bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–06–30
fifty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Ferroptotic stress drives liver aging and metabolic dysfunction.
  2. Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
  3. Lymphoid TCF1+CD39+CD8+ T cells maintain stem-like features and contribute to viral control.
  4. Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
  5. UK general election: five reasons it matters for science.
  6. Obesity-associated microbiomes instigate visceral adipose tissue inflammation by recruitment of distinct neutrophils.
  7. Families given cash with no strings spend more money on kids.
  8. Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.
  9. Maturation of germinal center B cells after influenza virus vaccination in humans.
  10. 'Epigenome editor' silences gene that causes deadly brain disorders.
  11. H3K9 methylation regulates heterochromatin silencing through incoherent feedforward loops.
  12. How researchers navigate a PhD later in life.
  13. A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion.
  14. Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
  15. Does Ozempic boost fertility? What the science says.
  16. Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident.
  17. Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.
  18. A fluorescent perilipin 2 knock-in mouse model reveals a high abundance of lipid droplets in the developing and adult brain.
  19. Structure of the Hir histone chaperone complex.
  20. Phage predation accelerates the spread of plasmid-encoded antibiotic resistance.
  21. Aged mice regain youthful muscles thanks to a compound that acts on the genes.
  22. Vaccination prevents cognitive impairment after breakthrough infection with SARS-CoV-2.
  23. Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
  24. Estonians gave their DNA to science - now they're learning their genetic secrets.
  25. Daily briefing: How this lab became one of the most successful in the world.
  26. What it means to be a successful male academic.
  27. Structural mechanism of bridge RNA-guided recombination.
  28. Deep learning-based prediction of one-year mortality in Finland is an accurate but unfair aging marker.
  29. Mef2d potentiates type-2 immune responses and allergic lung inflammation.
  30. Combined COVID-flu vaccines are coming: Moderna jab clears major test.
  31. Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.
  32. Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress.
  33. A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses.
  34. Myelin-reactive B cells exacerbate CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner.
  35. Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints.
  36. Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
  37. A high-density 1,024-channel probe for brain-wide recordings in non-human primates.
  38. The transitory origins of rivers.
  39. Open-ST: High-resolution spatial transcriptomics in 3D.
  40. Interconnected lineage trajectories link conventional and natural killer (NK)-like exhausted CD8+ T cells beneficial in type 1 diabetes.
  41. Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation.
  42. An epigenetic editor to silence genes.
  43. Borg extrachromosomal elements of methane-oxidizing archaea have conserved and expressed genetic repertoires.
  44. Untangling the genetics of beta cell dysfunction and death in type 1 diabetes.
  45. PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.
  46. The dance of gut microbes on the keto diet.
  47. TRIM26 deficiency enhancing liver regeneration through macrophage polarization and β-catenin pathway activation.
  48. Molecular insight into interactions between the Taf14, Yng1 and Sas3 subunits of the NuA3 complex.
  49. MethPhaser: methylation-based long-read haplotype phasing of human genomes.
  50. Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.
  51. The extracellular matrix integrates mitochondrial homeostasis.
  52. Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation.
  53. Comparative optimization of polysaccharide-based nanoformulations for cardiac RNAi therapy.
  54. METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.
  55. Ketamine for depression: slow-release pills could make treatment more accessible.
  56. How to network with the brightest minds in science.
  57. IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.
  58. Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure.
  59. Revised criteria for the diagnosis and staging of Alzheimer's disease.
  1. Nat Aging. 2024 Jun 26.
    Ferroptotic stress drives liver aging and metabolic dysfunction.
      
    DOI:  https://doi.org/10.1038/s43587-024-00654-8
  2. Nat Commun. 2024 Jun 25. 15(1): 5394
    Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
    Bam D Paneru, Julia Chini, Sam J McCright, Nicole DeMarco, Jessica Miller, Leonel D Joannas, Jorge Henao-Mejia, Paul M Titchenell, David M Merrick, Hee-Woong Lim, Mitchell A Lazar, David A Hill.
      Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
    DOI:  https://doi.org/10.1038/s41467-024-49632-z
  3. Nat Immunol. 2024 Jun 25.
    Lymphoid TCF1+CD39+CD8+ T cells maintain stem-like features and contribute to viral control.
      
    DOI:  https://doi.org/10.1038/s41590-024-01889-8
  4. Nature. 2024 Jun 26.
    Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
    Parul Mehrotra, Sophia Maschalidi, Laura Boeckaerts, Christian Maueröder, Rochelle Tixeira, Jonathan Pinney, Javier Burgoa Cardás, Vladimir Sukhov, Yunus Incik, Christopher J Anderson, Bing Hu, Burcu N Keçeli, Amanda Goncalves, Lieselotte Vande Walle, Nina Van Opdenbosch, Alexey Sergushichev, Esther Hoste, Umang Jain, Mohamed Lamkanfi, Kodi S Ravichandran.
      Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases1-4. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro-1), we identify unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.
    DOI:  https://doi.org/10.1038/s41586-024-07585-9
  5. Nature. 2024 Jun 26.
    UK general election: five reasons it matters for science.
    Jonathan O'Callaghan, Elizabeth Gibney.
      
    Keywords:  Politics
    DOI:  https://doi.org/10.1038/d41586-024-02110-4
  6. Nat Commun. 2024 Jun 27. 15(1): 5434
    Obesity-associated microbiomes instigate visceral adipose tissue inflammation by recruitment of distinct neutrophils.
    Dharti Shantaram, Rebecca Hoyd, Alecia M Blaszczak, Linda Antwi, Anahita Jalilvand, Valerie P Wright, Joey Liu, Alan J Smith, David Bradley, William Lafuse, YunZhou Liu, Nyelia F Williams, Owen Snyder, Caroline Wheeler, Bradley Needleman, Stacy Brethauer, Sabrena Noria, David Renton, Kyle A Perry, Prabha Nagareddy, Daniel Wozniak, Sahil Mahajan, Pranav S J B Rana, Maciej Pietrzak, Larry S Schlesinger, Daniel J Spakowicz, Willa A Hsueh.
      Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.
    DOI:  https://doi.org/10.1038/s41467-024-48935-5
  7. Nature. 2024 Jun 25.
    Families given cash with no strings spend more money on kids.
      
    Keywords:  Society
    DOI:  https://doi.org/10.1038/d41586-024-02097-y
  8. Cell. 2024 Jun 23. pii: S0092-8674(24)00631-7. [Epub ahead of print]
    Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.
    Stephanie Berger, Franziska Seeger, Ta-Yi Yu, Merve Aydin, Huilin Yang, Daniel Rosenblum, Laure Guenin-Macé, Caleb Glassman, Lauren Arguinchona, Catherine Sniezek, Alyssa Blackstone, Lauren Carter, Rashmi Ravichandran, Maggie Ahlrichs, Michael Murphy, Ingrid Swanson Pultz, Alex Kang, Asim K Bera, Lance Stewart, K Christopher Garcia, Shruti Naik, Jamie B Spangler, Florian Beigel, Matthias Siebeck, Roswitha Gropp, David Baker.
      Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.
    Keywords:  IL-17; IL-23R; Th17; autoinflammation; computational protein design; inflammatory bowel disease; oral biologics; protein engineering
    DOI:  https://doi.org/10.1016/j.cell.2024.05.052
  9. J Exp Med. 2024 Aug 05. pii: e20240668. [Epub ahead of print]221(8):
    Maturation of germinal center B cells after influenza virus vaccination in humans.
    Katherine M McIntire, Hailong Meng, Ting-Hui Lin, Wooseob Kim, Nina E Moore, Julianna Han, Meagan McMahon, Meng Wang, Sameer Kumar Malladi, Bassem M Mohammed, Julian Q Zhou, Aaron J Schmitz, Kenneth B Hoehn, Juan Manuel Carreño, Temima Yellin, Teresa Suessen, William D Middleton, Sharlene A Teefey, Rachel M Presti, Florian Krammer, Jackson S Turner, Andrew B Ward, Ian A Wilson, Steven H Kleinstein, Ali H Ellebedy.
      Germinal centers (GC) are microanatomical lymphoid structures where affinity-matured memory B cells and long-lived bone marrow plasma cells are primarily generated. It is unclear how the maturation of B cells within the GC impacts the breadth and durability of B cell responses to influenza vaccination in humans. We used fine needle aspiration of draining lymph nodes to longitudinally track antigen-specific GC B cell responses to seasonal influenza vaccination. Antigen-specific GC B cells persisted for at least 13 wk after vaccination in two out of seven individuals. Monoclonal antibodies (mAbs) derived from persisting GC B cell clones exhibit enhanced binding affinity and breadth to influenza hemagglutinin (HA) antigens compared with related GC clonotypes isolated earlier in the response. Structural studies of early and late GC-derived mAbs from one clonal lineage in complex with H1 and H5 HAs revealed an altered binding footprint. Our study shows that inducing sustained GC reactions after influenza vaccination in humans supports the maturation of responding B cells.
    DOI:  https://doi.org/10.1084/jem.20240668
  10. Nature. 2024 Jun 27.
    'Epigenome editor' silences gene that causes deadly brain disorders.
    Gemma Conroy.
      
    Keywords:  Diseases; Epigenetics
    DOI:  https://doi.org/10.1038/d41586-024-02115-z
  11. Sci Adv. 2024 Jun 28. 10(26): eadn4149
    H3K9 methylation regulates heterochromatin silencing through incoherent feedforward loops.
    Kannosuke Yabe, Asuka Kamio, Satoyo Oya, Tetsuji Kakutani, Mami Hirayama, Yuriko Tanaka, Soichi Inagaki.
      Histone H3 lysine-9 methylation (H3K9me) is a hallmark of the condensed and transcriptionally silent heterochromatin. It remains unclear how H3K9me controls transcription silencing and how cells delimit H3K9me domains to avoid silencing essential genes. Here, using Arabidopsis genetic systems that induce H3K9me2 in genes and transposons de novo, we show that H3K9me2 accumulation paradoxically also causes the deposition of the euchromatic mark H3K36me3 by a SET domain methyltransferase, ASHH3. ASHH3-induced H3K36me3 confers anti-silencing by preventing the demethylation of H3K4me1 by LDL2, which mediates transcriptional silencing downstream of H3K9me2. These results demonstrate that H3K9me2 not only facilitates but orchestrates silencing by actuating antagonistic silencing and anti-silencing pathways, providing insights into the molecular basis underlying proper partitioning of chromatin domains and the creation of metastable epigenetic variation.
    DOI:  https://doi.org/10.1126/sciadv.adn4149
  12. Nature. 2024 Jun 25.
    How researchers navigate a PhD later in life.
    Elizabeth Landau.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-02109-x
  13. Cell Host Microbe. 2024 Jun 17. pii: S1931-3128(24)00193-8. [Epub ahead of print]
    A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion.
    Desmond Richmond-Buccola, Samuel J Hobbs, Jasmine M Garcia, Hunter Toyoda, Jingjing Gao, Sichen Shao, Amy S Y Lee, Philip J Kranzusch.
      Cyclic oligonucleotide-based signaling system (CBASS) is an antiviral system that protects bacteria from phage infection and is evolutionarily related to human cGAS-STING immunity. cGAS-STING signaling is initiated by the recognition of viral DNA, but the molecular cues activating CBASS are incompletely understood. Using a screen of 975 type I CBASS operon-phage challenges, we show that operons with distinct cGAS/DncV-like nucleotidyltransferases (CD-NTases) and CD-NTase-associated protein (Cap) effectors exhibit marked patterns of phage restriction. We find that some type I CD-NTase enzymes require a C-terminal AGS-C immunoglobulin (Ig)-like fold domain for defense against select phages. Escaper phages evade CBASS via protein-coding mutations in virion assembly proteins, and acquired resistance is largely operon specific. We demonstrate that the phage Bas13 prohead protease interacts with the CD-NTase EcCdnD12 and can induce CBASS-dependent growth arrest in cells. Our results define phage virion assembly as a determinant of type I CBASS immune evasion and support viral protein recognition as a putative mechanism of cGAS-like enzyme activation.
    Keywords:  CBASS; CD-NTase; antiphage defense; viral assembly; viral immune evasion
    DOI:  https://doi.org/10.1016/j.chom.2024.05.021
  14. Nat Commun. 2024 Jun 25. 15(1): 5386
    Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues.
    Marlous Kamp, Jakub Surmacki, Marc Segarra Mondejar, Tim Young, Karolina Chrabaszcz, Fadwa Joud, Vincent Zecchini, Alyson Speed, Christian Frezza, Sarah E Bohndiek.
      Aberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.
    DOI:  https://doi.org/10.1038/s41467-024-49403-w
  15. Nature. 2024 Jun 26.
    Does Ozempic boost fertility? What the science says.
    Gillian Dohrn.
      
    Keywords:  Developmental biology; Diabetes; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-02045-w
  16. Sci Immunol. 2024 Jun 28. 9(96): eadj8356
    Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident.
    Erin D Lucas, Matthew A Huggins, Changwei Peng, Christine O'Connor, Abigail R Gress, Claire E Thefaine, Emma M Dehm, Yoshiaki Kubota, Stephen C Jameson, Sara E Hamilton.
      KLRG1+ CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1- memory subsets such as central and effector memory T cells. Thus, KLRG1+ memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1+ or KLRG1- memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.
    DOI:  https://doi.org/10.1126/sciimmunol.adj8356
  17. Cell. 2024 Jun 24. pii: S0092-8674(24)00639-1. [Epub ahead of print]
    Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain.
    Nicole Scott-Hewitt, Matthew Mahoney, Youtong Huang, Nils Korte, T Yvanka de Soysa, Daniel K Wilton, Emily Knorr, Kevin Mastro, Allison Chang, Allison Zhang, David Melville, Monica Schenone, Christina Hartigan, Beth Stevens.
      Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in both developmental and disease models, yet brain C1q protein levels increase significantly throughout aging. Here, we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a role of C1q in critical intracellular neuronal processes.
    Keywords:  C1q; RNA granule; RNA-binding protein; complement; liquid-liquid phase separation; microglia; neuroimmune; neuronal translation; polysome; ribonucleoprotein complex
    DOI:  https://doi.org/10.1016/j.cell.2024.05.058
  18. Nat Commun. 2024 Jun 28. 15(1): 5489
    A fluorescent perilipin 2 knock-in mouse model reveals a high abundance of lipid droplets in the developing and adult brain.
    Sofia Madsen, Ana C Delgado, Christelle Cadilhac, Vanille Maillard, Fabrice Battiston, Carla Marie Igelbüscher, Simon De Neck, Elia Magrinelli, Denis Jabaudon, Ludovic Telley, Fiona Doetsch, Marlen Knobloch.
      Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by labelling the endogenous LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are highly abundant in various cell types in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we also show that LDs are abundant during brain development and can be visualized using live imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2.
    DOI:  https://doi.org/10.1038/s41467-024-49449-w
  19. Mol Cell. 2024 Jun 20. pii: S1097-2765(24)00478-7. [Epub ahead of print]
    Structure of the Hir histone chaperone complex.
    Hee Jong Kim, Mary R Szurgot, Trevor van Eeuwen, M Daniel Ricketts, Pratik Basnet, Athena L Zhang, Austin Vogt, Samah Sharmin, Craig D Kaplan, Benjamin A Garcia, Ronen Marmorstein, Kenji Murakami.
      The evolutionarily conserved HIRA/Hir histone chaperone complex and ASF1a/Asf1 co-chaperone cooperate to deposit histone (H3/H4)2 tetramers on DNA for replication-independent chromatin assembly. The molecular architecture of the HIRA/Hir complex and its mode of histone deposition have remained unknown. Here, we report the cryo-EM structure of the S. cerevisiae Hir complex with Asf1/H3/H4 at 2.9-6.8 Å resolution. We find that the Hir complex forms an arc-shaped dimer with a Hir1/Hir2/Hir3/Hpc2 stoichiometry of 2/4/2/4. The core of the complex containing two Hir1/Hir2/Hir2 trimers and N-terminal segments of Hir3 forms a central cavity containing two copies of Hpc2, with one engaged by Asf1/H3/H4, in a suitable position to accommodate a histone (H3/H4)2 tetramer, while the C-terminal segments of Hir3 harbor nucleic acid binding activity to wrap DNA around the Hpc2-assisted histone tetramer. The structure suggests a model for how the Hir/Asf1 complex promotes the formation of histone tetramers for their subsequent deposition onto DNA.
    Keywords:  Asf1; H3/H4; HIRA; Hir; chromatin; crosslinking mass spectrometry; cryo-electron microscopy; histone chaperone; nucleosome; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2024.05.031
  20. Nat Commun. 2024 Jun 26. 15(1): 5397
    Phage predation accelerates the spread of plasmid-encoded antibiotic resistance.
    Chujin Ruan, Josep Ramoneda, Anton Kan, Timothy J Rudge, Gang Wang, David R Johnson.
      Phage predation is generally assumed to reduce microbial proliferation while not contributing to the spread of antibiotic resistance. However, this assumption does not consider the effect of phage predation on the spatial organization of different microbial populations. Here, we show that phage predation can increase the spread of plasmid-encoded antibiotic resistance during surface-associated microbial growth by reshaping spatial organization. Using two strains of the bacterium Escherichia coli, we demonstrate that phage predation slows the spatial segregation of the strains during growth. This increases the number of cell-cell contacts and the extent of conjugation-mediated plasmid transfer between them. The underlying mechanism is that phage predation shifts the location of fastest growth from the biomass periphery to the interior where cells are densely packed and aligned closer to parallel with each other. This creates straighter interfaces between the strains that are less likely to merge together during growth, consequently slowing the spatial segregation of the strains and enhancing plasmid transfer between them. Our results have implications for the design and application of phage therapy and reveal a mechanism for how microbial functions that are deleterious to human and environmental health can proliferate in the absence of positive selection.
    DOI:  https://doi.org/10.1038/s41467-024-49840-7
  21. Nature. 2024 Jun 26.
    Aged mice regain youthful muscles thanks to a compound that acts on the genes.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-024-02100-6
  22. Nat Immunol. 2024 Jun 25.
    Vaccination prevents cognitive impairment after breakthrough infection with SARS-CoV-2.
      
    DOI:  https://doi.org/10.1038/s41590-024-01869-y
  23. Sci Adv. 2024 Jun 28. 10(26): eadn5228
    Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
    Shalil Khanal, Yuanhang Liu, Adebowale O Bamidele, Alexander Q Wixom, Alexander M Washington, Nidhi Jalan-Sakrikar, Shawna A Cooper, Ivan Vuckovic, Song Zhang, Jun Zhong, Kenneth L Johnson, M Cristine Charlesworth, Iljung Kim, Yubin Yeon, Sangwoong Yoon, Yung-Kyun Noh, Chady Meroueh, Abdul Aziz Timbilla, Usman Yaqoob, Jinhang Gao, Yohan Kim, Fabrice Lucien, Robert C Huebert, Nissim Hay, Michael Simons, Vijay H Shah, Enis Kostallari.
      Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
    DOI:  https://doi.org/10.1126/sciadv.adn5228
  24. Nature. 2024 Jun 26.
    Estonians gave their DNA to science - now they're learning their genetic secrets.
    Ewen Callaway.
      
    Keywords:  Databases; Diseases; Genomics
    DOI:  https://doi.org/10.1038/d41586-024-02108-y
  25. Nature. 2024 Jun 27.
    Daily briefing: How this lab became one of the most successful in the world.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02148-4
  26. Nature. 2024 Jun 26.
    What it means to be a successful male academic.
    Dritjon Gruda.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-02105-1
  27. Nature. 2024 Jun;630(8018): 994-1002
    Structural mechanism of bridge RNA-guided recombination.
    Masahiro Hiraizumi, Nicholas T Perry, Matthew G Durrant, Teppei Soma, Naoto Nagahata, Sae Okazaki, Januka S Athukoralage, Yukari Isayama, James J Pai, April Pawluk, Silvana Konermann, Keitaro Yamashita, Patrick D Hsu, Hiroshi Nishimasu.
      Insertion sequence (IS) elements are the simplest autonomous transposable elements found in prokaryotic genomes1. We recently discovered that IS110 family elements encode a recombinase and a non-coding bridge RNA (bRNA) that confers modular specificity for target DNA and donor DNA through two programmable loops2. Here we report the cryo-electron microscopy structures of the IS110 recombinase in complex with its bRNA, target DNA and donor DNA in three different stages of the recombination reaction cycle. The IS110 synaptic complex comprises two recombinase dimers, one of which houses the target-binding loop of the bRNA and binds to target DNA, whereas the other coordinates the bRNA donor-binding loop and donor DNA. We uncovered the formation of a composite RuvC-Tnp active site that spans the two dimers, positioning the catalytic serine residues adjacent to the recombination sites in both target and donor DNA. A comparison of the three structures revealed that (1) the top strands of target and donor DNA are cleaved at the composite active sites to form covalent 5'-phosphoserine intermediates, (2) the cleaved DNA strands are exchanged and religated to create a Holliday junction intermediate, and (3) this intermediate is subsequently resolved by cleavage of the bottom strands. Overall, this study reveals the mechanism by which a bispecific RNA confers target and donor DNA specificity to IS110 recombinases for programmable DNA recombination.
    DOI:  https://doi.org/10.1038/s41586-024-07570-2
  28. Nat Aging. 2024 Jun 24.
    Deep learning-based prediction of one-year mortality in Finland is an accurate but unfair aging marker.
    Andrius Vabalas, Tuomo Hartonen, Pekka Vartiainen, Sakari Jukarainen, Essi Viippola, Rodosthenis S Rodosthenous, Aoxing Liu, Sara Hägg, Markus Perola, Andrea Ganna.
      Short-term mortality risk, which is indicative of individual frailty, serves as a marker for aging. Previous age clocks focused on predicting either chronological age or longer-term mortality. Aging clocks predicting short-term mortality are lacking and their algorithmic fairness remains unexamined. We developed a deep learning model to predict 1-year mortality using nationwide longitudinal data from the Finnish population (FinRegistry; n = 5.4 million), incorporating more than 8,000 features spanning up to 50 years. We achieved an area under the curve (AUC) of 0.944, outperforming a baseline model that included only age and sex (AUC = 0.897). The model generalized well to different causes of death (AUC > 0.800 for 45 of 50 causes), including coronavirus disease 2019, which was absent in the training data. Performance varied among demographics, with young females exhibiting the best and older males the worst results. Extensive prediction fairness analyses highlighted disparities among disadvantaged groups, posing challenges to equitable integration into public health interventions. Our model accurately identified short-term mortality risk, potentially serving as a population-wide aging marker.
    DOI:  https://doi.org/10.1038/s43587-024-00657-5
  29. Science. 2024 Jun 28. 384(6703): eadl0370
    Mef2d potentiates type-2 immune responses and allergic lung inflammation.
    Aydan C H Szeto, Paula A Clark, Ana C F Ferreira, Morgan Heycock, Emma L Griffiths, Eric Jou, Jonathan Mannion, Shi-Lu Luan, Sophie Storrar, Martin D Knolle, Patrycja Kozik, Helen E Jolin, Padraic G Fallon, Andrew N J McKenzie.
      Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.
    DOI:  https://doi.org/10.1126/science.adl0370
  30. Nature. 2024 Jun 28.
    Combined COVID-flu vaccines are coming: Moderna jab clears major test.
    Freda Kreier.
      
    Keywords:  Public health; Vaccines; Virology
    DOI:  https://doi.org/10.1038/d41586-024-02121-1
  31. J Exp Med. 2024 Sep 02. pii: e20232068. [Epub ahead of print]221(9):
    Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.
    Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng.
      Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
    DOI:  https://doi.org/10.1084/jem.20232068
  32. Nat Aging. 2024 Jun 25.
    Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress.
    Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, Dennis C Ko, Anna Mae Diehl.
      Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration.
    DOI:  https://doi.org/10.1038/s43587-024-00652-w
  33. Nat Immunol. 2024 Jun 25.
    A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses.
    Daniel P Chupp, Carlos E Rivera, Yulai Zhou, Yijiang Xu, Patrick S Ramsey, Zhenming Xu, Hong Zan, Paolo Casali.
      Humanized mice are limited in terms of modeling human immunity, particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated KitW-41J mutant immunodeficient pups with human cord blood CD34+ cells, followed by 17β-estradiol conditioning to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue, including Peyer's patches, and human thymic epithelial cells. These mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses, entailing somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon flagellin or Pfizer coronavirus disease 2019 mRNA vaccination, THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain, with blood incretion of human cytokines, including APRIL, BAFF, TGF-β, IL-4 and IFN-γ, all at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses, THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics.
    DOI:  https://doi.org/10.1038/s41590-024-01880-3
  34. Nat Commun. 2024 Jun 26. 15(1): 5404
    Myelin-reactive B cells exacerbate CD4+ T cell-driven CNS autoimmunity in an IL-23-dependent manner.
    Mohamed Reda Fazazi, Prenitha Mercy Ignatius Arokia Doss, Resel Pereira, Neva Fudge, Aryan Regmi, Charles Joly-Beauparlant, Irshad Akbar, Asmita Pradeep Yeola, Benoit Mailhot, Joanie Baillargeon, Philippe Grenier, Nicolas Bertrand, Steve Lacroix, Arnaud Droit, Craig S Moore, Olga L Rojas, Manu Rangachari.
      B cells and T cells collaborate in multiple sclerosis (MS) pathogenesis. IgH[MOG] mice possess a B cell repertoire skewed to recognize myelin oligodendrocyte glycoprotein (MOG). Here, we show that upon immunization with the T cell-obligate autoantigen, MOG[35-55], IgH[MOG] mice develop rapid and exacerbated experimental autoimmune encephalomyelitis (EAE) relative to wildtype (WT) counterparts, characterized by aggregation of T and B cells in the IgH[MOG] meninges and by CD4+ T helper 17 (Th17) cells in the CNS. Production of the Th17 maintenance factor IL-23 is observed from IgH[MOG] CNS-infiltrating and meningeal B cells, and in vivo blockade of IL-23p19 attenuates disease severity in IgH[MOG] mice. In the CNS parenchyma and dura mater of IgH[MOG] mice, we observe an increased frequency of CD4+PD-1+CXCR5- T cells that share numerous characteristics with the recently described T peripheral helper (Tph) cell subset. Further, CNS-infiltrating B and Tph cells from IgH[MOG] mice show increased reactive oxygen species (ROS) production. Meningeal inflammation, Tph-like cell accumulation in the CNS and B/Tph cell production of ROS were all reduced upon p19 blockade. Altogether, MOG-specific B cells promote autoimmune inflammation of the CNS parenchyma and meninges in an IL-23-dependent manner.
    DOI:  https://doi.org/10.1038/s41467-024-49259-0
  35. Nat Commun. 2024 Jun 26. 15(1): 5426
    Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints.
    Ethan C Veit, Madihah S Salim, Mariel J Jung, R Blake Richardson, Ian N Boys, Meghan Quinlan, Erika A Barrall, Eva Bednarski, Rachael E Hamilton, Caroline Kikawa, Nels C Elde, Adolfo García-Sastre, Matthew J Evans.
      Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.
    DOI:  https://doi.org/10.1038/s41467-024-49758-0
  36. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00728-9. [Epub ahead of print]43(7): 114400
    Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulates ADAR1-mediated immunity in the liver.
    Wei Liang Gan, Xi Ren, Vanessa Hui En Ng, Larry Ng, Yangyang Song, Vincent Tano, Jian Han, Omer An, Jinghe Xie, Bryan Y L Ng, Daryl Jin Tai Tay, Sze Jing Tang, Haoqing Shen, Shruti Khare, Kelvin Han Chung Chong, Dan Yock Young, Bin Wu, Ramanuj DasGupta, Leilei Chen.
      ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
    Keywords:  ADAR1; CP: Cell biology; CP: Immunology; EGFR; HCC; PGRN; RNA editing; immunosuppression; innate immunity; liver inflammation; macrophage infiltration
    DOI:  https://doi.org/10.1016/j.celrep.2024.114400
  37. Nat Neurosci. 2024 Jun 24.
    A high-density 1,024-channel probe for brain-wide recordings in non-human primates.
    Yang Liu, Huilin Jia, Hongji Sun, Shengyi Jia, Ziqian Yang, Ao Li, Anqi Jiang, Yuji Naya, Cen Yang, Shengyuan Xue, Xiaojian Li, Bingyan Chen, Jingjun Zhu, Chenghao Zhou, Minning Li, Xiaojie Duan.
      Large-scale neural population recordings with single-cell resolution across the primate brain remain challenging. Here we introduce the Neuroscroll probe that isolates single neuronal activities simultaneously from 1,024 densely spaced channels that are flexibly distributed across the shank of the probe. The Neuroscroll probe length is easily tunable for individual probes from 10 mm to 90 mm, covering the brain size of non-human primates and humans, and the probes remain intact and functional after repeated bending deformations. The Neuroscroll probes provided reliable recordings from large neural populations with high chronic stability up to 105 weeks in rats. Recording with each Neuroscroll probe yielded hundreds of well-isolated single units simultaneously from multiple brain regions distributed across the entire depth of the rhesus macaque brain. With the thousand simultaneously recorded channels, unprecedented probe length, excellent mechanical stability and flexible recording site distribution, the Neuroscroll probes enable a wide range of new experimental paradigms in system neuroscience studies with great versatility.
    DOI:  https://doi.org/10.1038/s41593-024-01692-6
  38. Science. 2024 Jun 28. 384(6703): 1402-1403
    The transitory origins of rivers.
    Judson W Harvey, Stephanie K Kampf.
      Streams that only flow occasionally are major contributors to river flow.
    DOI:  https://doi.org/10.1126/science.adq1714
  39. Cell. 2024 Jun 21. pii: S0092-8674(24)00636-6. [Epub ahead of print]
    Open-ST: High-resolution spatial transcriptomics in 3D.
    Marie Schott, Daniel León-Periñán, Elena Splendiani, Leon Strenger, Jan Robin Licha, Tancredi Massimo Pentimalli, Simon Schallenberg, Jonathan Alles, Sarah Samut Tagliaferro, Anastasiya Boltengagen, Sebastian Ehrig, Stefano Abbiati, Steffen Dommerich, Massimiliano Pagani, Elisabetta Ferretti, Giuseppe Macino, Nikos Karaiskos, Nikolaus Rajewsky.
      Spatial transcriptomics (ST) methods unlock molecular mechanisms underlying tissue development, homeostasis, or disease. However, there is a need for easy-to-use, high-resolution, cost-efficient, and 3D-scalable methods. Here, we report Open-ST, a sequencing-based, open-source experimental and computational resource to address these challenges and to study the molecular organization of tissues in 2D and 3D. In mouse brain, Open-ST captured transcripts at subcellular resolution and reconstructed cell types. In primary head-and-neck tumors and patient-matched healthy/metastatic lymph nodes, Open-ST captured the diversity of immune, stromal, and tumor populations in space, validated by imaging-based ST. Distinct cell states were organized around cell-cell communication hotspots in the tumor but not the metastasis. Strikingly, the 3D reconstruction and multimodal analysis of the metastatic lymph node revealed spatially contiguous structures not visible in 2D and potential biomarkers precisely at the 3D tumor/lymph node boundary. All protocols and software are available at https://rajewsky-lab.github.io/openst.
    Keywords:  HNSCC; cancer; metastasis; open source; resource; single cell; spatial transcriptomics; subcellular; three dimensional
    DOI:  https://doi.org/10.1016/j.cell.2024.05.055
  40. Commun Biol. 2024 Jun 27. 7(1): 773
    Interconnected lineage trajectories link conventional and natural killer (NK)-like exhausted CD8+ T cells beneficial in type 1 diabetes.
    Erin M Witkop, Kirsten Diggins, Alice Wiedeman, Elisavet Serti, Gerald Nepom, Vivian H Gersuk, Bryce Fuchs, S Alice Long, Peter S Linsley.
      Distinct Natural Killer (NK)-like CD57+ and PD-1+ CD8+ exhausted-like T cell populations (Tex) have both been linked to beneficial immunotherapy response in autoimmune type 1 diabetes (T1D) patients. The origins and relationships between these cell types are poorly understood. Here we show that while PD-1+ and CD57+ Tex populations are epigenetically similar, CD57+ Tex cells display unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also show reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex show unappreciated gene expression heterogeneity and share clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex-like populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.
    DOI:  https://doi.org/10.1038/s42003-024-06456-3
  41. JCI Insight. 2024 Jun 24. pii: e183445. [Epub ahead of print]9(12):
    Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation.
    Michelle Zuo, Naomi M Fettig, Louis-Philippe Bernier, Elisabeth Pössnecker, Shoshana Spring, Annie Pu, Xianjie I Ma, Dennis Sw Lee, Lesley A Ward, Anshu Sharma, Jens Kuhle, John G Sled, Anne-Katrin Pröbstel, Brian A MacVicar, Lisa C Osborne, Jennifer L Gommerman, Valeria Ramaglia.
      
    DOI:  https://doi.org/10.1172/jci.insight.183445
  42. Science. 2024 Jun 28. 384(6703): 1407-1408
    An epigenetic editor to silence genes.
    Madelynn N Whittaker, Kiran Musunuru.
      A new class of editor has improved delivery, durability, tunability, and safety.
    DOI:  https://doi.org/10.1126/science.adq3334
  43. Nat Commun. 2024 Jun 26. 15(1): 5414
    Borg extrachromosomal elements of methane-oxidizing archaea have conserved and expressed genetic repertoires.
    Marie C Schoelmerich, Lynn Ly, Jacob West-Roberts, Ling-Dong Shi, Cong Shen, Nikhil S Malvankar, Najwa Taib, Simonetta Gribaldo, Ben J Woodcroft, Christopher W Schadt, Basem Al-Shayeb, Xiaoguang Dai, Christopher Mozsary, Scott Hickey, Christine He, John Beaulaurier, Sissel Juul, Rohan Sachdeva, Jillian F Banfield.
      Borgs are huge extrachromosomal elements (ECE) of anaerobic methane-consuming "Candidatus Methanoperedens" archaea. Here, we used nanopore sequencing to validate published complete genomes curated from short reads and to reconstruct new genomes. 13 complete and four near-complete linear genomes share 40 genes that define a largely syntenous genome backbone. We use these conserved genes to identify new Borgs from peatland soil and to delineate Borg phylogeny, revealing two major clades. Remarkably, Borg genes encoding nanowire-like electron-transferring cytochromes and cell surface proteins are more highly expressed than those of host Methanoperedens, indicating that Borgs augment the Methanoperedens activity in situ. We reconstructed the first complete 4.00 Mbp genome for a Methanoperedens that is inferred to be a Borg host and predicted its methylation motifs, which differ from pervasive TC and CC methylation motifs of the Borgs. Thus, methylation may enable Methanoperedens to distinguish their genomes from those of Borgs. Very high Borg to Methanoperedens ratios and structural predictions suggest that Borgs may be capable of encapsulation. The findings clearly define Borgs as a distinct class of ECE with shared genomic signatures, establish their diversification from a common ancestor with genetic inheritance, and raise the possibility of periodic existence outside of host cells.
    DOI:  https://doi.org/10.1038/s41467-024-49548-8
  44. Mol Metab. 2024 Jun 22. pii: S2212-8778(24)00104-2. [Epub ahead of print] 101973
    Untangling the genetics of beta cell dysfunction and death in type 1 diabetes.
    Catherine C Robertson, Ruth M Elgamal, Belle A Henry-Kanarek, Peter Arvan, Shuibing Chen, Sangeeta Dhawan, Decio L Eizirik, John S Kaddis, Golnaz Vahedi, Stephen C J Parker, Kyle J Gaulton, Scott A Soleimanpour.
      Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We introduce genetic risk prediction models and discuss how they can be used to address disease heterogeneity. Finally, we present areas where investment will be critical for future use of genetics to address open questions and to develop new treatment and prevention strategies for T1D.
    DOI:  https://doi.org/10.1016/j.molmet.2024.101973
  45. Immunology. 2024 Jun 27.
    PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.
    Kun-Long Duan, Tian-Xiang Wang, Jian-Wei You, Hai-Ning Wang, Zhi-Qiang Wang, Zi-Xuan Huang, Jin-Ye Zhang, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, Dan Ye, Li Chen, Ronghua Liu, Hai-Xin Yuan.
      Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.
    Keywords:  B cell; mucosal immunology; reactive oxygen species
    DOI:  https://doi.org/10.1111/imm.13827
  46. Nat Metab. 2024 Jun 27.
    The dance of gut microbes on the keto diet.
    Jihyun Kim, Ara Koh.
      
    DOI:  https://doi.org/10.1038/s42255-024-01062-3
  47. Cell Death Dis. 2024 Jun 26. 15(6): 453
    TRIM26 deficiency enhancing liver regeneration through macrophage polarization and β-catenin pathway activation.
    Tingting Li, Wei Zhong, Mengqi Li, Zile Shao, Gongye Zhang, Weiwei Wang, Zhixing Gao, Xuemei Tan, Ziyi Xu, Fanghong Luo, Gang Song.
      Liver regeneration is a complex process involving the crosstalk between parenchymal and non-parenchymal cells, especially macrophages. However, the underlying mechanisms remain incompletely understood. Here, we identify the E3 ubiquitin ligase TRIM26 as a crucial regulator of liver regeneration. Following partial hepatectomy or acute liver injury induced by carbon tetrachloride, Trim26 knockout mice exhibit enhanced hepatocyte proliferation compared to wild-type controls, while adeno-associated virus (AAV)-mediated overexpression of Trim26 reverses the promotional effects. Mechanistically, Trim26 deficiency promotes the recruitment of macrophages to the liver and their polarization towards pro-inflammatory M1 phenotype. These M1 macrophages secrete Wnts, including Wnt2, which subsequently stimulate hepatocyte proliferation through the activation of Wnt/β-catenin signaling. In hepatocytes, Trim26 knockdown reduces the ubiquitination and degradation of β-catenin, thereby further enhancing Wnt/β-catenin signaling. Pharmacological inhibition of Wnt/β-catenin pathway by ICG-001 or depletion of macrophages by clodronate liposomes diminishes the pro-regenerative effects of Trim26 deficiency. Moreover, bone marrow transplantation experiments provide evidence that Trim26 knockout in myeloid cells alone can also promote liver regeneration, highlighting the critical role of macrophage Trim26 in this process. Taken together, our study uncovers TRIM26 as a negative regulator of liver regeneration by modulating macrophage polarization and Wnt/β-catenin signaling in hepatocytes, providing a potential therapeutic target for promoting liver regeneration in clinical settings.
    DOI:  https://doi.org/10.1038/s41419-024-06798-0
  48. Nat Commun. 2024 Jun 24. 15(1): 5335
    Molecular insight into interactions between the Taf14, Yng1 and Sas3 subunits of the NuA3 complex.
    Minh Chau Nguyen, Hosein Rostamian, Ana Raman, Pengcheng Wei, Dustin C Becht, Annette H Erbse, Brianna J Klein, Tonya M Gilbert, Gongyi Zhang, M Andres Blanco, Brian D Strahl, Sean D Taverna, Tatiana G Kutateladze.
      The NuA3 complex is a major regulator of gene transcription and the cell cycle in yeast. Five core subunits are required for complex assembly and function, but it remains unclear how these subunits interact to form the complex. Here, we report that the Taf14 subunit of the NuA3 complex binds to two other subunits of the complex, Yng1 and Sas3, and describe the molecular mechanism by which the extra-terminal domain of Taf14 recognizes the conserved motif present in Yng1 and Sas3. Structural, biochemical, and mutational analyses show that two motifs are sandwiched between the two extra-terminal domains of Taf14. The head-to-toe dimeric complex enhances the DNA binding activity of Taf14, and the formation of the hetero-dimer involving the motifs of Yng1 and Sas3 is driven by sequence complementarity. In vivo assays in yeast demonstrate that the interactions of Taf14 with both Sas3 and Yng1 are required for proper function of the NuA3 complex in gene transcription and DNA repair. Our findings suggest a potential basis for the assembly of three core subunits of the NuA3 complex, Taf14, Yng1 and Sas3.
    DOI:  https://doi.org/10.1038/s41467-024-49730-y
  49. Nat Commun. 2024 Jun 22. 15(1): 5327
    MethPhaser: methylation-based long-read haplotype phasing of human genomes.
    Yilei Fu, Sergey Aganezov, Medhat Mahmoud, John Beaulaurier, Sissel Juul, Todd J Treangen, Fritz J Sedlazeck.
      The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, a method that utilizes methylation signals from Oxford Nanopore Technologies to extend Single Nucleotide Variation (SNV)-based phasing. We demonstrate that haplotype-specific methylations extensively exist in Human genomes and the advent of long-read technologies enabled direct report of methylation signals. For ONT R9 and R10 cell line data, we increase the phase length N50 by 78%-151% at a phasing accuracy of 83.4-98.7% To assess the impact of tissue purity and random methylation signals due to inactivation, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing across HLA and multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. The concept of MethPhaser can also be extended to non-human diploid genomes. MethPhaser is available at https://github.com/treangenlab/methphaser .
    DOI:  https://doi.org/10.1038/s41467-024-49588-0
  50. Sci Immunol. 2024 Jun 28. 9(96): eadk4893
    Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.
    Jennifer A Foltz, Jennifer Tran, Pamela Wong, Changxu Fan, Evelyn Schmidt, Bryan Fisk, Michelle Becker-Hapak, David A Russler-Germain, Jeanette Johnson, Nancy D Marin, Celia C Cubitt, Patrick Pence, Joseph Rueve, Sushanth Pureti, Kimberly Hwang, Feng Gao, Alice Y Zhou, Mark Foster, Timothy Schappe, Lynne Marsala, Melissa M Berrien-Elliott, Amanda F Cashen, Jeffrey J Bednarski, Elana Fertig, Obi L Griffith, Malachi Griffith, Ting Wang, Allegra A Petti, Todd A Fehniger.
      Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18-activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.
    DOI:  https://doi.org/10.1126/sciimmunol.adk4893
  51. Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]
    The extracellular matrix integrates mitochondrial homeostasis.
    Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.
      Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
    Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2024.05.057
  52. Nat Commun. 2024 Jun 27. 15(1): 5446
    Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation.
    Hyun Huh, Jiayu Shen, Yogeeshwar Ajjugal, Aparna Ramachandran, Smita S Patel, Sang-Hyuk Lee.
      Mitochondrial transcription factor A (TFAM) employs DNA bending to package mitochondrial DNA (mtDNA) into nucleoids and recruit mitochondrial RNA polymerase (POLRMT) at specific promoter sites, light strand promoter (LSP) and heavy strand promoter (HSP). Herein, we characterize the conformational dynamics of TFAM on promoter and non-promoter sequences using single-molecule fluorescence resonance energy transfer (smFRET) and single-molecule protein-induced fluorescence enhancement (smPIFE) methods. The DNA-TFAM complexes dynamically transition between partially and fully bent DNA conformational states. The bending/unbending transition rates and bending stability are DNA sequence-dependent-LSP forms the most stable fully bent complex and the non-specific sequence the least, which correlates with the lifetimes and affinities of TFAM with these DNA sequences. By quantifying the dynamic nature of the DNA-TFAM complexes, our study provides insights into how TFAM acts as a multifunctional protein through the DNA bending states to achieve sequence specificity and fidelity in mitochondrial transcription while performing mtDNA packaging.
    DOI:  https://doi.org/10.1038/s41467-024-49728-6
  53. Nat Commun. 2024 Jun 26. 15(1): 5398
    Comparative optimization of polysaccharide-based nanoformulations for cardiac RNAi therapy.
    Han Gao, Sen Li, Zhengyi Lan, Da Pan, Gonna Somu Naidu, Dan Peer, Chenyi Ye, Hangrong Chen, Ming Ma, Zehua Liu, Hélder A Santos.
      Ionotropic gelation is widely used to fabricate targeting nanoparticles (NPs) with polysaccharides, leveraging their recognition by specific lectins. Despite the fabrication scheme simply involves self-assembly of differently charged components in a straightforward manner, the identification of a potent combinatory formulation is usually limited by structural diversity in compound collections and trivial screen process, imposing crucial challenges for efficient formulation design and optimization. Herein, we report a diversity-oriented combinatory formulation screen scheme to identify potent gene delivery cargo in the context of precision cardiac therapy. Distinct categories of cationic compounds are tested to construct RNA delivery system with an ionic polysaccharide framework, utilizing a high-throughput microfluidics workstation coupled with streamlined NPs characterization system in an automatic, step-wise manner. Sequential computational aided interpretation provides insights in formulation optimization in a broader scenario, highlighting the usefulness of compound library diversity. As a result, the out-of-bag NPs, termed as GluCARDIA NPs, are utilized for loading therapeutic RNA to ameliorate cardiac reperfusion damages and promote the long-term prognosis. Overall, this work presents a generalizable formulation design strategy for polysaccharides, offering design principles for combinatory formulation screen and insights for efficient formulation identification and optimization.
    DOI:  https://doi.org/10.1038/s41467-024-49804-x
  54. Nat Commun. 2024 Jun 26. 15(1): 5410
    METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.
    Chen Wang, Hideki Tanizawa, Connor Hill, Aaron Havas, Qiang Zhang, Liping Liao, Xue Hao, Xue Lei, Lu Wang, Hao Nie, Yuan Qi, Bin Tian, Alessandro Gardini, Andrew V Kossenkov, Aaron Goldman, Shelley L Berger, Ken-Ichi Noma, Peter D Adams, Rugang Zhang.
      METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.
    DOI:  https://doi.org/10.1038/s41467-024-49745-5
  55. Nature. 2024 Jun 27.
    Ketamine for depression: slow-release pills could make treatment more accessible.
    Helena Kudiabor.
      
    Keywords:  Drug discovery; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-024-02127-9
  56. Nature. 2024 Jun;630(8018): 1021-1023
    How to network with the brightest minds in science.
    Lesley Evans Ogden.
      
    Keywords:  Careers; Conferences and meetings; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-02086-1
  57. Nat Commun. 2024 Jun 26. 15(1): 5403
    IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.
    Catalina Abad, Iago Pinal-Fernandez, Clement Guillou, Gwladys Bourdenet, Laurent Drouot, Pascal Cosette, Margherita Giannini, Lea Debrut, Laetitia Jean, Sophie Bernard, Damien Genty, Rachid Zoubairi, Isabelle Remy-Jouet, Bernard Geny, Christian Boitard, Andrew Mammen, Alain Meyer, Olivier Boyer.
      Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.
    DOI:  https://doi.org/10.1038/s41467-024-49460-1
  58. Cell Rep. 2024 Jun 26. pii: S2211-1247(24)00723-X. [Epub ahead of print]43(7): 114395
    Macrophages preserve endothelial cell specialization in the adrenal gland to modulate aldosterone secretion and blood pressure.
    Zheng Fan, Mara Karakone, Shunmugam Nagarajan, Nadine Nagy, Wiebke Mildenberger, Ekaterina Petrova, Laura Catharina Hinte, Mitchell Bijnen, Philipp Häne, Eric Nelius, Jing Chen, Irina Ferapontova, Ferdinand von Meyenn, Francesco Trepiccione, Mesut Berber, David Penton Ribas, Anne Eichmann, Maria-Christina Zennaro, Norihiko Takeda, Jens W Fischer, Ariadni Spyroglou, Martin Reincke, Felix Beuschlein, Johannes Loffing, Melanie Greter, Christian Stockmann.
      Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called "haptosecretagogue" signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.
    Keywords:  CP: Cell biology; CP: Immunology; aldosterone; capillary homeostasis; endothelial cell heterogeneity; haptocrine secretion; hypertension; macrophages; subendothelial fibrosis; vascular endothelial growth factor
    DOI:  https://doi.org/10.1016/j.celrep.2024.114395
  59. Nat Med. 2024 Jun 28.
    Revised criteria for the diagnosis and staging of Alzheimer's disease.
    Clifford R Jack, Scott J Andrews, Thomas G Beach, Teresa Buracchio, Billy Dunn, Ana Graf, Oskar Hansson, Carole Ho, William Jagust, Eric McDade, Jose Luis Molinuevo, Ozioma C Okonkwo, Luca Pani, Michael S Rafii, Philip Scheltens, Eric Siemers, Heather M Snyder, Reisa Sperling, Charlotte E Teunissen, Maria C Carrillo.
      
    DOI:  https://doi.org/10.1038/s41591-024-02988-7
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