bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–02–16
33 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Rethinking success.
  2. Metabolite signaling promotes the recruitment of immunosuppressive cells to tumors.
  3. Human and mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome.
  4. Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom's Macroglobulinemia.
  5. Next generation lysosome: Brought to you by cGAS-STING.
  6. ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.
  7. Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.
  8. ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
  9. Engineering extrachromosomal DNA.
  10. Dense, continuous membrane labeling and expansion microscopy visualization of ultrastructure in tissues.
  11. Impairment of DET1 causes neurological defects and lethality in mice and humans.
  12. Bacterial translocation promotes trained immunity.
  13. How centuries of isolation shaped Greenlanders' unique genetics.
  14. Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.
  15. Retirement-age scientists just keep working.
  16. Enhancers activate from afar.
  17. Scientists fight Norway's language law, warning of talent exodus.
  18. Transcriptomic neuron types vary topographically in function and morphology.
  19. Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis.
  20. Intercellular bridges are essential for transposon repression and meiosis in the male germline.
  21. The integrated stress response regulates 18S nonfunctional rRNA decay in mammals.
  22. An mTOR paradox in sarcopenia via BCAA catabolism.
  23. Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis.
  24. Linking vaccine adjuvant mechanisms of action to function.
  25. Thalamic opioids from POMC satiety neurons switch on sugar appetite.
  26. HDAC9 association with heart disease linked to NLRP3 inflammasome activation.
  27. Dozens of new obesity drugs are coming: these are the ones to watch.
  28. Scientific societies need to modernize.
  29. Accelerated epigenetic aging in Huntington's disease involves polycomb repressive complex 1.
  30. Are PhDs losing their lustre? Why fewer students are enrolling in doctoral degrees.
  31. Oligonucleotide subsets selection by single nucleotide resolution barcode identification.
  32. 'Devastating' cuts to NIH grants by Trump's team put on hold by US judge.
  33. Are the Trump team's actions affecting your research? How to contact Nature.
  1. Science. 2025 Jan 02. 387(6735): 798
    Rethinking success.
    Salahuddin Mohammed.
      
    DOI:  https://doi.org/10.1126/science.adw5879
  2. Nat Immunol. 2025 Feb 10.
    Metabolite signaling promotes the recruitment of immunosuppressive cells to tumors.
      
    DOI:  https://doi.org/10.1038/s41590-025-02094-x
  3. Nat Commun. 2025 Feb 11. 16(1): 1533
    Human and mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome.
    Jay M Yarbro, Xian Han, Abhijit Dasgupta, Ka Yang, Danting Liu, Him K Shrestha, Masihuz Zaman, Zhen Wang, Kaiwen Yu, Dong Geun Lee, David Vanderwall, Mingming Niu, Huan Sun, Boer Xie, Ping-Chung Chen, Yun Jiao, Xue Zhang, Zhiping Wu, Surendhar R Chepyala, Yingxue Fu, Yuxin Li, Zuo-Fei Yuan, Xusheng Wang, Suresh Poudel, Barbora Vagnerova, Qianying He, Andrew Tang, Patrick T Ronaldson, Rui Chang, Gang Yu, Yansheng Liu, Junmin Peng.
      Murine models of Alzheimer's disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata and prioritized components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Our analysis of the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including Aβ-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identifies potential targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.
    DOI:  https://doi.org/10.1038/s41467-025-56853-3
  4. Nat Commun. 2025 Feb 10. 16(1): 1480
    Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom's Macroglobulinemia.
    Romanos Sklavenitis-Pistofidis, Yoshinobu Konishi, Daniel Heilpern-Mallory, Ting Wu, Nicholas Tsakmaklis, Michelle P Aranha, Zachary R Hunter, Alaa K Ali, Junko Tsuji, Nicholas J Haradhvala, Elizabeth D Lightbody, Katherine Towle, Laura Hevenor, Rizwan Romee, Edward L Briercheck, Eric L Smith, Christine-Ivy Liacos, Efstathios Kastritis, Meletios A Dimopoulos, Steven P Treon, Gad Getz, Irene M Ghobrial.
      Waldenstrom's Macroglobulinemia (WM) is an IgM-secreting bone marrow (BM) lymphoma that is preceded by an asymptomatic state (AWM). To dissect tumor-intrinsic and immune mechanisms of progression, we perform single-cell RNA-sequencing on 294,206 BM tumor and immune cells from 30 patients with AWM/WM, 26 patients with Smoldering Myeloma, and 23 healthy donors. Despite their early stage, patients with AWM present extensive immune dysregulation, including in normal B cells, with disease-specific immune hallmarks. Patient T and NK cells show systemic hypo-responsiveness to interferon, which improves with interferon administration and may represent a therapeutic vulnerability. MYD88-mutant tumors show transcriptional heterogeneity, which can be distilled in a molecular classification, including a DUSP22/CD9-positive subtype, and progression signatures which differentiate IgM MGUS from overt WM and can help advance WM research and clinical practice.
    DOI:  https://doi.org/10.1038/s41467-025-56323-w
  5. Immunity. 2025 Feb 11. pii: S1074-7613(25)00037-8. [Epub ahead of print]58(2): 265-267
    Next generation lysosome: Brought to you by cGAS-STING.
    Lei Wang, Wen Zhou.
      Renowned for driving interferon responses, the cGAS-STING pathway reveals a surprising role: lysosomal biogenesis. In this issue of Immunity, Xu et al. uncover how STING activates the transcription factor TFEB, linking innate immune sensing to enhanced pathogen clearance through lysosomal activity.
    DOI:  https://doi.org/10.1016/j.immuni.2025.01.012
  6. Cell. 2025 Feb 05. pii: S0092-8674(25)00096-0. [Epub ahead of print]
    ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation.
    Subhajit Poddar, Samuel D Chauvin, Christopher H Archer, Wei Qian, Jean A Castillo-Badillo, Xin Yin, W Miguel Disbennett, Cathrine A Miner, Joe A Holley, Teresa V Naismith, W Alexander Stinson, Xiaochao Wei, Yue Ning, Jiayuan Fu, Trini A Ochoa, Nehalee Surve, Shivam A Zaver, Kimberly A Wodzanowski, Katherine R Balka, Rajan Venkatraman, Canyu Liu, Kelly Rome, Will Bailis, Yoko Shiba, Sara Cherry, Sunny Shin, Clay F Semenkovich, Dominic De Nardo, Sunnie Yoh, Elisha D O Roberson, Sumit K Chanda, David J Kast, Jonathan J Miner.
      Stimulator of interferon genes (STING) transmits signals downstream of the cytosolic DNA sensor cyclic guanosine monophosphate-AMP synthase (cGAS), leading to transcriptional upregulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (STING-associated vasculopathy with onset in infancy [SAVI]) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi apparatus. Because pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell-type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.
    Keywords:  ArfGAP2; Golgi trafficking; SAVI; STING; antiviral immunity; autoinflammation; cGAS; chemokines; cytokines; interferon
    DOI:  https://doi.org/10.1016/j.cell.2025.01.027
  7. Nat Commun. 2025 Feb 13. 16(1): 1577
    Unraveling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics.
    Theo Perochon, Zeljka Krsnik, Marco Massimo, Yana Ruchiy, Alejandro Lastra Romero, Elyas Mohammadi, Xiaofei Li, Katherine R Long, Laura Parkkinen, Klas Blomgren, Thibault Lagache, David A Menassa, David Holcman.
      Mapping cellular organization in the developing brain presents significant challenges due to the multidimensional nature of the data, characterized by complex spatial patterns that are difficult to interpret without high-throughput tools. Here, we present DeepCellMap, a deep-learning-assisted tool that integrates multi-scale image processing with advanced spatial and clustering statistics. This pipeline is designed to map microglial organization during normal and pathological brain development and has the potential to be adapted to any cell type. Using DeepCellMap, we capture the morphological diversity of microglia, identify strong coupling between proliferative and phagocytic phenotypes, and show that distinct spatial clusters rarely overlap as human brain development progresses. Additionally, we uncover an association between microglia and blood vessels in fetal brains exposed to maternal SARS-CoV-2. These findings offer insights into whether various microglial phenotypes form networks in the developing brain to occupy space, and in conditions involving haemorrhages, whether microglia respond to, or influence changes in blood vessel integrity. DeepCellMap is available as an open-source software and is a powerful tool for extracting spatial statistics and analyzing cellular organization in large tissue sections, accommodating various imaging modalities. This platform opens new avenues for studying brain development and related pathologies.
    DOI:  https://doi.org/10.1038/s41467-025-56560-z
  8. Nat Commun. 2025 Feb 10. 16(1): 1508
    ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
    Isshin Shiiba, Naoki Ito, Hijiri Oshio, Yuto Ishikawa, Takahiro Nagao, Hiroki Shimura, Kyu-Wan Oh, Eiki Takasaki, Fuya Yamaguchi, Ryoan Konagaya, Hisae Kadowaki, Hideki Nishitoh, Takehito Tanzawa, Shun Nagashima, Ayumu Sugiura, Yuuta Fujikawa, Keitaro Umezawa, Yasushi Tamura, Byung Il Lee, Yusuke Hirabayashi, Yasushi Okazaki, Tomohiro Sawa, Ryoko Inatome, Shigeru Yanagi.
      The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-025-56666-4
  9. Nat Genet. 2025 Feb;57(2): 280
    Engineering extrachromosomal DNA.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02103-7
  10. Nat Commun. 2025 Feb 12. 16(1): 1579
    Dense, continuous membrane labeling and expansion microscopy visualization of ultrastructure in tissues.
    IMAXT Grand Challenge Consortium
      Lipid membranes are key to the nanoscale compartmentalization of biological systems, but fluorescent visualization of them in intact tissues, with nanoscale precision, is challenging to do with high labeling density. Here, we report ultrastructural membrane expansion microscopy (umExM), which combines an innovative membrane label and optimized expansion microscopy protocol, to support dense labeling of membranes in tissues for nanoscale visualization. We validate the high signal-to-background ratio, and uniformity and continuity, of umExM membrane labeling in brain slices, which supports the imaging of membranes and proteins at a resolution of ~60 nm on a confocal microscope. We demonstrate the utility of umExM for the segmentation and tracing of neuronal processes, such as axons, in mouse brain tissue. Combining umExM with optical fluctuation imaging, or iterating the expansion process, yields ~35 nm resolution imaging, pointing towards the potential for electron microscopy resolution visualization of brain membranes on ordinary light microscopes.
    DOI:  https://doi.org/10.1038/s41467-025-56641-z
  11. Proc Natl Acad Sci U S A. 2025 Feb 18. 122(7): e2422631122
    Impairment of DET1 causes neurological defects and lethality in mice and humans.
    Ozge Karayel, Allison Soung, Hem Gurung, Alexander F Schubert, Susan Klaeger, Marc Kschonsak, Aljazi Al-Maraghi, Ajaz A Bhat, Ammira S Alshabeeb Akil, Debra L Dugger, Joshua D Webster, Dorothy M French, Dhullipala Anand, Naharmal Soni, Khalid A Fakhro, Christopher M Rose, Seth F Harris, Ada Ndoja, Kim Newton, Vishva M Dixit.
      COP1 and DET1 are components of an E3 ubiquitin ligase that is conserved from plants to humans. Mammalian COP1 binds to DET1 and is a substrate adaptor for the CUL4A-DDB1-RBX1 RING E3 ligase. Transcription factor substrates, including c-Jun, ETV4, and ETV5, are targeted for proteasomal degradation to effect rapid transcriptional changes in response to cues such as growth factor deprivation. Here, we link a homozygous DET1R26W mutation to lethal developmental abnormalities in humans. Experimental cryo-electron microscopy of the DET1 complex with DDB1 and DDA1, as well as co-immunoprecipitation experiments, revealed that DET1R26W impairs binding to DDB1, thereby compromising E3 ligase function. Accordingly, human-induced pluripotent stem cells homozygous for DET1R26W expressed ETV4 and ETV5 highly, and exhibited defective mitochondrial homeostasis and aberrant caspase-dependent cell death when differentiated into neurons. Neuronal cell death was increased further in the presence of Det1-deficient microglia as compared to WT microglia, indicating that the deleterious effects of the DET1 p.R26W mutation may stem from the dysregulation of multiple cell types. Mice lacking Det1 died during embryogenesis, while Det1 deletion just in neural stem cells elicited hydrocephalus, cerebellar dysplasia, and neonatal lethality. Our findings highlight an important role for DET1 in the neurological development of mice and humans.
    Keywords:  COP1; DET1; E3 ligase; neurodevelopment; ubiquitin
    DOI:  https://doi.org/10.1073/pnas.2422631122
  12. Immunity. 2025 Feb 11. pii: S1074-7613(25)00036-6. [Epub ahead of print]58(2): 268-270
    Bacterial translocation promotes trained immunity.
    Maria Francesca Viola, Elvira Mass.
      Can bacteria that breach mucosal barriers drive long-lasting changes in immunity? In this issue of Immunity, Robles-Vera et al. describe how, in the context of colitis, bacteria breaching the intestinal barrier reprogram precursors in the bone marrow via Mincle-dependent signaling.
    DOI:  https://doi.org/10.1016/j.immuni.2025.01.011
  13. Nature. 2025 Feb 12.
    How centuries of isolation shaped Greenlanders' unique genetics.
    Freda Kreier.
      
    Keywords:  Genetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00443-2
  14. Nat Commun. 2025 Feb 10. 16(1): 1501
    Mitofusin 2 displays fusion-independent roles in proteostasis surveillance.
    Mariana Joaquim, Selver Altin, Maria-Bianca Bulimaga, Tânia Simões, Hendrik Nolte, Verian Bader, Camilla Aurora Franchino, Solenn Plouzennec, Karolina Szczepanowska, Elena Marchesan, Kay Hofmann, Marcus Krüger, Elena Ziviani, Aleksandra Trifunovic, Arnaud Chevrollier, Konstanze F Winklhofer, Elisa Motori, Margarete Odenthal, Mafalda Escobar-Henriques.
      Mitochondria are essential organelles and their functional state dictates cellular proteostasis. However, little is known about the molecular gatekeepers involved, especially in absence of external stress. Here we identify a role of MFN2 in quality control independent of its function in organellar shape remodeling. MFN2 ablation alters the cellular proteome, marked for example by decreased levels of the import machinery and accumulation of the kinase PINK1. Moreover, MFN2 interacts with the proteasome and cytosolic chaperones, thereby preventing aggregation of newly translated proteins. Similarly to MFN2-KO cells, patient fibroblasts with MFN2-disease variants recapitulate excessive protein aggregation defects. Restoring MFN2 levels re-establishes proteostasis in MFN2-KO cells and rescues fusion defects of MFN1-KO cells. In contrast, MFN1 loss or mitochondrial shape alterations do not alter protein aggregation, consistent with a fusion-independent role of MFN2 in cellular homeostasis. In sum, our findings open new possibilities for therapeutic strategies by modulation of MFN2 levels.
    DOI:  https://doi.org/10.1038/s41467-025-56673-5
  15. Science. 2025 Jan 02. 387(6735): 708
    Retirement-age scientists just keep working.
    Katie Langin.
      Desire to retain professional identity keeps Ph.D.s from stepping aside, survey shows.
    DOI:  https://doi.org/10.1126/science.adw6804
  16. Nat Cell Biol. 2025 Feb;27(2): 175
    Enhancers activate from afar.
    Sabrya Carim.
      
    DOI:  https://doi.org/10.1038/s41556-025-01628-7
  17. Nature. 2025 Feb 11.
    Scientists fight Norway's language law, warning of talent exodus.
    Linda Nordling.
      
    Keywords:  Careers; Education; Lab life; Language
    DOI:  https://doi.org/10.1038/d41586-025-00344-4
  18. Nature. 2025 Feb 12.
    Transcriptomic neuron types vary topographically in function and morphology.
    Inbal Shainer, Johannes M Kappel, Eva Laurell, Joseph C Donovan, Martin W Schneider, Enrico Kuehn, Irene Arnold-Ammer, Manuel Stemmer, Johannes Larsch, Herwig Baier.
      Neuronal phenotypic traits such as morphology, connectivity and function are dictated, to a large extent, by a specific combination of differentially expressed genes. Clusters of neurons in transcriptomic space correspond to distinct cell types and in some cases-for example, Caenorhabditis elegans neurons1 and retinal ganglion cells2-4-have been shown to share morphology and function. The zebrafish optic tectum is composed of a spatial array of neurons that transforms visual inputs into motor outputs. Although the visuotopic map is continuous, subregions of the tectum are functionally specialized5,6. Here, to uncover the cell-type architecture of the tectum, we transcriptionally profiled its neurons, revealing more than 60 cell types that are organized in distinct anatomical layers. We measured the visual responses of thousands of tectal neurons by two-photon calcium imaging and matched them with their transcriptional profiles. Furthermore, we characterized the morphologies of transcriptionally identified neurons using specific transgenic lines. Notably, we found that neurons that are transcriptionally similar can diverge in shape, connectivity and visual responses. Incorporating the spatial coordinates of neurons within the tectal volume revealed functionally and morphologically defined anatomical subclusters within individual transcriptomic clusters. Our findings demonstrate that extrinsic, position-dependent factors expand the phenotypic repertoire of genetically similar neurons.
    DOI:  https://doi.org/10.1038/s41586-024-08518-2
  19. Nat Commun. 2025 Feb 10. 16(1): 1489
    Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis.
    Raquel A Martínez García de la Torre, Julia Vallverdú, Zhenqing Xu, Silvia Ariño, Raquel Ferrer-Lorente, Laura Zanatto, Maria Mercado-Gómez, Beatriz Aguilar-Bravo, Paloma Ruiz-Blázquez, Maria Fernandez-Fernandez, Artur Navarro-Gascon, Albert Blasco-Roset, Paula Sànchez-Fernàndez-de-Landa, Joan Pera, Damia Romero-Moya, Paula Ayuso Garcia, Celia Martínez Sánchez, Laura Sererols Viñas, Paula Cantallops Vilà, Carmen I Cárcamo Giráldez, Andrew McQuillin, Marsha Y Morgan, Daniel Moya-Rull, Núria Montserrat, Delphine Eberlé, Bart Staels, Bénédicte Antoine, Mikel Azkargorta, Juan-José Lozano, Maria L Martínez-Chantar, Alessandra Giorgetti, Félix Elortza, Anna Planavila, Marta Varela-Rey, Ashwin Woodhoo, Antonio Zorzano, Isabel Graupera, Anna Moles, Mar Coll, Silvia Affo, Pau Sancho-Bru.
      Defining the trajectory of cells during differentiation and disease is key for uncovering the mechanisms driving cell fate and identity. However, trajectories of human cells remain largely unexplored due to the challenges of studying them with human samples. In this study, we investigate the proteome trajectory of iPSCs differentiation to hepatic stellate cells (diHSCs) and identify RORA as a key transcription factor governing the metabolic reprogramming of HSCs necessary for diHSCs' commitment, identity, and activation. Using RORA deficient iPSCs and pharmacologic interventions, we show that RORA is required for early differentiation and prevents diHSCs activation by reducing the high energetic state of the cells. While RORA knockout mice have enhanced fibrosis, RORA agonists rescue multi-organ fibrosis in in vivo models. Notably, RORA expression correlates negatively with liver fibrosis and HSCs activation markers in patients with liver disease. This study reveals that RORA regulates cell metabolic plasticity, important for mesoderm differentiation, pericyte quiescence, and fibrosis, influencing cell commitment and disease.
    DOI:  https://doi.org/10.1038/s41467-025-56024-4
  20. Nat Commun. 2025 Feb 10. 16(1): 1488
    Intercellular bridges are essential for transposon repression and meiosis in the male germline.
    Julia Sorkin, Kevin Tilton, Matthew A Lawlor, Shreya N Sarathy, Shun Liang, Angelina Albanese, Mashiat Rabbani, Saher S Hammoud, Christopher E Ellison, Florencia Pratto, Devanshi Jain.
      Germ cell connectivity via intercellular bridges is a widely conserved feature across metazoans. However, its functional significance is poorly understood. Intercellular bridges are essential for fertility in male mice as genetic ablation of a critical bridge component, TEX14, causes spermatogenic failure, but the underlying reasons are unknown. Here we utilized a Tex14 hypomorph with reduced intercellular bridges along with Tex14-null mice that completely lack bridges to examine the roles of germ cell connectivity during spermatogenesis. We report that in males deficient for TEX14 and intercellular bridges, germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair. They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis. Single-cell RNA-sequencing confirms sharing of transcripts between wild-type spermatids and demonstrates its partial attenuation in Tex14 hypomorphs, indicating that intercellular bridges enable cytoplasmic exchange between connected germ cells in testes. Our findings suggest that regulation of meiosis is non-cell-intrinsic and inform a model in which intercellular bridges influence critical meiotic events and protect germline genome integrity during spermatogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-56742-9
  21. Mol Cell. 2025 Feb 07. pii: S1097-2765(25)00047-4. [Epub ahead of print]
    The integrated stress response regulates 18S nonfunctional rRNA decay in mammals.
    Aaztli R Coria, Akruti Shah, Mohammad Shafieinouri, Sarah J Taylor, Emilien Orgebin, Wilfried Guiblet, Jennifer T Miller, Indra Mani Sharma, Colin Chih-Chien Wu.
      18S nonfunctional rRNA decay (NRD) detects and eliminates translationally nonfunctional 18S rRNA. Although this process is critical for ribosome quality control, the mechanisms underlying nonfunctional 18S rRNA turnover remain elusive, particularly in mammals. Here, we show that mammalian 18S NRD initiates through the integrated stress response (ISR) via GCN2. Nonfunctional 18S rRNA induces translational arrest at start sites. Biochemical analyses demonstrate that ISR activation limits translation initiation and attenuates collisions between scanning 43S preinitiation complexes and stalled nonfunctional ribosomes. The ISR promotes 18S NRD and 40S ribosomal protein turnover by RNF10-mediated ubiquitination. Ultimately, RIOK3 binds the resulting ubiquitinated 40S subunits and facilitates 18S rRNA decay. Overall, mammalian 18S NRD acts through GCN2, followed by ubiquitin-dependent 18S rRNA degradation involving the ubiquitin E3 ligase RNF10 and the atypical protein kinase RIOK3. These findings establish a dynamic feedback mechanism by which the GCN2-RNF10-RIOK3 axis surveils ribosome functionality at the translation initiation step.
    Keywords:  GCN2; RIOK3; integrated stress response; nonfunctional 18S rRNA; ribosome stalling
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.017
  22. Nat Aging. 2025 Feb 13.
    An mTOR paradox in sarcopenia via BCAA catabolism.
    Jerome N Feige.
      
    DOI:  https://doi.org/10.1038/s43587-025-00815-3
  23. Nat Commun. 2025 Feb 10. 16(1): 1483
    Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis.
    Qingwen Zhao, Xuan Cui, Qi Zhu, Feiyan Li, Ran Bao, Ting Shi, Haojie Liu, Wenjing Lv, Yingjiang Xu, Yue Gao, Qi-Qun Tang, Min Zhang, Dongning Pan.
      Lysine methyltransferase KMT5C catalyzes deposition of trimethylation on histone H4 lysine 20 (H4K20me3), an epigenetic marker usually associated with gene repression and maintenance of heterochromatin. KMT5C is widely expressed in a variety of tissues, however, its functional role in liver has not been explored. Here, we show Kmt5c is a fasting- and glucagon-induced gene in liver which regulates hepatic gluconeogenesis. Loss of KMT5C in hepatocytes results in downregulated gluconeogenic gene expression and compromised glucose output during fasting. KMT5C fosters gluconeogenesis through decreasing ubiquitination-mediated PGC-1α degradation, which is unexpectedly independent of its methyltransferase activity. In fact, KMT5C impedes the E3 ligase RNF34 binding to the C-terminal of PGC-1α and subsequent ubiquitination-associated degradation. The diabetic mice models and patients show elevated KMT5C levels in the livers, and KMT5C knockdown beneficially reduces gluconeogenesis and fasting blood glucose levels. In conclusion, the present study identifies KMT5C as a hepatic gluconeogenesis regulator by affecting PGC-1α stability.
    DOI:  https://doi.org/10.1038/s41467-025-56696-y
  24. Sci Immunol. 2025 Feb 14. 10(104): eado5937
    Linking vaccine adjuvant mechanisms of action to function.
    Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J Irvine.
      Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.
    DOI:  https://doi.org/10.1126/sciimmunol.ado5937
  25. Science. 2025 Jan 02. 387(6735): 750-758
    Thalamic opioids from POMC satiety neurons switch on sugar appetite.
    Marielle Minère, Hannah Wilhelms, Bojana Kuzmanovic, Sofia Lundh, Debora Fusca, Alina Claßen, Stav Shtiglitz, Yael Prilutski, Itay Talpir, Lin Tian, Brigitte Kieffer, Jon Davis, Peter Kloppenburg, Marc Tittgemeyer, Yoav Livneh, Henning Fenselau.
      High sugar-containing foods are readily consumed, even after meals and beyond fullness sensation (e.g., as desserts). Although reward-driven processing of palatable foods can promote overeating, the neurobiological mechanisms that underlie the selective appetite for sugar in states of satiety remain unclear. Hypothalamic pro-opiomelanocortin (POMC) neurons are principal regulators of satiety because they decrease food intake through excitatory melanocortin neuropeptides. We discovered that POMC neurons not only promote satiety in fed conditions but concomitantly switch on sugar appetite, which drives overconsumption. POMC neuron projections to the paraventricular thalamus selectively inhibited postsynaptic neurons through mu-opioid receptor signaling. This opioid circuit was strongly activated during sugar consumption, which was most notable in satiety states. Correspondingly, inhibiting its activity diminished high-sugar diet intake in sated mice.
    DOI:  https://doi.org/10.1126/science.adp1510
  26. Nat Rev Immunol. 2025 Feb 12.
    HDAC9 association with heart disease linked to NLRP3 inflammasome activation.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01144-7
  27. Nature. 2025 Feb;638(8050): 308-310
    Dozens of new obesity drugs are coming: these are the ones to watch.
    Elie Dolgin.
      
    Keywords:  Drug discovery; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-00404-9
  28. Nature. 2025 Feb;638(8050): 321
    Scientific societies need to modernize.
    Osvaldo Eric Ramirez-Bravo.
      
    Keywords:  Careers; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-025-00434-3
  29. Nat Commun. 2025 Feb 11. 16(1): 1550
    Accelerated epigenetic aging in Huntington's disease involves polycomb repressive complex 1.
    Baptiste Brulé, Rafael Alcalá-Vida, Noémie Penaud, Jil Scuto, Coline Mounier, Jonathan Seguin, Sina Vincent Khodaverdian, Brigitte Cosquer, Etienne Birmelé, Stéphanie Le Gras, Charles Decraene, Anne-Laurence Boutillier, Karine Merienne.
      Loss of epigenetic information during physiological aging compromises cellular identity, leading to de-repression of developmental genes. Here, we assessed the epigenomic landscape of vulnerable neurons in two reference mouse models of Huntington neurodegenerative disease (HD), using cell-type-specific multi-omics, including temporal analysis at three disease stages via FANS-CUT&Tag. We show accelerated de-repression of developmental genes in HD striatal neurons, involving histone re-acetylation and depletion of H2AK119 ubiquitination and H3K27 trimethylation marks, which are catalyzed by polycomb repressive complexes 1 and 2 (PRC1 and PRC2), respectively. We further identify a PRC1-dependent subcluster of bivalent developmental transcription factors that is re-activated in HD striatal neurons. This mechanism likely involves progressive paralog switching between PRC1-CBX genes, which promotes the upregulation of normally low-expressed PRC1-CBX2/4/8 isoforms in striatal neurons, alongside the down-regulation of predominant PRC1-CBX isoforms in these cells (e.g., CBX6/7). Collectively, our data provide evidence for PRC1-dependent accelerated epigenetic aging in HD vulnerable neurons.
    DOI:  https://doi.org/10.1038/s41467-025-56722-z
  30. Nature. 2025 Feb 13.
    Are PhDs losing their lustre? Why fewer students are enrolling in doctoral degrees.
    Diana Kwon.
      
    Keywords:  Government; Institutions; Policy
    DOI:  https://doi.org/10.1038/d41586-025-00425-4
  31. Nat Commun. 2025 Feb 12. 16(1): 1586
    Oligonucleotide subsets selection by single nucleotide resolution barcode identification.
    Woojin Kim, Mingweon Chon, Yoonhae Koh, Hansol Choi, Eunjin Choi, Hyewon Park, Yushin Jung, Taehoon Ryu, Sunghoon Kwon, Yeongjae Choi.
      Effective subset selection from complex oligonucleotide libraries is crucial for genomics, synthetic biology, and DNA data storage. The polymerase chain reaction, foundational for amplifying target subsets is limited by primer design and length for specificity, which constrains the scalability of oligo libraries and increases the synthesis burden for primers. We introduce an oligo subset selection methodology that utilizes sequence-specific cyclic nucleotide synthesis and blocking of the template oligos. This approach eliminates the need for primers for selective hybridization and enables the encoding and selection of hundreds of subsets with barcode lengths of fewer than five nucleotides. Moreover, cyclic selection enables a hierarchical data structure in the oligo library, enhancing the programmability. This advancement offers a scalable and cost-effective solution for handling complex oligo libraries.
    DOI:  https://doi.org/10.1038/s41467-025-56856-0
  32. Nature. 2025 Feb 10.
    'Devastating' cuts to NIH grants by Trump's team put on hold by US judge.
    Max Kozlov, Dan Garisto, Heidi Ledford.
      
    Keywords:  Funding; Government; Institutions; Law; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00436-1
  33. Nature. 2025 Feb 13.
    Are the Trump team's actions affecting your research? How to contact Nature.
      
    Keywords:  Funding; Government; Policy; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-00479-4
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