bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–01–11
28 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Active aldehydes drive metabolic exhaustion in CD8+ T cells.
  2. In vivo detection of immune responses via cytokine activity labeling.
  3. Evaluating music interventions to treat depression in people living with dementia.
  4. Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice.
  5. Illuminating the influence of natural daylight on human metabolism.
  6. The dorsal aortic compartment is a developmental source of brown adipose tissue in mice.
  7. The interpretable multimodal dimension reduction framework SpaHDmap enhances resolution in spatial transcriptomics.
  8. Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.
  9. Multiplexed lipid nanoparticle barcoding reveals tissue-dynamic kinetic insights and enriched cellular tropism in hepatic zones.
  10. Putting immune cells into 'night mode' reduces heart-attack damage.
  11. A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
  12. Blood biomarkers reveal pathways associated with multimorbidity.
  13. The complex role of nutrients in cancer spread.
  14. Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
  15. Extracellular BRICK1 drives heart repair after myocardial infarction in mice.
  16. sCellST predicts single-cell gene expression from H& E images.
  17. Membrane-protein-mediated phase separation orchestrates organelle contact sites.
  18. Multi-organ network of cardiometabolic disease-depression multimorbidity revealed by phenotypic and genetic analyses of MR images.
  19. Paracrine Hormonal Signals From Islet α-Cells Regulate Microtubule Dynamics in β-Cells to Promote Insulin Secretion in Mouse and Human Islets.
  20. Membrane editing with proximity labeling reveals regulators of lipid homeostasis.
  21. How to interpret 'zero-shot' results from generative EHR models.
  22. Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
  23. The differentiation and function of heterogeneous thymic dendritic cell subsets require signals provided by distinct thymocyte cell types.
  24. Home Hazards Increase Fall Risk in Older Adults With Visual Impairment.
  25. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
  26. Revealing high-resolution spatial metagenes from spatial transcriptomics.
  27. IL-17REL disarms inflammation.
  28. Mapping the spatiotemporal adaptation of eosinophils.
  1. Nat Immunol. 2026 Jan 08.
    Active aldehydes drive metabolic exhaustion in CD8+ T cells.
      
    DOI:  https://doi.org/10.1038/s41590-025-02413-2
  2. Cell. 2026 Jan 07. pii: S0092-8674(25)01424-2. [Epub ahead of print]
    In vivo detection of immune responses via cytokine activity labeling.
    Guangqing Lu, Shanshan Zhang, Mengyang Feng, Eunha Kim, Daniel Cho, Jae Hyun Kim, Hannah Caris, Lev Silberstein, Gloria B Choi, Jun R Huh.
      While much is known about the identity and regulation of cytokine-producing cells, the cell types that respond to cytokines remain largely uncharacterized. To address this knowledge gap, we developed "cytokine cellular locating platforms" (CyCLoPs), a reporter system that translates cytokine receptor engagement into a genetically traceable signal. In vitro, CyCLoPs demonstrated high specificity, robust signal-to-background ratios, and broad applicability for probing diverse cytokine receptor interactions. In vivo, interleukin (IL)-17A-CyCLoPs reporter mice enabled the identification of IL-17A-responsive intestinal epithelial cells predominantly localized in the ileal villi following commensal bacterial colonization. Interferon-gamma (IFN-γ)-CyCLoPs reporter mice allowed for the detection of IFN-γ-exposed CD8+ T cells within tumors, which expressed CD36, CD38, and leptin receptor and displayed gene signatures associated with reduced effector function. Collectively, CyCLoPs offers a platform for the direct visualization and characterization of cytokine-induced cellular responses and provides a tool for investigating how cytokines orchestrate distinct immunological outcomes in health and disease.
    Keywords:  CD8(+) T cell; IEC; IFN-γ; IL-17A; cytokine receptor; intestinal epithelial cell
    DOI:  https://doi.org/10.1016/j.cell.2025.12.011
  3. Nat Aging. 2026 Jan 09.
    Evaluating music interventions to treat depression in people living with dementia.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-025-01055-1
  4. Nat Commun. 2026 Jan 03.
    Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice.
    Ainara G Cabodevilla, Maria Concepcion Izquierdo, Debapriya Basu, Waqas Younis, Munichandra Babu Tirumalasetty, Qing Robert Miao, Dimitris Nasias, Jenny E Kanter, Tse Wing Winnie Ho, Jana Gjini, Edward Fisher, Jeffrey Kim, Warren L Lee, Karin Bornfeldt, Ira J Goldberg.
      Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl-/-) and LDLR knockdown (Ldlrkd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl-/-/Ldlrkd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease and prove that non-remnant TRLs are not benign.
    DOI:  https://doi.org/10.1038/s41467-025-68193-3
  5. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00531-5. [Epub ahead of print]38(1): 7-8
    Illuminating the influence of natural daylight on human metabolism.
    Ioannis G Lempesis, Frank A J L Scheer.
      Humankind currently lives largely under artificial light, potentially negatively impacting circadian-metabolic alignment and predisposing it to diseases. Harmsen et al.1 show that natural daylight exposure during office hours improves several metabolic parameters including glucose regulation, enhancing fat oxidation, and advancing muscle-clock circadian phase in individuals with type 2 diabetes.
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.017
  6. Nat Commun. 2026 Jan 07. 17(1): 286
    The dorsal aortic compartment is a developmental source of brown adipose tissue in mice.
    Sophie Heider, Cornelius Fischer, Ali Kerim Secener, Pedro Vallecillo-Garcı́a, Georgios Kotsaris, Zarah G Meisen, Verena Pawolski, Claudia Giesecke-Thiel, Thomas Conrad, Tim J Schulz, Sascha Sauer, Sigmar Stricker.
      White adipose tissue primarily stores energy while brown adipose tissue dissipates energy as heat, holding promise for therapeutic use. Brown adipose tissue in the anterior trunk is believed to derive from the somitic mesoderm, although some depots are of partially unknown origin. Here we show that the subscapular, lateral, cervical and peri-aortic brown adipose depots, but not the interscapular depot, are in part formed by a non-somitic source. Single-cell sequencing along with genetic lineage tracing indicates that at embryonic day 9.5 the dorsal aorta compartment harbors multipotent mesenchymal progenitors expressing the transcription factor Osr1. Spreading laterally from the dorsal aortic midline, these cells contribute to adipose, cartilage and myogenic lineages. This study uncovers an alternative source of brown adipose tissue and suggests that a fraction of dorsal aorta-associated mesenchymal Osr1+ cells may represent the in vivo correlate of a multipotent progenitor cell type so far only characterized in vitro, the mesoangioblast.
    DOI:  https://doi.org/10.1038/s41467-025-68147-9
  7. Nat Cell Biol. 2026 Jan 06.
    The interpretable multimodal dimension reduction framework SpaHDmap enhances resolution in spatial transcriptomics.
    Junjie Tang, Zihao Chen, Kun Qian, Siyuan Huang, Yang He, Shenyi Yin, Xinyu He, Buqing Ye, Yan Zhuang, Hongxue Meng, Jianzhong Jeff Xi, Ruibin Xi.
      Spatial transcriptomics (ST) technologies revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit considerable noise and sparsity, posing substantial challenges in deciphering subtle spatial structures and underlying biological activities. Here we introduce 'spatial high-definition embedding mapping' (SpaHDmap), an interpretable dimension reduction framework that enhances spatial resolution by integrating ST gene expression with high-resolution histology images. SpaHDmap incorporates non-negative matrix factorization into a deep learning framework, enabling the identification of high-resolution spatial metagenes (embeddings). Furthermore, SpaHDmap can simultaneously analyse multiple samples and is compatible with various types of histology images. Extensive evaluations on synthetic, public and newly sequenced ST datasets from various technologies and tissue types demonstrate that SpaHDmap can effectively produce high-resolution spatial metagenes, and detect refined spatial structures. SpaHDmap represents a powerful approach for integrating ST data and histology images, offering deeper insights into complex tissue structures and functions.
    DOI:  https://doi.org/10.1038/s41556-025-01838-z
  8. Nat Commun. 2026 Jan 06. 17(1): 57
    Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.
    Mi-Young Song, Yong Geun Jeon, Jae Do Yang, Young Jae Moon, Jae Bum Kim, Eun Ju Bae, Byung-Hyun Park.
      Mast cells (MCs) play a key role in obesity and insulin resistance, though the mechanisms driving adipose dysfunction remain unclear. We find that Sirt6 expression in MCs decreases with obesity in both male mice and humans. Selective depletion of Sirt6 in MCs worsens inflammation, fibrosis, and metabolic dysfunction in diet-induced obesity. Adoptive transfer of MC-deficient KitW-sh/W-sh mice with Sirt6-deficient MCs leads to greater weight gain on a high-fat diet compared to transfer with wild-type MCs; however, this effect is absent when the transferred MCs lack both Sirt6 and galectin-3. Mechanistically, Sirt6 deacetylates H3K9 at the Lgals3 promoter, inhibiting galectin-3 production and protecting against M1 macrophage polarization and adipose tissue fibrosis. Single-cell RNA sequencing reveals a fibroinflammatory MC subpopulation dominating in the adipose tissue of Sirt6 knockout mice. Targeting Sirt6 activation or galectin-3 inhibition in MCs may represent a therapeutic approach for obesity-associated adipose fibroinflammation and insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-025-66040-z
  9. Nat Commun. 2026 Jan 07.
    Multiplexed lipid nanoparticle barcoding reveals tissue-dynamic kinetic insights and enriched cellular tropism in hepatic zones.
    Stephen T Moore, Xizhen Lian, Amogh Vaidya, Sumanta Chatterjee, Julien Santelli, Yehui Sun, Lukas Farbiak, Hao Zhu, Daniel J Siegwart.
      Lipid nanoparticles (LNPs) efficiently deliver nucleic acids to cells in vivo and facilitate clinical applications including RNA-based vaccines and therapies. Discovery and optimization of LNPs remain challenging due to the complexity of input variables and low throughput workflows. To accelerate these processes, we report a broadly compatible barcoded Cre recombinase mRNA barcode platform that enables multiplexed LNP tracking in vivo in tdTomato reporter mice. We evaluate accumulation and degradation kinetics of mRNA encapsulated in Selective Organ Targeting (SORT) LNPs in the liver, lung, and spleen, and show that functional protein activity is associated with rapid organ enrichment. We further demonstrate how barcode multiplexing can streamline systematic kinetic studies, distinguish nanoparticles with distinct biological outcomes, and differentiate subtle, yet important, variations within a series of similar formulations. Finally, we use barcoding to identify and characterize nanoparticles with hepatic zonal bias and previously overlooked extrahepatic tropism. This approach could accelerate high resolution characterization of nanoparticles with desirable properties, enable large-scale systematic studies of diverse LNPs, and provide insights into optimizable parameters of LNP-mRNA delivery.
    DOI:  https://doi.org/10.1038/s41467-025-68103-7
  10. Nature. 2026 Jan 08.
    Putting immune cells into 'night mode' reduces heart-attack damage.
      
    Keywords:  Cell biology; Diseases; Health care
    DOI:  https://doi.org/10.1038/d41586-026-00008-x
  11. Nat Metab. 2026 Jan 08.
    A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
    Xiao Zhang, Sreejith S Panicker, Jordan M Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L Magee, Brian S Learman, Adam Kepecs, Gretchen A Meyer, Jun Liu, Steven A Thomas, Irfan J Lodhi, Ormond A MacDougald, Erica L Scheller.
      Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
    DOI:  https://doi.org/10.1038/s42255-025-01424-5
  12. Nat Med. 2026 Jan 05.
    Blood biomarkers reveal pathways associated with multimorbidity.
      
    DOI:  https://doi.org/10.1038/s41591-025-04165-w
  13. Nature. 2026 Jan 07.
    The complex role of nutrients in cancer spread.
    Sandhya Yadav, Tara TeSlaa.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-03988-4
  14. Nat Immunol. 2026 Jan 07.
    Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
    Yasuharu Haku, Koji Kitaoka, Koki Ichimaru, Tomoko Hirano, Jun Wang, Kazuhiro Sonomura, Asuka Maruo, Shuhei Hirose, Yu Wang, Katsuhiro Ito, Tomohiro Kozuki, Keiko Yurimoto, Mai Kiyono, Hidetaka Kosako, Toshi Menju, Hiroshi Date, Takashi Kobayashi, Koichi Omori, Tomonori Yaguchi, Tasuku Honjo, Kenji Chamoto.
      Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8+ T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8+ T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8+ T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.
    DOI:  https://doi.org/10.1038/s41590-025-02370-w
  15. Sci Transl Med. 2026 Jan 07. 18(831): eadx2876
    Extracellular BRICK1 drives heart repair after myocardial infarction in mice.
    Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W Niessen, Andrew L Koenig, Kory J Lavine, Andreas Pich, Yong Wang, Marc R Reboll, Mortimer Korf-Klingebiel, Kai C Wollert.
      Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell-endothelial cell interactions. Here, we identify the 75-amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-loxP-driven myeloid cell-selective genetic deletion of Brk1 or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.
    DOI:  https://doi.org/10.1126/scitranslmed.adx2876
  16. Nat Commun. 2026 Jan 09.
    sCellST predicts single-cell gene expression from H& E images.
    Loïc Chadoutaud, Marvin Lerousseau, Daniel Herrero-Saboya, Julian Ostermaier, Jacqueline Fontugne, Emmanuel Barillot, Thomas Walter.
      Understanding the spatial organization of individual cell types within tissue and how this organization is disrupted in disease, is a central question in biology and medicine. Hematoxylin and eosin-stained slides are widely available and provide detailed morphological context, while spatial gene expression profiling offers complementary molecular insights, though it remains costly and limited in accessibility. Predicting gene expression directly from histological images is therefore an attractive goal. However, existing approaches typically rely on small image patches, limiting resolution and the ability to capture fine-grained morphological variation. Here, we introduce a deep learning approach that predicts single-cell gene expression from morphology, matching patch-based methods on spot level prediction tasks. The model recovers biologically meaningful expression patterns across two cancer datasets and distinguishes fine cell populations. This approach enables molecular-level interpretation of standard histological slides at scale, offering new opportunities to study tissue organization and cellular diversity in health and disease.
    DOI:  https://doi.org/10.1038/s41467-025-67965-1
  17. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)00980-3. [Epub ahead of print]86(1): 135-149.e9
    Membrane-protein-mediated phase separation orchestrates organelle contact sites.
    Christian Hoffmann, Takahiro Nagao, Taka A Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi, Dragomir Milovanovic.
      Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed "membrane contact sites," assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.
    Keywords:  PDZD8; biomolecular condensates; endoplasmic reticulum; liquid-liquid phase separation; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.006
  18. Nat Commun. 2026 Jan 07.
    Multi-organ network of cardiometabolic disease-depression multimorbidity revealed by phenotypic and genetic analyses of MR images.
    Jingxuan Wang, Mianxin Liu, Feng Liu, Guangrui Yang, Zhongshang Yuan, Hao Huang, Zixuan Zhang, Lilong Wang, Ye Wu, Wenliang Fan, Shuxiao Shi, Meng Chen, Xuanwei Jiang, Qiaoling Yan, Jun Lan, Xiaoming Liu, Shuang Rong, Nannan Feng, Victor W Zhong.
      The development and progression of cardiometabolic diseases and depression multimorbidity involves pathophysiological processes across multiple organs. Using multi-organ imaging data from 31,246 UK Biobank participants, we investigate the multi-organ manifestations and their phenotypic connections and shared genetic architecture underlying the multimorbidity. Phenotypic analyses identify seven abdominal, 16 cardiac, and 107 brain traits forming 1418 abdomen-heart-brain cliques, with liver volume, myocardial wall thickness, and white matter hyperintensity volume as central nodes. Genetic analyses reveal 43 distinct genomic loci (21 novel) shared by these cliques, with the most widely shared loci mapped to genes NUDC, ARID1A, and CRHR1. The 224 protein-coding genes mapped by these loci are enriched in 39 biological processes related to cardiometabolic and neuropsychiatric functions, with 15 genes expressed across liver-heart-brain axis tissues. Combining biochemical and multi-organ imaging indicators significantly improves multimorbidity prediction. These findings uncover multi-organ network underlying physical-mental multimorbidity and highlight the necessity of holistic management.
    DOI:  https://doi.org/10.1038/s41467-025-68092-7
  19. Diabetes. 2026 Jan 09. pii: db241025. [Epub ahead of print]
    Paracrine Hormonal Signals From Islet α-Cells Regulate Microtubule Dynamics in β-Cells to Promote Insulin Secretion in Mouse and Human Islets.
    Kung-Hsien Ho, Syed N Barmaver, Shannon E Gibson, Ruiying Hu, Mahircan Yagan, Hamida K Ahmed, Appakalai N Balamurugan, David A Jacobson, Irina Kaverina, Guoqiang Gu.
      The microtubule network in β-cells attenuates insulin secretion by pulling insulin secretory granules away from the plasma membrane. Thus, high-glucose-induced microtubule remodeling is required for robust glucose-stimulated insulin secretion. We now demonstrate that hormones secreted by α-cells regulate microtubule dynamics in β-cells through receptors for glucagon (GcgR) and glucagon-like peptide 1 (GLP-1R). Activation of GcgR or GLP-1R destabilizes microtubules in β-cells, accompanied by increased insulin secretion. In contrast, inhibiting these receptors attenuates high-glucose-induced microtubule destabilization and decreases secretion. Supporting the physiological significance of this regulation, β-cells in islets with a higher α-cell-to-β-cell ratio exhibit more dynamic microtubules than those with a lower ratio, and a high-fat diet challenge in mice, which can compromise β-cell secretion, attenuates this effect in their islets. Within individual islets, β-cells located near α-cells show faster microtubule remodeling upon glucose stimulation than those more distant from α-cells. Consequently, islets with a higher α-cell-to-β-cell ratio secrete more insulin in response to glucose stimulation and plasma membrane depolarization, results recapitulated by exogenous glucagon stimulation or chemically induced microtubule destabilization in islets with lower α-cell-to-β-cell ratios. These combined results suggest that α-cells use glucagon-mediated and/or GLP-1-mediated paracrine signaling to fine-tune β-cell secretion via microtubule remodeling.
    ARTICLE HIGHLIGHTS: Glucagon/glucagon-like peptide 1 sensitizes glucose-induced microtubule remodeling in β-cells. Microtubule density in islets inversely correlates with the α-cell-to-β-cell ratio. Glucose-stimulated insulin secretion levels in single islets positively correlate with their α-cell-to-β-cell ratio. Glucagon and microtubule destabilization mobilize the same granule pool.
    DOI:  https://doi.org/10.2337/db24-1025
  20. Nat Chem Biol. 2026 Jan 07.
    Membrane editing with proximity labeling reveals regulators of lipid homeostasis.
    Reika Tei, Xiang-Ling Li, Lin Luan, Jeremy M Baskin.
      Cellular lipid metabolism is subject to strong homeostatic regulation, but the players involved in and mechanisms underlying these pathways remain largely uncharacterized. Here we develop a 'feeding-fishing' approach coupling membrane editing using optogenetic lipid-modifying enzymes (feeding) with organelle membrane proteomics through proximity labeling (fishing) to elucidate molecular players and pathways involved in the homeostasis of phosphatidic acid (PA), a multifunctional lipid central to glycerolipid metabolism. This approach identified several PA-metabolizing enzymes and lipid transfer proteins enriched in and depleted from PA-fed membranes. Mechanistic analysis revealed that PA homeostasis in the cytosolic leaflets of the plasma membrane and lysosomes is mediated by both local PA metabolism and the action of lipid transfer proteins that carry out interorganelle lipid transport before subsequent metabolism. More broadly, the interfacing of membrane editing to controllably modify membrane lipid composition with organelle membrane proteomics using proximity labeling represents a strategy for revealing mechanisms governing lipid homeostasis.
    DOI:  https://doi.org/10.1038/s41589-025-02104-x
  21. Nat Med. 2026 Jan 07.
    How to interpret 'zero-shot' results from generative EHR models.
    Suhana Bedi, Jason Alan Fries, Nigam H Shah.
      
    DOI:  https://doi.org/10.1038/s41591-025-04094-8
  22. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00529-7. [Epub ahead of print]38(1): 33-49.e10
    Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
    Fiorella Di Pastena, Jaya Gautam, James S V Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Theodoros Tsakiridis, Evangelia E Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Vijayaragavan Muralidharan, Matthew J Watt, Scott L Friedman, Dongdong Wang, Gregory R Steinberg.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.
    Keywords:  EVT0185; HSCs; MASH; acetate; acetyl-CoA metabolism; cholesterol; fibrosis; hepatic stellate cells; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.015
  23. Nat Immunol. 2026 Jan 08.
    The differentiation and function of heterogeneous thymic dendritic cell subsets require signals provided by distinct thymocyte cell types.
    Jayashree Srinivasan, Colin R Moore, Aparna Calindi, Bryan R Helm, Yilin Yang, John F Moore, Hilary J Selden, Cody N Heiser, Qi Liu, Ken S Lau, Lauren I R Ehrlich.
      Dendritic cells are essential for establishing thymic central tolerance; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional dendritic cell (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells. Mice blocked at different stages of T cell development revealed that CD4+ single-positive (CD4SP) and CD8SP thymocytes differentially support homeostasis and activation of type 1 cDCs (cDC1s) versus cDC2s/plasmacytoid DCs (pDCs), respectively. CD8SP thymocytes indirectly support pDC survival and cDC2 thymic migration, and they induce interferon signaling in cDCs, partly by promoting type 3 interferon expression by medullary thymic epithelial cells. By contrast, CD4SP thymocytes undergo cognate interactions with cDCs, inducing CD40 signaling required for activation of cDC1s. Activated cDC1s make nonredundant contributions to central tolerance. Together, this study comprehensively identifies distinct thymic DC subsets and elucidates requirements for cross-talk with thymocyte subsets that support their homeostasis, activation and function.
    DOI:  https://doi.org/10.1038/s41590-025-02371-9
  24. JAMA. 2026 Jan 09.
    Home Hazards Increase Fall Risk in Older Adults With Visual Impairment.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2025.23017
  25. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2515183123
    Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
    Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A Villeda, Hao Li.
      Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging-increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.
    Keywords:  Perturb-seq screening; liver aging; rejuvenation; replicative aging
    DOI:  https://doi.org/10.1073/pnas.2515183123
  26. Nat Cell Biol. 2026 Jan 08.
    Revealing high-resolution spatial metagenes from spatial transcriptomics.
      
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