bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–10–12
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Recycling enhancers.
  2. Proteotoxic shock is a mechanistic driver of T cell exhaustion.
  3. Autoimmune T cells identified in ALS.
  4. Daily briefing: Nobel Prize for discovery of 'brake' on immune system.
  5. Coronary artery disease-associated variants regulate vascular smooth muscle cell gene expression.
  6. The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
  7. New genetic insights show how modifiable risk factors influence brain aging.
  8. Daily briefing: The Nobel prizes' most prestigious rivals.
  9. Dissecting regulatory non-coding GWAS loci reveals fibroblast causal genes with pathophysiological relevance to heart failure.
  10. Enterobacteriaceae-derived cadaverine manipulates gut macrophage metabolism.
  11. Astrocytes make room for microglia.
  12. Targeting glycogen clearance to treat diabetic cardiomyopathy.
  13. Mapping causal non-coding variants in coronary artery disease.
  14. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  15. Rethinking India's plate to improve metabolic health.
  16. Incorporating meningeal immunity into vaccine development.
  17. Human Cell Aging Transcriptome Atlas (HCATA): a single-cell atlas of age-associated transcriptomic alterations across human tissues.
  18. Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
  19. Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.
  20. Automated classification of cellular expression in multiplexed imaging data with Nimbus.
  21. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  22. Natural directed evolution in gut microbiota.
  23. Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
  24. B cells promote atrial fibrillation via autoantibodies.
  25. BAF60a-dependent chromatin remodeling preserves β-cell function and contributes to the therapeutic benefits of GLP-1R agonists.
  26. Unlocking host response signatures in sepsis and critical illnesses.
  27. Medicine Nobel goes to scientists who revealed secrets of immune system 'regulation'.
  28. The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities.
  29. Research on immune system's 'police' garners Nobel.
  30. An "electric" microbial cue to control food intake behavior.
  1. Nat Genet. 2025 Oct;57(10): 2349
    Recycling enhancers.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-025-02385-x
  2. Nat Rev Immunol. 2025 Oct 07.
    Proteotoxic shock is a mechanistic driver of T cell exhaustion.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01236-4
  3. Nat Rev Immunol. 2025 Oct 08.
    Autoimmune T cells identified in ALS.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01233-7
  4. Nature. 2025 Oct 06.
    Daily briefing: Nobel Prize for discovery of 'brake' on immune system.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-03286-z
  5. Nat Cardiovasc Res. 2025 Oct 07.
    Coronary artery disease-associated variants regulate vascular smooth muscle cell gene expression.
    Nicolas Barbera, Lily Lei, Alexia Wallace, Faruk Erin, R Noah Perry, Hester M den Ruijter, Mete Civelek.
      Genome-wide association studies have identified over 300 genomic loci associated with coronary artery disease (CAD) risk, but identifying functional variants remains challenging due to linkage disequilibrium. Here we show a comprehensive functional characterization of CAD-associated variants in primary vascular smooth muscle cells (SMCs). We performed lentivirus-based massively parallel reporter assays (lentiMPRAs) on 25,892 CAD-associated variants, testing their allele-specific enhancer activity in quiescent and proliferative SMCs. We identified 122 candidate variants with enhancer activity and allelic imbalance, including 23 variants showing condition-biased and 41 showing sex-biased effects. Integrating lentiMPRA with CUT&RUN epigenome profiling and expression quantitative trait loci data, we prioritized 49 functionally relevant variants. CRISPRi experiments on eight variants confirmed their regulatory effects on nine variant-gene pairs: rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF) and rs4627080 (NRIP3). Our results fine-map the causal variants that confer CAD risk through their effects on vascular SMCs.
    DOI:  https://doi.org/10.1038/s44161-025-00714-1
  6. Cell Death Dis. 2025 Oct 06. 16(1): 693
    The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
    Jule Gerlach, Paola Pireddu, Xiaoqun Zhang, Simon Wetzel, Mara Mennuni, Dusanka Milenkovic, Hendrik Nolte, Fernanda da Silva Rodrigues, Niclas Branzell, Ibrahim Kaya, Rodolfo Garcia Villegas, Diana Rubalcava-Gracia, David Alsina, Regina Feederle, Per E Andrén, Thomas Langer, Per Svenningsson, Roberta Filograna.
      The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the genes encoding these proteins have been linked to severe disorders, including Parkinson's disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increase, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.
    DOI:  https://doi.org/10.1038/s41419-025-08030-z
  7. Nat Aging. 2025 Oct 09.
    New genetic insights show how modifiable risk factors influence brain aging.
      
    DOI:  https://doi.org/10.1038/s43587-025-00991-2
  8. Nature. 2025 Oct 03.
    Daily briefing: The Nobel prizes' most prestigious rivals.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-03275-2
  9. Nat Commun. 2025 Oct 10. 16(1): 9020
    Dissecting regulatory non-coding GWAS loci reveals fibroblast causal genes with pathophysiological relevance to heart failure.
    Richard Gill, Daniel R Lu, Ittai Eres, Jiamiao Lu, Jixin Cui, Chen Wang, Zhongsheng J Yu, Tracy Yamawaki, Hong Zhou, Baikang Pei, Junedh M Amrute, Yen-Sin Ang, Songli Wang, Kory J Lavine, Brandon Ason, Chi-Ming Li, Yi-Hsiang Hsu.
      Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. Here, we hypothesize that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. To test this, we utilized male primary cardiac fibroblasts to generate high-resolution Hi-C data and integrate it with functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. We identify several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and FURIN). We perform Perturb-seq in immortalized male cardiac fibroblasts to knock out putative regulatory elements, confirming regulatory relationships involving GJA1, CXCL12, and FURIN. Our results demonstrate that multi-omic approaches can delineate pathophysiologically relevant regulatory circuits connecting protein-coding genes to non-coding genetic variants associated with disease.
    DOI:  https://doi.org/10.1038/s41467-025-64070-1
  10. Nat Rev Immunol. 2025 Oct 07.
    Enterobacteriaceae-derived cadaverine manipulates gut macrophage metabolism.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01234-6
  11. Nat Neurosci. 2025 Oct;28(10): 2008
    Astrocytes make room for microglia.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-025-02082-2
  12. Nat Cardiovasc Res. 2025 Oct 09.
    Targeting glycogen clearance to treat diabetic cardiomyopathy.
    Nieves García-Quintáns, Juan A Bernal.
      
    DOI:  https://doi.org/10.1038/s44161-025-00733-y
  13. Nat Cardiovasc Res. 2025 Oct 07.
    Mapping causal non-coding variants in coronary artery disease.
    Stephen B Montgomery.
      
    DOI:  https://doi.org/10.1038/s44161-025-00715-0
  14. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  15. Nat Med. 2025 Oct 10.
    Rethinking India's plate to improve metabolic health.
      
    DOI:  https://doi.org/10.1038/s41591-025-04016-8
  16. Nat Commun. 2025 Oct 09. 16(1): 8981
    Incorporating meningeal immunity into vaccine development.
    Manisha Menon, Colin N Haile, David J Dowling.
      Meningeal immunity, a less-studied aspect of neuroimmune interactions, has recently come under the spotlight owing to the characterization of meningeal lymphatic vessels draining of the central nervous system (CNS). This changing landscape has begun to impact how vaccinologists and immunologists approach early pre-clinical vaccine development, including decentering the antigen, with a greater focus on the role of formulation science and route of delivery. Here, we review the current state of how concepts emerging from meningeal immunity are being incorporated into modern vaccine innovation, discovery, and development.
    DOI:  https://doi.org/10.1038/s41467-025-64476-x
  17. Commun Biol. 2025 Oct 09. 8(1): 1450
    Human Cell Aging Transcriptome Atlas (HCATA): a single-cell atlas of age-associated transcriptomic alterations across human tissues.
    Josh Bartz, Xiao Ma, Lei Zhang, Xiao Dong.
      Biological aging is associated with progressively more severe genetic and epigenetic alterations. While these changes are expected to affect the transcriptional profile of cells, the magnitude of that effect is unknown as the aging transcriptome is still poorly understood. Understanding the aging transcriptional landscape will give us greater insight into how cells are affected by and/or respond to the aging process. To facilitate the large-scale exploration of the aging transcriptome, we report the development of the Human Cell Aging Transcriptome Atlas (HCATA). HCATA, contains single-cell RNA-sequencing datasets from 76 publications totaling 92 million cells and 3,475 tissue-level samples across more than 50 tissue types with ages ranging from 0 to 103 years. HCATA includes a genome browser that allows users to interactively explore age-related differential expression, as well as functions to explore related pathways at the tissue and cell-type level. HCATA is publicly accessible at http://hcata-xiaodonglab.org:3304 .
    DOI:  https://doi.org/10.1038/s42003-025-08845-8
  18. Nat Commun. 2025 Oct 10. 16(1): 9022
    Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
    Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.
      Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.
    DOI:  https://doi.org/10.1038/s41467-025-64072-z
  19. Mol Metab. 2025 Oct 08. pii: S2212-8778(25)00174-7. [Epub ahead of print] 102267
    Adipocyte Heparan Sulfate Determines Type 2 Diabetes Susceptibility in Mice via FGF1-Mediated Glucose Regulation.
    Chung-Jui Yu, Ariane R Pessentheiner, Sihao Liu, Sarah Wax, Marissa L Maciej-Hulme, Chelsea D Painter, Bastian Ramms, Daniel R Sandoval, Anthony Quach, Natalie DeForest, G Michelle Ducasa, Chiara Tognaccini, Caroline Labib, Norah Al-Azzam, Friederike Haumann, Greg Trieger, Patrick Secrest, Amit Majithia, Aaron C Petrey, Kamil Godula, Annette R Atkins, Michael Downes, Ronald M Evans, Philip L S M Gordts.
      Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102267
  20. Nat Methods. 2025 Oct;22(10): 2161-2170
    Automated classification of cellular expression in multiplexed imaging data with Nimbus.
    Josef Lorenz Rumberger, Noah F Greenwald, Jolene S Ranek, Potchara Boonrat, Cameron Walker, Jannik Franzen, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Candace C Liu, Inna Averbukh, Hadeesha Piyadasa, Rami Vanguri, Iris Nederlof, Xuefei Julie Wang, David Van Valen, Marleen Kok, Sean C Bendall, Travis J Hollmann, Dagmar Kainmueller, Michael Angelo.
      Multiplexed imaging offers a powerful approach to characterize the spatial topography of tissues in both health and disease. To analyze such data, the specific combination of markers that are present in each cell must be enumerated to enable accurate phenotyping, a process that often relies on unsupervised clustering. We constructed the Pan-Multiplex (Pan-M) dataset containing 197 million distinct annotations of marker expression across 15 different cell types. We used Pan-M to create Nimbus, a deep learning model to predict marker positivity from multiplexed image data. Nimbus is a pretrained model that uses the underlying images to classify marker expression of individual cells as positive or negative across distinct cell types, from different tissues, acquired using different microscope platforms, without requiring any retraining. We demonstrate that Nimbus predictions capture the underlying staining patterns of the full diversity of markers present in Pan-M, and that Nimbus matches or exceeds the accuracy of previous approaches that must be retrained on each dataset. We then show how Nimbus predictions can be integrated with downstream clustering algorithms to robustly identify cell subtypes in image data. We have open-sourced Nimbus and Pan-M to enable community use at https://github.com/angelolab/Nimbus-Inference .
    DOI:  https://doi.org/10.1038/s41592-025-02826-9
  21. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  22. Science. 2025 Oct 09. 390(6769): 129-130
    Natural directed evolution in gut microbiota.
    Blair G Paul, John J Mekalanos.
      Bacteria undergo rapid genetic changes that are selected by alterations in the human gut environment.
    DOI:  https://doi.org/10.1126/science.aeb8597
  23. Nat Commun. 2025 Oct 06. 16(1): 8873
    Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
    Thashma Ganapathy, Juntao Yuan, Melody Yuen-Man Ho, Kelvin Ka-Lok Wu, Md Moinul Hoque, Baomin Wang, Xiaomu Li, Kai Wang, Martin Wabitsch, Xuejia Feng, Yongxia Niu, Kekao Long, Qizhou Lian, Yuyan Zhu, Kenneth King-Yip Cheng.
      Trimethylamine N-oxide (TMAO) contributes to cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) recognized as its primary source. Here we demonstrate that elevated adipocyte FMO3 and its derived TMAO trigger white adipose tissue (WAT) dysfunction and its related metabolic disorders in ageing. In adipocytes, ageing or p53 activation upregulates FMO3 and TMAO levels. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism and energy and lipid homeostasis in ageing and obese mice. These improvements are associated with reduced senescence, fibrosis and inflammation in WAT. Proteomics analysis identified TMAO-interacting proteins involved in inflammasome activation in adipocytes and macrophages. Mechanistically, TMAO binds to the central inflammasome adaptor protein ASC, promoting caspase-1 activation and interleukin-1β production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
    DOI:  https://doi.org/10.1038/s41467-025-63905-1
  24. Nat Cardiovasc Res. 2025 Oct 08.
    B cells promote atrial fibrillation via autoantibodies.
    Masahiro Yamazoe, Kenneth K Y Ting, I-Hsiu Lee, Aneesh Bapat, Andrew Lewis, Ling Xiao, Fadi E Pulous, Kyle Mentkowski, Alexandre Paccalet, Noor Momin, Hana Seung, Theresa Dolejsi, Nina Kumowski, Maximilian J Schloss, Yoshiko Iwamoto, Gustavo Ramos, Kenneth Chan, Charalambos Antoniades, Barbara Casadei, Filip K Swirski, Patrick T Ellinor, Kamila Naxerova, Steffen Pabel, Maarten Hulsmans, Matthias Nahrendorf.
      Atrial fibrillation, the most frequent cardiac arrhythmia, causes heart failure and stroke. Here we describe that combining the typical risk factors of atrial fibrillation (hypertension, obesity and mitral valve regurgitation (HOMER)) activates adaptive immunity in wild-type mice, ultimately causing electrical remodeling of cardiomyocytes. In HOMER mice, dendritic cells expanded in the left atria and heart-draining lymph nodes, where we detected cardiomyocyte-derived proteins. Systemically expanding B cells, while exposed to interferon-α, produced autoantibodies that disrupted calcium handling in cardiomyocytes. Depleting B cells by using μMT HOMER mice or plasma cells by using Mb1cre/+ Prdm1fl/fl HOMER mice reduced atrial fibrillation while mitigating the prolonged action potential duration we observed in the left atria of HOMER mice. CD20 antibody B cell depletion, a clinical tool in treating lymphoma and autoimmune disease, reduced atrial fibrillation fivefold in HOMER mice. Targeting humoral immunity may provide therapeutic avenues for patients with autoantibody-induced atrial fibrillation.
    DOI:  https://doi.org/10.1038/s44161-025-00724-z
  25. J Clin Invest. 2025 Oct 02. pii: e177980. [Epub ahead of print]
    BAF60a-dependent chromatin remodeling preserves β-cell function and contributes to the therapeutic benefits of GLP-1R agonists.
    Xinyuan Qiu, Ruo-Ran Wang, Qing-Qian Wu, Hongxing Fu, Shuaishuai Zhu, Wei Chen, Wen Wang, Haide Chen, Xiuyu Ji, Wenjing Zhang, Dandan Yan, Jing Yan, Li Jin, Rong Zhang, Mengjie Shi, Ping Luo, Yingqing Yang, Qintao Wang, Ziyin Zhang, Wei Ding, Xiaowen Pan, Chengbin Li, Bin Liang, Guoji Guo, Hai-Long Piao, Min Zheng, Yan Sheng, Lingyun Zhu, Cheng Hu, Zhuo-Xian Meng.
      Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β-cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β-cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β-cell function under metabolic stress conditions. BAF60a was downregulated in β-cells from obese and diabetic mice, monkeys, and humans. β-cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β-cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β-cells. A BAF60a V278M mutation associated with decreased β-cell GSIS function was identified in human subjects. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β-cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β-cells critical for glucose sensing and insulin secretion.
    Keywords:  Beta cells; Cell biology; Diabetes; Endocrinology; Insulin
    DOI:  https://doi.org/10.1172/JCI177980
  26. Nat Med. 2025 Oct 10.
    Unlocking host response signatures in sepsis and critical illnesses.
    Robert D Stevens, Carl Harris.
      
    DOI:  https://doi.org/10.1038/s41591-025-04005-x
  27. Nature. 2025 Oct 06.
    Medicine Nobel goes to scientists who revealed secrets of immune system 'regulation'.
    Miryam Naddaf, Elizabeth Gibney.
      
    Keywords:  Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-03193-3
  28. Nat Commun. 2025 Oct 10. 16(1): 9042
    The effect of type 2 diabetes genetic predisposition on non-cardiovascular comorbidities.
    Ana Luiza Arruda, Ozvan Bocher, Henry J Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C Wood, Ken Suzuki, Josep M Mercader, Cassandra N Spracklen, James B Meigs, Marijana Vujkovic, George Davey Smith, Jerome I Rotter, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini.
      Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts and erectile dysfunction are primarily attributed to adiposity and glucose regulation mechanisms, respectively. We observe opposing effect directions across different genetic ancestries for depression, asthma and chronic obstructive pulmonary disease. Our findings leverage the heterogeneity underpinning type 2 diabetes genetic predisposition to prioritize biological mechanisms underlying causal relationships with comorbidities.
    DOI:  https://doi.org/10.1038/s41467-025-64927-5
  29. Science. 2025 Oct 09. 390(6769): 112-113
    Research on immune system's 'police' garners Nobel.
    Catherine Offord.
      Three scientists honored for revealing how regulatory T cells prevent autoimmune disease.
    DOI:  https://doi.org/10.1126/science.aec9015
  30. Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00392-4. [Epub ahead of print]
    An "electric" microbial cue to control food intake behavior.
    Huixian Li, Daniel Mucida.
      The gut conveys nutritional, mechanical, and microbial signals to the brain to regulate physiology and behavior. Writing in Nature, Liu et al. reveal a colonic neuropod-vagus circuit that senses bacterial flagellin, highlighting microbial input as a rapid driver of feeding control and expanding paradigms of communication between the gut and the brain.
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.007
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