bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–03–16
forty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Do actin isoforms have unique functionalities at the protein level?
  2. VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
  3. Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.
  4. Exposing the exposome in aging.
  5. Maternal behavior promotes resilience to adolescent stress in mice through a microglia-neuron axis.
  6. How the NIH dominates the world's health research - in charts.
  7. Structural biology at the plasma membrane.
  8. The CREscendoing promise of HDAC targeting to limit atherosclerosis.
  9. Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
  10. How fast your brain ages is affected by these 64 genes.
  11. Redirecting immune signaling with cytokine adaptors.
  12. Public-health experts should be more political, not less.
  13. A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan.
  14. Novel mRNA isoforms in human microglia refine genetic associations with neurodegeneration.
  15. ATF4 drives regulatory T cell functional specification in homeostasis and obesity.
  16. So you've made a lab website. What should go on it?
  17. Man survives with titanium heart for 100 days - a world first.
  18. Cold is hot for slowing aging.
  19. SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation.
  20. A feedback circuitry involving γ-actin, β-actin and nonmuscle myosin-2 A controls tight junction and apical cortex mechanics.
  21. Memory consolidation accelerates.
  22. QRICH1 mediates an intracellular checkpoint for CD8+ T cell activation via the CARD11 signalosome.
  23. A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation.
  24. An enhanced framework for local genetic correlation analysis.
  25. Primary role of the Tol-Pal complex in bacterial outer membrane lipid homeostasis.
  26. #ScientistAtWork 2025: Nature is seeking stunning photographic images that capture researchers' working lives.
  27. GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis.
  28. The brain's building blocks for understanding social interactions.
  29. Robotic fingers can tell objects apart by touch.
  30. Liver-derived Neuregulin1α stimulates compensatory pancreatic β cell hyperplasia in insulin resistance.
  31. Who's likely to wake up from a coma? Brainwaves provide a clue.
  32. Sampling representational plasticity of simple imagined movements across days enables long-term neuroprosthetic control.
  33. Palliative care use in Taiwanese older adults.
  34. High-throughput screening identifies modulators of gene bursting.
  35. Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis.
  36. MEER: Extraordinary flourishing ecosystem in the deepest ocean.
  37. Immune molecule links COVID‑19 with severe inflammatory disorder in children.
  38. Hepatic stellate cells control liver zonation, size and functions via R-spondin 3.
  39. Making sense of fat in cancer.
  40. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
  41. Urgent call to close the gap in medical oxygen access.
  42. An organ that stores red blood cells for emergencies.
  1. Nat Commun. 2025 Mar 07. 16(1): 2240
    Do actin isoforms have unique functionalities at the protein level?
    James M Ervasti, Anna S Kashina, Benjamin J Perrin.
      
    DOI:  https://doi.org/10.1038/s41467-025-57103-2
  2. Nat Commun. 2025 Mar 11. 16(1): 2416
    VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
    Shamim Naghdi, Piyush Mishra, Soumya Sinha Roy, David Weaver, Ludivine Walter, Erika Davies, Anil Noronha Antony, Xuena Lin, Gisela Moehren, Mark A Feitelson, Christopher A Reed, Tullia Lindsten, Craig B Thompson, Hien T Dang, Jan B Hoek, Erik S Knudsen, György Hajnóczky.
      Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.
    DOI:  https://doi.org/10.1038/s41467-025-56898-4
  3. Nat Aging. 2025 Mar 13.
    Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.
    Shirin Schneeberger, Seung Joon Kim, Maria N Geesdorf, Ekaterina Friebel, Pascale Eede, Marina Jendrach, Anastasiya Boltengagen, Caroline Braeuning, Torben Ruhwedel, Andreas J Hülsmeier, Niclas Gimber, Marlene Foerster, Juliane Obst, Myrto Andreadou, Sarah Mundt, Jan Schmoranzer, Stefan Prokop, Wiebke Kessler, Tanja Kuhlmann, Wiebke Möbius, Klaus-Armin Nave, Thorsten Hornemann, Burkhard Becher, Julia M Edgar, Nikos Karaiskos, Christine Kocks, Nikolaus Rajewsky, Frank L Heppner.
      Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer's disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD.
    DOI:  https://doi.org/10.1038/s43587-025-00816-2
  4. Nat Aging. 2025 Mar 11.
    Exposing the exposome in aging.
    George Andrew S Inglis.
      
    DOI:  https://doi.org/10.1038/s43587-025-00845-x
  5. Nat Commun. 2025 Mar 08. 16(1): 2333
    Maternal behavior promotes resilience to adolescent stress in mice through a microglia-neuron axis.
    Hongyu Chen, Ruifeng Xu, Jianhao Wang, Feng Gao, Yida Lv, Xiang Li, Fang Li, Junqin Zhao, Xi Zhang, Jiabei Wang, Ruicheng Du, Yuke Shi, Hang Yu, Shuai Ding, Wenxin Li, Jing Xiong, Jie Zheng, Liang Zhao, Xin-Ya Gao, Zhi-Hao Wang.
      Early life experience modulates resilience to stress in later life. Previous research implicated maternal care as a key mediator of behavioral responses to the adversity in adolescence, but details of molecular mechanisms remain elusive. Here, we show social stress activates transcription factor C/EBPβ in mPFC neurons of adolescent mice, which transcriptionally upregulates Dnm1l and promotes mitochondrial dysfunction, thereby conferring stress susceptibility in adolescent mice. Moreover, different maternal separation differentially regulates adolescent stress susceptibility. Mechanistically, this differential effect depends on maternal behavior-stimulated IGF-1, which inhibits neuronal C/EBPβ through mTORC1-induced C/EBPβ-LIP translation. Furthermore, we identify maternal behavior-stimulated IGF-1 is mainly released from mPFC microglia. Notably, increased maternal care under an environmental enrichment condition or maternal behavior impairment induced by repeated MPOAEsr1+ cells inhibition in dams prevents or promotes stress susceptibility via microglial-to-neuronal IGF-1-C/EBPβ-DRP1 signaling. In this work, these findings have unveiled molecular mechanisms by which maternal behavior promotes stress resilience in adolescents.
    DOI:  https://doi.org/10.1038/s41467-025-57810-w
  6. Nature. 2025 Mar 10.
    How the NIH dominates the world's health research - in charts.
    Nisha Gaind.
      
    Keywords:  Funding; Medical research; Public health
    DOI:  https://doi.org/10.1038/d41586-025-00754-4
  7. Nat Methods. 2025 Mar;22(3): 453
    Structural biology at the plasma membrane.
    Rita Strack.
      
    DOI:  https://doi.org/10.1038/s41592-025-02640-3
  8. Immunity. 2025 Mar 11. pii: S1074-7613(25)00077-9. [Epub ahead of print]58(3): 520-522
    The CREscendoing promise of HDAC targeting to limit atherosclerosis.
    Máté G Kiss, Christoph J Binder.
      The factors that modulate the inflammatory response in atherosclerosis are not well defined. In this issue of Immunity, Asare et al. examine the impact of a cis-regulatory element (CRE) that controls expression of HDAC9 and find that HDAC9-mediated deacetylation of NLRP3 might be the mechanism by which genetic variants in this conserved CRE influence the inflammation associated with human atherosclerosis.
    DOI:  https://doi.org/10.1016/j.immuni.2025.02.010
  9. Cell. 2025 Mar 05. pii: S0092-8674(25)00194-1. [Epub ahead of print]
    Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
    Yi Fu, Max Land, Tamar Kavlashvili, Ruobing Cui, Minsoo Kim, Emily DeBitetto, Toby Lieber, Keun Woo Ryu, Elim Choi, Ignas Masilionis, Rahul Saha, Meril Takizawa, Daphne Baker, Marco Tigano, Caleb A Lareau, Ed Reznik, Roshan Sharma, Ronan Chaligne, Craig B Thompson, Dana Pe'er, Agnel Sfeir.
      Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.
    Keywords:  DOGMA-seq; end joining; mitochondrial pathologies; mtDNA; mtDNA deletion
    DOI:  https://doi.org/10.1016/j.cell.2025.02.009
  10. Nature. 2025 Mar 12.
    How fast your brain ages is affected by these 64 genes.
    Miryam Naddaf.
      
    Keywords:  Ageing; Brain; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-00766-0
  11. Nat Commun. 2025 Mar 11. 16(1): 2432
    Redirecting immune signaling with cytokine adaptors.
    Gita C Abhiraman, Karsten D Householder, Grayson E Rodriguez, Caleb R Glassman, Robert A Saxton, Cort B Breuer, Steven C Wilson, Leon Su, Michelle Yen, Cynthia Hsu, Venu G Pillarisetty, Nathan E Reticker-Flynn, K Christopher Garcia.
      Cytokines are signaling molecules that coordinate complex immune processes and are frequently dysregulated in disease. While cytokine blockade has become a common therapeutic modality, cytokine agonism has had limited utility due to the widespread expression of cytokine receptors with pleiotropic effects. To overcome this limitation, we devise an approach to engineer molecular switches, termed cytokine adaptors, that transform one cytokine signal into an alternative signal with a different functional output. Endogenous cytokines act to nucleate the adaptors, converting the cytokine-adaptor complex into a surrogate agonist for a different cytokine pathway. In this way, cytokine adaptors, which have no intrinsic agonist activity, can function as conditional, context-dependent agonists. We develop cytokine adaptors that convert IL-10 or TGF-β into IL-2 receptor agonists to reverse T cell suppression. We also convert the pro-inflammatory cytokines IL-23 or IL-17 into immunosuppressive IL-10 receptor agonists. Thus, we show that cytokine adaptors can convert immunosuppressive cytokines into immunostimulatory cytokines, or vice versa. Unlike other methods of immune conversion that require cell engineering, cytokine adaptors are soluble molecules that leverage endogenous cues from the microenvironment to drive context-specific signaling.
    DOI:  https://doi.org/10.1038/s41467-025-57681-1
  12. Nature. 2025 Mar;639(8054): 278
    Public-health experts should be more political, not less.
    Eric Reinhart.
      
    Keywords:  Policy; Public health
    DOI:  https://doi.org/10.1038/d41586-025-00728-6
  13. Nat Aging. 2025 Mar 07.
    A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan.
    Lorna Jayne, Aurora Lavin-Peter, Julian Roessler, Alexander Tyshkovskiy, Mateusz Antoszewski, Erika Ren, Aleksandar Markovski, Senmiao Sun, Hanqi Yao, Vijay G Sankaran, Vadim N Gladyshev, Robert T Brooke, Steve Horvath, Eric C Griffith, Sinisa Hrvatin.
      Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase healthspan, remain unknown. Here we demonstrate that the activity of a spatially defined neuronal population in the preoptic area, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor-like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves healthspan. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the decelerating effect of TLSs on aging is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that Tb is an important mediator of the aging processes.
    DOI:  https://doi.org/10.1038/s43587-025-00830-4
  14. Nat Genet. 2025 Mar;57(3): 492-493
    Novel mRNA isoforms in human microglia refine genetic associations with neurodegeneration.
      
    DOI:  https://doi.org/10.1038/s41588-025-02112-6
  15. Sci Immunol. 2025 Mar 14. 10(105): eadp7193
    ATF4 drives regulatory T cell functional specification in homeostasis and obesity.
    Ke Wang, Andrea Farrell, Enchen Zhou, Houji Qin, Zixuan Zeng, Kailun Zhou, Karina Cunha E Rocha, Dinghong Zhang, Gaowei Wang, Amha Atakilit, Dean Sheppard, Li-Fan Lu, Chunyu Jin, Wei Ying.
      Regulatory T cells (Tregs) have diverse functional specification in homeostasis and disease. However, how liver Tregs function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector Tregs expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector Treg transcriptional program, and ATF4-expressing Tregs promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor-β activation via integrin αvβ8. Treg-specific deletion of Atf4 resulted in reduced liver Tregs and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue Treg precursors under steady state. These findings demonstrate that ATF4 is important for regulating Treg functional specification in homeostasis and obesity.
    DOI:  https://doi.org/10.1126/sciimmunol.adp7193
  16. Nature. 2025 Mar 12.
    So you've made a lab website. What should go on it?
    William Mills.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-025-00287-w
  17. Nature. 2025 Mar 13.
    Man survives with titanium heart for 100 days - a world first.
    Smriti Mallapaty.
      
    Keywords:  Cardiovascular biology; Diseases; Health care; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00782-0
  18. Nat Aging. 2025 Mar 07.
    Cold is hot for slowing aging.
    Matteo Cerri.
      
    DOI:  https://doi.org/10.1038/s43587-025-00817-1
  19. Nat Commun. 2025 Mar 11. 16(1): 2430
    SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation.
    Pingping Lai, Guolin Miao, Yinqi Zhao, Yufei Han, Yanwei Li, Yiran Liu, Jiabao Guo, Wenxi Zhang, Xin Guo, Yitong Xu, Lianxin Zhang, Gonglie Chen, Zihao Zhou, Si Mei, Jingxuan Chen, Jinxuan Chen, Luzheng Xu, Chong Zhang, Yang Ding, Xiaoguang Dou, Shengmei Wen, Sin Man Lam, Guanghou Shui, Yuhui Wang, Wei Huang, Dongyu Zhao, Xunde Xian.
      Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.
    DOI:  https://doi.org/10.1038/s41467-025-57585-0
  20. Nat Commun. 2025 Mar 13. 16(1): 2514
    A feedback circuitry involving γ-actin, β-actin and nonmuscle myosin-2 A controls tight junction and apical cortex mechanics.
    Marine Maupérin, Yuze Sun, Thomas Glandorf, Tabea Anne Oswald, Niklas Klatt, Burkhard Geil, Annick Mutero-Maeda, Isabelle Méan, Lionel Jond, Andreas Janshoff, Jie Yan, Sandra Citi.
      Cytoplasmic β- and γ-actin isoforms, along with non-muscle myosin 2 isoforms, are tightly regulated in epithelial cells and compose the actomyosin cytoskeleton at the apical junctional complex. However, their specific role in regulating the mechanics of the membrane cortex and the organization of junctions, and which biomechanical circuitries modulate their expression remain poorly understood. Here, we show that γ-actin depletion in MDCK and other epithelial cells results in increased expression and junctional accumulation of β-actin and increased tight junction membrane tortuosity, both dependent on nonmuscle myosin-2A upregulation. The knock-out of γ-actin also decreases apical membrane stiffness and increases dynamic exchange of the cytoplasmic tight junction proteins like ZO-1 and cingulin, without affecting tight junction organization and barrier function. In summary, our findings uncover a biomechanical circuitry linking γ-actin to β-actin expression through nonmuscle myosin-2A and reveal γ-actin as a key regulator of tight junction and apical membrane cortex mechanics, and the dynamics of cytoskeleton-associated tight junction proteins in epithelial cells.
    DOI:  https://doi.org/10.1038/s41467-025-57428-y
  21. Nat Neurosci. 2025 Mar 11.
    Memory consolidation accelerates.
    Lluís Fuentemilla.
      
    DOI:  https://doi.org/10.1038/s41593-024-01851-9
  22. Sci Immunol. 2025 Mar 14. 10(105): eadn8715
    QRICH1 mediates an intracellular checkpoint for CD8+ T cell activation via the CARD11 signalosome.
    Nicole M Carter, Wihib D Hankore, Yong-Kang Yang, Chao Yang, Shelby M Hutcherson, Wyatt Fales, Anushka Ghosh, Piyusha Mongia, Sophie Mackinnon, Anna Brennan, Robert D Leone, Joel L Pomerantz.
      Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain-containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8+ T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8+ T cells by regulating numerous genes critical for CD8+ T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.
    DOI:  https://doi.org/10.1126/sciimmunol.adn8715
  23. Cell Metab. 2025 Feb 28. pii: S1550-4131(25)00062-2. [Epub ahead of print]
    A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation.
    Yu Wang, Yunxiao Zhang, Verina H Leung, Saba Heydari Seradj, Utku Sonmez, M Rocio Servin-Vences, Shuke Xiao, Xiangyu Ren, Leon Wang, Sassan A Mishkanian, Sejal A Kini, Jonathan Z Long, Darren J Lipomi, Li Ye, Ardem Patapoutian.
      Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.
    Keywords:  adipose; mechanosensation
    DOI:  https://doi.org/10.1016/j.cmet.2025.02.004
  24. Nat Genet. 2025 Mar 10.
    An enhanced framework for local genetic correlation analysis.
    Yuying Li, Yudi Pawitan, Xia Shen.
      Genetic correlation is a key parameter in the joint genetic model of complex traits, but it is usually estimated on a global genomic scale. Understanding local genetic correlations provides more detailed insight into the shared genetic architecture of complex traits. However, a state-of-the-art tool for local genetic correlation analysis, LAVA, is prone to false inference. Here we extend the high-definition likelihood (HDL) method to a local version, HDL-L, which performs genetic correlation analysis in small, approximately independent linkage disequilibrium blocks. HDL-L allows a more granular estimation of genetic variances and covariances. Simulations show that HDL-L offers more consistent heritability estimates and more efficient genetic correlation estimates compared with LAVA. HDL-L demonstrated robust performance across a wide range of simulations conducted under varying parameter settings. In the analysis of 30 phenotypes from the UK Biobank, HDL-L identified 109 significant local genetic correlations and showed a notable computational advantage. HDL-L proves to be a powerful tool for uncovering the detailed genetic landscape that underlies complex human traits, offering both accuracy and computational efficiency.
    DOI:  https://doi.org/10.1038/s41588-025-02123-3
  25. Nat Commun. 2025 Mar 07. 16(1): 2293
    Primary role of the Tol-Pal complex in bacterial outer membrane lipid homeostasis.
    Wee Boon Tan, Shu-Sin Chng.
      Gram-negative bacteria are defined by an outer membrane (OM) that contributes to envelope integrity and barrier function. Building this bilayer require proper assembly of lipopolysaccharides, proteins, and phospholipids, yet how the balance of these components is achieved is unclear. One system long known for ensuring OM stability is the Tol-Pal complex, which has been implicated in maintaining OM lipid homeostasis. However, assignment of Tol-Pal function has been challenging, owing to its septal localization and associated role(s) during division. Here, we uncouple the function of Tol-Pal in OM lipid homeostasis from its impact on cell division in Escherichia coli, by engineering a chimeric complex that loses septal enrichment. We demonstrate that this peripherally-localized Tol-Pal complex is fully capable of maintaining lipid balance in the OM, thus restoring OM integrity and barrier. Our work establishes the primary function of the Tol-Pal complex in OM lipid homeostasis, independent of its role during division.
    DOI:  https://doi.org/10.1038/s41467-025-57630-y
  26. Nature. 2025 Mar 10.
    #ScientistAtWork 2025: Nature is seeking stunning photographic images that capture researchers' working lives.
    Jack Leeming.
      
    Keywords:  Careers; Communication; Media
    DOI:  https://doi.org/10.1038/d41586-025-00673-4
  27. Nat Commun. 2025 Mar 12. 16(1): 2481
    GWAS identifies genetic loci, lifestyle factors and circulating biomarkers that are risk factors for sarcoidosis.
    Shuai Yuan, Jie Chen, Jiawei Geng, Sizheng Steven Zhao, James Yarmolinsky, Elizabeth V Arkema, Sarah Abramowitz, Michael G Levin, Kostas K Tsilidis, Stephen Burgess, Scott M Damrauer, Susanna C Larsson.
      Sarcoidosis is a complex inflammatory disease with a strong genetic component. Here, we perform a genome-wide association study in 9755 sarcoidosis cases to identify risk loci and map associated genes. We then use transcriptome-wide association studies and enrichment analyses to explore pathways involved in sarcoidosis and use Mendelian randomization to examine associations with modifiable factors and circulating biomarkers. We identify 28 genomic loci associated with sarcoidosis, with the C1orf141-IL23R locus showing the largest effect size. We observe gene expression patterns related to sarcoidosis in the spleen, whole blood, and lung, and highlight 75 tissue-specific genes through transcriptome-wide association studies. Furthermore, we use enrichment analysis to establish key roles for T cell activation, leukocyte adhesion, and cytokine production in sarcoidosis. Additionally, we find associations between sarcoidosis and genetically predicted body mass index, interleukin-23 receptor, and eight circulating proteins.
    DOI:  https://doi.org/10.1038/s41467-025-57829-z
  28. Nature. 2025 Mar 12.
    The brain's building blocks for understanding social interactions.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00738-4
  29. Nature. 2025 Mar 12.
    Robotic fingers can tell objects apart by touch.
      
    Keywords:  Engineering
    DOI:  https://doi.org/10.1038/d41586-025-00706-y
  30. Nat Commun. 2025 Mar 13. 16(1): 1950
    Liver-derived Neuregulin1α stimulates compensatory pancreatic β cell hyperplasia in insulin resistance.
    Takatomo Arai, Eriko Hayashi, Sumie Maeda, Tsutomu Matsubara, Hideki Fujii, Koya Shinohara, Arisu Sogabe, Sadatomo Wainai, Daishi Tanaka, Yutaro Ono, Yumika Ono, Minami Yoshikai, Yuriko Sorimachi, Cindy Yuet-Yin Kok, Masayuki Shimoda, Minoru Tanaka, Norifumi Kawada, Nobuhito Goda.
      Compensatory pancreatic islet hyperplasia is an adaptive response to increased systemic insulin demand, although factors meditating this response remain poorly understood. Here, we show that a liver-derived secreted protein, Neuregulin1α, promotes compensatory proliferation of pancreatic β cells in type 2 diabetes. Liver Neuregulin1α expression and serum Neuregulin1α levels increase in male mice fed an obesity-inducing diet. Male mice lacking either Neuregulin1 in liver or its receptor, ErbB3, in β cells deteriorate systemic glucose disposal due to impaired β cell expansion with reduced insulin secretion when fed the obesity-inducing diet. Mechanistically, Neuregulin1α activates ERBB2/3-ERK signaling to stimulate β cell proliferation without altering glucose-stimulated insulin secretion potential. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity but without type 2 diabetes serum Neuregulin1α levels increase, while in patient with MASLD and type 2 diabetes show markedly reduced levels of Neuregulin1α. These results suggest that Neuregulin1α serves as a hepatokine that can expand functional β cell mass in type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-025-57167-0
  31. Nature. 2025 Mar;639(8054): 279
    Who's likely to wake up from a coma? Brainwaves provide a clue.
      
    Keywords:  Brain
    DOI:  https://doi.org/10.1038/d41586-025-00606-1
  32. Cell. 2025 Mar 06. pii: S0092-8674(25)00157-6. [Epub ahead of print]188(5): 1208-1225.e32
    Sampling representational plasticity of simple imagined movements across days enables long-term neuroprosthetic control.
    Nikhilesh Natraj, Sarah Seko, Reza Abiri, Runfeng Miao, Hongyi Yan, Yasmin Graham, Adelyn Tu-Chan, Edward F Chang, Karunesh Ganguly.
      The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what the representational stability of simple well-rehearsed actions is, particularly in humans, and their adaptability to new contexts. Using an electrocorticography brain-computer interface (BCI) in tetraplegic participants, we found that the low-dimensional manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. The manifold's absolute location, however, demonstrated constrained day-to-day drift. Strikingly, neural statistics, especially variance, could be flexibly regulated to increase representational distances during BCI control without somatotopic changes. Discernability strengthened with practice and was BCI-specific, demonstrating contextual specificity. Sampling representational plasticity and drift across days subsequently uncovered a meta-representational structure with generalizable decision boundaries for the repertoire; this allowed long-term neuroprosthetic control of a robotic arm and hand for reaching and grasping. Our study offers insights into mesoscale representational statistics that also enable long-term complex neuroprosthetic control.
    Keywords:  brain-computer interface; control; deep learning; electrocorticography; learning; manifold; robot
    DOI:  https://doi.org/10.1016/j.cell.2025.02.001
  33. Nat Aging. 2025 Mar 11.
    Palliative care use in Taiwanese older adults.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-025-00843-z
  34. Nat Genet. 2025 Mar;57(3): 486
    High-throughput screening identifies modulators of gene bursting.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-025-02143-z
  35. Science. 2025 Mar 13. eado4188
    Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis.
    Hui Lin, Chuanshun Ma, Kui Cai, Lulu Guo, Xuemei Wang, Lin Lv, Chao Zhang, Jun Lin, Daolai Zhang, Chuan Ye, Tengwei Wang, Shenming Huang, Jifei Han, Zihao Zhang, Junyan Gao, Mingxiang Zhang, Zhao Pu, Fengyang Li, Yongyuan Guo, Xiaojun Zhou, Chengxue Qin, Fan Yi, Xiao Yu, Wei Kong, Changtao Jiang, Jin-Peng Sun.
      Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify FPR2 as a membrane receptor that specifically binds long-chain ceramides (C14-C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via Gi-cyclic AMP signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0 and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.
    DOI:  https://doi.org/10.1126/science.ado4188
  36. Cell. 2025 Mar 06. pii: S0092-8674(24)01480-6. [Epub ahead of print]188(5): 1175-1177
    MEER: Extraordinary flourishing ecosystem in the deepest ocean.
    Xiang Xiao, Jian Wang, Kang Ding.
      Here, we introduce the Mariana Trench Environment and Ecology Research (MEER) project, which provides the first systematic view of the ecosystem in the hadal zone.
    DOI:  https://doi.org/10.1016/j.cell.2024.12.037
  37. Nature. 2025 Mar 12.
    Immune molecule links COVID‑19 with severe inflammatory disorder in children.
      
    Keywords:  Diseases; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-00735-7
  38. Nature. 2025 Mar 12.
    Hepatic stellate cells control liver zonation, size and functions via R-spondin 3.
    Atsushi Sugimoto, Yoshinobu Saito, Guanxiong Wang, Qiuyan Sun, Chuan Yin, Ki Hong Lee, Yana Geng, Presha Rajbhandari, Celine Hernandez, Marcella Steffani, Jingran Qie, Thomas Savage, Dhruv M Goyal, Kevin C Ray, Taruna V Neelakantan, Deqi Yin, Johannes Melms, Brandon M Lehrich, Tyler M Yasaka, Silvia Liu, Michael Oertel, Tian Lan, Adrien Guillot, Moritz Peiseler, Aveline Filliol, Hiroaki Kanzaki, Naoto Fujiwara, Samhita Ravi, Benjamin Izar, Mario Brosch, Jochen Hampe, Helen Remotti, Josepmaria Argemi, Zhaoli Sun, Timothy J Kendall, Yujin Hoshida, Frank Tacke, Jonathan A Fallowfield, Storm K Blockley-Powell, Rebecca A Haeusler, Jonathan B Steinman, Utpal B Pajvani, Satdarshan P Monga, Ramon Bataller, Mojgan Masoodi, Nicholas Arpaia, Youngmin A Lee, Brent R Stockwell, Hellmut G Augustin, Robert F Schwabe.
      Hepatic stellate cells (HSCs) have a central pathogenetic role in the development of liver fibrosis. However, their fibrosis-independent and homeostatic functions remain poorly understood1-5. Here we demonstrate that genetic depletion of HSCs changes WNT activity and zonation of hepatocytes, leading to marked alterations in liver regeneration, cytochrome P450 metabolism and injury. We identify R-spondin 3 (RSPO3), an HSC-enriched modulator of WNT signalling, as responsible for these hepatocyte-regulatory effects of HSCs. HSC-selective deletion of Rspo3 phenocopies the effects of HSC depletion on hepatocyte gene expression, zonation, liver size, regeneration and cytochrome P450-mediated detoxification, and exacerbates alcohol-associated and metabolic dysfunction-associated steatotic liver disease. RSPO3 expression decreases with HSC activation and is inversely associated with outcomes in patients with alcohol-associated and metabolic dysfunction-associated steatotic liver disease. These protective and hepatocyte-regulating functions of HSCs via RSPO3 resemble the R-spondin-expressing stromal niche in other organs and should be integrated into current therapeutic concepts.
    DOI:  https://doi.org/10.1038/s41586-025-08677-w
  39. Science. 2025 Mar 14. 387(6739): 1147-1148
    Making sense of fat in cancer.
    Estela Jacinto.
      A lipid chaperone enables sensing of an essential fatty acid to drive tumor growth.
    DOI:  https://doi.org/10.1126/science.adw1956
  40. Nat Metab. 2025 Mar 10.
    A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
    Samantha Pretto, Qian Yu, Pierre Bourdely, Sarah Trusso Cafarello, Heleen H Van Acker, Joren Verelst, Elena Richiardone, Lotte Vanheer, Amir Roshanzadeh, Franziska Schneppenheim, Charlotte Cresens, Maria Livia Sassano, Jonas Dehairs, Martin Carion, Shehab Ismail, Patrizia Agostinis, Susana Rocha, Tobias Bald, Johan Swinnen, Cyril Corbet, Sophia Y Lunt, Bernard Thienpont, Mario Di Matteo, Massimiliano Mazzone.
      Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
    DOI:  https://doi.org/10.1038/s42255-025-01233-w
  41. Nat Med. 2025 Mar 11.
    Urgent call to close the gap in medical oxygen access.
    Karen O'Leary.
      
    Keywords:  Health care; Policy; Public health
    DOI:  https://doi.org/10.1038/d41591-025-00018-8
  42. Nature. 2025 Mar 11.
    An organ that stores red blood cells for emergencies.
      
    Keywords:  History; Physiology; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-00732-w
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