bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–03–30
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A map of mitochondrial biology reveals the energy landscape of the human brain.
  2. Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
  3. Oxidation of retromer complex controls mitochondrial translation.
  4. Lysosome repair fails in ageing and Alzheimer's disease.
  5. ImmGenMaps, an open-source cartography of the immune system.
  6. Ferroptosis spreads to neighboring cells via plasma membrane contacts.
  7. Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans.
  8. Treating neuroinflammation through the nose.
  9. Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer's disease neuropathology.
  10. Live-cell super-resolution microscopy reveals how molecules enter and exit the nucleus.
  11. General anaesthesia decreases the uniqueness of brain functional connectivity across individuals and species.
  12. SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome.
  13. 'Open source' AI isn't truly open - here's how researchers can reclaim the term.
  14. Drugs that target 'zombie' cells soothe an aching back.
  15. Metabolic constraint of human telomere length by nucleotide salvage efficiency.
  16. Vestibular nucleus mediation of motion sickness has implications for obesity control.
  17. Missense variants in FRS3 affect body mass index in populations of diverse ancestries.
  18. Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity.
  19. SIMVI disentangles intrinsic and spatial-induced cellular states in spatial omics data.
  20. Fast segmentation and multiplexing imaging of organelles in live cells.
  21. Alarmingly large care deficits globally for people living with dementia and disability.
  22. A BCAA-haem axis regulates brown fat function.
  23. Vestibular neurons link motion sickness, behavioural thermoregulation and metabolic balance in mice.
  24. FTO suppresses DNA repair by inhibiting PARP1.
  25. Chromatin accessibility landscape of mouse early embryos revealed by single-cell NanoATAC-seq2.
  26. Connectivity of single neurons classifies cell subtypes in mouse brains.
  27. Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue.
  28. Chromatin landscape at cis-regulatory elements orchestrates cell fate decisions in early embryogenesis.
  29. Spatial transcriptomic imaging of an intact organism using volumetric DNA microscopy.
  30. Fasting for weight loss is all the rage: what are the health benefits?
  1. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  2. Nat Commun. 2025 Mar 24. 16(1): 2749
    Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
    Alexandra E Preston, Joe N Frost, Megan R Teh, Mohsin Badat, Andrew E Armitage, Ruggiero Norfo, Sarah K Wideman, Muhammad Hanifi, Natasha White, Noémi Ba Roy, Christian Babbs, Bart Ghesquiere, James Davies, Andrew Jm Howden, Linda V Sinclair, Jim R Hughes, Mira Kassouf, Rob Beagrie, Douglas R Higgs, Hal Drakesmith.
      Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.
    DOI:  https://doi.org/10.1038/s41467-025-57683-z
  3. Nature. 2025 Mar 26.
    Oxidation of retromer complex controls mitochondrial translation.
    Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan Vornbäumen, Zehra Ordulu, Anthony P Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N Pavlova, Michael Lawrence, Justin F Gainor, Sean A Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J Ott, Brian Liau, Liron Bar-Peled.
      Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
    DOI:  https://doi.org/10.1038/s41586-025-08756-y
  4. Nat Cell Biol. 2025 Mar 26.
    Lysosome repair fails in ageing and Alzheimer's disease.
    Céline Vrancx, Wim Annaert.
      
    DOI:  https://doi.org/10.1038/s41556-024-01608-3
  5. Nat Immunol. 2025 Mar 26.
    ImmGenMaps, an open-source cartography of the immune system.
    ImmGenMaps Group
      
    DOI:  https://doi.org/10.1038/s41590-025-02119-5
  6. Nat Commun. 2025 Mar 26. 16(1): 2951
    Ferroptosis spreads to neighboring cells via plasma membrane contacts.
    Bernhard F Roeck, Sara Lotfipour Nasudivar, Michael R H Vorndran, Lena Schueller, F Isil Yapici, Matthias Rübsam, Silvia von Karstedt, Carien M Niessen, Ana J Garcia-Saez.
      Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
    DOI:  https://doi.org/10.1038/s41467-025-58175-w
  7. Nat Commun. 2025 Mar 26. 16(1): 2941
    Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans.
    Xia Wu, Dan Xiong, Rong Liu, Xingqiang Lai, Yuhan Tian, Ziying Xie, Li Chen, Lanqi Hu, Jingjing Duan, Xinyu Gao, Xian Zeng, Wei Dong, Ting Xu, Fang Fu, Xin Yang, Xinlai Cheng, Dariusz Plewczynski, Minji Kim, Wenjun Xin, Tianyun Wang, Andy Peng Xiang, Zhonghui Tang.
      Chromatin topology can impact gene regulation, but how evolutionary divergence in chromatin topology has shaped gene regulatory landscapes for distinctive human traits remains poorly understood. CTCF sites determine chromatin topology by forming domains and loops. Here, we show evolutionary divergence in CTCF-mediated chromatin topology at the domain and loop scales during primate evolution, elucidating distinct mechanisms for shaping regulatory landscapes. Human-specific divergent domains lead to a broad rewiring of transcriptional landscapes. Divergent CTCF loops concord with species-specific enhancer activity, influencing enhancer connectivity to target genes in a concordant yet constrained manner. Under this concordant mechanism, we establish the role of human-specific CTCF loops in shaping transcriptional isoform diversity, with functional implications for disease susceptibility. Furthermore, we validate the function of these human-specific CTCF loops using human forebrain organoids. This study advances our understanding of genetic evolution from the perspective of genome architecture.
    DOI:  https://doi.org/10.1038/s41467-025-58275-7
  8. Sci Signal. 2025 Mar 25. 18(879): eadx5434
    Treating neuroinflammation through the nose.
    Leslie K Ferrarelli.
      An antibody delivered nasally after brain injury induces a neuroprotective, anti-inflammatory response.
    DOI:  https://doi.org/10.1126/scisignal.adx5434
  9. Nat Commun. 2025 Mar 22. 16(1): 2842
    Brain 5-hydroxymethylcytosine alterations are associated with Alzheimer's disease neuropathology.
    Jinying Zhao, Tongjun Gu, Cheng Gao, Guanhong Miao, Helena Palma-Gudiel, Lei Yu, Jingyun Yang, Yanling Wang, Yujing Li, Junghwa Lim, Ronghua Li, Bing Yao, Hao Wu, Julie A Schneider, Nicholas Seyfried, Francine Grodstein, Philip L De Jager, Peng Jin, David A Bennett.
      5-hydroxymethylcytosine, also known as the sixth DNA base of the genome, plays an important role in brain aging and neurological disorders such as Alzheimer's disease. However, little is known about its genome-wide distribution and its association with Alzheimer's disease pathology. Here, we report a genome-wide profiling of 5-hydroxymethylcytosine in 1079 autopsied brains (dorsolateral prefrontal cortex) of older individuals and assess its association with multiple measures of Alzheimer's disease pathologies, including pathological diagnosis of Alzheimer's disease, amyloid-β load, and PHFtau tangle density. Of 197,765 5-hydroxymethylcytosine regions detected, we identified 2821 differentially hydroxymethylated regions associated with Alzheimer's disease neuropathology after controlling for multiple testing and covariates. Many differentially hydroxymethylated regions are located within known Alzheimer's disease loci, such as RIN3, PLCG2, ITGA2B, and USP6NL. Integrative multi-omics analyses support a potential mechanistic role of 5-hydroxymethylcytosine alterations in Alzheimer's disease. Our study presents a large-scale genome-wide atlas of 5-hydroxymethylcytosine in Alzheimer's brain and offers insight into the mechanism underlying Alzheimer's disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-58159-w
  10. Nature. 2025 Mar 24.
    Live-cell super-resolution microscopy reveals how molecules enter and exit the nucleus.
    Bernd Rieger, Enya S Berrevoets.
      
    Keywords:  Biotechnology; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00804-x
  11. Nat Hum Behav. 2025 Mar 24.
    General anaesthesia decreases the uniqueness of brain functional connectivity across individuals and species.
    Andrea I Luppi, Daniel Golkowski, Andreas Ranft, Rudiger Ilg, Denis Jordan, Danilo Bzdok, Adrian M Owen, Lorina Naci, Emmanuel A Stamatakis, Enrico Amico, Bratislav Misic.
      The human brain is characterized by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI scans acquired under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain, both with respect to the brains of other individuals and the brains of another species. Using functional connectivity, we report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organized: it co-localizes with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol and reversed upon recovery. Providing convergent evidence, we show that anaesthesia shifts the functional connectivity of the human brain closer to the functional connectivity of the macaque brain in a low-dimensional space. Finally, anaesthesia diminishes the match between spontaneous brain activity and cognitive brain patterns aggregated from the Neurosynth meta-analytic engine. Collectively, the present results reveal that anaesthetized human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.
    DOI:  https://doi.org/10.1038/s41562-025-02121-9
  12. Nat Commun. 2025 Mar 25. 16(1): 2893
    SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome.
    Bree J Tillett, Jacky Dwiyanto, Kate R Secombe, Thomas George, Vivian Zhang, Dovile Anderson, Emily Duggan, Rabina Giri, Dorothy Loo, Thomas Stoll, Mark Morrison, Jakob Begun, Michelle M Hill, Esteban N Gurzov, Kirstine J Bell, Sonia Saad, Christopher K Barlow, Darren J Creek, Chun Wie Chong, Eliana Mariño, Emma E Hamilton-Williams.
      Type 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis. Metabolomics showed arginine, glutamate, nucleotide and tryptophan metabolism were enriched following the SCFA-biotherapy, and found metabolites that correlated with glycemic control. Fecal microbiota transfer demonstrated that the microbiota of SCFA-responders delayed diabetes progression in humanized gnotobiotic mice. The protected mice increased similar metabolite pathways to the humans including producing aryl-hydrocarbon receptor ligands and reducing inflammatory mucosal immunity and increasing IgA production in the gut. These data demonstrate that a potent SCFA immunomodulator promotes multiple beneficial pathways and supports targeting the microbiota as an approach against T1D. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12618001391268.
    DOI:  https://doi.org/10.1038/s41467-025-58319-y
  13. Nature. 2025 Apr;640(8057): 9
    'Open source' AI isn't truly open - here's how researchers can reclaim the term.
    Stefano Maffulli.
      
    Keywords:  Computer science; Machine learning; Policy
    DOI:  https://doi.org/10.1038/d41586-025-00930-6
  14. Nature. 2025 Mar;639(8056): 841
    Drugs that target 'zombie' cells soothe an aching back.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00770-4
  15. Nat Commun. 2025 Mar 27. 16(1): 3000
    Metabolic constraint of human telomere length by nucleotide salvage efficiency.
    William Mannherz, Andrew Crompton, Noah Lampl, Suneet Agarwal.
      Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.
    DOI:  https://doi.org/10.1038/s41467-025-58221-7
  16. Nat Metab. 2025 Mar 21.
    Vestibular nucleus mediation of motion sickness has implications for obesity control.
      
    DOI:  https://doi.org/10.1038/s42255-025-01238-5
  17. Nat Commun. 2025 Mar 25. 16(1): 2694
    Missense variants in FRS3 affect body mass index in populations of diverse ancestries.
    DBDS Genomic Consortium
      Obesity is associated with adverse effects on health and quality of life. Improved understanding of its underlying pathophysiology is essential for developing counteractive measures. To search for sequence variants with large effects on BMI, we perform a multi-ancestry meta-analysis of 13 genome-wide association studies on BMI, including data derived from 1,534,555 individuals of European ancestry, 339,657 of Asian ancestry, and 130,968 of African ancestry. We identify an intergenic 262,760 base pair deletion at the MC4R locus that associates with 4.11 kg/m2 higher BMI per allele, likely through downregulation of MC4R. Moreover, a rare FRS3 missense variant, p.Glu115Lys, only found in individuals from Finland, associates with 1.09 kg/m2 lower BMI per allele. We also detect three other low-frequency FRS3 missense variants that associate with BMI with smaller effects and are enriched in different ancestries. We characterize FRS3 as a BMI-associated gene, encoding an adaptor protein known to act downstream of BDNF and TrkB, which regulate appetite, food intake, and energy expenditure through unknown signaling pathways. The work presented here contributes to the biological foundation of obesity by providing a convincing downstream component of the BDNF-TrkB pathway, which could potentially be targeted for obesity treatment.
    DOI:  https://doi.org/10.1038/s41467-025-57753-2
  18. Nat Commun. 2025 Mar 22. 16(1): 2840
    Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity.
    Gabriel L McKinsey, Nicolas Santander, Xiaoming Zhang, Kilian L Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos O Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E S Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas D Arnold.
      Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers Smad2 and Smad3 have a less polarized dysmature phenotype and correspondingly less severe neuromotor dysfunction. Our study describes the spatio-temporal regulation of TGFβ activation and signaling in the brain necessary to promote microglial development, and provides evidence for the adoption of microglial developmental signaling pathways in brain injury or disease.
    DOI:  https://doi.org/10.1038/s41467-025-57684-y
  19. Nat Commun. 2025 Mar 27. 16(1): 2990
    SIMVI disentangles intrinsic and spatial-induced cellular states in spatial omics data.
    Mingze Dong, David G Su, Harriet Kluger, Rong Fan, Yuval Kluger.
      Spatial omics technologies enable analysis of gene expression and interaction dynamics in relation to tissue structure and function. However, existing computational methods may not properly distinguish cellular intrinsic variability and intercellular interactions, and may thus fail to reliably capture spatial regulations. Here, we present Spatial Interaction Modeling using Variational Inference (SIMVI), an annotation-free deep learning framework that disentangles cell intrinsic and spatial-induced latent variables in spatial omics data with rigorous theoretical support. By this disentanglement, SIMVI enables estimation of spatial effects at a single-cell resolution, and empowers various downstream analyses. We demonstrate the superior performance of SIMVI across datasets from diverse platforms and tissues. SIMVI illuminates the cyclical spatial dynamics of germinal center B cells in human tonsil. Applying SIMVI to multiome melanoma data reveals potential tumor epigenetic reprogramming states. On our newly-collected cohort-level CosMx melanoma data, SIMVI uncovers space-and-outcome-dependent macrophage states and cellular communication machinery in tumor microenvironments.
    DOI:  https://doi.org/10.1038/s41467-025-58089-7
  20. Nat Commun. 2025 Mar 21. 16(1): 2769
    Fast segmentation and multiplexing imaging of organelles in live cells.
    Karl Zhanghao, Meiqi Li, Xingye Chen, Wenhui Liu, Tianling Li, Yiming Wang, Fei Su, Zihan Wu, Chunyan Shan, Jiamin Wu, Yan Zhang, Jingyan Fu, Peng Xi, Dayong Jin.
      Studying organelles' interactome at system level requires simultaneous observation of subcellular compartments and tracking their dynamics. Conventional multicolor approaches rely on specific fluorescence labeling, where the number of resolvable colors is far less than the types of organelles. Here, we use a lipid-specific dye to stain all the membrane-associated organelles and spinning-disk microscopes with an extended resolution of ~143 nm for high spatiotemporal acquisition. Due to the chromatic polarity sensitivity, high-resolution ratiometric images well reflect the heterogeneity of organelles. With deep convolutional neuronal networks, we successfully segmented up to 15 subcellular structures using one laser excitation. We further show that transfer learning can predict both 3D and 2D datasets from different microscopes, different cell types, and even complex systems of living tissues. We succeeded in resolving the 3D anatomic structure of live cells at different mitotic phases and tracking the fast dynamic interactions among six intracellular compartments with high robustness.
    DOI:  https://doi.org/10.1038/s41467-025-57877-5
  21. Nat Aging. 2025 Mar 21.
    Alarmingly large care deficits globally for people living with dementia and disability.
      
    DOI:  https://doi.org/10.1038/s43587-025-00849-7
  22. Nat Metab. 2025 Mar 25.
    A BCAA-haem axis regulates brown fat function.
      
    DOI:  https://doi.org/10.1038/s42255-025-01266-1
  23. Nat Metab. 2025 Mar 21.
    Vestibular neurons link motion sickness, behavioural thermoregulation and metabolic balance in mice.
    Longlong Tu, Xing Fang, Yongjie Yang, Meng Yu, Hailan Liu, Hesong Liu, Na Yin, Jonathan C Bean, Kristine M Conde, Mengjie Wang, Yongxiang Li, Olivia Z Ginnard, Qingzhuo Liu, Yuhan Shi, Junying Han, Yi Zhu, Makoto Fukuda, Qingchun Tong, Benjamin Arenkiel, Mingshan Xue, Yang He, Chunmei Wang, Yong Xu.
      Motion sickness is associated with thermoregulation and metabolic control, but the underlying neural circuitry remains largely unknown. Here we show that neurons in the medial vestibular nuclei parvocellular part (MVePC) mediate the hypothermic responses induced by motion. Reactivation of motion-sensitive MVePC neurons recapitulates motion sickness in mice. We show that motion-activated neurons in the MVePC are glutamatergic (MVePCGlu), and that optogenetic stimulation of MVePCGlu neurons mimics motion-induced hypothermia by signalling to the lateral parabrachial nucleus (LPBN). Acute inhibition of MVePC-LPBN circuitry abrogates motion-induced hypothermia. Finally, we show that chronic inhibition of MVePCGlu neurons prevents diet-induced obesity and improves glucose homeostasis without suppressing food intake. Overall, these findings highlight MVePCGlu neurons as a potential target for motion-sickness treatment and obesity control.
    DOI:  https://doi.org/10.1038/s42255-025-01234-9
  24. Nat Commun. 2025 Mar 25. 16(1): 2925
    FTO suppresses DNA repair by inhibiting PARP1.
    Tianyi Zhu, Jing Zhi Anson Tan, Lingrui Zhang, He Huang, Sooraj S Das, Flora Cheng, Pranesh Padmanabhan, Mathew J K Jones, Mihwa Lee, Albert Lee, Jocelyn Widagdo, Victor Anggono.
      Maintaining genomic integrity and faithful transmission of genetic information is essential for the survival and proliferation of cells and organisms. DNA damage, which threatens the integrity of the genome, is rapidly sensed and repaired by mechanisms collectively known as the DNA damage response. The RNA demethylase FTO has been implicated in this process; however, the underlying mechanism by which FTO regulates DNA repair remains unclear. Here, we use an unbiased quantitative proteomic approach to identify the proximal interactome of endogenous FTO protein. Our results demonstrate a direct interaction with the DNA damage sensor protein PARP1, which dissociates upon ultraviolet stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, accelerating DNA repair and promoting cell survival. Interestingly, FTO regulates PARP1 function and DNA damage response independent of its catalytic activity. We conclude that FTO is an endogenous negative regulator of PARP1 and the DNA damage response in cells beyond its role as an RNA demethylase.
    DOI:  https://doi.org/10.1038/s41467-025-58309-0
  25. Science. 2025 Mar 28. 387(6741): eadp4319
    Chromatin accessibility landscape of mouse early embryos revealed by single-cell NanoATAC-seq2.
    Mengyao Li, Zhenhuan Jiang, Xueqiang Xu, Xinglong Wu, Yun Liu, Kexuan Chen, Yuhan Liao, Wen Li, Xiao Wang, Yuqing Guo, Bo Zhang, Lu Wen, Kehkooi Kee, Fuchou Tang.
      In mammals, fertilized eggs undergo genome-wide epigenetic reprogramming to generate the organism. However, our understanding of epigenetic dynamics during preimplantation development at single-cell resolution remains incomplete. Here, we developed scNanoATAC-seq2, a single-cell assay for transposase-accessible chromatin using long-read sequencing for scarce samples. We present a detailed chromatin accessibility landscape of mouse preimplantation development, revealing distinct chromatin signatures in the epiblast, primitive endoderm, and trophectoderm during lineage segregation. Differences between zygotes and two-cell embryos highlight reprogramming in chromatin accessibility during the maternal-to-zygotic transition. Single-cell long-read sequencing enables in-depth analysis of chromatin accessibility in noncanonical imprinting, imprinted X chromosome inactivation, and low-mappability genomic regions, such as repetitive elements and paralogs. Our data provide insights into chromatin dynamics during mammalian preimplantation development and lineage differentiation.
    DOI:  https://doi.org/10.1126/science.adp4319
  26. Nat Methods. 2025 Mar 21.
    Connectivity of single neurons classifies cell subtypes in mouse brains.
    Lijuan Liu, Zhixi Yun, Linus Manubens-Gil, Hanbo Chen, Feng Xiong, Hongwei Dong, Hongkui Zeng, Michael Hawrylycz, Giorgio A Ascoli, Hanchuan Peng.
      Classification of single neurons at a brain-wide scale is a way to characterize the structural and functional organization of brains. Here we acquired and standardized a large morphology database of 20,158 mouse neurons and generated a potential connectivity map of single neurons based on their dendritic and axonal arbors. With such an anatomy-morphology-connectivity mapping, we defined neuron connectivity subtypes for neurons in 31 brain regions. We found that cell types defined by connectivity show distinct separation from each other. Within this context, we were able to characterize the diversity in secondary motor cortical neurons, and subtype connectivity patterns in thalamocortical pathways. Our findings underscore the importance of connectivity in characterizing the modularity of brain anatomy at the single-cell level. These results highlight that connectivity subtypes supplement conventionally recognized transcriptomic cell types, electrophysiological cell types and morphological cell types as factors to classify cell classes and their identities.
    DOI:  https://doi.org/10.1038/s41592-025-02621-6
  27. Mol Metab. 2025 Mar 24. pii: S2212-8778(25)00033-X. [Epub ahead of print] 102126
    Semaglutide and bariatric surgery induce distinct changes in the composition of mouse white adipose tissue.
    Margo P Emont, Adam L Essene, Anton Gulko, Nadejda Bozadjieva-Kramer, Christopher Jacobs, Soumya Nagesh, Randy J Seeley, Linus T Tsai, Evan D Rosen.
      Adipose tissue is a central player in energy balance and glucose homeostasis, expanding in the face of caloric overload in order to store energy safely. If caloric overload continues unabated, however, adipose tissue becomes dysfunctional, leading to systemic metabolic compromise in the form of insulin resistance and type 2 diabetes. Changes in adipose tissue during the development of metabolic disease are varied and complex, made all the more so by the heterogeneity of cell types within the tissue. Here we present detailed comparisons of atlases of murine WAT in the setting of diet-induced obesity, as well as after weight loss induced by either vertical sleeve gastrectomy (VSG) or treatment with the GLP-1 receptor agonist semaglutide. We focus on identifying populations of cells that return to a lean-like phenotype versus those that persist from the obese state, and examine pathways regulated in these cell types across conditions. These data provide a resource for the study of the cell type changes in WAT during weight loss, and paint a clearer picture of the differences between adipose tissue from lean animals that have never been obese, versus those that have.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102126
  28. Nat Commun. 2025 Mar 27. 16(1): 3007
    Chromatin landscape at cis-regulatory elements orchestrates cell fate decisions in early embryogenesis.
    Francesco Cardamone, Annamaria Piva, Eva Löser, Bastian Eichenberger, Mari Carmen Romero-Mulero, Fides Zenk, Emily J Shields, Nina Cabezas-Wallscheid, Roberto Bonasio, Guido Tiana, Yinxiu Zhan, Nicola Iovino.
      The establishment of germ layers during early development is crucial for body formation. The Drosophila zygote serves as a model for investigating these transitions in relation to the chromatin landscape. However, the cellular heterogeneity of the blastoderm embryo poses a challenge for gaining mechanistic insights. Using 10× Multiome, we simultaneously analyzed the in vivo epigenomic and transcriptomic states of wild-type, E(z)-, and CBP-depleted embryos during zygotic genome activation at single-cell resolution. We found that pre-zygotic H3K27me3 safeguards tissue-specific gene expression by modulating cis-regulatory elements. Furthermore, we demonstrate that CBP is essential for cell fate specification functioning as a transcriptional activator by stabilizing transcriptional factors binding at key developmental genes. Surprisingly, while CBP depletion leads to transcriptional arrest, chromatin accessibility continues to progress independently through the retention of stalled RNA Polymerase II. Our study reveals fundamental principles of chromatin-mediated gene regulation essential for establishing and maintaining cellular identities during early embryogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-57719-4
  29. Nat Biotechnol. 2025 Mar 27.
    Spatial transcriptomic imaging of an intact organism using volumetric DNA microscopy.
    Nianchao Qian, Joshua A Weinstein.
      Lymphatic, nervous and tumor tissues exhibit complex physiology arising from three-dimensional interactions within genetically unique microenvironments. Here we develop a technology capable of volumetrically imaging transcriptomes, genotypes and morphologies in a single measurement, without relying on prior knowledge of spatial organization or genetic sequences. Our method extends DNA microscopy into three dimensions at scales involving 107 molecules by forming a distributed intermolecular network of proximal unique DNA barcodes tagging complementary DNA molecules inside the specimen. After sequencing the DNA-encoded network, an image of molecular positions is inferred using geodesic spectral embeddings, a dimensionality reduction approach that we show to be especially suitable for this data-inverse problem. Applying whole-transcriptome volumetric DNA microscopy to intact zebrafish embryos, we demonstrate that three-dimensional image inference recapitulates zebrafish morphology and known gene expression patterns, capturing the spatial organization of gene sequences. Our extension of spatial genetic measurements to three dimensions, independent of prior templates, opens the door to detailed joint resolution of genomics and morphology in biological tissues.
    DOI:  https://doi.org/10.1038/s41587-025-02613-z
  30. Nature. 2025 Mar;639(8056): 855-857
    Fasting for weight loss is all the rage: what are the health benefits?
    Nic Fleming.
      
    Keywords:  Ageing; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-00895-6
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