bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–05–25
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Extending Minds with Generative AI.
  2. Clonal tracing with somatic epimutations reveals dynamics of blood ageing.
  3. Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis.
  4. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.
  5. Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation.
  6. Releasing the brakes on phagosomes.
  7. Smaller Pancreas Volume in Insulin-Dependent Monogenic Diabetes.
  8. Cholinergic regulation of thymocyte negative selection.
  9. Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
  10. Mice lacking this amino acid lost 30% of their body weight.
  11. Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
  12. A dynamic and multimodal framework to define microglial states.
  13. A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning.
  14. Programmable control of spatial transcriptome in live cells and neurons.
  15. DNA replication timing reveals genome-wide features of transcription and fragility.
  16. Human mitochondrial DNA in public metagenomes: Opportunity or privacy threat?
  17. Powerful CRISPR system inserts whole gene into human DNA.
  18. An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration.
  19. Intestinal neuron-associated macrophages in health and disease.
  20. GLP-1R agonists protect against Alzheimer's disease by rewiring energy regulation.
  21. AI listens for health conditions.
  22. Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.
  23. Unravelling cysteine-deficiency-associated rapid weight loss.
  24. CellWalker2: Multi-omic discovery using hierarchical cell type relationships.
  25. Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity.
  1. Nat Commun. 2025 May 19. 16(1): 4627
    Extending Minds with Generative AI.
    Andy Clark.
      
    DOI:  https://doi.org/10.1038/s41467-025-59906-9
  2. Nature. 2025 May 21.
    Clonal tracing with somatic epimutations reveals dynamics of blood ageing.
    Michael Scherer, Indranil Singh, Martina Maria Braun, Chelsea Szu-Tu, Pedro Sanchez Sanchez, Dominik Lindenhofer, Niels Asger Jakobsen, Verena Körber, Michael Kardorff, Lena Nitsch, Pauline Kautz, Julia Rühle, Agostina Bianchi, Luca Cozzuto, Robert Frömel, Sergi Beneyto-Calabuig, Caleb Lareau, Ansuman T Satpathy, Renée Beekman, Lars M Steinmetz, Simon Raffel, Leif S Ludwig, Paresh Vyas, Alejo Rodriguez-Fraticelli, Lars Velten.
      Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
    DOI:  https://doi.org/10.1038/s41586-025-09041-8
  3. Nat Aging. 2025 May 19.
    Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis.
    Chuantao Tu, Cheng Qian, Shuyu Li, De-Ying Lin, Zhi-Yang Liu, Wan-Gan Ouyang, Xin-Lei Kang, Fangyuan Chen, Shu Song, Shi-Qing Cai.
      With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.
    DOI:  https://doi.org/10.1038/s43587-025-00862-w
  4. Nat Aging. 2025 May 16.
    Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.
    ALLFTD Consortium
      The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00878-2
  5. Nat Cell Biol. 2025 May 22.
    Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation.
    Subhash B Arya, Samuel P Collie, Yang Xu, Martin Fernandez, Jonathan Z Sexton, Shyamal Mosalaganti, Pierre A Coulombe, Carole A Parent.
      Acute inflammation, characterized by a rapid influx of neutrophils, is a protective response that can lead to chronic inflammatory diseases when left unresolved. We previously showed that secretion of LTB4-containing exosomes via nuclear envelope-derived multivesicular bodies is required for effective neutrophil infiltration during inflammation. Here we report that the co-secretion of these exosomes with nuclear DNA facilitates the resolution of the neutrophil infiltrate in a mouse skin model of sterile inflammation. Activated neutrophils exhibit rapid and repetitive DNA secretion as they migrate directionally using a mechanism distinct from suicidal neutrophil extracellular trap release and cell death. Packaging of DNA in the lumen of nuclear envelope-multivesicular bodies is mediated by lamin B receptor and chromatin decondensation. These findings advance our understanding of neutrophil functions during inflammation and the physiological relevance of DNA secretion.
    DOI:  https://doi.org/10.1038/s41556-025-01671-4
  6. Nat Rev Immunol. 2025 May 21.
    Releasing the brakes on phagosomes.
    John Benjamin W Duncan, Kelsey Voss.
      
    DOI:  https://doi.org/10.1038/s41577-025-01189-8
  7. Diabetes. 2025 May 22. pii: db250318. [Epub ahead of print]
    Smaller Pancreas Volume in Insulin-Dependent Monogenic Diabetes.
    Jonathan M Williams, Melissa A Hilmes, Lisa R Letourneau-Freiberg, Balamurugan Kandasamy, Demetra Braun, Siri Atma W Greeley, Louis Philipson, Alvin C Powers, John Virostko, Daniel J Moore, Jordan J Wright.
       ARTICLE HIGHLIGHTS: Individuals with type 1 diabetes (T1D) have a markedly smaller pancreas, but the mechanism responsible for the reduction in size is unknown. How pancreas volume differs in individuals with specific forms of monogenic diabetes and how pancreas volume relates to the severity of insulin deficiency are unknown. Measured by MRI, individuals with permanent neonatal diabetes due to an INS gene mutation (INS-PND) or the HNF1B gene associated with maturity onset diabetes of the young had smaller pancreas than individuals without diabetes. Across all types of monogenic diabetes, individuals receiving insulin replacement therapy had smaller pancreas than individuals not using insulin. These results support the conclusion that insulin deficiency is a major factor contributing to changes in pancreas volume in T1D, INS-PND, and other forms of monogenic diabetes.
    DOI:  https://doi.org/10.2337/db25-0318
  8. Nat Immunol. 2025 May 21.
    Cholinergic regulation of thymocyte negative selection.
    Shaofeng Liu, Chunxing Zheng, Robert Nechanitzky, Ping Luo, Parameswaran Ramachandran, Dat Nguyen, Andrew J Elia, Soode Moghadas Jafari, Rhoda Law, Bryan E Snow, Andrew C Wakeham, Thorsten Berger, Hui Chen, Kyle T Gill, Ryan Mcwilliam, Jerome Fortin, Nastaran Fazel Modares, Mary E Saunders, Kiichi Murakami, Yangmin Qiu, Zhiwei You, Mahmood Mohtashami, Hai Qi, Pamela S Ohashi, Juan Carlos Zúñiga-Pflücker, Tak W Mak.
      The immune and nervous systems use a common chemical language for communication, namely, the cholinergic signaling involving acetylcholine (ACh) and its receptors (AChRs). Whether and how this language also regulates the development of the immune system is poorly understood. Here, we show that mouse CD4+CD8+ double-positive thymocytes express high levels of α9 nicotinic AChR (nAChR) and that this receptor controls thymic negative selection. α9 nAChR-deficient mice show an altered T cell receptor (TCR) repertoire and reduced CD4+ and CD8+ T cells in a mixed bone marrow chimera setting. α9 nAChR-mediated signaling regulates TCR strength and thymocyte survival. Thymic tuft cells, B cells and some T cells express choline acetyltransferase and are potential ACh sources, with ACh derived from T cells having the most important role. Furthermore, α9 nAChR deficiency during thymocyte development contributes to the altered development of autoimmune diseases in mice. Our results thus reveal a mechanism controlling immune cell development that involves cholinergic signaling.
    DOI:  https://doi.org/10.1038/s41590-025-02152-4
  9. Nat Neurosci. 2025 May 22.
    Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration.
    Janos Groh, Ruoqing Feng, Xidi Yuan, Lu Liu, Dennis Klein, Gladis Hutahaean, Elisabeth Butz, Zhen Wang, Lisa Steinbrecher, Jonas Neher, Rudolf Martini, Mikael Simons.
      Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial-immune interactions. Mechanistically, we show that the CXCL10-CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.
    DOI:  https://doi.org/10.1038/s41593-025-01955-w
  10. Nature. 2025 May 21.
    Mice lacking this amino acid lost 30% of their body weight.
    Rachel Fieldhouse.
      
    Keywords:  Diabetes; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-01597-9
  11. Nat Commun. 2025 May 20. 16(1): 4640
    Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
    Jordyn J VanPortfliet, Yuanjiu Lei, Muthumeena Ramanathan, Camila Guerra Martinez, Jessica Wong, Tim J Stodola, Brian R Hoffmann, Kathryn Pflug, Raquel Sitcheran, Stephen C Kneeland, Stephen A Murray, Peter J McGuire, Carolyn L Cannon, A Phillip West.
      Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.
    DOI:  https://doi.org/10.1038/s41467-025-59907-8
  12. Nat Neurosci. 2025 May 20.
    A dynamic and multimodal framework to define microglial states.
    Roman Sankowski, Marco Prinz.
      The widespread use of single-cell RNA sequencing has generated numerous purportedly distinct and novel subsets of microglia. Here, we challenge this fragmented paradigm by proposing that microglia exist along a continuum rather than as discrete entities. We identify a methodological over-reliance on computational clustering algorithms as the fundamental issue, with arbitrary cluster numbers being interpreted as biological reality. Evidence suggests that the observed transcriptional diversity stems from a combination of microglial plasticity and technical noise, resulting in terminology describing largely overlapping cellular states. We introduce a continuous model of microglial states, where cell positioning along the continuum is determined by biological aging and cell-specific molecular contexts. The model accommodates the dynamic nature of microglia. We advocate for a parsimonious approach toward classification and terminology that acknowledges the continuous spectrum of microglial states, toward a robust framework for understanding these essential immune cells of the CNS.
    DOI:  https://doi.org/10.1038/s41593-025-01978-3
  13. Nat Commun. 2025 May 18. 16(1): 4617
    A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning.
    Soohyun Kim, Caelan E Radford, Duo Xu, Jianing Zhong, Jonathan Do, Dominic M Pham, Katie A Travisano, Maria V Filsinger Interrante, Theodora U J Bruun, Valerie Rezek, Bailey Wilder, Martina Palomares, Michael S Seaman, Scott G Kitchen, Jesse D Bloom, Peter S Kim.
      Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.
    DOI:  https://doi.org/10.1038/s41467-025-60035-6
  14. Nature. 2025 May 21.
    Programmable control of spatial transcriptome in live cells and neurons.
    Mengting Han, Maylin L Fu, Yanyu Zhu, Alexander A Choi, Emmy Li, Jon Bezney, Sa Cai, Leann Miles, Yitong Ma, Lei S Qi.
      Spatial RNA organization has a pivotal role in diverse cellular processes and diseases1-4. However, functional implications of the spatial transcriptome remain largely unexplored due to limited technologies for perturbing endogenous RNA within specific subcellular regions1,5. Here we present CRISPR-mediated transcriptome organization (CRISPR-TO), a system that harnesses RNA-guided, nuclease-dead dCas13 for programmable control of endogenous RNA localization in live cells. CRISPR-TO enables targeted localization of endogenous RNAs to diverse subcellular compartments, including the outer mitochondrial membrane, p-bodies, stress granules, telomeres and nuclear stress bodies, across various cell types. It allows for inducible and reversible bidirectional RNA transport along microtubules via motor proteins, facilitating real-time manipulation and monitoring of RNA localization dynamics in living cells. In primary cortical neurons, we demonstrate that repositioned mRNAs undergo local translation along neurites and at neurite tips, and co-transport with ribosomes, with β-actin mRNA localization enhancing the formation of dynamic filopodial protrusions and inhibiting axonal regeneration. CRISPR-TO-enabled screening in primary neurons identifies Stmn2 mRNA localization as a driver of neurite outgrowth. By enabling large-scale perturbation of the spatial transcriptome, CRISPR-TO bridges a critical gap left by sequencing and imaging technologies, offering a versatile platform for high-throughput functional interrogation of RNA localization in living cells and organisms.
    DOI:  https://doi.org/10.1038/s41586-025-09020-z
  15. Nat Commun. 2025 May 19. 16(1): 4658
    DNA replication timing reveals genome-wide features of transcription and fragility.
    Francisco Berkemeier, Peter R Cook, Michael A Boemo.
      DNA replication in humans requires precise regulation to ensure accurate genome duplication and maintain genome integrity. A key indicator of this regulation is replication timing, which reflects the interplay between origin firing and fork dynamics. We present a high-resolution (1-kilobase) mathematical model that infers firing rate distributions from Repli-seq timing data across multiple cell lines, enabling a genome-wide comparison between predicted and observed replication. Notably, regions where the model and data diverge often overlap fragile sites and long genes, highlighting the influence of genomic architecture on replication dynamics. Conversely, regions of strong concordance are associated with open chromatin and active promoters, where elevated firing rates facilitate timely fork progression and reduce replication stress. In this work, we provide a valuable framework for exploring the structural interplay between replication timing, transcription, and chromatin organisation, offering insights into the mechanisms underlying replication stress and its implications for genome stability and disease.
    DOI:  https://doi.org/10.1038/s41467-025-59991-w
  16. Cell. 2025 May 15. pii: S0092-8674(25)00296-X. [Epub ahead of print]188(10): 2561-2566
    Human mitochondrial DNA in public metagenomes: Opportunity or privacy threat?
    Mohamed S Sarhan, Giacomo Antonello, Hansi Weissensteiner, Claudia Mengoni, Deborah Mascalzoni, Levi Waldron, Nicola Segata, Christian Fuchsberger.
      Human DNA is unavoidably present in metagenomic analyses of human microbiomes. While current protocols remove human DNA before submission to public repositories, mitochondrial DNA (mtDNA) has been overlooked and frequently persists. We discuss the privacy risks and research opportunities associated with mtDNA, urging consideration by the scientific, ethics, and legal communities.
    DOI:  https://doi.org/10.1016/j.cell.2025.03.023
  17. Nature. 2025 May 15.
    Powerful CRISPR system inserts whole gene into human DNA.
    Elie Dolgin.
      
    Keywords:  CRISPR-Cas9 genome editing; Gene therapy; Microbiology
    DOI:  https://doi.org/10.1038/d41586-025-01518-w
  18. Nat Commun. 2025 May 20. 16(1): 4441
    An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration.
    Matthew J Leventhal, Camila A Zanella, Byunguk Kang, Jiajie Peng, David Gritsch, Zhixiang Liao, Hassan Bukhari, Tao Wang, Ping-Chieh Pao, Serwah Danquah, Joseph Benetatos, Ralda Nehme, Samouil Farhi, Li-Huei Tsai, Xianjun Dong, Clemens R Scherzer, Mel B Feany, Ernest Fraenkel.
      Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in humans. We then used a network model to integrate these data with previously published Alzheimer's disease proteomics, lipidomics and genomics. Here, we computationally predict and experimentally confirm how HNRNPA2B1 and MEPCE enhance toxicity of the tau protein, a pathological feature of Alzheimer's disease. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human stem cell-derived neural progenitor cells. Our study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41467-025-59654-w
  19. Nat Immunol. 2025 May 21.
    Intestinal neuron-associated macrophages in health and disease.
    Nathalie Stakenborg, Maria Francesca Viola, Guy Boeckxstaens.
      Neuron-macrophage cross-talk in the intestine plays a crucial role in the maintenance of tissue homeostasis and the modulation of immune responses throughout life. Here, we describe how gut neuron-macrophage interactions shift macrophage phenotype and function from early development to adulthood and how this cross-talk modulates the macrophage function in response to infection and inflammation. We highlight how a neural microenvironment instructs a neuron-associated macrophage phenotype in the gut and show that their phenotype may resemble nerve-associated macrophages in other organs. Finally, we note that the loss of neuron-associated macrophages or a shift in their phenotype can contribute to enteric neurodegeneration in the gastrointestinal tract, causing gut motility disorders.
    DOI:  https://doi.org/10.1038/s41590-025-02150-6
  20. Nat Aging. 2025 May 20.
    GLP-1R agonists protect against Alzheimer's disease by rewiring energy regulation.
    Daxiang Na, Marc Schneeberger Pané.
      
    DOI:  https://doi.org/10.1038/s43587-025-00881-7
  21. Nature. 2025 May 22.
    AI listens for health conditions.
    Neil Savage.
      
    Keywords:  Diabetes; Diseases; Health care; Machine learning; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01598-8
  22. Nat Commun. 2025 May 18. 16(1): 4621
    Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.
    HPAP Consortium
      Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq. Compared to ND pancreas-draining lymph nodes (pLN), AAb+ and T1D donor pLNs display decreased CD4+ Treg and increased stem-like CD8+ T cell signatures, while only T1D donor pLNs exhibit naive T cell and NK cell differentiation. Mesenteric LNs have modulations only in CD4+ Tregs and naive cells, while splenocytes lack these perturbations. Further, T cell expression of activation markers and IL7 receptor correlate with T1D genetic risk. These results demonstrate tissue-restricted immune changes occur before and after T1D onset.
    DOI:  https://doi.org/10.1038/s41467-025-59626-0
  23. Nature. 2025 May 21.
    Unravelling cysteine-deficiency-associated rapid weight loss.
    Alan Varghese, Ivan Gusarov, Begoña Gamallo-Lana, Daria Dolgonos, Yatin Mankan, Ilya Shamovsky, Mydia Phan, Rebecca Jones, Maria Gomez-Jenkins, Eileen White, Rui Wang, Drew R Jones, Thales Papagiannakopoulos, Michael E Pacold, Adam C Mar, Dan R Littman, Evgeny Nudler.
      Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.
    DOI:  https://doi.org/10.1038/s41586-025-08996-y
  24. Cell Genom. 2025 May 20. pii: S2666-979X(25)00142-9. [Epub ahead of print] 100886
    CellWalker2: Multi-omic discovery using hierarchical cell type relationships.
    Zhirui Hu, Pawel F Przytycki, Katherine S Pollard.
      Tissues are composed of cells with a wide range of similarities to each other, yet existing methods for single-cell genomics treat cell types as discrete labels. To address this gap, we developed CellWalker2, a graph diffusion-based model for the annotation and mapping of multi-modal data. With our open-source software package, hierarchically related cell types can be probabilistically matched across contexts and used to annotate cells, genomic regions, or gene sets. Additional features include estimating statistical significance and enabling gene expression and chromatin accessibility to be jointly modeled. Through simulation studies, we show that CellWalker2 performs better than existing methods in cell-type annotation and mapping. We then use multi-omics data from the brain and immune system to demonstrate CellWalker2's ability to assign high-resolution cell-type labels to regulatory elements and TFs and to quantify both conserved and divergent cell-type relationships between species.
    Keywords:  cell type; comparative genomics; gene regulation; graph; hierarchical; multi-omics; single cell; transcription factors
    DOI:  https://doi.org/10.1016/j.xgen.2025.100886
  25. Nat Commun. 2025 May 23. 16(1): 4786
    Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity.
    Michael Kosicki, Dianne Laboy Cintrón, Pia Keukeleire, Max Schubach, Nicholas F Page, Ilias Georgakopoulos-Soares, Jennifer A Akiyama, Ingrid Plajzer-Frick, Catherine S Novak, Momoe Kato, Riana D Hunter, Kianna von Maydell, Sarah Barton, Patrick Godfrey, Erik Beckman, Stephan J Sanders, Martin Kircher, Len A Pennacchio, Nadav Ahituv.
      High-throughput massively parallel reporter assays (MPRAs) and phenotype-rich in vivo transgenic mouse assays are two potentially complementary ways to study the impact of noncoding variants associated with psychiatric diseases. Here, we investigate the utility of combining these assays. Specifically, we carry out an MPRA in induced human neurons on over 50,000 sequences derived from fetal neuronal ATAC-seq datasets and enhancers validated in mouse assays. We also test the impact of over 20,000 variants, including synthetic mutations and 167 common variants associated with psychiatric disorders. We find a strong and specific correlation between MPRA and mouse neuronal enhancer activity. Four out of five tested variants with significant MPRA effects affected neuronal enhancer activity in mouse embryos. Mouse assays also reveal pleiotropic variant effects that could not be observed in MPRA. Our work provides a catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.
    DOI:  https://doi.org/10.1038/s41467-025-60064-1
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