bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–03–23
33 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Nutrients shape T cell exhaustion.
  2. Quantitative characterization of cell niches in spatially resolved omics data.
  3. Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane.
  4. Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse.
  5. A guide to the Nature Index.
  6. Computational memory capacity predicts aging and cognitive decline.
  7. Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.
  8. Lewy body disease can spread via two distinct body-first routes.
  9. SIRT5 slows skeletal muscle ageing by alleviating inflammation.
  10. Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition.
  11. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  12. The brain's regulators.
  13. Genetic protection from type 1 diabetes resulting from accelerated insulin mRNA decay.
  14. How extreme lethargy can promote healthy ageing.
  15. Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments.
  16. Aspirin helps T cells to stop cancer spread.
  17. Vaccines save lives. Leaders must champion them.
  18. Your lab pollutes: here's how to stop it.
  19. Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.
  20. Social disadvantage accelerates aging.
  21. Sparse haplotype-based fine-scale local ancestry inference at scale reveals recent selection on immune responses.
  22. Machine learning reveals distinct neuroanatomical signatures of cardiovascular and metabolic diseases in cognitively unimpaired individuals.
  23. Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis.
  24. Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions.
  25. Asgard Arf GTPases can act as membrane-associating molecular switches with the potential to function in organelle biogenesis.
  26. Cancer research needs neuroscience and neuroscientists.
  27. Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice.
  28. Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
  29. Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
  30. Japan needs a fresh approach to innovation.
  31. Recycling dead bacteria to fuel macrophage immunometabolism.
  32. BASTA, a simple whole-blood assay for measuring β cell antigen-specific CD4+ T cell responses in type 1 diabetes.
  33. TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations.
  1. Nat Cell Biol. 2025 Mar;27(3): 371
    Nutrients shape T cell exhaustion.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s41556-025-01644-7
  2. Nat Genet. 2025 Mar 18.
    Quantitative characterization of cell niches in spatially resolved omics data.
    Sebastian Birk, Irene Bonafonte-Pardàs, Adib Miraki Feriz, Adam Boxall, Eneritz Agirre, Fani Memi, Anna Maguza, Anamika Yadav, Erick Armingol, Rong Fan, Gonçalo Castelo-Branco, Fabian J Theis, Omer Ali Bayraktar, Carlos Talavera-López, Mohammad Lotfollahi.
      Spatial omics enable the characterization of colocalized cell communities that coordinate specific functions within tissues. These communities, or niches, are shaped by interactions between neighboring cells, yet existing computational methods rarely leverage such interactions for their identification and characterization. To address this gap, here we introduce NicheCompass, a graph deep-learning method that models cellular communication to learn interpretable cell embeddings that encode signaling events, enabling the identification of niches and their underlying processes. Unlike existing methods, NicheCompass quantitatively characterizes niches based on communication pathways and consistently outperforms alternatives. We show its versatility by mapping tissue architecture during mouse embryonic development and delineating tumor niches in human cancers, including a spatial reference mapping application. Finally, we extend its capabilities to spatial multi-omics, demonstrate cross-technology integration with datasets from different sequencing platforms and construct a whole mouse brain spatial atlas comprising 8.4 million cells, highlighting NicheCompass' scalability. Overall, NicheCompass provides a scalable framework for identifying and analyzing niches through signaling events.
    DOI:  https://doi.org/10.1038/s41588-025-02120-6
  3. Nat Commun. 2025 Mar 19. 16(1): 2725
    Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane.
    Li Xie, Fei Kang, Tairan Qin, Youhou Kang, Tao Liang, Huanli Xie, Carol D Froese, Hong Xie, Aaron Au, Christopher M Yip, William S Trimble, Herbert Y Gaisano.
      Septin5 interacts with SNARE proteins to regulate exocytosis in neurons, but its role in pancreatic β-cells is unknown. Here, we report that Septin5 is abundant in rodent and human β-cells, deletion of which dramatically enhances biphasic glucose-stimulated insulin secretion, including in type 2 diabetes (T2D). Super-resolution imaging shows that Septin5 is preferentially assembled in microtubule-plasma membrane contact sites in a microtubule-dependent manner, which provides discrete harbor for secretory granule anchoring. By decreasing the stability of the cortical microtubule meshwork, Septin5 depletion increases insulin granule dynamics and access to the plasma membrane. Analysis of spatiotemporal coupling of fusion events and localized Ca2+ influx through L-type Ca2+ channels show that Septin5 depletion increases releasable granule pool clustering on Ca2+ channels, previously shown to be impaired in T2D, thus rectifying this T2D defect. Hence, inhibition of Septin5 can improve insulin secretion.
    DOI:  https://doi.org/10.1038/s41467-025-57421-5
  4. Nat Cardiovasc Res. 2025 Mar 17.
    Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse.
    Manuel E Cantu Gutierrez, Matthew C Hill, Gabrielle E Largoza, William B Gillespie, James F Martin, Joshua D Wythe.
      The vascular endothelium features unique molecular and functional properties across different vessel types, such as between arteries, veins and capillaries, as well as between different organs, such as the leaky sinusoidal endothelium of the liver versus the impermeable vessels of the brain. However, the transcriptional networks governing endothelial organ specialization remain unclear. Here we profile the accessible chromatin and transcriptional landscapes of the endothelium from the mouse liver, lung, heart, kidney, brain and retina, across developmental time, to identify potential transcriptional regulators of endothelial heterogeneity. We then determine which of these putative regulators are conserved in human brain endothelial cells, and using single-cell transcriptomic profiling, we define which regulatory networks are active during brain maturation. Finally, we show that the putative transcriptional regulators identified by these three approaches molecularly and functionally reprogram naive endothelial cells. Thus, this resource can be used to identify potential transcriptional regulators controlling the establishment and maintenance of organ-specific endothelial specialization.
    DOI:  https://doi.org/10.1038/s44161-025-00618-0
  5. Nature. 2025 Mar 19.
    A guide to the Nature Index.
      
    Keywords:  Databases; Energy
    DOI:  https://doi.org/10.1038/d41586-025-00748-2
  6. Nat Commun. 2025 Mar 20. 16(1): 2748
    Computational memory capacity predicts aging and cognitive decline.
    Mite Mijalkov, Ludvig Storm, Blanca Zufiria-Gerbolés, Dániel Veréb, Zhilei Xu, Anna Canal-Garcia, Jiawei Sun, Yu-Wei Chang, Hang Zhao, Emiliano Gómez-Ruiz, Massimiliano Passaretti, Sara Garcia-Ptacek, Miia Kivipelto, Per Svenningsson, Henrik Zetterberg, Heidi Jacobs, Kathy Lüdge, Daniel Brunner, Bernhard Mehlig, Giovanni Volpe, Joana B Pereira.
      Memory is a crucial cognitive function that deteriorates with age. However, this ability is normally assessed using cognitive tests instead of the architecture of brain networks. Here, we use reservoir computing, a recurrent neural network computing paradigm, to assess the linear memory capacities of neural-network reservoirs extracted from brain anatomical connectivity data in a lifespan cohort of 636 individuals. The computational memory capacity emerges as a robust marker of aging, being associated with resting-state functional activity, white matter integrity, locus coeruleus signal intensity, and cognitive performance. We replicate our findings in an independent cohort of 154 young and 72 old individuals. By linking the computational memory capacity of the brain network with cognition, brain function and integrity, our findings open new pathways to employ reservoir computing to investigate aging and age-related disorders.
    DOI:  https://doi.org/10.1038/s41467-025-57995-0
  7. Nat Commun. 2025 Mar 15. 16(1): 2569
    Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.
    Magdalena Sevilla-González, Kirk Smith, Ningyuan Wang, Aubrey E Jensen, Elizabeth M Litkowski, Hyunkyung Kim, Daniel A DiCorpo, Sarah Hsu, Jinrui Cui, Ching-Ti Liu, Chenglong Yu, John J McNeil, Paul Lacaze, Kenneth E Westerman, Kyong-Mi Chang, Philip S Tsao, Lawrence S Phillips, Mark O Goodarzi, Rob Sladek, Jerome I Rotter, Josée Dupuis, Jose C Florez, Jordi Merino, James B Meigs, Jin J Zhou, Sridharan Raghavan, Miriam S Udler, Alisa K Manning.
      Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.
    DOI:  https://doi.org/10.1038/s41467-025-57452-y
  8. Nat Neurosci. 2025 Mar 18.
    Lewy body disease can spread via two distinct body-first routes.
      
    DOI:  https://doi.org/10.1038/s41593-025-01911-8
  9. Nat Metab. 2025 Mar 14.
    SIRT5 slows skeletal muscle ageing by alleviating inflammation.
    Vera Gorbunova, Andrei Seluanov.
      
    DOI:  https://doi.org/10.1038/s42255-025-01228-7
  10. Nat Commun. 2025 Mar 20. 16(1): 2760
    Sublethal systemic LPS in mice enables gut-luminal pathogens to bloom through oxygen species-mediated microbiota inhibition.
    Sanne Kroon, Dejan Malcic, Lena Weidert, Lea Bircher, Leonardo Boldt, Philipp Christen, Patrick Kiefer, Anna Sintsova, Bidong D Nguyen, Manja Barthel, Yves Steiger, Melanie Clerc, Mathias K-M Herzog, Carmen Chen, Ersin Gül, Benoit Guery, Emma Slack, Shinichi Sunagawa, Julia A Vorholt, Lisa Maier, Christophe Lacroix, Annika Hausmann, Wolf-Dietrich Hardt.
      Endotoxin-driven systemic immune activation is a common hallmark across various clinical conditions. During acute critical illness, elevated plasma lipopolysaccharide triggers non-specific systemic immune activation. In addition, a compositional shift in the gut microbiota, including an increase in gut-luminal opportunistic pathogens, is observed. Whether a causal link exists between acute endotoxemia and abundance of gut-luminal opportunistic pathogens is incompletely understood. Here, we model acute, pathophysiological lipopolysaccharide concentrations in mice and show that systemic exposure promotes a 100-10'000-fold expansion of Klebsiella pneumoniae, Escherichia coli, Enterococcus faecium and Salmonella Typhimurium in the gut within one day, without overt enteropathy. Mechanistically, this is driven by a Toll-like receptor 4-dependent increase in gut-luminal oxygen species levels, which transiently halts microbiota fermentation and fuels growth of gut-luminal facultative anaerobic pathogens through oxidative respiration. Thus, systemic immune activation transiently perturbs microbiota homeostasis and favours opportunistic pathogens, potentially increasing the risk of infection in critically ill patients.
    DOI:  https://doi.org/10.1038/s41467-025-57979-0
  11. Nat Commun. 2025 Mar 19. 16(1): 2685
    Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
    Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.
      Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-57439-9
  12. Nat Immunol. 2025 Mar 19.
    The brain's regulators.
    Gustavo Gastão Davanzo, Jonathan Kipnis.
      
    DOI:  https://doi.org/10.1038/s41590-025-02116-8
  13. Cell. 2025 Mar 11. pii: S0092-8674(25)00206-5. [Epub ahead of print]
    Genetic protection from type 1 diabetes resulting from accelerated insulin mRNA decay.
    René van Tienhoven, Denis O'Meally, Tristan A Scott, Kevin V Morris, John C Williams, John S Kaddis, Arnaud Zaldumbide, Bart O Roep.
      Insulin gene (INS) variation and beta-cell stress are associated with the risk of development of type 1 diabetes (T1D) and autoimmunity against insulin. The unfolded protein response alleviating endoplasmic reticulum (ER) stress involves activation of inositol-requiring enzyme 1α (IRE1α) that impedes translation by mRNA decay. We discover that the IRE1α digestion motif is present in insulin mRNA carrying SNP rs3842752 (G>A). This SNP in the 3' untranslated region of INS associates with protection from T1D (INSP). ER stress in beta cells with INSP led to accelerated insulin mRNA decay compared with the susceptible INS variant (INSS). Human islets with INSP showed improved vitality and function and reversed diabetes more rapidly when transplanted into diabetic mice than islets carrying INSS only. Surrogate beta cells with INSP expressed less ER stress and INS-DRiP neoantigen. This explanation for genetic protection from T1D may act instead of or in concert with the previously proposed mechanism attributed to INS promoter polymorphism.
    Keywords:  ER stress; beta cell function; defective ribosomal product; genetic risk; immune tolerance; immunogenicity; insulin gene; neoantigen; type 1 diabetes; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cell.2025.02.018
  14. Nature. 2025 Mar;639(8055): 549
    How extreme lethargy can promote healthy ageing.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00707-x
  15. Nat Commun. 2025 Mar 20. 16(1): 2744
    Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments.
    Maike Becker, Stefanie Kälin, Anne H Neubig, Michael Lauber, Daria Opaleva, Hannah Hipp, Victoria K Salb, Verena B Ott, Beata Legutko, Roland E Kälin, Markus Hippich, Martin G Scherm, Lucas F R Nascimento, Isabelle Serr, Fabian Hosp, Alexei Nikolaev, Alma Mohebiany, Martin Krueger, Bianca Flachmeyer, Michael W Pfaffl, Bettina Haase, Chun-Xia Yi, Sarah Dietzen, Tobias Bopp, Stephen C Woods, Ari Waisman, Benno Weigmann, Matthias Mann, Matthias H Tschöp, Carolin Daniel.
      The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4+ T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4+ T cells reveals a Th1-like activation state, with increased Tbx21, Cxcr3 and Cd226 but decreased Ccr7 and S1pr1. Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-57918-z
  16. Nat Rev Immunol. 2025 Mar 17.
    Aspirin helps T cells to stop cancer spread.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01160-7
  17. Nature. 2025 Mar;639(8055): 546
    Vaccines save lives. Leaders must champion them.
      
    Keywords:  Epidemiology; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-00789-7
  18. Nature. 2025 Mar 14.
    Your lab pollutes: here's how to stop it.
    Marie Launay.
      
    Keywords:  Funding; Lab life; Scientific community; Sustainability
    DOI:  https://doi.org/10.1038/d41586-025-00500-w
  19. J Clin Invest. 2025 Mar 18. pii: e186478. [Epub ahead of print]
    Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.
    Yinkun Fu, Xin Peng, Hongyong Song, Xiaoyun Li, Yang Zhi, Jieting Tang, Yifan Liu, Ding Chen, Wenyan Li, Jing Zhang, Jing Ma, Ming He, Yimin Mao, Xu-Yun Zhao.
      Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
    Keywords:  Amino acid metabolism; Fibrosis; Hepatology; Metabolism; RNA processing
    DOI:  https://doi.org/10.1172/JCI186478
  20. Nat Med. 2025 Mar 14.
    Social disadvantage accelerates aging.
    Mika Kivimäki, Jaana Pentti, Philipp Frank, Fangyu Liu, Acer Blake, Solja T Nyberg, Jussi Vahtera, Archana Singh-Manoux, Tony Wyss-Coray, Keenan A Walker, Linda Partridge, Joni V Lindbohm.
      Social disadvantage, like advanced age, is a risk factor for a broad range of health conditions; however, whether it influences the aging process remains unclear. Here, using a multicohort approach, we investigated the associations of social disadvantage with age-related plasma proteins and age-related diseases. We found proteomic signatures of accelerated immune aging and 14 specific age-related proteins linked to social disadvantage during both early and later life. Individuals experiencing social disadvantage had an increased risk of 66 age-related diseases, with up to 39% of these associations mediated by the 14 age-related proteins (for example, DNAJB9, F2, HSPA1A, BGN). The main enriched pathway involved the upregulation of the pro-inflammatory regulator NF-κB24 and its downstream factor interleukin-8. Our findings support the hypothesis that social disadvantage throughout the life course may accelerate aging, a biological mechanism that could explain why social stratification plays such a fundamental role in determining human health.
    DOI:  https://doi.org/10.1038/s41591-025-03563-4
  21. Nat Commun. 2025 Mar 20. 16(1): 2742
    Sparse haplotype-based fine-scale local ancestry inference at scale reveals recent selection on immune responses.
    Yaoling Yang, Richard Durbin, Astrid K N Iversen, Daniel J Lawson.
      Increasingly efficient methods for inferring the ancestral origin of genome regions are needed to gain insights into genetic function and history as biobanks grow in scale. Here we describe two near-linear time algorithms to learn ancestry harnessing the strengths of a Positional Burrows-Wheeler Transform. SparsePainter is a faster, sparse replacement of previous model-based 'chromosome painting' algorithms to identify recently shared haplotypes, whilst PBWTpaint uses further approximations to obtain lightning-fast estimation optimized for genome-wide relatedness estimation. The computational efficiency gains of these tools for fine-scale local ancestry inference offer the possibility to analyse large-scale genomic datasets using different approaches. Application to the UK Biobank shows that haplotypes better represent ancestries than principal components, whilst linkage-disequilibrium of ancestry identifies signals of recent changes to population-specific selection for many genomic regions associated with immune responses, suggesting avenues for understanding the pathogen-immune system interplay on a historical timescale.
    DOI:  https://doi.org/10.1038/s41467-025-57601-3
  22. Nat Commun. 2025 Mar 19. 16(1): 2724
    Machine learning reveals distinct neuroanatomical signatures of cardiovascular and metabolic diseases in cognitively unimpaired individuals.
    Sindhuja Tirumalai Govindarajan, Elizabeth Mamourian, Guray Erus, Ahmed Abdulkadir, Randa Melhem, Jimit Doshi, Raymond Pomponio, Duygu Tosun, Murat Bilgel, Yang An, Aristeidis Sotiras, Daniel S Marcus, Pamela LaMontagne, Tammie L S Benzinger, Mark A Espeland, Colin L Masters, Paul Maruff, Lenore J Launer, Jurgen Fripp, Sterling C Johnson, John C Morris, Marilyn S Albert, R Nick Bryan, Susan M Resnick, Mohamad Habes, Haochang Shou, David A Wolk, Ilya M Nasrallah, Christos Davatzikos.
      Comorbid cardiovascular and metabolic risk factors (CVM) differentially impact brain structure and increase dementia risk, but their specific magnetic resonance imaging signatures (MRI) remain poorly characterized. To address this, we developed and validated machine learning models to quantify the distinct spatial patterns of atrophy and white matter hyperintensities related to hypertension, hyperlipidemia, smoking, obesity, and type-2 diabetes mellitus at the patient level. Using harmonized MRI data from 37,096 participants (45-85 years) in a large multinational dataset of 10 cohort studies, we generated five in silico severity markers that: i) outperformed conventional structural MRI markers with a ten-fold increase in effect sizes, ii) captured subtle patterns at sub-clinical CVM stages, iii) were most sensitive in mid-life (45-64 years), iv) were associated with brain beta-amyloid status, and v) showed stronger associations with cognitive performance than diagnostic CVM status. Integrating personalized measurements of CVM-specific brain signatures into phenotypic frameworks could guide early risk detection and stratification in clinical studies.
    DOI:  https://doi.org/10.1038/s41467-025-57867-7
  23. J Clin Invest. 2025 Mar 17. pii: e185217. [Epub ahead of print]135(6):
    Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis.
    Accelerating Medicines Partnership RA/SLE Network
      Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.
    Keywords:  Arthritis; Autoimmunity; Bioinformatics; Immunology; Rheumatology
    DOI:  https://doi.org/10.1172/JCI185217
  24. Cell. 2025 Mar 14. pii: S0092-8674(25)00209-0. [Epub ahead of print]
    Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions.
    Wenxue Li, Abhijit Dasgupta, Ka Yang, Shisheng Wang, Nisha Hemandhar-Kumar, Surendhar R Chepyala, Jay M Yarbro, Zhenyi Hu, Barbora Salovska, Eugenio F Fornasiero, Junmin Peng, Yansheng Liu.
      Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications such as phosphorylation are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood. Here, we present Turnover-PPT, a comprehensive resource mapping the abundance and lifetime of 11,000 proteins and 40,000 phosphosites in eight mouse tissues and various brain regions using advanced proteomics and stable isotope labeling. We reveal tissue-specific short- and long-lived proteins, strong correlations between interacting protein lifetimes, and distinct impacts of phosphorylation on protein turnover. Notably, we discover a remarkable pattern of turnover changes for peroxisome proteins in specific tissues and that phosphorylation regulates the stability of neurodegeneration-related proteins, such as Tau and α-synuclein. Thus, Turnover-PPT provides fundamental insights into protein stability, tissue dynamic proteotypes, and functional protein phosphorylation and is accessible via an interactive web-based portal at https://yslproteomics.shinyapps.io/tissuePPT.
    Keywords:  DIA-MS; TMT; brain regions; mouse tissues; protein lifetime; protein phosphorylation; protein turnover; proteomics; pulse SILAC
    DOI:  https://doi.org/10.1016/j.cell.2025.02.021
  25. Nat Commun. 2025 Mar 17. 16(1): 2622
    Asgard Arf GTPases can act as membrane-associating molecular switches with the potential to function in organelle biogenesis.
    Jing Zhu, Ruize Xie, Qiaoying Ren, Jiaming Zhou, Chen Chen, Meng-Xi Xie, You Zhou, Yan Zhang, Ningjing Liu, Jinchao Wang, Zhengwei Zhang, Xipeng Liu, Wupeng Yan, Qingqiu Gong, Liang Dong, Jinwei Zhu, Fengping Wang, Zhiping Xie.
      Inward membrane budding, i.e., the bending of membrane towards the cytosol, is essential for forming and maintaining eukaryotic organelles. In eukaryotes, Arf GTPases initiate this inward budding. Our research shows that Asgard archaea genomes encode putative Arf proteins (AArfs). AArfs possess structural elements characteristic of their eukaryotic counterparts. When expressed in yeast and mammalian cells, some AArfs displayed GTP-dependent membrane targeting. In vitro, AArf associated with both eukaryotic and archaeal membranes. In yeast, AArfs interacted with and were regulated by key organelle biogenesis players. Expressing an AArf led to a massive proliferation of endomembrane organelles including the endoplasmic reticulum and Golgi. This AArf interacted with Sec23, a COPII vesicle coat component, in a GTP-dependent manner. These findings suggest certain AArfs are membrane-associating molecular switches with the functional potential to initiate organelle biogenesis, and the evolution of a functional coat could be the next critical step towards establishing eukaryotic cell architecture.
    DOI:  https://doi.org/10.1038/s41467-025-57902-7
  26. Nat Neurosci. 2025 Mar 20.
    Cancer research needs neuroscience and neuroscientists.
    Michelle Monje, Frank Winkler.
      
    DOI:  https://doi.org/10.1038/s41593-025-01925-2
  27. Nat Commun. 2025 Mar 14. 16(1): 2528
    Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice.
    Dongmei Chi, Kun Zhang, Jianxing Zhang, Zhaoli He, Hongxia Zhou, Wan Huang, Yang Liu, Jingxiu Huang, Weian Zeng, Xiaohui Bai, Chaopeng Ou, Handong Ouyang.
      Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) is an important brain region involved in major depressive disorder (MDD). However, the underlying mechanism by which astrocytes within PFC contribute to MDD remains unclear. Using single-nucleus RNA sequencing analyses, we show a significant reduction in astrocytes and attenuated pleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1) signaling in astrocyte-to-excitatory neuron communication in the PFC of male MDD patients. We find reduced astrocytes and PTN in the dorsomedial PFC of male mice with depression induced by chronic restraint and social defeat stress. Knockdown of astrocytic PTN induces depression-related responses, which is reversed by exogenous PTN supplementation or overexpression of astrocytic PTN. The antidepressant effects exerted by astrocytic PTN require interaction with PTPRZ1 in excitatory neurons, and PTN-PTPRZ1 activates the AKT signaling pathway to regulate depression-related responses. Our findings indicate the PTN-PTPRZ1-AKT pathway may be a potential therapeutic target for MDD.
    DOI:  https://doi.org/10.1038/s41467-025-57924-1
  28. Nat Commun. 2025 Mar 14. 16(1): 2527
    Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
    Yasmyn E Winstanley, Ryan D Rose, Alexander P Sobinoff, Linda L Wu, Deepak Adhikari, Qing-Hua Zhang, Jadon K Wells, Lee H Wong, Hazel H Szeto, Sandra G Piltz, Paul Q Thomas, Mark A Febbraio, John Carroll, Hilda A Pickett, Darryl L Russell, Rebecca L Robker.
      The initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known. We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2 or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis. Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization. Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length.
    DOI:  https://doi.org/10.1038/s41467-025-57794-7
  29. Nat Commun. 2025 Mar 16. 16(1): 2597
    Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
    Haibin Deng, Liang Zhao, Huixiang Ge, Yanyun Gao, Yan Fu, Yantang Lin, Mojgan Masoodi, Tereza Losmanova, Michaela Medová, Julien Ott, Min Su, Wenxiang Wang, Ren-Wang Peng, Patrick Dorn, Thomas Michael Marti.
      Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB's role in countering mitochondria-associated ferroptosis independently of lactate's function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.
    DOI:  https://doi.org/10.1038/s41467-025-57906-3
  30. Nature. 2025 Mar;639(8055): 577
    Japan needs a fresh approach to innovation.
    Peter Gruss.
      
    Keywords:  Funding; Policy; Research management
    DOI:  https://doi.org/10.1038/d41586-025-00821-w
  31. Nat Immunol. 2025 Mar 19.
    Recycling dead bacteria to fuel macrophage immunometabolism.
    Shane M O'Carroll, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1038/s41590-025-02117-7
  32. Sci Transl Med. 2025 Mar 19. 17(790): eadt2124
    BASTA, a simple whole-blood assay for measuring β cell antigen-specific CD4+ T cell responses in type 1 diabetes.
    Matthew Lacorcia, Pushpak Bhattacharjee, Abby Foster, Melinda Y Hardy, Jason A Tye-Din, John A Karas, John M Wentworth, Fergus J Cameron, Stuart I Mannering.
      Type 1 diabetes (T1D) is an autoimmune disease where T cells mediate the destruction of the insulin-producing β cells found within the islets of Langerhans in the pancreas. Autoantibodies to β cell antigens are the only tests available to detect β cell autoimmunity. T cell responses to β cell antigens, which are known to cause T1D, can only be measured in research settings because of the complexity of assays and the large blood volumes required. Here, we describe the β cell antigen-specific T cell assay (BASTA). BASTA is a simple whole-blood assay that can detect human CD4+ T cell responses to β cell antigens by measuring antigen-stimulated interleukin-2 (IL-2) production. BASTA is both more sensitive and specific than the CFSE (carboxyfluorescein diacetate succinimidyl ester)-based proliferation assay. We used BASTA to identify the regions of preproinsulin that stimulated T cell responses specifically in blood from people with T1D. BASTA can be done with as little as 2 to 3 milliliters of blood. We found that effector memory CD4+ T cells are the primary producers of IL-2 in response to preproinsulin peptides. We then evaluated responses to individual and pooled preproinsulin peptides in a cross-sectional study of pediatric patients: without T1D, without T1D but with a first-degree relative with T1D, or diagnosed with T1D. In contrast with other preproinsulin peptides, full-length C-peptide (PI33-63) showed high specificity for T1D [area under the curve (AUC) = 0.86)]. We suggest that BASTA will be a useful tool for monitoring changes in β cell-specific CD4+ T cell responses both in research and clinical settings.
    DOI:  https://doi.org/10.1126/scitranslmed.adt2124
  33. J Cell Biol. 2025 May 05. pii: e202408050. [Epub ahead of print]224(5):
    TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations.
    Jiasheng Li, Jimeng Cui, Xinyu Li, Di Zhu, Zhenhua Chen, Xiahe Huang, Yingchun Wang, Qingfeng Wu, Ye Tian.
      Neuronal mitochondrial function is critical for orchestrating inter-tissue communication essential for overall fitness. Despite its significance, the molecular mechanism underlying the impact of prolonged mitochondrial stresses on neuronal activity and how they orchestrate metabolism and aging remains elusive. Here, we identified the evolutionarily conserved transmembrane protein XBX-6/TMBIM-2 as a key mediator in the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt). Our investigations reveal that intrinsic neuronal mitochondrial stress triggers spatiotemporal Ca2+ oscillations in a TMBIM-2-dependent manner through the Ca2+ efflux pump MCA-3. Notably, persistent Ca2+ oscillations at synapses of ADF neurons are critical for facilitating serotonin release and the subsequent activation of the neuronal-to-intestinal UPRmt. TMBIM2 expression diminishes with age; however, its overexpression counteracts the age-related decline in aversive learning behavior and extends the lifespan of Caenorhabditis elegans. These findings underscore the intricate integration of chronic neuronal mitochondrial stress into neurotransmission processes via TMBIM-2-dependent Ca2+ equilibrium, driving metabolic adaptation and behavioral changes for the regulation of aging.
    DOI:  https://doi.org/10.1083/jcb.202408050
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