bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–09–22
forty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A B cell receptor variant confers evolutionary protection against pathogens.
  2. Brain goop that traps hunger neurons drives obesity.
  3. Obesity is driven by a build-up of molecular mesh around hunger neurons.
  4. Islands are rich with languages spoken nowhere else.
  5. Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.
  6. Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes in Caenorhabditis elegans.
  7. The UK's $1-billion bet to create technologies that change the world.
  8. Science-policy advisers shape programmes that solve real-world problems.
  9. Challenges and recommendations for the translation of biomarkers of aging.
  10. Chemical restriction of PU.1 genomic binding sites activates alternate gene networks.
  11. A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.
  12. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
  13. Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation.
  14. A brain circuit that cements the memory of socially learnt food preferences.
  15. Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity.
  16. β2 integrins impose a mechanical checkpoint on macrophage phagocytosis.
  17. Obesity-drug pioneers win prestigious Lasker Award for medical science.
  18. Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool.
  19. Clathrin-associated carriers enable recycling through a kiss-and-run mechanism.
  20. Where did viruses come from? AlphaFold and other AIs are finding answers.
  21. Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements.
  22. Is bird flu spreading among people? Data gaps leave researchers in the dark.
  23. Savoring the sandwich.
  24. N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation.
  25. Fasting shapes chromatin architecture through an mTOR/RNA Pol I axis.
  26. Identifying genetic variants associated with chromatin looping and genome function.
  27. Activation of the NLRP1B inflammasome by caspase-8.
  28. Quantifiable blood TCR repertoire components associate with immune aging.
  29. Gut microbes fend off harmful bacteria by depriving them of nutrients.
  30. DNA Methylation signatures underpinning blood neutrophil to lymphocyte ratio during first week of human life.
  31. Improving primary healthcare with generative AI.
  32. Dynamic allostery drives autocrine and paracrine TGF-β signaling.
  33. Daily briefing: Common diabetes drug slows monkey brain-ageing.
  34. Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity.
  35. Structural basis of CDNF interaction with the UPR regulator GRP78.
  36. Should young kids take the new anti-obesity drugs? What the research says.
  37. Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions.
  38. A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.
  39. A developmental route to hematopoietic stem cells.
  40. Risk Factors for Immune Checkpoint Inhibitor-Induced Diabetes Identified.
  41. Suppressing appetite with taurine.
  1. Nat Immunol. 2024 Sep 17.
    A B cell receptor variant confers evolutionary protection against pathogens.
      
    DOI:  https://doi.org/10.1038/s41590-024-01953-3
  2. Nature. 2024 Sep 18.
    Brain goop that traps hunger neurons drives obesity.
    Max Kozlov.
      
    Keywords:  Brain; Diabetes; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03025-w
  3. Nature. 2024 Sep 18.
    Obesity is driven by a build-up of molecular mesh around hunger neurons.
    Alexander Dityatev.
      
    Keywords:  Metabolism; Neuroscience; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-02325-5
  4. Nature. 2024 Sep;633(8030): 497
    Islands are rich with languages spoken nowhere else.
      
    Keywords:  Language
    DOI:  https://doi.org/10.1038/d41586-024-02873-w
  5. Nat Commun. 2024 Sep 14. 15(1): 8066
    Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation.
    Juan C Landoni, Semin Erkul, Tuomas Laalo, Steffi Goffart, Riikka Kivelä, Karlo Skube, Anni I Nieminen, Sara A Wickström, James Stewart, Anu Suomalainen.
      High mitochondrial DNA (mtDNA) amount has been reported to be beneficial for resistance and recovery of metabolic stress, while increased mtDNA synthesis activity can drive aging signs. The intriguing contrast of these two mtDNA boosting outcomes prompted us to jointly elevate mtDNA amount and frequency of replication in mice. We report that high activity of mtDNA synthesis inhibits perinatal metabolic maturation of the heart. The offspring of the asymptomatic parental lines are born healthy but manifest dilated cardiomyopathy and cardiac collapse during the first days of life. The pathogenesis, further enhanced by mtDNA mutagenesis, involves prenatal upregulation of mitochondrial integrated stress response and the ferroptosis-inducer MESH1, leading to cardiac fibrosis and cardiomyocyte death after birth. Our evidence indicates that the tight control of mtDNA replication is critical for early cardiac homeostasis. Importantly, ferroptosis sensitivity is a potential targetable mechanism for infantile-onset cardiomyopathy, a common manifestation of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52164-1
  6. Nat Commun. 2024 Sep 19. 15(1): 8237
    Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes in Caenorhabditis elegans.
    Bryan L Gitschlag, Claudia V Pereira, James P Held, David M McCandlish, Maulik R Patel.
      Cells possess multiple mitochondrial DNA (mtDNA) copies, which undergo semi-autonomous replication and stochastic inheritance. This enables mutant mtDNA variants to arise and selfishly compete with cooperative (wildtype) mtDNA. Selfish mitochondrial genomes are subject to selection at different levels: they compete against wildtype mtDNA directly within hosts and indirectly through organism-level selection. However, determining the relative contributions of selection at different levels has proven challenging. We overcome this challenge by combining mathematical modeling with experiments designed to isolate the levels of selection. Applying this approach to many selfish mitochondrial genotypes in Caenorhabditis elegans reveals an unexpected diversity of evolutionary mechanisms. Some mutant genomes persist at high frequency for many generations, despite a host fitness cost, by aggressively outcompeting cooperative genomes within hosts. Conversely, some mutant genomes persist by evading inter-organismal selection. Strikingly, the mutant genomes vary dramatically in their susceptibility to genetic drift. Although different mechanisms can cause high frequency of selfish mtDNA, we show how they give rise to characteristically different distributions of mutant frequency among individuals. Given that heteroplasmic frequency represents a key determinant of phenotypic severity, this work outlines an evolutionary theoretic framework for predicting the distribution of phenotypic consequences among individuals carrying a selfish mitochondrial genome.
    DOI:  https://doi.org/10.1038/s41467-024-52596-9
  7. Nature. 2024 Sep;633(8030): 512-514
    The UK's $1-billion bet to create technologies that change the world.
    Nisha Gaind.
      
    Keywords:  Funding; Policy
    DOI:  https://doi.org/10.1038/d41586-024-02995-1
  8. Nature. 2024 Sep 18.
    Science-policy advisers shape programmes that solve real-world problems.
    Amy DePaul.
      
    Keywords:  Careers; Policy; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-03040-x
  9. Nat Aging. 2024 Sep 16.
    Challenges and recommendations for the translation of biomarkers of aging.
    Biomarkers of Aging Consortium
      Biomarkers of aging (BOA) are quantitative parameters that predict biological age and ideally its changes in response to interventions. In recent years, many promising molecular and omic BOA have emerged with an enormous potential for translational geroscience and improving healthspan. However, clinical translation remains limited, in part due to the gap between preclinical research and the application of BOA in clinical research and other translational settings. We surveyed experts in these areas to better understand current challenges for the translation of aging biomarkers. We identified six key barriers to clinical translation and developed guidance for the field to overcome them. Core recommendations include linking BOA to clinically actionable insights, improving affordability and availability to broad populations and validation of biomarkers that are robust and responsive at the level of individuals. Our work provides key insights and practical recommendations to overcome barriers impeding clinical translation of BOA.
    DOI:  https://doi.org/10.1038/s43587-024-00683-3
  10. Nat Genet. 2024 Sep 18.
    Chemical restriction of PU.1 genomic binding sites activates alternate gene networks.
      
    DOI:  https://doi.org/10.1038/s41588-024-01912-6
  11. Nature. 2024 Sep 18.
    A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.
    Borja Ocón, Menglan Xiang, Yuhan Bi, Serena Tan, Kevin Brulois, Aiman Ayesha, Manali Kunte, Catherine Zhou, Melissa LaJevic, Nicole Lazarus, Francesca Mengoni, Tanya Sharma, Stephen Montgomery, Jody E Hooper, Mian Huang, Tracy Handel, John R D Dawson, Irina Kufareva, Brian A Zabel, Junliang Pan, Eugene C Butcher.
      Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon, and skin are known1 2, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues (NIMT) remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the NIMT and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25 is induced on innate lymphocytes prior to emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25 characterizes B and T tissue resident memory and regulatory T lymphocytes in NIMT and lungs in humans and mediates lymphocyte homing to barrier epithelia of the airways, oral cavity, stomach, biliary and genitourinary tracts in mouse models. GPR25 is also expressed by T cells in cerebrospinal fluid and CXCL17 by neurons, suggesting a role in CNS immune regulation. We reveal widespread imprinting of GPR25 on regulatory T cells, suggesting a mechanistic link to population genetic evidence that GPR25 is protective in autoimmunity3,4. Our results define a GPR25-CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.
    DOI:  https://doi.org/10.1038/s41586-024-08043-2
  12. Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]
    Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.
      Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
    Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2024.08.029
  13. Nat Commun. 2024 Sep 18. 15(1): 8179
    Activation of osmo-sensitive LRRC8 anion channels in macrophages is important for micro-crystallin joint inflammation.
    Twinu Wilson Chirayath, Matthias Ollivier, Mete Kayatekin, Isabelle Rubera, Chinh Nghia Pham, Jonas Friard, Nathalie Linck, Hélene Hirbec, Christèle Combes, Mylène Zarka, Frédéric Lioté, Pascal Richette, Francois Rassendren, Vincent Compan, Christophe Duranton, Hang Korng Ea.
      Deposition of monosodium urate and calcium pyrophosphate (MSU and CPP) micro-crystals is responsible for painful and recurrent inflammation flares in gout and chondrocalcinosis. In these pathologies, the inflammatory reactions are due to the activation of macrophages responsible for releasing various cytokines including IL-1β. The maturation of IL-1β is mediated by the multiprotein NLRP3 inflammasome. Here, we find that activation of the NLRP3 inflammasome by crystals and concomitant production of IL-1β depend on cell volume regulation via activation of the osmo-sensitive LRRC8 anion channels. Both pharmacological inhibition and genetic silencing of LRRC8 abolish NLRP3 inflammasome activation by crystals in vitro and in mouse models of crystal-induced inflammation. Activation of LRRC8 upon MSU/CPP crystal exposure induces ATP release, P2Y receptor activation and intracellular calcium increase necessary for NLRP3 inflammasome activation and IL-1β maturation. We identify a function of the LRRC8 osmo-sensitive anion channels with pathophysiological relevance in the context of joint crystal-induced inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-52543-8
  14. Nature. 2024 Sep 18.
    A brain circuit that cements the memory of socially learnt food preferences.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03012-1
  15. Nat Commun. 2024 Sep 17. 15(1): 8158
    Endolysosomal dysfunction in radial glia progenitor cells leads to defective cerebral angiogenesis and compromised blood-brain barrier integrity.
    Ivan Bassi, Moshe Grunspan, Gideon Hen, Kishore A Ravichandran, Noga Moshe, Laura Gutierrez-Miranda, Stav R Safriel, Daria Kostina, Amitay Shen, Carmen Ruiz de Almodovar, Karina Yaniv.
      The neurovascular unit (NVU) is a complex multicellular structure that helps maintain cerebral homeostasis and blood-brain barrier (BBB) integrity. While extensive evidence links NVU alterations to cerebrovascular diseases and neurodegeneration, the underlying molecular mechanisms remain unclear. Here, we use zebrafish embryos carrying a mutation in Scavenger Receptor B2, a highly conserved endolysosomal protein expressed predominantly in Radial Glia Cells (RGCs), to investigate the interplay among different NVU components. Through live imaging and genetic manipulations, we demonstrate that compromised acidification of the endolysosomal compartment in mutant RGCs leads to impaired Notch3 signaling, thereby inducing excessive neurogenesis and reduced glial differentiation. We further demonstrate that alterations to the neuron/glia balance result in impaired VEGF and Wnt signaling, leading to severe vascular defects, hemorrhages, and a leaky BBB. Altogether, our findings provide insights into NVU formation and function and offer avenues for investigating diseases involving white matter defects and vascular abnormalities.
    DOI:  https://doi.org/10.1038/s41467-024-52365-8
  16. Nat Commun. 2024 Sep 18. 15(1): 8182
    β2 integrins impose a mechanical checkpoint on macrophage phagocytosis.
    Alexander H Settle, Benjamin Y Winer, Miguel M de Jesus, Lauren Seeman, Zhaoquan Wang, Eric Chan, Yevgeniy Romin, Zhuoning Li, Matthew M Miele, Ronald C Hendrickson, Daan Vorselen, Justin S A Perry, Morgan Huse.
      Phagocytosis is an intensely physical process that depends on the mechanical properties of both the phagocytic cell and its chosen target. Here, we employed differentially deformable hydrogel microparticles to examine the role of cargo rigidity in the regulation of phagocytosis by macrophages. Whereas stiff cargos elicited canonical phagocytic cup formation and rapid engulfment, soft cargos induced an architecturally distinct response, characterized by filamentous actin protrusions at the center of the contact site, slower cup advancement, and frequent phagocytic stalling. Using phosphoproteomics, we identified β2 integrins as critical mediators of this mechanically regulated phagocytic switch. Macrophages lacking β2 integrins or their downstream effectors, Talin1 and Vinculin, exhibited specific defects in phagocytic cup architecture and selective suppression of stiff cargo uptake. We conclude that integrin signaling serves as a mechanical checkpoint during phagocytosis to pair cargo rigidity to the appropriate mode of engulfment.
    DOI:  https://doi.org/10.1038/s41467-024-52453-9
  17. Nature. 2024 Sep 19.
    Obesity-drug pioneers win prestigious Lasker Award for medical science.
    Mariana Lenharo.
      
    Keywords:  Drug discovery; Health care; Medical research; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-03078-x
  18. Sci Adv. 2024 Sep 20. 10(38): eadn3816
    Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool.
    Julia Fröse, Jennifer Rowley, Ali Salehi Farid, Taha Rakhshandehroo, Paul Leclerc, Howard Mak, Harris Allen, Heydar Moravej, Leila Munaretto, Luis Millan-Barea, Elisabeth Codet, Hannah Glockner, Caron Jacobson, Michael Hemann, Mohammad Rashidian.
      CAR T cell therapy has revolutionized the treatment of a spectrum of blood-related malignancies. However, treatment responses vary among cancer types and patients. Accurate monitoring of CAR T cell dynamics is crucial for understanding and evaluating treatment efficacy. Positron emission tomography (PET) offers a comprehensive view of CAR T cell homing, especially in critical organs such as lymphoid structures and bone marrow. This information will help assess treatment response and predict relapse risk. Current PET imaging methods for CAR T require genetic modifications, limiting clinical use. To overcome this, we developed an antigen-based imaging approach enabling whole-body CAR T cell imaging. The probe detects CAR T cells in vivo without affecting their function. In an immunocompetent B cell leukemia model, CAR-PET signal in the spleen predicted early mortality risk. The antigen-based CAR-PET approach allows assessment of CAR T therapy responses without altering established clinical protocols. It seamlessly integrates with FDA-approved and future CAR T cell generations, facilitating broader clinical application.
    DOI:  https://doi.org/10.1126/sciadv.adn3816
  19. Nat Cell Biol. 2024 Sep 19.
    Clathrin-associated carriers enable recycling through a kiss-and-run mechanism.
    Jiachao Xu, Yu Liang, Nan Li, Song Dang, Amin Jiang, Yiqun Liu, Yuting Guo, Xiaoyu Yang, Yi Yuan, Xinyi Zhang, Yaran Yang, Yongtao Du, Anbing Shi, Xiaoyun Liu, Dong Li, Kangmin He.
      Endocytosis and recycling control the uptake and retrieval of various materials, including membrane proteins and lipids, in all eukaryotic cells. These processes are crucial for cell growth, organization, function and environmental communication. However, the mechanisms underlying efficient, fast endocytic recycling remain poorly understood. Here, by utilizing a biosensor and imaging-based screening, we uncover a recycling mechanism that couples endocytosis and fast recycling, which we name the clathrin-associated fast endosomal recycling pathway (CARP). Clathrin-associated tubulovesicular carriers containing clathrin, AP1, Arf1, Rab1 and Rab11, while lacking the multimeric retrieval complexes, are generated at subdomains of early endosomes and then transported along actin to cell surfaces. Unexpectedly, the clathrin-associated recycling carriers undergo partial fusion with the plasma membrane. Subsequently, they are released from the membrane by dynamin and re-enter cells. Multiple receptors utilize and modulate CARP for fast recycling following endocytosis. Thus, CARP represents a previously unrecognized endocytic recycling mechanism with kiss-and-run membrane fusion.
    DOI:  https://doi.org/10.1038/s41556-024-01499-4
  20. Nature. 2024 Sep 16.
    Where did viruses come from? AlphaFold and other AIs are finding answers.
    Ewen Callaway.
      
    Keywords:  Machine learning; Virology
    DOI:  https://doi.org/10.1038/d41586-024-02970-w
  21. Nat Commun. 2024 Sep 18. 15(1): 8209
    Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements.
    Florence M Chardon, Troy A McDiarmid, Nicholas F Page, Riza M Daza, Beth K Martin, Silvia Domcke, Samuel G Regalado, Jean-Benoît Lalanne, Diego Calderon, Xiaoyi Li, Lea M Starita, Stephan J Sanders, Nadav Ahituv, Jay Shendure.
      CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes. Applying this method to a library of 493 gRNAs targeting candidate cis-regulatory elements in both K562 cells and iPSC-derived excitatory neurons, we identify gRNAs capable of specifically upregulating intended target genes and no other neighboring genes within 1 Mb, including gRNAs yielding upregulation of six autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes in neurons. A consistent pattern is that the responsiveness of individual enhancers to CRISPRa is restricted by cell type, implying a dependency on either chromatin landscape and/or additional trans-acting factors for successful gene activation. The approach outlined here may facilitate large-scale screens for gRNAs that activate genes in a cell type-specific manner.
    DOI:  https://doi.org/10.1038/s41467-024-52490-4
  22. Nature. 2024 Sep 19.
    Is bird flu spreading among people? Data gaps leave researchers in the dark.
    Heidi Ledford.
      
    Keywords:  Diseases; Genomics; Public health; Virology
    DOI:  https://doi.org/10.1038/d41586-024-03089-8
  23. Science. 2024 Sep 20. 385(6715): 1382
    Savoring the sandwich.
    Kyle G Ratner.
      
    DOI:  https://doi.org/10.1126/science.adt1544
  24. Nat Commun. 2024 Sep 16. 15(1): 8119
    N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation.
    Jeremy Monroe, Daniel E Eyler, Lili Mitchell, Indrajit Deb, Abigail Bojanowski, Pooja Srinivas, Christine M Dunham, Bijoyita Roy, Aaron T Frank, Kristin S Koutmou.
      The ribosome utilizes hydrogen bonding between mRNA codons and aminoacyl-tRNAs to ensure rapid and accurate protein production. Chemical modification of mRNA nucleobases can adjust the strength and pattern of this hydrogen bonding to alter protein synthesis. We investigate how the N1-methylpseudouridine (m1Ψ) modification, commonly incorporated into therapeutic and vaccine mRNA sequences, influences the speed and fidelity of translation. We find that m1Ψ does not substantially change the rate constants for amino acid addition by cognate tRNAs or termination by release factors. However, we also find that m1Ψ can subtly modulate the fidelity of amino acid incorporation in a codon-position and tRNA dependent manner in vitro and in human cells. Our computational modeling shows that altered energetics of mRNA:tRNA interactions largely account for the context dependence of the low levels of miscoding we observe on Ψ and m1Ψ containing codons. The outcome of translation on modified mRNA bases is thus governed by the sequence context in which they occur.
    DOI:  https://doi.org/10.1038/s41467-024-51301-0
  25. Nat Cell Biol. 2024 Sep 19.
    Fasting shapes chromatin architecture through an mTOR/RNA Pol I axis.
    Nada Al-Refaie, Francesco Padovani, Johanna Hornung, Lorenz Pudelko, Francesca Binando, Andrea Del Carmen Fabregat, Qiuxia Zhao, Benjamin D Towbin, Elif Sarinay Cenik, Nicholas Stroustrup, Jan Padeken, Kurt M Schmoller, Daphne S Cabianca.
      Chromatin architecture is a fundamental mediator of genome function. Fasting is a major environmental cue across the animal kingdom, yet how it impacts three-dimensional (3D) genome organization is unknown. Here we show that fasting induces an intestine-specific, reversible and large-scale spatial reorganization of chromatin in Caenorhabditis elegans. This fasting-induced 3D genome reorganization requires inhibition of the nutrient-sensing mTOR pathway, acting through the regulation of RNA Pol I, but not Pol II nor Pol III, and is accompanied by remodelling of the nucleolus. By uncoupling the 3D genome configuration from the animal's nutritional status, we find that the expression of metabolic and stress-related genes increases when the spatial reorganization of chromatin occurs, showing that the 3D genome might support the transcriptional response in fasted animals. Our work documents a large-scale chromatin reorganization triggered by fasting and reveals that mTOR and RNA Pol I shape genome architecture in response to nutrients.
    DOI:  https://doi.org/10.1038/s41556-024-01512-w
  26. Nat Commun. 2024 Sep 18. 15(1): 8174
    Identifying genetic variants associated with chromatin looping and genome function.
    Sourya Bhattacharyya, Ferhat Ay.
      Here we present a comprehensive HiChIP dataset on naïve CD4 T cells (nCD4) from 30 donors and identify QTLs that associate with genotype-dependent and/or allele-specific variation of HiChIP contacts defining loops between active regulatory regions (iQTLs). We observe a substantial overlap between iQTLs and previously defined eQTLs and histone QTLs, and an enrichment for fine-mapped QTLs and GWAS variants. Furthermore, we describe a distinct subset of nCD4 iQTLs, for which the significant variation of chromatin contacts in nCD4 are translated into significant eQTL trends in CD4 T cell memory subsets. Finally, we define connectivity-QTLs as iQTLs that are significantly associated with concordant genotype-dependent changes in chromatin contacts over a broad genomic region (e.g., GWAS SNP in the RNASET2 locus). Our results demonstrate the importance of chromatin contacts as a complementary modality for QTL mapping and their power in identifying previously uncharacterized QTLs linked to cell-specific gene expression and connectivity.
    DOI:  https://doi.org/10.1038/s41467-024-52296-4
  27. Commun Biol. 2024 Sep 17. 7(1): 1164
    Activation of the NLRP1B inflammasome by caspase-8.
    Justin J Meade, Sarah Stuart, Jana Neiman-Zenevich, Christian Krustev, Stephen E Girardin, Jeremy Mogridge.
      Cleavage of the innate immune receptor NLRP1B by various microbial proteases causes the proteasomal degradation of its N-terminal fragment and the subsequent release of a C-terminal fragment that forms an inflammasome. We reported previously that metabolic stress caused by intracellular bacteria triggers NLRP1B activation, but the mechanism by which this occurs was not elucidated. Here we demonstrate that TLR4 signaling in metabolically stressed macrophages promotes the formation of a TRIF/RIPK1/caspase-8 complex. Caspase-8 activity, induced downstream of this TLR4 pathway or through a distinct TNF receptor pathway, causes cleavage and activation of NLRP1B, which facilitates the maturation of both pro-caspase-1 and pro-caspase-8. Thus, our findings indicate that caspase-8 and NLRP1B generate a positive feedback loop that amplifies cell death processes and promotes a pro-inflammatory response through caspase-1. The ability of NLRP1B to detect caspase-8 activity suggests that this pattern recognition receptor may play a role in the defense against a variety of pathogens that induce apoptosis.
    DOI:  https://doi.org/10.1038/s42003-024-06882-3
  28. Nat Commun. 2024 Sep 17. 15(1): 8171
    Quantifiable blood TCR repertoire components associate with immune aging.
    Jing Hu, Mingyao Pan, Brett Reid, Shelley Tworoger, Bo Li.
      T cell senescence alters the homeostasis of distinct T cell populations and results in decayed adaptive immune protection in older individuals, but a link between aging and dynamic T cell clone changes has not been made. Here, using a newly developed computational framework, Repertoire Functional Units (RFU), we investigate over 6500 publicly available TCR repertoire sequencing samples from multiple human cohorts and identify age-associated RFUs consistently across different cohorts. Quantification of RFU reduction with aging reveals accelerated loss under immunosuppressive conditions. Systematic analysis of age-associated RFUs in clinical samples manifests a potential link between these RFUs and improved clinical outcomes, such as lower ICU admission and reduced risk of complications, during acute viral infections. Finally, patients receiving bone marrow transplantation show a secondary expansion of the age-associated clones upon stem cell transfer from younger donors. Together, our results suggest the existence of a 'TCR clock' that could reflect the immune functions in aging populations.
    DOI:  https://doi.org/10.1038/s41467-024-52522-z
  29. Nature. 2024 Sep 18.
    Gut microbes fend off harmful bacteria by depriving them of nutrients.
    Eric G Pamer.
      
    Keywords:  Infection; Medical research; Microbiology
    DOI:  https://doi.org/10.1038/d41586-024-02803-w
  30. Nat Commun. 2024 Sep 17. 15(1): 8167
    DNA Methylation signatures underpinning blood neutrophil to lymphocyte ratio during first week of human life.
    EPIC-HIPC consortium
      Understanding of newborn immune ontogeny in the first week of life will enable age-appropriate strategies for safeguarding vulnerable newborns against infectious diseases. Here we conducted an observational study exploring the immunological profile of infants longitudinally throughout their first week of life. Our Expanded Program on Immunization - Human Immunology Project Consortium (EPIC-HIPC) studies the epigenetic regulation of systemic immunity using small volumes of peripheral blood samples collected from West African neonates on days of life (DOL) 0, 1, 3, and 7. Genome-wide DNA methylation and single nucleotide polymorphism markers are examined alongside matched transcriptomic and flow cytometric data. Integrative analysis reveals that a core network of transcription factors mediates dynamic shifts in neutrophil-to-lymphocyte ratios (NLR), which are underpinned by cell-type specific methylation patterns in the two cell types. Genetic variants are associated with lower NLRs at birth, and healthy newborns with lower NLRs at birth are more likely to subsequently develop sepsis. These findings provide valuable insights into the early-life determinants of immune system development.
    DOI:  https://doi.org/10.1038/s41467-024-52283-9
  31. Nat Med. 2024 Sep 18.
    Improving primary healthcare with generative AI.
    Winnie Yip.
      
    DOI:  https://doi.org/10.1038/s41591-024-03257-3
  32. Cell. 2024 Sep 12. pii: S0092-8674(24)00965-6. [Epub ahead of print]
    Dynamic allostery drives autocrine and paracrine TGF-β signaling.
    Mingliang Jin, Robert I Seed, Guoqing Cai, Tiffany Shing, Li Wang, Saburo Ito, Anthony Cormier, Stephanie A Wankowicz, Jillian M Jespersen, Jody L Baron, Nicholas D Carey, Melody G Campbell, Zanlin Yu, Phu K Tang, Pilar Cossio, Weihua Wen, Jianlong Lou, James Marks, Stephen L Nishimura, Yifan Cheng.
      TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.
    Keywords:  TGF-b signaling; TGF-b1; TGF-b3; activation; autocrine signaling; avb8 integrin; dynamic allostery; entropy redistribution; furin; latency; paracrine signaling; regulatory T cells; single-particle cryo-EM
    DOI:  https://doi.org/10.1016/j.cell.2024.08.036
  33. Nature. 2024 Sep 16.
    Daily briefing: Common diabetes drug slows monkey brain-ageing.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-03034-9
  34. Nat Genet. 2024 Sep 18.
    Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity.
    Samuel J Taylor, Jacob Stauber, Oliver Bohorquez, Goichi Tatsumi, Rajni Kumari, Joyeeta Chakraborty, Boris A Bartholdy, Emily Schwenger, Sriram Sundaravel, Abdelbasset A Farahat, Justin C Wheat, Mendel Goldfinger, Amit Verma, Arvind Kumar, David W Boykin, Kristy R Stengel, Gregory M K Poon, Ulrich Steidl.
      Transcription factor (TF) DNA-binding dynamics govern cell fate and identity. However, our ability to pharmacologically control TF localization is limited. Here we leverage chemically driven binding site restriction leading to robust and DNA-sequence-specific redistribution of PU.1, a pioneer TF pertinent to many hematopoietic malignancies. Through an innovative technique, 'CLICK-on-CUT&Tag', we characterize the hierarchy of de novo PU.1 motifs, predicting occupancy in the PU.1 cistrome under binding site restriction. Temporal and single-molecule studies of binding site restriction uncover the pioneering dynamics of native PU.1 and identify the paradoxical activation of an alternate target gene set driven by PU.1 localization to second-tier binding sites. These transcriptional changes were corroborated by genetic blockade and site-specific reporter assays. Binding site restriction and subsequent PU.1 network rewiring causes primary human leukemia cells to differentiate. In summary, pharmacologically induced TF redistribution can be harnessed to govern TF localization, actuate alternate gene networks and direct cell fate.
    DOI:  https://doi.org/10.1038/s41588-024-01911-7
  35. Nat Commun. 2024 Sep 18. 15(1): 8175
    Structural basis of CDNF interaction with the UPR regulator GRP78.
    Melissa A Graewert, Maria Volkova, Klara Jonasson, Juha A E Määttä, Tobias Gräwert, Samara Mamidi, Natalia Kulesskaya, Johan Evenäs, Richard E Johnsson, Dmitri Svergun, Arnab Bhattacharjee, Henri J Huttunen.
      Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52478-0
  36. Nature. 2024 Sep 17.
    Should young kids take the new anti-obesity drugs? What the research says.
    Julian Nowogrodzki.
      
    Keywords:  Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-02983-5
  37. Nat Commun. 2024 Sep 16. 15(1): 8131
    Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions.
    Kiyoka Saito, Mark van der Garde, Terumasa Umemoto, Natsumi Miharada, Julia Sjöberg, Valgardur Sigurdsson, Haruki Shirozu, Shunsuke Kamei, Visnja Radulovic, Mitsuyoshi Suzuki, Satoshi Nakano, Stefan Lang, Jenny Hansson, Martin L Olsson, Takashi Minami, Gunnar Gouras, Johan Flygare, Kenichi Miharada.
      Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. VldlrhighHSCs show higher erythroid potential, which is enhanced after acute anemia induction. VldlrhighHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays an important role in HSC regulation under severe anemic conditions.
    DOI:  https://doi.org/10.1038/s41467-024-52509-w
  38. Nat Commun. 2024 Sep 18. 15(1): 8195
    A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.
    Qing Bai, Enhua Shao, Denglei Ma, Binxuan Jiao, Seth D Scheetz, Karen A Hartnett-Scott, Vladimir A Ilin, Elias Aizenman, Julia Kofler, Edward A Burton.
      Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.
    DOI:  https://doi.org/10.1038/s41467-024-52173-0
  39. Nat Biotechnol. 2024 Sep 18.
    A developmental route to hematopoietic stem cells.
    Adam C Wilkinson, Marella F T R de Bruijn.
      
    DOI:  https://doi.org/10.1038/s41587-024-02398-7
  40. JAMA. 2024 Sep 20.
    Risk Factors for Immune Checkpoint Inhibitor-Induced Diabetes Identified.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2024.19134
  41. Sci Signal. 2024 Sep 17. 17(854): eadt0770
    Suppressing appetite with taurine.
    Annalisa M VanHook.
      The taurine metabolite N-acetyltaurine protects mice from diet-induced obesity by reducing food intake.
    DOI:  https://doi.org/10.1126/scisignal.adt0770
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