bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–06–01
28 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Pace of aging matters for healthspan and lifespan in older adults.
  2. Conservation of regulatory elements with highly diverged sequences across large evolutionary distances.
  3. Alternative cGAS signaling promotes herpes simplex encephalitis.
  4. In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
  5. IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints.
  6. CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
  7. Reverse electron transport drives metabolic changes in obesity.
  8. WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.
  9. A coordinated cellular network regulates tolerance to food.
  10. Methods for multiplexing single-cell multi-omics.
  11. Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy.
  12. How the brain spies on the gut: with help from newfound immune cells.
  13. Circular RNA-mediated inverse prime editing in human cells.
  14. Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.
  15. Europe can capture the US brain drain - if it acts fast.
  16. Splanchnic and Leg Glucagon Metabolism in Healthy and Type 1 Diabetes: First in Human Study Using [13C9, 15N1]-Glucagon.
  17. Multiple structures of RNA polymerase II isolated from human nuclei by ChIP-CryoEM analysis.
  18. The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
  19. Astrocyte morphogenesis requires self-recognition.
  20. Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers.
  21. Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
  22. Implementing digital health to support self-care of chronic diseases.
  23. The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer's disease.
  24. Super-resolution imaging technique for precision in vivo neuronal activity mapping.
  25. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
  26. Personalized molecular signatures of insulin resistance and type 2 diabetes.
  27. Human endothelial cells promote a human neural stem cell type B phenotype via Notch signaling.
  28. Mouse liver assembloids model periportal architecture and biliary fibrosis.
  1. Nat Aging. 2025 May 30.
    Pace of aging matters for healthspan and lifespan in older adults.
      
    DOI:  https://doi.org/10.1038/s43587-025-00903-4
  2. Nat Genet. 2025 May 27.
    Conservation of regulatory elements with highly diverged sequences across large evolutionary distances.
    Mai H Q Phan, Tobias Zehnder, Fiona Puntieri, Andreas Magg, Blanka Majchrzycka, Milan Antonović, Hannah Wieler, Bai-Wei Lo, Damir Baranasic, Boris Lenhard, Ferenc Müller, Martin Vingron, Daniel M Ibrahim.
      Developmental gene expression is a remarkably conserved process, yet most cis-regulatory elements (CREs) lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that CREs at the same genomic position remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. Here, we profiled the regulatory genome in mouse and chicken embryonic hearts at equivalent developmental stages and found that most CREs lack sequence conservation. To identify positionally conserved CREs, we introduced the synteny-based algorithm interspecies point projection, which identifies up to fivefold more orthologs than alignment-based approaches. We termed positionally conserved orthologs 'indirectly conserved' and showed that they exhibited chromatin signatures and sequence composition similar to sequence-conserved CREs but greater shuffling of transcription factor binding sites between orthologs. Finally, we validated indirectly conserved chicken enhancers using in vivo reporter assays in mouse. By overcoming alignment-based limitations, we revealed widespread functional conservation of sequence-divergent CREs.
    DOI:  https://doi.org/10.1038/s41588-025-02202-5
  3. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2423873122
    Alternative cGAS signaling promotes herpes simplex encephalitis.
    Liraz Shmuel-Galia, Zhaozhao Jiang, Laurel Stine, Sara Cahill, Sze-Ling Ng, Ruth Wilson, Richard Kumaran Kandasamy, Evelyn A Kurt-Jones, Joshi M Ramanjulu, John Bertin, Viera Kasparcova, G Scott Pesiridis, Katherine A Fitzgerald, Fiachra Humphries.
      During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutières syndrome, as well as Lupus and neurodegenerative diseases like Parkinson's disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study reports of an alternative cGAS response independent of cGAMP, highlighting a previously uncharacterized scaffold function for cGAS.
    Keywords:  HSV; cGAS; infection; mouse model; type I IFN
    DOI:  https://doi.org/10.1073/pnas.2423873122
  4. Nat Commun. 2025 May 30. 16(1): 5041
    In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
    Noah Peña, Yichen Hou, Christopher P Watkins, Sihao Huang, Wen Zhang, Christopher D Katanski, Tao Pan.
      Transfer RNA (tRNA) is the most abundant cellular RNA family in terms of copy numbers. It not only folds into defined structures but also has complex cellular interaction networks involving aminoacyl-tRNA synthetases, translation factors, and ribosomes. The human tRNAome is comprised of chromosomal-encoded tRNAs with a large sequence diversity and mitochondrial-encoded tRNAs with A/U-rich sequences and noncanonical tertiary interactions. How tRNA folding and interactions in a eukaryotic cell respond to stress is poorly understood. Here, we develop DM-DMS-MaPseq, which utilizes in vivo dimethyl-sulfate (DMS) chemical probing and mutational profiling (MaP) coupled with demethylase (DM) treatment in transcriptome-wide tRNA sequencing to profile structures and the cellular interactions of human chromosomal and mitochondrial-encoded tRNAs. We found that tRNAs maintain stable structures in vivo, but the in vivo DMS profiles are vastly different from those in vitro, which can be explained by their interactions with cellular proteins and the ribosome. We also identify cytosolic and mitochondrial tRNA structure and interaction changes upon arsenite treatment, a type of oxidative stress that induces translational reprogramming, which is consistent with global translation repression in both compartments. Our results reveal variations of tRNA structurome and dynamic interactome that have functional consequences in translational regulation.
    DOI:  https://doi.org/10.1038/s41467-025-59435-5
  5. J Exp Med. 2025 Jul 07. pii: e20231882. [Epub ahead of print]222(7):
    IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints.
    Adam J Fike, Kristen N Bricker, Michael V Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M Emrich, Julia L Weber, Sara A Luckenbill, Nicholas M Choi, Renan Sauteraud, Dajiang J Liu, Nancy J Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S M Rahman.
      How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in IRF7 uncovered the IRF7 role in regulating autoimmune germinal center (GC), plasma cell (PC), and autoantibody responses and disease. IRF7, however, was dispensable for foreign antigen-driven GC, PC, and antibody responses. Competitive bone marrow (BM) chimeras highlighted the importance of IRF7 in hematopoietic cells in spontaneous GC and PC differentiation. Single-cell RNAseq of SLE-prone B cells indicated IRF7-mediated B cell differentiation through GC and PC fates. Mechanistic studies revealed that IRF7 promoted B cell differentiation through GC and PC fates by regulating the transcriptome, translation, and metabolism of SLE-prone B cells. Mixed BM chimeras demonstrated a requirement for B cell-intrinsic IRF7 in IgG autoantibody production but not in the regulation of spontaneous GC and PC responses. Altogether, we delineate previously unknown B cell-intrinsic and -extrinsic mechanisms of IRF7-promoted spontaneous GC and PC responses, loss of tolerance, autoantibody production, and SLE development.
    DOI:  https://doi.org/10.1084/jem.20231882
  6. Nature. 2025 May 28.
    CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
    Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  7. Nature. 2025 May 28.
    Reverse electron transport drives metabolic changes in obesity.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01621-y
  8. Nat Commun. 2025 May 28. 16(1): 4945
    WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.
    Alissa J Trzeciak, Zong-Lin Liu, Mohamed Gatie, Adam S Krebs, Waleska Saitz Rojas, Anya J O'Neal, Ann K Baako, Zhaoquan Wang, Justin Nelson, Isabella C Miranda, Jazib Uddin, Allie Lipshutz, Jian Xie, Chou-Long Huang, Pedro H V Saavedra, Anna-Katerina Hadjantonakis, Michael Overholtzer, Michael S Glickman, Arohan R Subramanya, Thomas Vierbuchen, Jon Iker Etchegaray, Christopher D Lucas, Christopher N Parkhurst, Justin S A Perry.
      Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1riCre-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-59901-0
  9. Nature. 2025 May 27.
    A coordinated cellular network regulates tolerance to food.
    Anna Rudnitsky, Hanna Oh, Maya Margolin, Bareket Dassa, Inbar Shteinberg, Liat Stoler-Barak, Ziv Shulman, Ranit Kedmi.
      To absorb nutrients and support commensal microbes, the host induces tolerogenic immune responses via peripheral regulatory T cells (pTregs) 1,2. Prior studies identified type 1 dendritic cells (cDC1) as initiators of dietary pTregs3. However, we now report that food-specific pTreg cells are exclusively induced by the recently identified RORγt APCs4-8 and not by cDCs. Instead, our data suggest that pTreg-cDC1 interactions in steady-state limit the expansion of food-specific CD8αβ T cells. This regulation breaks during infection or food poisoning, enabling dietary CD8αβ T cells to expand and acquire effector functions in response to mimicked food antigens. Unlike in typical infections, after the pathogen is cleared, dietary CD8αβ T cells do not expand in response to their corresponding dietary antigens. Thus, we propose that in response to dietary antigens, tolerance is mediated by a circuit of dedicated antigen-presenting cells (APCs) and T cells. When the host is challenged by infection, this circuit permits the transient expansion of protective effector responses without compromising the overall strategy of tolerance that ensures safe food consumption.
    DOI:  https://doi.org/10.1038/s41586-025-09173-x
  10. Nat Methods. 2025 May 26.
    Methods for multiplexing single-cell multi-omics.
    Laura C Kida, Caleb A Lareau.
      
    DOI:  https://doi.org/10.1038/s41592-025-02657-8
  11. Nat Commun. 2025 May 27. 16(1): 4899
    Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy.
    Florence Borot, Olivier Humbert, Jeffrey T Ehmsen, Emily Fields, Sajeev Kohli, Stefan Radtke, Kyle Swing, Dnyanada Pande, Mark R Enstrom, George S Laszlo, Thiyagaraj Mayuranathan, Abdullah Mahmood Ali, Mitchell J Weiss, Jonathan S Yen, Gregory A Newby, Roland B Walter, David R Liu, Siddhartha Mukherjee, Hans-Peter Kiem.
      The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (>70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.
    DOI:  https://doi.org/10.1038/s41467-025-59713-2
  12. Nature. 2025 May 28.
    How the brain spies on the gut: with help from newfound immune cells.
    Gemma Conroy.
      
    Keywords:  Brain; Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01655-2
  13. Nat Commun. 2025 May 31. 16(1): 5057
    Circular RNA-mediated inverse prime editing in human cells.
    Ronghong Liang, Shan Wang, Yibo Cai, Zhenyu Li, Ka Ming Li, Jingjing Wei, Chao Sun, Haocheng Zhu, Kunling Chen, Caixia Gao.
      Prime editors are restricted to performing precise edits downstream of cleavage sites, thereby limiting their editing scope. Therefore, we develop inverse prime editors (iPEs) that act upstream of the nickase cleavage site by replacing nCas9-H840A with nCas9-D10A, but the editing efficiencies are limited. To address this limitation, we develop circular RNA-mediated iPEs (ciPEs), achieving editing efficiencies ranging from 0.1% to 24.7%. Further optimization using Rep-X helicase increases editing efficiencies to a range of 2.7%-55.4%. The Rep-X-assisted ciPE system thus expands the scope of editing and improves efficiencies at genomic sites that are previously difficult to target. The Rep-X-assisted ciPE system will complement canonical PE system in enabling more extensive and efficient editing across a wider range of the human genome.
    DOI:  https://doi.org/10.1038/s41467-025-59120-7
  14. Nat Commun. 2025 May 27. 16(1): 4887
    Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.
    Elvira Boršić, Taja Železnik Ramuta, Sara Orehek, Mateja Erdani Kreft, Matthias Geyer, Roman Jerala, Iva Hafner-Bratkovič.
      NLRP3 is a pattern recognition receptor forming an inflammasome in response to diverse pathogen and self-derived triggers, but molecular insights on NLRP3 activation are still lacking. Here, we drive ectopic NLRP3 to different subcellular locations in NLRP3-deficient macrophages to map the spatial activation profile of NLRP3, and find that NLRP3 variants enriched at the organellar membranes respond to canonical triggers similarly to wild-type NLRP3; however, unlike wild-type, these NLRP3 variants can be activated even in the absence of the polybasic phospholipid-binding segment. Mechanistically, membrane or protein scaffolds mediate NLRP3 clustering, which leads to the unfastening of the inactive NACHT domain conformation preceding the activated NLRP3 oligomer formation. Our data thus suggest that scaffold-promoted clustering is an important step in NLRP3 activation, enabling NLRP3 to sense distinct activator-induced cellular anomalies exhibited via lipid or protein assemblies, thereby establishing NLRP3 as the master sensor of perturbations in cell homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-60277-4
  15. Nature. 2025 May;641(8065): 1074
    Europe can capture the US brain drain - if it acts fast.
    Maria M Mota.
      
    Keywords:  Government; Policy; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-01567-1
  16. Diabetes. 2025 May 30. pii: db241064. [Epub ahead of print]
    Splanchnic and Leg Glucagon Metabolism in Healthy and Type 1 Diabetes: First in Human Study Using [13C9, 15N1]-Glucagon.
    F N U Ruchi, Michele Schiavon, Yogesh Yadav, Chiara Dalla Man, Claudio Cobelli, Akhilesh Pandey, Luke Wilkins, Rita Basu, Ananda Basu.
       ARTICLE HIGHLIGHTS: This study was conducted to assess splanchnic and leg glucagon metabolism in humans using stable glucagon isotopes. We wanted to evaluate whether splanchnic and leg glucagon metabolism differed between participants with no diabetes (ND) and those with type 1 diabetes (T1D) at glucagon concentrations spanning the physiological range. Whereas splanchnic glucagon extraction did not differ between participants with ND and those with T1D, leg glucagon extraction fell in those with ND but did not change in those with T1D as glucagon concentrations increased. Net splanchnic glucagon production did not change with exogenous glucagon infusion. Our study has implications for dual hormone closed loop control in T1D where glucagon is infused for prevention of hypoglycemia and for investigating the effects of emerging GLP-1, glucose-dependent insulinotropic polypeptide, and glucagon receptor agonists on endogenous glucagon secretion and clearance.
    DOI:  https://doi.org/10.2337/db24-1064
  17. Nat Commun. 2025 May 28. 16(1): 4724
    Multiple structures of RNA polymerase II isolated from human nuclei by ChIP-CryoEM analysis.
    Tomoya Kujirai, Junko Kato, Kyoka Yamamoto, Seiya Hirai, Takeru Fujii, Kazumitsu Maehara, Akihito Harada, Lumi Negishi, Mitsuo Ogasawara, Yuki Yamaguchi, Yasuyuki Ohkawa, Yoshimasa Takizawa, Hitoshi Kurumizaka.
      RNA polymerase II (RNAPII) is a central transcription enzyme that exists as multiple forms with or without accessory factors, and transcribes the genomic DNA packaged in chromatin. To understand how RNAPII functions in the human genome, we isolate transcribing RNAPII complexes from human nuclei by chromatin immunopurification, and determine the cryo-electron microscopy structures of RNAPII elongation complexes (ECs) associated with genomic DNA in distinct forms, without or with the elongation factors SPT4/5, ELOF1, and SPT6. This ChIP-cryoEM method also reveals the two EC-nucleosome complexes corresponding nucleosome disassembly/reassembly processes. In the structure of EC-downstream nucleosome, EC paused at superhelical location (SHL) -5 in the nucleosome, suggesting that SHL(-5) pausing occurs in a sequence-independent manner during nucleosome disassembly. In the structure of the EC-upstream nucleosome, EC directly contacts the nucleosome through the nucleosomal DNA-RPB4/7 stalk and the H2A-H2B dimer-RPB2 wall interactions, suggesting that EC may be paused during nucleosome reassembly. These representative EC structures transcribing the human genome provide mechanistic insights into understanding RNAPII transcription on chromatin.
    DOI:  https://doi.org/10.1038/s41467-025-59580-x
  18. Nat Aging. 2025 May 28.
    The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
    Lisonia Gkioni, Tobias Nespital, Maarouf Baghdadi, Carolina Monzó, Jitin Bali, Taim Nassr, Anna Lena Cremer, Andreas Beyer, Joris Deelen, Heiko Backes, Sebastian Grönke, Linda Partridge.
      Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.
    DOI:  https://doi.org/10.1038/s43587-025-00876-4
  19. Nature. 2025 May 28.
    Astrocyte morphogenesis requires self-recognition.
    John H Lee, Alina P Sergeeva, Göran Ahlsén, Seetha Mannepalli, Fabiana Bahna, Kerry M Goodman, Runzhe Xu, Baljit S Khakh, Joshua A Weiner, Lawrence Shapiro, Barry Honig, S Lawrence Zipursky.
      Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1-4. Clustered protocadherin (cPcdh) proteins, which comprise a large family of isoform-specific homophilic recognition molecules, have a pivotal role in the neuronal self-avoidance that is required for mammalian brain development5-7. The probabilistic expression of different cPcdh isoforms confers unique identities on neurons and forms the basis for neuronal processes to discriminate between self and non-self5,6,8. Whether this self-recognition mechanism also exists in astrocytes remains unknown. Here we report that γC3, a specific isoform in the Pcdhγ family, is enriched in human and mouse astrocytes. Using genetic manipulation, we demonstrate that γC3 acts autonomously to regulate astrocyte morphogenesis in the mouse visual cortex. To determine whether γC3 proteins act by promoting recognition between processes of the same astrocyte, we generated pairs of γC3 chimeric proteins that are capable of heterophilic binding to each other, but incapable of homophilic binding. Co-expression of complementary heterophilic binding isoform pairs in the same γC3-null astrocyte restored normal morphology. By contrast, chimeric γC3 proteins individually expressed in single γC3-null mutant astrocytes did not. These data establish that self-recognition mediated by γC3 contributes to astrocyte development in the mammalian brain.
    DOI:  https://doi.org/10.1038/s41586-025-09013-y
  20. Nat Commun. 2025 May 28. 16(1): 4961
    Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers.
    Estonian Biobank Research Team
      Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-60058-z
  21. Nat Cell Biol. 2025 May 28.
    Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
    Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D Fairn, Dante Neculai.
      Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER-PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER-PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.
    DOI:  https://doi.org/10.1038/s41556-025-01665-2
  22. Nat Med. 2025 May 28.
    Implementing digital health to support self-care of chronic diseases.
    Marie Löf, Ralph Maddison.
      
    DOI:  https://doi.org/10.1038/s41591-025-03729-0
  23. Nat Commun. 2025 May 27. 16(1): 4883
    The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer's disease.
    Kitty B Murphy, Di Hu, Leen Wolfs, Susan K Rohde, Gonzalo Leguía Fauró, Ivana Geric, Renzo Mancuso, Bart De Strooper, Sarah J Marzi.
      Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms change gene regulatory patterns that link back to biological function by shaping microglial transcriptomic and chromatin landscapes. We use RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia xenotransplantated into the brains of male APPNL-G-F mice. We identify widespread transcriptomic and epigenomic differences which are dependent on APOE genotype and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased phagocytic capabilities and DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform's protective role.
    DOI:  https://doi.org/10.1038/s41467-025-60099-4
  24. Nat Methods. 2025 May 26.
    Super-resolution imaging technique for precision in vivo neuronal activity mapping.
      
    DOI:  https://doi.org/10.1038/s41592-025-02691-6
  25. Nat Aging. 2025 May 27.
    Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
    Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li.
      Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00890-6
  26. Cell. 2025 May 21. pii: S0092-8674(25)00515-X. [Epub ahead of print]
    Personalized molecular signatures of insulin resistance and type 2 diabetes.
    Jeppe Kjærgaard, Ben Stocks, John Henderson, Jordana B Freemantle, David Rizo-Roca, Michele Puglia, Maria Madrazo Montoya, Daniel Andersson, Jesper Bäckdahl, Daniel Eriksson-Hogling, Jacob V Stidsen, Michael Wierer, Simon Rasmussen, Kei Sakamoto, Kurt Højlund, Mikael Rydén, Juleen R Zierath, Anna Krook, Atul S Deshmukh.
      Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.
    Keywords:  disease heterogeneity; glucose metabolism; phosphoproteomics; sex differences; signaling; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cell.2025.05.005
  27. Nat Commun. 2025 May 30. 16(1): 5031
    Human endothelial cells promote a human neural stem cell type B phenotype via Notch signaling.
    Brenda Gutierrez, Tzu Chia Liu, Carly Rodriguez, Oier Pastor-Alonso, Hannah Lambing, Mercedes F Paredes, Lisa A Flanagan.
      Neural stem and progenitor cell (NSPC) and vessel-forming endothelial cell (EC) communication throughout development and adulthood is vital for normal brain function. However, much remains unclear regarding coordinated regulation of these cells, particularly in humans. We find that contact with hECs increases hNSPC type B cells, which are GFAP-expressing adult NSPCs in the subventricular zone (SVZ), leading to generation of a human type B single-cell RNA sequencing (scRNAseq) dataset. Differential gene expression demonstrates an increase in Notch downstream mediators in type B hNSPCs after hEC contact. Blocking hNSPC Notch signaling, and reducing hEC expression of the Notch ligand DLL4, abrogates the effect of hECs on type B hNSPCs. We identify S100A6 and LeX as human type B cell markers, and analysis of the postnatal human SVZ confirms co-expression of GFAP, SOX2, S100A6, LeX and PROM1 in type B cells. Sites of contact are identified between type B hNSPCs and vasculature in the SVZ, providing evidence of human type B cell contact with hECs in the postnatal human brain. Thus, hEC contact promotes human type B cells via Notch signaling and these cells are in contact in stem cell niches in the human brain.
    DOI:  https://doi.org/10.1038/s41467-025-60194-6
  28. Nature. 2025 May 29.
    Mouse liver assembloids model periportal architecture and biliary fibrosis.
    Anna M Dowbaj, Aleksandra Sljukic, Armin Niksic, Cedric Landerer, Julien Delpierre, Haochen Yang, Aparajita Lahree, Ariane C Kühn, David Beers, Helen M Byrne, Sarah Seifert, Heather A Harrington, Marino Zerial, Meritxell Huch.
      Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Taken together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage, and how different cell types contribute to cholestatic disease and biliary fibrosis, in an all-in-one model.
    DOI:  https://doi.org/10.1038/s41586-025-09183-9
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