergistic enhancer of other drugs. Organic components of shilajit play also a role in transporting different mineral substances to their cellular targets.
5. Novel Investigations
Preclinical investigations about shilajit indicate its great potential uses in certain diseases, and various properties have been ascribed, including (1) antiulcerogenic properties [14]; (2) antioxidant properties [15, 16]; (3) cognitive and memory enhancer [1, 10, 17]; (4) antidiabetic properties [18]; (5) anxiolytic [12]; (6) antiallergic properties and immunomodulator [2, 19, 20]; (7) anti-inflammatory [21]; (8) analgesic [16]; antifungal properties [22]; (9) ability to interact positively with other drugs [23]; (10) protective properties in high altitudes [24]; (11) neuroprotective agent against cognitive disorders [1, and Farias et al. unpublished clinical trials]. Unfortunately shilajit lacks systematic documentation and well-established clinical trials on its antioxidative and immunomodulatory actions in humans, and it is expected that considering the reported benefits evidenced from trials will be obtained in the near future [25].
6. Patenting
A few patents already exist that protect the use of shilajit in India and Nepal, such as US Patent 5,405,613—vitamin/mineral composition [26]; US Patent application number<PHONE_NUMBER>5—Herbo-mineral composition [27]; US Patent number 6,440,436—Process for preparing purified shilajit composition from native shilajit [28]; US Patent number 6,558,712—Delivery system for pharmaceutical, nutritional and cosmetic ingredients [29]. Other recent patent about a phytocomplex with vitamins added is WO 2011/041920 [30].
7. Potential Risks
Studies indicate the shilajit consumption without preliminary purification may lead to risks of intoxication given the presence of mycotoxin, heavy metal ions, polymeric quinones (oxidant agents), and free radicals, among others [3]. Therefore, a purified, ready-for-use preparation for human consumption must be used. However, recent studies indicate that several ayurvedic products including shilajit and other Indian manufactured products commercialized by the Internet may contain detectable heavy metals levels as lead, mercury, and arsenic [31]. This study showed the presence of heavy metals and other minerals, including gems, is associated with the belief that when mixed with shilajit or other herbal preparations they generate a better response from the body in a synergic manner. This is what is known as rasa-shastra in ayurvedic medicine. Rasashastra experts claim that if this is prepared, administered, and consumed properly, it is safe and has therapeutic advantages [31]. It is worth considering that recent clinical reports indicate cases of lead poisoning in patients who have used ayurvedic products against weakening [32, 33].
8. Commentary and Discussion
Shilajit has a comfortable position as the rasayana because of its excellence, well known in the Eastern culture, and now being introduced with great interest in the occidental world. The vast majority of published papers on this theme are from India, leaving this sector of the planet as an expert in their field, since this is a product that is extracted, marketed, and investigated in these latitudes. However, this generates a segmentation of shilajit, relegating it only to what has always been assumed: a natural product that is part of natural alternative medicine and not as a result of medical and biotechnology innovation worldwide. This is evidenced quite clearly by reviewing the literature today, and note that the journals where studies on shilajit are published (jobs are plentiful) are mainly reviewed in the Eastern. Given this, it is necessary that shilajit break the cultural paradigm and enter into the rest of the world by the hand of rigorous research at the molecular and cellular levels, which could elucidate the interactions of the active ingredients of the different shilajit preparations with biomolecules. This will facilitate our understanding of their mechanisms of action.
9. Conclusion
Shilajit is a potent and very safe dietary supplement, potentially able to prevent several diseases, but its main medical application now appears to come from its actions in benefit of cognition and potentially as a dietary supplement to prevent Alzheimer’s disease. In essence, this is a nutraceutical product. Considering the expected impact of shilajit applications in the medical field, especially in neurological sciences, more investigations at the basic biological level are necessary, and certainly well-developed clinical trials, in order to understand how its active principles act at molecular and cellular levels.
Acknowledgments
These investigations have been supported by a CORFO Project 10ANT 8051, VRI FONDEF project, and FONDECYT 1110373 from CONICYT and a grant from the Alzheimer’s Association, USA. Authors acknowledge important collaboration of Constanza Maccioni.
References
1. A. Cornejo, J. M. Jiménez, L. Caballero, F. Melo, and R. B. Maccioni, “Fulvic acid inhibits aggregation and promotes disassembly of tau fibrils associated with alzheimer's disease,” Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 143–153, 2011. View at Publisher · View at Google Scholar · View at PubMed
2. S. Ghosal, “Chemistry of shilajit, an immunomodulatory Ayurvedic rasayan,” Pure and Applied Chemistry, vol. 62, no. 7, pp. 1285–1288, 1990.
3. R. N. Chopra, I. C. Chopra, K. L. Handa, and K. D. Kapoor, In Indigenous Drugs of India, U.N. Dhar & Sons, Calcutta, India, 1958.
4. S. P. Agarwal, R. Khanna, R. Karmarkar, M. K. Anwer, and R. K. Khar, “Shilajit: a review,” Phytotherapy Research, vol. 21, no. 5, pp. 401–405, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
5. S. Ghosal, J. P. Reddy, and V. K. Lal, “Shilajit I: chemical constituents,” Journal of Pharmaceutical Sciences, vol. 65, no. 5, pp. 772–773, 1976. View at Scopus
6. R. Khanna, M. Witt, M. Khalid Anwer, S. P. Agarwal, and B. P. Koch, “Spectroscopic characterization of fulvic acids extracted from the rock exudate shilajit,” Organic Geochemistry, vol. 39, no. 12, pp. 1719–1724, 2008. View at Publisher · View at Google Scholar · View at Scopus
7. P. Mittal, D. Kaushik, V. Gupta, P. Bansal, and S. Khokra, “Therapeutic potencial of “Shilajit Rasayana”—A Review,” International Journal of Pharmaceutical and Clinical Research, vol. 1, no. 2, pp. 47–49, 2009.
8. K. M. S. Islam, A. Schumacher, and J. M. Gropp, “Humic acid substances in animal agriculture,” Pakistan Journal of Nutrition, vol. 4, pp. 126–134, 2005.
9. A. V. Vucskits, I. Hullár, A. Bersényi, E. Andrásofszky, M. Kulcsár, and J. Szabó, “Effect of fulvic and humic acids on performance, immune response and thyroid function in rats,” Journal of Animal Physiology and Animal Nutrition, vol. 94, no. 6, pp. 721–728, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
10. I. A. Schepetkin, G. Xie, M. A. Jutila, and M. T. Quinn, “Complement-fixing activity of fulvic acid from shilajit and other natural sources,” Phytotherapy Research, vol. 23, no. 3, pp. 373–384, 2009. View at Publisher · View at Google Scholar · View at PubMed
11. Y. C. Kong, P. P. H. But, K. H. Ng, et al., “Chemical studies on a Nepalese Panacea—shilajit (I),” International Journal of Crude Drug Research, vol. 25, no. 3, pp. 179–182, 1987.
12. S. Ghosal, J. Lal, S. K. Singh, R. K. Goel, A. K. Jaiwal, and S. K. Bhattacharya, “The need for formulation of shilajit by its isolated active constituents,” Phytotherapy Research, vol. 5, no. 5, pp. 211–216, 1991. View at Publisher · View at Google Scholar
13. S. Ghosal, B. Mukherjee, and S. K. Bhattacharya, “Shilajit—a comparative study of the ancient and the modern scientific findings,” Indian Journal of Indigenous Medicine, vol. 17, pp. 1–10, 1995.
14. S. Ghosal, S. K. Singh, Y. Kumar et al., “Shilajit. 3. Antiulcerogenic of fulvic acids and 4-methoxy-6-carbomethoxybiphenyl isolated from shilaji,” Phytotherapy Research, vol. 2, no. 4, pp. 187–191, 1988.
15. S. Ghosal, S. Lata, Y. Kumar, B. Gaur, and N. Misra, “Interaction of shilajit with biogenic free radicals,” Indian Journal of Chemistry B, vol. 34, pp. 596–602, 1995.
16. S. K. Bhattacharya and A. P. Sen, “Effects of shilajit on biogenic free radicals,” Phytotherapy Research, vol. 9, no. 1, pp. 56–59, 1995. View at Publisher · View at Google Scholar
17. A. K. Jaiswal and S. K. Bhattacharya, “Effects of shilajit on memory, anxiety and brain monoamines in rats,” Indian Journal of Pharmacology, vol. 24, pp. 12–17, 1992.
18. S. K. Bhattacharya, “Shilajit attenuates streptozotocin induced diabetes mellitus and decrease in pancreatic islet superoxide dismutase activity in rats,” Phytotherapy Research, vol. 9, no. 1, pp. 41–44, 1995. View at Publisher · View at Google Scholar
19. C. Wang, Z. Wang, A. Peng, J. Hou, and W. Xin, “Interaction between fulvic acids of different origins and active oxygen radicals,” Science in China, Series C, vol. 39, no. 3, pp. 267–275, 1996.
20. S. Ghosal, J. Lal, S. K. Singh et al., “Mast cell protecting effects of shilajit and its constituents,” Phytotherapy Research, vol. 3, no. 6, pp. 249–252, 1989. View at Scopus
21. S. B. Acharya, M. H. Frotan, R. K. Goel, S. K. Tripathi, and P. K. Das, “Pharmacological actions of shilajit,” Indian Journal of Experimental Biology, vol. 26, no. 10, pp. 775–777, 1988. View at Scopus
22. Shalini and R. Srivastava, “Antifungal activity screening and hplc analysis of crude extract from Tectona grandis, shilajit, Valeriana wallachi,” Electronic Journal of Environmental, Agricultural and Food Chemistry, vol. 8, no. 4, pp. 218–229, 2009. View at Scopus
23. M. A. Mirza, S. P. Agarwal, M. A. Rahman et al., “Role of humic acid on oral drug delivery of an antiepileptic drug,” Drug Development and Industrial Pharmacy, vol. 37, no. 3, pp. 310–319, 2011. View at Publisher · View at Google Scholar · View at PubMed
24. H. Meena, H. K. Pandey, M. C. Arya, and Z. Ahmed, “Shilajit: a panacea for high-altitude problems,” International Journal of Ayurveda Research, vol. 1, no. 1, pp. 37–40, 2010.
25. E. Wilson, G. V. Rajamanickam, G. P. Dubey et al., “Review on shilajit used in traditional Indian medicine,” Journal of Ethnopharmacology, vol. 136, no. 1, pp. 1–9, 2011. View at Publisher · View at Google Scholar · View at PubMed
26. D. Rowland, “Vitamin/mineral composition,” US Patent no. 5405613,1995.
27. S. Ghosal, “Herbo-Mineral compositions,” US Patent application no.<PHONE_NUMBER>5, 2002.
28. S. Ghosal, “Process for preparing purified shilajit from native shilajit,” US Patent no. 6440436, 2002.
29. S. Ghosal, “Delivery system for pharmaceutical, nutritional and cosmetic ingredient,” US Patent no. 6558712, 2003.
30. R. B. Maccioni, L. Quiñones, I. Saavedra, and R. Sandoval, “Nutraceutical composition that comprises extract of shilajit, folic acid, vitamin B12 and vitamin B6 and the use thereof for preventing and/or treating neurodegenerative disease and/or the cognitive deterioration association with cerebral aging,” WO 2011/041920. PCT/CL2010/000043 April, 14. 2011.
31. R. B. Saper, R. S. Phillips, A. Sehgal et al., “Lead, mercury, and arsenic in US- and Indian-manufactured Ayurvedic medicines sold via the internet,” Journal of the American Medical Association, vol. 300, no. 8, pp. 915–923, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
32. S. N. Kales and R. B. Saper, “Ayurvedic lead poisoning: an under-recognized, international problem,” Indian Journal of Medical Sciences, vol. 63, no. 9, pp. 379–381, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
33. S. Singh, K. K. Mukherjee, K. D. Gill, and S. J. S. Flora, “Lead-induced peripheral neuropathy following ayurvedic medication,” Indian Journal of Medical Sciences, vol. 63, no. 9, pp. 408–410, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus | v0 |
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} | cccc_CC-MAIN-2013-20 | Bibliography: SF Calendar (If, May-June 1972)
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Title: SF Calendar (If, May-June 1972)
Author: uncredited
Year: 1972
Type: ESSAY
ISFDB Record Number: 851844
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06) | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:01:52.000Z | ffvs6jmbd6ilxpolzhzclca2fzeltbuw | {
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} | cccc_CC-MAIN-2013-20 | Nancy Pelosi's Bar Tab Proves That Absolute Power Corrupts, (Intoxicates)
by the Left Coast Rebel
Nancy (Nasty) Pelosi is a Horrible Woman. Yes she is, simply one of the worst of a lot of bad characters in Washington that stretches a mile long. The picture above is the only one that I could find of her with her mouth shut too, by the way. For every time that she does open it, I hear another precious freedom (or a trillion dollars) get whisked away. At a time when Americans are suffering Nancy Pelosi jetted over to Copenhagen with 3 military jets last month spending (millions?) at taxpayer's expense to prove what an elitist, smug, aristocrat she is.
The most ridiculous thing about aristocrats like Nasty Pelosi, Harry Reid, Schumer, Obama, Clinton(s), Frank....fill in the rest here, is that these 'royalty' preach to masses from atop the perch of the altruist socialist-progressive. They are for the little guy. They feel your pain. They will stick it to the man. And you know what? It is just a simple way to take away our freedoms and liberties, bring all income levels down to a lower level and increase the entire nation's misery. Except for them.
Today's leadership is probably one (if not the) worst in American history. They are power drunk and Nancy Pelosi is one of the drunkest of the drunks, literally:
Maker's Mark whiskey,
Courvoisier cognac,
Johnny Walker Red scotch,
Grey Goose vodka,
J&J brandy,
Bailey's Irish Crème,
Bacardi Light rum,
Jim Beam whiskey,
Beefeater gin,
Dewars scotch,
Bombay Sapphire gin,
Jack Daniels whiskey … and Corona beer
.
Nancy Pelosi's bar tab, paid for by the United States taxpayer, all above. 2 year cost to the taxpayer for drinks catered to her by you and I while gallivanting all over the nation (and world)?
--$101,000.00
Cost of the Air Force Fleet that she uses to whisk between DC and San Francisco over the last 2 years?
--$2,000,000.00
Why not, if we let them do this to us?
UPDATED:
Thomas Paine did some heavy lifting and the legwork involved digging up history on 'Queen' Pelosi including her lack of business experience whatsoever. It is quite illimunating when you read the background of someone like Pelosi. Thanks for the research Thomas. Visit his excellent site, Save Us From the World Improvers
| v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T07:12:50.000Z | pyrxnaaqiqtzkmu2usxj4evmxhc5llm7 | {
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} | cccc_CC-MAIN-2013-20 | Gas Mask!
From the Super Mario Wiki
Jump to: navigation, search
Wario using Gas Mask!.
Gas Mask! is the name of a Super Ability executed by Wario in Mario Strikers Charged. Wario will only be able to use Gas Mask! when he collects his special item, which is shown as his own head. When Wario uses Gas Mask!, he will fart, leaving a trail of toxic gas behind him. A player can use this ability at nearly any time, such as when he's standing up, or when Wario's getting back up from being tripped. Also, when using Gas Mask! while running, Wario runs a little bit faster, like when Waluigi uses Wall-Luigi!. When doing a one-timer and using Gas Mask!, the sound effects will play in slow motion. Any player (besides Wario or Kritter) that walks into this gas will have their controls flipped as if the player were holding his or her Wii Remote and Nunchuk sideways. This will sometimes lead the players into the Electric Fence, or on Thunder Island, straight off the edge. Wario can use this Super Ability four times in one item. Gas Mask! can be used to trap Wario in a corner, allowing a safe Mega Strike. However, if another player uses a Starman, they can run into the gas and get the ball back without any harmful effects. This Super Ability, like Wario's Wario Waft in Super Smash Bros. Brawl, probably caused the Crude Humour label on the ESRB Rating. However, the slightly rude things they do to each other could also cause the label.
If any opposing Captains walk into the gas, they will say something to Wario. For example, Mario will say "Mamma mia," and start choking, or say "Oh, Wario," and cough. Waluigi will tell Wario to change his pants, hold it in, or say "Oh, Wario, you're killing me!". For Daisy, she will say "Ohhh, Wario!!". If Bowser's Fire Storm! is used nearby Gas Mask!, a big explosion will occur, and if Wario is nearby, both Wario and Bowser will be sent flying.
[edit] Names in Other Languages
Language Name Meaning
Japanese ガスマスク！
Gasumasuku!
Gas mask!
Korean 가스 마스크!
gaseu maseukeu!
Gas mask! (from the Japanese name)
Personal tools | v0 |
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} | cccc_CC-MAIN-2013-20 | In House: Big SEO
Apr 10, 2007 • 10:17 am | (3) by | Filed Under Search Engine Strategies 2007 New York
What matters when doing big SEO for big brands or big sites with thousands of products? This session will discuss the problems and solutions that marketers run into when faced with such large issues and the best way to handle them.
Jeffery Rohrs opens the session welcoming everyone to the session. It is a very packed and hot session with this the first session about doing SEO in house. Looks like it will be a very good session.
Bill Hunt the CEO of Global Strategies starts first to talk about SEO for big brands. He begins talking about Enterprise key focus areas for large companies and what has the most success. He recommends integrating SEO best practices into the organization at the right levels. Next, implement internal protocols to minimize unexpected problems. Third, integrate search into the web development and management workflow. Style guides and web rule books are important to help dictate search practices. Style guides tell developers where exactly pixels go and so on. These documents can be very detailed but also very important part of the SEO process. Bill will next discuss proving the concept and discussing any missed opportunity matrix will get management support.
So how do you change management? You need to centralize your efforts for success. He puts up a very useful chart of the ways to integrate all the various parts of a big brand into the search marketing initiates. He gives the example of the management team has never met the web team. They meet and exchange cards and chat up the meeting. They can been in the same building but never interact. He says that you need to get these various groups together. Press release team, TV, advertising all need to be part of the process. In a large organization you need to segment the program and look at the infrastructure of the organization. He says they usually hold a best practices session and invites everyone to come. They look at it a couple ways. One from the brand level, group level, and corporate level. What will appeal to these various groups.
Bill broke the process down and asks where is the organization today. He recommends to have executive do searches in Google to see where they are. Having standards work very well in organization because it gives them something to follow. After you have identified the problems and set standards you need to next implement the SEO program. Finally you need to attack the web analytics and reporting tool framework. Bill says that search is one of the easiest to measure in the organization.
He talks next about site wide algorithm compliance audit. Look at things of link popularity, contextual relevancy. What is happening? He recommend building a template for page level audits by putting these into an excel spreadsheet. Start with the basics and work to more advanced topics. He says working with the big three is a good place to start. These are things such as the title tag, headers, and content. The second part to his recommendation is to integrate SEO into your content supply chain. He provides an example of mapping out the clients content creation work flow. There are many ways to track the content through a wiki, blog, articles, etc.. His company also takes a look at style guides. Monitor the infrastructure is also important in order to look for problems that big arise. Pages ranking for words that don’t make sense is a good idea to look at. He recommends creating a page ranking score card and additionally identifying a missed opportunity matrix. He next puts up a document showing the success for certain keywords.
One important ways to understand the cost of not ranking is to show missed opportunity for not ranking well. What does it cost in PPC when you don’t rank in the organic results.
Marshall Simmons from the New York Times starts saying they work with a lot of specific content and organization. He says there are a lot of challenges dealing with 11 million documents, such as looking at why an email registration wall might not be a good idea, also a paid subscription wall and dealing with journalists, editors and guides. The New York times has a company ego which makes it difficult to change different styles of writing and a lot of effort involved in changing the approach to content and SEO.
He next talks about About.com and the integration with the New York Times. About.com is very serious about search and says there will also be opportunity for growth in traffic. So how does About.com get results? They say organized, there is an on-site SEO program manager. They want to engage the team of marketing, technology, research, editorial, and even sales. The SEO are imbedded strategists. In charge of breaking down the areas that need to be analyzed. Small changes could generate major results, affecting vast majority of pages. He gives an example of moving the NYT registration wall back 5 pageviews. More making templates changes that affected entire sections. Cleaning up code is also important. Global search and replaces to remedy spam problems.
Marshall mentions that education is very a important part of the process. Everyone gets one sheet they can refer too. Do ongoing in-depth training sessions. Perform separate training session for technical staff, design, and editorial. Execute strategy and measure results on an ongoing basis. Funny, he says that metrics saves jobs! You have to track way is going on. You need to set baselines monthly, not weekly in order to no what is going on. If you are a publicly traded company these numbers are beneficial to report to investors and all those involved.
So what can big brands do today? Hire an in-house search specialist or SEO project manager. Establish an internal SEO team. Start looking at where you can make the most money. Use solutions like Omniture, WebTrends, Hitwise, etc.. Monitor spider visits, cozy up to IT and do some logfile analysis. Use those results to manage up. Think about metrics that make sense across the company.
Previous story: Blog Conduct for the Wild Wild Web
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Watchers
source: Getty Thesaurus of Geographic Names
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Hempstead County is a county located in the U.S. state of Arkansas. As of 2010, the population was 22,609. The county seat is Hope. Hempstead County is Arkansas's fourth county, formed on December 15, 1818, alongside Clark and Pulaski counties. The county is named for Edward Hempstead, a delegate to the U.S. Congress from the Missouri Territory, which included present-day Arkansas at the time. It is an alcohol prohibition or dry county.
Hempstead County is part of the Hope Micropolitan Statistical Area.
Historic Washington State Park is located in Hempstead County some nine miles northwest of Hope in the historic village of Washington, Arkansas. The state park opened in 1973 as "Old Washington Historic State Park", but the "Old" was dropped from the name in 2006. The park offers walking tours of the historic village, which contains more than a dozen historic structures from the 19th and early 20th centuries.
Timeline
Date Event Source
1818 County formed Source:Red Book: American State, County, and Town Sources
1819 Court records recorded Source:Red Book: American State, County, and Town Sources
1820 First census Source:Population of States and Counties of the United States: 1790-1990
1823 Marriage records recorded Source:Red Book: American State, County, and Town Sources
1826 Probate records recorded Source:Red Book: American State, County, and Town Sources
1880 No significant boundary changes after this year Source:Population of States and Counties of the United States: 1790-1990
1900 Land records recorded Source:Red Book: American State, County, and Town Sources
Population History
source: Source:Population of States and Counties of the United States: 1790-1990
Census Year Population
1820 2,248
1830 2,512
1840 4,921
1850 7,672
1860 13,989
1870 13,768
1880 19,015
1890 22,796
1900 24,101
1910 28,285
1920 31,602
1930 30,847
1940 32,770
1950 25,080
1960 19,661
1970 19,308
1980 23,635
1990 21,621
Research Tips
This page uses content from the English Wikipedia. The original content was at Hempstead County, Arkansas. The list of authors can be seen in the page history. As with WeRelate, the content of Wikipedia is available under the Creative Commons Attribution/Share-Alike License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:33:05.000Z | nodhiliyifjyirogdnvi5kzwy5sglxf6 | {
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} | cccc_CC-MAIN-2013-20 | Place:Redbank, Armstrong, Pennsylvania, United States
Watchers
NameRedbank
Alt namesRedbanksource: WeRelate abbreviation
TypeTownship
Located inArmstrong, Pennsylvania, United States
source: Family History Library Catalog
the text in this section is copied from an article in Wikipedia
Redbank Township can refer to the following U.S. locations:
Research Tips
This page uses content from the English Wikipedia. The original content was at Redbank Township, Pennsylvania. The list of authors can be seen in the page history. As with WeRelate, the content of Wikipedia is available under the Creative Commons Attribution/Share-Alike License. | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:43:58.000Z | tlg2vfl46uvn3wo5uvtm2zjyrornl2qu | {
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} | cccc_CC-MAIN-2013-20 | USB Palm OS Device as an LCD Display
From NAS-Central Buffalo - The Linkstation Wiki
(Difference between revisions)
Jump to: navigation, search
Revision as of 18:22, 29 June 2006
This article based on work done by Ramuk on Linkstationwiki.org
How to use a USB cabled Palm-OS device as an external (20x4) character LCD display for your Linkstation using the PalmOrb emulator
USB LCD : These instructions are essentially for a USB LCD Display, a USB docking Palm-OS device can emulate a USB LCD interface so that no external adapter is needed. The same instructions could be used with some modification to add an LCD with the Articles/PPCSerialHeader
Contents
Abstract
This article is for people that want to add an LCD display to their Linkstation, but don't want to crack it open, and happen to have a USB cabled Palm OS device lying around.
Prerequisites
This article assumes that you have installed Projects/FreeLink. A 2.6 Kernel Articles/GeneralUpgradeTo26-Kernel has better USB support, but a 2.4 Kernel would probably work as well. For these instructions you will need a USB cabled Palm-OS Device.
Method
• Install PalmOrb on your USB cabled Palm-OS Device. The v1.1a4 version has the most font options for a (20x4) emulated LCD, there are several other versions available on the sourceforge site. It emulates a Matrix Orbital LK204-25 LCD.
Configure the PalmOrb app to use the USB Port Menu -> Options -> Serial:Device:USB
• Install and remove LCDProc using apt-get (this should take care of any dependencies) The Debian Stable Version only has the LCDd Daemon program but not the lcdproc client, so you'll have to install lcdproc from a tarball. Kind of an ugly solution to get the dependencies resolved, but it works:
apt-get install lcdproc
apt-get remove lcdproc
• Get the LCD Proc tarball and compile/install it.
wget http://lcdproc.omnipotent.net/download/lcdproc-0.4.5.tar.gz
tar -xvzf lcdproc-0.4.5.tar.gz
cd lcdproc-0.4.5
./configure
make
make install
........
[MtxOrb]
# Matrix Orbital driver
# Select the output device to use [/dev/lcd]
device=/dev/ttyUSB0
#device=/dev/usb/tts/1
#device=/dev/ttyS1
# Set the display size [20x4]
size=20x4
........
• Attach the USB enabled Palm-OS device and start the PalmOrb app. Do a dmesg of your linkstation; if things went well you should see lines like this at the end:
usb 3-1: Handspring Visor / Palm OS converter now attached to ttyUSB0
usb 3-1: Handspring Visor / Palm OS converter now attached to ttyUSB1
• Run the LCDd (LCDproc Daemon) and LCDproc client with some options to see if it works.
LCDd &
lcdproc C M X
• Hopefully you got some output on the Palm-OS device as an LCD. For other clients Google:lcdproc to see what other LCDProc clients you can find. Or just go here: LCDProc Site:Clients
What's the point?
PALM AS A TERMINAL untested: Enable terminal access with this command: getty -h -L ttyUSB0 9600 vt100, and use a terminal program like ptelnet
Well if you happen to have a USB enabled older Palm OS PDA lying around and want an external LCD display for the price of nothing, now you have it!
Shell Scripts
#!/bin/sh
# lcdmon.sh
# Kill any LCDd that are running first, Start the Daemon and
# fork it to the background. Then run LCDProc with the Time option and
# fork it to the background.
# You can run lcdproc -? alone to see what options there are.
# Run another client: netlcdclient which gives U/Dl speed
# You could run this script at startup.
killall LCDd
LCDd &
lcdproc T &
netlcdclient -i eth0 -a LinkSTN -d
References
Personal tools | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T07:13:10.000Z | r44nc7f4t3pfwqkwthzsxvi67caadws2 | {
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} | cccc_CC-MAIN-2013-20 | to top
Building a Notification
This lesson explains how to create and issue a notification.
The examples in this class are based on the NotificationCompat.Builder class. NotificationCompat.Builder is in the Support Library. You should use NotificationCompat and its subclasses, particularly NotificationCompat.Builder, to provide the best notification support for a wide range of platforms.
Create a Notification Builder
When creating a notification, specify the UI content and actions with a NotificationCompat.Builder object. At bare minimum, a Builder object must include the following:
For example:
NotificationCompat.Builder mBuilder =
new NotificationCompat.Builder(this)
.setSmallIcon(R.drawable.notification_icon)
.setContentTitle("My notification")
.setContentText("Hello World!");
Define the Notification's Action
Although actions are optional, you should add at least one action to your notification. An action takes users directly from the notification to an Activity in your application, where they can look at the event that caused the notification or do further work. Inside a notification, the action itself is defined by a PendingIntent containing an Intent that starts an Activity in your application.
How you construct the PendingIntent depends on what type of Activity you're starting. When you start an Activity from a notification, you must preserve the user's expected navigation experience. In the snippet below, clicking the notification opens a new activity that effectively extends the behavior of the notification. In this case there is no need to create an artificial back stack (see Preserving Navigation when Starting an Activity for more information):
Intent resultIntent = new Intent(this, ResultActivity.class);
...
// Because clicking the notification opens a new ("special") activity, there's
// no need to create an artificial back stack.
PendingIntent resultPendingIntent =
PendingIntent.getActivity(
this,
0,
resultIntent,
PendingIntent.FLAG_UPDATE_CURRENT
);
Set the Notification's Click Behavior
To associate the PendingIntent created in the previous step with a gesture, call the appropriate method of NotificationCompat.Builder. For example, to start an activity when the user clicks the notification text in the notification drawer, add the PendingIntent by calling setContentIntent(). For example:
PendingIntent resultPendingIntent;
...
mBuilder.setContentIntent(resultPendingIntent);
Issue the Notification
To issue the notification:
• Get an instance of NotificationManager.
• Use the notify() method to issue the notification. When you call notify(), specify a notification ID. You can use this ID to update the notification later on. This is described in more detail in Managing Notifications.
• Call build(), which returns a Notification object containing your specifications.
• For example:
NotificationCompat.Builder mBuilder;
...
// Sets an ID for the notification
int mNotificationId = 001;
// Gets an instance of the NotificationManager service
NotificationManager mNotifyMgr =
(NotificationManager) getSystemService(NOTIFICATION_SERVICE);
// Builds the notification and issues it.
mNotifyMgr.notify(mNotificationId, mBuilder.build()); | v0 |
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Difference between revisions of "Vang Vieng"
From Wikitravel
Laos : Central Laos : Vang Vieng
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(updated listing FruitFriends)
(Tubing area)
Line 135: Line 135:
Westerners employed by the bars for food and accommodation hand out free shots and organise drinking games to encourage you to stick around; many will also offer promotions to encourage you to their visit twin bars in town later in the evening. The competition among the night bars is so fierce that the deals are often genuinely pretty amazing, and if you time it right you can go from bar to bar for free buckets and cheap deals.
Westerners employed by the bars for food and accommodation hand out free shots and organise drinking games to encourage you to stick around; many will also offer promotions to encourage you to their visit twin bars in town later in the evening. The competition among the night bars is so fierce that the deals are often genuinely pretty amazing, and if you time it right you can go from bar to bar for free buckets and cheap deals.
Too much alcohol or "special" or "happy" shakes which can contain cannabis, magic mushrooms or any manner of substance are not a good idea if you plan on going back in the river.
+
Too much alcohol or "special" or "happy" shakes which can contain cannabis, magic mushrooms or any manner of substance are not a good idea if you plan on going back in the river.
+
*<drink name="Fluid Bar and Restaurant" alt="" address="tam lom" directions="4 km north of town" phone="" url="http://www.vangvieng.biz" hours=""<EMAIL_ADDRESS>price="" lat="" long=""> Is filled with abstract art, strange sculptures and an eclectic mix of music. If you want a break from the norm this is the place to be.</drink>
+
===In town===
===In town===
Revision as of 12:31, 23 February 2013
Vang Vieng (ວັງວຽງ)(also Vang Viang) is a riverside town in Central Laos.
Contents
Understand
NOTE: The majority of the bars from the start of tubing into the town are closed, and it is unknown when, or even if, they will re-open: further available are in the Vientiane Times. Tubing without the drugs and alcohol remains available.
Once little more than a bus stop on the long journey between Vientiane at the Thai border and the World Heritage Site of Luang Prabang, it has managed to become a destination in its own right. Still not much more than three streets and a bus station, the main attractions are the river, laid back countryside and cave-filled rock formations.
Many who have travelled around South East Asia have heard about tubing, an activity that dominates the town and its visitors. Originally opened up by hedonistic backpackers, the atmosphere of the town itself is one of lethargy by day and debauchery by night: tourists sprawl out in the pillow-filled restaurants, termed "TV Bars", watching re-runs of US sitcoms, Friends and Family Guy episodes until the sun goes down, and then party heavily until the early hours.
A couple of kilometres upstream, the pulsating music, drinking games and drug-fuelled debauchery of the increasingly lively riverside "tubing" bars starts at lunch-time.
NOTE: Be aware that roughly one tourist dies every month while jumping or tubing. Several more get severe injuries - every month, as there are many sharp rocks not visible under the water in many places along the river.
Do not jump at all if you are drunk.
It's very difficult to always predict where you will land in the water while jumping and there are almost always some rocks nearby!
Vang Vieng may have established itself as the exception to the rule that Laos doesn't have nightlife. It does have potential as a base for adventure tourism which attracts a few more sedate foreign sightseers. However, it can be considered a noisy "back-packer hell" and so those wishing to avoid noisy, selfish teenagers away from their parents for the first time and instead seek something Laotian would do as well to either use Vang Vieng only as a base to explore the surrounding countryside or avoid it all together.
Get in
Vang Vieng is on Highway #13 between Vientiane and Luang Prabang - by bus (road and bus conditions permitting) about 6-8 hrs from Luang Prabang, around 3-4 hr from Vientiane.
Highway #13 is a sealed two lane road that is slowly deteriorating. The road between Vang Vieng and Luang Prabang is mountainous and boasts amazing scenery. The road between Vang Vieng and Vientiane is flatter and less interesting.
By bus
Tickets for tourist buses and minivans can be purchased at almost every guesthouse and should include transport to the bus station.
VIP buses from Vientiane cost about 50,000 kip. Minivans leave Vientiane all day and cost in between 35,000-50,000 kip. The Express bus to Vientiane costs 60,000 kip (Feb 2011). Slower local buses to Vientiane without air conditioning run in the early morning (5:30AM-10AM) and cost about 40,000 kip for a 5 hour journey - you can board them either at the northern bus station or the bus stop south of the airstrip.
From Luang Prabang, VIP buses cost 150,000 kip and minivans cost 120,000 kip (June 2012). If you're susceptible to motion sickness you'll be much better off on the slower bus than the minivan.
Get around
From the bus station
From Vientiane, buses will drop you off either at the old airstrip (from the Vietnam war, it's now just a giant gravel pad) and the tourist buses will drop you in front of a hotel on the main street in town. The airstrip is directly behind the main street, so in either case there is no need to take a tuk tuk or cyclo if you plan to stay in the main area of town. The island and bungalows along the river are about a 10 min walk away. Buses to and from the North of Laos leave from the new bus terminal 2 km North of town. When leaving Vang Vieng, transport to the bus station is usually included in the price of your ticket.
Around town
Vang Vieng is so small that everything is easily reachable by foot. If you want to venture outside of town, bicycles are widely available and can be rented from hotels or local businesses. You should not have to pay over 10,000 kip for a day's rental.
Motorcycle rentals are also widely available. It's quite easy to rent a motorcycle from a local business for only 40,000-60,000 kip. Petrol may not be included in the rental fee, so check before paying. If not included, it's an extra 10,000 kip (Nov 2012). Always check the details of the contract. At some places you will have to sign a contract which makes you responsible if something breaks or fails to function, even if it's normal wear and tear. If riding out of Vang Vieng to the surrounding villages, be very careful of buses, minivans and trucks, and take extra precautions against the poor road conditions. Gravel, potholes, mud puddles and other hazards litter the road, so it pays to keep your eyes on the road and not on the mountain scenery. Also you are not allowed to go out of the Vang Vieng district, so don't count on renting a bike here to go on a longer tour of the district.
Several tuk tuks are also scattered around town. 10,000 kip per person will be plenty to get to anywhere within Vang Vieng - it's also the price you'll pay to get to the tubing bars irrespective of how many other people are on board. It's better to sort out exact change with fellow passengers as tuk tuk drivers are notorious for giving incorrect change.
To rent a tuk-tuk for the day costs about 130,000-150,000 kip.
See
The town itself offers no real attractions, but the row of limestone karst mountains across the river provides a stunning backdrop and is the setting for some impressive caves.
• Tham Poukham - Blue Lagoon, (7 km west from town, maps provided where you can rent bicycles, accessible by mountain bike or motorbike. Be careful along the way, in recent years a number of imposters have shown up, all claiming to be the 'blue lagoon'. Keep to the main road and you should be OK). 8AM-6PM. A spring fed lagoon at the bottom of "Golden Cave". Nice place to relax, swim and play on the rope swing. The waters are inhabitated with a few hundred carp that will eat locally sold fish food out of your hand. The cave above requires a modest 100 m climb up a makeshift bamboo ladder. Once inside, there is a short walk to the Sleeping Golden Buddha and glimmering stalactites about 300 m further inside. 10,000 kip entry and 10,000 kip to rent a head-torch, mandatory if you go deeper into the cave than the Buddha (check the battery in advance). Guides for the cave advertised at 50,000 kip but this is probably negotiable. Guides are recommended as finding the best way to climb through the cave can be quite difficult.
• Padeng cave and Ring cave, (cross a footbridge over the river, follow the signs and white flags (garbage bags) on sticks through the field). Across the river a 1.5 km path marked by white flags cuts through the fields towards the limestone mountains. The smallest hill has very rickety ladders (which can be dangerous) to aid in climbing to the top. Halfway up the mountain is a cave. Another 1 km along the path past the mountain goes through a small forest and arrives at a cave. A few sleepy Laotians guard the cave's entrance and a hand painted sign says that guides are mandatory. It costs extra to go to the lagoon in the cave, and the guides will let you know that "tipping extra is ok". 10,000 kip for the hill, 15,000 kip for the cave, 30,000 kip to go to the cave lagoon.
• Xang Cave, (on the south end of the main road. Turn right at the sign to Jam Mee Guesthouse). Decent cave but not worth the 15,000 kip entrance fee plus 2,000 kip per person/3,000 kip per motorbike bridge crossing fee. The cave is well lit and has stairs running throughout that makes it an easy self-guided tour. One part has a really nice view of the farms surrounding the city. If you've been to other caves it's really not worth it.
Do
Vang Vieng bar with rope swing on tubing route
• Tubing, (There is an office in downtown Vang Vieng that now organizes all tube rentals. It's pretty easy to find--just ask around. They will rent you the tube and organize transportation up the river a few miles.). From around midday to 2PM is reasonable to go because earlier everyone else would be still asleep. Look at the magnificent view of the mountains rising directly beside the river. Many beer and other pit stops along the way. Also, try the diving stop and the swing. Some dry bags may not be of the best quality & so cameras can get ruined. To get the deposit back tubes have to be returned by 18:00. In winter temperatures fall from 16:00, so start back early. Ride at least one rapid before starting the party to avoid disturbing guests visiting the Organic Farm. The party scene has taken over and the owners use large loudspeakers, effectively blocking out any singing of birds. Beware of tubes getting stolen while stopping at bars, you may lose your deposit and the ride down. Tubes get stacked up at each bar so keep an eye on how many are left, especially at the first few bars where lots of people arrive without their own tube. If you're not used to drinking stromg alcohol: stick with beer, and for reasons of safety & common sense consider avoiding alcohol if entering the water. The amount of alcohol in buckets can be high, and the effect can kick in suddenly; you won't be the first one to be too drunk to make your way back on the river. During rainy season there is more water in the river and eye infections are common. 55,000 kip for the Tube + 60,000 kip deposit.
• Lao-style steam sauna.
• Kayaking the river. This covers the same part of the river as tubing (and a more untouched part further upriver). Kayaking includes lunch and different caves. Some of the caves takes more than an hour to walk through, with bats and other animals.
• Watch movies. The US TV-series Friends is shown at many restaurants, and seems to be very popular with the younger party crowd.
• Uncle Toms Trails, 2 (On the west side of the river (the path to the blue lagoon )), 856 (0)2029958903. Uncle Toms is a dirt bike tour operator offering tours of the beautiful trails around Vang Vieng. All new bikes, 125cc four stroke trail bikes. Prices are US$30 for a half day or US$55 for the full day.
• High swings. Playing on the very high swings over the river and sliding on a slide. Be careful: perforated eardrums, broken ribs, foot injuries and permanent hearing damage are common injuries, and deaths are not unknown. The local hospital is not equipped to diagnose or treat these serious injuries - Vientiane has the closest, if spartan, ENT facility but no English speaking specialists, so you may have to travel to Udon Thani for treatment. You might have to rely on other tourists for rescue. Most of these swings and slides have been taken down.
• Organic farm, 3 km north of Vang Vieng, close to where the main tubing run starts, is an organic farm offering volunteering opportunities. It is noise-free until about 11:00 and again when the last revellers return to town around 18:00. They teach the village children, build mud brick buildings, learn/teach farming, eat organic food and go to sleep at 22:00. The farm has also a kitchen and sells organic food. The organic farm has dormitory (30,000 kip ), budget and more luxurious rooms for rent.
• Rock climbing, [1]. There are walls suitable for first timers and professionals. The established climbing outfits in town are Adam rockclimbing and GreenDiscovery. A new shop opened in 2012, Central Climbers, managed by seasoned climber Nom.
• Hot Air Ballooning. A flight over the surrounding countryside with stunning views.
• SAELAO Project, (Nathong Village, 7km outside of Vang Vieng, near of Poukham Cave and the Blue Lagoon), 020 2292-8630, [2]. SAELAO project is trying to set an example of sustainable development for local people. There are different projects including building, organic farming and teaching English to the locals. They are always looking for volunteers, but if you don't have time to volunteer you can visit their restaurant to have lunch & learn about the project.
• Vang Vieng Paintball, Tham long road (Behind Fluid Bar, about half way to start of tubing), [3]. When you think of Vang Vieng, you think of tubing and drinking. Vang Vieng Paintball brings the first and only paintball field to Vang Vieng, located next to the river with spectacular views of the jungle and the mountains. Western run, you are guaranteed the quality and satisfaction you would expect from back home while saving well over half of what you would normally pay. Full service bar and a kitchen for all your needs. Any age welcome, please make sure to bring proper footwear, overalls will be supplied. $15.
• FruitFriends, ([email protected]), [4]. A transparent organisation providing volunteer the opportunity to immerse in Lao society. FruitFriends profits are used to execute community activities, building schools, set-up youth movement, English classes, ... If you want to participate in a transparent organisation respecting its staff and following the law on labor FruitFriends is the place to be. More information on their website www.fruitfriendslaos.org
Buy
The small shops scattered throughout Vang Vieng sell the standard assortment of snacks, trinkets, sunglasses, and bathing suits. The majority of tourists seem to leave with at least one T-shirt, vest or dress with "In the Tubing - Vang Vieng" emblazoned on it.
Prices for tourist packages are quoted in both kip and US dollars. Restaurants, hotels, and pretty much everything else is priced in kip. Most places will accept kip, US dollars and Thai baht for larger purchases.
There are several ATMs that now take all major credit cards but are known for running out of cash. Some tourists have reported only being able to use cards on the Maestro (Mastercard) network.
The Lao Development Bank changes money at good rates and processes cash advances. BCEL will also do cash advances on credit cards.
Eat
The numerous TV restaurants are interchangeable and all have a similar theme. When it comes to wifi some offer it free, others sell access. Others offer access only at certain times only. They all have similar menus. A selection of Lao, American, Italian, Chinese and Thai food is normally fresh but often of indifferent quality and poorly executed. Small serves average 20,000-45,000 kip.
For quick eats and late night snacks, numerous pancake and sandwich stalls dot the streets. But be careful, food hygiene may have been compromised by being in the heat all day and your gastro-intestinal system may react accordingly. The street running next to the river just to the west of the tube rental office has a few vendors selling large chicken and pork kebab skewers for 5,000 kip each.
• Mister Potato, (in the small street along the hospital) is a food cart with tables and chairs to sit. They serve fresh homemade beef sandwiches with potato twists and drinks. The set menu is good value..
Be aware that many restaurants offer "happy" shakes and pizzas: food or drink with the words "happy", "special" or "ecstatic" will contain marijuana or magic mushrooms
• B&P Restaurant & Bar, (in between Babylon guest house and Organic farm restaurant). Lao, Thai and Western cooking. Homebaked applepie with vanilla icecream accompanied with an espresso, cappuccino or a big pot of mulberry tea. Very cosy, clean and nice looking restaurant. Free wifi for customers. Friendly staff with a Lao/Dutch management.
• Jungle Bar, (turn left at the fork by the tubing centre, beside TCK Tours). Good quality food, relaxed environment with cheap meals. Does not play Friends or Family guy. The friendly owner, Jackie, serves good fruit shakes, pizza and Pad Thai.
• Q Bar and Restaurant, [5]. Food and drinks from as little as £1. Steak+drink for 30,000 kip, curry+drink 15,000 kip.
• Nisha Indian Food, only open from 2PM. Serves great Indian food.
• Organic Farm Cafe. Original and interesting menu. Deep-fried mulberry leaves in honey for 15,000 kip. Goat cheese sandwich for 30,000 kip.
• Peeping Som's Bar and Restaurant, Main Rd (just past Wat Kang, next to Chilllao Guesthouse). A small menu offering a change from most other restaurants in town. The English chef focuses on the quality of dishes, preferring to offer a few very well executed meals. Lao drinks such as Lao Hai, Flavoured Lao Lao also on offer.
• Pan's Place Guesthouse, (Pan's Place Resteraunt), (on the main street), Vang Vieng (300 Meters South of the centre), 023 511484, [6]. 7am - 11pm. Western-style menu, including: All day English Breakfast, Spaghetti Bolognase, Beef Goulash, Cottage Pie, fresh fruit shakes, snacks & drinks. Helpful & friendly staff under Kiwi/Lao management.
• The Meeting Place, 047 Ban Vieng Kaew (end of the main street, 3 blocks from city centre, beside Laos Haven Hotel & Spa), +856 23511900. 11am - 10pm. Newly opened restaurant that serves Thai, Lao & Western cuisine. A small, 20-seater establishment. Phad Thai, Spring rolls, Larb and Som Tum(green papaya salad) are their more specialised dishes. USD 3 onwards per pax.
Drink
Beerlao is available everywhere in Vang Vieng, but the drink of choice is a cheap plastic bucket filled with liquor and soft drinks. A bottle of Tiger Whisky costs the bar 10,000 kip, so around a third of a bottle goes into your bucket, normally with a choice of 7up or Pepsi, lime and Redbull.
Tubing area
The ramshackle wooden bars in the first stretch of the tubing area are too numerous to single out any individual ones and heave with people in the early afternoon even though many of them haven't rented tubes and some of them have no intention of even going in the water - there are plenty of pathways and bridges to get around. Lie on plastic mats by the river and drink Beer Lao, or dance the day away on an outdoor dance floor.
Westerners employed by the bars for food and accommodation hand out free shots and organise drinking games to encourage you to stick around; many will also offer promotions to encourage you to their visit twin bars in town later in the evening. The competition among the night bars is so fierce that the deals are often genuinely pretty amazing, and if you time it right you can go from bar to bar for free buckets and cheap deals.
Too much alcohol or "special" or "happy" shakes which can contain cannabis, magic mushrooms or any manner of substance are not a good idea if you plan on going back in the river.
In town
Beer and buckets are available all around Vang Vieng in bars covered with Christmas lights (including all the "TV restaurants") and the buckets are usually very strong because Lao whisky is cheaper than soft drinks. There's no shortage of choice but a distinct lack of diversity, especially if you're looking for live music.
• The Kangaroo Sunset Bar, Next to New Bridge, River Road., +856 20 7714291. Australian owned and claims to offer the coldest beer in town. Now run by an English guy and Lao woman. Has some things you cannot get anywhere else such as Marmite, Vegemite, Yorkshire tea, Branston pickle and chilli con carne. Beautiful view.
• Kiwi Sports Bar, In between the hospital and Pan's Place Guesthouse, +856<PHONE_NUMBER>. The cheapest beer in town. Play your own music. Free pool, dartboard, internet, whisky and sports on a 60" LCD. Excellent variety of Italian and Lao food. Also has mountain bikes for rent.
• Q-Bar, (on the main street). A club environment. Depending on the revolving staff of westerners they play Dnb, dubstep and pop. Open for food all day, and closes between 12 midnight-1AM, depending on the numbers.
• The Rising Sun (The Irish bar), +856 20 7928266 (), [7]. The only Irish pub in Vang Vieng. Regular live music, 2 free pool tables upstairs and downstairs and 3 TVs showing live sport. Cold beers and homemade pies.
• Sakura, (In the village centre), +856 20 6506993 (), [8]. Is a step above the standard Friends and Family guy bars. They have a projector, with a fairly solid library of both Hollywood and art House films, although you have to be lucky or go in with a sizeable group to get your first choice. They also offer dice roll bucket deals, if you're lucky you win a free bucket. Free wifi here but only available from 9AM-8PM.
The Island
For serious drinking, the bars referred too collectively as The Island, reached via some ramshackle bamboo and wood bridges are where most of the tubers end up after a day on the river, particularly after the bars in town start to close. The sandwich pancake pushers hover in a long line as people stumble over the bridge, waiting to prey on drunken western tourists. But be aware of trying to buy eye drops for conjunctivitis around this area. Stories abound of people being drunkenly extorted as much as 5x the normal price for conjuntivitis treatments.
• The Bamboo bar, stands out a bit from the rest and offers mojitos (also alcohol free) served in bamboo with bamboo straws whilst watching the late tubers come in and watching the sometimes spectacular sunsets and thunderstorms over the mountains. Located on the island in the river at the end of the tubing surrounded by bamboo. A sauna is being built for the high season and vegetarian buffet is ready after one hour on demand by a larger group. Cheaper bars close by also offer drinks and food.
• Limbo bar, so named for fire limbo stays open very late.
• Rock bar, offers a change in music.
• Joker Bar and Sunset Bar, stay open the latest.
Sleep
There are now a couple of halfway-decent midrange "hotels" and attempts at boutique style residences.
Generally though, double rooms go for US$6-15, make sure you see the room (and bathroom!) before paying. More local, low-key (which is pretty low-key in Vang Vieng to start with) places are by the market and more shiny set ups are on the main road. The party crowd tend to advocate a bungalow on the island, but expect it to be too noisy if you want to sleep during the night.
Most guesthouses have large TV-viewing areas, practically coated in the Southeast Asia signature triangular cushions, where they serve food. But be forewarned - you'll be hard pressed to find a place screening something other than the US sitcoms "Friends" and "Family Guy".
The Famous Spicy Laos Hostels is no more.
• Bee Bee Guest House. Full of great character just nearing the end of the main bar street. Rooms are clean and spacious and the family that runs this guesthouse speaks English and are always ready to help. Free wifi, all rooms have hot showers en suite, drinking water and supplies tourist information. Great roof views from the balconies, safe rooms and great price.Really nice people and staff. A pproximately 20 minute walk from the centre.
• Babylon Guest House, [9]. An established inimitable accommodation that's either loved or not. Being in the centre of town at the start of the main bar street many characterful guest enjoy the accommodation. With free wifi and internet for guest and a downstairs bar & organic restaurant. Politically incorrect jokes are a must and English speaking staff are helpful. All rooms have hot showers en suite. Great roof terrace views.
• Central Backpackers, (On the main road between Q-Bar and the Vip Bus stop), +856 23 511 593, [10]. At the heart of Vang Vieng just metres away from Bus stop, bars and markets. This new Hostel offers spacious and clean rooms (doubles, twins, triples and dorms) with safety lockers and balconys with great views of the surroundings. The Restaurant with attached Bar offers some tasty food and cheap drinks (Beers, Buckets & Cocktails). The friendly English speaking staff is always there to help you out. Big chill-out area with games of dart, drinking related activities and regular screening of TV shows & live sports. Great place to meet people. Free Wifi. Dorms from 30.000 kip / Doubles/Twins 80.000 Kip / Triples 120.000 Kip
• Champa Lao Bungalow. Cheap huts on the island down stairs with river view. 100,000 kip. Friendly local family and traditional-style rooms. Mountain view from the wooden porch with hammocks upstairs cost 40,000-70,000 kip. Breakfast included, tasty food and free wifi.
• Champa Lao Villa. Nice garden, tasty food, nice rooms. Breakfast included and free wifi. rooms 60,000-80,000 kip and also family rooms priced at around 250,000-200,000 kip.
• Chillao, (On the main road north of Q Bar), +856 23 511 328 (). checkout: 12pm. Centrally located, social hostel offering dorms and some of the cheapest single rooms in Vang Vieng. Adequately clean despite the rather unorthodox plumbing, dorm rooms have broken lockers, free wifi.. 20,000-70,000 kip.
• The Elephant Crossing Hotel, [11]. Small hotel. All the rooms have a view of the river, with a restaurant right next to the river. Good selection of food and beer, free wifi. US$30-50.
• Greenview Bungalows and Restaurant, +856 20 212 8086, +856 20 501 1679. Just across the road from the Phoudindeng Organic farm. Khamsone and his wife Some offer comfortable clean bungalows with hot showers, great Lao food, and occasional campfires and singalongs. A great place to escape the noise of downtown. Bicycle and motorbike rentals are available. Bungalows with double beds 70,000 kip, other double rooms for 40,000 kip..
• Island bar. Great view over the mountains from the restaurant. Midrange. Grumpy owner.
• Jammee Guesthouse, +856 20 5589 8945 (), [12]. New guesthouse on the quiet end of Vang Vieng village, but still within walking distance of the town centre with all the party activities. The surrounding views are stunning, the place is quiet and offers comfortable, large rooms, all with private bathroom, hot shower, and either king or queen size beds or twin singles all with innerspring mattresses, free wifi. All the rooms have a veranda or a secured balcony with mountain views. Also a dormitory is available with free mosquito nets provided. Free wifi is available in all rooms and throughout the guesthouse. Water, coffee, tea and bananas, pickup service are all free.
• Lucky Guest House. Great view over the mountains from the huts. Cheap huts on the Island. Friendly local family.
• Nam Song Garden. Lao born Malay's and Norwegian Arne's place. Great view over the mountains from the shaded garden. Fan rooms and bungalows from 40,000 kip. Free 24-hour wifi, towel, water refill, metal lock-boxes. Book exchange.
• Nana Guest House, (at the south end of the main street). 3 story, simple guest house. Friendly family-run staff, hot showers, a fourth-story balcony and laundry. Good for sleeping away from the raucousness further north.
• Pans Place Guesthouse, (on the main street). Clean rooms in a quiet location, 300 m from the centre of town and 200 m from the river. Restaurant open from 7AM till late, snacks and meals, internet cafe, with discount rates for guests. TV room with cable TV and DVDs, Communal balcony with views of the mountains and sunsets, Laundry service, free drinking water, All rooms have fans, comfortable beds and are mosquito-proofed.
• Phoudingdeang Organic farm, (3 km north of Vang Vieng). Peaceful and serene, an employer of orphans, mountain views. Simple short term rooms, long term residences in adobe houses.
• Sengdeuan Guest House, (just past the Kangaroo Sunset bar), +856 23 511138. checkout: 12 noon. All rooms come with towels, soap, bottled water & toilet paper included. The private pool in the garden has water in it from Feb-Nov. A great place to learn about the history of the area and the Hmong people. Fan rooms with own bathroom s/d 40,000/50,000 kip. Air-con 90,000 kip.
• Villa Vang Vieng Riverside, (Near the Kangaroo Sunset bar and the toll bridge), +856 23 511460 (), [13]. Located directly at the river, with a great view. Buildings and rooms are designed in Lao style. Fast, free wifi. US$30-US$50, incl. breakfast.
• Le Jardin Organique. Away from the party in a nice location with lovely looking rooms. Hot water doesn't get hot and some find the owners are difficult to deal with. $US18 per night for bungalows with hot water.
• Domon Guesthouse, (Beside River). Nice enough double room worth the extra money. Views from the balcony onto the river and towards the mountains are stunning, especially at sunset. 60,000 kip.
• Chanhthala Guest House. checkout: 11.30. Free wifi with towel and soap 25,000-50,000 kip.
• Laos Haven Hotel & Spa, 047 Ban Vieng Kaew, Formerly Tony's GH (end of the main street, 3 blocks from city centre), +856 23511900, [14]. Looks gorgeous from the outside but don't let that scare you away, reasonable prices with very clean basic rooms. Peaceful, quiet location just 5 minutes walk from the "center" of town where the bulk of the restaurants are. The family running the hotel speak very good English, and are very friendly and helpful. Booking of bus tickets, kayaking and other adventure tours through the manager may be cheaper than some other hotels/agents. Offers Spa facilities.
• Riverside Boutique Resort, Vang Vieng, Ban Viengkeo (On the right hand side, just before the toll bridge), +85623511726, [15]. checkin: 14:00; checkout: 12:00. Located on the banks of the Nam Song River, the Riverside Boutique Resort is a new luxury hotel with a French colonial architecture and a decor that promotes the ethnic diversity of Laos. The property and its large swimming pool offer stunning views over the limestone mountains of Vang Vieng. US$110-US$170. (18.920739490385518,102.44478464126587)
Stay safe
Thousands of tourists pass through Vang Vieng without incident every year, but the combination of outdoor activities, drink and drugs still makes it one of South East Asia's most dangerous destinations for travellers.
Even the town's main street can injure the unwary traveller: you'll need to watch out for the large holes in the pavement through to the drainage ditch below as they are not fenced off.
The medical care available in the town's hospital is rudimentary at best - for serious injuries you'll want to go to Vientiane, or better still, Thailand.
Watersports and alcohol
Floating downstream at a sedate pace in an inflated rubber tube shouldn't be a dangerous activity, provided you leave enough time to get back before darkness falls.
What raises the danger level is the bars offering a combination of strong alcoholic drinks and high platforms to jump from.
Whilst you may find that risk reduced somewhat by the dismantling of some of Vang Vieng's infamous ziplines, swings and slides following recent deaths, you're still going to have use your common sense. If you want to jump into the river, be very careful about where you do so - the Nam Song isn't very deep except where the bar staff have cleared rocks from the river bed. Don't even think of pushing others in: at least one person has died that way.
Needless to say, if the alcohol or drugs you've consumed may impair your ability to swim or climb out, don't enter the water, even on a rubber tube. Remember whisky buckets can be deceptively strong and their effects can kick in very quickly.
The river current is strong in many places - even those who are sober should avoid sapping their strength by swimming against it. It should be easy enough to swim across to shallower water instead.
Drugs
Historically accepted drugs, such as marijuana, mushrooms and opium are freely available in many bars and restaurants around town. The majority of bars have 'magic menus' with most of these things on. Consuming these drugs on the premises is fairly safe, although drugs are illegal in Laos and nothing is totally safe.
Southeast Asian 'crystal meth' is known as yabba and is available in both pill and smokeable forms. Formerly legal in Thailand as a way for longhall truck drivers to keep awake. Yabba is an epidemic due to its highly addictive qualities. Manufactured locally, the drug can be cut with any number of substances.
Aside from the drugs already mentioned it is inadvisable to attempt to purchase any other substances not freely available on the 'magic menus' around town. The dangers of most drugs should be well known to visitors, and additionally there is also a police presence. Plain-clothed policemen frequently take unsuspecting tourists to the local police station for smoking a joint. The usual outcome of this involves having your passport seized until you cough up a hefty fine typically of 3-5 million kip. Once the fine is paid however the matter is generally taken no further and the passport returned; however, the punishment will depend on the officer you are dealing with. Several local policemen are friendly with restauranteurs who sell opium, mushrooms, cannabis and yaba. Customers are not harassed at these establishments: the police wait until they leave. Some of the same police own guesthouses near the island. Never surrender your passport if you can help it, and often the best way out of the situation is simply to pay.
Medical Issues
A minor annoyance around Vang Vieng (refered too by locals and long time residents as the Vang Vieng plague) is conjunctivitis, or 'Pink Eye'. This is a viral, and sometimes bacterial, infection which can be caught from the river or other tubers. The onset of pink eye is often felt as an unnatural tiredness, and inability to properly fully open your eyes. If you sense this, or have been sharing buckets with people with pink eyes or wearing sunglasses at night, the best thing to do is shell out for eyedrops as soon as possible to prevent the onset. If this should happen late at night, be aware that eye drops alone should cost a maximum of 20,000 kip. Some of the late night pharmacies attempt to extort tourists, charging up to 5x the normal price for eyedrops.
As well as eye drops, general antibiotics are available from any pharmacy. In some cases eye drops will cause an intense stinging sensation, this can be soothed with an eye bath formula also available at pharmacies. Of course the sensible solution would be to rest your eyes and ease the drinking, but Vang Vieng's non-stop party atmosphere makes this a hard option for most.
Taxiboat
When tubing home late, taxi boats may offer to take you back for around 10k each. Howeber, they may just take you to somewhere else, stop and refuse to continue. If you don't want to pay the tuk tuk, the only way to get home is to walk.
Get out
• The adventurous can make their way Vientiane down the river by kayak. The trip should leave in the early morning, placing you in the capital by 6PM. For your belongings, dry bags are available or you can opt to place them in the accompanying van which will take them along and carry you at least part of the way. Expect to pay 170,000-220,000 kip
• You can book trips all the way to Bangkok (via Vientiane) but since you'll change mode of transport at least once anyway it's just as easy to arrange this trip at your own pace.
• Buses to Vietnam are notorious for taking even longer than expected and being a really unpleasant experience.
• Buses also go directly from Vang Vieng bus station to Udon Thani bus station. Bus departs at 9.30am (more like 10am) and schedulied to arrive at 5pm, though this may be on conservative. 100,000 kip for tickets if bought at the bus station.
Vang Vieng Bus Station
To Departs hours Approximate price (kip) Duration (hours) Comments Last update
Vientiane (Songthaew) Every 20 min' 40,000 kip June 2011
Vientiane (Local bus) 5:30,6:00,6:30,7:00,12:30,14:00 40,000 kip June 2011
Vientiane (Mini) 9:00 60,000 kip June 2011
Vientiane(Express bus) 10:30,13:30 60,000 Kip June 2011
Luang Prabang (MiniVan) 09:00,14:00 100,000 kip 10 h Sep 2012
Luang Prabang (Express) 10:00 90,000 kip June 2011
Phonsavan (Mini) 9:00 110,000 kip Oct 2012
Contact
Internet speed and reliability is variable but not bad by Laos standards. Internet cafes can be found all over the town.
Many guesthouses and restaraunts offer free wifi, although the latter generally expect you to buy something.
• Babylon Bar, has the fastest free wifi
• Sakura, has qood quality wifi (20,000 kip minimum spend)
• Pan's place, has qood quality Internet
This is a usable article. It has information for getting in as well as some complete entries for restaurants and hotels. An adventurous person could use this article, but please plunge forward and help it grow!
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Psychotropic drug initiation or increased dosage and the acute risk of falls: a prospective cohort study of nursing home residents
Murray A Echt, Elizabeth J Samelson, Marian T Hannan, Alyssa B Dufour and Sarah D Berry*
BMC Geriatrics 2013, 13:19 doi:10.1186/1471-2318-13-19
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First report of molecular diagnosis of Tunisian hemophiliacs A: Identification of 8 novel causative mutations
Hejer Elmahmoudi1*, Houssein Khodjet-el-khil1, Edvard Wigren2, Asma Jlizi1, Kaouther Zahra3, Dorothé Pellechia4, Christine Vinciguerra4, Balkis Meddeb3, Amel Ben A Elggaaied1 and Emna Gouider3
Author Affiliations
1 Laboratory of Genetics, Immunology and Human Pathologies, Tunis, Tunisia
2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
3 Hemophilia Treatment Center, Aziza Othmana Hospital, Tunis, Tunisia
4 Biological hematology department EAM 4174, Hospices Civils de Lyon Université de Lyon, Lyon, France
For all author emails, please log on.
Diagnostic Pathology 2012, 7:93 doi:10.1186/1746-1596-7-93
The electronic version of this article is the complete one and can be found online at: http://www.diagnosticpathology.org/content/7/1/93
Received:20 June 2012
Accepted:17 July 2012
Published:10 August 2012
© 2012 Elmahmoudi et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Introduction
Hemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder.
Aim
In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum.
Methods
We screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure.
Results
We identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles.
Conclusion
The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features.
Virtual slides
The virtual slide(s) for this article can be found here:
http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715 webcite
Keywords:
Hemophilia A; Mutations; Intron 22 inversion; Intron 1 inversion; Inhibitors; Molecular analysis; Tunisia
Introduction
Hemophilia A is an X linked hereditary bleeding disorder which results from a deficiency or abnormality in FVIII activity. The FVIII protein is composed of structural domains represented as A1-A2-B-A3-C1-C2 and is activated after the dissociation of the B domain. A large and heterogeneous spectrum of mutations has been identified in the F8 gene [1]. The most common mutations in severe hemophilia A are the intron 22 inversion mutations which occur in 45-50% of severe hemophilia A patients and the intron 1 inversion mutation which has been reported to be present in approximately 5% of patients with severe phenotypes [2,3]. The development of inhibitors in patients presents a major complication of treatment with FVIII, especially in patients with severe forms of hemophilia A [4]. The Hemophilia treatment centre of Aziza Othmana Hospital in Tunisia follows 143 hemophilia A patients. 72 of these patients have been diagnosed with severe, 49 with moderate and 22 with mild hemophilia A.
In a previous study we have determined the haplotype frequency in Tunisian hemophiliacs A concerning only single nucleotide polymorphisms (SNPs) [5]. Our aim in this study has been to identify the molecular genetics of hemophilia A patients for the first time in Tunisia. The characterization, molecular analysis and spectrum of these genetic alterations are reported in this paper.
Patients and methods
Patients
28 patients with hemophilia A from 22 unrelated families were included in this study. At the time of the study their age ranged between 4 to 38 years. 19 patients had severe form, 5 had moderate form and 4 had mild form of hemophilia A (Figure 1). All the patients gave informed consent for molecular studies.
Figure 1. Distribution of Tunisian hemophiliacs A according to their severity.
Molecular genetic analysis
DNA was extracted from whole blood samples using a phenol chloroform protocol. Severe hemophilia A patients were first screened for intron 22 inversion. Negative patients were then tested for intron 1 inversion. Intron 22 inversion was detected using LD PCR and confirmed with southern blot as described [6]. Intron 1 inversion was performed using the Bagnall’s protocol [7].
PCR amplification was performed for mild, moderate and severe hemophilia A patients without intron 22 or intron 1 inversions. The coding sequence of F8 gene was divided into 33 amplicons (200-480 bp). Exon 14 was divided into 8 fragments for PCR amplification and the other exons were amplified as unique fragments. Primer sequences, annealing temperatures and the size of PCR fragments are available from the corresponding author, on request. Mixtures of patients and wild type DNA were screened by denaturing high liquid performance (dHPLC) on a WAVE DNA Fragment Analysis System (Transgenomics, San Jose, USA). All large deletions were defined as a consistent absence of PCR amplification products. Altered profile revealed by dHPLC were then sequenced in both strands using ABI Dye Terminator Cycle Sequencing (Perkin-Elmer Applied Biosystems, Foster City, CA, USA) and analyzed using a capillary sequencer Genetic Analyser ABI PRISM310 (Perkin-Elmer Applied Biosystems, Foster City, CA, USA). Mutations were confirmed by a second PCR and sequencing. Results were analyzed using BLAST (http://www.ncbi.nlm webcite. nih.gov/blast) program in comparison with the wild-type F8 gene sequence. Mutation nomenclature was given according to HAMSTeRS as well as in parentheses according to the international recommendations for the description of sequence variants on the Human Genome Variation Society (HGVS) website (http://www.hgvs.org webcite).
Analysis of missense mutations
All identified F8 mutations were compared to those described in the HAMSTeRS database (http://www.HAMSTeRS.ac.uk/ webcite). PolyPhen software (Polymorphism Phenotyping) was used to perform the sequence alignment of the homologous FVIII from four mammalian species (human, murine, canine and pig) and to predict the possible impact of an amino acid substitution on the structure and function of FVIII. The 3D structure of FVIII was visualized using the PyMOL Molecular Graphics System (http://www.pymol.org webcite) [8].
Result
In this study, 28 hemophilia A patients from 22 unrelated families were investigated. In total we identified 23 different mutations, which included 5 intron 22 inversions, 8 substitutions, 6 insertions and 4 deletions identified in 4 severe hemophilia A patients (Figure 2, Tables 1 and 2). Among the 23 different mutations, 8 are novel mutations and have not been described in HAMSTeRS database or reported in recently published data. Of these novel mutations, 6 occur in severe hemophilia A patients (del exons 1–13, intron 22 inversion (18 kb, 15.5 kb and 14 kb), p.1595(1614)DfsX40, p.12(31)LfsX11, p.C179(198)R and p.N784(803)N) and 2 occur in moderate hemophilia A patients (p.727(746)SfsX7 and p.G520(539)R).
Figure 2. Frequencies of identified mutations according to their types.
Table 1. Identified types of intron 22 inversion in severe Tunisian hemophiliacs A
Table 2. Identified causative mutations in Tunisian hemophiliacs A
Analysis of the two novel missense mutations p.C179(198)R and p.G520(539)R using the PolyPhen Software suggested both mutations to be considered as structurally damaging. Further analysis, mapping the substitution sites on the 3D structure of FVIII, show that both of these mutated residues are involved in interaction that can be considered important for the structural integrity of the mature FVIII protein. Residue C179(198) forms a disulfide bond with the residue C153. The mutation p.C179(198)R disrupts this disulfide bond formation, and thereby most likely leads to destabilization of the A1 domain (Figure 3). The second novel mutation p.G520(539)R is located in the interface between the A1 and A2 domains. Substitution of this neutral glycine with a charged arginine probably disturbs the interactions in this interface and destabilizes the interaction between the A1 and A2 domains (Figure 3).
Figure 3. (A) Crystal structure of B domain-deleted factor VIII (PDB ID 2R7E). The domains are individually labeled and in different colors. The positions of the mutations studied in this article are indicated by arrows. Close-up views of the positions of the mutations with the mutated and nearby residues shown as stick models and hydrogen bonds as dashed lines. (B) The p.G520(539)R mutation located in the interface between the A1 and A2 domains and (C) the p.C179(198)R mutation located in A2 domain.
Discussion
We report the first molecular study performed in Tunisian hemophilia A patients belonging to Hemophilia Treatment Center of Aziza Othman Hospital. Our cohort consists of 28 patients from 22 unrelated families. Despite the limited number of our cohort, the novel mutations occur with a significant frequency (34%) indicating that our patients have a specific mutational profile in comparison with previously reported data. Each studied family was found to have its unique mutation except for one. Among the 18 identified point mutations 9 were located in exon 14, the largest exonic coding sequence of the F8 gene. The correlation between genotype/phenotype was assessed for the identified mutations in order to clarify the effect of mutations on the phenotype and to compare our data with previously reported data.
Severe hemophilia A patients
Inversions (5)
In the 19 patients with severe hemophilia A, intron 22 inversion was identified in 7 patients (36.84%) belonging to five different families, while no family present intron 1 inversion (0%). This result indicates that the intron 22 inversion, which is reported in severe hemophilia A in the general population with a frequency of 45%-50% [9], is less frequent in our patient cohort. The same tendency was found for the intron 1 inversion, which is reported with a frequency of 5% [10]. When we compare our findings with previous data from other Arab countries the frequencies of these 2 inversions are lower in our patients [11-14]. This result shows that our patients have a specific genetic profile which is confirmed by other molecular studies concerning our country [15]. Nevertheless, this data must be confirmed with a larger number of studied patients.
Among the identified intron 22 inversion types, the type I inversion was the most frequent in our patients (families 10, 11 and 12), which correlates with what previously has been reported in the literature [16]. The type II inversion was identified in one patient (family 9) and a novel atypical pattern (family 8) with 3 bands (18 kb, 15.5 kb and 14 kb), since the amplification of exons 22 and 23 gave the expected size this atypical pattern may be explained by a deletion of 2 kb in the INT22-h1 or in the INT22-h3 homologous regions (Table 1).
Insertions and deletions (8)
In our cohort of severe patients we identified 7 frameshift mutations (Table 2). All of them are associated with very low or undetectable FVIII:C in plasma leading to a severe phenotype as expected, since frameshift mutations resulting from insertions or/deletions in most cases lead to severe phenotypes [17]. The new large deletion spanning exons 1-13 was found in one patient with severe hemophilia A and was associated with development of inhibitors (family 4).
Substitutions (3)
We identified 3 substitutions in 3 unrelated families with severe hemophilia A (Table 2), among these the novel mutation p.C179(198)R, which occurs in exon 4 within the A1 domain (family 5). In the encoded protein this mutation substitutes a conserved cystein residue and disrupts the disulfide bond formation leading to destabilization of the A1 domain. The severe phenotype associated with this mutation is in accordance with previously reported genotype/phenotype correlation. For instance, the mutation p.C179(189)G, which is also associated with a severe phenotype, is reported twice in HAMSTeRS [18]. Previous studies have also highlighted that mutations of conserved amino acids in FVIII frequently are associated with a severe phenotype [19,20].
The second novel mutation, p.N784(803)N, is a silent mutation identified in one patient with severe hemophilia A (family 22). This silent mutation has no effect on the mature FVIII protein structure, but it might play a role in the expression levels of the protein, such as other silent mutations which have been recently identified [21]. To confirm this hypothesis we need to screen this point mutation in healthy individuals in order to exclude that it is not associated with a SNP, since it is not reported in the HAMSTeRS data base or in recent identified SNPs [22]. The exact effect of this mutation remains elusive and will be of interest for future studies to reveal. The finding that the mutation p.L7(26)P identified in family 17 is associated with a severe phenotype is in accordance with previous findings, which have shown that the same mutation causes a severe phenotype [23].
Inhibitor development
The type and location of the F8 gene mutation is an important determinant of inhibitor development in patients with severe hemophilia A. In a recent study, nonsense mutations and large deletions were shown to be associated with a higher risk of inhibitor development than intron 22 inversion, small deletions/insertions and missense mutations [24]. In our cohort no nonsense mutation was identified and only one patient with a large deletion spanning the exons 1–13 developed inhibitors. None of the patients with insertions/small deletions or missense mutations developed inhibitors. The low incidence of inhibitor development in our cohort (1/28) and (6/143) in total for all patients followed in Hemophilia Treatment Center [25] may be explained by the low frequency of nonsense mutations and large deletions in our cohort. In order to confirm this hypothesis we need to increase the number of the investigated hemophilia A patients in our study.
Moderate hemophilia A patients
Insertions (2)
The novel insertion c.2236-2237insT and the previously reported insertion c.3870-3871insA identified in family 7 and 20 respectively (Table 2), are due to insertions of a ‘T’ nucleotide in the stretch of 3Ts at codon 727(746) and of an ‘A’ nucleotide in the stretch of 9As at codon1271(1290). Insertions in the stretch of poly A nucleotides in exon 14 of the F8 gene are the cause of the moderate clinical severity in some cases [26,27]. Accordingly to these reported data, we can consider that also the new insertion of T in the stretches of poly T can be associated with moderate phenotype in our patient.
Substitutions and splicing site mutations (3)
The novel p.G520(539)R mutation associated with the moderate phenotype is located within the A1 domain and is part of the A1-A2 domain interface. Reported mutations in HAMSTeRS from position 516(525) to 521(540) located at A1-A2 interface are all associated with moderate or mild phenotypes http://www.HAMSTeRS.ac.uk/ webcite, [28]. Studies of residues involved in interaction at the A1-A2 domain interface have showed that reducing the charge and increasing hydrophobicity at this interface yield FVIII with improved stability [29,30]. Thus, the mutation p.G520(539)R, which increases the charge at the A1-A2 interface, most likely has the opposite effect and leads to destabilization of the protein. The reported missense mutation p.G479(488)R, which is associated with a moderate phenotype in our patients, is described in HAMSTeRS with mild moderate or severe form [20]. The splicing site mutations are often associated with a severe phenotype [31]. In contrast, the unique identified splicing mutation (ag/GGC > ac/GGC) in our study, which interferes in the splicing process resulting in the skipping of exon 15, is associated with a moderate phenotype (Table 2).
Mild hemophilia A patients
Substitutions (2)
The mutation p.A704(723)T is reported 9 times in the HAMSTeRS data base, in 5 cases it is associated with the mild form which is in accordance with our result (Table 2). On the other hand the p.L547(566)F has previously been reported in one severe patient while in our study it is associated with a mild form (Table 2). The discrepancy between mutations predicted to be responsible for severe, mild or moderate forms may be explained by the intervention of other hemostatic factors which can modify the clinical severity of hemophilia [32].
Conclusion
We report here the first molecular analysis of causative mutations in Tunisian hemophiliac A patients. In total we have identified 23 mutations including 8 novel mutations. In the future we will continue this study on patients from our Hemophilia Treatment Center in order to reinforce our understanding in the molecular defect of hemophilia A in Tunisia and to set up counseling genetic and the prenatal diagnosis for Tunisian families with hemophilia A.
Competing interests
The authors stated that they had no interests which might be perceived as posing a conflict or bias.
Authors’ contributions
EH performed the research, analyzed the data and wrote the paper; KH and JA analyzed the data; WE performed protein structure analysis and contributed in writing the paper; ZK contributed in the data collection; PD and VC performed the research; MB, EBAA and GE designed the research. All authors read and approved the final manuscript.
Acknowledgments
We are grateful to our patients for their help and cooperation. We acknowledge all the technicians belonging to Biological hematology department, CHRU Lyon, France for their help.
References
1. Graw J, Brackmann H, Oldenburg J, Schneppenheim R, Spannag M, Schwaab R: Haemophilia A: from mutation analysis to new therapies.
Nat Rev Genet 2005, 6:488-501. PubMed Abstract | Publisher Full Text
2. Zimmermann MA, Oldenburg J, Müller CR, Rost S: Unusual genomic rearrangements in introns 1 and 22 of the F8 gene.
Hamostaseologie. 2011, 31:69-73.
3. Antonarakis SE, Rossiter JP, Young M, et al.: Factor VIII gene inversions in severe hemophilia A: results of an international consortium study.
Blood 1995, 86:2206-2212. PubMed Abstract | Publisher Full Text
4. Gouw SC, Van Der Bom JG, Van Den Berg HM, Zewald RA, Ploos Van Amstel JK, Mauser-Bnschoten EP: Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients.
Haemophilia 2011, 17:275-281. PubMed Abstract | Publisher Full Text
5. Hejer E, Nejla B, Asma J, Kaouther Z, Balkis M, Amel BAE, Emna G: Factor VIII haplotypes frequencies in Tunisian hemophiliacs A.
Diagn Pathol 2011, 6:54-4. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text
6. Bagnall RD, Giannelli F, Green PM: Int22h-related inversions causing hemophilia A: novel insight into their origin and a new more discriminant PCR test for their detection.
J Thromb Haemost 2006, 4:591-598. PubMed Abstract | Publisher Full Text
7. Bagnall RD, Waseem N, Green PM, Giannelli F: Recurrent inversion breaking intron 1 ofthe factor VIII gene isa frequent cause of severehemophilia A.
Blood 2002, 99:168-174. PubMed Abstract | Publisher Full Text
8. DeLano WL: The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA; 2002.
9. Mantilla-Capacho JM, Beltrán-Miranda CP, Luna-Záizar H, Aguilar-López L, Esparza-Flores MA, López-Guido B, et al.: Frequency of intron 1 and 22 inversions of factor VIII gene in Mexican patients with severe hemophilia A.
Am J Hematol 2007, 82:283-287. PubMed Abstract | Publisher Full Text
10. Salazar-Sánchez L, Jiménez-Cruz G, Mendez M, Chaverri P, Alvarado P, Schröder W, Wulff K, Sandoval M, Herrmann FH, Pavlova A, Oldenburg J: Molecular analysis of FVIII gene in severe HA patients of Costa Rica.
Hämostaseologie 2010, 30:1150-1152. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
11. Abu-Amero K, Hellani A, Al-Mahed M, Al-Sheikh I: Spectrum of factor VIII mutations in Arab patients with severe haemophilia A.
Haemophilia 2008, 14:484-488. PubMed Abstract | Publisher Full Text
12. Owaidah TM, Alkhail HA, Zahrani HA, Musa AA, Saleh MA, Riash MA, et al.: Molecular genotyping of hemophilia A in Saudi Arabia: report of 2 novel mutations.
Blood Coagul Fibrinolysis 2009, 20:415-418. PubMed Abstract | Publisher Full Text
13. Awidi A, Ramahi M, Alhattab D, Mefleh R, Dweiri M, Bsoul N, et al.: Study of mutations in Jordanian patients with haemophilia A: identification of five novel mutations.
Haemophilia 2010, 16:136-142. PubMed Abstract | Publisher Full Text
14. Abou-Elew H, Ahmed H, Raslan H, Abdelwahab M, Hammoud R, Mokhtar D, et al.: Genotyping of intron 22-related rearrangements of F8 by inverse-shifting PCR in Egyptian hemophilia A patients.
Ann Hematol 2011, 90:579-584. PubMed Abstract | Publisher Full Text
15. Khodjet-El-Khil H, Fadhlaoui-Zid K, Gusmão L, Alves C, Benammar-Elgaaied A, Amorim A: Substructure of a Tunisian Berber population as inferred from 15 autosomal short tandem repeat loci.
Hum Biol 2008, 80:435-448. PubMed Abstract | Publisher Full Text
16. Andrikovics H, Klein I, Bors A, Nemes L, Marosi A, Váradi A, Tordai A: Analysis of large structural changes of the factor VIII gene, involving intron 1 and 22, in severe hemophilia A.
Haematologica 2003, 88:778-784. PubMed Abstract | Publisher Full Text
17. De Brasi , Candela , De , Candela , Cermelj , Slavutsky , Larripa , Bianco , De Tezanos P: Intron 22 factor VIII gene inversions in Argentine families with severe haemophilia A.
Haemophilia 2000, 6:21-22. PubMed Abstract | Publisher Full Text
18. Nakaya S, Liu ML, Thompson AR: Some factor VIII exon14 frameshift mutations cause moderately severe haemophilia A.
Br J Haematol 2001, 115:977-982. PubMed Abstract | Publisher Full Text
19. Bogdanova N, Markoff A, Pollmann H, Nowak-Göttl U, Eisert R, Wermes C, et al.: Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A.
Hum Mutat 2005, 26:249-254. PubMed Abstract | Publisher Full Text
20. Cutler JA, Mitchell MJ, Smith MP, Savidge GF: The identification and classification of 41 novel mutations in the factor VIII gene (F8C).
Hum Mutat 2002, 19:274-278. PubMed Abstract | Publisher Full Text
21. Thomas VO, Hansen Ane Y, Steffensen , Lars J, Mette K, Andersen BE, Finn CN: The silent mutation nucleotide 744 G → A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping.
Breast Cancer Research and Treatment 2010, 19:547-550.
22. Viel KR, Machiah DK, Warren DM, Khachidze M, Buil A, Fernstrom K, et al.: A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.
Blood 2007, 109:3713-3724. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
23. Boekhorst J, Verbruggen B, Lavergne JM, Costa JM, Schoormans SCM, Brons PPT, et al.: Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population.
Br J Haematol 2005, 131:109-117. PubMed Abstract | Publisher Full Text
24. Gouw SC, van den Berg HM, Oldenburg J, Astermark J, de Groot PG, Margaglione M, et al.: F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis.
Blood 2012, 119:2922-2934. PubMed Abstract | Publisher Full Text
25. Gouw SC, Van Der Bom JG, Van Den Berg HM, Zewald RA, Ploos Van Amstel JK, Mauser-Bunschoten EP: Influence of the type of F8 gene mutation on inhibitor development in a single center cohort of severe haemophilia A patients.
Haemophilia 2011, 17:275-281. PubMed Abstract | Publisher Full Text
26. Nakaya S, Miao-Liang L, Arthur R: Some factor VIII exon 14 frameshift mutations cause moderately severe haemophilia A.
Br J Haematol 2001, 115:977-982. PubMed Abstract | Publisher Full Text
27. Akkarepatumwong V, Intorasoot S, Oranwiroon S, Thano-Otarakul P, Pung-Amritt P, Veerakul G, et al.: Frameshift mutations with severe and moderate clinical phenotypes in Thai hemophilia A patients.
Hum Mutat 2000, 16:530-531. PubMed Abstract | Publisher Full Text
28. Habart D, Kalabova D, Novotny M, Vorlova Z: Thirty-four novel mutations detected in factor VIII gene by multiplex CSGE: modeling of 13 novel amino acid substitutions.
J Thromb Haemost 2003, 1:773-781. PubMed Abstract | Publisher Full Text
29. Wakabayashi H, Fay PJ: Identification of residues contributing to A2 domain-dependent structural stability in factor VIII and factor VIIIa.
J Biol Chem 2008, 283:11645-11651. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
30. Wakabayashi H, Griffiths AE, Fay PJ: Combining mutations of charged residues at the A2 domain interface enhances factor VIII stabilityover single point mutations.
J Thromb Haemost 2009, 7:438-444. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
31. Liu M, Murphy MEP, Thompson AR: A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins.
Br J Haematol 1998, 103:1051-1060. PubMed Abstract | Publisher Full Text
32. Nichols WC, Amano K, Cacheris PM, Figueiredo MS, Michaelides K, Schwaab R, et al.: Moderation of hemophilia A phenotype by the factor V R506Q mutation.
Blood 1996, 15:1183-1187. | v0 |
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Anthropocene
Environmental Archaeology:
Anthropocene
This article has been reviewed by the following Topic Editor: Jay Gulledge
Introduction
The Earth at night, demonstrating the global extent of human influence.
The Anthropocene defines Earth's most recent geologic time period as being human-influenced, or anthropogenic, based on overwhelming global evidence that atmospheric, geologic, hydrologic, biospheric and other earth system processes are now altered by humans. The word combines the root "anthropo", meaning "human" with the root "-cene", the standard suffix for "epoch" in geologic time. The Anthropocene is distinguished as a new period either after or within the Holocene, the current epoch, which began approximately 10,000 years ago (about 8000 BC) with the end of the last glacial period.
Origins of the term
Anthropocene is a new term, proposed in 2000 by Nobel Prize winning scientist Paul Crutzen. A similar term, Anthrocene, was coined by Andrew Revkin in his 1992 book Global Warming: Understanding the Forecast, but was not adopted by scientists. Crutzen noted that the term originated in 2000 at "a conference where someone said something about the Holocene. I suddenly thought this was wrong. The world has changed too much. So I said: 'No, we are in the Anthropocene.' I just made up the word on the spur of the moment. Everyone was shocked. But it seems to have stuck."[1]. Crutzen then proceeded to use the term in print in 2000[2]. In 2008, Zalasiewicz and colleagues published the first proposal for the formal adoption of the Anthropocene epoch by geologists, and this adoption is now pending [3].
Evidence for the Anthropocene
Figure 1: Increase in atmospheric carbon dioxide, 1744 to 2005. (Source: PhysicalGeography.net)
Geologic epochs are distinguished from one another based on geological observations, such as the composition of sediment layers and other tools of paleoclimatology. To justify the identification of a new Anthropocene epoch, it must therefore be demonstrated that evidence of anthropogenic global change is present at such a level that it can be distinguished using geologic indicators despite natural variability in these across the Holocene.
The most commonly cited and readily measured global change associated with humans is the rise of greenhouse gases, especially carbon dioxide and methane, around the beginning of the Industrial Revolution, together with the associated rise in global temperatures and sea level caused by this global warming. Other key indicators include massive global increases in soil erosion caused by land clearing and soil tillage for agriculture; massive deforestation; and massive extinctions of species caused by hunting and the widespread destruction of natural habitats.
When did the Anthropocene begin?
Human alteration of land surfaces.
The originator of the Anthropocene terminology, Paul Crutzen, favors the beginning of the Industrial Revolution as the starting point for the Anthropocene. In a 2002 paper in the journal Nature he stated: "The Anthropocene could be said to have started in the late eighteenth century, when analyses of air trapped in polar ice showed the beginning of growing global concentrations of carbon dioxide and methane."[4]. Zalasiewicz et al. are in general agreement with Crutzen that the Anthropocene is best identified at the beginning of the Industrial Revolution, though they also propose the beginning of the nuclear era in the 1960s as a useful date, due to the global presence of radioactive isotopes in sediments at this time.
However, as yet, there is no official start date for the Anthropocene. Moreover, William Ruddiman proposes that globally significant human alteration of greenhouse gas concentrations and associated climate change, extensive land clearing and soil erosion, and mass species extinctions actually began approximately 8,000 years ago with the rise of farming and the global spread of human populations in the latter stages of the first Agricultural Revolution. For this reason, the Anthropocene might be considered to begin 8,000 years ago. On the other hand, this "Early Anthropocene" definition is difficult to differentiate from the Holocene epoch which began only 2,000 to 4,000 years earlier.
See also
Notes
1. ^ Fred Pearce, F. 2007. With Speed and Violence. Page 21. ISBN:<PHONE_NUMBER>.
2. ^ Crutzen, P. J., and E. F. Stoermer. 2000. The "Anthropocene". ''Global Change Newsletter''. 41: 17-18.
3. ^ Zalasiewicz, J., M. Williams, A. Smith, T. L. Barry, A. L. Coe, P. R. Bown, P. Brenchley, D. Cantrill, A. Gale, P. Gibbard, F. J. Gregory, M. W. Hounslow, A. C. Kerr, P. Pearson, R. Knox, J. Powell, C. Waters, J. Marshall, M. Oates, P. Rawson, and P. Stone. 2008. Are we now living in the Anthropocene? GSA Today 18:4-8.
4. ^ Crutzen, P. J. 2002. Geology of mankind. Nature 415:23-23.
Further Reading
• Crutzen, P. J. 2002. Geology of mankind. Nature 415:23-23.
• Ruddiman, W. F. 2003. The anthropogenic greenhouse era began thousands of years ago. Climatic Change 61:261-293.
• Ruddiman, W. F. 2007. The early anthropogenic hypothesis: Challenges and responses. Reviews of Geophysics 45:RG4001.
• Ruddiman, W. E. 2005. Plows, Plagues, and Petroleum: How Humans Took Control of Climate. Princeton University Press. ISBN:<PHONE_NUMBER>.
• De Vries, B. and J. Goudsblom. 2002. Mappae Mundi: Humans and their Habitats in a Long-term Socio-ecological Perspective: Myths, Maps and Models. Amsterdam University Press. ISBN:<PHONE_NUMBER>.
• Zalasiewicz, J., M. Williams, A. Smith, T. L. Barry, A. L. Coe, P. R. Bown, P. Brenchley, D. Cantrill, A. Gale, P. Gibbard, F. J. Gregory, M. W. Hounslow, A. C. Kerr, P. Pearson, R. Knox, J. Powell, C. Waters, J. Marshall, M. Oates, P. Rawson, and P. Stone. 2008. Are we now living in the Anthropocene? GSA Today 18:4-8.
External links
Citation
Erle Ellis (Lead Author);Jay Gulledge (Topic Editor) "Anthropocene". In: Encyclopedia of Earth. Eds. Cutler J. Cleveland (Washington, D.C.: Environmental Information Coalition, National Council for Science and the Environment). [First published in the Encyclopedia of Earth September 10, 2008; Last revised Date May 30, 2012; Retrieved May 18, 2013 <http://www.eoearth.org/article/Anthropocene?topic=49578>
The Author
Dr. Erle Ellis is Associate Professor of Geography and Environmental Systems at the University of Maryland, Baltimore County, where he teaches Environmental Science, Landscape Ecology and Biogeochemistry. His research focuses on ecological processes in anthropogenic landscapes at local, regional and global scales, and their transformation by population growth and industrially-based technologies. He has studied long-term changes in nitrogen balance in village ecosystems of China's Tai Lake Re ... (Full Bio) | v0 |
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Dr. Delissio received her B.S. in Biology from Tufts University, during which time she had her first tropical field ecology experience at Hummingbird Cay in the Bahamas. She then worked as a laboratory technician at M.I.T. where the C. elegans DNA she sequenced contributed to Nobel Prize-winning work on programmed cell death. Unable to spend another summer indoors, she went back to school at Boston University and studied tropical forest ecology in Malaysian Borneo with Richard Primack, one of the world's leading Conservation Biologists, for which she received her Ph.D.. Upon graduation, Dr. Delissio took a position at Salem State College, where she has continued until this time. Her current interests include climate change, tropical forests, small island ecology, and science education.
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DJ Bomba Tomba is the host of the KGBH radio station in Anywhere City. He is a heavy drinker, as evidenced by these events he talks about during his broadcast:
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Abstract and Applied Analysis
Volume 2013 (2013), Article ID 678154, 6 pages
http://dx.doi.org/10.1155/2013/678154
Research Article
Positive Definiteness of High-Order Subdifferential and High-Order Optimality Conditions in Vector Optimization Problems
1Department of Mathematics, Yunnan University, Kunming, Yunnan 650091, China
2School of Science, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
Received 15 October 2012; Accepted 26 December 2012
Academic Editor: Gue Lee
Copyright © 2013 He Qinghai and Zhang Binbin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
We obtain a new Taylor's formula in terms of the order subdifferential of a function from to . As its applications in optimization problems, we build order sufficient optimality conditions of this kind of functions and order necessary conditions for strongly -quasiconvex functions.
1. Introduction
For a function from to , Luc [1] studied the order subdifferential of it, established a Taylor-type formula in terms of such order subdifferential, and applied such Taylor-type formula to consider two-order optimality conditions in vector optimization and characterizations of quasiconvex functions. In vector optimization, notions of Pareto solution, weak Pareto solution, sharp minima and weak sharp minima are very important; see [214] and the references therein. Some authors have attained many necessary or sufficient optimality conditions in optimization problems. In particular, Zheng and Yang provided some results on sharp minima, and weak sharp minima for high-order smooth vector optimization problems in Banach spaces. By the tools of nonsmooth analysis, many optimality conditions were obtained; for examples, one can see [6, 7, 15, 16] and the references therein. Such optimality conditions play a key role in many issues of mathematical programming such as sensitivity analysis and error bounds.
Motivated by Luc [1] and Zheng and Yang [17], in this paper, we consider the order subdifferential and optimality conditions of a vector-valued function from to . We will first prove a new Taylor's formula in the terms of order subdifferential for functions from to , which is analogous to that for real-valued functions in [1]. Then, under the positive definiteness assumption of order subdifferential, we will use this formula to derive order optimality conditions of weak Pareto and Pareto solutions in the terms of order subdifferential for a function from to . Finally, we will define a kind of strongly -quasiconvex functions and prove a necessary condition in the terms of (th order subdifferential for such kind of functions. Our results extend the corresponding results in [1] for functions from to to that for vector-valued functions from to and in [17] for functions in smooth setting to that in nonsmooth setting, respectively.
The outline of the paper is as follows. In the next section, we give some notions and preliminary results in vector optimization problems. In Section 3, we build our Taylor's formula in the terms of order subdifferential for a function from to . In Section 4, as applications in optimization problems, we establish some optimality conditions in terms of th order subdifferential. In Section 5, we give a necessary condition in the terms of th order subdifferential for a strongly -quasiconvex vector-valued function.
2. Preliminaries
Let be Banach spaces, the dual space of , a closed convex cone with , and the dual cone of ; that is, For , we define and if and , respectively. Let be a subset of and . Recall that (i) is a weak Pareto point of if there exists no point such that ; (ii) is a Pareto point of if there exists no point such that ; (iii) is an ideal point of if for all . Let , , and denote the sets of all weak Pareto, Pareto, and ideal points of , respectively. It is easy to verify that
Let be equipped with the norm .
Let be -linear and symmetric mapping [17]; that is, for any and , where is an arbitrary permutation of . Let be a mapping. It is known that its derivative is -linear, symmetric, and continuous mapping if is -time smooth.
Let be a function from to and be a closed convex cone. Consider the following vector optimization problem A vector is said to be a local weak Pareto (resp., Pareto and ideal) solution of (4) if there exists such that is a weak Pareto (resp., Pareto and ideal) point of , where denotes the open ball with center and radius . We say that is a sharp Pareto solution of (4) of order if there exist such that where .
We denote by , the class of -time differentiable mappings from to whose th order derivatives are locally Lipschitz mappings and by the class of locally Lipschitz functions from to . By Rademacher's theorem (see [18]), for any , , its th order derivative is a function differentiable almost everywhere. The th order subdifferential of at is defined as “generalized Jacobian” of at in Clarke's sense [18] as follows: It is worth mentioning that each element in is a linear and symmetric mapping from to . For more details about , we refer the reader to [18].
It is similar to the proof of Lemma 2.1 in [1], and one can verify the following chain rule.
Lemma 1. Let in , be a function from to defined by for every , and let be a function from to . Then,
3. A New Taylor's Formula in Form of High-Order Subdifferential
By Lemma 1, we have the following Taylor-type formula for a vector-valued function from to which will be useful in the sequel.
Theorem 2. Let , , and be as in Lemma 1. Then, there exists such that where denotes and
Proof. Let be a vector satisfying We only need to show that there exists such that Let be as Lemma 1. Set and Let be arbitrarily given. Since the function is locally Lipschitz and , applying Lebourg mean value theorem [18, Theorem 2.3.7 and Theorem 2.3.9], there exists such that Noting that and each have derivatives which are continuous, it follows that they are strictly -differentiable. We have Here, the first equation holds by Propositions 7.4.3(b), and 7.3.5 in [19] and the second holds by Proposition 7.3.9 in [19]. By the chain rule [19, Theorem 7.4.5(a)], we also have Hence, we have From (13) and (16), we have Together with Lemma 1, it follows that that is, Since is arbitrary in and is convex and compact, by the separation theorem, we can easily show that . Hence, we can take such that . The proof is completed.
Corollary 3. Let be as in Theorem 2 and . Then, for every , there exist and a -linear mapping from to such that
Proof. By Theorem 2, for a given , there exists such that Let be an element minimizing the distance from to the convex and compact set . Set Then, from (21), we obtain the formula of the corollary. Moreover, since the mapping is upper continuous, nonempty, convex, and compact valued (see [18]), for any , there exists such that, for all (where denotes the closed unit ball of ), where denotes the closed unit ball of the space of all bounded linear operators from to . If , then With this we obtain . The proof is completed.
4. The Positive Definiteness of High-Order Subdifferential and Optimality Conditions
Recall [17] that -linear symmetric mapping is said to be positively definite (resp., positively semidefinite) with respect to the ordering cone if where denotes . If is odd and the ordering cone is pointed (i.e., ), then is positively semidefinite if and only if ; see [17].
By the separation theorem, it is easy to verify that a -linear symmetric mapping is positively semidefinite with respect to the ordering cone if and only if the composite is positively semidefinite for any . Recall that a mapping is -convex if Noting that is -convex if and only if is convex for all , one can see that a twice differentiable function is -convex if and only if is positively semidefinite for all .
Inspired by the notion of positive definiteness, we introduce positive definiteness of the th order subdifferential for functions.
Definition 4. Let be a function from to and a closed convex cone of . We say that the th order subdifferential mapping is positively definite at with respect to the ordering cone if each is positively definite with respect to .
Proposition 5. Let be a function from to , and let be a closed convex cone of . Suppose that the subdifferential mapping is positively definite at with respect to . Then, there exists such that where .
Proof. From [17, Proposition 3.4], for any , there exists such that If the conclusion is not true, then, for every natural number , there exist , and such that Since and are compact, we can assume that , (passing to a subsequence if necessary). Then, for all . But from (28), for large enough , we have which is a contradiction with (29). The proof is completed.
Under the positive definiteness assumption, we will provide a th order sufficient condition for to be a sharp local Pareto solution of (4) for a function .
Theorem 6. Let be a function from to , a closed convex cone of , and . Suppose that there exists with such that , and that is positively definite at with respect to the ordering cone . Then, is a local Pareto solution of (4), and there exist such that
Proof. Since is positively definite with respect to , by Proposition 5, there exists such that Noting that and , we have that Let for all . Since is a function, so is . Noting that with Corollary 3, there exist and -linear mapping with such that It follows that there exists such that for all . Since , it follows from (34) and (36) that On the other hand, for any , one has This implies that (32) holds. It remains to show that is a local Pareto solution of (4). Let such that . Then, . It follows from (32) that , and hence . This shows that is a local Pareto solution of (4).
In Theorem 6, if is a -convex function, then is a global Pareto solution of (4).
Theorem 7. Let be a -convex function from to , a closed convex cone of , and . Suppose that there exists with such that and that is positively definite. Then, is a global Pareto solution of (4), and there exists such that
Proof. Similar to the proof of Theorem 6, one can show that (39) implies that is a global Pareto solution of (4). It remains to show that (39) holds. By Theorem 6, there exist such that (32) holds. Since is -convex, it is easy to verify that is a convex function. Let . Then, Hence, . Letting , it follows from (32) that (39) holds. The proof is completed.
With = in Theorem 7 replaced by a stronger assumption, we have the following sufficient condition for sharp ideal solutions of (4).
Theorem 8. Let be a function from to , a closed convex cone of , and . Suppose that and that is positively definite at with respect to the ordering cone . Then, there exist such that
Proof. By Theorem 6, we need only to show that there exists such that (41) holds. Since is positively definite, there exists such that It follows that On the other hand, since , with Corollary 3, we can assume that for any close to , there exists -linear symmetric and continuous mapping from to such that and Hence, there exists such that This and (44) imply that (41) holds. The proof is completed.
5. th Order Necessary Conditions for Strongly -Quasiconvex Functions
We recall that a function from to is quasiconvex if, for every and for every , one has . Inspired by this, we introduce the notion of strong -quasiconvexity for functions from to . A function from to is said to be strongly -quasiconvex if, for every and for every , one has Using the generalized Hessian (see [20]), Luc [1] gave a second-order criterion for quasiconvex functions. We will give a th order necessary codition for a function to be strongly -quasiconvex.
Theorem 9. Let be a strongly -quasiconvex function from to , an odd number and the closed pointed ordering cone. Then, for any with , there exists such that .
Proof. Suppose that the conclusion is not true. Then, there exist some , with such that . Since is open and is compact, there exists such that Since is upper continuous, for the previous , there exists such that for any . Noting that is closed convex, from (48) and (49), we have From Theorem 2, for any , we can take such that Noting that is even, we have and , for all .
On the other hand, since is -quasiconvex and , one has or . This is a contradiction.
If and , then . We have the following.
Corollary 10 (see [1]). Let be a quasiconvex function from to and an odd number. Then, for any with , one has , where .
Acknowledgments
This research was supported by the National Natural Science Foundations, China (Grant no. 11061039, 11061038, and 11261067), an internal Grant of Hong Kong Polytechnic University (G-YF17), and IRTSTYN.
References
1. D. T. Luc, “Taylor's formula for Ck,1 functions,” SIAM Journal on Optimization, vol. 5, no. 3, pp. 659–669, 1995. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
2. A. Göpfert, H. Riahi, C. Tammer, and C. Zălinescu, Variational Methods in Partially Ordered Spaces, vol. 17 of CMS Books in Mathematics, Springer, New York, NY, USA, 2003. View at Zentralblatt MATH · View at MathSciNet
3. V. V. Gorokhovik, Vypuklye i Negladkie Zadachi Vektornoi Optimizatsii, Nauka i Tekhnika, Minsk, Russia, 1990. View at Zentralblatt MATH · View at MathSciNet
4. J. Jahn, Vector Optimization: Theory, Applications and Extensions, Operations Research and Decision Theory, Springer, New York, NY, USA, 2004. View at Zentralblatt MATH · View at MathSciNet
5. J. J. Ye and Q. J. Zhu, “Multiobjective optimization problem with variational inequality constraints,” Mathematical Programming, vol. 96, no. 1, pp. 139–160, 2003. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
6. X. Y. Zheng and X. Q. Yang, “Weak sharp minima for semi-infinite optimization problems with applications,” SIAM Journal on Optimization, vol. 18, no. 2, pp. 573–588, 2007. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
7. M. Studniarski and D. E. Ward, “Weak sharp minima: characterizations and sufficient conditions,” SIAM Journal on Control and Optimization, vol. 38, no. 1, pp. 219–236, 1999. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
8. M. I. Henig, “Existence and characterization of efficient decisions with respect to cones,” Mathematical Programming, vol. 23, no. 1, pp. 111–116, 1982. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
9. G. Isac, “Pareto optimization in infinite-dimensional spaces: the importance of nuclear cones,” Journal of Mathematical Analysis and Applications, vol. 182, no. 2, pp. 393–404, 1994. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
10. M. Minami, “Weak Pareto-optimal necessary conditions in a nondifferentiable multiobjective program on a Banach space,” Journal of Optimization Theory and Applications, vol. 41, no. 3, pp. 451–461, 1983. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
11. A. Zaffaroni, “Degrees of efficiency and degrees of minimality,” SIAM Journal on Control and Optimization, vol. 42, no. 3, pp. 1071–1086, 2003. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
12. X. Y. Zheng, X. M. Yang, and K. L. Teo, “Sharp minima for multiobjective optimization in Banach spaces,” Set-Valued Analysis, vol. 14, no. 4, pp. 327–345, 2006. View at Publisher · View at Google Scholar · View at MathSciNet
13. X. Y. Zheng and K. F. Ng, “The Fermat rule for multifunctions on Banach spaces,” Mathematical Programming, vol. 104, no. 1, pp. 69–90, 2005. View at Publisher · View at Google Scholar · View at MathSciNet
14. G. Y. Chen, X. X. Huang, and X. Q. Yang, Vector Optimization: Set-Valued and Variational Analysis, Springer, New York, NY, USA, 2005. View at MathSciNet
15. J. V. Burke and S. Deng, “Weak sharp minima revisited. II. Application to linear regularity and error bounds,” Mathematical Programming, vol. 104, no. 2-3, pp. 235–261, 2005. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
16. R. Ellaia and A. Hassouni, “Characterization of nonsmooth functions through their generalized gradients,” Optimization, vol. 22, no. 3, pp. 401–416, 1991. View at Publisher · View at Google Scholar · View at Zentralblatt MATH · View at MathSciNet
17. X. Y. Zheng and X. Q. Yang, “Conic positive definiteness and sharp minima of fractional orders in vector optimization problems,” Journal of Mathematical Analysis and Applications, vol. 391, no. 2, pp. 619–629, 2012. View at Publisher · View at Google Scholar · View at MathSciNet
18. F. H. Clarke, Optimization and Nonsmooth Analysis, John Wiley & Sons, New York, NY, USA, 1983. View at MathSciNet
19. S. Winfried, Nonsmooth Analysis, Springer, Berlin, Germany, 2007.
20. J. B. Hiriart-Urruty, J. J. Strodiot, and V. H. Nguyen, “Generalized Hessian matrix and second-order optimality conditions for problems with C1,1 data,” Applied Mathematics and Optimization, vol. 11, no. 1, pp. 43–56, 1984. View at Publisher · View at Google Scholar · View at MathSciNet | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:12:44.000Z | ckp7a4yfixjy6vjdlqja5bu4ltsyjzks | {
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} | cccc_CC-MAIN-2013-20 | Bibliography: Constantine in Love
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Title: Constantine in Love
Author: M. Christian
Year: 2001
Type: SHORTFICTION
Storylen: shortfiction
Language: English
ISFDB Record Number: 1128052
User Rating: This title has fewer than 5 votes. VOTE
Current Tags: None Add Tags
Publications:
Copyright (c) 1995-2011 Al von Ruff.
ISFDB Engine - Version 4.00 (04/24/06) | v0 |
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} | cccc_CC-MAIN-2013-20 | OpenWetWare:Mission
From OpenWetWare
Revision as of 11:50, 8 February 2008 by Barry Canton (Talk | contribs)
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The goals of OWW are to support open sharing of research, education, publication, and discussion in biological sciences and engineering. We promote and support collaborations among researchers, students, and others who are working towards these goals. We believe that open sharing of research improves the quality and pace of scientific and engineering research.
We are taking three approaches to achieve our mission
Contents
1. Lower the technical barriers to sharing and dissemination of knowledge in biological research
Scientific and engineering research have strong traditions of publishing research. However, the pace of publishing research (often 6-12 months) has lagged the pace of research. Moreover, much of the information generated in the course of research fails to get captured in research articles (the traditional mechanism for sharing research). Thus, we advocate new, faster timescale publishing mediums like OpenWetWare that can capture biological knowledge as it is generated to complement the existing scientific publishing mechanisms. We are always seeking new tools and technologies that make this open sharing of research easier.
2. Build a community of researchers in biology and biological engineering that values practices and innovates the open sharing of information
Peer review is a fundamental part of biological research. We use it to assess papers for publication, talks to be presented at conferences, grant proposals for funding and job hiring and promotion. Thus, an important part of our mission to promote the open sharing of research is building a community that recognizes and values that sharing.
3. Integrate OpenWetWare into existing and future reward structures in research
Ultimately, for the open sharing and digitization of research to be standard practice in scientific research, it will need to be integrated into existing reward structures in science. Researchers need to "receive credit" when they make their protocols, datasets, model files etc. freely available to others. We consider this to be a critical but long-term goal of OpenWetWare.
Reference
Personal tools | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T07:21:30.000Z | psltz5vosfkglxkaop5qd3xouvu3u7sq | {
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} | cccc_CC-MAIN-2013-20 | Vic Darchinyan determined to face Donaire for return match - coach
PanARMENIAN.Net - Several days ago, promoter Bob Arum named Guillermo Rigondeaux, Abner Mares and Vic Darchinyan as possible contenders for an April 13 fight vs. Nonito Donaire.
As Darchinyan’s coach Vazgen Badalyan told PanARMENIAN.Net the boxer is currently negotiating for a fight.
“Vic himself told me he’s got his mind set on facing Donaire for a return match. Promoters are currently in talks, yet the agreement hasn't been reached yet,” the coach said.
Badalyan, however, confessed to advising Darchinyan against a Donaire bout.
Donaire beat Darchinyan in 2007, and a rematch was never made despite some negotiations over that time.
Partner news
Top stories
European Individual Chess Championship ended in Polish town of Legnica, with 24 chess players winning World Cup qualifications.
Gor Minasyan won silver medal, Andranik Karapetyan and Izabella Yalyan both won bronze at Junior World Championships in Lima.
The chief coach noted that the Greco-Roman wrestlers will participate in Mariupol-hosted tournament in June.
Hrant Melkumyan tied the game with Czech Republic’s Viktor Láznička to take the 18th spot with 6,5 points.
Partner news | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T08:09:00.000Z | w2gtubbo5ymz4bljgfzddssstuve6kp5 | {
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} | cccc_CC-MAIN-2013-20 | Person:Hannah Ward (5)
Watchers
Hannah Ward
b.ABT 1676 Sudbury, MA
d.UNKNOWN
m. 10 Jul 1675
1. Hannah WardABT 1676 -
m. bef Sept 1694
1. Eleazar Cobleigh1719 -
Facts and Events
Name[1][2] Hannah Ward
Unknown Hannah Taylor
Gender Female
Birth? ABT 1676 Sudbury, MA
Death? UNKNOWN
Reference Number? 3024
Marriage bef Sept 1694 when wife Hannah is called Cobleigh in administration of her step-father's estate
to John Cobleigh
Deacon William Ward, father of Eleazar, gave a legacy in his will to "Hannah, now wife of Richard Taylor of Sudbury, and also to Hannah, daughter of said Hannah by my son Eleazar, deceased."
Probably adopted by Richard Taylor; she is "Tailor" on her marriage record.
References
1. Lusk, Elizabeth Barber. (Correspondence began in October 2004.), Email of 31 May 2006.
2. Savage, James. A Genealogical Dictionary of the First Settlers of New England: Showing Three Generations of Those Who Came Before May, 1692, on the Basis of Farmer's Register. (Boston: Little, Brown, and Co, 1860-1862). | v0 |
2024-06-03T21:29:47.544Z | 2013-05-18T06:20:42.000Z | pl3at72ynnuqmyxspjbpqibpbeificpv | {
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} | cccc_CC-MAIN-2013-20 | Walid Al-Saqaf
Contributor profile · 4 posts · joined 23 September 2008
RSS feed for » Walid Al-Saqaf
View all contributors »
Walid Al-Saqaf is a print/online journalist turned cyber activist. He is the founder and administrator of Yemen Portal (yemenportal.net), a news and multi-content aggregator focused on content on his country (Yemen). His website got banned from access in Yemen by the authorities presumably for content the government considered harmful to ‘the national interest'. In response, he started an anti-censorship campaign (through blocked.arabiaportal.net) that resonated internationally. He currently stands as one of a few Arab cyber activists working on censorship circumventing technologies, the latest being the “Access YemenPortal” Firefox plug-in that was inspired by Iranian Hamed Saber's “Access Flickr!” extension. Walid holds a Master in Global Journalism and is currently pursuing his PhD at Örebro University in Sweden. He can be reached on admin [at] yemenportal [dot] net.
Email Walid Al-Saqaf
Latest posts by Walid Al-Saqaf
4 May 2009
Yemeni authorities prevents 6 newspapers from distribution
Yemeni government ordered the confiscation of six national newspapers, whose copies were pulled from the news stands and markets across the country yesterday alleging their role in promoting secessionism and anti-unity rhetoric. The move, according to observers, is unprecedented in recent Yemeni history and marks a serious downturn in the country's level of press freedom, which had already suffered several blows in the recent past.
6 February 2009
Yemeni online journalist sends urgent appeal after death threats and hacking of his website
Mohamed Al-Jabali, the editor of Akhbaralasr news website is the latest casualty in a wave of intimidations targeting bloggers and online journalists in Yemen. In a statement made yesterday, Al-Jabali appealed for protection after receiving death threats in the capital Sanaa from the regime’s security apparatus. This comes just after his website was also hacked. The hackers, whom Al-Jabali said are elements of the regime, published a sarcastic entry on the front page with a picture of a monkey and an insult on the owner of the website Al-Jabali.
23 November 2008
Yemeni blogger appeals to prevent possible assassination
In a rather emotional entry posted on his blog, Nashwan Abdu Ali Ghanim, a Yemeni blogger with blogs on maktoobblogs.com and kitab.com called upon international advocacy groups and the Arab Bloggers Union to come for his rescue upon escaping 'three failed assassination attempts'. Ghanim believes that his latest blog entry noting the involvement of senior Yemeni officials in the plotting of the attack carried out against the U.S. embassy in Sana'a on September 17, 2008 triggered a new wave of harassments and life-threatening acts.
23 September 2008
Yemen: Loui Has Been Set Free!
Yemen Hurr website announced yesterday in a press release that its founder and editor-in-chief Loui Al-Moayed has been released from prison yesterday after about more than 70 days in detention.... | v0 |
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