bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–03–09
39 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Tissue directives.
  2. Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells.
  3. Mapping the developmental trajectory and recruitment of memory-phenotype Ly49+CD8+ T cells.
  4. Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
  5. Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes.
  6. Famsin and fasting adaptation: A glucagon connection.
  7. A deep learning strategy to identify cell types across species from high-density extracellular recordings.
  8. Neutrophils are dispensable for Shigella control: macrophages take centre stage.
  9. Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
  10. Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
  11. Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization.
  12. Dynamic STING repression orchestrates immune cell development and function.
  13. Train clinical AI to reason like a team of doctors.
  14. Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.
  15. Structural mechanism of LINE-1 target-primed reverse transcription.
  16. CXCL12 drives natural variation in coronary artery anatomy across diverse populations.
  17. 'Perfect potato' designed thanks to unearthed genetic diversity.
  18. Three AI-powered steps to faster, smarter peer review.
  19. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate.
  20. Endogenous opioid receptors and the feast or famine of maladaptive feeding.
  21. Trouble at the border: An invading gut bacterium can break tolerance to self-RNA.
  22. Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.
  23. Against the odds: 12 women who beat bias to succeed in science.
  24. How the brain decides whether to persist - and when to give up.
  25. Behind every great woman in science, there's another great woman in science.
  26. A single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants.
  27. Reproducible image-based profiling with Pycytominer.
  28. Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
  29. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
  30. Why women's brains are more resilient: it could be their 'silent' X chromosome.
  31. PerturbView: scalable image-based perturbation screens in cells and tissues.
  32. Toward personalized clinical interventions for perinatal depression: Leveraging precision functional mapping.
  33. Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.
  34. Clonal dynamics and somatic evolution of haematopoiesis in mouse.
  35. SnapShot: Brain-targeting anti-obesity medications.
  36. Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
  37. Trained immunity causes myeloid cell hypercoagulability.
  38. Mouse with a mammoth's pelt makes superfuzzy debut.
  39. DOTS: DNA origami tension sensors for studying T cell mechanobiology.
  1. Nat Immunol. 2025 Mar;26(3): 330
    Tissue directives.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-025-02108-8
  2. Nat Commun. 2025 Mar 02. 16(1): 2109
    Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells.
    Wenyang Li, Robert P Sparks, Cheng Sun, Yang Yang, Lorena Pantano, Rory Kirchner, Nahid Arghiani, Arden Weilheimer, Benjamin J Toles, Jennifer Y Chen, Sean P Moran, Victor Barrera, Zixiu Li, Peng Zhou, Meghan L Brassil, David Wrobel, Shannan J Ho Sui, Gary Aspnes, Michael Schuler, Jennifer Smith, Benjamin D Medoff, Chan Zhou, Carine M Boustany-Kari, Jörg F Rippmann, Daniela M Santos, Julia F Doerner, Alan C Mullen.
      Hepatic stellate cells (HSCs) are activated with chronic liver injury and transdifferentiate into myofibroblasts, which produce excessive extracellular matrices that form the fibrotic scar. While the progression of fibrosis is understood to be the cause of end-stage liver disease, there are no approved therapies directed at interfering with the activity of HSC myofibroblasts. Here, we perform a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts to identify gene products necessary for the fibrotic phenotype of HSCs. We find that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient in Abhd17b are also protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, our data suggest that ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include interaction with MYO1B to modulate gene expression and HSC migration. Together, our results provide an analysis of the phenotypic consequences for siRNAs targeting RNAs from >9500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-025-56900-z
  3. Nat Rev Immunol. 2025 Mar 05.
    Mapping the developmental trajectory and recruitment of memory-phenotype Ly49+CD8+ T cells.
    Guillaume J Trusz, Verena van der Heide.
      
    DOI:  https://doi.org/10.1038/s41577-025-01156-3
  4. Nat Commun. 2025 Mar 06. 16(1): 2250
    Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
    Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.
      Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
    DOI:  https://doi.org/10.1038/s41467-025-57286-8
  5. Nat Commun. 2025 Feb 28. 16(1): 2064
    Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes.
    Junyoung Park, Andrés Peña-Tauber, Lia Talozzi, Michael D Greicius, Yann Le Guen.
      Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.
    DOI:  https://doi.org/10.1038/s41467-025-57315-6
  6. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00058-0. [Epub ahead of print]37(3): 561-563
    Famsin and fasting adaptation: A glucagon connection.
    Siming Li, Ziyi Meng, Jiandie D Lin.
      Starvation triggers an organismal adaptive response that is orchestrated by endocrine factors. In this issue of Cell Metabolism, Long et al.1 uncover a famsin-glucagon axis that relays gut-derived hormonal cues to systemic glucose homeostasis during fasting.
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.030
  7. Cell. 2025 Feb 25. pii: S0092-8674(25)00110-2. [Epub ahead of print]
    A deep learning strategy to identify cell types across species from high-density extracellular recordings.
    Maxime Beau, David J Herzfeld, Francisco Naveros, Marie E Hemelt, Federico D'Agostino, Marlies Oostland, Alvaro Sánchez-López, Young Yoon Chung, Michael Maibach, Stephen Kyranakis, Hannah N Stabb, M Gabriela Martínez Lopera, Agoston Lajko, Marie Zedler, Shogo Ohmae, Nathan J Hall, Beverley A Clark, Dana Cohen, Stephen G Lisberger, Dimitar Kostadinov, Court Hull, Michael Häusser, Javier F Medina.
      High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but fail to reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals and reveal the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetics and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep learning classifier that predicts cell types with greater than 95% accuracy based on the waveform, discharge statistics, and layer of the recorded neuron. The classifier's predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously recorded cell types during behavior.
    Keywords:  Neuropixels; cell-type identification; cerebellar cortex; cerebellum; circuit mapping; classification; machine learning; variational autoencoder
    DOI:  https://doi.org/10.1016/j.cell.2025.01.041
  8. Nat Rev Immunol. 2025 Mar 05.
    Neutrophils are dispensable for Shigella control: macrophages take centre stage.
    Didem Ağaç Çobanoğlu, James P Allison.
      
    DOI:  https://doi.org/10.1038/s41577-025-01157-2
  9. Nat Commun. 2025 Feb 28. 16(1): 2053
    Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Josef P Clark, Timothy W Rhoads, Tiaira J Porter, Kevin W Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.
    DOI:  https://doi.org/10.1038/s41467-025-57363-y
  10. Nature. 2025 Mar 05.
    Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
    Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.
      The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
    DOI:  https://doi.org/10.1038/s41586-025-08667-y
  11. Cell. 2025 Feb 20. pii: S0092-8674(25)00158-8. [Epub ahead of print]
    Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization.
    Zhiguang Chang, Xuan Guo, Xuefei Li, Yan Wang, Zhongsheng Zang, Siyu Pei, Weiqi Lu, Yang Li, Jian-Dong Huang, Yichuan Xiao, Chenli Liu.
      Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy's dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.
    Keywords:  CD8(+) T cells; IL-10R; bacterial immunotherapy; hysteresis; solid tumor microenvironment; synthetic biology
    DOI:  https://doi.org/10.1016/j.cell.2025.02.002
  12. Sci Immunol. 2025 Mar 07. 10(105): eado9933
    Dynamic STING repression orchestrates immune cell development and function.
    Kennady Knox, Devon Jeltema, Nicole Dobbs, Kun Yang, Cong Xing, Kun Song, Zhen Tang, Gustavo Torres-Ramirez, Jiefu Wang, Shan Gao, Tuoqi Wu, Chen Yao, Jian Wang, Nan Yan.
      STING is an essential component of the innate immune system, yet homeostatic STING expression patterns and regulation are unknown. Using Sting1IRES-EGFP reporter and conditional Sting1 transgenic mice, we found that regulation of STING expression is critical for immune cell development and functionality. STING expression was repressed in neutrophils, and forced STING expression or signaling drove systemic inflammatory disease. During T lymphocyte development, STING expression was restricted at the double-positive stage via epigenetic silencing by DNA methyltransferase 1. Forced STING expression or signaling impaired T lymphocyte development independent of type I interferon and promoted lineage commitment to innate-like γδ T cells over adaptive αβ T cells. In the tumor microenvironment, CD8+ T lymphocytes repressed STING expression, correlating with features of T cell exhaustion in syngeneic mouse tumors and human colorectal cancer. Our data demonstrate the necessity of controlled, rather than ubiquitous, STING expression, uncovering a previously unappreciated dimension of STING pathobiology.
    DOI:  https://doi.org/10.1126/sciimmunol.ado9933
  13. Nature. 2025 Mar;639(8053): 32-34
    Train clinical AI to reason like a team of doctors.
    Christopher R S Banerji, Tapabrata Chakraborti, Aya Abdelsalam Ismail, Florian Ostmann, Ben D MacArthur.
      
    Keywords:  Computer science; Machine learning; Policy; Public health
    DOI:  https://doi.org/10.1038/d41586-025-00618-x
  14. Nat Genet. 2025 Mar 04.
    Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.
    Genes & Health Research Team
      Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
    DOI:  https://doi.org/10.1038/s41588-024-02064-3
  15. Science. 2025 Mar 06. eads8412
    Structural mechanism of LINE-1 target-primed reverse transcription.
    George E Ghanim, Hongmiao Hu, Jerome Boulanger, Thi Hoang Duong Nguyen.
      Long interspersed element-1 (LINE-1) retrotransposons are the only active autonomous transposable elements in humans. They propagate by reverse transcribing their mRNA into new genomic locations by a process called target-primed reverse transcription (TPRT). Here, we present four cryo-electron microscopy structures of the human LINE-1 TPRT complex, revealing the conformational dynamics of ORF2p and its extensive remodeling of the target DNA for TPRT initiation. We observe nicking of the DNA second strand during reverse transcription of the first strand. Structure prediction identifies high-confidence binding sites for LINE-1-associated factors, namely PCNA and PABPC1, on ORF2p. Together with our structural data, this suggests a mechanism by which these factors regulate retrotransposition and proposes a model for TPRT that accounts for retrotransposition outcomes observed in cells.
    DOI:  https://doi.org/10.1126/science.ads8412
  16. Cell. 2025 Mar 03. pii: S0092-8674(25)00161-8. [Epub ahead of print]
    CXCL12 drives natural variation in coronary artery anatomy across diverse populations.
    Million Veteran Program
      Coronary arteries have a specific branching pattern crucial for oxygenating heart muscle. Among humans, there is natural variation in coronary anatomy with respect to perfusion of the inferior/posterior left heart, which can branch from either the right arterial tree, the left, or both-a phenotype known as coronary dominance. Using angiographic data for >60,000 US veterans of diverse ancestry, we conducted a genome-wide association study of coronary dominance, revealing moderate heritability and identifying ten significant loci. The strongest association occurred near CXCL12 in both European- and African-ancestry cohorts, with downstream analyses implicating effects on CXCL12 expression. We show that CXCL12 is expressed in human fetal hearts at the time dominance is established. Reducing Cxcl12 in mice altered coronary dominance and caused septal arteries to develop away from Cxcl12 expression domains. These findings indicate that CXCL12 patterns human coronary arteries, paving the way for "medical revascularization" through targeting developmental pathways.
    Keywords:  Cxcl12; GWAS; anatomy; coronary artery; dominance; heritability; human development; mouse models; population genetics; vascular patterning
    DOI:  https://doi.org/10.1016/j.cell.2025.02.005
  17. Nature. 2025 Mar 05.
    'Perfect potato' designed thanks to unearthed genetic diversity.
      
    Keywords:  Agriculture; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-00187-z
  18. Nature. 2025 Mar 04.
    Three AI-powered steps to faster, smarter peer review.
    Dritjon Gruda.
      
    Keywords:  Careers; Lab life; Publishing
    DOI:  https://doi.org/10.1038/d41586-025-00526-0
  19. Sci Immunol. 2025 Mar 07. 10(105): eado3032
    Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate.
    Yinghui J Huang, Shin Foong Ngiow, Amy E Baxter, Sasikanth Manne, Simone L Park, Jennifer E Wu, Omar Khan, Josephine R Giles, E John Wherry.
      Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.
    DOI:  https://doi.org/10.1126/sciimmunol.ado3032
  20. Nat Commun. 2025 Mar 06. 16(1): 2270
    Endogenous opioid receptors and the feast or famine of maladaptive feeding.
    Ames K Sutton Hickey, Bridget A Matikainen-Ankney.
      Maladaptive feeding comprises unhealthy eating patterns that jeopardize survival, including over- and underconsumption. These behaviors are often coordinated by endogenous opioid receptors (EORs). Here, we explore the involvement of EORs in obesity and anorexia nervosa (AN), two disorders associated with dysregulated feeding behavior and relevant animal models. While seemingly opposing metabo-psychiatric states, our goal is to highlight common circuit and synaptic mechanisms underlying obesity and AN with a focus on EOR functionality. We examine the neural substrates underlying maladaptive feeding and comorbid conditions including pain, suggesting a role for EOR-driven plasticity in the pathogenesis of both obesity and AN.
    DOI:  https://doi.org/10.1038/s41467-025-57515-0
  21. Sci Immunol. 2025 Mar 07. 10(105): eadx0218
    Trouble at the border: An invading gut bacterium can break tolerance to self-RNA.
    Rachael A Clark.
      Mouse anti-RNA antibodies triggered by gut E. gallinarum correlate with self-RNA autoantibodies and lupus severity in humans.
    DOI:  https://doi.org/10.1126/sciimmunol.adx0218
  22. Sci Immunol. 2025 Mar 07. 10(105): eado1710
    Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.
    Benjamin Klein, Mack B Reynolds, Bin Xu, Mehrnaz Gharaee-Kermani, Yiqing Gao, Celine C Berthier, Svenja Henning, Lam C Tsoi, Shannon N Loftus, Kelsey E McNeely, Christine M Goudsmit, Amanda M Victory, Craig Dobry, Grace A Hile, Feiyang Ma, Jessica L Turnier, Johann E Gudjonsson, Mary X O'Riordan, J Michelle Kahlenberg.
      Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. We show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV) B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is up-regulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. In patient-derived samples, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB exposure, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) activation compared with the more conventional B-DNA. ZBP1 knockdown abrogates UVB-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.
    DOI:  https://doi.org/10.1126/sciimmunol.ado1710
  23. Nature. 2025 Mar;639(8053): 29-31
    Against the odds: 12 women who beat bias to succeed in science.
    Georgina Ferry.
      
    Keywords:  History; Lab life; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-00617-y
  24. Nature. 2025 Mar 05.
    How the brain decides whether to persist - and when to give up.
    Felicity Nelson.
      
    Keywords:  Animal behaviour; Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00675-2
  25. Nature. 2025 Mar;639(8053): 261-264
    Behind every great woman in science, there's another great woman in science.
    Amanda Heidt.
      
    Keywords:  Careers; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-025-00620-3
  26. Sci Transl Med. 2025 Mar 05. 17(788): eadr0942
    A single-cell atlas of circulating immune cells over the first 2 months of age in extremely premature infants.
    Oluwabunmi Olaloye, Weihong Gu, Arne Gehlhaar, Burhanuddin Sabuwala, Chino K Eke, Yujia Li, Tessa Kehoe, Rohit Farmer, Gisela Gabernet, Carrie L Lucas, John S Tsang, Saquib A Lakhani, Sarah N Taylor, George Tseng, Steven H Kleinstein, Liza Konnikova.
      Extremely premature infants (EPIs) who are born before 30 weeks of gestation are susceptible to infection; however, the trajectory of their peripheral immunity is poorly understood. Here, we undertook longitudinal analyses of immune cells from 250 μl of whole blood at 1 week, 1 month, and 2 months from 10 EPIs and compared these with samples from healthy adults and with preterm and full-term cord blood samples. Single-cell suspensions from individual samples were split to perform single-cell RNA sequencing, T and B cell receptor sequencing, and phosphoprotein mass cytometry. The trajectories of circulating T, B, myeloid, and natural killer cells in EPIs over the first 2 months of life were distinct from those of full-term infants. In EPIs, peripheral T cell development rapidly progressed over the first month of life, with an increase in the proportion of naïve CD4+, regulatory, and cycling T cells, accompanied by greater STAT5 (signal transducer and activator of transcription 5) signaling. EPI memory CD4+ T cells showed a T helper 1 (TH1) predominance compared with TH2 skewing of central memory-like T cells in full-term infants, and B cells from 2-month-old EPIs exhibited increased signatures of activation and differentiation. Both B and T cells from 2-month-old EPIs displayed increased interferon signatures compared with cells from full-term infants. In conclusion, we demonstrated the feasibility of longitudinal multiomic analyses in EPIs using minute amounts of blood and developed a resource describing peripheral immune development in EPIs that suggested ongoing activation in early life.
    DOI:  https://doi.org/10.1126/scitranslmed.adr0942
  27. Nat Methods. 2025 Mar 03.
    Reproducible image-based profiling with Pycytominer.
    Erik Serrano, Srinivas Niranj Chandrasekaran, Dave Bunten, Kenneth I Brewer, Jenna Tomkinson, Roshan Kern, Michael Bornholdt, Stephen J Fleming, Ruifan Pei, John Arevalo, Hillary Tsang, Vincent Rubinetti, Callum Tromans-Coia, Tim Becker, Erin Weisbart, Charlotte Bunne, Alexandr A Kalinin, Rebecca Senft, Stephen J Taylor, Nasim Jamali, Adeniyi Adeboye, Hamdah Shafqat Abbasi, Allen Goodman, Juan C Caicedo, Anne E Carpenter, Beth A Cimini, Shantanu Singh, Gregory P Way.
      Advances in high-throughput microscopy have enabled the rapid acquisition of large numbers of high-content microscopy images. Next, whether by deep learning or classical algorithms, image analysis pipelines commonly produce single-cell features. To process these single cells for downstream applications, we present Pycytominer, a user-friendly, open-source Python package that implements the bioinformatics steps key to image-based profiling. We demonstrate Pycytominer's usefulness in a machine-learning project to predict nuisance compounds that cause undesirable cell injuries.
    DOI:  https://doi.org/10.1038/s41592-025-02611-8
  28. Nat Genet. 2025 Mar 06.
    Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.
    Regeneron Genetics Center
      Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.
    DOI:  https://doi.org/10.1038/s41588-025-02074-9
  29. Nature. 2025 Mar 05.
    Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide.
    Laetitia Coassolo, Niels B Danneskiold-Samsøe, Quennie Nguyen, Amanda Wiggenhorn, Meng Zhao, David Cheng-Hao Wang, David Toomer, Jameel Lone, Yichao Wei, Aayan Patel, Irene Liparulo, Deniz Kavi, Lianna W Wat, Saranya Chidambaranathan Reghupaty, Julie Jae Kim, Tina Asemi, Ewa Bielczyk-Maczynska, Veronica L Li, Maria Dolores Moya-Garzon, Nicole A J Krentz, Andreas Stahl, Danny Hung-Chieh Chou, Liqun Luo, Katrin J Svensson.
      Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1)1,2. However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.
    DOI:  https://doi.org/10.1038/s41586-025-08683-y
  30. Nature. 2025 Mar 05.
    Why women's brains are more resilient: it could be their 'silent' X chromosome.
    Katherine Bourzac.
      
    Keywords:  Brain; Genetics; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00682-3
  31. Nat Rev Immunol. 2025 Mar 05.
    PerturbView: scalable image-based perturbation screens in cells and tissues.
    Takamasa Kudo.
      
    DOI:  https://doi.org/10.1038/s41577-025-01153-6
  32. Sci Adv. 2025 Mar 07. 11(10): eadt8104
    Toward personalized clinical interventions for perinatal depression: Leveraging precision functional mapping.
    Laura Pritschet, Emily Beydler, Sheila Shanmugan.
      Precision functional mapping has the potential to quantify risk of perinatal depression among women through individual-specific neurobiological markers.
    DOI:  https://doi.org/10.1126/sciadv.adt8104
  33. Nat Commun. 2025 Mar 06. 16(1): 2239
    Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.
    Greta Ehlers, Annika Marie Tödtmann, Lisa Holsten, Maike Willers, Julia Heckmann, Jennifer Schöning, Maximilian Richter, Anna Sophie Heinemann, Sabine Pirr, Alexander Heinz, Christian Dopfer, Kristian Händler, Matthias Becker, Johanna Büchel, Achim Wöckel, Constantin von Kaisenberg, Gesine Hansen, Karsten Hiller, Joachim L Schultze, Christoph Härtel, Wolfgang Kastenmüller, Martin Vaeth, Thomas Ulas, Dorothee Viemann.
      Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.
    DOI:  https://doi.org/10.1038/s41467-025-57357-w
  34. Nature. 2025 Mar 05.
    Clonal dynamics and somatic evolution of haematopoiesis in mouse.
    Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia.
      Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.
    DOI:  https://doi.org/10.1038/s41586-025-08625-8
  35. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00064-6. [Epub ahead of print]37(3): 790-790.e1
    SnapShot: Brain-targeting anti-obesity medications.
    Jonas Petersen, Valdemar Brimnes Ingemann Johansen, Christoffer Clemmensen.
      Advances in the understanding of homeostatic regulation of body weight and the neurobiology of appetite, combined with innovations in medicinal chemistry, have paved the way for safe and effective weight loss medications. Long-acting GLP-1 receptor agonists have revolutionized obesity treatment, and, together with emerging GLP-1-based multi-agonists and combination therapies, offer significant potential to combat cardiometabolic diseases and a range of other chronic health challenges. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.006
  36. Sci Adv. 2025 Mar 07. 11(10): eadr0690
    Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
    Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adr0690
  37. Sci Adv. 2025 Mar 07. 11(10): eads0105
    Trained immunity causes myeloid cell hypercoagulability.
    Aisling M Rehill, Seán McCluskey, Anna E Ledwith, Tristram A J Ryan, Betül Ünlü, Gemma Leon, Hugo Charles-Messance, Edmund H Gilbert, Paula Klavina, Emily A Day, Judith Coppinger, Jamie M O'Sullivan, Corrina McMahon, James S O'Donnell, Annie M Curtis, Luke A J O'Neill, Frederick J Sheedy, Roger J S Preston.
      The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell "trained immunity" describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase-mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan-trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.
    DOI:  https://doi.org/10.1126/sciadv.ads0105
  38. Science. 2025 Mar 07. 387(6738): 1029
    Mouse with a mammoth's pelt makes superfuzzy debut.
    Phie Jacobs.
      Birth of rodent with coat genetically modified to resemble the extinct species raises ethical and conservation concerns.
    DOI:  https://doi.org/10.1126/science.adx2132
  39. Nat Rev Immunol. 2025 Mar 04.
    DOTS: DNA origami tension sensors for studying T cell mechanobiology.
    Sarah Al Abdullatif.
      
    DOI:  https://doi.org/10.1038/s41577-025-01152-7
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