bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–01–26
thirty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. RELMβ sets the threshold for microbiome-dependent oral tolerance.
  2. Mechanosensitive neurons innervating the gut and heart control metabolic and emotional state.
  3. Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.
  4. Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.
  5. Multiscale footprints reveal the organization of cis-regulatory elements.
  6. How hosting Ukrainian scientists offers a template for supporting other scholars at risk.
  7. The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes.
  8. Want to become a professor? Here's how hiring criteria differ by country.
  9. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease.
  10. Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
  11. Multimodal cell mapping with optimal transport.
  12. A data-driven latent variable approach to validating the research domain criteria framework.
  13. Cancer cells 'poison' the immune system with tainted mitochondria.
  14. The maternal X chromosome affects cognition and brain ageing in female mice.
  15. A high-performance GRAB sensor reveals differences in the dynamics and molecular regulation between neuropeptide and neurotransmitter release.
  16. RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses.
  17. China's cheap, open AI model DeepSeek thrills scientists.
  18. Brucella abortus impairs T lymphocyte responsiveness by mobilizing IL-1RA-secreting omental neutrophils.
  19. Resolving native GABAA receptor structures from the human brain.
  20. KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice.
  21. Our Future Health: a unique global resource for discovery and translational research.
  22. Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease.
  23. Postprandial parasympathetic signals promote lung type 2 immunity.
  24. The molecular basis of Human FN3K mediated phosphorylation of glycated substrates.
  25. Programming of synthetic regulatory DNA for cell-type targeting in humans.
  26. A scalable system using mini-organs to test personalized RNA therapy.
  27. Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia.
  28. Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution.
  29. SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.
  30. Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.
  31. The surprising link between muscle and the reproductive system.
  32. Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders.
  1. Nature. 2025 Jan 22.
    RELMβ sets the threshold for microbiome-dependent oral tolerance.
    Emmanuel Stephen-Victor, Gavin A Kuziel, Monica Martinez-Blanco, Bat-Erdene Jugder, Mehdi Benamar, Ziwei Wang, Qian Chen, Gabriel L Lozano, Azza Abdel-Gadir, Ye Cui, Jason Fong, Elisa Saint-Denis, Iris Chang, Kari C Nadeau, Wanda Phipatanakul, Angela Zhang, Farida Abi Farraj, Faye Holder-Niles, Daniel Zeve, David T Breault, Klaus Schmitz-Abe, Rima Rachid, Elena Crestani, Seth Rakoff-Nahoum, Talal A Chatila.
      Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis1,2. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ)3,4 is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELMβ disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes. Tolerance is maintained by the local production of indole derivatives driving FA protective RORγt+ regulatory T (Treg) cells5 through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ mediates a gut immune-epithelial circuit regulating tolerance to food antigens-a novel mode of innate control of adaptive immunity through microbiome editing-and identify targetable candidates in this circuit for prevention and treatment of FA.
    DOI:  https://doi.org/10.1038/s41586-024-08440-7
  2. Nat Metab. 2025 Jan 17.
    Mechanosensitive neurons innervating the gut and heart control metabolic and emotional state.
      
    DOI:  https://doi.org/10.1038/s42255-024-01208-3
  3. Nat Commun. 2025 Jan 20. 16(1): 867
    Palmitoylation-dependent regulation of GPX4 suppresses ferroptosis.
    Bin Huang, Hui Wang, Shuo Liu, Meng Hao, Dan Luo, Yi Zhou, Ying Huang, Yong Nian, Lei Zhang, Bo Chu, Chengqian Yin.
      S-palmitoylation is a reversible and widespread post-translational modification, but its role in the regulation of ferroptosis has been poorly understood. Here, we elucidate that GPX4, an essential regulator of ferroptosis, is reversibly palmitoylated on cysteine 66. The acyltransferase ZDHHC20 palmitoylates GPX4 and increases its protein stability. ZDHHC20 depletion or inhibition of protein palmitoylation by 2-BP sensitizes cancer cells to ferroptosis. Moreover, we identify APT2 as the depalmitoylase of GPX4. Genetic silencing or pharmacological inhibition of APT2 with ML349 increases GPX4 palmitoylation, thereby stabilizing the protein and conferring resistance to ferroptosis. Notably, disrupting GPX4 palmitoylation markedly potentiates ferroptosis in xenografted and orthotopically implanted tumor models, and inhibits tumor metastasis through blood vessels. In the chemically induced colorectal cancer model, knockout of APT2 significantly aggravates cancer progression. Furthermore, pharmacologically modulating GPX4 palmitoylation impacts liver ischemia-reperfusion injury. Overall, our findings uncover the intricate network regulating GPX4 palmitoylation, highlighting its pivotal role in modulating ferroptosis sensitivity.
    DOI:  https://doi.org/10.1038/s41467-025-56344-5
  4. Nat Commun. 2025 Jan 17. 16(1): 765
    Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.
    Alexia Carré, Fatoumata Samassa, Zhicheng Zhou, Javier Perez-Hernandez, Christiana Lekka, Anthony Manganaro, Masaya Oshima, Hanqing Liao, Robert Parker, Annalisa Nicastri, Barbara Brandao, Maikel L Colli, Decio L Eizirik, Jahnavi Aluri, Deep Patel, Marcus Göransson, Orlando Burgos Morales, Amanda Anderson, Laurie Landry, Farah Kobaisi, Raphael Scharfmann, Lorella Marselli, Piero Marchetti, Sylvaine You, Maki Nakayama, Sine R Hadrup, Sally C Kent, Sarah J Richardson, Nicola Ternette, Roberto Mallone.
      Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8+ T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8+ T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-55908-9
  5. Nature. 2025 Jan 22.
    Multiscale footprints reveal the organization of cis-regulatory elements.
    Yan Hu, Max A Horlbeck, Ruochi Zhang, Sai Ma, Rojesh Shrestha, Vinay K Kartha, Fabiana M Duarte, Conrad Hock, Rachel E Savage, Ajay Labade, Heidi Kletzien, Alia Meliki, Andrew Castillo, Neva C Durand, Eugenio Mattei, Lauren J Anderson, Tristan Tay, Andrew S Earl, Noam Shoresh, Charles B Epstein, Amy J Wagers, Jason D Buenrostro.
      Cis-regulatory elements (CREs) control gene expression and are dynamic in their structure and function, reflecting changes in the composition of diverse effector proteins over time1. However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.
    DOI:  https://doi.org/10.1038/s41586-024-08443-4
  6. Nature. 2025 Jan 20.
    How hosting Ukrainian scientists offers a template for supporting other scholars at risk.
    Benjamin Plackett.
      
    Keywords:  Careers; Institutions; Lab life; Society
    DOI:  https://doi.org/10.1038/d41586-024-04024-7
  7. Nat Commun. 2025 Jan 17. 16(1): 770
    The widely used Ucp1-Cre transgene elicits complex developmental and metabolic phenotypes.
    Manasi Suchit Halurkar, Oto Inoue, Archana Singh, Rajib Mukherjee, Meghana Ginugu, Christopher Ahn, Christian Louis Bonatto Paese, Molly Duszynski, Samantha A Brugmann, Hee-Woong Lim, Joan Sanchez-Gurmaches.
      Bacterial artificial chromosome transgenic models, including most Cre-recombinases, enable potent interrogation of gene function in vivo but require rigorous validation as limitations emerge. Due to its high relevance to metabolic studies, we perform comprehensive analysis of the Ucp1-CreEvdr line which is widely used for brown fat research. Hemizygotes exhibit major brown and white fat transcriptomic dysregulation, indicating potential altered tissue function. Ucp1-CreEvdr homozygotes also show high mortality, tissue specific growth defects, and craniofacial abnormalities. Mapping the transgene insertion site reveals insertion in chromosome 1 accompanied by large genomic alterations disrupting several genes expressed in a range of tissues. Notably, Ucp1-CreEvdr transgene retains an extra Ucp1 gene copy that may be highly expressed under high thermogenic burden. Our multi-faceted analysis highlights a complex phenotype arising from the presence of the Ucp1-CreEvdr transgene independently of intended genetic manipulations. Overall, comprehensive validation of transgenic mice is imperative to maximize discovery while mitigating unexpected, off-target effects.
    DOI:  https://doi.org/10.1038/s41467-024-54763-4
  8. Nature. 2025 Jan 22.
    Want to become a professor? Here's how hiring criteria differ by country.
    Smriti Mallapaty.
      
    Keywords:  Institutions; Peer review; Research management
    DOI:  https://doi.org/10.1038/d41586-025-00143-x
  9. Cell. 2025 Jan 14. pii: S0092-8674(24)01379-5. [Epub ahead of print]
    Long somatic DNA-repeat expansion drives neurodegeneration in Huntington's disease.
    Robert E Handsaker, Seva Kashin, Nora M Reed, Steven Tan, Won-Seok Lee, Tara M McDonald, Kiely Morris, Nolan Kamitaki, Christopher D Mullally, Neda R Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A McCarroll.
      In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG)n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life.
    Keywords:  CAG; DNA repeats; Huntington’s disease; neurodegeneration; repeat instability; single-nucleus RNA-seq; somatic expansion; striatal projection neurons; triplet repeat disorders
    DOI:  https://doi.org/10.1016/j.cell.2024.11.038
  10. Nat Cancer. 2025 Jan 17.
    Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
    Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.
      Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.
    DOI:  https://doi.org/10.1038/s43018-024-00895-x
  11. Nature. 2025 Jan 22.
    Multimodal cell mapping with optimal transport.
      
    Keywords:  Cell biology; Computational biology and bioinformatics; Machine learning
    DOI:  https://doi.org/10.1038/d41586-025-00107-1
  12. Nat Commun. 2025 Jan 18. 16(1): 830
    A data-driven latent variable approach to validating the research domain criteria framework.
    S K L Quah, B Jo, C Geniesse, L Q Uddin, J A Mumford, D M Barch, D A Fair, I H Gotlib, R A Poldrack, M Saggar.
      Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns, we employ a latent variable approach using bifactor analysis. We examine 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with 6192 participants. A curated subset of 37 maps with a balanced representation of RDoC domains constitute the training set, and the remaining held-out maps form the internal validation set. External validation is conducted using 36 peak coordinate activation maps from Neurosynth, using terms of RDoC constructs as seeds for topic meta-analysis. Here, we show that a bifactor model incorporating a task-general domain and splitting the cognitive systems domain better fits the examined corpus of tfMRI data than the current RDoC framework. We also identify the domain of arousal and regulatory systems as underrepresented. Our data-driven validation supports revising the RDoC framework to reflect underlying brain circuitry more accurately.
    DOI:  https://doi.org/10.1038/s41467-025-55831-z
  13. Nature. 2025 Jan 22.
    Cancer cells 'poison' the immune system with tainted mitochondria.
    Asher Mullard.
      
    Keywords:  Cancer; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-025-00176-2
  14. Nature. 2025 Jan 22.
    The maternal X chromosome affects cognition and brain ageing in female mice.
    Samira Abdulai-Saiku, Shweta Gupta, Dan Wang, Francesca Marino, Arturo J Moreno, Yu Huang, Deepak Srivastava, Barbara Panning, Dena B Dubal.
      Female mammalian cells have two X chromosomes, one of maternal origin and one of paternal origin. During development, one X chromosome randomly becomes inactivated1-4. This renders either the maternal X (Xm) chromosome or the paternal X (Xp) chromosome inactive, causing X mosaicism that varies between female individuals, with some showing considerable or complete skew of the X chromosome that remains active5-7. Parent-of-X origin can modify epigenetics through DNA methylation8,9 and possibly gene expression; thus, mosaicism could buffer dysregulated processes in ageing and disease. However, whether X skew or its mosaicism alters functions in female individuals is largely unknown. Here we tested whether skew towards an active Xm chromosome influences the brain and body-and then delineated unique features of Xm neurons and Xp neurons. An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm-mediated acceleration of biological or epigenetic ageing of the hippocampus, a key centre for learning and memory, in female mice. Several genes were imprinted on the Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci. CRISPR-mediated activation of Xm-imprinted genes improved cognition in ageing female mice. Thus, the Xm chromosome impaired cognition, accelerated brain ageing and silenced genes that contribute to cognition in ageing. Understanding how Xm impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain ageing.
    DOI:  https://doi.org/10.1038/s41586-024-08457-y
  15. Nat Commun. 2025 Jan 18. 16(1): 819
    A high-performance GRAB sensor reveals differences in the dynamics and molecular regulation between neuropeptide and neurotransmitter release.
    Xiju Xia, Yulong Li.
      The co-existence and co-transmission of neuropeptides and small molecule neurotransmitters within individual neuron represent a fundamental characteristic observed across various species. However, the differences regarding their in vivo spatiotemporal dynamics and underlying molecular regulation remain poorly understood. Here, we develop a GPCR-activation-based (GRAB) sensor for detecting short neuropeptide F (sNPF) with high sensitivity and spatiotemporal resolution. Furthermore, we investigate the in vivo dynamics and molecular regulation differences between sNPF and acetylcholine (ACh) from the same neurons. Interestingly, our findings reveal distinct spatiotemporal dynamics in the release of sNPF and ACh. Notably, our results indicate that distinct synaptotagmins (Syt) are involved in these two processes, as Syt7 and Sytα for sNPF release, while Syt1 for ACh release. Thus, this high-performance GRAB sensor provides a robust tool for studying neuropeptide release and shedding insights into the unique release dynamics and molecular regulation that distinguish neuropeptides from small molecule neurotransmitters.
    DOI:  https://doi.org/10.1038/s41467-025-56129-w
  16. Nat Commun. 2025 Jan 17. 16(1): 777
    RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses.
    Eleni Kabrani, Ali Rahjouei, Maria Berruezo-Llacuna, Svenja Ebeling, Tannishtha Saha, Robert Altwasser, Veronica Delgado-Benito, Rushad Pavri, Michela Di Virgilio.
      The establishment of protective immune responses relies on the ability of terminally differentiated B cells to secrete a broad variety of antigen-specific antibodies with different effector functions. RIF1 is a multifunctional protein that promotes antibody isotype diversification via its DNA end protection activity during class switch recombination. In this study, we showed that RIF1 ablation resulted in increased plasmablast formation ex vivo and enhanced terminal differentiation into plasma cells upon immunization. Mechanistically, this phenotype is independent from RIF1's role in DNA repair and class switch recombination, and reflects its ability to modulate the transcriptional status of a subset of BLIMP1 target genes. Therefore, here we show that, in addition to promoting antibody diversification, RIF1 fine-tunes the kinetics of late B cell differentiation, thus providing an additional layer of control in the establishment of humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-025-56166-5
  17. Nature. 2025 Jan 23.
    China's cheap, open AI model DeepSeek thrills scientists.
    Elizabeth Gibney.
      
    Keywords:  Mathematics and computing
    DOI:  https://doi.org/10.1038/d41586-025-00229-6
  18. Nat Commun. 2025 Jan 20. 16(1): 862
    Brucella abortus impairs T lymphocyte responsiveness by mobilizing IL-1RA-secreting omental neutrophils.
    Joaquin M Pellegrini, Gabriela González-Espinoza, Raheleh R Shayan, Lisiena Hysenaj, Thomas Rouma, Vilma Arce-Gorvel, Hugues Lelouard, Dimitri Popoff, Yun Zhao, Sean Hanniffy, Amanda Castillo-Zeledón, Maite Loperena-Barber, Javier Celis-Gutierrez, Cyrille Mionnet, Mile Bosilkovski, Javier Solera, Eric Muraille, Elías Barquero-Calvo, Edgardo Moreno, Raquel Conde-Álvarez, Ignacio Moriyón, Jean-Pierre Gorvel, Sylvie Mémet.
      Immune evasion strategies of Brucella, the etiologic agent of brucellosis, a global zoonosis, remain partially understood. The omentum, a tertiary lymphoid organ part of visceral adipose tissue, has never been explored as a Brucella reservoir. We report that B. abortus infects and replicates within murine omental macrophages. Throughout the chronic phase of infection, the omentum accumulates macrophages, monocytes and neutrophils. The maintenance of PD-L1+Sca-1+ macrophages, monocytes and neutrophils in the omentum depends on the wadC-encoded determinant of Brucella LPS. We demonstrate that PD-L1+Sca-1+ murine omental neutrophils produce high levels of IL-1RA leading to T cell hyporesponsiveness. These findings corroborate brucellosis patient analysis of whole blood displaying upregulation of PDL1 and Ly6E genes, and of serum exhibiting high levels of IL-1RA. Overall, the omentum, a reservoir for B. abortus, promotes bacterial persistence and causes CD4+ and CD8+ T cell immunosuppression by IL-1RA secreted by PD-L1+Sca-1+ neutrophils.
    DOI:  https://doi.org/10.1038/s41467-024-55799-2
  19. Nature. 2025 Jan 22.
    Resolving native GABAA receptor structures from the human brain.
    Jia Zhou, Colleen M Noviello, Jinfeng Teng, Haley Moore, Bradley Lega, Ryan E Hibbs.
      Type A GABA (γ-aminobutyric acid) receptors (GABAA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics1,2. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABAA receptors in the human brain have been inferred from subunit localization in tissue1,3, functional measurements and structural analysis from recombinant expression4-7 and in mice8. However, the arrangements of subunits that co-assemble physiologically in native human GABAA receptors remain unknown. Here we isolated α1 subunit-containing GABAA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABAA receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABAA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABAA receptor signalling and targeted pharmacology in the human brain.
    DOI:  https://doi.org/10.1038/s41586-024-08454-1
  20. Cell. 2025 Jan 13. pii: S0092-8674(24)01432-6. [Epub ahead of print]
    KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice.
    Tara I McIntyre, Omar Valdez, Nathan P Kochhar, Brittany Davidson, Bushra Samad, Longhui Qiu, Kenneth Hu, Alexis J Combes, Adrian Erlebacher.
      Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.
    Keywords:  H3K27me3; KDM6B; epigenetic programming; fibroblasts; mouse pregnancy; parturition; progesterone; uterus
    DOI:  https://doi.org/10.1016/j.cell.2024.12.019
  21. Nat Med. 2025 Jan 21.
    Our Future Health: a unique global resource for discovery and translational research.
    Michael B Cook, Saskia C Sanderson, John E Deanfield, Fiona Reddington, Andrew Roddam, David J Hunter, Raghib Ali.
      
    DOI:  https://doi.org/10.1038/s41591-024-03438-0
  22. Cell. 2025 Jan 15. pii: S0092-8674(24)01429-6. [Epub ahead of print]
    Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease.
    Rafael Valdés-Mas, Avner Leshem, Danping Zheng, Yotam Cohen, Lara Kern, Niv Zmora, Yiming He, Corine Katina, Shimrit Eliyahu-Miller, Tal Yosef-Hevroni, Liron Richman, Barbara Raykhel, Shira Allswang, Reut Better, Merav Shmueli, Aurelia Saftien, Nyssa Cullin, Fernando Slamovitz, Dragos Ciocan, Kyanna S Ouyang, Uria Mor, Mally Dori-Bachash, Shahar Molina, Yishai Levin, Koji Atarashi, Ghil Jona, Jens Puschhof, Alon Harmelin, Noa Stettner, Minhu Chen, Jotham Suez, Kenya Honda, Wolfgang Lieb, Corinna Bang, Michal Kori, Nitsan Maharshak, Yifat Merbl, Oren Shibolet, Zamir Halpern, Dror S Shouval, Raanan Shamir, Andre Franke, Suhaib K Abdeen, Hagit Shapiro, Alon Savidor, Eran Elinav.
      Host-microbiome-dietary interactions play crucial roles in regulating human health, yet their direct functional assessment remains challenging. We adopted metagenome-informed metaproteomics (MIM), in mice and humans, to non-invasively explore species-level microbiome-host interactions during commensal and pathogen colonization, nutritional modification, and antibiotic-induced perturbation. Simultaneously, fecal MIM accurately characterized the nutritional exposure landscape in multiple clinical and dietary contexts. Implementation of MIM in murine auto-inflammation and in human inflammatory bowel disease (IBD) characterized a "compositional dysbiosis" and a concomitant species-specific "functional dysbiosis" driven by suppressed commensal responses to inflammatory host signals. Microbiome transfers unraveled early-onset kinetics of these host-commensal cross-responsive patterns, while predictive analyses identified candidate fecal host-microbiome IBD biomarker protein pairs outperforming S100A8/S100A9 (calprotectin). Importantly, a simultaneous fecal nutritional MIM assessment enabled the determination of IBD-related consumption patterns, dietary treatment compliance, and small intestinal digestive aberrations. Collectively, a parallelized dietary-bacterial-host MIM assessment functionally uncovers trans-kingdom interactomes shaping gastrointestinal ecology while offering personalized diagnostic and therapeutic insights into microbiome-associated disease.
    Keywords:  biomarker; diet; inflammatory bowel disease; metagenome-informed metaproteomics; microbiome
    DOI:  https://doi.org/10.1016/j.cell.2024.12.016
  23. Neuron. 2025 Jan 12. pii: S0896-6273(24)00919-X. [Epub ahead of print]
    Postprandial parasympathetic signals promote lung type 2 immunity.
    Hongjie Chen, Xin Zhou, Tingting Liu, Jiaqi Liu, Di Wu, Xia Xu, Shanwu Ma, Guangliang Qiang, Jian Chen, Ying Cao, Wei Fu, Jing Yang.
      Lung type 2 immunity protects against pathogenic infection, but its dysregulation causes asthma. Although it has long been observed that symptoms of asthmatic patients often become exaggerated following food intake, the pathophysiological mechanism underlying this postprandial phenomenon is incompletely understood. Here, we report that lung type 2 immunity in mice is enhanced after feeding, which correlates with parasympathetic activation. Also, local parasympathetic innervations exhibit spatial engagement with such immune responses mediated by group 2 innate lymphoid cells (ILC2s). Pharmacologic or surgical blockage of parasympathetic signals diminishes lung type 2 immunity. Conversely, chemogenetic manipulation of parasympathetic inputs and their upstream neurocircuit is sufficient to modulate those immune responses. We then show that the cholinergic receptor muscarinic 4 (Chrm4) for the parasympathetic neurotransmitter acetylcholine is expressed in mouse or human lung ILC2s, and the Chrm4 deletion mitigates ILC2-mediated lung inflammation. These results have revealed a critical neuroimmune function of the gut-brain-lung reflex.
    Keywords:  Chrm4; ILC2s; cholinergic receptor muscarinic 4; food intake; group 2 innate lymphoid cells; lung type 2 immunity; parasympathetic signal
    DOI:  https://doi.org/10.1016/j.neuron.2024.12.020
  24. Nat Commun. 2025 Jan 22. 16(1): 941
    The molecular basis of Human FN3K mediated phosphorylation of glycated substrates.
    Ankur Garg, Kin Fan On, Yang Xiao, Elad Elkayam, Paolo Cifani, Yael David, Leemor Joshua-Tor.
      Glycation, a non-enzymatic post-translational modification occurring on proteins, can be actively reversed via site-specific phosphorylation of the fructose-lysine moiety by FN3K kinase, to impact the cellular function of the target protein. A regulatory axis between FN3K and glycated protein targets has been associated with conditions like diabetes and cancer. However, the molecular basis of this relationship has not been explored so far. Here, we determined a series of crystal structures of HsFN3K in the apo-state, and in complex with different nucleotide analogs together with a sugar substrate mimic to reveal the features important for its kinase activity and substrate recognition. Additionally, the dynamics in sugar substrate binding during the kinase catalytic cycle provide important mechanistic insights into HsFN3K function. Our structural work provides the molecular basis for rational small molecule design targeting FN3K.
    DOI:  https://doi.org/10.1038/s41467-025-56207-z
  25. Mol Cell. 2025 Jan 16. pii: S1097-2765(24)01036-0. [Epub ahead of print]85(2): 205-207
    Programming of synthetic regulatory DNA for cell-type targeting in humans.
    Leandro N Ventimiglia, Aleksej Zelezniak.
      In a recent study in Nature, Gosai et al.1 introduce a framework to engineer and validate synthetic DNA regulatory elements showing cell-type-specific activity in human cell lines, closing the distance to the machine-driven design of functional regulatory sequences with therapeutic applications in humans.
    DOI:  https://doi.org/10.1016/j.molcel.2024.12.019
  26. Nature. 2025 Jan 22.
    A scalable system using mini-organs to test personalized RNA therapy.
    Ronald A M Buijsen.
      
    Keywords:  Biotechnology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00078-3
  27. Nat Commun. 2025 Jan 22. 16(1): 918
    Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia.
    Megumi Andoh, Natsuki Shinoda, Yusuke Taira, Tasuku Araki, Yuka Kasahara, Haruki Takeuchi, Masayuki Miura, Yuji Ikegaya, Ryuta Koyama.
      Caspases are known to mediate neuronal apoptosis during brain development. However, here we show that nonapoptotic activation of caspase-3 at presynapses drives microglial synaptic phagocytosis. Real-time observation and spatiotemporal manipulation of synaptic caspase-3 in the newly established, mouse-derived culture system demonstrate that increased neuronal activity triggers localized presynaptic caspase-3 activation, facilitating synaptic tagging by complements. High-resolution live imaging reveals that caspase-3 activation promotes synapse-selective complement-dependent microglial phagocytosis without axonal shearing. Furthermore, activity-dependent caspase-3 activation at inhibitory presynapses induces microglial phagocytosis in mice and increases seizure susceptibility. This increased susceptibility is reversed by genetic depletion of microglial complement receptors. Thus, localized, nonapoptotic caspase activity guides complement-dependent microglial synaptic phagocytosis and remodels neuronal circuits.
    DOI:  https://doi.org/10.1038/s41467-025-56342-7
  28. Cell. 2025 Jan 12. pii: S0092-8674(24)01425-9. [Epub ahead of print]
    Spatiotemporal and genetic cell lineage tracing of endodermal organogenesis at single-cell resolution.
    Ke-Ran Li, Pei-Long Yu, Qi-Qi Zheng, Xin Wang, Xuan Fang, Lin-Chen Li, Cheng-Ran Xu.
      During early mammalian development, the endoderm germ layer forms the foundation of the respiratory and digestive systems through complex patterning. This intricate process, guided by a series of cell fate decisions, remains only partially understood. Our study introduces innovative genetic tracing codes for 14 distinct endodermal regions using novel mouse strains. By integrating high-throughput and high-precision single-cell RNA sequencing with sophisticated imaging, we detailed the spatiotemporal and genetic lineage differentiation of the endoderm at single-cell resolution. We discovered an unexpected multipotentiality within early endodermal regions, allowing differentiation into various organ primordia. This research illuminates the complex and underestimated phenomenon where endodermal organs develop from multiple origins, prompting a reevaluation of traditional differentiation models. Our findings advance understanding in developmental biology and have significant implications for regenerative medicine and the development of advanced organoid models, providing insights into the intricate mechanisms that guide organogenesis.
    Keywords:  cellular differentiation; five-dimensional cell lineage tracing; genetic lineage tracing; mouse endodermal organogenesis; multi-origin organs; single-cell RNA sequencing; spatiotemporal analysis
    DOI:  https://doi.org/10.1016/j.cell.2024.12.012
  29. EMBO J. 2025 Jan 17.
    SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis.
    Li Shi, Hao Chen, Yuxin Zhang, Donghao An, Mengyao Qin, Wanting Yu, Bin Wen, Dandan He, Haiping Hao, Jing Xiong.
      Metabolic requirements of dividing hepatocytes are prerequisite for liver regeneration after injury. In contrast to transcriptional dynamics during liver repair, its metabolic dependencies remain poorly defined. Here, we screened metabolic genes differentially regulated during liver regeneration, and report that SLC13A2, a transporter for TCA cycle intermediates, is decreased in rapid response to partial hepatectomy in mice and recovered along restoration of liver mass and function. Liver-specific overexpression or depletion of SLC13A2 promoted or attenuated liver regeneration, respectively. SLC13A2 increased cleavage of SREBP2, and expression of cholesterol metabolism genes, including LDLR and HMGCR. Mechanistically, SLC13A2 promotes import of citrate into hepatocytes, serving as building block for ACLY-dependent acetyl-CoA formation and de novo synthesis of cholesterol. In line, the pre-administration of the HMGCR inhibitor lovastatin abolished SLC13A2-mediated liver regeneration. Similarly, ACLY inhibition suppressed SLC13A2-promoted cholesterol synthesis for hepatocellular proliferation and liver regeneration in vivo. In sum, this study demonstrates that citrate transported by SLC13A2 acts as an intermediate metabolite to restore the metabolic homeostasis during liver regeneration, suggesting SLC13A2 as a potential drug target after liver damage.
    Keywords:  ATP-citate Lyase; Cell Division; De Novo Cholesterol Synthesis; Metabolic Remodeling; Partial Hepatectomy; TCA Cycle
    DOI:  https://doi.org/10.1038/s44318-025-00362-y
  30. Science. 2025 Jan 24. 387(6732): eadn7277
    Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.
    Lloyd D Harvey, Mona Alotaibi, Yi-Yin Tai, Ying Tang, Hee-Jung J Kim, Neil J Kelly, Wei Sun, Chen-Shan C Woodcock, Sanya Arshad, Miranda K Culley, Wadih El Khoury, Rong Xie, Yassmin Al Aaraj, Jingsi Zhao, Neha Hafeez, Rashmi J Rao, Siyi Jiang, Vinny Negi, Anna Kirillova, Dror Perk, Annie M Watson, Claudette M St Croix, Donna B Stolz, Ji Young Lee, Mary Hongying Cheng, Manling Zhang, Samuel Detmer, Edward Guzman, Rajith S Manan, Rajan Saggar, Kathleen J Haley, Aaron B Waxman, Satoshi Okawa, Tae-Hwi Schwantes-An, Michael W Pauciulo, Bing Wang, Amy Webb, Caroline Chauvet, Daniel G Anderson, William C Nichols, Ankit A Desai, Robert Lafyatis, S Mehdi Nouraie, Haodi Wu, Jeffrey G McDonald, Susan Cheng, Ivet Bahar, Thomas Bertero, Raymond L Benza, Mohit Jain, Stephen Y Chan.
      Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 (NCOA7) deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes. This oxysterol signature overlapped with a plasma metabolite signature associated with human PAH mortality. Mice deficient for endothelial Ncoa7 or exposed to an inflammatory bile acid developed worsened PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism rs11154337, which alters endothelial immunoactivation and is associated with human PAH mortality. An NCOA7-activating agent reversed endothelial immunoactivation and rodent PAH. Thus, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol processes to endothelial inflammation and PAH.
    DOI:  https://doi.org/10.1126/science.adn7277
  31. Nature. 2025 Jan 23.
    The surprising link between muscle and the reproductive system.
      
    Keywords:  Physiology
    DOI:  https://doi.org/10.1038/d41586-025-00129-9
  32. Cell. 2025 Jan 20. pii: S0092-8674(24)01435-1. [Epub ahead of print]
    Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders.
    Sool Lee, Jessica C McAfee, Jiseok Lee, Alejandro Gomez, Austin T Ledford, Declan Clarke, Hyunggyu Min, Mark B Gerstein, Alan P Boyle, Patrick F Sullivan, Adriana S Beltran, Hyejung Won.
      A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches and CRISPR perturbation. In vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve the regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.
    Keywords:  CROP-seq; GWAS; MPRA; cross-disorder; fine-mapping; functional validation; pleiotropy; psychiatric disorders; variant-gene mapping
    DOI:  https://doi.org/10.1016/j.cell.2024.12.022
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