bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–08–04
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Multiorgan biological age shows that no organ system is an island.
  2. Charged-up butterflies draw pollen through the air.
  3. Putting the STING in MS.
  4. The mathematician who helps Olympic swimmers go faster.
  5. How neuroinflammation weakens muscles.
  6. Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
  7. The pathogens that could spark the next pandemic.
  8. Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.
  9. The influence of HLA genetic variation on plasma protein expression.
  10. Blocking an inflammatory protein slows the pace of ageing.
  11. Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.
  12. Genome-wide discovery for biomarkers using quantile regression at biobank scale.
  13. Never trust a single myeloid marker: Ly6G on repair-promoting lung macrophages.
  14. Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues.
  15. Adult neurogenesis improves spatial information encoding in the mouse hippocampus.
  16. Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.
  17. Voting for ecological protection.
  18. Stunning trial shows twice-yearly shots can prevent HIV infection.
  19. Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport.
  20. The choroid plexus synergizes with immune cells during neuroinflammation.
  21. Fish can tell the direction of sounds - here's how.
  22. The fork protection complex promotes parental histone recycling and epigenetic memory.
  23. Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
  24. A chemogenetic screen reveals that Trpv1-expressing neurons control regulatory T cells in the gut.
  25. Mental maps help monkeys to navigate without sensory input.
  26. Cell fate decision by a morphogen-transcription factor-chromatin modifier axis.
  27. Mapping gut feelings and immune control.
  28. A joint bacterial effort to produce vitamin B12.
  29. Sexual harassment in science: biologists in India speak out.
  30. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
  31. Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.
  32. Black holes made from light? Impossible, say physicists.
  33. The future of Mars Colony Two.
  34. Immature B cell homing shapes human lymphoid tissue structure and function.
  35. Longitudinal variation in resilient psychosocial functioning is associated with ongoing cortical myelination and functional reorganization during adolescence.
  36. People are more error-prone after committing an error.
  37. Chromosome components central to cell division evolve rapidly.
  38. Calcineurin promotes adaptation to chronic stress through two distinct mechanisms.
  39. Development of an epigenetic clock resistant to changes in immune cell composition.
  40. Is that a durian? No, it's a weird ancient mollusc.
  41. Daily briefing: AI fed on a diet of AI-generated data spews nonsense.
  42. Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease.
  43. Predatory conferences are on the rise. Here are five ways to tackle them.
  44. IFN versus AHR-JUN.
  45. A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.
  46. MethSCAn: accurate exploratory analysis of single-cell methylomes.
  47. Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits.
  1. Nat Aging. 2024 Aug 02.
    Multiorgan biological age shows that no organ system is an island.
      
    DOI:  https://doi.org/10.1038/s43587-024-00690-4
  2. Nature. 2024 Jul 30.
    Charged-up butterflies draw pollen through the air.
      
    Keywords:  Biophysics
    DOI:  https://doi.org/10.1038/d41586-024-02491-6
  3. Nat Immunol. 2024 Aug;25(8): 1309
    Putting the STING in MS.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01930-w
  4. Nature. 2024 Jul 31.
    The mathematician who helps Olympic swimmers go faster.
    Davide Castelvecchi.
      
    Keywords:  Mathematics and computing; Physics
    DOI:  https://doi.org/10.1038/d41586-024-02514-2
  5. Nat Rev Immunol. 2024 Jul 29.
    How neuroinflammation weakens muscles.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01074-w
  6. Sci Adv. 2024 Aug 02. 10(31): eadp0443
    Opa1 processing is dispensable in mouse development but is protective in mitochondrial cardiomyopathy.
    Sofia Ahola, Lilli A Pazurek, Fiona Mayer, Philipp Lampe, Steffen Hermans, Lore Becker, Oana V Amarie, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Dietmar Riedel, Hendrik Nolte, Thomas Langer.
      Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
    DOI:  https://doi.org/10.1126/sciadv.adp0443
  7. Nature. 2024 Aug 02.
    The pathogens that could spark the next pandemic.
    Smriti Mallapaty.
      
    Keywords:  Infection; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-024-02513-3
  8. Nat Commun. 2024 Aug 02. 15(1): 6540
    Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.
    Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul.
      Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.
    DOI:  https://doi.org/10.1038/s41467-024-50949-y
  9. Nat Commun. 2024 Jul 31. 15(1): 6469
    The influence of HLA genetic variation on plasma protein expression.
    Chirag Krishna, Joshua Chiou, Saori Sakaue, Joyce B Kang, Stephen M Christensen, Isac Lee, Melis Atalar Aksit, Hye In Kim, David von Schack, Soumya Raychaudhuri, Daniel Ziemek, Xinli Hu.
      Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-50583-8
  10. Nature. 2024 Aug;632(8023): 35-36
    Blocking an inflammatory protein slows the pace of ageing.
    Richard A Miller.
      
    Keywords:  Ageing; Immunology; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-02300-0
  11. Nat Commun. 2024 Aug 01. 15(1): 6480
    Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.
    Yasmin K Alshoubaki, Bhavana Nayer, Yen-Zhen Lu, Ekaterina Salimova, Sin Nee Lau, Jean L Tan, Daniela Amann-Zalcenstein, Peter F Hickey, Gonzalo Del Monte-Nieto, Ajithkumar Vasanthakumar, Mikaël M Martino.
      Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.
    DOI:  https://doi.org/10.1038/s41467-024-50806-y
  12. Nat Commun. 2024 Jul 31. 15(1): 6460
    Genome-wide discovery for biomarkers using quantile regression at biobank scale.
    Chen Wang, Tianying Wang, Krzysztof Kiryluk, Ying Wei, Hugues Aschard, Iuliana Ionita-Laza.
      Genome-wide association studies (GWAS) for biomarkers important for clinical phenotypes can lead to clinically relevant discoveries. Conventional GWAS for quantitative traits are based on simplified regression models modeling the conditional mean of a phenotype as a linear function of genotype. We draw attention here to an alternative, lesser known approach, namely quantile regression that naturally extends linear regression to the analysis of the entire conditional distribution of a phenotype of interest. Quantile regression can be applied efficiently at biobank scale, while having some unique advantages such as (1) identifying variants with heterogeneous effects across quantiles of the phenotype distribution; (2) accommodating a wide range of phenotype distributions including non-normal distributions, with invariance of results to trait transformations; and (3) providing more detailed information about genotype-phenotype associations even for those associations identified by conventional GWAS. We show in simulations that quantile regression is powerful across both homogeneous and various heterogeneous models. Applications to 39 quantitative traits in the UK Biobank demonstrate that quantile regression can be a helpful complement to linear regression in GWAS and can identify variants with larger effects on high-risk subgroups of individuals but with lower or no contribution overall.
    DOI:  https://doi.org/10.1038/s41467-024-50726-x
  13. Sci Immunol. 2024 Aug 02. 9(98): eadq7306
    Never trust a single myeloid marker: Ly6G on repair-promoting lung macrophages.
    Chrysante S Iliakis, Andreas Wack.
      Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection-and they are Ly6G positive (see related Research Article by Ruscitti et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.adq7306
  14. Nature. 2024 Jul 31.
    Turbinate-homing IgA-secreting cells originate in the nasal lymphoid tissues.
    Jingjing Liu, Liat Stoler-Barak, Hadas Hezroni-Bravyi, Adi Biram, Sacha Lebon, Natalia Davidzohn, Merav Kedmi, Muriel Chemla, David Pilzer, Marina Cohen, Ori Brenner, Moshe Biton, Ziv Shulman.
      Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens1, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear2. Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs)3. Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA+ B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses.
    DOI:  https://doi.org/10.1038/s41586-024-07729-x
  15. Nat Commun. 2024 Jul 30. 15(1): 6410
    Adult neurogenesis improves spatial information encoding in the mouse hippocampus.
    M Agustina Frechou, Sunaina S Martin, Kelsey D McDermott, Evan A Huaman, Şölen Gökhan, Wolfgang A Tomé, Ruben Coen-Cagli, J Tiago Gonçalves.
      Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus. Ablating adult neurogenesis blocks the effect of enrichment and lowers spatial information, as does the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreases the calcium activity of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast with previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.
    DOI:  https://doi.org/10.1038/s41467-024-50699-x
  16. Science. 2024 Aug 02. 385(6708): adl2992
    Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.
    Zhao Sun, Ji-Sun Kwon, Yudong Ren, Shawei Chen, Courtney K Walker, Xinguo Lu, Kitra Cates, Hande Karahan, Sanja Sviben, James A J Fitzpatrick, Clarissa Valdez, Henry Houlden, Celeste M Karch, Randall J Bateman, Chihiro Sato, Steven J Mennerick, Marc I Diamond, Jungsu Kim, Rudolph E Tanzi, David M Holtzman, Andrew S Yoo.
      Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD. Reprogrammed LOAD neurons exhibit Aβ-dependent neurodegeneration, and treatment with β- or γ-secretase inhibitors before (but not subsequent to) Aβ deposit formation mitigated neuronal death. Moreover inhibiting age-associated retrotransposable elements in LOAD neurons reduced both Aβ deposition and neurodegeneration. Our study underscores the efficacy of modeling late-onset neuropathology of LOAD through high-efficiency miRNA-based neuronal reprogramming.
    DOI:  https://doi.org/10.1126/science.adl2992
  17. Science. 2024 Aug 02. 385(6708): 505
    Voting for ecological protection.
    Maya Mayrose.
      
    DOI:  https://doi.org/10.1126/science.adq6377
  18. Nature. 2024 Aug 02.
    Stunning trial shows twice-yearly shots can prevent HIV infection.
      
    Keywords:  HIV infections
    DOI:  https://doi.org/10.1038/d41586-024-02493-4
  19. Nat Commun. 2024 Jul 30. 15(1): 6394
    Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport.
    Peter Wotherspoon, Hannah Johnston, David J Hardy, Rachel Holyfield, Soi Bui, Giedrė Ratkevičiūtė, Pooja Sridhar, Jonathan Colburn, Charlotte B Wilson, Adam Colyer, Benjamin F Cooper, Jack A Bryant, Gareth W Hughes, Phillip J Stansfeld, Julien R C Bergeron, Timothy J Knowles.
      The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. It acts by removing ectopic lipids from the outer leaflet of the outer membrane and returning them to the inner membrane through three proteinaceous assemblies: the MlaA-OmpC complex, situated within the outer membrane; the periplasmic phospholipid shuttle protein, MlaC; and the inner membrane ABC transporter complex, MlaFEDB, proposed to be the founding member of a structurally distinct ABC superfamily. While the function of each component is well established, how phospholipids are exchanged between components remains unknown. This stands as a major roadblock in our understanding of the function of the pathway, and in particular, the role of ATPase activity of MlaFEDB is not clear. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD.
    DOI:  https://doi.org/10.1038/s41467-024-50615-3
  20. Cell. 2024 Jul 25. pii: S0092-8674(24)00717-7. [Epub ahead of print]
    The choroid plexus synergizes with immune cells during neuroinflammation.
    Huixin Xu, Peter Lotfy, Sivan Gelb, Aja Pragana, Christine Hehnly, Lillian I J Byer, Frederick B Shipley, Miriam E Zawadzki, Jin Cui, Liwen Deng, Milo Taylor, Mya Webb, Hart G W Lidov, Mark L Andermann, Isaac M Chiu, Jose Ordovas-Montanes, Maria K Lehtinen.
      The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.
    Keywords:  adhesion molecules; bacterial infection; blood-CSF barrier; choroid plexus; colony-stimulating factor 1; epiplexus macrophages; epithelial cells; immune recruitment; neuroinflammation
    DOI:  https://doi.org/10.1016/j.cell.2024.07.002
  21. Nature. 2024 Jul 31.
    Fish can tell the direction of sounds - here's how.
    Emily Bates.
      
    Keywords:  Animal behaviour; Physics
    DOI:  https://doi.org/10.1038/d41586-024-02518-y
  22. Cell. 2024 Jul 26. pii: S0092-8674(24)00777-3. [Epub ahead of print]
    The fork protection complex promotes parental histone recycling and epigenetic memory.
    Sebastian Jespersen Charlton, Valentin Flury, Yutaka Kanoh, Aitana Victoria Genzor, Leonie Kollenstart, Wantong Ao, Peter Brøgger, Melanie Bianca Weisser, Marek Adamus, Nicolas Alcaraz, Charlotte M Delvaux de Fenffe, Francesca Mattiroli, Guillermo Montoya, Hisao Masai, Anja Groth, Geneviève Thon.
      The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator of symmetric parental histone inheritance. Mrc1 mutants in a key connector domain disrupted segregation of parental histones to the lagging strand comparable to Mcm2 histone-binding mutants. Both mutants showed clonal and asymmetric loss of H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning of H3-H4 tetramers by Mrc1 and Mcm2, with the Mrc1 connector domain bridging histone and Mcm2 binding. Biochemical and functional analysis validated this model and revealed a duality in Mrc1 function: disabling histone binding in the connector domain disrupted lagging-strand recycling while another histone-binding mutation impaired leading strand recycling. We propose that Mrc1 toggles histones between the lagging and leading strand recycling pathways, in part by intra-replisome co-chaperoning, to ensure epigenetic transmission to both daughter cells.
    Keywords:  Claspin; DNA replication; H3K9 methylation; chromatin replication; epigenetic inheritance; epigenome maintenance; fission yeast; heterochromatin; histone chaperone; histone recycling; mouse embryonic stem cells
    DOI:  https://doi.org/10.1016/j.cell.2024.07.017
  23. Nat Commun. 2024 Jul 31. 15(1): 6438
    Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
    Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.
      Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.
    DOI:  https://doi.org/10.1038/s41467-024-50104-7
  24. Science. 2024 Aug 02. 385(6708): eadk1679
    A chemogenetic screen reveals that Trpv1-expressing neurons control regulatory T cells in the gut.
    Yangyang Zhu, Kimberly A Meerschaert, Silvia Galvan-Pena, Na-Ryum Bin, Daping Yang, Himanish Basu, Ryo Kawamoto, Amre Shalaby, Stephen D Liberles, Diane Mathis, Christophe Benoist, Isaac M Chiu.
      Neuroimmune cross-talk participates in intestinal tissue homeostasis and host defense. However, the matrix of interactions between arrays of molecularly defined neuron subsets and of immunocyte lineages remains unclear. We used a chemogenetic approach to activate eight distinct neuronal subsets, assessing effects by deep immunophenotyping, microbiome profiling, and immunocyte transcriptomics in intestinal organs. Distinct immune perturbations followed neuronal activation: Nitrergic neurons regulated T helper 17 (TH17)-like cells, and cholinergic neurons regulated neutrophils. Nociceptor neurons, expressing Trpv1, elicited the broadest immunomodulation, inducing changes in innate lymphocytes, macrophages, and RORγ+ regulatory T (Treg) cells. Neuroanatomical, genetic, and pharmacological follow-up showed that Trpv1+ neurons in dorsal root ganglia decreased Treg cell numbers via the neuropeptide calcitonin gene-related peptide (CGRP). Given the role of these neurons in nociception, these data potentially link pain signaling with gut Treg cell function.
    DOI:  https://doi.org/10.1126/science.adk1679
  25. Nature. 2024 Jul 29.
    Mental maps help monkeys to navigate without sensory input.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02471-w
  26. Nat Commun. 2024 Jul 29. 15(1): 6365
    Cell fate decision by a morphogen-transcription factor-chromatin modifier axis.
    Jin Ming, Lihui Lin, Jiajun Li, Linlin Wu, Shicai Fang, Tao Huang, Yu Fu, Dong Liu, Wenhui Zhang, Chen Li, Yongzheng Yang, Yi Huang, Yue Qin, Junqi Kuang, Xingnan Huang, Liman Guo, Xiaofei Zhang, Jing Liu, Jiekai Chen, Chengchen Zhao, Bo Wang, Duanqing Pei.
      Cell fate decisions remain poorly understood at the molecular level. Embryogenesis provides a unique opportunity to analyze molecular details associated with cell fate decisions. Works based on model organisms have provided a conceptual framework of genes that specify cell fate control, for example, transcription factors (TFs) controlling processes from pluripotency to immunity1. How TFs specify cell fate remains poorly understood. Here we report that SALL4 relies on NuRD (nucleosome-remodeling and deacetylase complex) to interpret BMP4 signal and decide cell fate in a well-controlled in vitro system. While NuRD complex cooperates with SALL4 to convert mouse embryonic fibroblasts or MEFs to pluripotency, BMP4 diverts the same process to an alternative fate, PrE (primitive endoderm). Mechanistically, BMP4 signals the dissociation of SALL4 from NuRD physically to establish a gene regulatory network for PrE. Our results provide a conceptual framework to explore the rich landscapes of cell fate choices intrinsic to development in higher organisms involving morphogen-TF-chromatin modifier pathways.
    DOI:  https://doi.org/10.1038/s41467-024-50144-z
  27. Science. 2024 Aug 02. 385(6708): 496-497
    Mapping gut feelings and immune control.
    Nathalie Vergnolle.
      A chemogenetic screen reveals links between nociceptors and gut immune function.
    DOI:  https://doi.org/10.1126/science.adq9533
  28. Nature. 2024 Jul 31.
    A joint bacterial effort to produce vitamin B12.
      
    Keywords:  Biochemistry; Microbiology
    DOI:  https://doi.org/10.1038/d41586-024-02474-7
  29. Nature. 2024 Jul 29.
    Sexual harassment in science: biologists in India speak out.
    Gayathri Vaidyanathan.
      
    Keywords:  Ethics; Policy; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02400-x
  30. Nat Commun. 2024 Jul 28. 15(1): 6357
    Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.
    James R Occean, Na Yang, Yan Sun, Marshall S Dawkins, Rachel Munk, Cedric Belair, Showkat Dar, Carlos Anerillas, Lin Wang, Changyou Shi, Christopher Dunn, Michel Bernier, Nathan L Price, Julie S Kim, Chang-Yi Cui, Jinshui Fan, Moitrayee Bhattacharyya, Supriyo De, Manolis Maragkakis, Rafael de Cabo, Simone Sidoli, Payel Sen.
      DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.
    DOI:  https://doi.org/10.1038/s41467-024-50725-y
  31. Nat Commun. 2024 Jul 29. 15(1): 6390
    Harnessing intestinal tryptophan catabolism to relieve atherosclerosis in mice.
    Mouna Chajadine, Ludivine Laurans, Tobias Radecke, Nirmala Mouttoulingam, Rida Al-Rifai, Emilie Bacquer, Clara Delaroque, Héloïse Rytter, Marius Bredon, Camille Knosp, José Vilar, Coralie Fontaine, Nadine Suffee, Marie Vandestienne, Bruno Esposito, Julien Dairou, Jean Marie Launay, Jacques Callebert, Alain Tedgui, Hafid Ait-Oufella, Harry Sokol, Benoit Chassaing, Soraya Taleb.
      Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-024-50807-x
  32. Nature. 2024 Aug 02.
    Black holes made from light? Impossible, say physicists.
      
    Keywords:  Astronomy and astrophysics
    DOI:  https://doi.org/10.1038/d41586-024-02505-3
  33. Nature. 2024 Aug 02.
    The future of Mars Colony Two.
    Jeff Hecht.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-02453-y
  34. J Exp Med. 2024 Sep 02. pii: e20240085. [Epub ahead of print]221(9):
    Immature B cell homing shapes human lymphoid tissue structure and function.
    Jo Spencer, Chiara Dionisi.
      Shortly after the emergence of newly formed human B cells from bone marrow as transitional cells, they diverge along two developmental pathways that can be distinguished by the level of IgM they express and migratory biases. Here, we propose that differential tissue homing of immature B cell subsets contributes to human lymphoid tissue structure and function.
    DOI:  https://doi.org/10.1084/jem.20240085
  35. Nat Commun. 2024 Jul 29. 15(1): 6283
    Longitudinal variation in resilient psychosocial functioning is associated with ongoing cortical myelination and functional reorganization during adolescence.
    NSPN Consortium
      Adolescence is a period of dynamic brain remodeling and susceptibility to psychiatric risk factors, mediated by the protracted consolidation of association cortices. Here, we investigated whether longitudinal variation in adolescents' resilience to psychosocial stressors during this vulnerable period is associated with ongoing myeloarchitectural maturation and consolidation of functional networks. We used repeated myelin-sensitive Magnetic Transfer (MT) and resting-state functional neuroimaging (n = 141), and captured adversity exposure by adverse life events, dysfunctional family settings, and socio-economic status at two timepoints, one to two years apart. Development toward more resilient psychosocial functioning was associated with increasing myelination in the anterolateral prefrontal cortex, which showed stabilized functional connectivity. Studying depth-specific intracortical MT profiles and the cortex-wide synchronization of myeloarchitectural maturation, we further observed wide-spread myeloarchitectural reconfiguration of association cortices paralleled by attenuated functional reorganization with increasingly resilient outcomes. Together, resilient/susceptible psychosocial functioning showed considerable intra-individual change associated with multi-modal cortical refinement processes at the local and system-level.
    DOI:  https://doi.org/10.1038/s41467-024-50292-2
  36. Nat Commun. 2024 Jul 30. 15(1): 6422
    People are more error-prone after committing an error.
    Tyler J Adkins, Han Zhang, Taraz G Lee.
      Humans tend to slow down after making an error. A longstanding account of this post-error slowing is that people are simply more cautious. However, accuracy typically does not improve following an error, leading some researchers to suggest that an initial 'orienting' response may initially impair performance immediately following error. Unfortunately, characterizing the nature of this error-based impairment remains a challenge in standard tasks that use free response times. By exerting control over the timing of responses, we reveal the time course of stimulus-response processing. Participants are less accurate after an error even when given ample time to make a response. A computational model of response preparation rules out the possibility that errors lead to slower cognitive processing. Instead, we find that the efficacy of cognitive processing in producing an intended response is impaired following errors. Following an error, participants commit more slips of action that tend to be a repetition of the previous mistake. Rather than a strategic shift along a single speed-accuracy tradeoff function, post-error slowing observed in free response time tasks may be an adaptive response to impaired cognitive processing that reflects an altered relationship between the speed and accuracy of responses.
    DOI:  https://doi.org/10.1038/s41467-024-50547-y
  37. Nature. 2024 Aug 02.
    Chromosome components central to cell division evolve rapidly.
      
    Keywords:  Cell biology; DNA sequencing; Genomics
    DOI:  https://doi.org/10.1038/d41586-024-02523-1
  38. Mol Biol Cell. 2024 Jul 31. mbcE24030122
    Calcineurin promotes adaptation to chronic stress through two distinct mechanisms.
    Mackenzie J Flynn, Nicholas W Harper, Rui Li, Lihua Julie Zhu, Michael J Lee, Jennifer A Benanti.
      Adaptation to environmental stress requires coordination between stress-defense programs and cell cycle progression. The immediate response to many stressors has been well characterized, but how cells survive in challenging environments long-term is unknown. Here, we investigate the role of the stress-activated phosphatase calcineurin (CN) in adaptation to chronic CaCl2 stress in Saccharomyces cerevisiae. We find that prolonged exposure to CaCl2 impairs mitochondrial function and demonstrate that cells respond to this stressor using two CN-dependent mechanisms - one that requires the downstream transcription factor Crz1 and another that is Crz1-independent. Our data indicate that CN maintains cellular fitness by promoting cell cycle progression and preventing CaCl2-induced cell death. When Crz1 is present, transient CN activation suppresses cell death and promotes adaptation despite high levels of mitochondrial loss. However, in the absence of Crz1, prolonged activation of CN prevents mitochondrial loss and further cell death by upregulating glutathione (GSH) biosynthesis genes thereby mitigating damage from reactive oxygen species. These findings illustrate how cells maintain long-term fitness during chronic stress and suggest that CN promotes adaptation in challenging environments by multiple mechanisms.
    DOI:  https://doi.org/10.1091/mbc.E24-03-0122
  39. Commun Biol. 2024 Aug 02. 7(1): 934
    Development of an epigenetic clock resistant to changes in immune cell composition.
    Alan Tomusiak, Ariel Floro, Ritesh Tiwari, Rebeccah Riley, Hiroyuki Matsui, Nicolas Andrews, Herbert G Kasler, Eric Verdin.
      Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age. Here, we found that human naive CD8+ T cells, which decrease in frequency during aging, exhibit an epigenetic age 15-20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created an epigenetic clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock shows a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming.
    DOI:  https://doi.org/10.1038/s42003-024-06609-4
  40. Nature. 2024 Aug 01.
    Is that a durian? No, it's a weird ancient mollusc.
    Ewen Callaway.
      
    Keywords:  Evolution; Palaeontology
    DOI:  https://doi.org/10.1038/d41586-024-02522-2
  41. Nature. 2024 Jul 25.
    Daily briefing: AI fed on a diet of AI-generated data spews nonsense.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02490-7
  42. Nat Commun. 2024 Jul 31. 15(1): 6430
    Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease.
    Abolfazl Doostparast Torshizi, Dongnhu T Truong, Liping Hou, Bart Smets, Christopher D Whelan, Shuwei Li.
      Parkinson's disease is highly heterogeneous across disease symptoms, clinical manifestations and progression trajectories, hampering the identification of therapeutic targets. Despite knowledge gleaned from genetics analysis, dysregulated proteome mechanisms stemming from genetic aberrations remain underexplored. In this study, we develop a three-phase system-level proteogenomic analytical framework to characterize disease-associated proteins and dysregulated mechanisms. Proteogenomic analysis identified 577 proteins that enrich for Parkinson's disease-related pathways, such as cytokine receptor interactions and lysosomal function. Converging lines of evidence identified nine proteins, including LGALS3, CSNK2A1, SMPD3, STX4, APOA2, PAFAH1B3, LDLR, HSPB1, BRK1, with potential roles in disease pathogenesis. This study leverages the largest population-scale proteomics dataset, the UK Biobank Pharma Proteomics Project, to characterize genetically-driven protein disturbances associated with Parkinson's disease. Taken together, our work contributes to better understanding of genome-proteome dynamics in Parkinson's disease and sets a paradigm to identify potential indirect mediators connected to GWAS signals for complex neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-024-50718-x
  43. Nature. 2024 Aug;632(8023): 7
    Predatory conferences are on the rise. Here are five ways to tackle them.
      
    Keywords:  Careers; Conferences and meetings; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-02445-y
  44. Nat Immunol. 2024 Aug;25(8): 1309
    IFN versus AHR-JUN.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-024-01927-5
  45. Cell Metab. 2024 Jul 23. pii: S1550-4131(24)00275-4. [Epub ahead of print]
    A microbial metabolite inhibits the HIF-2α-ceramide pathway to mediate the beneficial effects of time-restricted feeding on MASH.
    Yi Zhang, Xuemei Wang, Jun Lin, Jia Liu, Kai Wang, Qixing Nie, Chuan Ye, Lulu Sun, Yanpeng Ma, Ruize Qu, Yuejian Mao, Xuguang Zhang, Hua Lu, Pengyan Xia, Dongyu Zhao, Guang Wang, Zhipeng Zhang, Wei Fu, Changtao Jiang, Yanli Pang.
      Time-restricted feeding (TRF) is a potent dietary intervention for improving metabolic diseases, including metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH). However, the mechanism of this efficacy has remained elusive. Here, we show that TRF improves MASLD, which is associated with a significant enrichment of Ruminococcus torques (R. torques). Mechanistically, R. torques suppresses the intestinal HIF-2α-ceramide pathway via the production of 2-hydroxy-4-methylpentanoic acid (HMP). We identify rtMor as a 4-methyl-2-oxopentanoate reductase that synthesizes HMP in R. torques. Finally, we show that either the colonization of R. torques or oral HMP supplementation can ameliorate inflammation and fibrosis in a MASH mouse model. These findings identify R. torques and HMP as potential TRF mimetics for the treatment of metabolic disorders.
    Keywords:  MASLD/MASH; bacterial metabolites; gut microbiota; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.004
  46. Nat Methods. 2024 Jul 31.
    MethSCAn: accurate exploratory analysis of single-cell methylomes.
      
    DOI:  https://doi.org/10.1038/s41592-024-02348-w
  47. Nat Commun. 2024 Aug 03. 15(1): 6562
    Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits.
    Tao Zhu, Chunjiao Xia, Ranran Yu, Xinkai Zhou, Xingbing Xu, Lin Wang, Zhanxiang Zong, Junjiao Yang, Yinmeng Liu, Luchang Ming, Yuxin You, Dijun Chen, Weibo Xie.
      Unraveling the regulatory mechanisms that govern complex traits is pivotal for advancing crop improvement. Here we present a comprehensive regulome atlas for rice (Oryza sativa), charting the chromatin accessibility across 23 distinct tissues from three representative varieties. Our study uncovers 117,176 unique open chromatin regions (OCRs), accounting for ~15% of the rice genome, a notably higher proportion compared to previous reports in plants. Integrating RNA-seq data from matched tissues, we confidently predict 59,075 OCR-to-gene links, with enhancers constituting 69.54% of these associations, including many known enhancer-to-gene links. Leveraging this resource, we re-evaluate genome-wide association study results and discover a previously unknown function of OsbZIP06 in seed germination, which we subsequently confirm through experimental validation. We optimize deep learning models to decode regulatory grammar, achieving robust modeling of tissue-specific chromatin accessibility. This approach allows to predict cross-variety regulatory dynamics from genomic sequences, shedding light on the genetic underpinnings of cis-regulatory divergence and morphological disparities between varieties. Overall, our study establishes a foundational resource for rice functional genomics and precision molecular breeding, providing valuable insights into regulatory mechanisms governing complex traits.
    DOI:  https://doi.org/10.1038/s41467-024-50787-y
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