bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–12–01
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Old enlarged nucleoli open the door to the cell's demise.
  2. Pregnancy stress.
  3. Keeping endogenous retroviruses at bay.
  4. Features of membrane protein sequence direct post-translational insertion.
  5. IL-4 promotes immunotherapy resistance.
  6. Promotion of TLR7-MyD88-dependent inflammation and autoimmunity in mice through stem-loop changes in Lnc-Atg16l1.
  7. Macrophages and nociceptor neurons form a sentinel unit around fenestrated capillaries to defend the synovium from circulating immune challenge.
  8. Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
  9. Racing the clock.
  10. 3D imaging of the synovium defines an immune defense system at the blood-joint barrier.
  11. A cross-disciplinary research framework at institution level and beyond.
  12. Transposable element 5mC methylation state of blood cells predicts age and disease.
  13. The brain tames autoimmunity.
  14. Split-pool barcoding serves up an epigenomic smorgasbord.
  15. Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.
  16. Estimating uncertainty in reference-based cell type annotation in single-cell genomics.
  17. Let the data talk: embrace exploratory research.
  18. Spatial mapping of Alzheimer's disease across genetic subtypes.
  19. Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer's disease.
  20. Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling.
  21. The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
  22. Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis.
  23. TH1 responses in type 2 diabetes.
  24. Internet use linked to better mental health in older adults.
  25. Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors.
  26. 'That's funny': creative solutions for time-starved researchers.
  27. Eight ways to say thanks to your lab colleagues as the year draws to a close.
  28. Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.
  29. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma.
  30. Human CD8+ T cell map with single-cell transcriptome and TCR information.
  31. Evidence of oldest known alphabet unearthed among Syrian tomb treasures.
  32. Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.
  33. Neuronal diversity and stereotypy at multiple scales through whole brain morphometry.
  34. Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA.
  35. Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics.
  36. Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
  37. Redefining PD1 as a guardian of stem-like T cells.
  38. Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes.
  39. Tlr7 drives sex differences in age- and Alzheimer's disease-related demyelination.
  40. A panoramic view of cell population dynamics in mammalian aging.
  41. Raising a glass to the Four Friends Doing Science journal club.
  42. Adaptation in human immune cells residing in tissues at the frontline of infections.
  43. Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.
  44. A vaccine platform targeting lung-resident memory CD4+ T-cells provides protection against heterosubtypic influenza infections in mice and ferrets.
  45. Single-cell genomics breaks new ground in cell cycle detection.
  46. Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis.
  47. Evidence of 'disability bias' in research grant awards.
  48. Dysregulated RBM24 phosphorylation impairs APOE translation underlying psychological stress-induced cardiovascular disease.
  49. A brain-to-liver signal mediates the inhibition of liver regeneration under chronic stress in mice.
  50. In vivo gene editing of T-cells in lymph nodes for enhanced cancer immunotherapy.
  1. Nat Aging. 2024 Nov 26.
    Old enlarged nucleoli open the door to the cell's demise.
      
    DOI:  https://doi.org/10.1038/s43587-024-00779-w
  2. Nat Immunol. 2024 Dec;25(12): 2169
    Pregnancy stress.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-024-02031-4
  3. Nat Aging. 2024 Nov 29.
    Keeping endogenous retroviruses at bay.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00785-y
  4. Nat Commun. 2024 Nov 25. 15(1): 10198
    Features of membrane protein sequence direct post-translational insertion.
    Ilya A Kalinin, Hadas Peled-Zehavi, Alon B D Barshap, Shai A Tamari, Yarden Weiss, Reinat Nevo, Nir Fluman.
      The proper folding of multispanning membrane proteins (MPs) hinges on the accurate insertion of their transmembrane helices (TMs) into the membrane. Predominantly, TMs are inserted during protein translation, via a conserved mechanism centered around the Sec translocon. Our study reveals that the C-terminal TMs (cTMs) of numerous MPs across various organisms bypass this cotranslational route, necessitating an alternative posttranslational insertion strategy. We demonstrate that evolution has refined the hydrophilicity and length of the C-terminal tails of these proteins to optimize cTM insertion. Alterations in the C-tail sequence disrupt cTM insertion in both E. coli and human, leading to protein defects, loss of function, and genetic diseases. In E. coli, we identify YidC, a member of the widespread Oxa1 family, as the insertase facilitating cTMs insertion, with C-tail mutations disrupting the productive interaction of cTMs with YidC. Thus, MP sequences are fine-tuned for effective collaboration with the cellular biogenesis machinery, ensuring proper membrane protein folding.
    DOI:  https://doi.org/10.1038/s41467-024-54575-6
  5. Nat Immunol. 2024 Dec;25(12): 2169
    IL-4 promotes immunotherapy resistance.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-024-02032-3
  6. Nat Commun. 2024 Nov 25. 15(1): 10224
    Promotion of TLR7-MyD88-dependent inflammation and autoimmunity in mice through stem-loop changes in Lnc-Atg16l1.
    Zongheng Yang, Shuchen Ji, Lun Liu, Shuo Liu, Bingjing Wang, Yuanwu Ma, Xuetao Cao.
      Uncontrolled TLR signaling can cause inflammatory immunopathology and trigger autoimmune diseases. For example, TLR7 promotes pathogenesis of systemic lupus erythematosus. However, whether RNA structural changes affect nucleic acids-sensing TLRs signaling and impact disease progression is unclear. Here by iCLIP-seq we identify a TLR7-binding long non-coding RNA, Lnc-Atg16l1, and find that it promotes TLR7 and other MyD88-dependent TLRs signaling in various types of immune cells. Depletion of Lnc-Atg16l1 attenuates development of TLR7-linked autoimmune phenotypes in the mouse SLE model. Mechanistically, we find that Lnc-Atg16l1 binds to TLR7 at bases near U84 and MyD88 at bases around A129. The analysis of Lnc-Atg16l1 in situ structures show that it strengthens the interaction between TIR domain of TLR7 and MyD88 through specific stem-loop structure changes as a molecular scaffold after TLR7 activation to promote TLR7 downstream signaling. Therefore, we discover a mechanism for host RNA regulation of innate signaling and autoimmune disease through its structural changes. These findings provide insights into the pro-inflammatory function of self RNA in a structure-dependent manner and suggest a potential target for TLR-related autoimmune disorders.
    DOI:  https://doi.org/10.1038/s41467-024-54674-4
  7. Nat Immunol. 2024 Dec;25(12): 2270-2283
    Macrophages and nociceptor neurons form a sentinel unit around fenestrated capillaries to defend the synovium from circulating immune challenge.
    Tetsuo Hasegawa, Colin Y C Lee, Andrew J Hotchen, Aaron Fleming, Rahul Singh, Kunimichi Suzuki, Michisuke Yuzaki, Masahiko Watanabe, Mark A Birch, Andrew W McCaskie, Nikolett Lénárt, Krisztina Tóth, Ádám Dénes, Zhaoyuan Liu, Florent Ginhoux, Nathan Richoz, Menna R Clatworthy.
      A wide variety of systemic pathologies, including infectious and autoimmune diseases, are accompanied by joint pain or inflammation, often mediated by circulating immune complexes (ICs). How such stimuli access joints and trigger inflammation is unclear. Whole-mount synovial imaging revealed PV1+ fenestrated capillaries at the periphery of the synovium in the lining-sublining interface. Circulating ICs extravasated from these PV1+ capillaries, and nociceptor neurons and three distinct macrophage subsets formed a sentinel unit around them. Macrophages showed subset-specific responses to systemic IC challenge; LYVE1+CX3CR1+ macrophages orchestrated neutrophil recruitment and activated calcitonin gene-related peptide+ (CGRP+) nociceptor neurons via interleukin-1β. In contrast, major histocompatibility complex class II+CD11c+ (MHCII+CD11c+) and MHCII+CD11c- interstitial macrophages formed tight clusters around PV1+ capillaries in response to systemic immune stimuli, a feature enhanced by nociceptor-derived CGRP. Altogether, we identify the anatomical location of synovial PV1+ capillaries and subset-specific macrophage-nociceptor cross-talk that forms a blood-joint barrier protecting the synovium from circulating immune challenges.
    DOI:  https://doi.org/10.1038/s41590-024-02011-8
  8. Nature. 2024 Nov 27.
    Fungal symbiont transmitted by free-living mice promotes type 2 immunity.
    Yun Liao, Iris H Gao, Takato Kusakabe, Woan-Yu Lin, Alexander Grier, Xiangyu Pan, Olga Morzhanaeva, Terrance P Shea, Hiroshi Yano, Danielle Karo-Atar, Kaitlin A Olsen, Ji Hoon Oh, Kurt J Vandegrift, Irah L King, Christina A Cuomo, David Artis, Barbara Rehermann, Neil Lipman, Iliyan D Iliev.
      The gut mycobiota is crucial for intestinal homeostasis and immune function1. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08213-2
  9. Science. 2024 Nov 29. 386(6725): 1062
    Racing the clock.
    Cecilia Padilla Iglesias, Erika C Freeman.
      
    DOI:  https://doi.org/10.1126/science.adu7742
  10. Nat Immunol. 2024 Dec;25(12): 2182-2183
    3D imaging of the synovium defines an immune defense system at the blood-joint barrier.
      
    DOI:  https://doi.org/10.1038/s41590-024-02016-3
  11. Nat Commun. 2024 Nov 29. 15(1): 10399
    A cross-disciplinary research framework at institution level and beyond.
    Apostolos Argyris, Emilio Hernández-García, Maxi San Miguel.
      
    DOI:  https://doi.org/10.1038/s41467-024-54703-2
  12. Nat Aging. 2024 Nov 27.
    Transposable element 5mC methylation state of blood cells predicts age and disease.
    Francesco Morandini, Jinlong Y Lu, Cheyenne Rechsteiner, Aladdin H Shadyab, Ramon Casanova, Beverly M Snively, Andrei Seluanov, Vera Gorbunova.
      Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer.
    DOI:  https://doi.org/10.1038/s43587-024-00757-2
  13. Nat Immunol. 2024 Dec;25(12): 2169
    The brain tames autoimmunity.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-024-02033-2
  14. Nat Genet. 2024 Nov 25.
    Split-pool barcoding serves up an epigenomic smorgasbord.
    Vijay Ramani.
      
    DOI:  https://doi.org/10.1038/s41588-024-01980-8
  15. Nat Commun. 2024 Nov 28. 15(1): 10102
    Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.
    María C M Aboy-Pardal, Marta C Guadamillas, Carlos R Guerrero, Mauro Català-Montoro, Mónica Toledano-Donado, Sara Terrés-Domínguez, Dácil M Pavón, Víctor Jiménez-Jiménez, Daniel Jimenez-Carretero, Moreno Zamai, Cintia Folgueira, Ana Cerezo, Fidel-Nicolás Lolo, Rubén Nogueiras, Guadalupe Sabio, Miguel Sánchez-Álvarez, Asier Echarri, Ricardo Garcia, Miguel A Del Pozo.
      Adipocytes expand massively to accommodate excess energy stores and protect the organism from lipotoxicity. Adipose tissue expandability is at the center of disorders such as obesity and lipodystrophy; however, little is known about the relevance of adipocyte biomechanics on the etiology of these conditions. Here, we show in male mice in vivo that the adipocyte plasma membrane undergoes caveolar domain reorganization upon lipid droplet expansion. As the lipid droplet grows, caveolae disassemble to release their membrane reservoir and increase cell surface area, and transfer specific caveolar components to the LD surface. Adipose tissue null for caveolae is stiffer, shows compromised deformability, and is prone to rupture under mechanical compression. Mechanistically, phosphoacceptor Cav1 Tyr14 is required for caveolae disassembly: adipocytes bearing a Tyr14Phe mutation at this residue are stiffer and smaller, leading to decreased adiposity in vivo; exhibit deficient transfer of Cav1 and EHD2 to the LD surface, and show distinct Cav1 molecular dynamics and tension adaptation. These results indicate that Cav1 phosphoregulation modulates caveolar dynamics as a relevant component of the homeostatic mechanoadaptation of the differentiated adipocyte.
    DOI:  https://doi.org/10.1038/s41467-024-54224-y
  16. Nat Genet. 2024 Nov 26.
    Estimating uncertainty in reference-based cell type annotation in single-cell genomics.
      
    DOI:  https://doi.org/10.1038/s41588-024-01995-1
  17. Nature. 2024 Nov;635(8040): 788
    Let the data talk: embrace exploratory research.
    Balazs Aczel.
      
    Keywords:  Psychology; Research management; Sociology
    DOI:  https://doi.org/10.1038/d41586-024-03826-z
  18. Nat Genet. 2024 Nov 25.
    Spatial mapping of Alzheimer's disease across genetic subtypes.
    Alexi Nott, Inge R Holtman.
      
    DOI:  https://doi.org/10.1038/s41588-024-01895-4
  19. Nat Commun. 2024 Nov 23. 15(1): 10174
    Single-cell transcriptomics unveils molecular signatures of neuronal vulnerability in a mouse model of prion disease that overlap with Alzheimer's disease.
    Jessy A Slota, Lise Lamoureux, Kathy L Frost, Babu V Sajesh, Stephanie A Booth.
      Understanding why certain neurons are more sensitive to dysfunction and death caused by misfolded proteins could provide therapeutically relevant insights into neurodegenerative disorders. Here, we harnessed single-cell transcriptomics to examine live neurons isolated from prion-infected female mice, aiming to identify and characterize prion-vulnerable neuronal subsets. Our analysis revealed distinct transcriptional responses across neuronal subsets, with a consistent pathway-level depletion of synaptic gene expression in damage-vulnerable neurons. By scoring neuronal damage based on the magnitude of depleted synaptic gene expression, we identified a diverse spectrum of prion-vulnerable glutamatergic, GABAergic, and medium spiny neurons. Comparison between prion-vulnerable and resistant neurons highlighted baseline gene expression differences that could influence neuronal vulnerability. For instance, the neuroprotective cold-shock protein Rbm3 exhibited higher baseline gene expression in prion-resistant neurons and was robustly upregulated across diverse neuronal classes upon prion infection. We also identified vulnerability-correlated transcripts that overlapped between prion and Alzheimer's disease. Our findings not only demonstrate the potential of single-cell transcriptomics to identify damage-vulnerable neurons, but also provide molecular insights into neuronal vulnerability and highlight commonalties across neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-024-54579-2
  20. Immunity. 2024 Nov 22. pii: S1074-7613(24)00495-3. [Epub ahead of print]
    Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling.
    Masato Ogishi, Koji Kitaoka, Kim L Good-Jacobson, Darawan Rinchai, Baihao Zhang, Jun Wang, Vincent Gies, Geetha Rao, Tina Nguyen, Danielle T Avery, Taushif Khan, Megan E Smithmyer, Joseph Mackie, Rui Yang, Andrés Augusto Arias, Takaki Asano, Khoren Ponsin, Matthieu Chaldebas, Peng Zhang, Jessica N Peel, Jonathan Bohlen, Romain Lévy, Simon J Pelham, Wei-Te Lei, Ji Eun Han, Iris Fagniez, Maya Chrabieh, Candice Laine, David Langlais, Conor Gruber, Fatima Al Ali, Mahbuba Rahman, Caner Aytekin, Basilin Benson, Matthew J Dufort, Clara Domingo-Vila, Kunihiko Moriya, Mark Shlomchik, Gulbu Uzel, Paul E Gray, Daniel Suan, Kahn Preece, Ignatius Chua, Satoshi Okada, Shunsuke Chikuma, Hiroshi Kiyonari, Timothy I Tree, Dusan Bogunovic, Philippe Gros, Nico Marr, Cate Speake, Richard A Oram, Vivien Béziat, Jacinta Bustamante, Laurent Abel, Bertrand Boisson, Anne-Sophie Korganow, Cindy S Ma, Matthew B Johnson, Kenji Chamoto, Stéphanie Boisson-Dupuis, Tasuku Honjo, Jean-Laurent Casanova, Stuart G Tangye.
      T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1-/- and Cd274-/-Pdcd1lg2-/- mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy.
    Keywords:  IL-21; PD-1; PD-L1; T follicular helper cells; antibody; c-Myc; humoral immunity; memory B cells
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.014
  21. Sci Immunol. 2024 Nov 29. 9(101): eadk2954
    The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
    Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J DeBerardinis, Tuoqi Wu, Chen Yao.
      During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell-intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure.
    DOI:  https://doi.org/10.1126/sciimmunol.adk2954
  22. Nat Commun. 2024 Nov 29. 15(1): 10372
    Vascular FLRT2 regulates venous-mediated angiogenic expansion and CNS barriergenesis.
    C Llaó-Cid, B Peguera, P Kobialka, L Decker, J Vogenstahl, N Alivodej, S Srivastava, J Jin, B C Kirchmaier, C Milla, H Schlierbach, A Schänzer, T Acker, M Segarra, A Acker-Palmer.
      Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific regulator of CNS vascular development.
    DOI:  https://doi.org/10.1038/s41467-024-54570-x
  23. Nat Immunol. 2024 Dec;25(12): 2169
    TH1 responses in type 2 diabetes.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-02030-5
  24. Nat Med. 2024 Nov 26.
    Internet use linked to better mental health in older adults.
    Karen O'Leary.
      
    Keywords:  Depression; Public health; Technology
    DOI:  https://doi.org/10.1038/d41591-024-00081-7
  25. Nat Cardiovasc Res. 2024 Nov 29.
    Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors.
    José Gabriel Barcia Durán, Dayasagar Das, Michael Gildea, Letizia Amadori, Morgane Gourvest, Ravneet Kaur, Natalia Eberhardt, Panagiotis Smyrnis, Burak Cilhoroz, Swathy Sajja, Karishma Rahman, Dawn M Fernandez, Peter Faries, Navneet Narula, Rami Vanguri, Ira J Goldberg, Edward A Fisher, Jeffrey S Berger, Kathryn J Moore, Chiara Giannarelli.
      Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.
    DOI:  https://doi.org/10.1038/s44161-024-00563-4
  26. Nature. 2024 Nov 28.
    'That's funny': creative solutions for time-starved researchers.
    John Tregoning, Richard Tillotson.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-03426-x
  27. Nature. 2024 Nov;635(8040): 1029-1030
    Eight ways to say thanks to your lab colleagues as the year draws to a close.
    Anne Marie Conlon.
      
    Keywords:  Careers; Lab life; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03829-w
  28. Nat Commun. 2024 Nov 24. 15(1): 10184
    Bacterial single-cell RNA sequencing captures biofilm transcriptional heterogeneity and differential responses to immune pressure.
    Lee E Korshoj, Tammy Kielian.
      Biofilm formation is an important mechanism of survival and persistence for many bacterial pathogens. These multicellular communities contain subpopulations of cells that display metabolic and transcriptional diversity along with recalcitrance to antibiotics and host immune defenses. Here, we present an optimized bacterial single-cell RNA sequencing method, BaSSSh-seq, to study Staphylococcus aureus diversity during biofilm growth and transcriptional adaptations following immune cell exposure. BaSSSh-seq captures extensive transcriptional heterogeneity during biofilm compared to planktonic growth. We quantify and visualize transcriptional regulatory networks across heterogeneous biofilm subpopulations and identify gene sets that are associated with a trajectory from planktonic to biofilm growth. BaSSSh-seq also detects alterations in biofilm metabolism, stress response, and virulence induced by distinct immune cell populations. This work facilitates the exploration of biofilm dynamics at single-cell resolution, unlocking the potential for identifying biofilm adaptations to environmental signals and immune pressure.
    DOI:  https://doi.org/10.1038/s41467-024-54581-8
  29. Nat Immunol. 2024 Nov 28.
    Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma.
    Benjamin Y Lu, Liliana E Lucca, Wesley Lewis, Jiping Wang, Catarina V Nogueira, Sebastian Heer, Violeta Rayon-Estrada, Pierre-Paul Axisa, Sarah M Reeves, Nicholas C Buitrago-Pocasangre, Giang H Pham, Mina L Kojima, Wei Wei, Lilach Aizenbud, Antonietta Bacchiocchi, Lin Zhang, Joseph J Walewski, Veronica Chiang, Kelly Olino, James Clune, Ruth Halaban, Yuval Kluger, Anthony J Coyle, Jan Kisielow, Franz-Josef Obermair, Harriet M Kluger, David A Hafler.
      Effective anti-tumor immunity is driven by cytotoxic CD8+ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8+ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR+CD8+ regulatory T cells target other tumor-antigen-specific CD8+ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8+ T cells and implicate KIR+CD8+ regulatory T cells as a cellular mediator of immune evasion in human cancer.
    DOI:  https://doi.org/10.1038/s41590-024-02023-4
  30. Nat Methods. 2024 Nov 29.
    Human CD8+ T cell map with single-cell transcriptome and TCR information.
      
    DOI:  https://doi.org/10.1038/s41592-024-02529-7
  31. Nature. 2024 Nov 26.
    Evidence of oldest known alphabet unearthed among Syrian tomb treasures.
    Miryam Naddaf.
      
    Keywords:  Archaeology
    DOI:  https://doi.org/10.1038/d41586-024-03876-3
  32. Cell Death Dis. 2024 Nov 24. 15(11): 856
    Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.
    Yizhou Yu, Civia Z Chen, Ivana Celardo, Bryan Wei Zhi Tan, James D Hurcomb, Nuno Santos Leal, Rebeka Popovic, Samantha H Y Loh, L Miguel Martins.
      Alzheimer's disease (AD) is the most common form of age-related dementia. In AD, the death of neurons in the central nervous system is associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. Mitochondria are signal transducers of metabolic and biochemical information, and their impairment can compromise cellular function. Mitochondria compartmentalise several pathways, including folate-dependent one-carbon (1C) metabolism and electron transport by respiratory complexes. Mitochondrial 1C metabolism is linked to electron transport through complex I of the respiratory chain. Here, we analysed the proteomic changes in a fly model of AD by overexpressing a toxic form of Aβ (Aβ-Arc). We found that expressing Aβ-Arc caused alterations in components of both complex I and mitochondrial 1C metabolism. Genetically enhancing mitochondrial 1C metabolism through Nmdmc improved mitochondrial function and was neuroprotective in fly models of AD. We also found that exogenous supplementation with the 1C donor folinic acid improved mitochondrial health in both mammalian cells and fly models of AD. We found that genetic variations in MTHFD2L, the human orthologue of Nmdmc, were linked to AD risk. Additionally, Mendelian randomisation showed that increased folate intake decreased the risk of developing AD. Overall, our data suggest enhancement of folate-dependent 1C metabolism as a viable strategy to delay the progression and attenuate the severity of AD.
    DOI:  https://doi.org/10.1038/s41419-024-07179-3
  33. Nat Commun. 2024 Nov 26. 15(1): 10269
    Neuronal diversity and stereotypy at multiple scales through whole brain morphometry.
    Yufeng Liu, Shengdian Jiang, Yingxin Li, Sujun Zhao, Zhixi Yun, Zuo-Han Zhao, Lingli Zhang, Gaoyu Wang, Xin Chen, Linus Manubens-Gil, Yuning Hang, Qiaobo Gong, Yuanyuan Li, Penghao Qian, Lei Qu, Marta Garcia-Forn, Wei Wang, Silvia De Rubeis, Zhuhao Wu, Pavel Osten, Hui Gong, Michael Hawrylycz, Partha Mitra, Hongwei Dong, Qingming Luo, Giorgio A Ascoli, Hongkui Zeng, Lijuan Liu, Hanchuan Peng.
      We conducted a large-scale whole-brain morphometry study by analyzing 3.7 peta-voxels of mouse brain images at the single-cell resolution, producing one of the largest multi-morphometry databases of mammalian brains to date. We registered 204 mouse brains of three major imaging modalities to the Allen Common Coordinate Framework (CCF) atlas, annotated 182,497 neuronal cell bodies, modeled 15,441 dendritic microenvironments, characterized the full morphology of 1876 neurons along with their axonal motifs, and detected 2.63 million axonal varicosities that indicate potential synaptic sites. Our analyzed six levels of information related to neuronal populations, dendritic microenvironments, single-cell full morphology, dendritic and axonal arborization, axonal varicosities, and sub-neuronal structural motifs, along with a quantification of the diversity and stereotypy of patterns at each level. This integrative study provides key anatomical descriptions of neurons and their types across a multiple scales and features, contributing a substantial resource for understanding neuronal diversity in mammalian brains.
    DOI:  https://doi.org/10.1038/s41467-024-54745-6
  34. Nat Commun. 2024 Nov 28. 15(1): 10359
    Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA.
    Julia L Gross, Rahul Basu, Clinton J Bradfield, Jing Sun, Sinu P John, Sanchita Das, John P Dekker, David S Weiss, Iain D C Fraser.
      The immunologic consequences of using bactericidal versus bacteriostatic antibiotic treatments are unclear. We observed a bacteriostatic (growth halting) treatment was more protective than a bactericidal (bacteria killing) treatment in a murine peritonitis model. To understand this unexpected difference, we compared macrophage responses to bactericidal treated bacteria or bacteriostatic treated bacteria. We found that Gram-negative bacteria treated with bactericidal drugs induced more proinflammatory cytokines than those treated with bacteriostatic agents. Bacterial DNA - released only by bactericidal treatments - exacerbated inflammatory signaling through TLR9. Without TLR9 signaling, the in vivo efficacy of bactericidal drug treatment was rescued. This demonstrates that antibiotics can act in important ways distinct from bacterial inhibition: like causing treatment failure by releasing DNA that induces excessive inflammation. These data establish a novel link between how an antibiotic affects bacterial physiology and subsequent immune system engagement, which may be relevant for optimizing treatments to simultaneously clear bacteria and modulate inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-54497-3
  35. Nat Commun. 2024 Nov 29. 15(1): 10387
    Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics.
    Daniel Munro, Nava Ehsan, Seyed Mehdi Esmaeili-Fard, Alexander Gusev, Abraham A Palmer, Pejman Mohammadi.
      RNA sequencing has the potential to reveal many modalities of transcriptional regulation, such as various splicing phenotypes, but studies on gene regulation are often limited to gene expression due to the complexity of extracting and analyzing multiple RNA phenotypes. Here, we present Pantry, a framework to efficiently generate diverse RNA phenotypes from RNA sequencing data and perform downstream integrative analyses with genetic data. Pantry generates phenotypes from six modalities of transcriptional regulation (gene expression, isoform ratios, splice junction usage, alternative TSS/polyA usage, and RNA stability) and integrates them with genetic data via QTL mapping, TWAS, and colocalization testing. We apply Pantry to Geuvadis and GTEx data, finding that 4768 of the genes with no identified eQTL in Geuvadis have QTL in at least one other transcriptional modality, resulting in a 66% increase in genes over eQTL mapping. We further found that the QTL exhibit modality-specific functional properties that are further reinforced by joint analysis of different RNA modalities. We also show that generalizing TWAS to multiple RNA modalities approximately doubles the discovery of unique gene-trait associations, and enhances identification of regulatory mechanisms underlying GWAS signal in 42% of previously associated gene-trait pairs.
    DOI:  https://doi.org/10.1038/s41467-024-54840-8
  36. Nat Commun. 2024 Nov 26. 15(1): 10268
    Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
    Jesse Kreger, Jazlyn A Mooney, Darryl Shibata, Adam L MacLean.
      Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.
    DOI:  https://doi.org/10.1038/s41467-024-54711-2
  37. Nat Rev Immunol. 2024 Nov 25.
    Redefining PD1 as a guardian of stem-like T cells.
    Matthew Jackson, Eileen E Parkes.
      
    DOI:  https://doi.org/10.1038/s41577-024-01117-2
  38. Nat Commun. 2024 Nov 27. 15(1): 10277
    Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes.
    Sujit K Mohanty, Kanhaiya Singh, Manishekhar Kumar, Sumit S Verma, Rajneesh Srivastava, Surya C Gnyawali, Ravichand Palakurti, Ajay K Sahi, Mohamed S El Masry, Pradipta Banerjee, Sedat Kacar, Yashika Rustagi, Priyanka Verma, Subhadip Ghatak, Edward Hernandez, J Peter Rubin, Savita Khanna, Sashwati Roy, Mervin C Yoder, Chandan K Sen.
      Tissue nanotransfection (TNT) topically delivers Etv2, Foxc2, and Fli1 (EFF) plasmids increasing vasculogenic fibroblasts (VF) and promoting vascularization in ischemic murine skin. Human dermal fibroblasts respond to EFF nanoelectroporation with elevated expression of endothelial genes in vitro, which is linked to increased ten-eleven translocase 1/2/3 (TET) expression. Single cell RNA sequencing dependent validation of VF induction reveals a TET-dependent transcript signature. TNTEFF also induces TET expression in vivo, and fibroblast-specific EFF overexpression leads to VF-transition, with TET-activation correlating with higher 5-hydroxymethylcytosine (5-hmC) levels in VF. VF emergence requires TET-dependent demethylation of endothelial genes in vivo, enhancing VF abundance and restoring perfusion in diabetic ischemic limbs. TNTEFF improves perfusion and wound closure in diabetic mice, while increasing VF in cultured human skin explants. Suppressed in diabetes, TET1/2/3 play a critical role in TNT-mediated VF formation which supports de novo blood vessel development to rescue diabetic ischemic tissue.
    DOI:  https://doi.org/10.1038/s41467-024-54385-w
  39. Science. 2024 Nov 29. 386(6725): eadk7844
    Tlr7 drives sex differences in age- and Alzheimer's disease-related demyelination.
    Chloe Lopez-Lee, Lay Kodama, Li Fan, Daphne Zhu, Jingjie Zhu, Man Ying Wong, Pearly Ye, Kendra Norman, Nessa R Foxe, Laraib Ijaz, Fangmin Yu, Hao Chen, Gillian K Carling, Eileen R Torres, Rachel D Kim, Dena B Dubal, Shane A Liddelow, Subhash C Sinha, Wenjie Luo, Li Gan.
      Alzheimer's disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss. In an AD-related mouse model expressing APOE4, XY sex chromosomes heightened interferon (IFN) response and tau-induced demyelination. The X-linked gene, Toll-like receptor 7 (Tlr7), regulated sex-specific IFN response to myelin. Deletion of Tlr7 dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that Tlr7 plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.
    DOI:  https://doi.org/10.1126/science.adk7844
  40. Science. 2024 Nov 28. eadn3949
    A panoramic view of cell population dynamics in mammalian aging.
    Zehao Zhang, Chloe Schaefer, Weirong Jiang, Ziyu Lu, Jasper Lee, Andras Sziraki, Abdulraouf Abdulraouf, Brittney Wick, Maximilian Haeussler, Zhuoyan Li, Gesmira Molla, Rahul Satija, Wei Zhou, Junyue Cao.
      To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals more than 3,000 unique cellular states and over 200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts of cellular dynamics during lifespan progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our "cell-omics" strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.
    DOI:  https://doi.org/10.1126/science.adn3949
  41. Nature. 2024 Nov 28.
    Raising a glass to the Four Friends Doing Science journal club.
    Miloš Tišma, Jovana Kaljević.
      
    Keywords:  Careers; Lab life; Research management
    DOI:  https://doi.org/10.1038/d41586-024-03534-8
  42. Nat Commun. 2024 Nov 28. 15(1): 10329
    Adaptation in human immune cells residing in tissues at the frontline of infections.
    Irepan Salvador-Martínez, Jesus Murga-Moreno, Juan C Nieto, Clara Alsinet, David Enard, Holger Heyn.
      Human immune cells are under constant evolutionary pressure, primarily through their role as first line of defence against pathogens. Most studies on immune adaptation are, however, based on protein-coding genes without considering their cellular context. Here, using data from the Human Cell Atlas, we infer the gene adaptation rate of the human immune landscape at cellular resolution. We find abundant cell types, like progenitor cells during development and adult cells in barrier tissues, to harbour significantly increased adaptation rates. We confirm the adaptation of tissue-resident T and NK cells in the adult lung located in compartments directly facing external challenges, such as respiratory pathogens. Analysing human iPSC-derived macrophages responding to various challenges, we find adaptation in early immune responses. Together, our study suggests host benefits to control pathogen spread at early stages of infection, providing a retrospect of forces that shaped the complexity, architecture, and function of the human body.
    DOI:  https://doi.org/10.1038/s41467-024-54603-5
  43. Nat Commun. 2024 Nov 25. 15(1): 10142
    Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.
    Mustafa Titiz, Lorenzo Landini, Daniel Souza Monteiro de Araujo, Matilde Marini, Viola Seravalli, Martina Chieca, Pasquale Pensieri, Marco Montini, Gaetano De Siena, Benedetta Pasquini, Silvia Vannuccini, Luigi Francesco Iannone, Thiago M Cunha, Giulia Brancolini, Elisa Bellantoni, Irene Scuffi, Alessandra Mastricci, Martina Tesi, Mariarosaria Di Tommaso, Felice Petraglia, Pierangelo Geppetti, Romina Nassini, Francesco De Logu.
      Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis.
    DOI:  https://doi.org/10.1038/s41467-024-54486-6
  44. Nat Commun. 2024 Nov 29. 15(1): 10368
    A vaccine platform targeting lung-resident memory CD4+ T-cells provides protection against heterosubtypic influenza infections in mice and ferrets.
    Kwang Hyun Ko, Hyun Shik Bae, Jeong Woo Park, Jin-Sun Lee, Somin Park, Jun Heo, Hyunsoo Park, Jaeseok Choi, Eunseo Bae, Woonsung Na, Seong-Hyun Park, Baik-Lin Seong, Seung Hyun Han, Dong-Ho Kim, Seung Bin Cha.
      Lung tissue-resident memory T (TRM) cells induced by influenza vaccination are crucial for heterosubtypic immunity upon re-exposure to the influenza virus, enabling rapid and robust responses upon reactivation. To enhance the efficacy of influenza vaccines, we induce the generation of lung TRM cells following intranasal vaccination with a commercial influenza vaccine adjuvanted with NexaVant (NVT), a TLR3 agonist-based adjuvant. We demonstrate that intranasal immunization with the NVT-adjuvanted vaccine provides improved protection against influenza virus infections by inducing the generation of CD4+ TRM cells in the lungs in a type I interferon-dependent manner. These pulmonary CD4+ TRM cells provide potent mucosal immunity and cross-protection against heterosubtypic infections in both mouse and ferret models. This vaccine platform has the potential to significantly improve conventional intramuscular influenza vaccines by providing broader protection.
    DOI:  https://doi.org/10.1038/s41467-024-54620-4
  45. Nat Genet. 2024 Nov 29.
    Single-cell genomics breaks new ground in cell cycle detection.
    Qian Du.
      
    DOI:  https://doi.org/10.1038/s41588-024-01987-1
  46. Immunity. 2024 Nov 26. pii: S1074-7613(24)00519-3. [Epub ahead of print]
    Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis.
    Lucy MacDonald, Aziza Elmesmari, Domenico Somma, Jack Frew, Clara Di Mario, Roopa Madhu, Audrey Paoletti, Theodoros Simakou, Olympia M Hardy, Barbara Tolusso, Denise Campobasso, Simone Perniola, Marco Gessi, Maria Rita Gigante, Luca Petricca, Dario Bruno, Lavinia Agra Coletto, Roberta Benvenuto, John D Isaacs, Andrew Filby, David McDonald, Jasmine P X Sim, Nigel Jamieson, Kevin Wei, Maria Antonietta D'Agostino, Neal L Millar, Simon Milling, Charles McSharry, Elisa Gremese, Karen Affleck, Kenneth F Baker, Iain B McInnes, Thomas D Otto, Ilya Korsunsky, Stefano Alivernini, Mariola Kurowska-Stolarska.
      Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL+ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7+ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints.
    Keywords:  T cells; arthritis; dendritic cells; disease remission; immune tolerance; spatial transcriptomics; synovial tissue
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.004
  47. Nature. 2024 Nov;635(8040): 815
    Evidence of 'disability bias' in research grant awards.
    Fei Qi.
      
    Keywords:  Funding; Lab life; Policy; Research management
    DOI:  https://doi.org/10.1038/d41586-024-03868-3
  48. Nat Commun. 2024 Nov 23. 15(1): 10181
    Dysregulated RBM24 phosphorylation impairs APOE translation underlying psychological stress-induced cardiovascular disease.
    He Yang, Lei Sun, Xuemei Bai, Bingcheng Cai, Zepeng Tu, Chen Fang, Yusheng Bian, Xiaoyu Zhang, Xudong Han, Dayin Lv, Chi Zhang, Bo Li, Shaoxiang Luo, Bingbing Du, Lan Li, Yufeng Yao, Zhiqiang Dong, Zhuowei Huang, Guanhua Su, Hui Li, Qing K Wang, Min Zhang.
      Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD.
    DOI:  https://doi.org/10.1038/s41467-024-54519-0
  49. Nat Commun. 2024 Nov 28. 15(1): 10361
    A brain-to-liver signal mediates the inhibition of liver regeneration under chronic stress in mice.
    Yanyu Zhou, Xiaoqi Lin, Yingfu Jiao, Dan Yang, Zhengyu Li, Ling Zhu, Yixuan Li, Suqing Yin, Quanfu Li, Saihong Xu, Dan Tang, Song Zhang, Weifeng Yu, Po Gao, Liqun Yang.
      As the ability of liver regeneration is pivotal for liver disease patients, it will be of high significance and importance to identify the missing piece of the jigsaw influencing the liver regeneration. Here, we report that chronic stress impairs the liver regeneration capacity after partial hepatectomy with increased mortality in male mice. Anatomical tracing and functional mapping identified a neural circuit from noradrenergic neurons in the locus coeruleus (LC) to serotonergic neurons in the rostral medullary raphe region (rMR), which critically contributes to the inhibition of liver regeneration under chronic stress. In addition, hepatic sympathetic nerves were shown to be critical for the inhibitory effects on liver regeneration by releasing norepinephrine (NE), which acts on adrenergic receptor β2 (ADRB2) to block the proinflammatory macrophage activation. Collectively, we reveal a "brain-to-liver" neural connection that mediates chronic stress-evoked deficits in liver regeneration, thus shedding important insights into hepatic disease therapy.
    DOI:  https://doi.org/10.1038/s41467-024-54827-5
  50. Nat Commun. 2024 Nov 25. 15(1): 10218
    In vivo gene editing of T-cells in lymph nodes for enhanced cancer immunotherapy.
    Jin Qu, Yuan Wang, Chuxiao Xiong, Mingxue Wang, Xingdao He, Weibin Jia, Cheuk Yin Li, Tianlong Zhang, Zixun Wang, Wei Li, Becki Yi Kuang, Peng Shi.
      Immune checkpoint blockade (ICB) therapy, while promising for cancer treatment, faces challenges like unexpected side effects and limited objective responses. Here, we develop an in vivo gene-editing strategy for improving ICB cancer therapy in a lastingly effective manner. The approach uses a conductive hydrogel-based electroporation system to enable nucleofection of programmed cell death protein 1 (PD1) targeted CRISPR-Cas9 DNAs into T-cells directly within the lymph nodes, and subsequently produces PD1-deficient T-cells to combat tumor growth, metastasis and recurrence in different melanoma models in mice. Following in vivo gene editing, animals show enhanced cellular and humoral immune responses along with multi-fold increases of effector T-cells infiltration to the solid tumors, preventing tumor recurrence and prolonging their survival. These findings provide a proof-of-concept for direct in vivo T-cell engineering via localized gene-editing for enhanced cancer immunotherapy, and also unlock the possibilities of using this method to treat more complex human diseases.
    DOI:  https://doi.org/10.1038/s41467-024-54292-0
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