bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–11–01
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Fats that think?
  2. An epigenetic regulator that promotes NK cell function.
  3. Lactate takes a shortcut into mitochondria to power the heart.
  4. MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
  5. Methylated GRP94 promotes liver fibrosis progression by enhancing endoplasmic reticulum stress.
  6. Multiplexed deep visual proteomics resolves spatial heterogeneity and rare endocrine states in human pancreatic islets.
  7. Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.
  8. Immunity at scale.
  9. How the pandemic changed trust in science - in four charts.
  10. A microbiome-reactive TMIGD2hi Th17 subset is spatially enriched at the intestinal epithelium and expanded in inflammatory bowel disease.
  11. DR-GEM enables self-supervised machine learning for single-cell embeddings and annotations.
  12. Genetic variants shape single-cell chromatin accessibility and disease risk.
  13. Applying digital twins to prevent preterm births.
  14. Long-Term Steroid Use Tied to Adverse Cardiovascular Effects.
  15. Oral small-molecule GLP-1 receptor agonist for obesity in people from Japan.
  16. A CD4-lineage erythro-myeloid progenitor within the adult bone marrow defines an alternative pathway for macrophage generation.
  17. Metabolic licensing of innate immune memory.
  18. Could measuring immune health reshape medical care?
  19. Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease.
  20. Spatial single-cell mapping of transcriptional differences across genetic backgrounds in mouse brains.
  21. Cholesterol binding stabilizes the activated state of THIK-1 and promotes atherosclerosis.
  22. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  23. I built the UK government's metascience unit - here's what countries need to know.
  24. Regular exercise augments gut-brain communication and visceral feedback control of appetite.
  25. The maternal-fetal interface is an early hematopoietic niche enriched in distinct erythro-myeloid progenitors.
  26. The EMPROR's new groove.
  27. Alzheimer's disease genetics converges on microglial and neuronal dysregulation.
  28. Maternal Autoimmune Diseases and Offspring Type 1 Diabetes.
  29. Metabolic heterogeneity of obesity.
  30. Intensive BP Lowering Reduces Cardiovascular Risk in Adults With CKD.
  1. Science. 2026 Oct 29. 394(6823): 499-500
    Fats that think?
    Gioele La Manno.
      Lipids are not just building blocks of brain cells but central players in cell diversity and organization.
    DOI:  https://doi.org/10.1126/science.ael6217
  2. Nat Rev Immunol. 2026 Oct 27.
    An epigenetic regulator that promotes NK cell function.
    Juliana Lourenco, Arthur Mortha.
      
    DOI:  https://doi.org/10.1038/s41577-026-01370-7
  3. Nature. 2026 Oct 28.
    Lactate takes a shortcut into mitochondria to power the heart.
    Trace Thome, Zolt Arany.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-03261-2
  4. Nature. 2026 Oct 28.
    MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, James Carrington, Luis Cedeño-Rosario, Giulia C Napoli, Ji Eon Kim, Thirupura S Shankar, Marisa J Brothwell, Rana Hamouche, Álvaro J Narbona-Pérez, Jing Ling, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, David R Eberhardt, Jing Li, Claire E Stanley, Queren A Alcantara, Tarun Yadav, Ryan L Maves, Wojciech I Swiatek, Nicholas A Offei, Bhavya Blaze, Sumangala P Shetty, Dipayan Chaudhuri, Tingting Hong, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Eleni Tseliou, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion and injury stressors1. Oxidation of carbohydrate substrates is thought to converge on the cytosolic generation of pyruvate, which is transported by the mitochondrial pyruvate carrier (MPC) for entry into the tricarboxylic acid cycle2. Here we find that glucose-derived carbon is oxidized in mouse myocardium even when the MPC is genetically ablated. Using genetic and pharmacological tools, we demonstrate that lactate monocarboxylate transporter 1 (MCT1, encoded by Slc16a1) is required for the oxidation of glucose carbon by MPC-deficient myocardium. We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes. Together with matrix-localized LDHB, MCT1 enables mitochondrial lactate conversion to pyruvate and NADH, directly fueling the electron transport chain. Loss of MCT1 impairs lactate oxidation, disrupts metabolic flexibility and accelerates the development of heart failure with increased mortality after hyperactivation of the neurohormonal axis or ischemia-reperfusion injury. Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.
    DOI:  https://doi.org/10.1038/s41586-026-11182-3
  5. Cell Death Dis. 2026 Aug 05. pii: 910. [Epub ahead of print]17(1):
    Methylated GRP94 promotes liver fibrosis progression by enhancing endoplasmic reticulum stress.
    Xinyi Liu, Kejia Lu, Zitao Jiao, Yahui Zou, Hui Li, Wei Jiang, Xiaowei Zhang.
      Liver fibrosis is a crucial and potentially reversible stage in the progression from chronic liver diseases towards liver cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress is closely related to hepatic stellate cell (HSC) activation and liver fibrosis. Liver fibrosis is frequently accompanied by a global increase in hepatic protein methylation. This suggests that there may be potential unexplored connections among ER stress, protein methylation, and liver fibrosis. Here, we identify PRMT1-mediated methylation of the ER chaperone GRP94 at arginine 395 as a critical event that drives HSC activation and liver fibrogenesis. Using proteomic profiling of liver tissues from mouse models induced by carbon tetrachloride (CCl4) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), combined with studies in human hepatic stellate cells (primary HSCs and the LX2 cell line), we identify that methylation of GRP94 stabilizes the protein by inhibiting its ubiquitination. This modification potentiates the PERK-eIF2α-ATF4 arm of the ER stress response, leading to upregulation of the fibrogenic genes ACTA2 and COL1A1 and promoting HSC activation. Pharmacological inhibition of PRMT1 with MS023 reverses GRP94 methylation, suppresses HSC activation, and attenuates fibrosis progression in both cellular systems and murine models. This finding positions the crosstalk between ER stress and protein arginine methylation as a central node in the pathogenesis of liver fibrosis, suggesting that targeting the methylation of GRP94 may be a potential therapeutic strategy of liver fibrosis.
    DOI:  https://doi.org/10.1038/s41419-026-09159-1
  6. Nat Commun. 2026 Sep 25. pii: 11138. [Epub ahead of print]17(1):
    Multiplexed deep visual proteomics resolves spatial heterogeneity and rare endocrine states in human pancreatic islets.
    Mariya Mardamshina, Nicolai Dorka, Marvin Thielert, Frida Björklund, Frederic Ballllosera Navarro, Anna Martinez Casals, Ferenc Kovacs, Christophe Avenel, Jocelyn E Manning Fox, Peter Horvath, Carolina Wählby, Patrick E MacDonald, Matthias Mann, Emma Lundberg.
      Understanding tissue function requires connecting spatial cellular context with molecular depth, yet such integration remains challenging in complex organs like the pancreas. We develop multiplexed Deep Visual Proteomics (mxDVP), an end-to-end workflow combining high-plex imaging, automated computational analysis, and spatially guided ultra-sensitive mass spectrometry. Powered by PIPΣX, an open-source image analysis framework enabling whole-slide membrane-aware segmentation, annotation, and laser microdissection export, mxDVP achieves >6000 protein identifications from as few as 100 small islet cells. Applied to human pancreatic islets, mxDVP segments over 860,000 cells and resolves twelve endocrine subtypes, including rare polyhormonal and intermediate-state populations that exhibit spatial organization patterns, co-expression of INSM1 and SCG3, and hybrid α/β/δ signatures. These findings reveal a spectrum of endocrine heterogeneity and spatial organization. By integrating imaging and deep proteomics in an accessible framework, mxDVP enables discovery of rare cell states whose biological roles depend on tissue architecture.
    DOI:  https://doi.org/10.1038/s41467-026-77890-6
  7. Nat Cardiovasc Res. 2026 Oct 27.
    Manipulation of ER-mitochondria interactions with mitofusin modulators reduces cardiac damage during myocardial infarction in mice.
    Joshua L Axelrod, Zuzana Nichtová, Timothy Schneider, Jaehoon Lee, Ryan Pekson, Dongze Qin, Madeeha Ghazi, Vinay Kumar, Victoria Margulets, Lorrie A Kirshenbaum, Gaetano Santulli, György Csordás, John W Calvert, Richard N Kitsis.
      Mitofusin (MFN) 1 and MFN2 are large outer mitochondrial membrane GTPases. Dimerization of MFNs on adjacent mitochondria mediates mitochondrial fusion. MFN2, but not MFN1, also resides at the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) membrane, and dimerization of MFNs on ER/SR and mitochondria tethers the two organelles. Here we report that cell-permeable peptides that perturb MFN conformations regulate myocardial infarct size by impacting ER/SR-mitochondria interactions and Ca2+ transfer independently of changes in mitochondrial fusion. MFN activators increase ER/SR-mitochondria proximity, promote ER/SR to mitochondria Ca2+ transfer and exacerbate infarct size in mice, with effects dependent on MFN2, but not MFN1, and on mitochondrial calcium uniporter, which transports Ca2+ into the mitochondrial matrix. Conversely, although ER/SR-mitochondria proximity is not affected, MFN inhibitors reduce mitochondrial Ca2+ transfer and infarct size, even when their administration is delayed until reperfusion. These findings demonstrate the feasibility of acutely modulating ER/SR-mitochondria interactions and Ca2+ dynamics and suggest that pharmacological MFN inhibition may provide a new therapeutic strategy to limit cardiac damage during reperfused myocardial infarction.
    DOI:  https://doi.org/10.1038/s44161-026-00903-6
  8. Science. 2026 Oct 29. 394(6823): 500
    Immunity at scale.
    Zuri A Sullivan.
      The brain can serve as a host defense effector.
    DOI:  https://doi.org/10.1126/science.ael6235
  9. Nature. 2026 Oct 28.
    How the pandemic changed trust in science - in four charts.
    Miryam Naddaf.
      
    Keywords:  Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-026-03248-z
  10. Immunity. 2026 Oct 26. pii: S1074-7613(26)00401-2. [Epub ahead of print]
    A microbiome-reactive TMIGD2hi Th17 subset is spatially enriched at the intestinal epithelium and expanded in inflammatory bowel disease.
    Thomas K Pedersen, Tanvi Jain, Åsa Segerstolpe, Crystal Lin, Angela R Shih, Luezhen Yuan, Orr Ashenberg, Marco E Kaper, Shaina W Twardus, Rocco Ricciardi, Helena Lau, James J Moon, Susanne Brix, Ramnik J Xavier, Daniel B Graham.
      Subsets of intestinal CD4+ T cells directly recognize commensal bacteria and coordinate tolerance versus protective immunity. Our limited understanding of CD4+ T cell specificities and corresponding functional phenotypes has created a barrier to deciphering the mechanisms of mucosal homeostasis and inflammation mediated by the adaptive immune system. To address this, we leveraged an immunodominant Bacteroidetes epitope in SusC to perform single-cell profiling of the SusC-specific and total CD4+ T cell landscapes in intestinal tissues of patients with inflammatory bowel disease (IBD). By analyzing phenotypes and T cell receptor specificities in parallel, we uncovered phenotypic diversification of T helper 17 (Th17) cells in IBD and identified an epithelial-localized, SusC-reactive Th17 subset that is BACH2lo, GZMAhi, and expresses the costimulatory receptor TMIGD2. Together, our results highlight the utility of tracking commensal-specific T cell responses to define specialized subsets of Th17 cells associated with loss of tolerance to the microbiome.
    Keywords:  IBD; T cells; inflammation; inflammatory bowel disease; microbiome; mucosal immunology; single-cell RNA sequencing; single-cell TCR sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.026
  11. Nat Commun. 2026 09 24. pii: 11088. [Epub ahead of print]17(1):
    DR-GEM enables self-supervised machine learning for single-cell embeddings and annotations.
    Christine Yiwen Yeh, Min Woo Sun, Dixian Zhu, Livnat Jerby.
      Dimensionality reduction and clustering are instrumental to single-cell and spatial genomics data analysis. Here we show that existing methods tend to fit oversampled classes and miss more unique signals and patterns, such as rare cell types and states. We find that the problem in such cases is not primarily data scarcity per se, but the model equating abundance with importance. Addressing this, we present "Distributionally Robust and latent Group-AwarE consensus Machine learning" or DR-GEM, a self-supervised meta-algorithm that uses the reconstruction error to reorient the model attention to patterns it initially missed and applies balanced consensus learning to increase robustness and filter low-quality data. We apply DR-GEM to synthetic and real-world single-cell, spatial transcriptomics, and Perturb-seq datasets and demonstrate that it outperforms existing methods in obtaining reliable embeddings, recovering rare cell types, filtering noise, mitigating cell-level and patient-level underrepresentation, and uncovering held-out genetic and spatial features. We thus surface and address an underappreciated problem and present a self-supervised framework to help support AI-based and data-driven discoveries.
    DOI:  https://doi.org/10.1038/s41467-026-77908-z
  12. Nature. 2026 Oct 28.
    Genetic variants shape single-cell chromatin accessibility and disease risk.
    Angli Xue, Jianan Fan, Oscar A Dong, Hao Lawrence Huang, Ling Chen, Peter C Allen, Eleanor Spenceley, Eszter Sagi-Zsigmond, Blake Bowen, Albert Henry, Anna S E Cuomo, Hope A Tanudisastro, Zhen Qiao, Elizabeth Dorans, Eyal Ben-David, Kyle Kai-How Farh, Linfeng Hu, Yijia Christiana Liu, Drew R Neavin, Arthur S Lee, Anne Senabouth, Caitlin Bartie, Rachael A McCloy, Venessa Chin, Wei Zhou, Alkes L Price, Katrina M de Lange, Gemma A Figtree, Alex W Hewitt, Daniel G MacArthur, Joseph E Powell.
      Understanding how genetic variation shapes gene regulation at single-cell resolution is crucial for elucidating complex disease mechanisms1, but has been limited by the lack of large-scale single-cell multi-omics data2-4. Here we present single-cell assay for transposase-accessible chromatin with sequencing of 3.5 million peripheral blood mononuclear cells from 1,042 donors with matched whole-genome sequencing. Across 28 immune cell types, we tested 440,996 chromatin accessibility peaks and identified 243,225 chromatin accessibility quantitative trait loci (caQTLs) at 100,483 peaks, 60% of them cell-type specific. Rare variant analysis identified 38,161 associated peaks, with predicted transcription factor-binding disruption implicated at individual loci. Colocalization with expression QTLs (eQTLs) from single-cell RNA sequencing data (5.4 million peripheral blood mononuclear cells)5 defined 28,834 candidate cis-regulatory elements. Across genome-wide association studies for 16 diseases and 44 blood traits, caQTLs colocalized 4.5-22.6% more signals than eQTLs alone. Cell-type-specific and tissue-specific context, distal effects and multi-causal-variant models raised genome-wide association study-eQTL concordance from approximately 16% to approximately 65%. Cell state further modulates genetic effects, with 27% of over 200,000 caQTL-cell-state interactions lacking a main effect. At the inflammatory bowel disease risk gene ADCY7, accessibility effects varied with genotype and G protein-mediated pathway activity in CD4+ T cells. A graph neural network trained on both eQTL and caQTL layers inferred peak-gene links in unpaired multiome data with up to 17.2% higher accuracy than QTL-agnostic data, uncovering 128 additional transcription factor-target pairs (22% increase). Together, these results show that genetic variants shape chromatin accessibility in a cell-type-specific and cell-state-specific manner, influencing immune function and disease risk.
    DOI:  https://doi.org/10.1038/s41586-026-11173-4
  13. Nat Med. 2026 Oct 29.
    Applying digital twins to prevent preterm births.
    Karen O'Leary.
      
    Keywords:  Machine Learning; Pregnancy outcome; Translational research
    DOI:  https://doi.org/10.1038/d41591-026-00056-w
  14. JAMA. 2026 Oct 30.
    Long-Term Steroid Use Tied to Adverse Cardiovascular Effects.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.20038
  15. Lancet Diabetes Endocrinol. 2026 Oct 30. pii: S2213-8587(26)00253-6. [Epub ahead of print]
    Oral small-molecule GLP-1 receptor agonist for obesity in people from Japan.
    Neil Tanday, Alexander Dimitri Miras.
      
    DOI:  https://doi.org/10.1016/S2213-8587(26)00253-6
  16. Nat Immunol. 2026 Nov;27(11): 2293-2305
    A CD4-lineage erythro-myeloid progenitor within the adult bone marrow defines an alternative pathway for macrophage generation.
    Shweta Tikoo, Rohit Jain, Brendon Martinez, Renhua Song, Matthias Wielscher, Carlos Márquez-Burgoa, Anastasiya Hladik, Simone Rizzetto, Lisa E Shaw, Minoo Ghannadan, Stephanie A Gerhofer, Andrew J Mitchell, Maria Elizabeth Torres-Pacheco, Fabio Luciani, Matthias Farlik, Justin J L Wong, Sylvia Knapp, Philipp Starkl, Stuart T Fraser, Steffen Jung, Wolfgang Weninger.
      Tissue-resident macrophages originate from distinct developmental sources, but their adult replenishment is thought to depend exclusively on circulating monocytes. Here we identify a previously unrecognized CD4-lineage erythro-myeloid progenitor (EMPROR) in the adult bone marrow that provides an alternative pathway for macrophage generation. EMPROR cells are phenotypically and transcriptionally distinct from hematopoietic stem cells, common myeloid progenitors and monocyte precursors, lacking Csf1r and Ccr2 while expressing Cd4 and Kit. Single-cell RNA sequencing, RNA velocity analysis and lineage assays reveal macrophage, neutrophil, megakaryocytic and erythroid potential. EMPROR cells generate perivascular and tumor-associated macrophages independently of CCR2-mediated monocyte recruitment and contribute to erythroid and granulocytic lineages under inflammatory and neoplastic conditions. Transcriptomic comparisons position EMPROR cells closest to embryonic erythro-myeloid progenitors, indicating the persistence of an embryonic-like program in adult bone marrow. These findings reveal an alternative pathway of adult myelopoiesis that sustains macrophage diversity beyond the classical monocyte lineage.
    DOI:  https://doi.org/10.1038/s41590-026-02686-1
  17. Sci Immunol. 2026 Oct 30. 11(124): eaek9099
    Metabolic licensing of innate immune memory.
    Musa M Mhlanga, Andrew A Pieper.
      NAD+ is revealed to be a metabolic signal that preserves an epigenetic mark central to trained immunity by inhibiting the histone demethylase KDM5a (see related Research Article by Jin et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.aek9099
  18. Nature. 2026 Oct;658(8138): 1128-1130
    Could measuring immune health reshape medical care?
    Hugo J W L Aerts, Nicolai J Birkbak, John S Tsang, Eric J Topol.
      
    Keywords:  Health care; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-03396-2
  19. Nat Commun. 2026 Oct 27. pii: 11136. [Epub ahead of print]17(1):
    Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease.
    Jisu Jung, Eun Seo Park, Na Keum Lee, Jung-Jae Lee, Uijin Juang, Qingzhi Huang, Young Suk Park, Hyung Joon Kim, Jung-Kwon Kim, Tae Jung Oh, Jae Myoung Suh, Jae Bum Kim, Joon Ho Moon, Jong Kyoung Kim, Sung Hee Choi.
      The cellular complexity of adipose tissue plays a critical role in the pathogenesis of metabolic disease; however, mechanisms underlying adipose dysfunction remain poorly understood. Here, we constructed a single-nucleus and bulk transcriptomic atlas of human visceral adipose tissues from an ethnically homogeneous cohort with defined metabolic states: lean with normal glucose tolerance, obesity, and obesity with type 2 diabetes. Single-nucleus RNA sequencing (snRNA-seq) revealed a fibro-inflammatory subpopulation of adipose stem cells and adipocytes characterized by high THBS1 expression, which were enriched in individuals with obesity and obesity with type 2 diabetes compared to lean controls. Through complementary in vitro (human primary ASCs, THP-1 macrophages, and Matrigel-captured mature adipocytes), ex vivo (mouse and human visceral adipose tissue explants), and in vivo (gain-of-function and antibody-mediated neutralization) experiments, we demonstrated that THBS1 promoted adipose fibrosis and inflammation via macrophage-mediated TGFβ activation, impairing adipogenesis and adipocyte function. Inhibition of THBS1 attenuated fibro-inflammatory features in metabolically dysfunctional adipose tissues. Moreover, THBS1 levels in plasma and adipocytes correlated with metabolic traits, including BMI and HbA1c. Collectively, our study provides a cellular atlas of human visceral adipose tissues across metabolic disease states and identifies THBS1 as a key pathogenic driver and potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-77107-w
  20. Nat Methods. 2026 Oct 30.
    Spatial single-cell mapping of transcriptional differences across genetic backgrounds in mouse brains.
    Zachary Hemminger, Gabriela Tam, Haley De Ocampo, Aihui Wang, Thomas Underwood, Fangming Xie, Qiuying Zhao, Dongyuan Song, Jingyi Jessica Li, Hongwei Dong, Roy Wollman.
      Genetic variation can alter organ structure and function. Comparative statistical analysis of organs across genetic backgrounds requires spatial, single-cell, atlas-scale data in replicates. Here we introduce atlas-scale transcriptome localization using aggregate signatures (ATLAS), a scalable tissue mapping method that learns transcriptional signatures from single-cell RNA sequencing data, encodes them in situ with tens of thousands of oligonucleotide probes and decodes them to infer cell types and imputed transcriptomes. We validated ATLAS against direct MERFISH measurements of marker genes and through quantitative comparisons to four other technologies. We profiled 40 million cells across more than 400 coronal sections from central brains of five male and five female C57BL/6J mice and five male BTBR T+tf/J mice, an idiopathic autism model. Our analysis revealed more than 40 significant differences in cell-type distributions and identified 16 regional composition changes across male-female and B6-BTBR comparisons. ATLAS thus enables systematic comparative studies, facilitating organ-level structure-function analysis of disease models.
    DOI:  https://doi.org/10.1038/s41592-026-03289-2
  21. EMBO Rep. 2026 Oct 30.
    Cholesterol binding stabilizes the activated state of THIK-1 and promotes atherosclerosis.
    Zonglin Dai, Yang Li, Zhiyuan Hou, Guifang Duan, Zixi Hu, Ao Yang, Qian Wang, Weize Wang, Juan Luo, Peng Zuo, Yue Yin, Yuxin Yin.
      Atherosclerosis, a chronic inflammatory disorder, remains a leading cause of global morbidity and mortality. While cholesterol is known to activate the NLRP3-IL-1β pathway and promote plaque formation, the underlying mechanisms remain incompletely understood. Here, we identify the tandem pore domain halothane-inhibited potassium channel 1 (THIK-1) as a mediator of IL-1β release during atherosclerosis progression. Using high-resolution cryo-electron microscopy (cryo-EM), we determine the structure of THIK-1 in its apo form and in complex with the activator arachidonic acid, and the inhibitors halothane and C101248 as well as the structure of the disease-related THIK-1 R92S variant. Structural analyses reveal that cholesterol unexpectedly stabilizes the arachidonic acid-binding pocket within THIK-1. Complementary cellular assays confirm that cholesterol amplifies the arachidonic acid-induced inflammatory response in macrophages, which can be effectively suppressed by the THIK-1 inhibitors halothane and C101248. Moreover, treatment with C101248 markedly reduces atherosclerotic plaque development in Apoe-deficient mice fed a high-cholesterol diet. Collectively, these findings elucidate a cholesterol-dependent mechanism of THIK-1 regulation and highlight THIK-1 as a regulator of atherosclerosis.
    DOI:  https://doi.org/10.1038/s44319-026-00921-2
  22. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  23. Nature. 2026 Nov;659(8139): 9
    I built the UK government's metascience unit - here's what countries need to know.
    Jen Gold.
      
    Keywords:  Funding; Policy; Research management
    DOI:  https://doi.org/10.1038/d41586-026-03502-4
  24. Mol Metab. 2026 Oct 28. pii: S2212-8778(26)00147-X. [Epub ahead of print] 102463
    Regular exercise augments gut-brain communication and visceral feedback control of appetite.
    Diba Borgmann, Dylan M Rausch, Sofia Lundh, Shad Hassan, Cansu Tokgöz, Annika Glatzel, Leonie Cabot, Malou Cajsa Ten Voorde, Cecilie Bæch-Laursen, Paula Sanchis Tortosa, Claus Brandt, Heiko Backes, Tune H Pers, Henning Fenselau.
       OBJECTIVES: Regular exercise is widely accepted to support long-term body weight management; however, the neurobiological adaptations that contribute to the beneficial effects of habitual physical activity beyond increases in energy expenditure per se remain unclear. Here, we investigated whether regular exercise alters gut-brain communication and visceral feedback control of feeding.
    METHODS: Mice were subjected to regular voluntary wheel running. Energy expenditure and feeding were assessed under basal conditions and following an overnight fast. Nutrients were delivered directly into the stomach by intragastric infusion. Brain-wide responses to intragastric nutrient delivery were assessed using positron emission tomography (PET). Single-cell sequencing and histological analyses were used to determine nutrient-responsive neuronal populations in the caudal brainstem. Genetic associations with body weight were evaluated using GWAS data.
    RESULTS: Intragastric nutrient delivery suppressed feeding more strongly in exercising mice. Brain-wide PET revealed enhanced responses to intragastric nutrients in various brain regions. Single-cell sequencing identified several nutrient-responsive caudal brainstem populations, including a previously unrecognized population marked by expression of fibrinogen C domain containing 1 (FIBCD1). Regular exercise selectively enhanced the nutrient-evoked activation of FIBCD1 neurons. Histological analyses demonstrate that FIBCD1 neurons are also present in the human brainstem, and GWAS data suggest a potential relevance of this neuron population to body-weight regulation.
    CONCLUSIONS: Regular exercise enhances behavioral and brain responses to intragastric nutrient delivery and sensitizes FIBCD1 neurons in the brainstem of mice. These findings reveal an exercise-associated adaptation of gut-brain communication that may contribute to improved matching of caloric intake to energy expenditure.
    Keywords:  Brainstem; Energy expenditure; Exercise; Feeding behavior; Fibcd1; Gut-brain-axis
    DOI:  https://doi.org/10.1016/j.molmet.2026.102463
  25. Nat Immunol. 2026 Nov;27(11): 2306-2321
    The maternal-fetal interface is an early hematopoietic niche enriched in distinct erythro-myeloid progenitors.
    Rohit Jain, Shweta Tikoo, Carlos Márquez-Burgoa, Stephanie A Gerhofer, Brendon Martinez, Mariagiovanna Barresi, Dörte Symmank, Minoo Ghannadan, Barbara Öhler, Anna-Lena Höbler, Rafael de Freitas E Silva, Dirk Baumjohann, Susanne Feil, Robert Feil, Sylvia Knapp, Philipp Starkl, Wilfried Ellmeier, Steffen Jung, Jürgen Pollheimer, Stuart T Fraser, Wolfgang Weninger.
      Embryonic hematopoiesis is thought to occur exclusively in the extraembryonic yolk sac before hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros region. Here we identify a previously unrecognized hematopoietic site at the maternal-fetal interface in mice, termed MIXER (Maternally Interfaced eXtraEmbRyonic) tissue, which develops contemporaneously with the yolk sac and exhibits robust hematopoietic activity. MIXER contains abundant hematopoietic precursors, including classical CSF1R+ erythro-myeloid progenitors and a unique embryonic CD4+CSF1R- Erythro-Myeloid PRogenitOR (eEMPROR) population. Lineage-tracing experiments demonstrate that eEMPROR cells contribute to select macrophage subpopulations during fetal development, primarily in the perivascular space. Notably, early human placental villi, before HSC emergence, also harbor CD4+ nucleated erythrocytes, indicating a conserved hematopoietic role for the maternal-fetal interface. These findings establish MIXER as an anatomically distinct niche for embryonic hematopoiesis and expand the developmental map of blood cell emergence in mammals.
    DOI:  https://doi.org/10.1038/s41590-026-02683-4
  26. Nat Immunol. 2026 Nov;27(11): 2190-2192
    The EMPROR's new groove.
    Karina J Nance, Helen S Goodridge.
      
    DOI:  https://doi.org/10.1038/s41590-026-02672-7
  27. Nature. 2026 Oct 28.
    Alzheimer's disease genetics converges on microglial and neuronal dysregulation.
    LifeLines Cohort Study
      Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 20501. AD is highly heritable, with twin-based heritability estimates of 60-80%2. Although 1,200 causal loci are predicted to exist for AD3, approximately 80 loci have been associated with AD in two recent studies4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found6. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.
    DOI:  https://doi.org/10.1038/s41586-026-11206-y
  28. JAMA Pediatr. 2026 Oct 26.
    Maternal Autoimmune Diseases and Offspring Type 1 Diabetes.
    Mikael Knip.
      
    DOI:  https://doi.org/10.1001/jamapediatrics.2026.5217
  29. Nat Med. 2026 Oct 27.
    Metabolic heterogeneity of obesity.
    Gordon I Smith, Max C Petersen, Sean M Hartig, Samuel Klein.
      Multi-organ-system insulin resistance is the key pathogenic driver of obesity-related metabolic complications and diseases, such as atherogenic dyslipidemia, metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, there is considerable heterogeneity in insulin sensitivity among people with obesity. Some are considered to have metabolically healthy obesity, with normal insulin sensitivity in conjunction with normal fasting blood glucose, oral glucose tolerance, plasma lipid profile and intrahepatic triglyceride content. In this Review, we discuss metabolic differences at the cellular, organ-system and systemic levels between people with metabolically healthy and metabolically unhealthy obesity; we also discuss heterogeneity in the therapeutic effects of weight reduction. A better understanding of the differences between metabolically divergent groups and the physiological responses to weight loss can help identify the factors responsible for the link between excess adiposity and metabolic dysfunction and disease.
    DOI:  https://doi.org/10.1038/s41591-026-04718-7
  30. JAMA. 2026 Oct 30.
    Intensive BP Lowering Reduces Cardiovascular Risk in Adults With CKD.
    Sari Richmond.
      
    DOI:  https://doi.org/10.1001/jama.2026.20039
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