bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–03–01
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Digital medicine for infectious diseases.
  2. Parkinson's disease affects network of brain regions that controls whole-body action.
  3. How an exercise-activated enzyme helps to keep the brain young.
  4. Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis.
  5. Intermittent fasting evicts long-lived plasma cells from survival niche.
  6. Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
  7. RUNX phosphorylation specifies CD8+ T cell lineage during positive selection.
  8. Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory.
  9. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  10. Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes.
  11. AI-Driven Diabetes Prevention Program-Reply.
  12. Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
  13. DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage senescence.
  14. Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality.
  15. White adipocyte thermogenesis is not an artefact but an in vivo phenomenon.
  16. The protein carriers of hundreds of lipids have been identified.
  17. Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
  18. OMICmAge quantifies biological age by integrating multi-omics with electronic medical records.
  19. CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis.
  20. Evolving epigenomics of immune cells at single-nucleus resolution in children en route to type 1 diabetes.
  21. CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
  22. Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease.
  23. Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis.
  24. Automated insulin delivery systems and improved glycaemic outcomes in type 1 diabetes: what comes next?
  25. Investigating the Spectrum of Normoglycemia: Time in Glycemic Ranges and Their Association With Metabolic Outcomes in Individuals Without Diabetes.
  26. The Arp2/3 complex controls the development of homeostatic microglia.
  27. Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data.
  28. Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy.
  29. Flexible paths to multicellularity.
  30. Fasting impairs humoral immunological memory by β-hydroxybutyrate-mediated depletion of plasma cells.
  1. Nat Commun. 2026 Feb 23. pii: 1943. [Epub ahead of print]17(1):
    Digital medicine for infectious diseases.
      
    DOI:  https://doi.org/10.1038/s41467-026-69871-6
  2. Nature. 2026 Feb 25.
    Parkinson's disease affects network of brain regions that controls whole-body action.
      
    Keywords:  Brain; Neuroscience; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-026-00573-1
  3. Nature. 2026 Feb 25.
    How an exercise-activated enzyme helps to keep the brain young.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-026-00515-x
  4. Nat Commun. 2026 Feb 25.
    Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis.
    Evgenij Fiskin, Gökcen Eraslan, Maria B Alora-Palli, Tanvi Jain, Juan Manuel Leyva-Castillo, Sean Kim, Heather Choe, Caleb A Lareau, Helena Lau, Emily P Finan, Isabella Teixeira-Soldano, Brenna LaBere, Anne Chu, Brian Woods, Janet Chou, Michal Slyper, Julia Waldman, Sabina Islam, Lynda Schneider, Wanda Phipatanakul, Craig Platt, Orit Rozenblatt-Rosen, Toni M Delorey, Orr Ashenberg, Jacques Deguine, Gideon P Smith, Raif S Geha, Aviv Regev, Ramnik J Xavier.
      In atopic dermatitis (AD), skin barrier and immune dysfunction result in chronic tissue inflammation, yet our understanding of the tissue ecosystem remains incomplete. Here, we generate a multi-modal census of 280,518 cells from whole skin tissue samples from 17 adults, including 11 AD patients, integrating it with 430,186 cell profiles from four previous studies into a comprehensive human skin cell atlas. Reconstruction of keratinocyte differentiation revealed disrupted cornification in AD associated with signals from an immune and stromal multicellular community - comprising MMP12+ and migratory dendritic cells (DCs), cycling innate lymphoid cells (ILC), natural killer cells, inflammatory CCL19+ IL4I1+ fibroblasts, and clonally expanded IL13+IL22+IL26+ T cells connected by intercellular feedback loops predicted to impact community assembly. Subsets from this community, along with disrupted cornified keratinocytes, were enriched in GWAS, suggesting that dysfunction in this communication network may initiate AD. Our work highlights disease-associated cell subsets and interactions in chronic skin inflammation.
    DOI:  https://doi.org/10.1038/s41467-026-69587-7
  5. Nat Rev Immunol. 2026 Feb 27.
    Intermittent fasting evicts long-lived plasma cells from survival niche.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-026-01286-2
  6. Nat Commun. 2026 Feb 24.
    Male obesity causes adipose mitochondrial dysfunction in F1 mouse progeny via a let-7-DICER axis.
    Chien Huang, Joo-Hyun Park, Ali Altıntaş, Natasa Stanic, Kristine Kyle de Leon, Signe Isacson, Panagiotis Kalogeropoulos, Hande Topel, Tobias Madsen, Sebastian Zanner, Phillip Mm Ruppert, Rocio Valdebenito, Jesper Havelund, Bjørk Ditlev Marcher Larsen, Yen-Ting Chien, Wen-Chi Huang, Yovita Permata Budi, Yi-Fan Jiang, Andréa Livia Rocha, Niedson Correia Lima-Junior, Karolina Szczepanowska, Jan-Wilm Lackmann, Aleksandra Trifunovic, Eva Kildall Hejbøl, Sönke Detlefsen, Ida Engberg Jepsen, Stefanie Hansborg Kolstrup, Ricardo Laguna-Barraza, Javier Martin-Gonzalez, Konstantin Khodosevich, Nils J Færgeman, Marcelo A Mori, Marc R Friedländer, Anita Öst, Romain Barrès, Jan-Wilhelm Kornfeld.
      Male obesity negative affects gametic function and offspring metabolism. We here describe that (F0) obesity and weight loss in male mice reversibly alter metabolism and impair adipose mitochondrial function. These metabolic aberrations are transmitted to male offsprings (F1), which display reduced mitochondrial gene expression. Mechanistically, we identify microRNAs let-7d/e as epigenetic mediators induced in obese F0 sperm and in F0/F1 adipose tissue, where they silence the miRNA processor DICER1 and impair mitochondrial activity. Microinjecting let-7d/e into lean zygotes phenocopies the paternal obesity phenotype, inducing glucose intolerance and mitochondrial gene suppression in sired offspring. Single-cell RNA sequencing of blastomeres reveals that let-7d/e impair oxidative metabolism in early embryos. Furthermore, lifestyle-induced weight loss in males with obesity downregulates human HSA-LET-7D/E in semen, indicating a conserved role for let-7 in transmission of metabolic health. These findings demonstrate that microRNA let-7 in sperm reprograms offspring metabolism by modulating mitochondrial function during early development.
    DOI:  https://doi.org/10.1038/s41467-026-69686-5
  7. Nat Immunol. 2026 Feb 27.
    RUNX phosphorylation specifies CD8+ T cell lineage during positive selection.
      
    DOI:  https://doi.org/10.1038/s41590-026-02455-0
  8. Nat Immunol. 2026 Feb 24.
    Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory.
    Sina Frischholz, Ev-Marie Schuster, Myriam Grotz, Christine Schülein, Julia Benz, Katharina Kocher, Lucia Klotz, Szilard Varga, Theresa Hiltner, Rayya Alsalameh, Jan Esse, Johannes Träger, Jürgen Held, Frederik Graw, Jürgen Pahle, Bernd Spriewald, Luca Gattinoni, Veit R Buchholz, Felix Drost, Benjamin Schubert, Simon Rothenfußer, Dirk H Busch, Christian Bogdan, Kilian Schober.
      Metabolic activity shapes cell fate but remains challenging to capture in vivo with high resolution. Here we performed longitudinal metabolic and phenotypic profiling of human antigen-specific CD8+ T cells after yellow fever vaccination using flow cytometry and single-cell RNA sequencing. As assessed by protein translation rates, CD8+ T cells upregulated glycolysis to fuel anabolic needs for proliferation but predominantly used oxidative phosphorylation for energy production during the acute phase (days 7-28) after vaccination. Simultaneously, CD8+CD62L+CD45RA- central memory T cells were the most metabolically active subset, whereas CD8+CD62L-CD45RA+ effector T cells underwent metabolic shutdown. Weakly differentiated CD8+CD62L+CD45RA+CD95- naive-like memory T cells showed minimal activity, relied solely on oxidative phosphorylation and were preferentially maintained 26 years postvaccination, reinforcing the link between cellular quiescence and longevity. Our study highlights quiescence as a key feature for long-term immunological memory formation in humans.
    DOI:  https://doi.org/10.1038/s41590-026-02421-w
  9. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  10. Nat Med. 2026 Feb 23.
    Genetic regulation across germline and somatic variation on the Y chromosome contributes to type 2 diabetes.
    FinnGen
      Our understanding of the biological role of the Y chromosome remains limited. Here, we systematically profile germline Y haplogroups and somatic loss of the Y chromosome (LOY) in 122,683 East Asian males from BioBank Japan and 181,472 European males from the UK Biobank. A phenome-wide scan uncovers male-specific genetic regulation of complex traits, including pleiotropic effects of the Japanese-specific haplogroup D on height and type 2 diabetes (T2D). LOY increases T2D risk in East Asians but is associated with reduced T2D risk in Europeans. In East Asians, LOY contributes to T2D incidence particularly among males with lower polygenic risk scores, providing a compensatory explanation for disease risk beyond germline genetics. Incorporating sex-chromosome variation improves polygenic prediction of T2D risk in both sexes. Single-cell analyses reveal cell type-specific accumulation of LOY across tissues and disease contexts, with LOY in pancreatic β cells potentially impairing glucose metabolism. Our study demonstrates the clinical relevance of Y chromosome variation for diabetes risk prediction and management.
    DOI:  https://doi.org/10.1038/s41591-026-04213-z
  11. JAMA. 2026 Feb 23.
    AI-Driven Diabetes Prevention Program-Reply.
    Benjamin Lalani, Nestoras Mathioudakis.
      
    DOI:  https://doi.org/10.1001/jama.2025.26494
  12. Nat Metab. 2026 Feb 23.
    Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.
    Maryam Ahmadian, A Melisa Aksu, Preetveer Dhillon, Zane J Zerbel, Yosip Kelemen, Oluwafemi Gbayisomore, Nicolás Gómez-Banoy, Serena J Chen, Shannon M Reilly.
      Energy stored in adipocytes as triglycerides is mobilized via lipolysis, releasing fatty acids and glycerol into the circulation. Re-esterification of fatty acids that remain within the adipose tissue is the primary driver of adipocyte ATP consumption. Paradoxically, re-esterification suppresses respiration in lipolytic adipocytes. We previously found that STAT3 drives respiration by inhibiting re-esterification via GPAT3. Here we show that free fatty acids drive uncoupled respiration in complex with the ATP/ADP carriers. The impacts of lipolysis and re-esterification on uncoupled respiration correspond with fatty acids, not fatty acyl-CoAs or beta-oxidation. Under standard housing conditions, brown adipocyte uncoupling via uncoupling protein 1 is the dominant thermogenic pathway. However, in obese thermoneutral-adapted mice, uncoupled respiration in white adipocytes contributes to thermogenesis and cold tolerance, independent of brown adipose tissue or muscle activity. Our results suggest that uncoupled respiration in white adipocytes contributes to whole-body energy expenditure and could be a promising target for obesity treatment.
    DOI:  https://doi.org/10.1038/s42255-026-01467-2
  13. Nat Commun. 2026 Feb 24.
    DNA-PK-mediated phosphorylation of STAT6 establishes a non-canonical type 2 immunity axis to prevent macrophage senescence.
    Zhao Zhou, Xinmeng Li, Yushuang Wang, Long Liang, Chunyang Wang, Yongchang Sun, Dongmei Wu, Yifu Qiu.
      Macrophage senescence drives inflammaging, a chronic, age-related inflammation. To date, the protective mechanisms against inflammaging are poorly defined. Here, we identify DNA-PK-mediated phosphorylation of murine STAT6 at serine 807 (Ser807) as a crucial post-translational modification for preventing macrophage senescence. Ser807 phosphorylation blocks STAT6 ubiquitination-mediated degradation and promotes STAT6 partnering with PU.1 to activate DNA repair genes. Macrophages lacking Ser807 phosphorylation exhibit DNA repair defects, undergo senescence, and fuel inflammaging. In vivo, the phosphor-null STAT6 mutant (STAT6(S807A)) accelerates macrophage senescence, tissue fibrosis, and systemic aging. Adoptive transfer of phosphomimetic STAT6(S807E)-expressing macrophages rescues accelerated aging. Importantly, phosphorylation of human STAT6 at the homologous residue (Ser817) is significantly reduced in the lungs of patients with chronic obstructive pulmonary disease (COPD), correlating with increased DNA damage and senescence. Thus, our findings reveal a DNA-PK-STAT6 axis enacting a non-canonical type 2 immunity via DNA repair to prevent macrophage senescence, presenting a therapeutic target for healthy aging.
    DOI:  https://doi.org/10.1038/s41467-026-69996-8
  14. Nat Commun. 2026 Feb 21.
    Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality.
    Carter R Palmer, Jinghui Song, Bing Yang, Chien-Ju Chen, Dinh Diep, Kimberly Conklin, Nongluk Plongthongkum, Hannah S Indralingam, Christine S Liu, Joshua Kurtz, Qiwen Hu, Linnea Ransom, Anis Shahnaee, Annie Hiniker, Rebecca D Hodge, C Dirk Keene, Ed Lein, Peter Kharchenko, Nathan R Zemke, Jerold Chun, Bing Ren, Kun Zhang.
      Distinct regional functionality of the human cortex is orchestrated by diverse cellular and molecular processes, yet the underlying regulatory mechanisms remain poorly understood. We performed multiomic single-cell and spatial characterization of nine regions of the human cortex to define the gene regulatory networks and transcription factors that govern cell-type and region specificity. With the combined data of over three million cells, two striking patterns of cortical neuron specialization were uncovered: a rostral-caudal spatial pattern of calcium regulatory machinery, and subunit switching of multiple signaling receptor families across the transmodal-sensory axis. Gene regulatory network analysis revealed putative transcriptional regulators of cortical neuron specialization with cell-type- and region-specific gene regulation patterns. While regionalization was observed in gene expression, chromatin accessibility, and spatial distributions, these modalities exhibited distinct cortical patterns. Our findings illuminate critical neuronal pathways that vary throughout the cortex and the gene regulatory networks that establish cortical regionalization in the human brain.
    DOI:  https://doi.org/10.1038/s41467-026-69368-2
  15. Nat Metab. 2026 Feb 25.
    White adipocyte thermogenesis is not an artefact but an in vivo phenomenon.
      
    DOI:  https://doi.org/10.1038/s42255-026-01473-4
  16. Nature. 2026 Feb 25.
    The protein carriers of hundreds of lipids have been identified.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00570-4
  17. Nat Commun. 2026 Feb 24.
    Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.
    Eleanor Meader, Morgan T Walcheck, Mindy R Leder, Patrice Delaney, Marcelo Falchetti, Ran Jing, Christopher Li, Netra K Kambli, Paul J Wrighton, Wade W Sugden, Mohamad A Najia, Isaac M Oderberg, Vivian M Taylor, Zachary C LeBlanc, Eleanor D Quenzer, Sung-Eun Lim, Thorsten Schlaeger, George Q Daley, Wolfram Goessling, Trista E North.
      Embryonic hematopoietic stem and progenitor cells (HSPCs) have the clinically valuable ability to undergo substantial proliferative expansion while maintaining multipotency, which remains difficult to replicate in culture. Here, we show that newly specified HSPCs achieve this unique state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of mitophagy-reporter zebrafish indicate that mitophagy initiates during endothelial-to-hematopoietic transition and colonization of secondary niches. Knockdown of bnip3lb reduces mitophagy and HSPC numbers in the caudal hematopoietic tissue by promoting myeloid-biased differentiation and apoptosis, which can be rescued by antioxidant exposure. Conversely, chemical or genetic induction of mitophagy enhances embryonic HSPC and lymphoid progenitor numbers. Significantly, compound-mediated mitophagy activation improves ex vivo function of HSPCs derived from human-induced pluripotent stem cells, enhancing serial-replating hematopoietic colony forming potential.
    DOI:  https://doi.org/10.1038/s41467-026-69593-9
  18. Nat Aging. 2026 Feb 25.
    OMICmAge quantifies biological age by integrating multi-omics with electronic medical records.
    Qingwen Chen, Varun B Dwaraka, Natàlia Carreras-Gallo, Jenel F Armstrong, Raghav Sehgal, M Austin Argentieri, Anne Richmond, Andrea Aparicio, Kevin Mendez, Yulu Chen, Sofina Begum, Priyadarshini Kachroo, Nicole Prince, Tao Guo, Hannah Went, Tavis Mendez, Aaron Lin, Logan Turner, Mahdi Moqri, Su H Chu, Rachel S Kelly, Scott T Weiss, Nicholas J W Rattray, Vadim N Gladyshev, Elizabeth Karlson, Craig E Wheelock, Ewy A Mathé, Amber Dahlin, Michael J McGeachie, Riccardo E Marioni, Albert T Higgins-Chen, Ryan Smith, Jessica Lasky-Su.
      Biological aging reflects complex cellular and biochemical processes that can be measured across multiple omic layers. Using routine clinical laboratory data from ~31,000 participants in the Mass General Brigham Biobank, we developed EMRAge, a biomarker of mortality risk that can be broadly recapitulated across electronic medical records. Here we show that EMRAge can be modeled using elastic net regression with DNA methylation and multi-omics to generate DNAmEMRAge and OMICmAge, respectively. Both biomarkers are strongly associated with incident and prevalent chronic diseases and mortality, performing comparably or better than current biomarkers across discovery (Massachusetts General Brigham Aging Biobank Cohort, n = 3,451) and validation cohorts (TruDiagnostic, n = 14,213; Generation Scotland, n = 18,672). Importantly, OMICmAge leverages epigenetic biomarker proxies to integrate proteomic, metabolomic and clinical domains while remaining quantifiable from DNA methylation alone. This framework establishes an accessible, scalable measure of biological aging with potential to reveal molecular interconnections that shape healthspan and disease risk.
    DOI:  https://doi.org/10.1038/s43587-026-01073-7
  19. Nature. 2026 Feb 25.
    CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis.
    Lingzhi Wu, Jianqin Wang, Yawei Wang, Junhan Yang, Yuanhang Yao, Yonglun Wang, Dong Huang, Yating Hu, Xinxuan Xu, Renqian Wang, Wenjing Du, Yiting Shi, Quan Li, Lu Liu, Yuangang Zhu, Shijie Li, Feng-Jung Chen, Xiuqin Zhang, Xiao Wang, Qiang Guo, Li Xu, Peng Li, Xiao-Wei Chen.
      Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases-the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospholipids onto the lumenal apolipoprotein B (APOB), in a poorly defined process7-10. Here we show that the ER protein CLCC1 regulates cellular lipid partition and, consequently, systemic lipid homeostasis by participating in trans-bilayer equilibration of phospholipids. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby supporting lipoprotein biogenesis and the subsequent bulk lipid transport. Loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and, consequently, accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis. The results reveal that phospholipid scrambling at the ER is essential for establishing a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13-16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.
    DOI:  https://doi.org/10.1038/s41586-026-10161-y
  20. Nat Commun. 2026 Feb 25.
    Evolving epigenomics of immune cells at single-nucleus resolution in children en route to type 1 diabetes.
    Tomi Pastinen, Elin Grundberg, Todd Bradley, Jarno Honkanen, Warren A Cheung, Arja Vuorela, Jeffrey J Johnston, Byunggil Yoo, Santosh Khanal, Rebecca McLennan, Jorma Ilonen, Outi Vaarala, Jeffrey P Krischer, Mikael Knip.
      The appearance of diabetes-associated autoantibodies is the first detectable sign of the disease process leading to type 1 diabetes (T1D). Evidence suggests that T1D is a heterogenous disease, where the type of antibodies first formed implies subtypes. Here, we leverage longitudinal samples collected from 98 European TRIGR participants (49 children who subsequently presented with T1D, and 49 matched controls), and profile single-cell epigenomics at different time points of disease development. Quantitation of cell and nuclei populations, complemented by analysis of transcriptome and open-chromatin states, indicates robust, early, replicable monocyte lineage differences between cases and controls, suggesting the early emergence of heightened pro-inflammatory cytokine secretion among cases. The order of autoantibody emergence in cases shows variation across lymphoid and myeloid cells, potentially indicating divergence in the cellular immune response. The strong monocytic lineage representation in peripheral blood immune cells before seroconversion and the weaker differential coordination of these gene networks close to clinical diagnosis emphasize the importance of early life as a critical phase in T1D development.
    DOI:  https://doi.org/10.1038/s41467-026-69923-x
  21. Nature. 2026 Feb 25.
    CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly.
    Alyssa J Mathiowetz, Emily S Meymand, Güneş Parlakgül, Niek van Hilten, Emily F Torres, Leonardo L Artico, Kirandeep K Deol, Mike Lange, Stephany P Pang, Cody E Doubravsky, Melissa A Roberts, Danielle M Jorgens, Reena Zalpuri, Misun Kang, Casadora Boone, Brian W Parks, Yaohuan Zhang, David W Morgens, Emily Tso Newman, Yingjiang Zhou, Saswata Talukdar, Michael Grabe, Gregory Ku, Tim P Levine, Ana Paula Arruda, James A Olzmann.
      Imbalances in lipid storage and secretion lead to hepatic steatosis, the accumulation of lipid droplets in hepatocytes1,2. Our understanding of the mechanisms that govern the channelling of neutral lipids in hepatocytes towards cytosolic lipid droplets or secreted lipoproteins remains incomplete3,4. Here we performed a series of CRISPR-Cas9 screens under different metabolic states that led to the identification of CLCC1 as a critical regulator of neutral lipid storage and secretion in hepatocytes. Loss of CLCC1 resulted in the buildup of large lipid droplets in hepatoma cells and Clcc1 knockout in mice caused liver steatosis. Lipid droplets were present in the lumen of the endoplasmic reticulum of the Clcc1-knockout hepatocytes and exhibited properties of lipoproteins, indicating a profound shift in neutral lipid flux. The loss of CLCC1 also led to the accumulation of nuclear membrane herniations accompanied by a reduction in nuclear pores. Remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1 and Brr6, factors that promote nuclear envelope fusion during nuclear pore complex assembly. Molecular dynamics simulations and mutagenesis studies support a model in which CLCC1 mediates membrane bending and fusion. We propose that CLCC1 mediates membrane fusion to promote hepatic neutral lipid flux and nuclear pore complex assembly.
    DOI:  https://doi.org/10.1038/s41586-025-10064-4
  22. Nature. 2026 Feb 25.
    Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease.
    Ahmed Disouky, Mark A Sanborn, K R Sabitha, Mostafa M Mostafa, Ivan Alejandro Ayala, David A Bennett, Yisha Lu, Yi Zhou, C Dirk Keene, Sandra Weintraub, Tamar Gefen, M-Marsel Mesulam, Changiz Geula, Mark Maienschein-Cline, Jalees Rehman, Orly Lazarov.
      The existence of human hippocampal neurogenesis has long been disputed1-12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.
    DOI:  https://doi.org/10.1038/s41586-026-10169-4
  23. Cell Metab. 2026 Feb 23. pii: S1550-4131(26)00016-1. [Epub ahead of print]
    Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis.
    Eva Novoa, Tamara Parracho, Julica Inderhees, Amaia Rodriguez, Cristina Riobello, Jose Iglesias-Moure, Anabel Fernández-Iglesias, Sara Martinez-Martinez, Ana Senra, Samuel Seoane, Marcos Fondevila, Cristina Iglesias, Alba Cabaleiro, Natalia da Silva Lima, Valentina Dorta, Borja López-Picallo, Lucia Ramos-Lage, Ashwin Woodhoo, Miguel Fidalgo, Maria L Martínez-Chantar, Francisco Javier Cubero, Miguel López, Carlos Dieguez, Diana Guallar, Vincent Prevot, Robert Schwabe, Gema Frühbeck, Javier Crespo, Marta Varela-Rey, Maria J Gonzalez-Rellan, Jordi Gracia-Sancho, Paula Iruzubieta, Markus Schwaninger, Ruben Nogueiras.
      Phosphoenolpyruvate carboxykinase 1 (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1 (TGF-β1)-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid (TCA) cycle activity, but PCK1 overexpression reduces acetyl-coenzyme A (CoA), limiting TCA cycle intermediates and ameliorating HSC activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.
    Keywords:  PCK1; glycolysis; hepatic stellate cells; liver fibrosis; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.016
  24. Lancet Diabetes Endocrinol. 2026 Feb 23. pii: S2213-8587(25)00406-1. [Epub ahead of print]
    Automated insulin delivery systems and improved glycaemic outcomes in type 1 diabetes: what comes next?
    Dessi P Zaharieva.
      
    DOI:  https://doi.org/10.1016/S2213-8587(25)00406-1
  25. Diabetes Care. 2026 Feb 26. pii: dc252154. [Epub ahead of print]
    Investigating the Spectrum of Normoglycemia: Time in Glycemic Ranges and Their Association With Metabolic Outcomes in Individuals Without Diabetes.
    Anastasia Godneva, Moshe Phillip, Eran Segal, Smadar Shilo.
       OBJECTIVE: To characterize the distribution of time in tight and broader glycemic ranges in adults without diabetes and to examine cross-sectional and longitudinal associations with metabolic health.
    RESEARCH DESIGN AND METHODS: We analyzed continuous glucose monitoring data from 8,687 adults (40-70 years, 54% women) in the Human Phenotype Project, each contributing 1,149 ± 279 glucose readings from FreeStyle Libre Pro sensors. Age- and sex-adjusted correlations linked time-in-range metrics with 45 clinical phenotypes encompassing adiposity, vascular, and liver markers, sleep indices, and nutrition. Cox models tested associations of time above glycemic thresholds with incident metabolic disease over 2.6 ± 1.3 years.
    RESULTS: Participants spent a median 93.0% (interquartile range [IQR] 91.8-98.2) of continuous glucose monitor time within 70-140 mg/dL and 95.2% (IQR 95.1-99.8) within 70-180 mg/dL. Time <140 mg/dL and 180 mg/dL was 97.7% (IQR 97.6-97.8) and 99.9% (IQR 99.9-99.9), respectively. Lower time <140 mg/dL correlated with higher waist circumference, visceral fat, triglycerides, blood pressure, serum ALT, and liver attenuation, and with lower HDL cholesterol and mean nocturnal oxygen saturation. Associations weakened using the <180 mg/dL threshold. Lower time <180 mg/dL and <140 mg/dL was associated with higher risk of incident metabolic disease (hazard ratio 1.21 [95% CI 1.15-1.26] and 1.34 [95% CI 1.26-1.42], respectively).
    CONCLUSIONS: We provide population references for time spent in different glycemic ranges by adults without diabetes. Although our study is observational and not designed to establish causality, our findings suggest that even within normoglycemic ranges, less time <140 mg/dL is associated with unfavorable health parameters and higher incident metabolic disease risk.
    DOI:  https://doi.org/10.2337/dc25-2154
  26. EMBO Rep. 2026 Feb 27.
    The Arp2/3 complex controls the development of homeostatic microglia.
    Shima Safaiyan, Maximilian Frosch, Tom Bickel, Gianni Monaco, Roie Dvir, Christian Madry, Lance Fredrick Pahutan Bosch, Katrin Kierdorf, Metello Innocenti, Josef Priller, Marco Prinz, Tim Lämmermann.
      Microglial dynamics and homeostasis are crucial for maintaining central nervous system (CNS) function. To fulfill their homeostatic functions, microglia develop into ramified cells with highly dynamic cell protrusions. However, the detailed mechanisms underlying this developmental transition are largely unknown. Here, we investigate the role of the Actin-related protein 2/3 (Arp2/3) complex, a critical actin nucleator that controls the formation of actin branches, for the biology of tissue-resident microglia. By conditionally targeting Arpc4 in mice, we show that Arp2/3 depletion in tissue-resident microglia causes phenotypes beyond previously reported functions in other immune cell types. Our results identify an important role of Arp2/3 for controlling the developmental transition of microglia into cells with ramified morphology, homeostatic gene profile, and surveillance function in the CNS. Together, our results link actin remodeling to microglial maturation and activation, highlighting the Arp2/3 complex as a critical factor for maintaining the plasticity and preventing pathological activation of endogenous microglia.
    Keywords:  Actin; Arp2/3 Complex; Microglia; Myelin Degeneration; TGFβ Signaling
    DOI:  https://doi.org/10.1038/s44319-026-00721-8
  27. Nat Commun. 2026 Feb 24.
    Clinically distinct metabotypes of pediatric MASLD identified through unsupervised clustering of NASH CRN data.
    Helaina E Huneault, Pradeep Tiwari, Zachery R Jarrell, Matthew Ryan Smith, Chih-Yu Chen, Ana Ramirez Tovar, Cristian Sanchez-Torres, Scott Gillespie, Shasha Bai, Rodrigo M Carrillo-Larco, Ajay K Jain, Katherine P Yates, Brent A Neuschwander-Tetri, Jeffrey B Schwimmer, Stavra A Xanthakos, Jean P Molleston, Cynthia A Behling, Mark H Fishbein, Terryl J Hartman, Francisco J Pasquel, Rishikesan Kamaleswaran, Dean P Jones, Jean A Welsh, Miriam B Vos.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, yet treatment remains "one size fits all," despite phenotypic heterogeneity. We analyzed clinical and metabolomics data from 514 children (ages 5-18, 73% male) with biopsy-proven MASLD across three NASH Clinical Research Network studies. Unsupervised clustering of clinical data identified three distinct metabotypes: early-mild (49.4%, youngest, lowest lipids, liver enzymes, insulin resistance), cardiometabolic (36.8%, highest waist circumference, lipids, uric acid, SBP), and inflammatory-fibrotic (13.8%, highest liver enzymes, steatohepatitis, advanced fibrosis). Integrative network and pathway enrichment analyses revealed alterations in tryptophan metabolism within the inflammatory-fibrotic group, including elevated kynurenine pathway metabolites, which were significantly correlated with fibrosis stage. Branched-chain amino acid degradation, butanoate, and purine metabolism demonstrated greater enrichment in the cardiometabolic group. Here, we show that pediatric MASLD subtypes differ in clinical and metabolic features, providing a framework for targeted interventions, with validation needed in independent cohorts.
    DOI:  https://doi.org/10.1038/s41467-026-69735-z
  28. Nat Cardiovasc Res. 2026 Feb;5(2): 138-154
    Targeting immunometabolic pathways with AZD1656 alleviates inflammation and metabolic dysfunction in type 2 diabetic cardiomyopathy.
    Stephanie Anderson, Anja Karlstaedt, Megan Young, Loucia Karatzia, Fenn Cullen, Jianmin Chen, Caroline E O'Riordan, Michael R Barnes, Zorana Štaka, Lauren J Albee, Conor Garrod-Ketchley, Sanushi Dambure, Hiran A Prag, Filip Cvetko, Jack J J J Miller, Christoph Thiemermann, Andrew J M Lewis, Michael P Murphy, David M Smith, Sian M Henson, Damian J Tyler, Dunja Aksentijevic.
      Type 2 diabetes (T2D) precipitates diabetic cardiomyopathy (dbCM), a condition characterized by chronic inflammation, metabolic dysregulation and impaired cardiac performance. Here we show that the glucokinase activator AZD1656, originally developed for glycemic control but later identified to have immunomodulatory effects, reverses cardiac dysfunction and metabolic remodeling in dbCM. In obese, hyperglycemic db/db mice with diastolic dysfunction, 6 weeks of AZD1656 treatment improved myocardial performance, reduced infarct size and enhanced post-ischaemic recovery. Integrated metabolic, functional and histological analyses revealed restoration of mitochondrial metabolism and attenuation of fibrosis. Mechanistically, AZD1656 remodeled the cardiac immune landscape by promoting infiltration of regulatory T cells. These findings demonstrate a link between cardiac inflammation and metabolic remodeling in dbCM and highlight that modulation of immune cells and metabolism can protect the diabetic heart. Targeting immunometabolic pathways may therefore offer a therapeutic strategy to alleviate cardiac dysfunction and reduce infarct vulnerability in T2D.
    DOI:  https://doi.org/10.1038/s44161-025-00769-0
  29. Nature. 2026 Feb 25.
    Flexible paths to multicellularity.
    Jaruwatana Sodai Lotharukpong, Susana M Coelho.
      
    Keywords:  Evolution
    DOI:  https://doi.org/10.1038/d41586-026-00292-7
  30. Immunity. 2026 Feb 23. pii: S1074-7613(26)00003-8. [Epub ahead of print]
    Fasting impairs humoral immunological memory by β-hydroxybutyrate-mediated depletion of plasma cells.
    Yiming Zhu, Baoshan Ding, Haimei Lv, Hui Xu, Jiamei Chen, Juan Xu, Qian Wu, Xiaoxiao Hao, Yunqi Hu, Jian Guo, Jun Chen, Chaofeng Liang, Yuzhuang Li, Jiawen Wu, Nan Cao, Jijun Zhao, Guangwen Ren, Hua Jin, Yiwen Zhang, Yiping Li, Hui Zhang, Chunliang Xu.
      Humoral immunological memory mediated by memory B cells (MBCs) and long-lived plasma cells (LLPCs) is critical for sustained protection following infection or vaccination. LLPCs protect the hosts by secreting protective neutralizing antibodies over extended periods. However, the mechanism regulating their survival and thus the durability of protective antibodies remains unclear. Here, we showed in human and mouse models that intermittent fasting impaired humoral immunological memory by accelerating antibody decay. Fasting selectively depleted LLPCs while sparing MBCs in mice. Mechanistically, this effect was mediated by increased extracellular β-hydroxybutyrate, a ketone body produced during fasting, which acted through the hydroxycarboxylic acid receptor 2 (HCAR2) on plasma cells. Activation of the HCAR2-Gαi-adenylate cyclase-cAMP axis by β-hydroxybutyrate downregulated CXCR4, leading plasma cells to exit their bone marrow niche and undergo apoptosis in the periphery. These findings reveal that fasting-induced metabolic signals regulate humoral immunity duration and suggest that diet and lifestyle could influence vaccine effectiveness.
    Keywords:  fasting; humoral immunological memory; intermittent fasting; ketogenic diet; ketone bodies; long-lived plasma cells; neutralizing antibody; plasma cells; vaccines; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.002
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