bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒05‒05
58 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Inflammatory fibroblasts remodeling in colitis.
  2. Keeping neonatal intestines happy.
  3. Climbing out of the pit.
  4. Human SHARPIN deficiency is linked to inborn errors of cell death.
  5. Daily briefing: Gaze upon the most detailed Moon maps ever made.
  6. N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
  7. AnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics.
  8. The ouroboros of autoimmunity.
  9. Zombie malaria parasites.
  10. UTIs make life miserable - scientists are finding new ways to tackle them.
  11. How bioinformatics led one scientist home to Lithuania.
  12. Everlasting first impressions in B cells.
  13. A snapshot of Lithuania's life-sciences landscape.
  14. Genomic deletion of Bcl6 differentially affects conventional dendritic cell subsets and compromises Tfh/Tfr/Th17 cell responses.
  15. A fellow engineer and presidential rival.
  16. Baseline JAK-STAT signaling maintains immune cell homeostasis.
  17. How I'm supporting other researchers who have moved to Lithuania.
  18. CD8+ T-cell responses towards conserved influenza B virus epitopes across anatomical sites and age.
  19. New role for TLR9.
  20. Nextgen Voices: Preventing Bad Behavior.
  21. The Benjamin Button effect on stem cells: Reversing the clock on aging immunity.
  22. Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
  23. Cyclodipeptide oxidase is an enzyme filament.
  24. Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.
  25. A magnetic liquid makes for an injectable sensor in living tissue.
  26. I fell out of love with the lab, and in love with business.
  27. Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.
  28. Cachd1 interacts with Wnt receptors and regulates neuronal asymmetry in the zebrafish brain.
  29. Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
  30. Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.
  31. Primordial germ cell DNA demethylation and development require DNA translesion synthesis.
  32. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.
  33. Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
  34. Mount Etna's spectacular smoke rings and more - April's best science images.
  35. Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells.
  36. Reassessing data quality underlying the recently updated floristic map of the world.
  37. Galectin-3 impairs calcium transients and β-cell function.
  38. Scientists tried to give people COVID - and failed.
  39. Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.
  40. Elephant-nose fish 'see' farther by electric sensing when in groups.
  41. Found: the dial in the brain that controls the immune system.
  42. Bird flu virus has been spreading among US cows for months, RNA reveals.
  43. Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.
  44. Never mind little green men: life on other planets might be purple.
  45. Male-female comparisons are powerful in biomedical research - don't abandon them.
  46. Temporal dynamics and genomic programming of plasma cell fates.
  47. Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.
  48. Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
  49. Dad's microbiome can affect offspring's health - in mice.
  50. A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.
  51. Daily briefing: What scientists think of Netflix's 3 Body Problem.
  52. Stress during pubertal development affects female sociosexual behavior in mice.
  53. Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality.
  54. Multimodal decoding of human liver regeneration.
  55. Structural basis of TRPV1 modulation by endogenous bioactive lipids.
  56. The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.
  57. Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank.
  58. Cells destroy donated mitochondria to build blood vessels.
  1. Nat Immunol. 2024 May;25(5): 719
    Inflammatory fibroblasts remodeling in colitis.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-01839-4
  2. Nat Immunol. 2024 May;25(5): 719
    Keeping neonatal intestines happy.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01840-x
  3. Science. 2024 May 03. 384(6695): 594
    Climbing out of the pit.
    Will Hart.
      
    DOI:  https://doi.org/10.1126/science.adq1101
  4. Nat Immunol. 2024 May;25(5): 733-734
    Human SHARPIN deficiency is linked to inborn errors of cell death.
      
    DOI:  https://doi.org/10.1038/s41590-024-01838-5
  5. Nature. 2024 Apr 26.
    Daily briefing: Gaze upon the most detailed Moon maps ever made.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01266-3
  6. Immunity. 2024 Apr 26. pii: S1074-7613(24)00209-7. [Epub ahead of print]
    N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation.
    Alexander D Gitlin, Allie Maltzman, Yuzuka Kanno, Klaus Heger, Rohit Reja, Alexander F Schubert, Linsey J Wierciszewski, Homer Pantua, Sharookh B Kapadia, Seth F Harris, Joshua D Webster, Kim Newton, Vishva M Dixit.
      The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.
    Keywords:  Toll-like receptors; cytokines; inflammation; innate immunity; signal transduction
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.004
  7. Nat Commun. 2024 May 03. 15(1): 3744
    AnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics.
    Aanchal Mongia, Fatema Tuz Zohora, Noah G Burget, Yeqiao Zhou, Diane C Saunders, Yue J Wang, Marcela Brissova, Alvin C Powers, Klaus H Kaestner, Golnaz Vahedi, Ali Naji, Gregory W Schwartz, Robert B Faryabi.
      Cellular composition and anatomical organization influence normal and aberrant organ functions. Emerging spatial single-cell proteomic assays such as Image Mass Cytometry (IMC) and Co-Detection by Indexing (CODEX) have facilitated the study of cellular composition and organization by enabling high-throughput measurement of cells and their localization directly in intact tissues. However, annotation of cell types and quantification of their relative localization in tissues remain challenging. To address these unmet needs for atlas-scale datasets like Human Pancreas Analysis Program (HPAP), we develop AnnoSpat (Annotator and Spatial Pattern Finder) that uses neural network and point process algorithms to automatically identify cell types and quantify cell-cell proximity relationships. Our study of data from IMC and CODEX shows the higher performance of AnnoSpat in rapid and accurate annotation of cell types compared to alternative approaches. Moreover, the application of AnnoSpat to type 1 diabetic, non-diabetic autoantibody-positive, and non-diabetic organ donor cohorts recapitulates known islet pathobiology and shows differential dynamics of pancreatic polypeptide (PP) cell abundance and CD8+ T cells infiltration in islets during type 1 diabetes progression.
    DOI:  https://doi.org/10.1038/s41467-024-47334-0
  8. Nat Immunol. 2024 May;25(5): 743-754
    The ouroboros of autoimmunity.
    Jean-Laurent Casanova, Jessica Peel, Jean Donadieu, Anna-Lena Neehus, Anne Puel, Paul Bastard.
      Human autoimmunity against elements conferring protective immunity can be symbolized by the 'ouroboros', a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte-macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.
    DOI:  https://doi.org/10.1038/s41590-024-01815-y
  9. Science. 2024 May 03. 384(6695): 513-514
    Zombie malaria parasites.
    Jane M Carlton, Aubrey J Cunnington.
      Natural infections are distinct from those of laboratory-or zombie-strains.
    DOI:  https://doi.org/10.1126/science.adp0001
  10. Nature. 2024 May 02.
    UTIs make life miserable - scientists are finding new ways to tackle them.
    Carissa Wong.
      
    Keywords:  Drug discovery; Infection; Vaccines
    DOI:  https://doi.org/10.1038/d41586-024-01322-y
  11. Nature. 2024 May 01.
    How bioinformatics led one scientist home to Lithuania.
    Jacqui Thornton.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Careers; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-01141-1
  12. Sci Immunol. 2024 May 03. 9(95): eadq0015
    Everlasting first impressions in B cells.
    Soyeon Kim, Jonathan S Maltzman.
      Initial imprinting by type 1 interferons shapes memory B cell generation in chronic viral infection.
    DOI:  https://doi.org/10.1126/sciimmunol.adq0015
  13. Nature. 2024 May 01.
    A snapshot of Lithuania's life-sciences landscape.
    Jacqui Thornton.
      
    Keywords:  CRISPR-Cas9 genome editing; Careers
    DOI:  https://doi.org/10.1038/d41586-024-01139-9
  14. Nat Commun. 2024 Apr 30. 15(1): 3554
    Genomic deletion of Bcl6 differentially affects conventional dendritic cell subsets and compromises Tfh/Tfr/Th17 cell responses.
    Hongkui Xiao, Isabel Ulmert, Luisa Bach, Johanna Huber, Hamsa Narasimhan, Ilia Kurochkin, Yinshui Chang, Signe Holst, Urs Mörbe, Lili Zhang, Andreas Schlitzer, Carlos-Filipe Pereira, Barbara U Schraml, Dirk Baumjohann, Katharina Lahl.
      Conventional dendritic cells (cDC) play key roles in immune induction, but what drives their heterogeneity and functional specialization is still ill-defined. Here we show that cDC-specific deletion of the transcriptional repressor Bcl6 in mice alters the phenotype and transcriptome of cDC1 and cDC2, while their lineage identity is preserved. Bcl6-deficient cDC1 are diminished in the periphery but maintain their ability to cross-present antigen to CD8+ T cells, confirming general maintenance of this subset. Surprisingly, the absence of Bcl6 in cDC causes a complete loss of Notch2-dependent cDC2 in the spleen and intestinal lamina propria. DC-targeted Bcl6-deficient mice induced fewer T follicular helper cells despite a profound impact on T follicular regulatory cells in response to immunization and mounted diminished Th17 immunity to Citrobacter rodentium in the colon. Our findings establish Bcl6 as an essential transcription factor for subsets of cDC and add to our understanding of the transcriptional landscape underlying cDC heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-024-46966-6
  15. Science. 2024 May 03. 384(6695): 504
    A fellow engineer and presidential rival.
    Rodrigo Pérez Ortega.
      
    DOI:  https://doi.org/10.1126/science.adq1748
  16. Nat Immunol. 2024 May;25(5): 741-742
    Baseline JAK-STAT signaling maintains immune cell homeostasis.
      
    DOI:  https://doi.org/10.1038/s41590-024-01805-0
  17. Nature. 2024 May 01.
    How I'm supporting other researchers who have moved to Lithuania.
    Jacqui Thornton.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Careers; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-01142-0
  18. Nat Commun. 2024 Apr 29. 15(1): 3387
    CD8+ T-cell responses towards conserved influenza B virus epitopes across anatomical sites and age.
    Tejas Menon, Patricia T Illing, Priyanka Chaurasia, Hayley A McQuilten, Chloe Shepherd, Louise C Rowntree, Jan Petersen, Dene R Littler, Grace Khuu, Ziyi Huang, Lilith F Allen, Steve Rockman, Jane Crowe, Katie L Flanagan, Linda M Wakim, Thi H O Nguyen, Nicole A Mifsud, Jamie Rossjohn, Anthony W Purcell, Carolien E van de Sandt, Katherine Kedzierska.
      Influenza B viruses (IBVs) cause substantive morbidity and mortality, and yet immunity towards IBVs remains understudied. CD8+ T-cells provide broadly cross-reactive immunity and alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted by 5 HLAs have been identified currently. A broader array of conserved IBV T-cell epitopes is needed to develop effective cross-reactive T-cell based IBV vaccines. Here we identify 9 highly conserved IBV CD8+ T-cell epitopes restricted to HLA-B*07:02, HLA-B*08:01 and HLA-B*35:01. Memory IBV-specific tetramer+CD8+ T-cells are present within blood and tissues. Frequencies of IBV-specific CD8+ T-cells decline with age, but maintain a central memory phenotype. HLA-B*07:02 and HLA-B*08:01-restricted NP30-38 epitope-specific T-cells have distinct T-cell receptor repertoires. We provide structural basis for the IBV HLA-B*07:02-restricted NS1196-206 (11-mer) and HLA-B*07:02-restricted NP30-38 epitope presentation. Our study increases the number of IBV CD8+ T-cell epitopes, and defines IBV-specific CD8+ T-cells at cellular and molecular levels, across tissues and age.
    DOI:  https://doi.org/10.1038/s41467-024-47576-y
  19. Nat Immunol. 2024 May;25(5): 719
    New role for TLR9.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-024-01837-6
  20. Science. 2024 May 03. 384(6695): 518
    Nextgen Voices: Preventing Bad Behavior.
      
    DOI:  https://doi.org/10.1126/science.adq1492
  21. Sci Immunol. 2024 May 03. 9(95): eadq0013
    The Benjamin Button effect on stem cells: Reversing the clock on aging immunity.
    Luciana Conde, Carolina Lucas.
      Antibody-based therapy depletes myeloid-biased hematopoietic stem cells (my-HSCs) to rejuvenate the immune system and improve immune responses in aged mice.
    DOI:  https://doi.org/10.1126/sciimmunol.adq0013
  22. Nat Commun. 2024 Apr 30. 15(1): 3653
    Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
    Bingjie Guan, Youdong Liu, Bowen Xie, Senlin Zhao, Abudushalamu Yalikun, Weiwei Chen, Menghua Zhou, Qi Gu, Dongwang Yan.
      Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.
    DOI:  https://doi.org/10.1038/s41467-024-48100-y
  23. Nat Commun. 2024 Apr 27. 15(1): 3574
    Cyclodipeptide oxidase is an enzyme filament.
    Michael P Andreas, Tobias W Giessen.
      Modified cyclic dipeptides represent a widespread class of secondary metabolites with diverse pharmacological activities, including antibacterial, antifungal, and antitumor. Here, we report the structural characterization of the Streptomyces noursei enzyme AlbAB, a cyclodipeptide oxidase (CDO) carrying out α,β-dehydrogenations during the biosynthesis of the antibiotic albonoursin. We show that AlbAB is a megadalton heterooligomeric enzyme filament containing covalently bound flavin mononucleotide cofactors. We highlight that AlbAB filaments consist of alternating dimers of AlbA and AlbB and that enzyme activity is crucially dependent on filament formation. We show that AlbA-AlbB interactions are highly conserved suggesting that other CDO-like enzymes are likely enzyme filaments. As CDOs have been employed in the structural diversification of cyclic dipeptides, our results will be useful for future applications of CDOs in biocatalysis and chemoenzymatic synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-48030-9
  24. Nat Metab. 2024 May 02.
    Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.
    Hu Wang, Jiaxing Wang, Hao Cui, Chenyu Fan, Yuzhou Xue, Huiying Liu, Hui Li, Jianping Li, Houhua Li, Ying Sun, Wengong Wang, Jiangping Song, Changtao Jiang, Ming Xu.
      Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.
    DOI:  https://doi.org/10.1038/s42255-024-01036-5
  25. Nature. 2024 May;629(8011): 263
    A magnetic liquid makes for an injectable sensor in living tissue.
      
    Keywords:  Materials science
    DOI:  https://doi.org/10.1038/d41586-024-01262-7
  26. Nature. 2024 May 01.
    I fell out of love with the lab, and in love with business.
    Jacqui Thornton.
      
    Keywords:  Biotechnology; Business; CRISPR-Cas9 genome editing; Careers; Industry
    DOI:  https://doi.org/10.1038/d41586-024-01140-2
  27. Nat Commun. 2024 Apr 29. 15(1): 3631
    Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.
    Irene H Flønes, Lilah Toker, Dagny Ann Sandnes, Martina Castelli, Sepideh Mostafavi, Njål Lura, Omnia Shadad, Erika Fernandez-Vizarra, Cèlia Painous, Alexandra Pérez-Soriano, Yaroslau Compta, Laura Molina-Porcel, Guido Alves, Ole-Bjørn Tysnes, Christian Dölle, Gonzalo S Nido, Charalampos Tzoulis.
      Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-024-47867-4
  28. Science. 2024 May 03. 384(6695): 573-579
    Cachd1 interacts with Wnt receptors and regulates neuronal asymmetry in the zebrafish brain.
    Gareth T Powell, Ana Faro, Yuguang Zhao, Heather Stickney, Laura Novellasdemunt, Pedro Henriques, Gaia Gestri, Esther Redhouse White, Jingshan Ren, Weixian Lu, Rodrigo M Young, Thomas A Hawkins, Florencia Cavodeassi, Quenten Schwarz, Elena Dreosti, David W Raible, Vivian S W Li, Gavin J Wright, E Yvonne Jones, Stephen W Wilson.
      Neurons on the left and right sides of the nervous system often show asymmetric properties, but how such differences arise is poorly understood. Genetic screening in zebrafish revealed that loss of function of the transmembrane protein Cachd1 resulted in right-sided habenula neurons adopting left-sided identity. Cachd1 is expressed in neuronal progenitors, functions downstream of asymmetric environmental signals, and influences timing of the normally asymmetric patterns of neurogenesis. Biochemical and structural analyses demonstrated that Cachd1 can bind simultaneously to Lrp6 and Frizzled family Wnt co-receptors. Consistent with this, lrp6 mutant zebrafish lose asymmetry in the habenulae, and epistasis experiments support a role for Cachd1 in modulating Wnt pathway activity in the brain. These studies identify Cachd1 as a conserved Wnt receptor-interacting protein that regulates lateralized neuronal identity in the zebrafish brain.
    DOI:  https://doi.org/10.1126/science.ade6970
  29. Nat Metab. 2024 Apr 30.
    Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.
    Shan Jiang, Taolin Yuan, Florian A Rosenberger, Arnaud Mourier, Nathalia R V Dragano, Laura S Kremer, Diana Rubalcava-Gracia, Fynn M Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann, Nils-Göran Larsson.
      The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3-5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.
    DOI:  https://doi.org/10.1038/s42255-024-01038-3
  30. Nat Commun. 2024 May 02. 15(1): 3606
    Disease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls.
    Answer ALS Consortium
      Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.
    DOI:  https://doi.org/10.1038/s41467-024-47758-8
  31. Nat Commun. 2024 May 03. 15(1): 3734
    Primordial germ cell DNA demethylation and development require DNA translesion synthesis.
    Pranay Shah, Ross Hill, Camille Dion, Stephen J Clark, Abdulkadir Abakir, Jeroen Willems, Mark J Arends, Juan I Garaycoechea, Harry G Leitch, Wolf Reik, Gerry P Crossan.
      Mutations in DNA damage response (DDR) factors are associated with human infertility, which affects up to 15% of the population. The DDR is required during germ cell development and meiosis. One pathway implicated in human fertility is DNA translesion synthesis (TLS), which allows replication impediments to be bypassed. We find that TLS is essential for pre-meiotic germ cell development in the embryo. Loss of the central TLS component, REV1, significantly inhibits the induction of human PGC-like cells (hPGCLCs). This is recapitulated in mice, where deficiencies in TLS initiation (Rev1-/- or PcnaK164R/K164R) or extension (Rev7 -/-) result in a > 150-fold reduction in the number of primordial germ cells (PGCs) and complete sterility. In contrast, the absence of TLS does not impact the growth, function, or homeostasis of somatic tissues. Surprisingly, we find a complete failure in both activation of the germ cell transcriptional program and in DNA demethylation, a critical step in germline epigenetic reprogramming. Our findings show that for normal fertility, DNA repair is required not only for meiotic recombination but for progression through the earliest stages of germ cell development in mammals.
    DOI:  https://doi.org/10.1038/s41467-024-47219-2
  32. Nat Genet. 2024 Apr 30.
    Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.
    Million Veteran Program
      Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.
    DOI:  https://doi.org/10.1038/s41588-024-01714-w
  33. Nat Metab. 2024 May 03.
    Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.
    Juhong Wang, Yannan Yang, Fei Shao, Ying Meng, Dong Guo, Jie He, Zhimin Lu.
      Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01037-4
  34. Nature. 2024 May 03.
    Mount Etna's spectacular smoke rings and more - April's best science images.
    Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-024-01250-x
  35. Cell Stem Cell. 2024 Apr 26. pii: S1934-5909(24)00137-1. [Epub ahead of print]
    Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells.
    Huijuan Hua, Yaqi Wang, Xiaofeng Wang, Shusen Wang, Yunlu Zhou, Yinan Liu, Zhen Liang, Huixia Ren, Sufang Lu, Shuangshuang Wu, Yong Jiang, Yue Pu, Xiang Zheng, Chao Tang, Zhongyang Shen, Cheng Li, Yuanyuan Du, Hongkui Deng.
      Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for β cell maturation. Limiting intracellular accumulation of ceramides in hPSC-β cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic β cells and highlight the importance of ceramide homeostasis in function acquisition.
    Keywords:  ceramide homeostasis; functional maturation; hPSC-β cells
    DOI:  https://doi.org/10.1016/j.stem.2024.04.010
  36. Nat Commun. 2024 May 02. 15(1): 3674
    Reassessing data quality underlying the recently updated floristic map of the world.
    Hong Qian.
      
    DOI:  https://doi.org/10.1038/s41467-024-47543-7
  37. Nat Commun. 2024 May 01. 15(1): 3682
    Galectin-3 impairs calcium transients and β-cell function.
    Qian Jiang, Qijin Zhao, Yibing Chen, Chunxiao Ma, Xiaohong Peng, Xi Wu, Xingfeng Liu, Ruoran Wang, Shaocong Hou, Lijuan Kong, Yanjun Wan, Shusen Wang, Zhuo-Xian Meng, Bing Cui, Liangyi Chen, Pingping Li.
      In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-47959-1
  38. Nature. 2024 May 01.
    Scientists tried to give people COVID - and failed.
    Ewen Callaway.
      
    Keywords:  Infection; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-024-01284-1
  39. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2321836121
    Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.
    José L Fachi, Blanda Di Luccia, Susan Gilfillan, Hao-Wei Chang, Christina Song, Jiye Cheng, Marina Cella, Marco Aurelio Vinolo, Jeffrey I Gordon, Marco Colonna.
      Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.
    Keywords:  Clostridioides difficile colitis; IL-22 signaling; epithelial barrier; gut microbiota composition; short-chain fatty acids
    DOI:  https://doi.org/10.1073/pnas.2321836121
  40. Nature. 2024 Apr 29.
    Elephant-nose fish 'see' farther by electric sensing when in groups.
      
    Keywords:  Animal behaviour; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00464-3
  41. Nature. 2024 May 01.
    Found: the dial in the brain that controls the immune system.
    Giorgia Guglielmi.
      
    Keywords:  Brain; Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-01259-2
  42. Nature. 2024 Apr 27.
    Bird flu virus has been spreading among US cows for months, RNA reveals.
    Smriti Mallapaty.
      
    Keywords:  Genomics; Public health; Virology
    DOI:  https://doi.org/10.1038/d41586-024-01256-5
  43. Sci Immunol. 2024 May 03. 9(95): eadk0865
    Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.
    Rui Li, Yanting Lei, Ayman Rezk, Diego A Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C Goldstein, Brenda L Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or.
      Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adk0865
  44. Nature. 2024 May;629(8011): 263
    Never mind little green men: life on other planets might be purple.
      
    Keywords:  Exoplanets
    DOI:  https://doi.org/10.1038/d41586-024-01261-8
  45. Nature. 2024 May;629(8010): 37-40
    Male-female comparisons are powerful in biomedical research - don't abandon them.
    Arthur P Arnold, Sabra L Klein, Margaret M McCarthy, Jeffrey S Mogil.
      
    Keywords:  Diseases; Immunology; Neuroscience; Society
    DOI:  https://doi.org/10.1038/d41586-024-01205-2
  46. Nat Immunol. 2024 May 02.
    Temporal dynamics and genomic programming of plasma cell fates.
    Godhev Kumar Manakkat Vijay, Ming Zhou, Kairavee Thakkar, Abigail Rothrauff, Amanpreet Singh Chawla, Dianyu Chen, Louis Chi-Wai Lau, Peter Habib Gerges, Kashish Chetal, Prabal Chhibbar, Jingyu Fan, Jishnu Das, Alok Joglekar, Lisa Borghesi, Nathan Salomonis, Heping Xu, Harinder Singh.
      Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using single-cell RNA sequencing and B cell antigen receptor sequencing in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveals a new PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters in the GC.
    DOI:  https://doi.org/10.1038/s41590-024-01831-y
  47. Nat Commun. 2024 Apr 30. 15(1): 3666
    Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection.
    Sungmin Moon, Seunghan Han, In-Hwan Jang, Jaechan Ryu, Min-Seok Rha, Hyung-Ju Cho, Sang Sun Yoon, Ki Taek Nam, Chang-Hoon Kim, Man-Seong Park, Je Kyung Seong, Won-Jae Lee, Joo-Heon Yoon, Youn Wook Chung, Ji-Hwan Ryu.
      Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection.
    DOI:  https://doi.org/10.1038/s41467-024-47963-5
  48. Proc Natl Acad Sci U S A. 2024 May 07. 121(19): e2322164121
    Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.
    Vi T Tang, Jie Xiang, Zhimin Chen, Joseph McCormick, Prabhodh S Abbineni, Xiao-Wei Chen, Mark Hoenerhoff, Brian T Emmer, Rami Khoriaty, Jiandie D Lin, David Ginsburg.
      Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two SAR1 paralogs, SAR1A and SAR1B. While these paralogs exhibit ~90% amino acid sequence identity, it is unknown whether they perform distinct or overlapping functions in vivo. We now report that genetic inactivation of Sar1a in mice results in lethality during midembryogenesis. We also confirm previous reports that complete deficiency of murine Sar1b results in perinatal lethality. In contrast, we demonstrate that deletion of Sar1b restricted to hepatocytes is compatible with survival, though resulting in hypocholesterolemia that can be rescued by adenovirus-mediated overexpression of either SAR1A or SAR1B. To further examine the in vivo function of these two paralogs, we genetically engineered mice with the Sar1a coding sequence replacing that of Sar1b at the endogenous Sar1b locus. Mice homozygous for this allele survive to adulthood and are phenotypically normal, demonstrating complete or near-complete overlap in function between the two SAR1 protein paralogs in mice. These data also suggest upregulation of SAR1A gene expression as a potential approach for the treatment of SAR1B deficiency (chylomicron retention disease) in humans.
    Keywords:  COPII; SAR1; endoplasmic reticulum
    DOI:  https://doi.org/10.1073/pnas.2322164121
  49. Nature. 2024 May 01.
    Dad's microbiome can affect offspring's health - in mice.
    Benjamin Thompson, Nick Petrić Howe.
      
    Keywords:  Astronomy and astrophysics; Cancer; Genomics; Molecular biology; Palaeontology
    DOI:  https://doi.org/10.1038/d41586-024-01313-z
  50. Nat Commun. 2024 May 01. 15(1): 2869
    A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.
    Bani Mukhopadhyay, Cheryl Marietta, Pei-Hong Shen, Abdul Oiseni, Faridoddin Mirshahi, Maria Mazzu, Colin Hodgkinson, Eli Winkler, Qiaoping Yuan, Daniel Miranda, George Kunos, Arun J Sanyal, David Goldman.
      Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-47085-y
  51. Nature. 2024 May 01.
    Daily briefing: What scientists think of Netflix's 3 Body Problem.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-01317-9
  52. Nat Commun. 2024 Apr 30. 15(1): 3610
    Stress during pubertal development affects female sociosexual behavior in mice.
    Yassine Bentefour, Julie Bakker.
      Puberty is a crucial phase for the development of female sexual behavior. Growing evidence suggests that stress during this period may interfere with the development of sexual behavior. However, the neural circuits involved in this alteration remain elusive. Here, we demonstrated in mice that pubertal stress permanently disrupted sexual performance without affecting sexual preference. This was associated with a reduced expression and activation of neuronal nitric oxide synthase (nNOS) in the ventrolateral part of the ventromedial hypothalamus (VMHvl). Fiber photometry revealed that VMHvl nNOS neurons are strongly responsive to male olfactory cues with this activation being substantially reduced in pubertally stressed females. Finally, treatment with a NO donor partially restored sexual performance in pubertally stressed females. This study provides insights into the involvement of VMHvl nNOS in the processing of olfactory cues important for the expression of female sexual behavior. In addition, exposure to stress during puberty disrupts the integration of male olfactory cues leading to reduced sexual behavior.
    DOI:  https://doi.org/10.1038/s41467-024-47300-w
  53. J Clin Invest. 2024 May 01. pii: e176640. [Epub ahead of print]134(9):
    Integrated longitudinal multiomics study identifies immune programs associated with acute COVID-19 severity and mortality.
    IMPACC Network
      BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).
    Keywords:  Adaptive immunity; COVID-19; Immunology; Innate immunity
    DOI:  https://doi.org/10.1172/JCI176640
  54. Nature. 2024 May 01.
    Multimodal decoding of human liver regeneration.
    K P Matchett, J R Wilson-Kanamori, J R Portman, C A Kapourani, F Fercoq, S May, E Zajdel, M Beltran, E F Sutherland, J B G Mackey, M Brice, G C Wilson, S J Wallace, L Kitto, N T Younger, R Dobie, D J Mole, G C Oniscu, S J Wigmore, P Ramachandran, C A Vallejos, N O Carragher, M M Saeidinejad, A Quaglia, R Jalan, K J Simpson, T J Kendall, J A Rule, W M Lee, M Hoare, C J Weston, J C Marioni, S A Teichmann, T G Bird, L M Carlin, N C Henderson.
      The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-024-07376-2
  55. Nat Struct Mol Biol. 2024 May 02.
    Structural basis of TRPV1 modulation by endogenous bioactive lipids.
    William R Arnold, Adamo Mancino, Frank R Moss, Adam Frost, David Julius, Yifan Cheng.
      TRP ion channels are modulated by phosphoinositide lipids, but the underlying structural mechanisms remain unclear. The capsaicin- and heat-activated receptor, TRPV1, has served as a model for deciphering lipid modulation, which is relevant to understanding how pro-algesic agents enhance channel activity in the setting of inflammatory pain. Identification of a pocket within the TRPV1 transmembrane core has provided initial clues as to how phosphoinositide lipids bind to and regulate the channel. Here we show that this regulatory pocket in rat TRPV1 can accommodate diverse lipid species, including the inflammatory lipid lysophosphatidic acid, whose actions are determined by their specific modes of binding. Furthermore, we show that an empty-pocket channel lacking an endogenous phosphoinositide lipid assumes an agonist-like state, even at low temperature, substantiating the concept that phosphoinositide lipids serve as negative TRPV1 modulators whose ejection from the binding pocket is a critical step toward activation by thermal or chemical stimuli.
    DOI:  https://doi.org/10.1038/s41594-024-01299-2
  56. Nat Commun. 2024 May 02. 15(1): 3711
    The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.
    Di Wu, Renhong Yan, Siyuan Song, Andrew K Swansiger, Yaning Li, James S Prell, Qiang Zhou, Carol V Robinson.
      The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc)2. When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.
    DOI:  https://doi.org/10.1038/s41467-024-47948-4
  57. Nat Commun. 2024 May 02. 15(1): 3707
    Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank.
    Zhening Liu, Hangkai Huang, Jiarong Xie, Yingying Xu, Chengfu Xu.
      Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC [HRQ4vsQ1: 0.48 (95% CI: 0.33-0.69) and 0.48 (95% CI: 0.28-0.81), respectively] and CLD mortality [HRQ4vsQ1: 0.21 (95% CI: 0.13-0.33) and 0.15 (95% CI: 0.08-0.30), respectively], whereas plasma levels of saturated fatty acids are positively associated with these outcomes [HRQ4vsQ1: 3.55 (95% CI: 2.25-5.61) for HCC and 6.34 (95% CI: 3.68-10.92) for CLD mortality]. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.
    DOI:  https://doi.org/10.1038/s41467-024-47960-8
  58. Nature. 2024 May 01.
    Cells destroy donated mitochondria to build blood vessels.
    Chantell S Evans.
      
    Keywords:  Cardiovascular biology; Cell biology; Diabetes; Regeneration
    DOI:  https://doi.org/10.1038/d41586-024-01233-y
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