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('LID', '10.1016/S2352-3026(24)00385-5') | Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1-2 study. | Chari, Ajai, Touzeau, Cyrille, Schinke, Carolina, Minnema, Monique C, Berdeja, Jesus G, Oriol, Albert, van de Donk, Niels W C J, Rodríguez-Otero, Paula, Morillo, Daniel, Martinez-Chamorro, Carmen, Mateos, María-Victoria, Costa, Luciano J, Caers, Jo, Rasche, Leo, Krishnan, Amrita, Ye, Jing Christine, Karlin, Lionel, Lipe, Brea, Vishwamitra, Deeksha, Skerget, Sheri, Verona, Raluca, Ma, Xuewen, Qin, Xiang, Ludlage, Hein, Campagna, Michela, Masterson, Tara, Hilder, Brandi, Tolbert, Jaszianne, Renaud, Thomas, Goldberg, Jenna D, Kane, Colleen, Heuck, Christoph, San-Miguel, Jesus, Moreau, Philippe | BACKGROUND: Talquetamab is the first GPRC5D × CD3 bispecific antibody approved for relapsed or refractory multiple myeloma. In phase 1 of the MonumenTAL-1 study, initial results of subcutaneous talquetamab 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks showed preliminary clinical activity. We describe safety and activity results in patients treated with talquetamab, including patients who had received previous T-cell redirection therapy (TCR). This post-hoc analysis was done with more mature median follow-up to evaluate duration of response in patients treated with talquetamab 0·8 mg/kg every 2 weeks. METHODS: MonumenTAL-1 is a multicentre, open-label, phase 1-2 study of talquetamab, phase 1 of which has previously been published. The 0·4 mg/kg once a week and 0·8 mg/kg every 2 weeks recommended subcutaneous doses identified in phase 1 were evaluated in phase 2 in patients who were 18 years of age or older, had at least three previous lines of therapy, had an Eastern Cooperative Oncology Group performance status of 0 to 2, and were naive or exposed to previous TCR. The primary endpoint was overall response rate assessed by independent review committee in all patients who received at least one dose of talquetamab. Safety was assessed in all patients who received at least one dose of talquetamab. This study was registered with ClinicalTrials.gov, NCT03399799 (phase 1) and NCT04634552 (phase 2). FINDINGS: Between Jan 3, 2018, and Feb 20, 2023, 735 patients were screened across all phase 1-2 cohorts. Of these, 537 patients screened for inclusion were treated across phase 1 and 2 cohorts, of whom 1983 (27%) patients were excluded from the study, most commonly due to not meeting eligibility criteria or not having measurable disease. As of Oct 11, 2023, 375 patients had received recommended talquetamab doses across three groups: 143 (0·4 mg/kg once a week group) and 154 (0·8 mg/kg every 2 weeks group) TCR-naive patients and 78 with previous TCR who received either recommended dose (previous TCR group). 217 (58%) of 375 patients were male and 158 (42%) were female. 325 (87%) of 375 patients were White and 32 (9%) patients were Black. Median follow-up was 25·6 months (IQR 8·5-25·9) in the 0·4 mg/kg once a week group, 19·4 months (9·2-20·7) in the 0·8 mg/kg every 2 weeks group, and 16·8 months (7·6-18·7) in the previous TCR group. Overall response rate was 74% (106 of 143 patients, 95% CI 66-81) in the 0·4 mg/kg once a week group, 69% (107 of 154 patients, 62-77) in the 0·8 mg/kg every 2 weeks group, and 67% (52 of 78 patients, 55-77) in the previous TCR group. Most common adverse events in the 0·4 mg/kg once a week, 0·8 mg/kg every 2 weeks, and previous TCR groups were cytokine release syndrome (113 [79%] of 143 patients, 115 [75%] of 154 patients, and 57 [73%] of 78 patients), taste changes (103 [72%], 110 [71%], and 59 [76%]), and infections (85 [59%], 105 [68%], and 59 [76%]). Most common grade 3-4 adverse events were neutropenia (44 [31%], 33 [21%], and 37 [47%]), anaemia (45 [31%], 40 [26%], and 21 [27%]), and lymphopenia (37 [26%], 40 [26%], and 13 [17%]). Fatal adverse events occurred in five patients in the 0·4 mg/kg once a week group, seven patients in the 0·8 mg/kg every 2 weeks group, and no patients in the previous TCR group; none were related to treatment. INTERPRETATION: Talquetamab continued to demonstrate high overall response rates in heavily pretreated patients with relapsed or refractory multiple myeloma with longer follow-up in this post-hoc analysis. Overall response rate was promising in patients with previous TCR, including therapies targeting BCMA. On-target, off-tumour adverse events were common but led to few treatment discontinuations. FUNDING: Janssen. | The Lancet. Haematology | 13/03/2025 |
('LID', '10.1038/s42255-025-01254-5') | The cyclic metabolic switching theory of intermittent fasting. | Mattson, Mark P | Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices. | Nature metabolism | 14/03/2025 |
('LID', '10.1021/ol502883x') | Regioselective decarboxylative direct C-H arylation of boron dipyrromethenes (BODIPYs) at 2,6-positions: a facile access to a diversity-oriented BODIPY library. | Luo, Liang, Wu, Di, Li, Wei, Zhang, Shuai, Ma, Yuanhong, Yan, Su, You, Jingsong | A palladium-catalyzed regioselective decarboxylative direct C-H arylation of boron dipyrromethenes (BODIPYs) at the 2,6-positions has been developed as a late-stage approach to rapidly assemble a diversity-oriented BODIPY library. With the complement of this protocol, the direct C-H arylation of BODIPYs becomes regiocontrollable at α- and β-positions. A new type of indole-fused BODIPY exhibiting bright red/NIR fluorescence with a large molar extinction coefficient (145,500 M(-1) cm(-1)) and a high quantum yield (71%) has been synthesized for the first time. | Organic letters | 05/12/2014 |
('LID', '10.1093/jimmun/vkaf001') | The transcription factor RORα is required for the development of type 1 innate lymphoid cells in adult bone marrow. | Abe, Shinya, Kagao, Moe, Asahi, Takuma, Kato, Ryoma, Tani-Ichi, Shizue, Shimba, Akihiro, Ishibashi, Riki, Miyachi, Hitoshi, Kitano, Satsuki, Miyazaki, Masaki, Rodewald, Hans-Reimer, Toyoshima, Fumiko, Ikuta, Koichi | Type 1 innate lymphoid cells (ILC1s) respond to infections and tumors by producing IFN-γ. Although RAR-related orphan receptor α (RORα) is required for ILC2s and some ILC3s, its role in ILC1 development remains controversial. To investigate the role of RORα in ILC1s, we analyzed bone marrow (BM) chimeras of RORα-deficient mice. ILC1s derived from RORα-deficient BM cells were significantly reduced in various tissues, including the intestine, indicating a hematopoietic cell-intrinsic need for RORα in ILC1 development. Developmental stage-specific RORα-deficient mice showed a decrease in adult liver and BM IL-7R+ ILC1s and an increase in BM NK cells, whereas fetal liver ILC1s and adult liver IL-7R- ILC1s remained unchanged. Furthermore, RORα is primarily required for IL-7R+ precursor stages and partially affects small intestine ILC1 after differentiation. This study suggests that RORα promotes ILC1 differentiation while suppressing NK cell differentiation at the ILC precursor stage in the adult BM. | Journal of immunology (Baltimore, Md. : 1950) | 13/03/2025 |
('LID', '10.1126/science.adr3314') | Trypanosome doublet microtubule structures reveal flagellum assembly and motility mechanisms. | Xia, Xian, Shimogawa, Michelle M, Wang, Hui, Liu, Samuel, Wijono, Angeline, Langousis, Gerasimos, Kassem, Ahmad M, Wohlschlegel, James A, Hill, Kent L, Zhou, Z Hong | The flagellum of Trypanosoma brucei drives the parasite's characteristic screw-like motion and is essential for its replication, transmission, and pathogenesis. However, the molecular details of this process remain unclear. Here, we present high-resolution (up to 2.8 angstrom) cryo-electron microscopy structures of T. brucei flagellar doublet microtubules (DMTs). Integrated modeling identified 154 different axonemal proteins inside and outside the DMT and, together with genetic and proteomic interrogation, revealed conserved and trypanosome-specific foundations of flagellum assembly and motility. We captured axonemal dynein motors in their pre-power stroke state. Comparing atomic models between pre- and post-power strokes defined how dynein structural changes drive sliding of adjacent DMTs during flagellar beating. This study illuminates structural dynamics underlying flagellar motility and identifies pathogen-specific proteins to consider for therapeutic interventions targeting neglected diseases. | Science (New York, N.Y.) | 14/03/2025 |
('LID', '10.1186/s12974-025-03401-x') | Do microglia metabolize fructose in Alzheimer's disease? | Sturno, Annalise M, Hassell, James E Jr, Lanaspa, Miguel A, Bruce, Kimberley D | Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with a complex etiology. While emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals. Therefore, alternative treatments are much needed. Microglia, the brain resident macrophages, have the potential to be novel therapeutic targets as they regulate many facets of AD, including lipid droplet (LD) accumulation, amyloid beta (Aβ) clearance, and neuroinflammation. To carry out such functions, microglia undergo phenotypic changes, which are linked to shifts in metabolism and substrate utilization. While homeostatic microglia are driven by oxidative phosphorylation (OXPHOS) and glycolysis, in aging and AD, microglia shift further towards glycolysis. Interestingly, this "metabolic reprogramming" may be linked to an increase in fructose metabolism. In the brain, microglia predominantly express the fructose transporter SLC2A5 (GLUT5), and enzymes involved in fructolysis and endogenous fructose production, with their expression being upregulated in aging and disease. Here, we review evidence for fructose uptake, breakdown, and production in microglia. We also evaluate emerging literature targeting fructose metabolism in the brain and periphery to assess its ability to modulate microglial function in AD. The ability of microglia to transport and utilize fructose, coupled with the well-established role of fructose in metabolic dysfunction, supports the notion that microglial fructose metabolism may be a novel potential therapeutic target for AD. | Journal of neuroinflammation | 15/03/2025 |
('LID', '10.1158/2159-8290.CD-24-0805') | Aged and BRCA mutated stromal cells drive epithelial cell transformation. | Garcia, Geyon L, Orellana, Taylor, Gorecki, Grace, Frisbie, Leonard, Baruwal, Roja, Suresh, Swathi, Goldfeld, Ester, Beddows, Ian, MacFawn, Ian P, Britt, Ananya K, Hale, Macy M, Elhaw, Amal Taher, Isett, Brian R, Hempel, Nadine, Bao, Riyue, Shen, Hui, Buckanovich, Ronald J, Finkel, Toren, Drapkin, Ronny, Soong, T Rinda, Bruno, Tullia C, Atiya, Huda I, Coffman, Lan G | The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear presenting critical barriers in prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently HGSOC. Here we report that an epigenetically altered mesenchymal stem cell niche, termed high risk MSC (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal 'field effect' extending beyond the borders of STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of FTE resulting in metastatic cancer in vivo, indicating hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention. | Cancer discovery | 14/03/2025 |
('LID', '10.1186/s12876-025-03756-8') | The association between the dietary index for gut microbiota and non-alcoholic fatty liver disease and liver fibrosis: evidence from NHANES 2017-2020. | Zheng, Ce, Qi, Zeming, Chen, Rui, Liao, Zhixiong, Xie, Lanfeng, Zhang, Fumang | BACKGROUND: Imbalance in the gut microbiota is a key factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. The Dietary Index for Gut Microbiota (DI-GM) integrates the potential relationship between diet and gut microbiota diversity. This study aims to investigate the association between DI-GM and the risk of NAFLD and liver fibrosis, providing theoretical support for dietary intervention strategies. METHODS: This study utilized data from NHANES 2017-2020, including 6,181 eligible adult participants. The relationship between DI-GM and the risk of NAFLD and liver fibrosis was assessed using DI-GM quartiles, multivariate logistic regression, and restricted cubic spline (RCS) analysis. Subgroup analysis was performed to explore the predictive role of DI-GM in different populations. All analyses were weighted to ensure the representativeness of the results. RESULTS: DI-GM was negatively associated with the risks of NAFLD and liver fibrosis. As DI-GM scores increased, the risk of NAFLD and liver fibrosis significantly decreased (52.81%, 43.16%, 40.40%, and 31.98%, p < 0.05; 17.52%, 9.04%, 7.21%, and 6.78%, p < 0.05). Multivariate logistic regression analysis revealed that, in the unadjusted model (Model 1), for each unit increase in DI-GM, the risk of NAFLD decreased by 6.9% (OR = 0.931, 95% CI: 0.886-0.979, p < 0.001), while the risk of liver fibrosis decreased by 15.6% (OR = 0.844, 95% CI: 0.757-0.941, p < 0.05). In the quartile analysis, individuals in the highest DI-GM quartile (Q4) had a 58% lower risk of NAFLD compared to those in the lowest quartile (Q1) (OR = 0.42, 95% CI: 0.219-0.806, p < 0.001). The results remained significant even after adjusting for covariates. RCS analysis showed that DI-GM had a nonlinear relationship with the risks of NAFLD and liver fibrosis, with inflection points at scores of 2 and 5, indicating enhanced protective effects. CONCLUSION: This study reveals a negative association between DI-GM and the risk of NAFLD and liver fibrosis, highlighting the potential role of healthy dietary patterns in the prevention and management of NAFLD and liver fibrosis through gut microbiota modulation, providing a theoretical basis for dietary interventions. | BMC gastroenterology | 12/03/2025 |
('LID', '10.1186/s10020-025-01150-4') | Metrnl ameliorates myocardial ischemia-reperfusion injury by activating AMPK-mediated M2 macrophage polarization. | Chen, De-Xin, Feng, Yang-Yi, Wang, Hai-Yan, Lu, Chuang-Hong, Liu, De-Zhao, Gong, Chen, Xue, Yan, Na, Na, Huang, Feng | BACKGROUND: Meteorin-like hormone (Metrnl) is prominently expressed in activated M2 macrophages and has demonstrated potential therapeutic effects in a range of cardiovascular diseases by modulating inflammatory responses. Nevertheless, its precise role and the underlying mechanisms in myocardial ischemia/reperfusion injury (MI/RI) are not fully understood. This study examined whether Metrnl can mitigate MI/RI through the AMPK-mediated polarization of M2 macrophages. METHODS: In vivo, adeno-associated virus 9 containing the F4/80 promoter (AAV9-F4/80) was utilized to overexpress Metrnl in mouse cardiac macrophages before MI/RI surgery. In vitro, mouse bone marrow-derived macrophages (BMDMs) were treated with recombinant protein Metrnl, and the human cardiomyocyte cell line AC16 was subjected to hypoxia/reoxygenation (H/R) after co-culture with the supernatant of these macrophages. Cardiac function was assessed via echocardiography, H&E staining, and Evans blue-TTC staining. Inflammatory infiltration was evaluated by RT-qPCR and ELISA, apoptosis by Western blotting and TUNEL staining, and macrophage polarization by immunofluorescence staining and flow cytometry. RESULTS: In vivo, Metrnl overexpression in cardiac macrophages significantly attenuated MI/RI, as evidenced by reduced myocardial infarct size, enhancement of cardiac function, diminished inflammatory cell infiltration, and decreased cardiomyocyte apoptosis. Furthermore, Metrnl overexpression promoted M1 to M2 macrophage polarization. In vitro, BMDMs treated with Metrnl shifted towards M2 polarization, characterized by decreased expression of inflammatory cytokines (IL-1β, MCP-1, TNF-α) and increased expression of the anti-inflammatory cytokine IL-10. Additionally, supernatant from Metrnl-treated macrophages protected AC16 cells from apoptosis under H/R conditions, as evidenced by decreased BAX expression and increased BCL-2 expression. However, these effects of Metrnl were inhibited by the AMPK inhibitor Compound C. CONCLUSIONS: Metrnl alleviates MI/RI by activating AMPK-mediated M2 macrophage polarization to attenuate inflammatory response and cardiomyocyte apoptosis. This study highlights the therapeutic potential of Metrnl in MI/RI, and identifies it as a promising target for the treatment of ischemic heart disease. | Molecular medicine (Cambridge, Mass.) | 13/03/2025 |
('LID', '10.1038/s41592-025-02623-4') | A systematic benchmark of Nanopore long-read RNA sequencing for transcript-level analysis in human cell lines. | Chen, Ying, Davidson, Nadia M, Wan, Yuk Kei, Yao, Fei, Su, Yan, Gamaarachchi, Hasindu, Sim, Andre, Patel, Harshil, Low, Hwee Meng, Hendra, Christopher, Wratten, Laura, Hakkaart, Christopher, Sawyer, Chelsea, Iakovleva, Viktoriia, Lee, Puay Leng, Xin, Lixia, Ng, Hui En Vanessa, Loo, Jia Min, Ong, Xuewen, Ng, Hui Qi Amanda, Wang, Jiaxu, Koh, Wei Qian Casslynn, Poon, Suk Yeah Polly, Stanojevic, Dominik, Tran, Hoang-Dai, Lim, Kok Hao Edwin, Toh, Shen Yon, Ewels, Philip Andrew, Ng, Huck-Hui, Iyer, N Gopalakrishna, Thiery, Alexandre, Chng, Wee Joo, Chen, Leilei, DasGupta, Ramanuj, Sikic, Mile, Chan, Yun-Shen, Tan, Boon Ooi Patrick, Wan, Yue, Tam, Wai Leong, Yu, Qiang, Khor, Chiea Chuan, Wüstefeld, Torsten, Lezhava, Alexander, Pratanwanich, Ploy N, Love, Michael I, Goh, Wee Siong Sho, Ng, Sarah B, Oshlack, Alicia, Göke, Jonathan | The human genome contains instructions to transcribe more than 200,000 RNAs. However, many RNA transcripts are generated from the same gene, resulting in alternative isoforms that are highly similar and that remain difficult to quantify. To evaluate the ability to study RNA transcript expression, we profiled seven human cell lines with five different RNA-sequencing protocols, including short-read cDNA, Nanopore long-read direct RNA, amplification-free direct cDNA and PCR-amplified cDNA sequencing, and PacBio IsoSeq, with multiple spike-in controls, and additional transcriptome-wide N(6)-methyladenosine profiling data. We describe differences in read length, coverage, throughput and transcript expression, reporting that long-read RNA sequencing more robustly identifies major isoforms. We illustrate the value of the SG-NEx data to identify alternative isoforms, novel transcripts, fusion transcripts and N(6)-methyladenosine RNA modifications. Together, the SG-NEx data provide a comprehensive resource enabling the development and benchmarking of computational methods for profiling complex transcriptional events at isoform-level resolution. | Nature methods | 13/03/2025 |
('LID', '10.1016/j.jare.2025.03.011') | Trained immunity using probiotics and inactivated pathogens enhances resistance to Salmonella enterica serovar Typhimurium infection by activating the cGAS-STING signal pathway in mice and chickens. | Jia, Junpeng, Ji, Wenxin, Xiong, Ningna, Lin, Jian, Yang, Qian | INTRODUCTION: Concerns about antibiotic resistance have prompted interest in alternative strategies for enhancing disease resistance, particularly in livestock and poultry production. OBJECTIVES: This study explored the role of trained immunity in enhancing resistance to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection in mice and chickens. METHODS: We investigated the effects of probiotics and inactivated pathogenic bacterial strains on host immunity in Toll-like receptor 2-deficient mice (TLR2(-)/(-)) to assess whether these effects were related to bacterial outer membrane components such as peptidoglycan (PNG), lipoarabinomannan (LAM) and lipoteichoic acid (LTA). Bacterial genomes were evaluated for their ability to enhance the host immune system. Macrophage-depletion models were used to identify the key immune cells involved in trained immunity, with a focus on the cGAS-STING pathway. RESULTS: Probiotics and inactivated pathogenic strains enhanced host immunity and protected against S. Typhimurium infection. As demonstrated in the TLR2-deficient mice, the effects were not dependent on bacterial outer membrane components. Instead, bacterial genomes played a significant role in activating trained immunity. Macrophages were identified as the primary cells that mediated the response with the cGAS-STING pathway playing a crucial role. The results observed using the mouse models led to investigating the potential application of trained immunity in poultry. CONCLUSION: Trained immunity activated by probiotics and inactivated bacterial pathogens enhanced resistance against S. Typhimurium infection via macrophage activation and involved the cGAS-STING pathway. These findings highlight the potential of trained immunity as an alternative strategy for disease prevention in both livestock and poultry. | Journal of advanced research | 12/03/2025 |
('LID', '10.30773/pi.2021.0311') | Internet Addiction and Online Gaming Disorder in Children and Adolescents During COVID-19 Pandemic: A Systematic Review. | Putra, Patria Yudha, Fithriyah, Izzatul, Zahra, Zulfa | The Indonesian government has enforced several social restrictions to prevent the spread of the coronavirus disease-2019 (COVID-19) virus, such as closures of in-person schools, public areas, and playgrounds as well as reduced outdoor activities. These restrictions will affect mental health of school-age children and adolescents. The internet is chosen as one of the media to keep academic activities running, but excessive internet use will increase internet addiction and online gaming disorder. This study aimed to understand the prevalence and psychological impacts of internet addiction and online gaming disorder on children and adolescents globally during the pandemic. Systematic searches were carried out on the PubMed, ProQuest, and Google Scholar search engines. All studies were assessed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 criteria and the Newcastle Ottawa Scale. Five studies met the criteria for assessing internet addiction and online gaming disorder cases in children and adolescents. Four studies discussed internet addiction, and one study addressed the negative impacts of online gaming on children and adolescents during the COVID-19 pandemic. There has been an increase in internet use and online gaming disruption in children and adolescents in almost all parts of Asian and Australian countries during the COVID-19 pandemic period. | Psychiatry investigation | 00/03/2023 |
('LID', '10.1002/cam4.70659') | Identification and Validation of Four Serum Biomarkers With Optimal Diagnostic and Prognostic Potential for Gastric Cancer Based on Machine Learning Algorithms. | Liu, Yi, Bian, Bingxian, Chen, Shiyu, Zhou, Bingqian, Zhang, Peng, Shen, Lisong, Chen, Hui | BACKGROUND: Gastric cancer (GC) is considered a highly heterogeneous disease, and currently, a comprehensive approach encompassing molecular data from various biological levels is lacking. METHODS: This study conducted different analyses, including the identification of differentially expressed genes (DEGs), weighted correlation networks (WGCNA), single-cell RNA sequencing (scRNA-seq), mRNA expression-based stemness index (mRNAsi), and multiCox analysis, utilizing data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Subsequently, the machine learning algorithms including least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), combined with multiCox analysis were exploited to identify hub genes. These findings were then validated through the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, and were experimentally confirmed in GC samples by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Integrated analysis of TCGA and GEO databases, coupled with LASSO regression and RF algorithms, allowed us to identify 18 hub genes encoding differentially expressed secreted proteins in GC. The results of RT-PCR and bioinformatics analysis revealed four promising biomarkers with optimal diagnostic and prognostic potential. ROC analysis and Kaplan-Meier curves highlighted CHI3L1, FCGBP, VSIG2, and TFF2 as promising biomarkers for GC, offering superior modeling accuracy. These findings were further confirmed by RT-PCR and ELISA, affirming the clinical utility of these four biomarkers. Additionally, CIBERSORT analysis indicated a potential correlation between the four biomarkers and the infiltration of B memory cells and Treg cells. CONCLUSION: This study unveiled four promising biomarkers present in the serum of patients with GC, which could serve as powerful indicators of GC and provide valuable insights for further research into GC pathogenesis. | Cancer medicine | 00/03/2025 |
('LID', '10.1016/j.ccell.2025.02.008') | Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia. | Pham-Danis, Catherine, Novak, Amanda J, Danis, Etienne, McClellan, Samantha M, Leach, Lillie, Yarnell, Michael C, Ebmeier, Christopher C, Tasian, Sarah K, Kohler, M Eric | Chimeric antigen receptor (CAR) T cells induce responses in patients with relapsed/refractory leukemia; however, long-term efficacy is frequently limited by relapse. The inability to target antigen-low cells is an intrinsic vulnerability of second-generation CAR T cells and underlies most relapses following CD22BBz CAR T cell therapy. Here, we interrogate CD22BBz CAR signaling in response to low antigen and find inefficient phosphorylation of the linker for activation of T cells (LAT) limiting downstream signaling. To overcome this, we designed the adjunctive LAT-activating CAR T cell (ALA-CART) platform, pairing a second-generation CAR with a LAT-CAR incorporating the intracellular domain of LAT. ALA-CART cells demonstrate reduced differentiation during manufacturing and increased LAT phosphorylation, MAPK signaling, and AP-1 activity. ALA-CART cells show improved cytotoxicity, proliferation, persistence, and efficacy against antigen-low leukemias that were refractory to clinically active CD22BBz CAR T cells. Restoration of LAT signaling through the ALA-CART platform represents a promising strategy for overcoming multiple mechanisms of CAR T cell failure. | Cancer cell | 10/03/2025 |
('LID', '10.1038/s41593-025-01896-4') | Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis. | Cheng, Man, Lu, Dan, Li, Kexin, Wang, Yan, Tong, Xiwen, Qi, Xiaolong, Yan, Chuanzhu, Ji, Kunqian, Wang, Junlin, Wang, Wei, Lv, Huijiao, Zhang, Xu, Kong, Weining, Zhang, Jian, Ma, Jiaxin, Li, Keru, Wang, Yaheng, Feng, Jingyu, Wei, Panpan, Li, Qiushuang, Shen, Chengyong, Fu, Xiang-Dong, Ma, Yuanwu, Zhang, Xiaorong | Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS. | Nature neuroscience | 11/03/2025 |
('LID', '10.1016/j.ajcnut.2025.03.011') | Energy intake is associated with dietary macronutrient densities: inversely with protein and monounsaturated fat and positively with polyunsaturated fat and carbohydrate among postmenopausal females. | Prentice, Ross L, Aragaki, Aaron K, Zheng, Cheng, Manson, JoAnn E, Tinker, Lesley F, Schoeller, Dale A, Ravelli, Michele N, Raftery, Daniel, Gowda, G A Nagana, Navarro, Sandi L, Huang, Ying, Mossavar-Rahmani, Yasmin, Wallace, Robert B, Johnson, Karen C, Lampe, Johanna W, Neuhouser, Marian L | BACKGROUND: Associations of the macronutrient composition of the diet with total energy intake (EI) are uncertain, as are associations of macronutrient composition with self-reported energy underreporting. OBJECTIVES: We aim to estimate associations of biomarker-assessed EI with both biomarker-assessed and self-reported macronutrient component densities in a Women's Health Initiative (WHI) sub-cohort of postmenopausal U.S. females. Secondarily, we examine energy underreporting using food records, recalls and frequencies, for association with macronutrient densities. DESIGN AND METHODS: We used a previously proposed EI biomarker equation based on doubly-labeled water (DLW) and updated biomarker equations for several macronutrient component densities, to estimate EI and macronutrient component densities in a WHI nutritional biomarkers sub-cohort (n=436; 2007-2009). We used linear regression of EI biomarker values on biomarker and self-reported macronutrient component densities, and of log-EI underreporting values on biomarker densities, to examine targeted associations. RESULTS: Using biomarker assessments, the geometric mean (95% CI) for EI corresponding to a 20% increment in carbohydrate density was 2.0% (0.1%, 3.9%) higher, and for a 20% protein density increment was 2.1% (0.5%, 3.7%) lower. The former was attributable to added sugars. Similarly, EI values for 20% increments in polyunsaturated (PUFA), and monounsaturated (MUFA) fatty acids densities were respectively 1.4% (0.3%, 2.6%) higher, and 1.5% (0.1%, 2.9%) lower. Pertinent associations were either not detected or were substantially attenuated if instead self-reported macronutrient densities were used. Also, EI underreporting was strongly related to self-reported macronutrient densities using food records, recalls, or frequencies. CONCLUSIONS: Among U.S. postmenopausal females lower EI was associated with diets relatively high in protein or MUFA, and higher EI was associated with diets relatively high in PUFA or added sugars. These associations are of public health importance, but are mostly missed using self-reported dietary density assessments. Self-reported energy underestimation is substantially associated with self-reported macronutrient densities. This study is registered with clinicaltrials.gov identifier: NCT00000611. | The American journal of clinical nutrition | 13/03/2025 |
('LID', '10.1073/pnas.2420452122') | Triggering and modulation of a complex behavior by a single peptidergic command neuron in Drosophila. | Fernandez-Acosta, Magdalena, Zanini, Rebeca, Heredia, Fabiana, A Volonté, Yanel, Menezes, Juliane, Prüger, Katja, Ibarra, Julieta, Arana, Maite, Pérez, María S, Veenstra, Jan A, Wegener, Christian, Gontijo, Alisson M, Garelli, Andrés | At the end of their growth phase, Drosophila larvae remodel their bodies, glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process-termed pupariation-is triggered by a surge in the hormone ecdysone. Substrate attachment is achieved by a pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone is critical for unlocking progression of the pupariation motor program toward GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, using cell-type-specific RNA interference and behavioral monitoring, we identify Myoinhibiting peptide (Mip) as a neuromodulator of multiple GSB action components, such as tetanic contraction, peristaltic contraction alternation, and head-waving. Mip is required in a pair of brain descending neurons, which act temporally downstream of Dilp8-Lgr3 signaling. Mip modulates GSB via ventral nerve cord neurons expressing its conserved receptor, sex peptide receptor (SPR). Silencing of Mip descending neurons by hyperpolarization completely abrogates GSB, while their optogenetic activation at a restricted competence time window triggers GSB-like behavior. Hence, Mip descending neurons have at least two functions: to act as GSB command neurons and to secrete Mip to modulate GSB action components. Our results provide insight into conserved aspects of Mip-SPR signaling in animals, reveal the complexity of GSB control, and contribute to the understanding of how multistep innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling. | Proceedings of the National Academy of Sciences of the United States of America | 18/03/2025 |
('LID', '10.1038/s41591-025-03599-6') | Immune history shapes human antibody responses to H5N1 influenza viruses. | Garretson, Tyler A, Liu, Jiaojiao, Li, Shuk Hang, Scher, Gabrielle, Santos, Jefferson J S, Hogan, Glenn, Vieira, Marcos Costa, Furey, Colleen, Atkinson, Reilly K, Ye, Naiqing, Ort, Jordan T, Kim, Kangchon, Hernandez, Kevin A, Eilola, Theresa, Schultz, David C, Cherry, Sara, Cobey, Sarah, Hensley, Scott E | Avian H5N1 influenza viruses are circulating widely in cattle and other mammals and pose a risk for a human pandemic. Previous studies suggest that older humans are more resistant to H5N1 infections due to childhood imprinting with other group 1 viruses (H1N1 and H2N2); however, the immunological basis for this is incompletely understood. Here we measured H5N1 antibody responses in sera from 157 individuals born between 1927 and 2016. We show that antibody titers to historical and recent H5N1 strains are highest in older individuals and correlate more strongly with birth year than with age, consistent with immune imprinting. Young children, who were likely not yet exposed to seasonal influenza viruses, had low levels of H5-specific antibodies. We also measured H5N1 antibody responses in sera from 100 individuals before and after receiving an A/Vietnam/1203/2004 H5N1 vaccine. We found that both younger and older humans produced H5-reactive antibodies to the A/Vietnam/1203/2004 vaccine strain and to a contemporary clade 2.3.4.4b strain, with higher seroconversion rates in young children who had lower levels of antibodies before vaccination. These studies suggest that younger individuals might benefit more from vaccination than older individuals in the event of an H5N1 pandemic. | Nature medicine | 13/03/2025 |
('LID', '10.1093/ndt/gfae253') | The role of the intestinal microbiome in cognitive decline in patients with kidney disease. | Wagner, Carsten A, Frey-Wagner, Isabelle, Ortiz, Alberto, Unwin, Robert, Liabeuf, Sophie, Suzumoto, Yoko, Iervolino, Anna, Stasi, Alessandra, Di Marzo, Vincenzo, Gesualdo, Loreto, Massy, Ziad A | Cognitive decline is frequently seen in patients with chronic kidney disease (CKD). The causes of cognitive decline in these patients are likely to be multifactorial, including vascular disease, uraemic toxins, blood-brain barrier leakage, and metabolic and endocrine changes. Gut dysbiosis is common in patients with CKD and contributes to the increase in uraemic toxins. However, the gut microbiome modulates local and systemic levels of several metabolites such as short-chain fatty acids or derivatives of tryptophan metabolism, neurotransmitters, endocannabinoid-like mediators, bile acids, hormones such as glucagon-like peptide 1 (GLP1) or cholecystokinin (CCK). These factors can affect gut function, immunity, autonomic nervous system activity and various aspects of brain function. Key areas include blood-brain barrier integrity, nerve myelination and survival/proliferation, appetite, metabolism and thermoregulation, mood, anxiety and depression, stress and local inflammation. Alterations in the composition of the gut microbiota and the production of biologically active metabolites in patients with CKD are well documented and are favoured by low-fiber diets, elevated urea levels, sedentary lifestyles, slow stool transit times and polypharmacy. In turn, dysbiosis can modulate brain function and cognitive processes, as discussed in this review. Thus, the gut microbiome may contribute to alterations in cognition in patients with CKD and may be a target for therapeutic interventions using diet, prebiotics and probiotics. | Nephrology, dialysis, transplantation : official publication of the European | 13/03/2025 |
('LID', '10.1038/s41598-025-93738-3') | Relationship between serum uric acid levels and metabolism associated fatty liver disease in postmenopausal women based on NHANES 2017-2020. | Zhou, Xiaoding, Yue, Zongxiang, He, Shuming, Yuan, Fengjuan, He, Xingrui, Wang, Jiaqi, Wang, Rong, Luo, Ya, Yi, Qiong | Studies have shown that postmenopausal women have more metabolic abnormalities than premenopausal women. No consensus exists on how serum uric acid (sUA) affects metabolism-associated fatty liver disease (MAFLD) in postmenopausal women.This prospective observational study examined this link using National Health and Nutrition Examination Survey (NHANES) 2017 to 2020 data. We divided women's sUA levels into four quartiles and used logistic regression, subgroup analyses, and restricted triple spline methods to compare the prevalence of MAFLD in postmenopausal and non-menopausal women. We also used histograms to analyze the effect of BMI-based indices. This population-based study involved 4477 women, including 1139 postmenopausal women aged 55-73 years. Multivariate logistic regression showed that, in the fully adjusted model, we found that participants in the highest quartile of sUA had a statistically significant 254% increased risk of MAFLD compared with participants in the lowest quartile (OR: 3.54; 95% CI 3.54 1.47-8.55; P < 0.001). Subgroup analyses showed no significant interaction between sUA levels and specific subgroups P( > 0.05 for all interactions). Additionally, RCS and threshold analysis showed a linear correlation (P = 0.186) and an ideal inflection point of 4.6 (P = 0.818) to the left. Right of the inflection point, the effect size was 1.524 (95% CI 1.291-1.814; P < 0.01). Histograms demonstrated that postmenopausal BMI increased sUA's influence on MAFLD and higher sUA levels and BMI may enhance the prevalence of MAFLA in US postmenopausal women. The results of this study suggest that monitoring sUA levels in the postmenopausal period is critical in determining the occurrence of and interventions for MAFLD. | Scientific reports | 15/03/2025 |
('LID', '10.1186/s13024-025-00819-y') | Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers. | Thal, Dietmar Rudolf, Poesen, Koen, Vandenberghe, Rik, De Meyer, Steffi | Alzheimer's disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of phosphorylated transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate the extent of these AD and co-pathologies in patients, several biomarkers have been developed. Specific tracers target and visualize Aβ plaques, p-τ and αSyn pathology or inflammation by positron emission tomography. In addition to these imaging biomarkers, cerebrospinal fluid, and blood-based biomarker assays reflecting AD-specific or non-specific processes are either already in clinical use or in development. In this review, we will introduce the pathological lesions of the AD brain, the related biomarkers, and discuss to what extent the respective biomarkers estimate the pathology determined at post-mortem histopathological analysis. It became evident that initial stages of Aβ plaque and p-τ pathology are not detected with the currently available biomarkers. Interestingly, p-τ pathology precedes Aβ deposition, especially in the beginning of the disease when biomarkers are unable to detect it. Later, Aβ takes the lead and accelerates p-τ pathology, fitting well with the known evolution of biomarker measures over time. Some co-pathologies still lack clinically established biomarkers today, such as TDP-43 pathology or cortical microinfarcts. In summary, specific biomarkers for AD-related pathologies allow accurate clinical diagnosis of AD based on pathobiological parameters. Although current biomarkers are excellent measures for the respective pathologies, they fail to detect initial stages of the disease for which post-mortem analysis of the brain is still required. Accordingly, neuropathological studies remain essential to understand disease development especially in early stages. Moreover, there is an urgent need for biomarkers reflecting co-pathologies, such as limbic predominant, age-related TDP-43 encephalopathy-related pathology, which is known to modify the disease by interacting with p-τ. Novel biomarker approaches such as extracellular vesicle-based assays and cryptic RNA/peptides may help to better detect these co-pathologies in the future. | Molecular neurodegeneration | 14/03/2025 |
('LID', '10.1126/scitranslmed.adn2635') | Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice. | Liu, Ning, Jiang, Yinghua, Xiu, Yuwen, Tortelote, Giovane G, Xia, Winna, Wang, Yingjie, Li, Yadan, Shi, Samuel, Han, Jinrui, Vidoudez, Charles, Niamnud, Aim, Kilgore, Mitchell D, Zhou, Di, Shi, Mengxuan, Graziose, Stephen A, Fan, Jia, Katakam, Prasad V G, Dumont, Aaron S, Wang, Xiaoying | Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI. | Science translational medicine | 12/03/2025 |
('LID', '10.1001/jamapsychiatry.2025.0033') | Circulating Blood-Based Proteins in Psychopathology and Cognition: A Mendelian Randomization Study. | Bhattacharyya, Upasana, John, Jibin, Lam, Max, Fisher, Jonah, Sun, Benjamin, Baird, Denis, Burgess, Stephen, Chen, Chia-Yen, Lencz, Todd | IMPORTANCE: Peripheral (blood-based) biomarkers for psychiatric illness could benefit diagnosis and treatment, but research to date has typically been low throughput, and traditional case-control studies are subject to potential confounds of treatment and other exposures. Large-scale 2-sample mendelian randomization (MR) can examine the potentially causal impact of circulating proteins on neuropsychiatric phenotypes without these confounds. OBJECTIVE: To identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) as well as cognitive task performance (CTP). DESIGN, SETTING, AND PARTICIPANTS: In a 2-sample MR design, significant proteomic quantitative trait loci were used as candidate instruments, obtained from 2 large-scale plasma proteomics datasets: the UK Biobank Pharma Proteomics Project (2923 proteins per 34 557 UK individuals) and deCODE Genetics (4719 proteins per 35 559 Icelandic individuals). Data analysis was performed from November 2023 to November 2024. EXPOSURE: Genetic influence on circulating levels of proteins in plasma. MAIN OUTCOMES AND MEASURES: Outcome measures were summary statistics drawn from recent large-scale genome-wide association studies for SCZ (67 323 cases and 93 456 controls), BD (40 463 cases and 313 436 controls), MDD (166 773 cases and 507 679 controls), and CTP (215 333 individuals). MR was carried out for each phenotype, and proteins that showed statistically significant (Bonferroni-corrected P < .05) associations from MR analysis were used for pathway, protein-protein interaction, drug target enrichment, and potential druggability analysis for each outcome phenotype separately. RESULTS: MR analysis revealed 113 Bonferroni-corrected associations (46 novel) involving 91 proteins across the 4 outcome phenotypes. Immune-related proteins, such as interleukins and complement factors, showed pleiotropic effects across multiple outcome phenotypes. Drug target enrichment analysis provided support for repurposing of anti-inflammatory agents for SCZ, amantadine for BD, retinoic acid for MDD, and duloxetine for CTP. CONCLUSIONS AND RELEVANCE: Identifying potentially causal effects of circulating proteins on neuropsychiatric phenotypes suggests potential biomarkers and offers insights for the development of innovative therapeutic strategies. The study also reveals pleiotropic effects of many proteins across different phenotypes, indicating shared etiology among serious psychiatric conditions and cognition. | JAMA psychiatry | 12/03/2025 |
('LID', '10.1186/s40359-023-01479-7') | Stimulating creativity in the classroom: examining the impact of sense of place on students' creativity and the mediating effect of classmate relationships. | Zhang, Jianzhen, Yang, Yukun, Ge, Jiahao, Liang, Xiaoyu, An, Zhenni | BACKGROUND: Although previous studies have found a close relationship between sense of place and creativity, few studies have been conducted considering the micro-environment of the classroom. The mediating role of classmate relationships in the association between students' sense of place and creativity remains unclear. METHODS: This study explores classmate relationships as a mediating factor in the relationship between sense of place and creativity. Therefore, we considered a sample of 1555 Chinese high-school students and used a paper-based questionnaire survey. Data analysis was performed using SPSS 24.0, PROCESS 3.2 plugin, and AMOS. RESULTS: Sense of place in the micro-environment of the classroom has a significant positive predictive effect on creativity. Sense of place also has a significant positive predictive effect on peer relationships. The mediation analysis reveals that peer relationships play a mediating role in the relationship between the sense of place and creativity. CONCLUSIONS: This study revealed the associations between sense of place, classmate relationships, and creativity. Creativity is better expressed in students with a strong sense of place in the classroom. Moreover, a student's sense of place can enhance their creativity by influencing their peer relationships. These findings enrich the research in educational psychology within the classroom, providing new insights for fostering creativity. | BMC psychology | 07/12/2023 |
('LID', '10.1038/s41593-025-01914-5') | Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration. | Omar, Omar M F, Kimble, Amy L, Cheemala, Ashok, Tyburski, Jordan D, Pandey, Swati, Wu, Qian, Reese, Bo, Jellison, Evan R, Hao, Bing, Li, Yunfeng, Yan, Riqiang, Murphy, Patrick A | Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases. | Nature neuroscience | 14/03/2025 |
('LID', '10.1186/s40560-025-00776-0') | The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2024. | Shime, Nobuaki, Nakada, Taka-Aki, Yatabe, Tomoaki, Yamakawa, Kazuma, Aoki, Yoshitaka, Inoue, Shigeaki, Iba, Toshiaki, Ogura, Hiroshi, Kawai, Yusuke, Kawaguchi, Atsushi, Kawasaki, Tatsuya, Kondo, Yutaka, Sakuraya, Masaaki, Taito, Shunsuke, Doi, Kent, Hashimoto, Hideki, Hara, Yoshitaka, Fukuda, Tatsuma, Matsushima, Asako, Egi, Moritoki, Kushimoto, Shigeki, Oami, Takehiko, Kikutani, Kazuya, Kotani, Yuki, Aikawa, Gen, Aoki, Makoto, Akatsuka, Masayuki, Asai, Hideki, Abe, Toshikazu, Amemiya, Yu, Ishizawa, Ryo, Ishihara, Tadashi, Ishimaru, Tadayoshi, Itosu, Yusuke, Inoue, Hiroyasu, Imahase, Hisashi, Imura, Haruki, Iwasaki, Naoya, Ushio, Noritaka, Uchida, Masatoshi, Uchi, Michiko, Umegaki, Takeshi, Umemura, Yutaka, Endo, Akira, Oi, Marina, Ouchi, Akira, Osawa, Itsuki, Oshima, Yoshiyasu, Ota, Kohei, Ohno, Takanori, Okada, Yohei, Okano, Hiromu, Ogawa, Yoshihito, Kashiura, Masahiro, Kasugai, Daisuke, Kano, Ken-Ichi, Kamidani, Ryo, Kawauchi, Akira, Kawakami, Sadatoshi, Kawakami, Daisuke, Kawamura, Yusuke, Kandori, Kenji, Kishihara, Yuki, Kimura, Sho, Kubo, Kenji, Kuribara, Tomoki, Koami, Hiroyuki, Koba, Shigeru, Sato, Takehito, Sato, Ren, Sawada, Yusuke, Shida, Haruka, Shimada, Tadanaga, Shimizu, Motohiro, Shimizu, Kazushige, Shiraishi, Takuto, Shinkai, Toru, Tampo, Akihito, Sugiura, Gaku, Sugimoto, Kensuke, Sugimoto, Hiroshi, Suhara, Tomohiro, Sekino, Motohiro, Sonota, Kenji, Taito, Mahoko, Takahashi, Nozomi, Takeshita, Jun, Takeda, Chikashi, Tatsuno, Junko, Tanaka, Aiko, Tani, Masanori, Tanikawa, Atsushi, Chen, Hao, Tsuchida, Takumi, Tsutsumi, Yusuke, Tsunemitsu, Takefumi, Deguchi, Ryo, Tetsuhara, Kenichi, Terayama, Takero, Togami, Yuki, Totoki, Takaaki, Tomoda, Yoshinori, Nakao, Shunichiro, Nagasawa, Hiroki, Nakatani, Yasuhisa, Nakanishi, Nobuto, Nishioka, Norihiro, Nishikimi, Mitsuaki, Noguchi, Satoko, Nonami, Suguru, Nomura, Osamu, Hashimoto, Katsuhiko, Hatakeyama, Junji, Hamai, Yasutaka, Hikone, Mayu, Hisamune, Ryo, Hirose, Tomoya, Fuke, Ryota, Fujii, Ryo, Fujie, Naoki, Fujinaga, Jun, Fujinami, Yoshihisa, Fujiwara, Sho, Funakoshi, Hiraku, Homma, Koichiro, Makino, Yuto, Matsuura, Hiroshi, Matsuoka, Ayaka, Matsuoka, Tadashi, Matsumura, Yosuke, Mizuno, Akito, Miyamoto, Sohma, Miyoshi, Yukari, Murata, Satoshi, Murata, Teppei, Yakushiji, Hiromasa, Yasuo, Shunsuke, Yamada, Kohei, Yamada, Hiroyuki, Yamamoto, Ryo, Yamamoto, Ryohei, Yumoto, Tetsuya, Yoshida, Yuji, Yoshihiro, Shodai, Yoshimura, Satoshi, Yoshimura, Jumpei, Yonekura, Hiroshi, Wakabayashi, Yuki, Wada, Takeshi, Watanabe, Shinichi, Ijiri, Atsuhiro, Ugata, Kei, Uda, Shuji, Onodera, Ryuta, Takahashi, Masaki, Nakajima, Satoshi, Honda, Junta, Matsumoto, Tsuguhiro | The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions. | Journal of intensive care | 14/03/2025 |
('LID', '10.1126/sciimmunol.adp7193') | ATF4 drives regulatory T cell functional specification in homeostasis and obesity. | Wang, Ke, Farrell, Andrea, Zhou, Enchen, Qin, Houji, Zeng, Zixuan, Zhou, Kailun, Cunha E Rocha, Karina, Zhang, Dinghong, Wang, Gaowei, Atakilit, Amha, Sheppard, Dean, Lu, Li-Fan, Jin, Chunyu, Ying, Wei | Regulatory T cells (T(regs)) have diverse functional specification in homeostasis and disease. However, how liver T(regs) function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector T(regs) expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector T(reg) transcriptional program, and ATF4-expressing T(regs) promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor-β activation via integrin αvβ8. T(reg)-specific deletion of Atf4 resulted in reduced liver T(regs) and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue T(reg) precursors under steady state. These findings demonstrate that ATF4 is important for regulating T(reg) functional specification in homeostasis and obesity. | Science immunology | 14/03/2025 |
('LID', '10.1590/1806-9282.65.2.110') | The overexpression of lncRNA H19 as a diagnostic marker for coronary artery disease. | Xiong, Gang, Jiang, Xuejun, Song, Tao | OBJECTIVE: Our study aimed to investigate the diagnostic value of lncRNA H19 for coronary artery disease (CAD) and to explore its possible mechanisms. METHODS: A total of 30 CAD patients and 30 healthy individuals, as well as patients with different cardiovascular diseases, were included in this study. Blood was drawn from each participant to prepare serum samples, and the expression of lncRNA H19 was detected using qRT-PCR. The ROC curve analysis was used to analyze the diagnostic value of H19 for CAD. The effects of patients' basic information and lifestyle on H19 expression were analyzed. The plasma level of TGF-β1 was measured by ELISA. The H19 overexpression in the human primary coronary artery endothelial cell (HCAEC) line was constructed, and the effects of H19 overexpression on the TGF-β1 expression were analyzed using Western blot. The results of H19 expression were specifically upregulated in patients with CAD but not in healthy individuals and patients with other types of cardiovascular diseases. The ROC curve analysis showed that the H19 expression level could be used to predict CAD accurately. Gender, age, and patients' lifestyle had no significant effects on H19 expression, but H19 expression was higher in patients with a longer course of disease in comparison with the controls. H19 expression was positively correlated with the serum level of TGF-β1, and H19 overexpression significantly increased TGF-β1 protein level in HCAEC. CONCLUSION: H19 overexpression participates in the pathogenesis of CAD by increasing the expression level of TGF-β1, and H19 expression level may serve as a diagnostic marker for CAD. | Revista da Associacao Medica Brasileira (1992) | 00/02/2019 |
('LID', '10.1021/jacs.7b09792') | Through-Space Activation Can Override Substituent Effects in Electrophilic Aromatic Substitution. | Guan, Liangyu, Holl, Maxwell Gargiulo, Pitts, Cody Ross, Struble, Mark D, Siegler, Maxime A, Lectka, Thomas | Electrophilic aromatic substitution (EAS) represents one of the most important classes of reactions in all of chemistry. One of the "iron laws" of EAS is that an electron-rich aromatic ring will react more rapidly than an electron-poor ring with suitable electrophiles. In this report, we present unique examples of electron-deficient arenes instead undergoing preferential substitution in intramolecular competition with more electron-rich rings. These results were made possible by exploiting the heretofore unknown propensity of a hydrogen-bonding OH-arene interaction to switch to the alternative HO-arene interaction in order to provide activation. In an extreme case, this through-space HO-arene activation is demonstrated to overcome the deactivating effect of a trifluoromethyl substituent, making an otherwise highly electron-deficient ring the site of exclusive reactivity in competition experiments. Additionally, the HO-arene activation promotes tetrabromination of an increasingly more electron-deficient arene before the unactivated "control" ring undergoes monobromination. It is our hope that these results will shed light on biological interactions as well as provide new strategies for the electrophilic substitution of aromatic rings. | Journal of the American Chemical Society | 25/10/2017 |
('AID', '10.1186/1471-2334-6-28') | A prospective study of hearing changes after beginning zidovudine or didanosine in HIV-1 treatment-naïve people. | Schouten, Jeffrey T, Lockhart, David W, Rees, Thomas S, Collier, Ann C, Marra, Christina M | BACKGROUND: While hearing loss in HIV-infected people after beginning nucleoside reverse transcriptase inhibitors (NRTIs) has been reported, there have been no prospective studies that measured hearing changes longitudinally in treatment-naïve HIV-infected subjects following initiation of regimens containing NRTIs. The goal of this study was to conduct a prospective assessment of the contribution of zidovudine (ZDV) and didanosine (ddI) to hearing loss. METHODS/DESIGN: A prospective observational pilot study to determine whether ZDV or ddI, alone or in combination, are associated with sensorineural hearing loss in HIV-infected persons. Changes in hearing levels at all frequencies and in low and high frequency pure tone averages were measured at baseline, 16, and 32 weeks after initiating antiretroviral therapy. DISCUSSION: Treatment with ZDV and ddI did not result in loss of hearing, even after taking into account noise exposure, immune status and age. The results of this prospective pilot study do not support the notion that treatment with nucleoside antiretrovirals damages hearing. | BMC infectious diseases | 20/02/2006 |
('AID', '10.1094/MPMI.1997.10.9.1045') | Cloning and characterization of a cDNA encoding an elicitor of Phytophthora parasitica var. nicotianae that shows cellulose-binding and lectin-like activities. | Mateos, F V, Rickauer, M, Esquerré-Tugayé, M T | Phytophthora parasitica var. nicotianae produces a 34-kDa glycoprotein elicitor (CBEL) that is localized in the cell wall. A cDNA encoding the protein moiety of this elicitor was cloned and characterized. The deduced amino acid sequence consisted of two direct repeats of a cysteine-rich domain, joined by a Thr/Pro-rich region. Although having no general homology with published sequences, the positions of the cysteine residues in the two repeats show a conserved pattern, similar to that of the cellulose-binding domain of fungal glycanases. CBEL did not possess hydrolytic activity on a variety of glycans, but bound to fibrous cellulose and plant cell walls. In addition, it exerted a lectin-like hemagglutinating activity. Infiltration of tobacco leaves (cultivar 46-8) with this molecule elicited necrosis and defense gene expression at 150 nM. Elicitor pretreatment of this tobacco cultivar resulted in protection against subsequent inoculation with an otherwise virulent race of P. parasitica var. nicotianae. All these biological activities were exerted within a low concentration range. This is the first report that a fungal elicitor exhibits cellulose-binding and lectin-like activities. The possible implications of such a multifunctional elicitor in plant-microbe interactions are discussed. | Molecular plant-microbe interactions : MPMI | 00/12/1997 |
('LID', '10.1038/s41413-025-00413-4') | SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch. | Deng, Yaoge, Hou, Mingzhuang, Wu, Yubin, Liu, Yang, Xia, Xiaowei, Yu, Chenqi, Yu, Jianfeng, Yang, Huilin, Zhang, Yijian, Zhu, Xuesong | Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired mitophagy. SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA. | Bone research | 14/03/2025 |
('LID', '10.1038/s41598-025-93642-w') | Association between dietary protein intake and bone mineral density based on NHANES 2011-2018. | Chen, Xingxing, Fu, Yonghua, Zhu, Zhongxin | This study examines the relationship between dietary protein intake and bone mineral density (BMD) using data from the 2011-2018 National Health and Nutrition Examination Survey (NHANES), addressing existing controversies in current evidence. This cross-sectional study included 16,775 participants. Dietary protein intake, the exposure variable, was collected with the use of two 24-h dietary recall methods and usual intake was assessed by the National Cancer Institute (NCI) method. While whole-body BMD, the outcome variable, was measured with dual-energy X-ray absorptiometry. Covariates included demographic, socioeconomic, and health factors. Weighted multivariable regression and generalized additive models were used for the association between dietary protein intake and BMD. After adjusting for covariates, a positive association was found between protein intake and BMD. Each additional gram of protein consumed was significantly associated with a BMD increase of 0.0003 g/cm(2) (95% CI 0.0001, 0.0004, P = 0.0003). Subgroup analysis by gender and ethnicity revealed significant positive correlations in women and Mexican Americans. Additionally, a saturation threshold effect was observed in women at 60.70 g/day and in non-Hispanic whites at 135.53 g/day, where the correlation was no longer significant beyond these thresholds. The study demonstrates a positive association between dietary protein intake and BMD, although this relationship is complex and nonlinear with varying effects across different populations. Specifically, positive correlation is only significant below a specific threshold level in some populations. These findings suggest the need for personalized dietary guidelines and provide important insights for clinical nutritional interventions and bone health management. | Scientific reports | 13/03/2025 |
('LID', '10.1016/j.ahj.2025.03.003') | Design and Rationale of the CORE -TIMI 72a and CORE2 -TIMI 72b Trials of Olezarsen in Patients with Severe Hypertriglyceridemia. | Marston, Nicholas A, Bergmark, Brian A, Alexander, Veronica J, Karwatowska-Prokopczuk, Ewa, Kang, Yu Mi, Moura, Filipe A, Prohaska, Thomas A, Zimerman, Andre, Zhang, Shuanglu, Murphy, Sabina A, Tsimikas, Sotirios, Giugliano, Robert P, Sabatine, Marc S | Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 500 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglycerides and triglyceride-rich remnants. Olezarsen has been evaluated in patients with predominantly moderate HTG (150-499 mg/dl) and a rare genetic condition known as Familial Chylomicronemia Syndrome (FCS), with TG lowering effects of 53% and 44%, respectively, and reductions in pancreatitis among the FCS population. However, no dedicated trial has tested olezarsen in patients with severe HTG. In these two pivotal phase 3 trials, CORE -TIMI 72a (NCT05079919) and CORE2 -TIMI 72b (NCT05552326), over 1,000 patients with severe HTG will be randomized in a 2:1 fashion to either olezarsen (80 mg or 50 mg dose) or matching placebo. Patients will be treated for a total of 53 weeks and evaluated for the primary endpoint of percent change in TGs from baseline to 6 months compared to placebo. Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis. Together, CORE -TIMI 72a (NCT05079919) and CORE2 -TIMI 72b (NCT05552326) are designed to establish the efficacy and safety of olezarsen in patients with severe HTG. | American heart journal | 08/03/2025 |
('LID', '10.1073/pnas.2411554122') | N6-methyladnosine of vRNA facilitates influenza A virus replication by promoting the interaction of vRNA with polymerase proteins. | Wang, Qian, Xu, Shuai, Shen, Wentao, Wei, Yanli, Han, Lu, Wang, Zhengxiang, Yu, Yingying, Liu, Minxuan, Liu, Junwen, Deng, Guohua, Chen, Hualan, Zhu, Qiyun | N6-methyladnosine (m(6)A) modification is present in both positive- and negative-strand RNA of influenza A virus (IAV) and affects the replication and pathogenicity of IAV. However, little is known about the regulatory mechanism of m(6)A in IAV RNA. In the present study, we identified the m(6)A methylation of the viral RNA of different IAV subtypes and confirmed that m(6)A modification promotes the polymerase activity and replication of IAV. By mutating m(6)A motifs on the multiple viral RNAs (vRNAs) of IAV, we revealed that m(6)A deficiency in vRNA suppresses the expression of viral genes and the replication of the virus in vitro. In addition, m(6)A deficiency in vRNA reduced the pathogenicity of IAV in a mouse model. Mechanistically, m(6)A deficiency in vRNA suppresses the assembly of the viral ribonucleoprotein (vRNP) complex by impairing the interaction between vRNA and vRNP proteins in an m(6)A methyltransferase-dependent manner, but not the m(6)A reader proteins. Together, our findings reveal an important role for m(6)A on viral RNAs in facilitating the activity of the polymerase complex and the replication and pathogenicity of IAV, which provides insights for the development of novel anti-influenza strategies. | Proceedings of the National Academy of Sciences of the United States of America | 18/03/2025 |
('LID', '10.1212/WNL.0000000000213465') | Functional Outcome in Patients With Carotid Artery Dissection Undergoing Thrombectomy or Standard Medical Treatment. | Sykora, Marek, Poli, Sven, Giannakakis, Michael, Mbroh, Joshua, Exposito, Alexandra Gomez, Krebs, Stefan, Posekany, Alexandra, Katan, Mira, Wegener, Susanne, De Marchis, Gian Marco, Gattringer, Thomas, Deutschmann, Hannes A, Mayer-Suess, Lukas, Fiehler, Jens, Ernemann, Ulrike, Hennersdorf, Florian, Dobrocky, Tomas, Kulcsár, Zsolt, Mordasini, Pasquale, Psychogios, Marios, Loewe, Christian, Gizewski, Elke R, Nolte, Christian H, Neumann, Christian, Fischer, Urs, Ferrari, Julia | BACKGROUND AND OBJECTIVES: Whether thrombectomy compared with best medical treatment (BMT) improves outcome in patients with stroke and carotid artery dissection (CAD) is unknown. METHODS: This was an international observational study based on prospective nationwide Austrian, German, and Swiss stroke registries. Patients with large vessel occlusion (LVO) due to CAD were compared according to treatment modality (thrombectomy vs BMT including intravenous thrombolysis) and to admission stroke severity NIH Stroke Scale (NIHSS) <6 vs NIHSS ≥6. The primary outcome was the favorable functional outcome (modified Rankin Score 0-2) at 3 months. RESULTS: Of 1,023 patients (mean age 54 years, 72% males), 516 received thrombectomy and 507 received BMT. After robust adjustment, thrombectomy was associated with favorable outcome in patients presenting with NIHSS ≥6 (adjusted risk ratio (aRR) = 1.77, 95% CI 1.44-2.17). In those presenting with NIHSS <6, thrombectomy was associated with unfavorable outcome (aRR 1.68, CI 1.1-2.56) as compared with BMT. DISCUSSION: Thrombectomy improved functional outcome in patients with LVO due to CAD and admission NIHSS ≥6, but not NIHSS <6 points. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with LVO due to CAD and admission NIHSS ≥6 points, thrombectomy compared with BMT significantly increases the probability of favorable outcome. | Neurology | 08/04/2025 |
('LID', '10.1186/s12877-025-05814-y') | A fall risk prediction model based on the CHARLS database for older individuals in China. | Liang, Xue-Zhen, Chai, Jin-Lian, Li, Guang-Zheng, Li, Wei, Zhang, Bo-Chun, Zhou, Zhong-Qi, Li, Gang | BACKGROUND: Falls represent the second leading cause of injury-related mortality among older adults globally. The occurrence of falls is the consequence of the interaction of numerous complex risk factors. The objective of this study was to develop a validated fall risk prediction model for the Chinese older individuals. METHODS: The study used data from the China Health and Retirement Longitudinal Study (CHARLS), a dataset representative of the Chinese population. Thirty-eight indicators including biological factors, behavioral factors and health status were analyzed in this study. The study cohort was randomly divided into the training set (70%) and the validation set (30%). Variables were screened using LASSO regression analysis, the best predictive model based on 10-fold cross-validation, logistic regression model was applied to explore the correlates of fall risk in the older individuals, a nomogram was constructed to develop the predictive model, calibration curves were applied to assess the accuracy of the nomogram model, and predictive performance was assessed by area under the receiver operating characteristic curve and decision curve analysis. RESULT: A total of 4,913 cases from the 2015 CHARLS database for people aged 60 years and older were ultimately included, and a total of 1,082 (22.02%) of the older individuals had experienced a fall within two years. Multivariate logistic regression analysis showed that Sleeping time, Hearing, Grip strength, ADL score, Cognition, Depression, Health, KD, and Pain DRUG were predictors of fall risk in the older individuals. These factors were used to construct nomogram models that showed good agreement and accuracy. The AUC value for the predictive model was 0.644 (95% CI = 0.621-0.666), with a specificity of 0.695 and a sensitivity of 0.522. For the internal validation set, the AUC value was 0.644 (95% CI = 0.611-0.678), with a specificity of 0.629 and a sensitivity of 0.577. The Hosmer-Lemeshow test value of the model for the training set is p = 0.9368 and for the validation set is p = 0.8545 (both > 0.05). The calibration curves show a more significant agreement between the nomogram model and the actual observations. The ROC and DCA indicate a better predictive performance of the nomogram. CONCLUSION: The comprehensive nomogram constructed in this study is a promising and convenient tool for assessing the risk of falls in the Chinese older individuals and to help older adults understand the risk level of falls, avoid and eliminate modifiable risk factors, and reduce the incidence of falls. CLINICAL TRIAL NUMBER: Not applicable. | BMC geriatrics | 13/03/2025 |
('LID', '10.1186/s12933-025-02668-x') | Association between the triglyceride glucose-Chinese visceral adiposity index and new-onset stroke risk: a national cohort study. | Wang, Mengdie, Gao, Bing, Huang, Fei | BACKGROUND: Numerous studies have investigated the effect of an integrated index that combines the triglyceride‒glucose (TyG) index with various obesity indicators on stroke incidence. However, how to use the TyG index and the Chinese Visceral Adiposity Index (CVAI) for stroke prevention remains unclear. This study examined the associations between dynamic changes in the TyG-CVAI index and cumulative, baseline, and new-onset stroke risk. METHODS: Data from 3,769 participants in the China Health and Retirement Longitudinal Study(CHARLS) were analyzed, concentrating on the baseline TyG-CVAI, TyG-CVAI in 2015, and the cumulative TyG-CVAI derived from these. The fluctuations of the TyG-CVAI index were grouped into three clusters using K-means clustering analysis. Logistic regression models were used to examine the relationship between the TyG-CVAI index and new-onset stroke risk. Restricted cubic splines (RCS) were employed to investigate potential nonlinear relationships while assessing the predictive capability by receiver operating characteristic curve. RESULTS: During the follow-up period, 181 participants experienced stroke events. The stroke incidence rates in Clusters 1, 2, and 3 were 2.42%, 8.72%, and 4.37%, respectively. After adjustment for confounding factors, Cluster 2 with high and increasing TyG-CVAI index (OR = 3.16, 95% CI 1.94-5.22), the Q3 group with high cumulative TyG-CVAI index (OR = 2.53, 95% CI 1.60-4.02), and the Q3 group with high baseline TyG-CVAI index (OR = 2.49, 95% CI 1.57-3.95),which were all correlated with an elevated risk of new-onset stroke. The RCS analysis disclosed a U-shaped relationship between cumulative and baseline TyG-CVAI index and stroke risk. CONCLUSION: The fluctuations in and baseline, and cumulative TyG-CVAI index are independently correlated with an increased risk of stroke. The TyG-CVAI index is anticipated to be a more efficient and significant indicator for evaluating early stroke. | Cardiovascular diabetology | 12/03/2025 |
('LID', '10.1038/s41598-025-89888-z') | Thyroid function and multiple sclerosis: a two-sample mendelian randomization study and mediation analysis. | Ren, Yinghao, Wang, Xin, Wang, Weiliang, Wang, Zeyu | Multiple sclerosis (MS) is a prevalent neurological disorder with a complex etiology, often associated with thyroid function. However, the causal relationship between these two conditions remains poorly understood. This study aimed to elucidate the causal relationship between thyroid function and MS using a bidirectional Mendelian randomization (MR) approach and to investigate the potential mediating role of immune cells. We conducted a two-sample MR analysis using summary statistics from large-scale genome-wide association studies (GWAS). We included results from sensitivity tests such as MR-Egger, weighted median, and leave-one-out analyses to support the robustness and reliability of the findings. The inverse variance-weighted (IVW) method was the primary approach, with sensitivity analyses conducted using seven additional MR methods. Furthermore, multivariable MR and mediation analysis were conducted to uncover potential mediating immune cells underlying the observed associations. The MR analysis showed that Hypothyroidism and elevated Thyroid-Stimulating Hormone (TSH) levels(normal) reduced the risk of MS (P = 0.012, OR (95%CI) :0.914(0.851, 0.98); P = 0.020, OR (95%CI) :0.88(0.789, 0.98)). Free thyroxine (FT4) increased the risk of MS (P = 0.020, OR (95%CI) :1.268(1.051, 1.53)). Mediation analysis showed evidence of indirect effect of FT4 on MS through "HLA DR on CD33br HLA DR + CD14" and "IgD- CD27- %B cell" with a mediated proportion of 39.16% (positive effect), 78.53% (reverse effect) of the total effect. This study provided genetic evidence that FT4 may increase the risk of developing MS. "HLA DR on CD33br HLA DR + CD14" and "IgD- CD27- %B cell", mediated the causal relationship between thyroid function and MS, highlighting the importance of further investigating their roles in these conditions. | Scientific reports | 15/03/2025 |
('LID', '10.1038/s41541-025-01093-1') | A highly stable lyophilized mRNA vaccine for Herpes Zoster provides potent cellular and humoral responses. | Munoz-Moreno, Raquel, Allaj, Viola, Gadee, Eddie, Button, Julie M, Diaz, Fernando, Maddur, Mohan S, Chen, Wei, Hu, Cheng Hui, Martinez, Lyndsey, Giannakou, Andreas, Campbell, Adam Lee, Miteva, Yana, Guo, Pengbo, Huang, Bridget, Shi, Shuai, Lotvin, Jason, Tompkins, Kristin, Allen, Pirada Suphaphiphat, Solórzano, Alicia | Herpes zoster (HZ) is a painful vesicular rash that occurs upon varicella-zoster virus (VZV) reactivation in older adults and immunocompromised individuals. Although there is currently an approved vaccine for the prevention of shingles, its administration is commonly associated with high reactogenicity. This highlights the need to develop new vaccine alternatives with long lasting immunity and improved tolerability upon administration. In the present study, 10 different vaccine candidate designs using two different codon optimizations targeting the VZV glycoprotein E (gE) were generated. A subset of mRNA constructs were formulated into lipid nanoparticles and assessed for their ability to induce specific cellular and humoral immune responses following vaccination in mice. Notably, the selected mRNA vaccine candidates induced high levels of antibodies and robust CD4(+) but also CD8(+) immune responses. Moreover, we showed that our alternate lyophilized vaccine provides comparable immunogenicity to current liquid frozen formulations and is stable under long-term storage conditions. | NPJ vaccines | 14/03/2025 |
('LID', '10.1073/pnas.2418739122') | RGMb drives macrophage infiltration to aggravate kidney disease. | Kong, Yonglun, Yue, Ming, Xu, Chunhua, Zhang, Jing, Hong, Huiling, Lu, Jiahuan, Wang, Yang, Zhang, Xiaoyi, Chen, Qiuju, Yang, Chen, Liu, Hua-Feng, Qin, Jinzhong, Zhou, Jingying, Lee, Nam Y, Lin, Bin, Tian, Xiaoyu, Freeman, Gordon J, Xia, Yin | The importance of macrophages in kidney diseases has been well established; however, the mechanisms underlying the infiltration of macrophages into injured kidneys are not well understood. RGMb is a member of the repulsive guidance molecule (RGM) family. RGMb can be expressed on the cell surface but a large portion of RGMb is localized intracellularly. Among various immune cell types, macrophages express the highest levels of RGMb, but the biological functions of RGMb in macrophages remain largely unknown. We find that RGMb promoted macrophage migration in vitro and that in vivo, RGMb enhanced infiltration of macrophages into injured kidneys and aggravated kidney inflammation and injury in mice. Mechanistically, RGMb bound to TAB1 inside the cell and facilitated the interaction between TRAF6 ubiquitin ligase and TAB1, thereby promoting TRAF6-mediated K63-linked polyubiquitination and phosphorylation of TAK1, followed by increased αTAT1 phosphorylation and α-tubulin acetylation. The resulting changes in the cytoskeleton promoted macrophage migration in vitro and in vivo. Deletion of Rgmb in macrophages markedly reduced TAK1 phosphorylation, αTAT1 phosphorylation, and α-tubulin acetylation and attenuated macrophage infiltration, renal inflammation, tubular injury, and interstitial fibrosis during kidney injury. Our results suggest that macrophage RGMb promotes kidney disease by increasing macrophage infiltration via the TRAF6-TAB1-TAK1/αTAT1/α-tubulin cascade. | Proceedings of the National Academy of Sciences of the United States of America | 18/03/2025 |
('LID', '10.1016/j.clnu.2025.03.001') | Sarcopenic obesity and the risk of atrial fibrillation in non-diabetic older adults: A prospective cohort study. | Yu, Xinyi, Chao, Jincheng, Wang, Xin, Dun, Siyi, Song, Huajing, Guo, Yuqi, Zhang, Hua, Yao, Yanli, Liu, Zhendong, Wang, Juan, Liu, Weike | BACKGROUND: Evidence of an association between sarcopenic obesity (SO) and the risk of long-term atrial fibrillation (AF) is lacking, and the underlying involvement of insulin resistance (IR) and inflammation is not clear. METHODS: This community-based prospective cohort study evaluated sarcopenia, obesity, and baseline clinical characteristics in 4321 non-diabetic older adults between 2007 and 2011. Sarcopenia was identified using skeletal muscle mass/body weight (SMM/BW), appendicular lean mass (ALM)/BW, and handgrip strength (HGS), and obesity was identified by fat mass (FM)/BW. The association of sarcopenia and obesity with AF risk was determined by Kaplan-Meier analysis and a Cox proportional hazards model. Interaction analysis, a restricted cubic splines model, mediation analysis, and a Fine-Gray competing-risk model were also used. RESULTS: Over an average of 10.9 years of follow-up, 546 (11.98 per 1000 person-years) participants developed AF. Low SMM/BW, low ALM/BW, low HGS, high FM/BW, sarcopenia and obesity, were significantly associated with an increased AF risk. There was a significant synergistic relationship between sarcopenia and obesity in the increased AF risk [hazard ratio (HR): 2.029, 95 % confidence interval (CI): 1.639-2.512]. Compared with participants without sarcopenia and obesity, AF risk was the highest in those with SO (HR: 2.669, 95 % CI: 2.110-3.377], followed by sarcopenia alone (HR: 1.980, 95%CI: 1.453-2.699) and obesity (HR: 1.839, 95%CI: 1.475-2.292). Mediation analysis found that estimated glucose disposal rate (a surrogate marker of IR), high-sensitivity C-reactive protein, and galectin-3 were mediating factors in the increased AF risk caused by SO, accounting for 34.87 %, 27.56 %, and 21.05 % of the total effect, respectively. CONCLUSIONS: SO significantly increased AF risk in these non-diabetic older individuals. Sarcopenia and obesity not only acted alone but also exhibit had a synergistic relationship to increase AF risk. IR and inflammation mediated the increased AF risk associated with SO. | Clinical nutrition (Edinburgh, Scotland) | 04/03/2025 |
('LID', '10.1002/path.6417') | Thrombospondin-1 binds to integrin β3 to inhibit vascular calcification through suppression of NF-κB pathway. | Liu, Fang, Liang, Qingchun, Li, Li, Gong, Yuan, Li, Mingxi, Feng, Liyun, Chen, An, Ye, Yuanzhi, Lan, Zirong, Li, Yining, Ou, Jing-Song, Lu, Lihe, Yan, Jianyun | Vascular calcification is an important risk factor related to all-cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP-1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme-linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMC(S) and human arterial rings. Smooth muscle cell-specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein-protein interaction database STRING (http://string-db.org/) analysis and coimmunoprecipitation assays revealed THBS1 bound to integrin β3. Reduction of integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA-seq analysis revealed that THBS1 overexpression modulated the nuclear factor-kappa B (NF-κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF-κB signal was abolished by knockdown of integrin β3. In conclusion, THBS1 interacts with integrin β3 to inhibit vascular calcification through suppression of NF-κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland. | The Journal of pathology | 14/03/2025 |
('LID', '10.1038/s41522-025-00672-3') | Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis. | Dalal, Rajdeep, Sadhu, Srikanth, Batra, Aashima, Goswami, Sandeep, Dandotiya, Jyotsna, K V, Vinayakadas, Yadav, Rahul, Singh, Virendra, Chaturvedi, Kartikey, Kannan, Rahul, Kumar, Shakti, Kumar, Yashwant, Rathore, Deepak Kumar, Salunke, Deepak B, Ahuja, Vineet, Awasthi, Amit | Gut microbiota-derived metabolites play a crucial role in modulating the inflammatory response in inflammatory bowel disease (IBD). In this study, we identify gut microbiota-derived succinate as a driver of inflammation in ulcerative colitis (UC) by activating succinate-responsive, colitogenic helper T (Th) cells that secrete interleukin (IL)-9. We demonstrate that colitis is associated with an increase in succinate-producing gut bacteria and decrease in succinate-metabolizing gut bacteria. Similarly, UC patients exhibit elevated levels of succinate-producing gut bacteria and luminal succinate. Intestinal colonization by succinate-producing gut bacteria or increased succinate availability, exacerbates colonic inflammation by activating colitogenic Th9 cells. In contrast, intestinal colonization by succinate-metabolizing gut bacteria, blocking succinate receptor signaling with an antagonist, or neutralizing IL-9 with an anti-IL-9 antibody alleviates inflammation by reducing colitogenic Th9 cells. Our findings underscore the role of gut microbiota-derived succinate in driving colitogenic Th9 cells and suggesting its potential as a therapeutic target for treating IBD. | NPJ biofilms and microbiomes | 13/03/2025 |
('LID', '10.1186/s13052-025-01910-2') | Association between autoimmune disease and neurodevelopmental disorder: a Mendelian randomization analysis. | Qin, Jiangwei, Zhang, Yunfan, Hu, Ruolan, Lin, Mingying, Yu, Ruixin, Hua, Yimin, Li, Yifei | INTRODUCTION: Neurodevelopmental disorders such as attention deficit and disruptive behaviour disorders (ADHD), autism spectrum disorder (ASD), and schizophrenia have been increasingly prevalent recently. Previous research has demonstrated that inflammatory activity from autoimmune diseases is involved in neurological diseases. However, some studies question the association between inflammatory activities and neurodevelopmental disorders. Herein, we attempt to clarify this relationship using Mendelian randomization (MR) analysis. METHODS: We used systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes mellitus (T1D) to represent autoimmune diseases. First, we conducted MR analysis to examine associated SNPs between autoimmune and neurodevelopmental disorders. Second, we performed bidirectional MR analysis to identify 429 types of signalling peptides and proteins or relevant receptors with causality reported diseases. Finally, we compared the genes with the gene loci identified in the available TWAS-hub site. RESULTS: The MR results of autoimmune diseases on neurodevelopmental disorders did not present any significant association in all models. However, we identified 20-45 factors in ADHD, ASD, and schizophrenia, including semaphorin 3, IL-27 receptor subunit alpha, and fibroblast growth factor 16, which were considered clinically significant pro-inflammatory mediators. GO and KEGG enrichment analyses revealed unequal integrities among the three neurodevelopmental diseases, and we failed to identify a shared pathway linking autoimmune diseases and neurodevelopmental disorders. TWAS analysis indicated that CHRNA5 potentially mediates inflammatory activities in schizophrenia. CONCLUSION: According to our data, we failed to identify an association between autoimmune diseases and neurodevelopmental disorders. However, we demonstrated that some pro-inflammatory factors are involved in neurodevelopmental disorders. | Italian journal of pediatrics | 13/03/2025 |
('LID', '10.1097/HEP.0000000000001304') | CAD manipulates tumor intrinsic DHO/UBE4B/NF-κB pathway and fuels macrophage cross-talk, promoting hepatocellular carcinoma metastasis. | Pan, Jiaomeng, Zhang, Mao, Rao, Dongning, Ma, Junjie, Shen, Xia, Qin, Haokai, Gan, Kun, Lin, Jian, Huang, Yingying, Sang, Chen, Zhang, Juan, Ma, Jiaqiang, Wu, Yingcheng, Tang, Zheng, Gao, Daming, Gao, Qiang, Yang, Liuxiao, Fan, Jia | BACKGROUND AND AIMS: Portal vein tumor thrombosis (PVTT), an indicator of clinical metastasis, significantly shortens hepatocellular carcinoma (HCC) patients' lifespan, and no effective treatment has been established. We aimed to illustrate mechanisms underlying PVTT formation and tumor metastasis, and identified potential targets for clinical intervention. APPROACH AND RESULTS: Multi-omics data of 159 HCC patients (including 37 cases with PVTT) was analyzed to identify contributors to PVTT formation and tumor metastasis. In vitro and in vivo experiments were performed to confirm the critical role of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) in HCC metastasis. Metabolomics and transcriptomics techniques, single-cell RNA sequencing, combined with experimental verification were complemented to illustrate mechanisms underlying CAD induced pro-metastatic efficacy. Analysis of proteogenomic data of HCC cohort identified CAD as the key contributor to PVTT formation and tumor metastasis in HCC. Further experiments confirmed that high CAD expression could significantly promote HCC metastasis, and vice versa. Mechanistically, CAD manipulated de novo pyrimidine anabolism, leading to dihydroorotic acid (DHO) accumulation which directly bound to ubiquitination factor E4B (UBE4B). UBE4B subsequently regulated JAK1 ubiquitination and activated the NF-κB pathway to promote epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, CAD generated an immunosuppressive milieu conducive to HCC metastasis by recruiting and reprogramming macrophages into a "pro-tumor" phenotype. Consequently, the metastatic capability of HCC was remarkably enhanced. CONCLUSION: Therapy targeting CAD may offer a promising approach to curb HCC metastasis by reducing tumor cells' metastatic potential and also shifting the tumor microenvironment towards a less pro-metastatic state. | Hepatology (Baltimore, Md.) | 12/03/2025 |
('LID', '10.1182/blood.2024027516') | Therapeutic switch from plasma to recombinant ADAMTS13 for patients with congenital TTP from Japanese real-world data. | Sakai, Kazuya, Hamamura, Atsushi, Yoshimura, Yoshiko, Abe, Miyuki, Ogawa, Yoshiyuki, Tanaka, Kazuki, Hattori, Norimichi, Tokugawa, Tazuko, Kanai, Rie, Ikejiri, Fumiyoshi, Takeyama, Masahiro, Taoka, Teruhisa, Fujita, Naoki, Kanaya, Minoru, Koh, Katsuyoshi, Shiragami, Hiroshi, Azumi, Hidekazu, Saito, Kenki, Matsumoto, Masanori | Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage caused by pathogenic ADAMTS13 variants. ADAMTS13 containing product including fresh frozen plasma (FFP) and plasma-derived Factor VIII concentrates are commonly used to supply ADAMTS13; however, frequent hospital visits and allergic reactions are major drawbacks. A recombinant ADAMTS13 (rADAMTS13) was recently developed to address these issues. However, real-world evidence has not been reported owing to the rarity of this condition. This study compared the efficacy and safety of FFP and rADAMTS13 in 14 Japanese patients, including five patients with end-stage renal disease who were excluded from the phase III trial. The median peak level of ADAMTS13 activity 15 min after rADAMTS13 administration was significantly higher than that after FFP (68.4% vs. 15.9%, p<0.001). ADAMTS13 activity 1 week after rADAMTS13 administration was well maintained compared with FFP infusion (11.6% vs. 5.1%, p<0.001). Patients reported no allergic reactions after rADAMTS13 administration and appreciated the convenience of a single infusion of rADAMTS13, suggesting that rADAMTS13 is a safe and effective alternative to FFP in patients with cTTP. This is the first publication of patients with cTTP who switched FFP to novel rADAMTS13 from Japanese real-world-data. | Blood | 16/03/2025 |
('LID', '10.1002/14651858.CD006027.pub3') | Nonsteroidal anti-inflammatory drugs (NSAIDs) for acute renal colic. | Afshar, Kourosh, Gill, Jagdeep, Mostafa, Hanan, Noparast, Maryam | BACKGROUND: Urolithiasis (urinary stones) is a common disease with an increasing incidence globally. It often presents with renal colic, which is characterised by acute and intense abdominal pain. The first step in the management of renal colic is pain control. Various medications, including narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), antispasmodics, and others, have been used for this condition. NSAIDs are amongst the most commonly used drugs for renal colic. They act by reducing inflammation and lowering the pressure inside the urinary collecting system. This review updates a previous Cochrane Systematic Review (Afshar 2015), focusing exclusively on NSAIDs. OBJECTIVES: To assess the benefits and harms of different nonsteroidal anti-inflammatory drugs (NSAIDs) for the management of pain in adults with acute renal colic. SEARCH METHODS: We performed a comprehensive search of the Cochrane Library, MEDLINE, Embase, Google Scholar, trial registries, and conference proceedings up to 25 August 2023. We applied no restrictions on publication language or status. SELECTION CRITERIA: We included randomised (or quasi-randomised) controlled trials (RCTs) assessing the effects of NSAIDs in the management of renal colic adult patients (i.e. study participants over 16 years of age). We included studies that compared NSAIDs versus placebo, one NSAID versus another, or different doses or routes of administration of the same NSAID. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data from the included studies. Primary outcomes included pain up to one hour after treatment as measured by a validated patient-reported tool, the need for rescue medication up to six hours after treatment, and serious adverse events up to one week after treatment. Secondary outcomes included pain recurrence, significant pain relief, and minor adverse events. We performed meta-analysis using the random-effects model. We rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: Our search identified 29 RCTs for inclusion in the review. The 29 studies involved a total of 3593 participants who were randomly allocated to treatment with an NSAID or placebo. The mean age of participants ranged from 27 to 47 years across the studies. Participants used a 10 cm visual analogue scale (VAS) to indicate the extent of their pain. NSAIDs versus placebo NSAIDs may reduce renal colic pain in 30 minutes compared to placebo (mean difference (MD) -3.84 cm, 95% confidence interval (CI) -6.41 to -1.27; I(2) = 95%; 3 studies, 250 participants; low-certainty evidence). The evidence is very uncertain about the effect of NSAIDs on the need for rescue medication (risk ratio (RR) 0.24, 95% CI 0.11 to 0.53; I(2) = 73%; 4 studies, 280 participants; very low-certainty evidence). NSAID versus NSAID Piroxicam may result in little to no difference in renal colic pain at 30 minutes compared to diclofenac (MD 0.01 cm, 95% CI -1.50 to 1.52; I² = 78%; 2 studies, 144 participants; low-certainty evidence). Parecoxib likely results in little to no difference in renal colic pain at 30 minutes compared to ketoprofen (MD 0.03 cm, 95% CI -0.59 to 0.65; 1 study, 337 participants; moderate-certainty evidence). Lornoxicam likely results in little to no difference in renal colic pain at 30 minutes compared to other NSAIDs (MD -0.22 cm, 95% CI -0.69 to 0.24; I² = 12%; 2 studies, 170 participants; moderate-certainty evidence). Ketorolac may result in little to no difference in renal colic pain at 60 minutes (MD 0.23 cm, 95% CI -1.16 to 1.62, 1 study, 57 participants; low-certainty evidence) and need for rescue medication within 120 minutes (RR 1.76, 95% CI 0.73 to 4.24; I² = 0%; 2 studies, 114 participants; low-certainty evidence) compared to diclofenac. Intravenous (IV) ketorolac may result in little to no difference in renal colic pain at 30 minutes compared to IV ibuprofen (MD 1.36 cm, 95% CI 0.85 to 1.87; I² = 84%; 2 studies, 361 participants; low-certainty evidence). IV ketorolac may result in less chance of significant pain relief within 30 minutes compared to IV ibuprofen (RR 0.17, 95 CI 0.04 to 0.73; 1 study, 240 participants; low-certainty evidence). Ketoprofen likely results in little to no difference in renal colic pain at 30 minutes compared to diclofenac (MD -0.43 cm, 95% CI -1.18 to 0.32; 1 study, 80 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of ketoprofen on significant pain relief within 40 minutes compared to diclofenac (RR 1.38, 95% CI 1.08 to 1.78; 1 study, 80 participants; very low-certainty evidence). Indomethacin likely results in little to no difference in renal colic pain at 30 minutes compared to diclofenac (MD 0.20 cm, 95% CI -0.90 to 1.30; 1 study, 83 participants; moderate-certainty evidence). Pirprofen may result in a large reduction in the need for rescue medication within 30 minutes compared to indomethacin (RR 0.58, 95% CI 0.41 to 0.82; 1 study, 205 participants; low-certainty evidence). Intravenous NSAIDs likely result in little to no difference in renal colic pain at 30 minutes compared to intramuscular NSAIDs (MD -0.34 cm, 95% CI -1.19 to 0.51; I(2) = 42%; 2 studies, 134 participants; moderate-certainty evidence). Intravenous NSAIDs may reduce the need for rescue medication within 30 minutes compared to rectal NSAIDs (RR 0.35, 95% CI 0.14 to 0.88; 1 study, 116 participants; low-certainty evidence). The evidence is uncertain regarding the potential harms of NSAIDs. Risk of bias We judged the risk of bias in the studies to be moderate to high. This was due to a high proportion of unknown risk judgments for concealment bias and a high risk of selective reporting bias. AUTHORS' CONCLUSIONS: NSAIDs may reduce pain in adult patients with renal colic compared to placebo. Comparing one NSAID against another, IV ketorolac may be less effective than IV ibuprofen, and pirprofen may result in less need for rescue medication than indomethacin. The intravenous route of administration is probably similar to the intramuscular route but may be better than the rectal route. The evidence is uncertain regarding the potential harms of NSAIDs. We were not able to perform subgroup analysis based on our predefined criteria because there were no eligible studies. | The Cochrane database of systematic reviews | 14/03/2025 |
('LID', '10.1016/j.phymed.2025.156628') | Effective-compounds of Jinshui Huanxian Formula acts as an SRC inhibitor to inhibit HK2-mediated H3K18 lactation and improve pulmonary fibrosis. | Zheng, Jiaping, Du, Yan, Shao, Wenbo, Li, Jiansheng, Zhao, Peng, Zhang, Qin | BACKGROUND: The Active Ingredient Composition of Jinshui Huanxian Formula (ECC-JHF) consists of five active ingredients: icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, which demonstrate notable therapeutic effects on pulmonary fibrosis. PURPOSE: Inhibition of glycolysis has been demonstrated to be effective in treating experimental idiopathic pulmonary fibrosis (IPF). This research seeks to explore the impact of aerobic glycolysis on the mitigation of pulmonary fibrosis through ECC-JHF. METHODS: A pulmonary fibrosis mouse model was generated through the administration of bleomycin (Bleomycin). The degree of pulmonary fibrosis was analyzed through hematoxylin and eosin (H&E) staining as well as Masson's trichrome staining. Western Blot (WB), Immunofluorescence (IF), and real-time quantitative PCR (Q-PCR) assay for fibroblast activation markers and glycolysis-related genes in lung tissues. The Lactic Acid (LA) Content Assay Kit was employed to quantify lactate concentrations in lung tissues and fibroblast cultures. Immunoprecipitation (IP) was applied to detect lactylated modified protein levels, and mass spectrometry (MS) was used to analyze lactate substrate profiles in fibroblasts. WB was employed to detect the lactate modification level of histone H3K18 (H3K18la). The targets of ECC-JHF were analyzed using network pharmacology, while molecular docking and cellular enthusiasm transfer analysis (CETSA) examined the binding of ECC-JHF to SRC. The influence of ECC-JHF on SRC activation was assessed using WB. SRC small interfering RNA (siSRC) was designed and transfected into L929 cells to validate the function of SRC in the inhibition of fibroblast activation by ECC-JHF. RESULTS: In BLM-induced pulmonary fibrosis mice, ECC-JHF significantly reduced alveolar inflammation and collagen deposition. In lung tissues and fibroblasts, ECC-JHF notably inhibited the expression of HK2, lactate levels, and lactylated modifying proteins. IP-MS and WB analyses showed that ECC-JHF significantly reduced H3K18la levels. Network pharmacology analysis, molecular docking and CETSA results indicated that SRC serves as a key target for ECC-JHF. siSRC effectively mitigated the impact of ECC-JHF on the expression of HK2, levels of H3K18la, and the activation of fibroblasts. CONCLUSION: ECC-JHF may improve pulmonary fibrosis by inhibiting SRC activation, blocking HK2-mediated lactate production, down-regulating H3K18la levels, and inhibiting fibroblast activation. Our results serve as a significant reference for the advancement of ECC-JHF and the exploration of IPF. | Phytomedicine : international journal of phytotherapy and phytopharmacology | 08/03/2025 |
('LID', '10.1038/s41419-025-07504-4') | CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis. | Wang, Zhijie, Wu, Haicong, Chang, Xin, Song, Yihang, Chen, Yan, Yan, Ziwei, Gu, Lun, Pang, Ruxi, Xia, Tian, He, Zixuan, Li, Zhaoshen, Wang, Shuling, Bai, Yu | Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial reactive oxygen species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD). | Cell death & disease | 15/03/2025 |
('LID', '10.1186/s12872-025-04510-4') | Hemorrhage risk associated with triple antithrombotic therapy: a focused real-world pharmacovigilance disproportional analysis study. | Sridharan, Kannan, Sivaramakrishnan, Gowri | BACKGROUND: Triple antithrombotic therapy (TAT), combining dual antiplatelet therapy (DAPT) with oral anticoagulants, is commonly used in patients requiring long-term anticoagulation following acute coronary syndrome or percutaneous coronary intervention. However, TAT may increase the risk of hemorrhage. There is a dearth of data regarding the risks of bleeding with various oral anticoagulants in TAT in comparison with DAPT and individual anticoagulants and antiplatelets due to which we carried out the present study examining the real-world pharmacovigilance data. METHODS: Data were extracted from the USFDA Adverse Event Reporting System (AERS) from March 2004 to June 2024 using the Standardized MedDRA Query (SMQ) code for "haemorrhages." We employed the "case-non-case" approach in disproportionality analysis to detect safety signals for hemorrhage among anticoagulant, antiplatelet, dual antiplatelet and triple antithrombotic combinations. Reports including combinations of DAPT (acetylsalicylic acid and clopidogrel) with oral anticoagulants (acenocoumarol, apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin) were analyzed. Signal detection used both frequentist (reporting odds ratio [ROR], proportional reporting ratio and Bayesian (Bayesian Confidence Propagation Neural Network, Multi-Item Gamma Poisson Shrinker algorithms. The lower limit of 95% confidence interval of ROR above 1 indicates higher reporting risk of bleeding. Following outcomes were evaluated for each TAT: death, disability and hospitalization. RESULTS: Of 20,626 unique reports, 812 involved TAT, 3,820 DAPT, and 15,995 individual antiplatelets. Most cases occurred in elderly patients (age ≥ 65 years) with a predominance of male patients. Rivaroxaban combined with DAPT presented the highest hemorrhage signal (ROR: 82.84; 95% CI, 60.77-112.92), while apixaban showed the lowest (ROR: 13.11; 95% CI, 9.39-18.3) and the other anticoagulants are as follows: warfarin (ROR: 15.96; 95% CI: 18.36), dabigatran (ROR: 27.32; 95% CI: 20.03-37.26) and acenocoumarol (ROR: 43.98; 95% CI: 17.21-112.4). Mortality and hospitalization rates varied significantly among treatments, with rivaroxaban linked to the highest mortality. CONCLUSION: This study highlights the elevated hemorrhage risk associated with TAT, particularly with rivaroxaban, while apixaban appears safer in terms of bleeding and mortality. These findings underscore the need for cautious monitoring of bleeding outcomes with anticoagulant regimens, particularly rivaroxaban combinations for optimizing patient outcomes. However, the signals obtained in this study need to be validated in future trials. | BMC cardiovascular disorders | 14/03/2025 |
('LID', '10.1111/all.16526') | The Omics Landscape of Long COVID-A Comprehensive Systematic Review to Advance Biomarker, Target and Drug Discovery. | Baalbaki, Nadia, Slob, Elise M A, Kazer, Samuel W, I Abdel-Aziz, Mahmoud, Bogaard, Harm Jan, Golebski, Korneliusz, Maitland-van der Zee, Anke H | An estimated 10% of coronavirus disease (COVID-19) survivors suffer from persisting symptoms referred to as long COVID (LC), a condition for which approved treatment options are still lacking. This systematic review (PROSPERO: CRD42024499281) aimed to explore the pathophysiological mechanisms underlying LC and potential treatable traits across symptom-based phenotypes. We included studies with primary data, written in English, focusing on omics analyses of human samples from LC patients with persistent symptoms of at least 3 months. Our search in PubMed and Embase, conducted on January 8, 2024, identified 642 studies, of which 29 met the inclusion criteria after full-text assessment. The risk of bias was evaluated using the Joanna Briggs Institute appraisal tool. The synthesis of omics data, including genomics, transcriptomics, proteomics, metabolomics, and metagenomics, revealed common findings associated with fatigue, cardiovascular, pulmonary, neurological, and gastrointestinal phenotypes. Key findings included mitochondrial dysfunction, dysregulated microRNAs associated with pulmonary dysfunction, tissue impairment, blood-brain barrier disruption, coagulopathy, vascular dysfunction, microbiome disturbances, microbial-derived metabolite production and persistent inflammation. Limitations include cross-study heterogeneity and variability in sampling methods. Our review emphasizes the complexity of LC and the need for further longitudinal omics-integrated studies to advance the development of biomarkers and targeted treatments. | Allergy | 14/03/2025 |
('LID', '10.1016/j.genhosppsych.2025.03.005') | Associations of exercise snacks with cognitive function among older adults in NHANES 2011-2014. | Wu, Junyu, Wang, Yufei, Qiu, Peng, Li, Youqiang | BACKGROUND: With an aging global population, dementia incidence is rapidly increasing, affecting 50 million people worldwide. While physical activity has been linked to cognitive enhancement, the specific effects of intermittent short bouts of exercise, termed 'exercise snacks' (ES), on cognitive function (CF) in older adults are not well understood. METHODS: We analyzed data from 2549 adults aged ≥60 years from the 2011-2014 National Health and Nutrition Examination Survey cycles. CF was assessed using standardized tests, and physical activity data were obtained from accelerometer measurements. ES was defined as 2-5 min of moderate-to-vigorous physical activity. Regression analyses, smoothed curve fitting, and threshold effect analyses were conducted, adjusting for relevant covariates. RESULTS: Significant positive associations were found between CF and daily average Monitor-Independent Movement Summary specific to ES (MIMS-ES: β = 0.0001, 95 % CI: 0.0001-0.0001) and total time spent on ES (Time-ES: β = 0.0021, 95 % CI: 0.0014-0.0029). Each additional unit of MIMS-ES and each minute of ES daily increased CF scores by 0.0001 and 0.0021 points, respectively, suggesting benefits for cognitive health in aging populations. An inverted U-shaped relationship was observed, with inflection points at 2522.82 units/day for MIMS-ES and 91.57 min/day for Time-ES, indicating diminishing cognitive benefits beyond these thresholds. CONCLUSION: ES was associated with higher CF. This practical form of physical activity offers an effective strategy for cognitive health and mitigating age-related decline, presenting a more accessible alternative to traditional continuous exercise. | General hospital psychiatry | 13/03/2025 |
('LID', '10.1016/j.neuron.2025.02.005') | PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD. | Zhang, Zhe, Fu, Xiujuan, Wright, Noelle, Wang, Weiren, Ye, Yingzhi, Asbury, Julie, Li, Yini, Zhu, Chengzhang, Wu, Rong, Wang, Shaopeng, Sun, Shuying | The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the repeat expansion in C9ORF72. Dipeptide repeat (DPR) proteins translated from both sense and antisense repeats, especially arginine-rich DPRs (R-DPRs), contribute to neurodegeneration. Through CRISPR interference (CRISPRi) screening in human-derived neurons, we identified receptor-type tyrosine-protein phosphatase S (PTPσ) as a strong modifier of poly-GR-mediated toxicity. We showed that reducing PTPσ promotes the survival of both poly-GR- and poly-PR-expressing neurons by elevating phosphatidylinositol 3-phosphate (PI3P), accompanied by restored early endosomes and lysosomes. Remarkably, PTPσ knockdown or inhibition substantially rescues the PI3P-endolysosomal defects and improves the survival of C9ORF72-ALS/FTD patient-derived neurons. Furthermore, the PTPσ inhibitor diminishes GR toxicity and rescues pathological and behavioral phenotypes in mice. Overall, these findings emphasize the critical role of PI3P-mediated endolysosomal deficits induced by R-DPRs in disease pathogenesis and reveal the therapeutic potential of targeting PTPσ in C9ORF72-ALS/FTD. | Neuron | 10/03/2025 |
('LID', '10.1016/j.jecp.2018.08.014') | Infants' sensitivity to nonadjacent vowel dependencies: The case of vowel harmony in Hungarian. | Gonzalez-Gomez, Nayeli, Schmandt, Silvana, Fazekas, Judit, Nazzi, Thierry, Gervain, Judit | Vowel harmony is a linguistic phenomenon whereby vowels within a word share one or several of their phonological features, constituting a nonadjacent, and thus challenging, dependency to learn. It can be found in a large number of agglutinating languages, such as Hungarian and Turkish, and it may apply both at the lexical level (i.e., within word stems) and at the morphological level (i.e., between stems and their affixes). Thus, it might affect both lexical and morphological development in infants whose native language has vowel harmony. The current study asked at what age infants learning an irregular harmonic language, Hungarian, become sensitive to vowel harmony within word stems. In a head-turn preference study, 13-month-old, but not 10-month-old, Hungarian-learning infants preferred listening to nonharmonic VCV (vowel-consonant-vowel) pseudowords over vowel-harmonic ones. A control experiment with 13-month-olds exposed to French, a nonharmonic language, showed no listening preference for either of the sequences, suggesting that this finding cannot be explained by a universal preference for nonharmonic sequences but rather reflects language-specific knowledge emerging between 10 and 13 months of age. We discuss the implications of this finding for morphological and lexical learning. | Journal of experimental child psychology | 00/02/2019 |
('AID', '10.1021/ja0320018') | Asymmetric total synthesis of dendrobatid alkaloids: preparation of indolizidine 251F and its 3-desmethyl analogue using an intramolecular Schmidt reaction strategy. | Wrobleski, Aaron, Sahasrabudhe, Kiran, Aubé, Jeffrey | Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F. | Journal of the American Chemical Society | 05/05/2004 |
('AID', '10.1016/s0277-9536(99)00171-9') | Different tuberculosis in men and women: beliefs from focus groups in Vietnam. | Long, N H, Johansson, E, Diwan, V K, Winkvist, A | After decades in decline, tuberculosis (TB) has been increasing worldwide. In 1993, the World Health Organisation declared TB a global emergency. Passive case-finding is an important part of TB control programmes, and this is strongly affected by people's perceptions and beliefs of TB and society's behaviour towards TB sufferers. The aim of this study was to describe the perceptions and beliefs of Vietnamese people regarding TB and its risk factors with special reference to differences between men and women. Sixteen focus group discussions (FGDs) were organised in four districts representing different regions in Vietnam and consisting of men and women, TB patients and non-TB participants. In general, participants had good knowledge of TB being a dangerous, contagious and infectious disease, caused by germs. However, traditional beliefs in different types of TB still exist, mainly among older people in rural areas, but also resorted to by other people once ill. Four main types of TB were reported: (1) 'Lao truyen' (hereditary TB), handed down from older generations to latter ones through 'family blood', regardless of sexes; (2) 'Lao luc' (physical TB), caused by hard work, more men affected; (3) 'Lao tam' (mental TB), caused by too much worrying-more women affected; and (4) 'Lao phoi' (lung TB), dangerous and caused by TB germs, transmitted through the respiratory system-more men affected. Other general risk factors were also mentioned. Men were perceived to get TB more often than women, as they were more exposed to risk factors during both work and leisure time. These traditional beliefs may contribute to long delays to TB diagnosis and increased social stigma and isolation of TB patients and their families due to erroneous beliefs in transmission routes. Our findings demonstrate areas where TB control programmes may be improved. | Social science & medicine (1982) | 00/09/1999 |
('AID', '10.1016/s0964339702000654') | A description of patients' report of endotracheal tube discomfort. | Grap, Mary Jo, Blecha, Tracy, Munro, Cindy | The purpose of this descriptive study was to describe the type, location, and amount of endotracheal tube (ETT) discomfort. Twenty-two subjects (mean age 49.2 years) who had experienced ETT intubation for at least 6 hours (mean: 25.9 hours) after cardiac surgery, completed a 100-mm Visual Analogue Scale related to their experience with the endotracheal tube within 24 hours after extubation. A semi-structured interview was also conducted. There was no relationship between the duration of intubation and the level of discomfort described (r = -0.24; P = 0.29) or between the duration of intubation and whether medications relieved the discomfort (r = 0.34; P = 17). All subjects described some level of discomfort. The majority stated the discomfort was in the throat area. However, 27% (n = 6) described the discomfort as located in the chest. There was no difference in the level of discomfort based on discomfort location (f = -0.14; P = 0.71). The discomfort locations support the notion that ETT irritation occurs at multiple levels (i.e. pharyngeal, laryngeal, and tracheal mucosal areas). In addition, interventions that focus on ETT stability will not be sufficient to reduce discomfort but must re-focus nursing attention on reducing ETT movement as well as the movement of all ventilator tubing. | Intensive & critical care nursing | 00/08/2002 |
('LID', '10.1016/S0140-6736(25)00405-2') | Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study. | Jogiraju, Vamshi, Pawar, Pallavi, Yager, Jenna, Ling, John, Shen, Gong, Chiu, Anna, Hughes, Emma, Palaparthy, Ramesh, Carter, Christoph, Singh, Renu | BACKGROUND: Long-acting antiretrovirals can address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and adherence. In two phase 3 trials, twice-yearly subcutaneous lenacapavir was safe and highly efficacious for PrEP in diverse populations. Furthering long-acting PrEP efforts, this study assessed the pharmacokinetics and safety of two once-yearly intramuscular lenacapavir formulations. METHODS: This phase 1, open-label study in participants aged 18-55 years without HIV evaluated the pharmacokinetics, safety, and tolerability of two lenacapavir free acid formulations administered by ventrogluteal intramuscular injection as a single 5000 mg dose (formulation 1 with 5% w/w ethanol, formulation 2 with 10% w/w ethanol). Pharmacokinetic samples were collected at prespecified timepoints up to 56 weeks. Lenacapavir plasma concentrations were measured with a validated liquid chromatography-tandem mass spectrometry method and summarised with non-compartmental analysis. Pharmacokinetic parameters evaluated included the area under the concentration-time curve for the once-yearly dosing interval calculated from days 1 to 365 (AUC(days 1-365)), peak plasma concentration, time to reach peak plasma concentration, and trough concentration (C(trough)). Plasma concentration data from phase 3 studies of twice-yearly subcutaneous lenacapavir (PURPOSE 1 and PURPOSE 2) were pooled for comparison with once-yearly intramuscular lenacapavir formulations. Safety and tolerability, including participant-reported pain scores, were assessed. FINDINGS: 20 participants received lenacapavir formulation 1 and 20 received lenacapavir formulation 2. For estimation of pharmacokinetic parameters, sample size varied over time with at least 13 participants (formulation 1) and at least 19 participants (formulation 2) due to early discontinuations for reasons unrelated to the study drug. Following administration of intramuscular lenacapavir, concentrations increased rapidly, and median time to maximum concentration was 84·1 days (IQR 56·1-112·0) for formulation 1 and 69·9 days (55·3-105·5) for formulation 2. The highest median concentration of once-yearly intramuscular lenacapavir (247·0 ng/mL [IQR 184·0-346·0] for formulation 1, 336·0 ng/mL [233·5-474·3] for formulation 2) remained above the highest median twice-yearly subcutaneous lenacapavir concentration (67·3 ng/mL [46·8-91·4]). Median C(trough) at the end of 52 weeks for formulation 1 was 57·0 ng/mL (IQR 49·9-72·4) and for formulation 2 was 65·6 ng/mL (41·8-87·1), exceeding the median twice-yearly subcutaneous lenacapavir C(trough) of 23·4 ng/mL (15·7-34·3) at the end of 26 weeks. Median AUC(days 1-365) for formulation 1 was 1011·1 h*μg/mL (IQR 881·0-1490·2) and for formulation 2 was 1274·0 h*μg/mL (1177·3-1704·8). Adverse events were mostly grade 1 or 2. The most common was injection-site pain (16 [80%] participants given formulation 1, 15 [75%] given formulation 2), which was generally mild, resolved within 1 week, and was substantially reduced by pretreatment with ice. INTERPRETATION: Following administration of once-yearly intramuscular lenacapavir, median plasma concentrations exceeded those associated with efficacy in phase 3 studies of twice-yearly subcutaneous lenacapavir for PrEP for at least 56 weeks. Both formulations were safe and well tolerated. These data show the potential for biomedical HIV prevention with a once-yearly dosing interval. FUNDING: Gilead Sciences. | Lancet (London, England) | 10/03/2025 |
('LID', '10.1186/s13643-025-02792-5') | Summarizing attributable factors and evaluating risk of bias of Mendelian randomization studies for Alzheimer's dementia and cognitive status: a systematic review and meta-analysis. | Meng, Xiaoni, Li, Xiaochun, Cao, Meiling, Dong, Jing, Wang, Haotian, Cao, Weijie, Liu, Di, Wang, Youxin | BACKGROUND: No effective treatment is available to delay or reverse the onset and progression of Alzheimer's dementia (AD). Mild cognitive impairment, a clinical state between normal aging and AD, may offer the proper window for AD intervention and treatment. This systematic review aimed to summarize evidence from Mendelian randomization (MR) studies exploring factors attributable to AD and related cognitive status and to assess its credibility. METHODS: We searched PubMed, Embase, MEDLINE, and the Cochrane Library to identify MR studies investigating the associations between any factor and AD and related cognitive status. The risk of bias in MR studies was evaluated using nine signaling questions tailored to identify potential biases based on the STROBE-MR guidelines. RESULTS: A total of 125 eligible publications were examined, including 106 AD-related MR studies reporting 674 records and 28 cognition-related MR studies reporting 141 records. We identified 185 unique causal risk factors for AD and 49 for cognitive status. More than half of the MR studies reporting AD or cognitive status outcomes exhibited poor methodological quality, with a high risk of bias observed in 59% of the AD-related studies and 64% of the cognitive-related studies. CONCLUSIONS: This systematic review summarized modifiable factors and omics signatures, providing a database of MR studies on AD and related cognitive status. The evaluation of bias risk in MR studies serves to raise awareness and improve overall quality. A critical appraisal checklist for assessing the risk of bias may pave the way for the development of a standardized tool. SYSTEMATIC REVIEW REGISTRATION: The review protocol was registered with the Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42023213990. | Systematic reviews | 13/03/2025 |
('LID', '10.1038/s41467-025-57936-x') | A TaSnRK1α-TaCAT2 model mediates resistance to Fusarium crown rot by scavenging ROS in common wheat. | Yang, Xia, Zhang, Leilei, Wei, Jiajie, Liu, Lexin, Liu, Di, Yan, Xiangning, Yuan, Minjie, Zhang, Lingran, Zhang, Ning, Ren, Yan, Chen, Feng | Fusarium crown rot (FCR) is a serious underlying disease to threaten wheat yield and quality recently. Here, we identify a catalase antioxidant enzyme (TaCAT2) through genome wide association study (GWAS) and whole-exome sequencing (WES) in two nested bi-parental populations. We verify the function of TaCAT2 regulating wheat FCR resistance by genetic transformation. Moreover, we screen a sucrose non-fermenting-1-related protein kinase alpha subunit (TaSnRK1α) interacting with TaCAT2, and subsequently find that TaSnRK1α phosphorylates TaCAT2. We next identify an FCR-resistance haplotype TaCAT2(Ser214), and confirm that Ser214 of TaCAT2 is a key phosphorylation site for TaSnRK1α. We also find that TaSnRK1α results in higher protein accumulation in TaCAT2(Ser214) than in TaCAT2(Thr214), which possibly contribute to scavenging ROS (reactive oxygen species) in TaCAT2(Ser214) wheat plants. Furthermore, the function of TaSnRK1α regulating FCR resistance is verified by genetic transformation. Taken together, we propose a TaSnRK1α-TaCAT2 model to mediate FCR resistance by scavenging the ROS in wheat plants. | Nature communications | 15/03/2025 |
('LID', '10.1016/j.ecoenv.2025.118029') | A network toxicology and machine learning approach to investigate the mechanism of kidney injury from melamine and cyanuric acid co-exposure. | Wang, Zhan, Zhou, Zhaokai, Zhao, Zihao, Zhang, Junjie, Zhang, Shengli, Li, Luping, Fan, Yingzhong, Li, Qi | BACKGROUND: Within the past two decades, high-profile cases of melamine (MA) exposure have raised significant toxicological concerns, particularly regarding food adulteration. While widely used as a fundamental organic chemical intermediate in various household products, MA's potential for unexpected toxicological synergy with its homolog, cyanuric acid (CA), remains a concern. This study aimed to investigate the nephrotoxicity of combined melamine and cyanuric acid (MC) exposure and its underlying mechanisms in rats through an integrative approach, combining network toxicology (NT), bioinformatics, and experimental validation. MATERIALS AND METHODS: Rats were exposed to MC at doses of 0/0 mg/kg/day (Control) and 63/63 mg/kg/day (MC) for four weeks. Kidney pathology, injury markers, and RNA sequencing (RNA-seq) data were analyzed to identify differentially expressed genes between the two groups. Bioinformatics analysis, including pathway enrichment and immune microenvironment analysis, was conducted to elucidate the underlying mechanisms of MC-induced kidney injury. Potential target proteins were identified using ChEMBL, STITCH, and GeneCards databases, and hub genes were screened using three machine learning algorithms: LASSO regression, Random Forest, and Molecular Complex Detection. Molecular docking simulations were performed to assess the interactions between MC and the identified hub genes. RESULTS: MC exposure resulted in severe kidney morphological and histological changes, as well as elevated levels of kidney injury and fibrosis markers. RNA-seq analysis revealed significant enrichment of immuno-inflammatory and apoptosis-related pathways in the MC group. Immune microenvironment analysis confirmed the infiltration of pro-inflammatory immune cells. Network toxicology analysis identified 20 potential targets associated with MC-induced kidney injury. Two hub genes, Ren and Casp3, were identified as key regulators of the renin-angiotensin-aldosterone system (RAAS) activation and apoptosis, respectively. Further experimental validation, including Western blotting and immunofluorescence, confirmed the upregulation of these proteins. Molecular docking simulations demonstrated strong binding affinities between MC and the two hub proteins. CONCLUSION: MC exposure induces significant kidney injury and fibrosis. The activation of the RAAS pathway and apoptosis plays a crucial role in MC-mediated nephrotoxicity. However, additional vivo experimental validation is lacking. Future studies should focus on further exploration for the mechanism of MC-induced nephrotoxicity and more rigorous experimental validation. | Ecotoxicology and environmental safety | 14/03/2025 |
('LID', '10.1016/j.numecd.2025.103907') | Associations between iron status and diabetic kidney disease: A nationwide study. | Gong, Liya, Mai, Yanpei, Wu, Ziqi, Luo, Jingwen, Wen, Ge | BACKGROUND AND AIM: Iron status plays a crucial role in various physiological processes, and its dysregulation is associated with numerous health conditions. However, research on the relationship between iron status and diabetic kidney disease (DKD) is quite limited. Therefore, this study aims to investigate the connection between iron status and DKD. METHODS AND RESULTS: This population-based cross-sectional survey included adult diabetes patients from five National Health and Nutrition Examination Survey (NHANES) cycles spanning 1999 to 2006 and 2017 to 2018. Regression models were used to assess the impact of iron status on the prevalence of diabetic nephropathy. Restricted cubic spline models further explored potential nonlinear dose-response relationships. Subgroup analyses clarified the effects of other covariates on these associations. Iron and TIBC were negatively correlated with DKD, albuminuria, and low estimated glomerular filtration rate (eGFR). TSAT was negatively correlated with DKD and showed an "L"-shaped nonlinear correlation with albuminuria and low-eGFR. Ferritin exhibited a "J"-shaped nonlinear correlation with DKD, albuminuria, and low-eGFR. Subgroup analysis revealed that the association between TIBC and reduced risk of low eGFR was more pronounced in individuals with hypertension. The associations between iron and TSAT with a reduced risk of DKD were more significant in smokers, while the association between ferritin and an increased risk of albuminuria was also more pronounced in smokers. CONCLUSIONS: In diabetic patients, iron status is closely associated with DKD. Monitoring these iron status markers can help improve the prevention and management of kidney health in diabetic patients. | Nutrition, metabolism, and cardiovascular diseases : NMCD | 07/02/2025 |
('LID', '10.1186/s12882-025-04028-z') | The global, regional, and national patterns of change in the burden of chronic kidney disease from 1990 to 2021. | Guo, Jiaowei, Jiao, Wenyue, Xia, Shujun, Xiang, Xiadan, Zhang, Yuan, Ge, Xiao, Sun, Qice | BACKGROUND: Chronic kidney disease (CKD) is a major global public health problem with increasing prevalence and a huge health and economic burden. Diabetes mellitus and hypertension are major risk factors for CKD, and CKD is associated with cardiovascular disease and end-stage renal disease. Understanding the prevalence and burden of CKD is essential for the development of prevention and control strategies. METHODS: Using data from the Global Burden of Disease Study (GBD) 2021 study, this study analyzed the incidence, prevalence, and disability-adjusted life years (DALYs) of CKD at global, regional, and national levels between 1990 and 2021. Decomposition analysis, health inequalities and frontier analysis were used to analyse the changes. RESULTS: This study analyzed the global regional and national burden, trends, and disparities of CKD from 1990 to 2021 and found that the global burden of CKD had increased significantly, in line with trends in population ageing and population growth, and with significant variations between regions. There were 673.7 million people with CKD worldwide in 2021, accounting for 8.54% of the global population, a 92.0% increase from 1990. Despite a slight decline in age-standardized prevalence rate (ASPR), the absolute number of CKD cases increased. Central Asia had the highest prevalence of CKD, while Central Latin America had the highest rate of DALYs and incidence for CKD. In 2021, At the national level, China had the highest number of new CKD cases. The country with the highest ASPR and age-standardized DALYs rate (ASDR) of CKD was Mauritius. Globally, age-standardized incidence rate (ASIR) and ASDR were on the rise in almost all countries/regions, suggesting that the impact of CKD on global health is increasing. Population growth and ageing were major factors contributing to the increasing burden of CKD, especially in China and low Socio-demographic Index (SDI) regions. In addition, the cross-national study of health inequalities in CKD showed that, although there have been improvements in global health over time, health inequalities continue to exist. The frontier analysis revealed a considerable degree of heterogeneity in the effective differences across the spectrum of socio-demographic indices. CONCLUSION: CKD is a global health problem, the burden of which varies between regions and countries. A multifaceted approach is necessary to prevent and control CKD, including population-level interventions targeting risk factors, improvements in the accessibility and quality of health care, and measures to address health inequalities. | BMC nephrology | 13/03/2025 |
('LID', '10.1302/2046-3758.143.BJR-2024-0207.R1') | Evaluation of the causal relationship between 28 circulating biomarkers and osteoarthritis : a bidirectional Mendelian randomization study. | Zhu, Xiao-Wei, Zheng, Xiao, Wang, Lu, Liu, Jia, Yang, Man, Liu, Ya-Qi, Qian, Yun, Luo, Yuan, Zhang, Lei | AIMS: Circulating biochemistry markers are commonly used to monitor and detect disease-induced dysfunctions including osteoarthritis (OA). However, the causal nature of this relationship is nevertheless largely unknown, due to unmeasured confounding factors from observational studies. We aimed to reveal the causal relationship between 28 circulating biochemistry markers and OA pathogenesis. METHODS: We conducted a comprehensive bidirectional two-sample Mendelian randomization (MR) study between 28 circulating biomarkers and six OA types, using large-scale genome-wide association study (GWAS) summary statistics data from a UK Biobank cohort (n = 450,243) and the latest OA meta-analysis (n = 826,690). We replicated the significant results of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in an independent large GWAS dataset obtained from the Global Lipids Genetics Consortium (GLGC) (n > 800,000). RESULTS: Using 73 to 792 instrumental variables for biomarkers, this large MR analysis identified 11 causal associations at the Bonferroni corrected significance level of 2.98 × 10(-4), involving seven biomarkers and five OA types. LDL-C (odds ratio (OR) per SD increase 0.90, 95% CI 0.86 to 0.93), apolipoprotein B (OR 0.86, 95% CI 0.82 to 0.91), TC (OR 0.90, 95% CI 0.86 to 0.94), calcium (OR 0.82, 95% CI 0.75 to 0.90), and glucose (OR 0.81, 95% CI 0.73 to 0.89) are causally associated with a reduced risk of OA, while phosphate (OR 1.18, 95% CI 1.08 to 1.30) and aspartate aminotransferase (OR 1.15, 95% CI 1.07 to 1.24) are causally associated with an increased risk. Analysis of GLGC summary statistics successfully replicated LDL-C (OR 0.93, 95% CI 0.90 to 0.96) and TC (OR 0.92, 95% CI 0.89 to 0.95). CONCLUSION: This comprehensive bidirectional MR analysis provides new insights into the prevention and treatment of OA, as well as understanding the biological mechanism underlying OA pathogenesis. | Bone & joint research | 17/03/2025 |
('LID', '10.1080/15384047.2025.2472432') | The search for a TNBC vaccine: the guardian vaccine. | Fines, Cory, McCarthy, Helen, Buckley, Niamh | Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC. | Cancer biology & therapy | 00/12/2025 |
('LID', '10.1186/s12944-025-02508-7') | Associations between the cardiometabolic index and atherosclerotic cardiovascular disease acorss different glucose metabolism statuses: insights from NHANES, 1999-2020. | Wei, Qiong, Cheng, Xu, Li, Min, Wu, Keying, Chen, Meng, Zhang, Dongmei | BACKGROUND: The cardiometabolic index (CMI) serves as a significant marker of diabetes mellitus (DM) and may predict the potential for cardiovascular disease development. Nevertheless, the correlation between CMI and atherosclerotic cardiovascular disease (ASCVD) among individuals exhibiting varying glucose metabolism statuses (GMS) continues to be unclear. METHODS: Overall, 24,006 individuals aged 20 and above were enrolled in the research, drawn from the National Health and Nutrition Examination Survey (NHANES) database. Individuals in the study was classified into three distinct categories according to the level of fasting plasma glucose or glycated haemoglobin: normal glucose regulation, prediabetes, and DM. Multivariate logistic regression models and smoothed curve-fitting techniques were applied to investigate the correlation between CMI and ASCVD risk across varying GMS. Additionally, subgroup analyses stratified by relevant factors were performed to identify potential effect modifiers in this relationship. RESULTS: Overall, 2352 participants (9.8%) with ASCVD were included. An increasing trend in ASCVD risk was observed for each successive CMI tertile. After adjusting for all related covariates, a significantly positive association was observed between CMI and ASCVD (P = 0.0004). Participants with DM in the highest CMI tertile had a 114% higher ASCVD risk compared to those in the lowest tertile (OR = 2.14; 95% CI = 1.30-3.53). Smoothed curve-fitting consistently confirmed the correlation between CMI and ASCVD across diverse GMS. Subgroup analyses and interaction tests highlighted statistically significant differences within the drinking status subgroup (P-interaction = 0.0479) and GMS subgroups (P-interaction = 0.0397). CONCLUSION: This research suggests a positive association between ASCVD and CMI in adults in the United States, particularly among individuals with DM. | Lipids in health and disease | 15/03/2025 |
('LID', '10.1016/j.ajcnut.2025.03.009') | Regular-fat and low-fat dairy foods and cardiovascular diseases: Perspectives for future dietary recommendations. | Lamarche, Benoît, Astrup, Arne, Eckel, Robert H, Feeney, Emma, Givens, Ian, Krauss, Ronald M, Legrand, Philippe, Micha, Renata, Michalski, Marie-Caroline, Soedamah-Muthu, Sabita, Sun, Qi, Kok, Frans J | Most current dietary guidelines for the prevention of cardiovascular diseases (CVD) recommend the consumption of low-fat dairy in place of regular-fat dairy foods, one of the main sources of dietary saturated fatty acids (SFAs). Here, we summarise the data presented and discussions held - relating to the validity of such recommendations - between a panel of international nutrition research experts at a high-level closed workshop on 'Saturated Fat in Dairy and Cardiovascular Diseases', which took place in Amsterdam on 15-16 April 2024. The most recent evidence indicates that overall, consumption of milk, yogurt and cheese, irrespective of fat content, is neutrally associated with CVD risk. There is also no evidence yet from randomized controlled trials that consumption of regular-fat milk, yogurt and cheese has different effects on a broad array of cardiometabolic risk factors when compared to consumption of low-fat milk, yogurt and cheese. Thus, the body of evidence does not support differentiation between regular-fat and low-fat dairy foods in dietary guidelines for both adults and children. Strategies focusing primarily on reduction of energy-dense, nutrient-poor foods, the main source of SFAs in Western diets, rather than on the fat content of dairy foods, are more likely to benefit the population's cardiovascular health. Future research is needed to understand better the place of regular-fat and low-fat dairy foods within healthy eating patterns. | The American journal of clinical nutrition | 13/03/2025 |
('LID', '10.1126/sciadv.adr4443') | Inhibiting EZH2 complements steroid effects in Duchenne muscular dystrophy. | Jeon, Eun Young, Kwak, Yejin, Kang, Hyeji, Kim, Hanbyeol, Jin, Se Young, Park, Soojin, Kim, Ryeo Gyeong, Ko, Dayoung, Won, Jae-Kyung, Cho, Anna, Jung, Inkyung, Lee, Chul-Hwan, Park, Jeongbin, Kim, Hyun-Young, Chae, Jong-Hee, Choi, Murim | Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by dystrophin gene mutations. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in patients with DMD and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors to Dmd mutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD. | Science advances | 14/03/2025 |
('LID', '10.1016/j.ajhg.2025.02.016') | Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations. | Guillouet, Charlotte, Agostini, Valeria, Baujat, Geneviève, Cocciadiferro, Dario, Pippucci, Tommaso, Lesieur-Sebellin, Marion, Georget, Mathieu, Schatz, Ulrich, Fauth, Christine, Louie, Raymond J, Rogers, Curtis, Davis, Jessica M, Konstantopoulou, Vassiliki, Mayr, Johannes A, Bouman, Arjan, Wilke, Martina, VanNoy, Grace E, England, Eleina M, Park, Kristen L, Brown, Kathleen, Saenz, Margarita, Novelli, Antonio, Digilio, Maria Cristina, Mastromoro, Gioia, Rongioletti, Mauro Ciro Antonio, Piacentini, Gerardo, Kaiyrzhanov, Rauan, Guliyeva, Sughra, Hasanova, Lala, Shears, Deborah, Bhatnagar, Ishita, Stals, Karen, Klaas, Oliver, Horvath, Judit, Bouvagnet, Patrice, Witmer, P Dane, MacCarrick, Gretchen, Cisarova, Katarina, Good, Jean-Marc, Gorokhova, Svetlana, Boute, Odile, Smol, Thomas, Bruel, Ange-Line, Patat, Olivier, Broadbent, Julia R, Tan, Tiong Y, Tan, Natalie B, Lyonnet, Stanislas, Busa, Tiffany, Graziano, Claudio, Amiel, Jeanne, Gordon, Christopher T | The Mediator complex regulates protein-coding gene transcription by coordinating the interaction of upstream enhancers with the basal transcription machinery at the promoter. Pathogenic variants in Mediator subunits typically lead to neurodevelopmental or neurodegenerative disorders with variable clinical presentations, designated as MEDopathies. Here, we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. The 26 variants identified were comprised of eight predicted protein-truncating (three intragenic deletions, two frameshifts, and one nonsense and two essential splice site variants) and 18 missense or in-frame duplication variants affecting conserved residues, without clear correlation between phenotypic severity and variant type combination. Three-dimensional modeling indicated that the missense and duplication variants likely have a destabilizing effect on the structural elements of the protein. Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied. Homozygous mutant med16 zebrafish presented growth delay and increased mortality compared with wild-type fish, and Med16 knockout mice are preweaning lethal, highlighting the conserved requirement of MED16 for development. Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy, emphasizing the importance of Mediator during neurodevelopment and suggesting that some tissues are particularly sensitive to the loss of certain subunits. | American journal of human genetics | 11/03/2025 |
('LID', '10.1016/S0140-6736(25)00046-7') | Safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, W, Y, and X when co-administered with routine childhood vaccines at ages 9 months and 15 months in Mali: a single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial. | Diallo, Fatoumata, Haidara, Fadima C, Tapia, Milagritos D, Dominguez Islas, Clara P, Alderson, Mark R, Hausdorff, William P, Martellet, Lionel, Hosken, Nancy, Kapse, Dhananjay, Kulkarni, Prasad S, Townsend-Payne, Kelly, Vanni, Francesca, Posavad, Christine M, Sow, Samba O, Kotloff, Karen L, Chen, Wilbur H | BACKGROUND: Invasive meningococcal disease is a devastating public health problem for the African meningitis belt. We assessed the safety and immunogenicity of a pentavalent meningococcal conjugate vaccine targeting serogroups A, C, Y, W, and X (NmCV-5) relative to a licensed, quadrivalent meningococcal conjugate vaccine (MenACWY-TT) when co-administered with routine childhood vaccines at ages 9 months and 15 months. METHODS: In this single-centre, double-blind, randomised, controlled, phase 3, non-inferiority trial, children aged 9-11 months who had completed their local infant Expanded Program on Immunization (EPI) vaccines were recruited at the Centre pour le Développement des Vaccins in Bamako, Mali. Participants were randomly assigned (1:1·2) at their 9-month EPI visits to receive a meningococcal vaccine at either their 9-month or 15-month EPI vaccination visits. At each participant's designated EPI visit, they were randomly assigned a second time (2:1) to receive either NmCV-5 or MenACWY-TT. Study vaccines and designated EPI vaccines were prepared and administered by assigned unmasked study personnel. Parents or guardians, investigators, and all other trial staff were masked to meningococcal vaccine assignments. The meningococcal vaccines were co-administered with a measles and rubella vaccine (first dose) and a yellow fever vaccine at age 9 months or with a measles and rubella vaccine (second dose) at age 15 months. The primary endpoint, seroprotective response, was defined as a rabbit complement serum bactericidal antibody titre of 8 or higher, with the estimand, given as the difference in the proportions of participants for each of the five meningococcal serogroups who showed this response 28 days after vaccination, assessed in the per-protocol population. The prespecified non-inferiority margin was -10% for all five serogroups in both age groups. The non-inferiority of the NmCV-5 seroprotective response to serogroup X was evaluated in comparison with the lowest seroprotective response for MenACWY-TT among serogroups A, C, W, or Y. Safety was a secondary endpoint, assessed over 6 months in a modified intention-to-treat population that included all participants who received a randomly assigned meningococcal vaccine. This trial is registered with ClinicalTrials.gov, NCT05093829. FINDINGS: Between March 24 and Aug 15, 2022, 1325 participants were enrolled and randomly assigned to receive a meningococcal vaccine at either age 9 months (n=602) or age 15 months (n=723). Meningococcal vaccines were administered to 600 of the 602 participants assigned to the 9-month vaccination group during that same period. Between Sept 27, 2022, and Feb 6, 2023, 600 participants received meningococcal vaccines at their 15-month visits. In both groups, 400 participants received NmCV-5 and 200 participants received MenACWY-TT. The per-protocol population assessed in the non-inferiority analysis included 564 participants vaccinated at age 9 months (373 who received NmCV-5 and 191 who received MenACWY-TT) and 549 participants vaccinated at age 15 months (367 who received NmCV-5 and 182 who received MenACWY-TT). Among the participants in the per-protocol population who received NmCV-5 at age 9 months, the difference in seroprotection prevalence for NmCV-5 relative to MenACWY-TT was 0·0% (95% CI -1·0 to 2·0) for serogroup A, -0·5% (-2·3 to 1·9) for serogroup C, -3·0% (-6·3 to 0·8) for serogroup W, and -3·0% (-5·4 to -0·4) for serogroup Y. For serogroup X, non-inferiority was assessed relative to seroprotection for serogroup W in participants who received MenACWY-TT, with a difference of 2·3% (95% CI 0·3 to 4·7). The difference in the prevalence of seroprotection among the participants who received NmCV-5 at age 15 months relative to participants who received MenACWY-TT at age 15 months was 0·8% (95% CI -0·6 to 3·7) for serogroup A, -0·8% (-3·3 to 2·5) for serogroup C, 0·3% (-1·8 to 3·5) for serogroup W, and 1·4% (-0·6 to 4·8) for serogroup Y. For serogroup X, non-inferiority was assessed in relation to seroprotection for serogroup Y in participants who received MenACWY-TT, with a difference of 1·9% (95% CI 0·0 to 4·4). NmCV-5 responses in both age groups were non-inferior to MenACWY-TT responses for all five serogroups. Six serious adverse events were recorded but none were deemed related to vaccination. INTERPRETATION: When compared with a licensed, quadrivalent meningococcal conjugate vaccine, and given alongside other routine vaccines, a single dose of NmCV-5 was safe and elicited a non-inferior immune response in infants aged 9 months and young children aged 15 months. FUNDING: US National Institutes of Health, UK Foreign, Commonwealth & Development Office, and Serum Institute of India. | Lancet (London, England) | 11/03/2025 |
('LID', '10.1016/j.jaci.2025.02.038') | IRF2BP2 Deficiency: An important form of common variable immunodeficiency with inflammation. | Udemgba, Chioma, Pillay, Bethany, Shafer, Samantha, Alberstadt, Angelika, Abers, Michael, Gilliaux, Olivier, Chen, Karin, Rae, William, Hanitsch, Leif, Von Bernuth, Horst, Neves, Joao Farela, Raje, Nikita, Moens, Leen, van Hagen, P Martin, Bergerson, Jenna, Hartog, Nicholas, Niehues, Tim, Dückers, Gregor, Falcone, Emilia, Keller, Michael, Hsu, Amy, Meyts, Isabelle, Holland, Steven M | BACKGROUND: Interferon regulatory factor-2 binding protein-2 (IRF2BP2) is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency. OBJECTIVE: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test thirty-four individuals with IRF2BP2 variants. METHODS: We collected 34 subjects across 18 families with mutations in IRF2BP2. Records were abstracted for clinical phenotypes. Functional testing was performed on peripheral blood mononuclear cells (PBMCs). Nuclear factor of activated T cells (NFAT) luciferase gene reporter constructs and quantitative cDNA determinations were used to evaluate repressor activity associated with ectopic expression of various IRF2BP2 mutant constructs in Jurkat cells. RESULTS: Most subjects had immunodeficiency (91%, n = 30/33) with variable gastrointestinal (65%, n= 20/31) and inflammatory or autoimmune features (57%, n=17/30), including chronic abdominal pain, colitis, diarrhea, constipation, vitiligo, alopecia, and migratory rashes. There was a reduced frequency of memory B-cells with poor immunoglobulin production and reduced calcium flux in response to B-cell receptor stimuli. PBMCs had increased apoptosis in vitro compared to healthy controls. Impaired IRF2BP2 repression of NFAT activation was observed using patient-derived mutant IRF2BP2 constructs compared to wild-type. Similarly, TNF-α transcript levels were higher using patient-derived mutations compared to wild-type IRF2BP2 constructs. CONCLUSIONS: IRF2BP2 deficiency causes a complex immunodeficiency including gastrointestinal and inflammatory disorders as well as impaired B-cell maturation. Impaired repression of the NFAT pathway appears to enhance proinflammatory signaling through proinflammatory cytokine expression. | The Journal of allergy and clinical immunology | 14/03/2025 |
('LID', '10.1186/s12885-025-13902-w') | Global, regional, and national burden of kidney cancer and attributable risk factors in adults aged 65 years and older from 1990 to 2021 and projections to 2040. | Zhou, Nan, Bai, Hongjing, Zhang, Ziyan, Yu, Baofeng, Zhao, Hong, Li, Jinbo, Zheng, Guoping | BACKGROUND: Identifying the past and future burden of kidney cancer (KC) and its temporal trends among older adults (≥ 65 years) at global, regional, and national levels is critical for effective prevention strategies. METHODS: The age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated using data from the Global Burden of Disease (GBD) study from 1990 to 2021. These indicators were stratified by sex, age, and socio-demographic index (SDI). The correlation between these indicators and SDI was assessed. Temporal trends were quantified using the annual average percentage change (AAPC), and future trends from 2022 to 2040 were predicted using the Bayesian age-period-cohort (BAPC) model. RESULTS: The global age-standardized incidence rate (ASIR) of KC among older adults increased from 21.73 per 100,000 people in 1990 to 26.74 per 100,000 people in 2021, with an AAPC of 0.67%. Age-standardized DALYs rate (ASDR) remained stable, while significant increases were observed in age-standardized prevalence (AAPC = 1.24%, 95%CI: 1.14-1.34%) and mortality rate (AAPC = 0.13%, 95%CI: 0.05-0.22%). From 1990 to 2021, males consistently exhibited a higher disease burden than females, additionally, the ASIR of KC increased significantly in all age subgroups. Regions with higher SDI levels also showed a greater disease burden, while Oceania had the lowest burden of KC in 2021. The ASIR increased in almost all countries and territories. Czechia showed the highest ASIR (92.25 per 100,000 people) and ASDR (819.88 per 100,000 people). Smoking and high body mass index (BMI) remained significant risk factors for DALYs and mortality in the older population, and their effects were greatest in high SDI region. Furthermore, the burden of KC is expected to continue to decline through 2040. CONCLUSIONS: The global burden of KC among older adults increased from 1990 to 2021, with notable regional and national variations. However, it is projected to continue to decline through 2040. The management of smoking and high BMI remain major challenges for people with KC, necessitating targeted clinical guidelines, particularly focusing on males and the older adults. | BMC cancer | 15/03/2025 |
('LID', '10.1038/s41467-025-57651-7') | Axonal RNA localization is essential for long-term memory. | de Queiroz, Bruna R, Laghrissi, Hiba, Rajeev, Seetha, Blot, Lauren, De Graeve, Fabienne, Dehecq, Marine, Hallegger, Martina, Dag, Ugur, Dunoyer de Segonzac, Marion, Ramialison, Mirana, Cazevieille, Chantal, Keleman, Krystyna, Ule, Jernej, Hubstenberger, Arnaud, Besse, Florence | Localization of mRNAs to neuronal terminals, coupled to local translation, has emerged as a prevalent mechanism controlling the synaptic proteome. However, the physiological regulation and function of this process in the context of mature in vivo memory circuits has remained unclear. Here, we combined synaptosome RNA profiling with whole brain high-resolution imaging to uncover mRNAs with different localization patterns in the axons of Drosophila Mushroom Body memory neurons, some exhibiting regionalized, input-dependent, recruitment along axons. By integrating transcriptome-wide binding approaches and functional assays, we show that the conserved Imp RNA binding protein controls the transport of mRNAs to Mushroom Body axons and characterize a mutant in which this transport is selectively impaired. Using this unique mutant, we demonstrate that axonal mRNA localization is required for long-term, but not short-term, behavioral memory. This work uncovers circuit-dependent mRNA targeting in vivo and demonstrates the importance of local RNA regulation in memory consolidation. | Nature communications | 15/03/2025 |
('LID', '10.1016/j.metabol.2025.156186') | Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling. | Xiu, Chunmei, Zhang, Lei, Zhang, Chenxi, Zhang, Yuannan, Luo, Xi, Zhang, Ziyi, Zhao, Hangkai, Ji, Kaizhong, Chen, Zhiyuan, He, Guangxu, Chen, Jianquan | Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis (DNL) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases. | Metabolism: clinical and experimental | 11/03/2025 |
('LID', '10.1186/s12876-025-03754-w') | Efficacy and safety of pembrolizumab in advanced gastric and gastroesophageal junction cancer: a systematic review and meta-analysis. | Ji, Xiaoying, Wang, Guoping, Pan, Dandan, Xu, Shanxia, Lei, Xinming | BACKGROUND: Pembrolizumab, a PD-1 inhibitor, has shown potential for treating advanced gastric and gastroesophageal junction (GEJ) cancer. This meta-analysis evaluates its efficacy and safety, alone or combined with chemotherapy, in this population. METHODS: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched up to October 31, 2024. Twelve studies comprising 4,069 patients were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR), adverse events (AEs), and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Pembrolizumab combined with chemotherapy significantly improved OS (MD = 1.92 months; 95% CI: 0.94 to 2.91) and ORR (MD = 11.05%; 95% CI: 6.29 to 15.82) compared to chemotherapy alone. Pembrolizumab monotherapy did not show a significant effect on OS (MD = 0.24 months; 95% CI: -1.15 to 1.63) and was associated with a significant reduction in PFS (MD = -2.28 months; 95% CI: -2.85 to -1.71) compared to chemotherapy alone. For safety, pembrolizumab monotherapy significantly reduced the risk of AEs (OR = 0.68; 95% CI: 0.57 to 0.81) and grade ≥ 3 AEs (OR = 0.39; 95% CI: 0.30 to 0.51) compared to chemotherapy. Pembrolizumab combined with chemotherapy did not significantly alter the risk of AEs (OR = 1.01; 95% CI: 0.90 to 1.13) or grade ≥ 3 AEs (OR = 1.12; 95% CI: 0.99 to 1.27) compared to chemotherapy alone. CONCLUSION: Pembrolizumab combined with chemotherapy improves survival and response rates with a manageable safety profile in advanced gastric and GEJ cancers. Monotherapy shows limited efficacy, highlighting the need for combination strategies and patient selection. | BMC gastroenterology | 14/03/2025 |
('LID', '10.1172/JCI186673') | TET2 suppresses vascular calcification by forming inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation. | He, Dayu, Ma, Jianshuai, Zhou, Ziting, Qi, Yanli, Lian, Yaxin, Wang, Feng, Yin, Huiyong, Zhang, Huanji, Zhang, Tingting, Huang, Hui | Osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) has been recognized as the principal mechanism underlying vascular calcification (VC). Runt-related transcription factor 2 (RUNX2) in VSMCs plays a pivotal role because it constitutes an essential osteogenic transcription factor for bone formation. As a key DNA demethylation enzyme, ten-eleven translocation 2 (TET2) is crucial in maintaining the VSMC phenotype. However, whether TET2 involves in VC progression remains elusive. Here we identified a substantial downregulation of TET2 in calcified human and mouse arteries, as well as human primary VSMCs. In vitro gain- and loss-of function experiments demonstrated TET2 regulated VC. Subsequently, in vivo knockdown of TET2 significantly exacerbated VC in both vitamin D3 and adenine-diet-induced chronic kidney disease (CKD) mice models. Mechanistically, TET2 binds to and suppresses the activity of the P2 promoter within the RUNX2 gene, whereas an enzymatic loss-of-function mutation of TET2 has a comparable effect. Furthermore, TET2 forms a complex with histone deacetylases 1/2 (HDAC1/2 ) to deacetylate H3K27ac on the P2 promoter, thereby inhibiting its transcription. Moreover, SNIP1 is indispensable for TET2 to interact with HDAC1/2 to exert inhibitory effect on VC, and knockdown of SNIP1 accelerated VC in mice. Collectively, our findings imply that TET2 might serve as a potential therapeutic target for VC. | The Journal of clinical investigation | 11/03/2025 |
('LID', '10.1016/j.foodres.2025.116087') | Probiotic-fermented ginger-processed Gastrodia elata BI. Ameliorates AlCl(3)-induced cognitive dysfunction in an Alzheimer's disease rat model by regulating the gut microbiota and CREB/BDNF pathway. | Huang, Junyuan, Lai, Lanyu, Su, Yilin, Chen, Jianping, Li, Pan, Du, Bing | Gastrodia elata BI., which is an edible plant, has been reported in previous studies to possess a strong capacity for alleviating the symptoms of Alzheimer's disease (AD). This study focuses on ginger-processed and fermented Gastrodia elata BI. (FGGE) to investigate its effects on behaviour, brain neuroregulation, and the gut microbiota in an AlCl(3)-induced AD rat model, and to explore the underlying mechanisms. Results indicate that FGGE significantly improved novel object recognition and the correct alternation rate in the Y-maze test for AD rats. In addition, FGGE alleviated brain oxidative stress and restored the anti-inflammatory response, cholinergic function, and tissue morphology in the hippocampus. Furthermore, FGGE activated the cAMP response element-binding protein/brain-derived neurotrophic factor signalling pathway, reversing neural network abnormalities and enhancing neural regulation. FGGE also promoted the proliferation of bacteria negatively associated with AD, such as Methanosphaera and Lactobacillus, thereby restoring gut microbiota balance. The mechanisms by which FGGE alleviates AD may involve the modulation of the gut-brain axis, ultimately mitigating AD symptoms. FGGE represents an innovative functional food with significant therapeutic potential and promising application prospects. | Food research international (Ottawa, Ont.) | 00/04/2025 |
('LID', '10.1016/j.redox.2025.103550') | FOXO3a-BAP1 axis regulates neuronal ferroptosis in early brain injury after subarachnoid hemorrhage. | Liu, Chengli, Tian, Qi, Li, Zhijie, Wang, Guijun, Han, Wenrui, Jiang, Shengming, Sun, Zhou, Xu, Qingqing, Wang, Long, Liao, Jianming, Li, Mingchang | Subarachnoid hemorrhage (SAH) is a serious and common disease and accounts for about 10 % of acute stroke cases. BRCA-associated protein 1 (BAP1) belongs to the ubiquitin C-terminal hydrolases (UCHs) family, which plays an important role in cell metabolism and cell death, but its role in early brain injury (EBI) after SAH requires further study. Forkhead box protein O3a (FOXO3a) is a transcription factor involved in the regulation of cellular function and survival in the nervous system, including the oxidative stress response and neuronal death. This study aimed to explore the effect of FOXO3a and BAP1 on neuronal ferroptosis in the pathogenesis of EBI after SAH. In this study, the overexpression of BAP1 significantly inhibited GPX4 expression and exacerbated the degree of lipid peroxidation and ferroptosis in neurons after SAH. BAP1 regulated the transcription level of the SLC7A11 promoter by H2Aub. FOXO3a could transcriptionally regulate BAP1 to influence the levels of SLC7A11 and GPX4, and mediate lipid peroxidation and neuronal ferroptosis after SAH. Silencing FOXO3 and BAP1 significantly improved neurological deficit and cerebral edema, and reduced oxidative stress damage in SAH mice. After SAH, BAP1 could directly bind to the FKH-DBD + NLS domain located in FOXO3a protein through the UCH domain, and mediates deubiquitination of FOXO3a protein by the K48 site to maintain the stability of FOXO3a. Our findings elucidate the impact of FOXO3a and BAP1 on SLC7A11-related ferroptosis following SAH both in vivo and in vitro, and the inhibition of the FOXO3a-BAP1 axis can significantly attenuate neuronal damage and ferroptosis in EBI after SAH. | Redox biology | 27/02/2025 |
('LID', '10.1016/j.nut.2025.112718') | Efficacy of vitamin D replacement therapy on 28 cases of myalgic encephalomyelitis/chronic fatigue syndrome after COVID-19 vaccination. | Kodama, Shinichiro, Konishi, Nafuko, Hirai, Yuriko, Fujisawa, Akinori, Nakata, Mitsuko, Teramukai, Satoshi, Fukushima, Masanori | BACKGROUND: Prolonged symptoms have been reported following both COVID-19 infection and vaccination, with some cases leading to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Of 80 patients presenting to our hospital with postvaccination syndrome, 28 met the diagnostic criteria for ME/CFS. We conducted a retrospective study on these 28 patients. METHODS: We measured serum 25-hydroxyvitamin D levels in 28 patients who developed ME/CFS after COVID-19 vaccination between August 2022 and February 2024. Vitamin D replacement therapy included dietary counseling, sun exposure recommendations, and oral vitamin D supplementation. We evaluated changes in blood vitamin D levels and symptom improvement. RESULTS: At initial visit, 27 of 28 patients diagnosed with ME/CFS had insufficient or deficient serum 25-hydroxyvitamin D levels (16 ± 4 ng/mL, mean ± SD). Following vitamin D replacement therapy, we observed an increase in blood vitamin D levels (28 ± 5 ng/mL) associated with a decrease in ME/CFS diagnostic symptoms (from 10.3 ± 2.1 to 3.3 ± 2.0). Notably, 23 of 28 patients (82%) no longer met ME/CFS diagnostic criteria after the therapy. Among the symptoms, sleep problems showed the most improvement (71%), followed by autonomic symptoms (68%). CONCLUSIONS: For patients developing ME/CFS after COVID-19 vaccination with insufficient or deficient vitamin D levels, appropriate vitamin D replacement therapy under medical guidance may lead to symptomatic relief. We are preparing a randomized controlled trial to evaluate the efficacy of vitamin D replacement therapy in individuals with ME/CFS who have developed vitamin D deficiency following COVID-19 infection or vaccination. | Nutrition (Burbank, Los Angeles County, Calif.) | 18/02/2025 |
('LID', '10.1016/j.ctrv.2025.102921') | First-line treatment of locally advanced cervical carcinoma: An updated systematic review and Bayesian network meta-analysis. | Petrelli, Fausto, Riboldi, Valentina, Bruschieri, Lorenza, Villa, Antonella, Cribiu', Fulvia Milena, Borgonovo, Karen, Ghilardi, Mara, Ghidini, Antonio, Seghezzi, Silvia, Stefani, Agostina De, Trevisan, Francesca | INTRODUCTION: Locally advanced cervical carcinoma (LACC) remains a significant global health issue, particularly in low- and middle-income countries (LMICs), where disease burden is highest. While cisplatin-based chemoradiotherapy (CTRT) has long been the cornerstone of first-line treatment, its toxicities, including nephrotoxicity and hematologic adverse events, limit its use in certain patients. Advances in systemic therapies, including immune checkpoint inhibitors and induction chemotherapy, offer new avenues for improving outcomes. This study aimed to evaluate the efficacy of various first-line regimens for LACC through a systematic review and Bayesian network meta-analysis (NMA), focusing on overall survival (OS) and progression-free survival (PFS). MATERIALS AND METHODS: This analysis adhered to PRISMA guidelines and included Phase III randomized controlled trials (RCTs) evaluating first-line treatments for LACC. The primary outcome was OS, expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), while PFS was secondary. A comprehensive search of PubMed, EMBASE, and Cochrane Library was conducted through November 2024. Statistical analysis used a Bayesian NMA framework, with treatments ranked by surface under the cumulative ranking curve (SUCRA). RESULTS: Pembrolizumab + CTRT improved OS (HR, 0.67; 95 % CI, 0.50-0.90), while induction chemotherapy with carboplatin/paclitaxel followed by CTRT showed significant benefit (HR, 0.60; 95 % CI, 0.40-0.90). RT + cisplatin and 5-fluorouracil (5-FU) also improved OS (HR, 0.66; 95 % CI, 0.44-0.99), ranking highest in SUCRA analysis (98 %). CONCLUSION: Three promising strategies-pembrolizumab-based regimens, induction chemotherapy followed by CTRT, and RT + CDDP + 5-FU-offer substantial survival benefits, advancing treatment options for LACC. | Cancer treatment reviews | 10/03/2025 |
('LID', '10.1002/14651858.CD001703.pub4') | Antidepressants for low back pain and spine-related leg pain. | Ferraro, Michael C, Urquhart, Donna M, Ferreira, Giovanni E, Wewege, Michael A, Abdel Shaheed, Christina, Traeger, Adrian C, Hoving, Jan L, Visser, Eric J, McAuley, James H, Cashin, Aidan G | BACKGROUND: Antidepressants are commonly used to treat low back pain and spine-related leg pain. However, their benefits and harms are uncertain. This is an update of a 2008 Cochrane review of antidepressants for non-specific low back pain. OBJECTIVES: To assess the benefits and harms of antidepressants for non-specific low back pain and spine-related leg pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and EU Clinical Trials Register from inception to 14 November 2024. SELECTION CRITERIA: We included randomised controlled trials that compared antidepressants with placebo, usual care, or no treatment/waiting list. Participants were 18 years of age or older with non-specific low back pain or spine-related leg pain of any duration. We excluded participants with low back pain due to spinal fracture, inflammatory disease, aortic dissection, malignancy, or infection. Primary outcomes were pain intensity and disability, measured at short-term follow-up (> 4 to 14 weeks post-randomisation), and total adverse events. Secondary outcomes were serious adverse events, withdrawals due to adverse events, depressive symptoms, and health-related quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently screened records to determine study inclusion, extracted data, and evaluated risk of bias using RoB 1 tool. Where possible, we conducted meta-analyses. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 26 randomised controlled trials. Eighteen studies included 2535 participants with non-specific low back pain, seven studies included 329 participants with spine-related leg pain, and one study included 68 participants with either condition. Most participants had pain lasting more than three months, with a mean duration between 18 months and 20 years. Mean ages ranged from 27 to 59 years. Studies evaluated serotonin and norepinephrine reuptake inhibitors (SNRIs; eight studies), selective serotonin reuptake inhibitors (SSRIs; two studies), tricyclic antidepressants (TCAs; 14 studies), tetracyclic antidepressants (TeCAs; two studies), or 'other antidepressants' (two studies). All studies were placebo-controlled. Outcomes were measured at short-term follow-up in 73% of studies. All included studies had at least one domain judged at high risk of bias, with 69% at high risk of attrition bias. Non-specific low back pain (benefits) Moderate-certainty evidence demonstrated that SNRIs probably have a small effect on pain intensity (mean difference (MD) (0 to 100 scale) -5.25, 95% confidence interval (CI) -7.17 to -3.34; I(2) = 0; 4 studies, 1415 participants) and a trivial effect on disability (MD (0 to 24 scale) -0.91, 95% CI -1.30 to -0.51; I(2) = 0; 4 studies, 1348 participants) at short-term follow-up. Low-certainty evidence showed that SSRIs may have little to no effect on pain intensity (MD 1.20, 95% CI -4.90 to 7.30; I(2) = 0; 3 studies, 199 participants) and disability (MD -2.20 (0 to 100 scale), 95% CI -8.11 to 3.71; 1 study, 92 participants) at short-term follow-up. Moderate-certainty evidence demonstrated that TCAs probably have little to no effect on pain intensity (MD -2.00, 95% CI -7.25 to 3.24; I² = 31%; 4 studies, 417 participants), but probably have a small effect on disability (MD (0 to 24 scale) -1.76, 95% CI -2.70 to -0.82; I(2) = 0; 3 studies, 330 participants) at short-term follow-up. The effects of TeCAs (MD -4.50, 95% CI -17.59 to 8.59; 1 study, 52 participants) and other antidepressants (MD -5.40, 95% CI -23.08 to 12.28; 1 study, 39 participants) on pain intensity at short-term follow-up are unclear (very low-certainty evidence). No studies assessed the effects of TeCAs or other antidepressants on disability. Spine-related leg pain (benefits) The effects of SNRIs on pain intensity (MD -46.10, 95% CI -89.29 to -2.91; 1 study, 11 participants) and disability (MD (0 to 100 scale) -4.40, 95% CI -20.25 to 11.45; 1 study, 11 participants) at short-term follow-up are very uncertain (very low-certainty evidence). Low-certainty evidence showed TCAs may have a large effect on pain intensity at short-term follow-up (MD -23.00, 95% CI -32.12 to -13.88; 1 study, 60 participants), and a moderate effect on disability (MD (0 to 100 scale) -13.00, 95% CI -19.42 to -6.58; 1 study, 60 participants). There were no studies that assessed the effects of SSRIs, TeCAs, or other antidepressants in people with spine-related leg pain. Non-specific low back pain and spine-related leg pain (harms) Moderate-certainty evidence demonstrated that SNRIs probably increase the risk of adverse events (risk ratio (RR) 1.17, 95% CI 1.07 to 1.27; I(2) = 0%; 5 studies, 1510 participants), but it is unclear whether they increase the risk of serious adverse events (Peto odds ratio (OR) 1.75, 95% CI 0.79 to 3.89; 5 studies, 1510 participants; very low-certainty evidence). It is unclear whether TCAs increase the risk of adverse events (RR 1.76, 95% CI 0.79 to 3.90; 7 studies, 474 participants; low-certainty evidence) or serious adverse events (Peto OR 6.64, 95% CI 0.41 to 106.72; I² = 0%; 1 study, 142 participants; very low-certainty evidence). It is unclear whether SSRIs (RR 1.83, 95% CI 0.14 to 24.19; I² = 95%; 2 studies, 107 participants; very low-certainty evidence) or TeCAs increase the risk of adverse events (RR 0.93, 95% CI 0.79 to 1.09; 1 study, 52 participants; very low-certainty evidence). No studies assessed the risk of serious adverse events for these classes. No studies measured total adverse events for other antidepressants. It is unclear whether other antidepressants increase the risk of serious adverse events (Peto OR 0.90, 95% CI 0.16 to 4.96; 1 study, 42 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: We found that in people with non-specific low back pain, SNRIs probably have small effects on pain intensity, trivial effects on disability, and are probably associated with adverse effects. TCAs probably do not reduce low back pain intensity, but may have a small effect on disability. The effects of antidepressants on spine-related leg pain are uncertain, though SNRIs and TCAs might be prioritised over other classes for future investigations. Evidence for the safety of SSRIs, TCAs, TeCAs, and other antidepressants in non-specific low back pain and spine-related leg pain remains unclear. | The Cochrane database of systematic reviews | 10/03/2025 |
('LID', '10.3390/nu17050838') | A Multi-Level Approach to Childhood Obesity Prevention and Management: Lessons from Japan and the United States. | Oudat, Qutaibah, Messiah, Sarah E, Ghoneum, Alia Dawlat | BACKGROUND: Childhood obesity is a pressing global public health challenge, marked by significant disparities in prevalence and management across countries. Japan and the United States offer contrasting approaches to addressing this issue, presenting a valuable opportunity for comparative analysis. OBJECTIVE: This review examines the effectiveness of public health policies, cultural dietary habits, and lifestyle factors in combating childhood obesity in Japan and the United States. It aims to identify actionable insights to inform global strategies for obesity prevention. RESULTS: Japan exhibits one of the lowest childhood obesity rates globally, attributed to prevention-focused policies such as the food education program, stringent school lunch standards, and culturally ingrained healthy eating practices. These efforts are complemented by active lifestyle promotion through urban planning and school-based physical education programs. In contrast, the United States faces higher obesity rates due to systemic challenges, including socioeconomic disparities, reliance on processed foods, sedentary lifestyles, and inconsistent implementation of federal programs like the National School Lunch Program (NSLP) and Supplemental Nutrition Assistance Program Education (SNAP-Ed). CONCLUSIONS: This review highlights Japan's success in aligning public health initiatives with cultural norms to achieve sustainable outcomes. In the United States, systemic barriers and cultural disconnects hinder obesity prevention efforts. Recommendations include adopting integrated, prevention-focused policies, addressing socioeconomic inequities, redesigning urban environments to promote active living, and fostering global collaboration. This comparative analysis underscores the importance of culturally tailored, multidimensional strategies for addressing childhood obesity and improving public health outcomes worldwide. | Nutrients | 28/02/2025 |
('LID', '10.1002/advs.202417827') | Flavonifractor Plautii or Its Metabolite Desaminotyrosine as Prophylactic Agents for Alleviating Myocardial Ischemia/Reperfusion Injury. | Du, Heng, Liu, Xu, Shen, Jianghua, Yuan, Hailong, Zhang, Hao, Xi, Gan, Li, Yujing, Wang, Yuhan, Zhang, Jiahe, Yang, Chaofan, Xu, Pengfei, Wang, Jiawan, Wang, Fang, Liu, Siqi, Zhou, Yanan, Gu, Qi, Lu, Jingjing, Wei, Tuo, Gao, Zeyu, Zang, Jingyi, Wang, Jun, Song, Moshi | Myocardial ischemia/reperfusion (I/R) injury is a major contributor to myocardial damage, leading to adverse cardiac remodeling and dysfunction. Recent studies have highlighted the potential of gut microbiota-derived metabolites in modulating cardiac outcomes. Here, the cardioprotective effects of a commensal bacterium Flavonifractor plautii (F. plautii) and its metabolite desaminotyrosine (DAT) against myocardial I/R injury are investigated. We showed that prophylactic gavage of F. plautii attenuates myocardial I/R injury as evidenced by improved cardiac function and reduced cardiac injury. We also found that its metabolite DAT recapitulates these cardioprotective effects against myocardial I/R injury. Transcriptomic analysis has revealed that DAT preserves cardiac tissue and attenuates immune responses against myocardial I/R injury. Mechanistically, DAT promotes cardiomyocyte survival through the modulation of the nicotinamide adenine dinucleotide phosphate (NADP(+)/NADPH) ratio. Further, DAT suppressed macrophage proinflammatory activities and cardiac inflammation via the reduction in interleukin-6 (IL-6) production. Taken together, our findings indicate that F. plautii and its metabolite DAT exert pleiotropic cardioprotective effects against myocardial I/R injury, suggesting them as potential prophylactic therapeutic options for alleviating myocardial I/R injury. | Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 16/03/2025 |
('LID', '10.1186/s12974-025-03405-7') | Unlocking the therapeutic potential of tumor-derived EVs in ischemia-reperfusion: a breakthrough perspective from glioma and stroke. | Hao, Zhongnan, Guan, Wenxin, Wei, Wei, Li, Meihua, Xiao, Zhipeng, Sun, Qinjian, Pan, Yongli, Xin, Wenqiang | Clinical studies have revealed a bidirectional relationship between glioma and ischemic stroke, with evidence of spatial overlap between the two conditions. This connection arises from significant similarities in their pathological processes, including the regulation of cellular metabolism, inflammation, coagulation, hypoxia, angiogenesis, and neural repair, all of which involve common biological factors. A significant shared feature of both diseases is the crucial role of extracellular vesicles (EVs) in mediating intercellular communication. Extracellular vesicles, with their characteristic bilayer structure, encapsulate proteins, lipids, and nucleic acids, shielding them from enzymatic degradation by ribonucleases, deoxyribonucleases, and proteases. This structural protection facilitates long-distance intercellular communication in multicellular organisms. In gliomas, EVs are pivotal in intracranial signaling and shaping the tumor microenvironment. Importantly, the cargos carried by glioma-derived EVs closely align with the biological factors involved in ischemic stroke, underscoring the substantial impact of glioma on stroke pathology, particularly through the crucial roles of EVs as key mediators in this interaction. This review explores the pathological interplay between glioma and ischemic stroke, addressing clinical manifestations and pathophysiological processes across the stages of hypoxia, stroke onset, progression, and recovery, with a particular focus on the crucial role of EVs and their cargos in these interactions. | Journal of neuroinflammation | 15/03/2025 |
('LID', '10.1016/S2352-3018(25)00011-6') | Prevention and control of HPV-related cancers in people living with HIV. | Uusküla, Anneli, Tisler, Anna, DeHovitz, Jack, Murenzi, Gad, Castle, Philip E, Clifford, Gary | The advent of effective antiretroviral therapy (ART) has increased the lifespan of many people living with HIV. As a result, cancers driven by high-risk human papillomavirus (HPV) infection have emerged as an increasingly important cause of mortality in this population. The complex interplay between HIV and HPV necessitates a deep understanding of the HPV-related cancer burden in people living with HIV and the integration of effective prevention strategies into their care. Although cervical cancer is a global concern, anal cancer is more important among people living with HIV in settings where HIV is more concentrated among men who have sex with men. High HPV prevalence, coupled with resource constraints, particularly in sub-Saharan Africa, where the majority of people living with HIV reside, creates substantial barriers to successful prevention and management of HPV-related malignancies. Implementing preventive measures, such as HPV vaccination and comprehensive screening programmes, is crucial and will require addressing existing health inequities and developing tailored interventions for people living with HIV. The development of enhanced secondary prevention tools and innovative treatment modalities is essential to mitigate the burden of HPV-associated cancers and improve the overall health outcomes for this vulnerable population. | The lancet. HIV | 11/03/2025 |
('LID', '10.1038/s41388-025-03337-9') | CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis. | Bai, Xiaoming, Duan, Tinghong, Shao, Jiaofang, Zhang, Yutong, Xing, Guangyuan, Wang, Jie, Liu, Xue, Wang, Min, He, Yuanqiao, Wang, Hai, Zhang, Zhi-Yuan, Ni, Min, Zhou, Jin-Yong, Pan, Jinshun | Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future. | Oncogene | 16/03/2025 |
('LID', '10.1016/j.tranon.2025.102347') | Single cell analysis reveals that SPP1(+) macrophages enhance tumor progression by triggering fibroblast extracellular vesicles. | Wang, Haocheng, Qiu, Bowen, Li, Xinyu, Ying, Yao, Wang, Yue, Chen, Hungchen, Zeng, Fanan, Shi, Junyao, Huang, Junpeng, Wu, Ziying, Chen, Zequn, Che, Xiao, Li, Qingzhong, Fan, Yingming, Li, Bingyao, Wang, Qun, Huang, Chengyu, Chen, Yixuan, Li, Ting, Mo, Ke, Wang, Qian, Cui, Chunhui | Patients with liver metastatic colorectal cancer (mCRC) have a poor prognosis and are the leading cause of death in colorectal cancer (CRC) patients, but the mechanisms associated with CRC metastasis have not been fully elucidated. In this study, we obtained data from the Gene Expression Omnibus database and characterized the single-cell profiles of CRC, mCRC and healthy samples at single-cell resolution, and explored the cells that influence CRC metastasis. We find that AQP1(+) CRC identified as highly malignant tumor cells exhibited proliferative and metastatic characteristics. Immunosuppressive properties are present in the tumor microenvironment (TME), while NOTCH3(+) Fib is identified to play a facilitating role in the metastatic colonization of CRC. Importantly, we reveal that tumor-associated macrophages (TAM) characterized by SPP1-specific high expression may be involved in TME remodeling through intercellular communication. Specifically, SPP1(+) TAM mediates the generation of Fib-derived extracellular vesicle through the APOE-LRP1 axis, which in turn delivers tumor growth-promoting factors in the TME. This study deepens the understanding of the mechanism of TME in mCRC and lays the scientific foundation for the development of therapeutic regimens for mCRC patients. | Translational oncology | 13/03/2025 |
('LID', '10.1038/s41408-025-01253-5') | Daratumumab-based quadruplet versus triplet induction regimens in transplant-eligible newly diagnosed multiple myeloma: a systematic review and meta-analysis. | Souto Filho, João Tadeu Damian, Cantadori, Lucas Oliveira, Crusoe, Edvan de Queiroz, Hungria, Vania, Maiolino, Angelo | The treatment landscape for transplant-eligible patients with newly diagnosed multiple myeloma (TE-NDMM) has evolved with the introduction of daratumumab-based quadruplet regimens. Adding daratumumab to traditional triplet regimens has demonstrated improved response rates and progression-free survival (PFS). However, the impact on long-term outcomes, particularly overall survival (OS), remains uncertain. This systematic review and meta-analysis aimed to compare the survival outcomes of these quadruplet regimens with triplets. Conducted in adherence to Cochrane Collaboration and PRISMA guidelines and registered on PROSPERO (CRD42024571946), the study involved searching PubMed, Embase, and Cochrane databases, from inception to June 2024. We included randomized clinical trials (RCT) and non-randomized controlled studies (NRCS) that compared daratumumab-based quadruplet regimens to triplets, focusing on OS and PFS, with a minimum follow-up of 18 months. The meta-analysis included 3327 TE-NDMM patients from four studies, comprising three RCT and one NRCS. Daratumumab-based regimens were administered to 1328 (40%) patients. The analysis revealed that daratumumab-based quadruplet regimens significantly improved both OS (pooled HR 0.60; 95% CI 0.48-0.75; P < 0.00001; I² = 0%) and PFS (pooled HR 0.49; 95% CI 0.37-0.65; P < 0.00001; I² = 52%). A per-protocol subgroup analysis comparing D-VRD to VRD further confirmed these benefits, with significant improvements in both OS (pooled HR 0.68; 95% CI 0.48-0.97; P = 0.03; I² = 0%) and PFS (pooled HR 0.41; 95% CI 0.31-0.54; P < 0.00001; I² = 0%). This meta-analysis consolidates evidence that daratumumab-based quadruplet regimens significantly improve OS, compared to triplet regimens for TE-NDMM patients. | Blood cancer journal | 13/03/2025 |
('LID', '10.1080/07391102.2025.2478466') | Exploring the anti-diabetic potential of barnyard millet: insights from virtual screening, MD simulation and MM-PBSA. | Mhaske, Pallavi Sukdev, Nathan, Bharathi, Nallusamy, Saranya, Raman, Renuka, Sampathkumar, Vellaikumar, Kathirvel, Pavitra, Ravikumar, Caroline Nirmala, Sathyaseelan, Chakkarai, Selvakumar, Divya | Barnyard millet (Echinochloa frumentacea) is a nutritionally superior grain and a rich source of dietary fiber, and protein. It helps in managing health and dietary issues such as malnutrition, diabetes, obesity, and celiac disease. Its low content of slowly digestible carbohydrates promotes a gradual release of glucose, helping to maintain stable blood glucose levels. The present study aims to identify and screen phytochemicals in the barnyard millet and explore its anti-diabetic activity through an in-silico study. Gas chromatography-mass spectrometry (GC-MS) analyses of the seed extract revealed the occurrence of 73 bioactive compounds that are known to possess a variety of pharmacological activities. Based on the virtual screening analysis, phytochemicals interacted with five different diabetic targets, with diosgenin demonstrating the lowest binding affinity across four receptors. Specifically, diosgenin showed a binding affinity of -9.2 kcal/mol with the Insulin receptor (PDB ID: 1IR3), -8.7 kcal/mol with Peroxisome proliferator-activated receptors (PDB ID: 3G9E), -7.5 kcal/mol with Tyrosine phosphatase 1-beta (2F70), and -6.5 kcal/mol with the Glucagon receptor (PDB ID: 5EE7). For Aldose reductase (PDB ID: 4XZH), Docosahexaenoic acid exhibited the lowest binding affinity of -9.9 kcal/mol. The dynamic behavior of 2F70-Diosgenin docked complexes throughout a 500 ns trajectory run was investigated further. The RMSD and RMSF analyses reveal that the complex remains structurally stable. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complex are stable. These results suggest that the 2F70-Diosgenin complex is stable, highlighting its potential for further wet lab validation. | Journal of biomolecular structure & dynamics | 14/03/2025 |
('LID', '10.1080/19490976.2025.2477816') | Microbial micronutrient sharing, gut redox balance and keystone taxa as a basis for a new perspective to solutions targeting health from the gut. | Steinert, Robert E, Rehman, Ateequr, Sadabad, Mehdi Sadaghian, Milanese, Alessio, Wittwer-Schegg, Jonas, Burton, Jeremy P, Spooren, Anneleen | In health, the gut microbiome functions as a stable ecosystem maintaining overall balance and ensuring its own survival against environmental stressors through complex microbial interaction. This balance and protection from stressors is maintained through interactions both within the bacterial ecosystem as well as with its host. As a consequence, the gut microbiome plays a critical role in various physiological processes including maintaining the structure and function of the gut barrier, educating the gut immune system, and modulating the gut motor, digestive/absorptive, as well as neuroendocrine system all of which are crucial for human health and disease pathogenesis. Pre- and probiotics, widely available and clinically established, offer various health benefits primarily by beneficially modulating the gut microbiome. However, their clinical outcomes can vary significantly due to differences in host physiology, diets, individual microbiome compositions, and other environmental factors. This perspective paper highlights emerging scientific insights into the importance of microbial micronutrient sharing, gut redox balance, keystone species, and the gut barrier in maintaining a diverse and functional microbial ecosystem, and their relevance to human health. We propose a novel approach that targets microbial ecosystems and keystone taxa performance by supplying microbial micronutrients in the form of colon-delivered vitamins, and precision prebiotics [e.g. human milk oligosaccharides (HMOs) or synthetic glycans] as components of precisely tailored ingredient combinations to optimize human health. Such a strategy may effectively support and stabilize microbial ecosystems, providing a more robust and consistent approach across various individuals and environmental conditions, thus, overcoming the limitations of current single biotic solutions. | Gut microbes | 00/12/2025 |
('LID', '10.1038/s41408-025-01253-5') | Daratumumab-based quadruplet versus triplet induction regimens in transplant-eligible newly diagnosed multiple myeloma: a systematic review and meta-analysis. | Souto Filho, João Tadeu Damian, Cantadori, Lucas Oliveira, Crusoe, Edvan de Queiroz, Hungria, Vania, Maiolino, Angelo | The treatment landscape for transplant-eligible patients with newly diagnosed multiple myeloma (TE-NDMM) has evolved with the introduction of daratumumab-based quadruplet regimens. Adding daratumumab to traditional triplet regimens has demonstrated improved response rates and progression-free survival (PFS). However, the impact on long-term outcomes, particularly overall survival (OS), remains uncertain. This systematic review and meta-analysis aimed to compare the survival outcomes of these quadruplet regimens with triplets. Conducted in adherence to Cochrane Collaboration and PRISMA guidelines and registered on PROSPERO (CRD42024571946), the study involved searching PubMed, Embase, and Cochrane databases, from inception to June 2024. We included randomized clinical trials (RCT) and non-randomized controlled studies (NRCS) that compared daratumumab-based quadruplet regimens to triplets, focusing on OS and PFS, with a minimum follow-up of 18 months. The meta-analysis included 3327 TE-NDMM patients from four studies, comprising three RCT and one NRCS. Daratumumab-based regimens were administered to 1328 (40%) patients. The analysis revealed that daratumumab-based quadruplet regimens significantly improved both OS (pooled HR 0.60; 95% CI 0.48-0.75; P < 0.00001; I² = 0%) and PFS (pooled HR 0.49; 95% CI 0.37-0.65; P < 0.00001; I² = 52%). A per-protocol subgroup analysis comparing D-VRD to VRD further confirmed these benefits, with significant improvements in both OS (pooled HR 0.68; 95% CI 0.48-0.97; P = 0.03; I² = 0%) and PFS (pooled HR 0.41; 95% CI 0.31-0.54; P < 0.00001; I² = 0%). This meta-analysis consolidates evidence that daratumumab-based quadruplet regimens significantly improve OS, compared to triplet regimens for TE-NDMM patients. | Blood cancer journal | 13/03/2025 |
('LID', '10.1080/07391102.2025.2478466') | Exploring the anti-diabetic potential of barnyard millet: insights from virtual screening, MD simulation and MM-PBSA. | Mhaske, Pallavi Sukdev, Nathan, Bharathi, Nallusamy, Saranya, Raman, Renuka, Sampathkumar, Vellaikumar, Kathirvel, Pavitra, Ravikumar, Caroline Nirmala, Sathyaseelan, Chakkarai, Selvakumar, Divya | Barnyard millet (Echinochloa frumentacea) is a nutritionally superior grain and a rich source of dietary fiber, and protein. It helps in managing health and dietary issues such as malnutrition, diabetes, obesity, and celiac disease. Its low content of slowly digestible carbohydrates promotes a gradual release of glucose, helping to maintain stable blood glucose levels. The present study aims to identify and screen phytochemicals in the barnyard millet and explore its anti-diabetic activity through an in-silico study. Gas chromatography-mass spectrometry (GC-MS) analyses of the seed extract revealed the occurrence of 73 bioactive compounds that are known to possess a variety of pharmacological activities. Based on the virtual screening analysis, phytochemicals interacted with five different diabetic targets, with diosgenin demonstrating the lowest binding affinity across four receptors. Specifically, diosgenin showed a binding affinity of -9.2 kcal/mol with the Insulin receptor (PDB ID: 1IR3), -8.7 kcal/mol with Peroxisome proliferator-activated receptors (PDB ID: 3G9E), -7.5 kcal/mol with Tyrosine phosphatase 1-beta (2F70), and -6.5 kcal/mol with the Glucagon receptor (PDB ID: 5EE7). For Aldose reductase (PDB ID: 4XZH), Docosahexaenoic acid exhibited the lowest binding affinity of -9.9 kcal/mol. The dynamic behavior of 2F70-Diosgenin docked complexes throughout a 500 ns trajectory run was investigated further. The RMSD and RMSF analyses reveal that the complex remains structurally stable. The binding free energies were computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology. The calculation results show that the predicted free energies of the complex are stable. These results suggest that the 2F70-Diosgenin complex is stable, highlighting its potential for further wet lab validation. | Journal of biomolecular structure & dynamics | 14/03/2025 |
('LID', '10.1080/19490976.2025.2477816') | Microbial micronutrient sharing, gut redox balance and keystone taxa as a basis for a new perspective to solutions targeting health from the gut. | Steinert, Robert E, Rehman, Ateequr, Sadabad, Mehdi Sadaghian, Milanese, Alessio, Wittwer-Schegg, Jonas, Burton, Jeremy P, Spooren, Anneleen | In health, the gut microbiome functions as a stable ecosystem maintaining overall balance and ensuring its own survival against environmental stressors through complex microbial interaction. This balance and protection from stressors is maintained through interactions both within the bacterial ecosystem as well as with its host. As a consequence, the gut microbiome plays a critical role in various physiological processes including maintaining the structure and function of the gut barrier, educating the gut immune system, and modulating the gut motor, digestive/absorptive, as well as neuroendocrine system all of which are crucial for human health and disease pathogenesis. Pre- and probiotics, widely available and clinically established, offer various health benefits primarily by beneficially modulating the gut microbiome. However, their clinical outcomes can vary significantly due to differences in host physiology, diets, individual microbiome compositions, and other environmental factors. This perspective paper highlights emerging scientific insights into the importance of microbial micronutrient sharing, gut redox balance, keystone species, and the gut barrier in maintaining a diverse and functional microbial ecosystem, and their relevance to human health. We propose a novel approach that targets microbial ecosystems and keystone taxa performance by supplying microbial micronutrients in the form of colon-delivered vitamins, and precision prebiotics [e.g. human milk oligosaccharides (HMOs) or synthetic glycans] as components of precisely tailored ingredient combinations to optimize human health. Such a strategy may effectively support and stabilize microbial ecosystems, providing a more robust and consistent approach across various individuals and environmental conditions, thus, overcoming the limitations of current single biotic solutions. | Gut microbes | 00/12/2025 |
('LID', '10.1016/j.cellsig.2025.111715') | Neurodegenerative diseases: Epigenetic regulatory mechanisms and therapeutic potential. | Men, Jianbing, Wang, Xinyue, Zhou, Yunnuo, Huang, Yumeng, Zheng, Yue, Wang, Yingze, Yang, Shuang, Chen, Nan, Yan, Nan, Duan, Xiaoxu | Neurodegenerative diseases (NDDs) are a class of diseases in which the progressive loss of subtype-specific neurons leads to dysfunction. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others. Previous studies have demonstrated that the pathogenesis of NDDs involves various mechanisms, including genetic factors, oxidative stress, apoptosis, and the immune response. Recent studies have shown that epigenetic regulation mediates the interactions between DNA methylation, chromatin remodeling, histone modification, and non-coding RNAs, thus affecting gene transcription. A growing body of research links epigenetic modifications to crucial pathways involved in the occurrence and development of NDDs. Epigenetics has also been found to regulate and maintain nervous system function, and its imbalance is closely related to the occurrence and development of NDDs. The present review summarizes focuses on the role of epigenetic modifications in the pathogenesis of NDDs and provides an overview of the key genes regulated by DNA methylation, histone modification, and non-coding RNAs in NDDs. Further, the current research status of epigenetics in NDDs is summarized and the potential application of epigenetics in the clinical diagnosis and treatment of NDDs is discussed. | Cellular signalling | 13/03/2025 |
('LID', '10.1038/s41392-025-02145-7') | Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances. | Jiang, Qiu, Liu, Jie, Huang, Shan, Wang, Xuan-Yue, Chen, Xiaowei, Liu, Guang-Hui, Ye, Keqiang, Song, Weihong, Masters, Colin L, Wang, Jun, Wang, Yan-Jiang | In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases. | Signal transduction and targeted therapy | 10/03/2025 |
('LID', '10.1002/gps.70069') | Changes in the Disease Burden of Depressive Disorders Among Middle-Aged and Older Adults (Aged 45-89) in China Over 30 years: Insights From the Global Burden of Disease Study 2021. | Xiao, Yu, Chen, Ting-Ting, Zhang, Zhou, Liu, Liang, Du, Na | OBJECTIVES: In China, depressive disorder (DD) among middle-aged and older adults is a significant public health concern. This research utilized the latest Global Burden of Disease Study (GBD) database to evaluate the evolving disease burden of DD in this demographic over the past 3 decades. METHODS: Data on the incidence and disability-adjusted life years (DALY) of DD among people aged 45-89 in China between 1992 and 2021 were collected from the GBD 2021. The age-period-cohort (APC) model was applied to determine the effects of age, period, and cohort on the incidence and DALY rates of DD. RESULTS: (1) Over the last 30 years, there was a 6.49% increase in the overall age-standardized incidence rate (ASIR) and a 3.99% increase in age-standardized DALY rates (ASDR) for DD among middle-aged and older adults in China, with females consistently exhibiting higher ASIR and ASDR than males. In 2020, COVID-19 significantly increased the ASIR and ASDR of DD in the population, especially in females. (2) The APC analysis revealed an annual net drift of 0.38% in incidence and 0.17% in DALY rate. For both genders, local drifts of incidence were negative for the 45-54 age group and positive for the 55-89 age group; DALY rates showed negative local drifts for the 45-59 age group and positive for the 60-89 age group. (3) Incidence and DALY rates increased with age, displaying a trend of initial decline followed by an increase in period effects, but a trend of initial increase followed by a decrease in cohort effects. Moreover, the impacts of age, period, and cohort exhibited gender differences. CONCLUSIONS: Our findings provide a comprehensive and in-depth perspective for studying the changing trends of DD's burden in China and for identifying targeted prevention and treatment policies for DD from different aspects. | International journal of geriatric psychiatry | 00/03/2025 |
('LID', '10.1038/s41586-025-08706-8') | Perception of viral infections and initiation of antiviral defence in rice. | Huang, Yu, Yang, Jialin, Sun, Xi, Li, Jiahao, Cao, Xiaoqiang, Yao, Shengze, Han, Yanhong, Chen, Changtian, Du, Linlin, Li, Shuo, Ji, Yinghua, Zhou, Tong, Wang, He, Han, Jia-Jia, Wang, Wenming, Wei, Chunhong, Xie, Qi, Yang, Zhirui, Li, Yi | Crop production faces persistent threats from insect-vector-borne viral diseases(1,2). Recent advancements have revealed the intricate immune mechanisms that plants deploy against viral pathogens(3-8). However, the molecular mechanisms through which plant hosts recognize viral infections and initiate antiviral defence at disease onset have not been elucidated. Here, through the natural infection of rice by inoculation with insect vectors carrying the natural forms of viruses, we show that viral coat proteins are perceived by the RING1-IBR-RING2-type ubiquitin ligase (RBRL), initiating the first step of the natural antiviral response in rice. RBRL subsequently targets an adaptor protein of the transcriptional repression complex of the jasmonate pathway, NOVEL INTERACTOR OF JAZ 3 (NINJA3), for degradation through the ubiquitination system, inducing jasmonate signalling and activating downstream antiviral defence. We further show that this phenomenon is a universal molecular mechanism used by rice plants to perceive viral infections and initiate antiviral signalling cascades. This approach is important not only for obtaining a deeper understanding of virus-host interactions but also for further disease resistance breeding. | Nature | 12/03/2025 |
('LID', '10.1186/s12951-025-03284-3') | Functional nanozyme system for synergistic tumor immunotherapy via cuproptosis and ferroptosis activation. | Gu, Lina, Sun, Ying, Bai, Tingjie, Shao, Sijie, Tang, Shumin, Xue, Panpan, Cai, Wanlin, Qin, Xian, Zeng, Xuemei, Yan, Shuangqian | Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed CussOMEp, comprising a copper-based nanovector (CussNV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. CussNV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, CussOMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), CussOMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis. | Journal of nanobiotechnology | 15/03/2025 |
('LID', '10.1038/s41467-025-57590-3') | Single-cell and chromatin accessibility profiling reveals regulatory programs of pathogenic Th2 cells in allergic asthma. | Khan, Matarr, Alteneder, Marlis, Reiter, Wolfgang, Krausgruber, Thomas, Dobnikar, Lina, Madern, Moritz, Waldherr, Monika, Bock, Christoph, Hartl, Markus, Ellmeier, Wilfried, Henriksson, Johan, Boucheron, Nicole | Lung pathogenic T helper type 2 (pTh2) cells are important in mediating allergic asthma, but fundamental questions remain regarding their heterogeneity and epigenetic regulation. Here we investigate immune regulation in allergic asthma by single-cell RNA sequencing in mice challenged with house dust mite, in the presence and absence of histone deacetylase 1 (HDAC1) function. Our analyses indicate two distinct highly proinflammatory subsets of lung pTh2 cells and pinpoint thymic stromal lymphopoietin (TSLP) and Tumour Necrosis Factor Receptor Superfamily (TNFRSF) members as important drivers to generate pTh2 cells in vitro. Using our in vitro model, we uncover how signalling via TSLP and a TNFRSF member shapes chromatin accessibility at the type 2 cytokine gene loci by modulating HDAC1 repressive function. In summary, we have generated insights into pTh2 cell biology and establish an in vitro model for investigating pTh2 cells that proves useful for discovering molecular mechanisms involved in pTh2-mediated allergic asthma. | Nature communications | 15/03/2025 |
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