bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–07–02
63 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
  2. Gut microbial fatty acid isomerization modulates intraepithelial T cells.
  3. CNS-associated macrophages shape the inflammatory response in a mouse model of Parkinson's disease.
  4. What I owe my mentor.
  5. Targeted cross-linker delivery for the in situ mapping of protein conformations and interactions in mitochondria.
  6. The HIV-1 capsid core is an opportunistic nuclear import receptor.
  7. Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
  8. GDF15 promotes weight loss by enhancing energy expenditure in muscle.
  9. Histone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells.
  10. Hexasome-INO80 complex reveals structural basis of noncanonical nucleosome remodeling.
  11. Transcriptional and chromatin profiling of human blood innate lymphoid cell subsets sheds light on HIV-1 pathogenesis.
  12. cGLRs are a diverse family of pattern recognition receptors in innate immunity.
  13. An unnatural enzyme with endonuclease activity towards small non-coding RNAs.
  14. Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.
  15. Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome.
  16. Striatal cholinergic interneuron membrane voltage tracks locomotor rhythms in mice.
  17. Staving off cell death.
  18. Energy burn in muscle boosted by a hormonal signalling axis.
  19. Human PBMC scRNA-seq-based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity.
  20. Nuclear myosin VI maintains replication fork stability.
  21. A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity.
  22. A human protein that holds bird flu viruses at bay.
  23. mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
  24. Mapping RNA translation.
  25. Distinct metabolic requirements regulate B cell activation and germinal center responses.
  26. Fast fragmenting mitochondria by TORC2.
  27. High-resolution omics of vascular ageing and inflammatory pathways in neurodegeneration.
  28. PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis.
  29. The long non-coding RNA NEAT1 is a ΔNp63 target gene modulating epidermal differentiation.
  30. Image-seq: image-guided cell isolation for spatially resolved transcriptomic analysis.
  31. Myeloid-derived growth factor alleviates non-alcoholic fatty liver disease alleviates in a manner involving IKKβ/NF-κB signaling.
  32. Single-cell multiomic analyses sheds light on mitochondrial mutational selection.
  33. Integrating lipid metabolism, pheromone production and perception by Fruitless and Hepatocyte Nuclear Factor 4.
  34. The kiss a cell can't forget: tracking cell-cell interactions with uLIPSTIC.
  35. Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis.
  36. A selective autophagy receptor VISP1 induces symptom recovery by targeting viral silencing suppressors.
  37. Circadian clocks are modulated by compartmentalized oscillating translation.
  38. A spatially resolved single-cell genomic atlas of the adult human breast.
  39. Insights into the genetic architecture of multiple sclerosis severity.
  40. Inhibition of AIM2 inflammasome activation by SOX/ORF37 promotes lytic replication of Kaposi's sarcoma-associated herpesvirus.
  41. Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation.
  42. B cells ferment sugar before they (affinity) mature.
  43. Efficient A-to-C base editing with high specificity.
  44. T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS.
  45. New COVID jabs are coming - who should get them?
  46. Demonstration of quantum-digital payments.
  47. Memory Day report.
  48. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes.
  49. Integrative dissection of gene regulatory elements at base resolution.
  50. In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting.
  51. Editorial Expression of Concern.
  52. Did our human ancestors eat each other? Carved-up bone offers clues.
  53. Adventitial fibroblast-ILC2 niche restrains liver fibrosis.
  54. Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix.
  55. Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity.
  56. Exercise increases the metabolic benefits of weight loss.
  57. Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity.
  58. The nucleotide receptor STING translocates to the phagosomes to negatively regulate anti-fungal immunity.
  59. Early chromosome condensation by XIST builds A-repeat RNA density that facilitates gene silencing.
  60. Continuous synthesis of E. coli genome sections and Mb-scale human DNA assembly.
  61. Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles.
  62. Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.
  63. Time-restricted feeding makes the mouse run like a pro.
  1. Nat Genet. 2023 Jun 29.
    Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.
    Caleb A Lareau, Sonia M Dubois, Frank A Buquicchio, Yu-Hsin Hsieh, Kopal Garg, Pauline Kautz, Lena Nitsch, Samantha D Praktiknjo, Patrick Maschmeyer, Jeffrey M Verboon, Jacob C Gutierrez, Yajie Yin, Evgenij Fiskin, Wendy Luo, Eleni P Mimitou, Christoph Muus, Rhea Malhotra, Sumit Parikh, Mark D Fleming, Lena Oevermann, Johannes Schulte, Cornelia Eckert, Anshul Kundaje, Peter Smibert, Santosha A Vardhana, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Suneet Agarwal, Leif S Ludwig.
      Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics.
    DOI:  https://doi.org/10.1038/s41588-023-01433-8
  2. Nature. 2023 Jun 28.
    Gut microbial fatty acid isomerization modulates intraepithelial T cells.
    Xinyang Song, Haohao Zhang, Yanbo Zhang, Byoungsook Goh, Bin Bao, Suelen S Mello, Ximei Sun, Wen Zheng, Francesca S Gazzaniga, Meng Wu, Fangfang Qu, Qiangzong Yin, Michael S Gilmore, Sungwhan F Oh, Dennis L Kasper.
      The human gut microbiome constantly converts natural products derived from the host and diet into numerous bioactive metabolites1-3. Dietary fats are essential micronutrients that undergo lipolysis to release free fatty acids (FAs) for absorption in the small intestine4. Gut commensal bacteria modify some unsaturated FAs-for example, linoleic acid (LA)-into various intestinal FA isomers that regulate host metabolism and have anticarcinogenic properties5. However, little is known about how this diet-microorganism FA isomerization network affects the mucosal immune system of the host. Here we report that both dietary factors and microbial factors influence the level of gut LA isomers (conjugated LAs (CLAs)) and that CLAs in turn modulate a distinct population of CD4+ intraepithelial lymphocytes (IELs) that express CD8αα in the small intestine. Genetic abolition of FA isomerization pathways in individual gut symbionts significantly decreases the number of CD4+CD8αα+ IELs in gnotobiotic mice. Restoration of CLAs increases CD4+CD8αα+ IEL levels in the presence of the transcription factor hepatocyte nuclear factor 4γ (HNF4γ). Mechanistically, HNF4γ facilitates CD4+CD8αα+ IEL development by modulating interleukin-18 signalling. In mice, specific deletion of HNF4γ in T cells leads to early mortality from infection by intestinal pathogens. Our data reveal a new role for bacterial FA metabolic pathways in the control of host intraepithelial immunological homeostasis by modulating the relative number of CD4+ T cells that were CD4+CD8αα+.
    DOI:  https://doi.org/10.1038/s41586-023-06265-4
  3. Nat Commun. 2023 06 26. 14(1): 3753
    CNS-associated macrophages shape the inflammatory response in a mouse model of Parkinson's disease.
    Maximilian Frosch, Lukas Amann, Marco Prinz.
      
    DOI:  https://doi.org/10.1038/s41467-023-39061-9
  4. Science. 2023 Jun 30. 380(6652): 1398
    What I owe my mentor.
    Zoe Weiss.
      
    DOI:  https://doi.org/10.1126/science.adj3873
  5. Nat Commun. 2023 Jun 30. 14(1): 3882
    Targeted cross-linker delivery for the in situ mapping of protein conformations and interactions in mitochondria.
    Yuwan Chen, Wen Zhou, Yufei Xia, Weijie Zhang, Qun Zhao, Xinwei Li, Hang Gao, Zhen Liang, Guanghui Ma, Kaiguang Yang, Lihua Zhang, Yukui Zhang.
      Current methods for intracellular protein analysis mostly require the separation of specific organelles or changes to the intracellular environment. However, the functions of proteins are determined by their native microenvironment as they usually form complexes with ions, nucleic acids, and other proteins. Here, we show a method for in situ cross-linking and analysis of mitochondrial proteins in living cells. By using the poly(lactic-co-glycolic acid) (PLGA) nanoparticles functionalized with dimethyldioctadecylammonium bromide (DDAB) to deliver protein cross-linkers into mitochondria, we subsequently analyze the cross-linked proteins using mass spectrometry. With this method, we identify a total of 74 pairs of protein-protein interactions that do not exist in the STRING database. Interestingly, our data on mitochondrial respiratory chain proteins ( ~ 94%) are also consistent with the experimental or predicted structural analysis of these proteins. Thus, we provide a promising technology platform for in situ defining protein analysis in cellular organelles under their native microenvironment.
    DOI:  https://doi.org/10.1038/s41467-023-39485-3
  6. Nat Commun. 2023 Jun 24. 14(1): 3782
    The HIV-1 capsid core is an opportunistic nuclear import receptor.
    Guangai Xue, Hyun Jae Yu, Cindy Buffone, Szu-Wei Huang, KyeongEun Lee, Shih Lin Goh, Anna T Gres, Mehmet Hakan Guney, Stefan G Sarafianos, Jeremy Luban, Felipe Diaz-Griffero, Vineet N KewalRamani.
      The movement of viruses and other large macromolecular cargo through nuclear pore complexes (NPCs) is poorly understood. The human immunodeficiency virus type 1 (HIV-1) provides an attractive model to interrogate this process. HIV-1 capsid (CA), the chief structural component of the viral core, is a critical determinant in nuclear transport of the virus. HIV-1 interactions with NPCs are dependent on CA, which makes direct contact with nucleoporins (Nups). Here we identify Nup35, Nup153, and POM121 to coordinately support HIV-1 nuclear entry. For Nup35 and POM121, this dependence was dependent cyclophilin A (CypA) interaction with CA. Mutation of CA or removal of soluble host factors changed the interaction with the NPC. Nup35 and POM121 make direct interactions with HIV-1 CA via regions containing phenylalanine glycine motifs (FG-motifs). Collectively, these findings provide additional evidence that the HIV-1 CA core functions as a macromolecular nuclear transport receptor (NTR) that exploits soluble host factors to modulate NPC requirements during nuclear invasion.
    DOI:  https://doi.org/10.1038/s41467-023-39146-5
  7. Science. 2023 Jun 30. 380(6652): 1372-1380
    Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.
    Tao Zhang, Daichao Xu, Elijah Trefts, Mingming Lv, Hiroyuki Inuzuka, Guobin Song, Min Liu, Jianlin Lu, Jianping Liu, Chen Chu, Min Wang, Huibing Wang, Huyan Meng, Hui Liu, Yuan Zhuang, Xingxing Xie, Fabin Dang, Dongxian Guan, Yuqin Men, Shuwen Jiang, Cong Jiang, Xiaoming Dai, Jing Liu, Zhen Wang, Peiqiang Yan, Jingchao Wang, Zhenbo Tu, Mrigya Babuta, Emily Erickson, Alissandra L Hillis, Christian C Dibble, John M Asara, Gyongy Szabo, Piotr Sicinski, Ji Miao, Yu-Ru Lee, Lifeng Pan, Reuben J Shaw, Junying Yuan, Wenyi Wei.
      Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
    DOI:  https://doi.org/10.1126/science.abn1725
  8. Nature. 2023 Jun 28.
    GDF15 promotes weight loss by enhancing energy expenditure in muscle.
    Dongdong Wang, Logan K Townsend, Geneviève J DesOrmeaux, Sara M Frangos, Battsetseg Batchuluun, Lauralyne Dumont, Rune Ehrenreich Kuhre, Elham Ahmadi, Sumei Hu, Irena A Rebalka, Jaya Gautam, Maria Joy Therese Jabile, Chantal A Pileggi, Sonia Rehal, Eric M Desjardins, Evangelia E Tsakiridis, James S V Lally, Emma Sara Juracic, A Russell Tupling, Hertzel C Gerstein, Guillaume Paré, Theodoros Tsakiridis, Mary-Ellen Harper, Thomas J Hawke, John R Speakman, Denis P Blondin, Graham P Holloway, Sebastian Beck Jørgensen, Gregory R Steinberg.
      Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.
    DOI:  https://doi.org/10.1038/s41586-023-06249-4
  9. Nat Commun. 2023 06 26. 14(1): 3791
    Histone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells.
    Marko Dunjić, Felix Jonas, Gilad Yaakov, Roye More, Yoav Mayshar, Yoach Rais, Ayelet-Hashahar Orenbuch, Saifeng Cheng, Naama Barkai, Yonatan Stelzer.
      Eviction of histones from nucleosomes and their exchange with newly synthesized or alternative variants is a central epigenetic determinant. Here, we define the genome-wide occupancy and exchange pattern of canonical and non-canonical histone variants in mouse embryonic stem cells by genetically encoded exchange sensors. While exchange of all measured variants scales with transcription, we describe variant-specific associations with transcription elongation and Polycomb binding. We found considerable exchange of H3.1 and H2B variants in heterochromatin and repeat elements, contrasting the occupancy and little exchange of H3.3 in these regions. This unexpected association between H3.3 occupancy and exchange of canonical variants is also evident in active promoters and enhancers, and further validated by reduced H3.1 dynamics following depletion of H3.3-specific chaperone, HIRA. Finally, analyzing transgenic mice harboring H3.1 or H3.3 sensors demonstrates the vast potential of this system for studying histone exchange and its impact on gene expression regulation in vivo.
    DOI:  https://doi.org/10.1038/s41467-023-39477-3
  10. Science. 2023 Jun 29. eadf6287
    Hexasome-INO80 complex reveals structural basis of noncanonical nucleosome remodeling.
    Min Zhang, Anna Jungblut, Franziska Kunert, Luis Hauptmann, Thomas Hoffmann, Olga Kolesnikova, Felix Metzner, Manuela Moldt, Felix Weis, Frank DiMaio, Karl-Peter Hopfner, Sebastian Eustermann.
      Loss of H2A-H2B histone dimers is a hallmark of actively transcribed genes, but how the cellular machinery functions in the context of non-canonical nucleosomal particles remains largely elusive. Here, we report the structural mechanism for ATP-dependent chromatin remodeling of hexasomes by the INO80 complex. We show how INO80 recognizes non-canonical DNA and histone features of hexasomes emerging from the loss of H2A-H2B. A large structural re-arrangement switches the catalytic core of INO80 into a distinct, spin-rotated mode of remodeling, while its nuclear actin module remains tethered to long stretches of unwrapped linker DNA. Direct sensing of an exposed H3-H4 histone interface activates INO80, independently of the H2A-H2B acidic patch. Our findings reveal how the loss of H2A-H2B grants remodelers access to a different, yet unexplored, layer of energy-driven chromatin regulation.
    DOI:  https://doi.org/10.1126/science.adf6287
  11. EMBO J. 2023 Jun 29. e114153
    Transcriptional and chromatin profiling of human blood innate lymphoid cell subsets sheds light on HIV-1 pathogenesis.
    Yetao Wang, Lawrence Lifshitz, Noah J Silverstein, Esther Mintzer, Kevin Luk, Pamela StLouis, Michael A Brehm, Scot A Wolfe, Steven G Deeks, Jeremy Luban.
      Innate lymphoid cells (ILCs) are a diverse population of cells that include NK cells and contribute to tissue homeostasis and repair, inflammation, and provide protection from infection. The interplay between human blood ILCs, as well as their responses to HIV-1 infection, remains poorly understood. This study used transcriptional and chromatin profiling to explore these questions. Transcriptional profiling and flow cytometry analysis support that there are four main ILC subsets found in human blood. Unlike in mice, human NK cells expressed the tissue repair protein amphiregulin (AREG). AREG production was induced by TCF7/WNT, IL-2, and IL-15, and inhibited by TGFB1, a cytokine increased in people living with HIV-1. In HIV-1 infection, the percentage of AREG+ NK cells correlated positively with the numbers of ILCs and CD4+ T cells but negatively with the concentration of inflammatory cytokine IL-6. NK-cell knockout of the TGFB1-stimulated WNT antagonist RUNX3 increased AREG production. Antiviral gene expression was increased in all ILC subsets from HIV-1 viremic people, and anti-inflammatory gene MYDGF was increased in an NK-cell subset from HIV-1-infected people whose viral load was undetectable in the absence of antiretroviral therapy. The percentage of defective NK cells in people living with HIV-1 correlated inversely with ILC percentage and CD4+ T-cell counts. CD4+ T cells and their production of IL-2 prevented the loss of NK-cell function by activating mTOR. These studies clarify how ILC subsets are interrelated and provide insight into how HIV-1 infection disrupts NK cells, including an uncharacterized homeostatic function in NK cells.
    Keywords:  HIV-1; NK cells; amphiregulin; homeostasis; innate lymphoid cells
    DOI:  https://doi.org/10.15252/embj.2023114153
  12. Cell. 2023 Jun 20. pii: S0092-8674(23)00590-1. [Epub ahead of print]
    cGLRs are a diverse family of pattern recognition receptors in innate immunity.
    Yao Li, Kailey M Slavik, Hunter C Toyoda, Benjamin R Morehouse, Carina C de Oliveira Mann, Anamaria Elek, Shani Levy, Zhenwei Wang, Kepler S Mears, Jingjing Liu, Dmitry Kashin, Ximing Guo, Tali Mass, Arnau Sebé-Pedrós, Frank Schwede, Philip J Kranzusch.
      Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
    Keywords:  STING; cGAS; cGLR; cyclic dinucleotides; innate immunity; pattern recognition receptor
    DOI:  https://doi.org/10.1016/j.cell.2023.05.038
  13. Nat Commun. 2023 Jun 24. 14(1): 3777
    An unnatural enzyme with endonuclease activity towards small non-coding RNAs.
    Noreen Ahmed, Nadine Ahmed, Didier A Bilodeau, John Paul Pezacki.
      Endonucleases are enzymes that cleave internal phosphodiester bonds within double-stranded DNA or RNA and are essential for biological functions. Herein, we use genetic code expansion to create an unnatural endonuclease that cleaves non-coding RNAs including short interfering RNA (siRNA) and microRNAs (miRNAs), a function that does not exist in nature. We introduce a metal-chelating unnatural amino acid, (2,2'-bipyridin-5-yl)alanine (BpyAla) to impart endonuclease activity to the viral suppressor of RNA silencing protein p19. Upon binding of copper, the mutant p19-T111BpyAla displays catalytic site-specific cleavage of siRNA and human miRNAs. Catalysis is confirmed using fluorescence polarization and fluorescence turn-on. Global miRNA profiling reveals that the engineered enzyme cleaves miRNAs in a human cell line. The therapeutic potential is demonstrated by targeting miR-122, a critical host factor for the hepatitis C virus (HCV). Unnatural endonuclease function is shown to deplete miR-122 levels with similar effects to an antagomir that reduces HCV levels therapeutically.
    DOI:  https://doi.org/10.1038/s41467-023-39105-0
  14. Nat Metab. 2023 06;5(6): 955-967
    Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.
    Alessandro Bitto, Anthony S Grillo, Takashi K Ito, Ian B Stanaway, Bao M G Nguyen, Kejun Ying, Herman Tung, Kaleb Smith, Ngoc Tran, Gunnar Velikanje, Silvan R Urfer, Jessica M Snyder, Jacob Barton, Ayush Sharma, Ernst-Bernhard Kayser, Lu Wang, Daniel L Smith, J Will Thompson, Laura DuBois, William DePaolo, Matt Kaeberlein.
      Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.
    DOI:  https://doi.org/10.1038/s42255-023-00815-w
  15. Nat Commun. 2023 Jun 30. 14(1): 3870
    Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome.
    Tim Flerlage, Jeremy Chase Crawford, E Kaitlynn Allen, Danielle Severns, Shaoyuan Tan, Sherri Surman, Granger Ridout, Tanya Novak, Adrienne Randolph, Alina N West, Paul G Thomas.
      Acute respiratory distress syndrome (ARDS), termed pediatric ARDS (pARDS) in children, is a severe form of acute respiratory failure (ARF). Pathologic immune responses are implicated in pARDS pathogenesis. Here, we present a description of microbial sequencing and single cell gene expression in tracheal aspirates (TAs) obtained longitudinally from infants with ARF. We show reduced interferon stimulated gene (ISG) expression, altered mononuclear phagocyte (MNP) transcriptional programs, and progressive airway neutrophilia associated with unique transcriptional profiles in patients with moderate to severe pARDS compared to those with no or mild pARDS. We additionally show that an innate immune cell product, Folate Receptor 3 (FOLR3), is enriched in moderate or severe pARDS. Our findings demonstrate distinct inflammatory responses in pARDS that are dependent upon etiology and severity and specifically implicate reduced ISG expression, altered macrophage repair-associated transcriptional programs, and accumulation of aged neutrophils in the pathogenesis of moderate to severe pARDS caused by RSV.
    DOI:  https://doi.org/10.1038/s41467-023-39593-0
  16. Nat Commun. 2023 06 26. 14(1): 3802
    Striatal cholinergic interneuron membrane voltage tracks locomotor rhythms in mice.
    Sanaya N Shroff, Eric Lowet, Sudiksha Sridhar, Howard J Gritton, Mohammed Abumuaileq, Hua-An Tseng, Cyrus Cheung, Samuel L Zhou, Krishnakanth Kondabolu, Xue Han.
      Rhythmic neural network activity has been broadly linked to behavior. However, it is unclear how membrane potentials of individual neurons track behavioral rhythms, even though many neurons exhibit pace-making properties in isolated brain circuits. To examine whether single-cell voltage rhythmicity is coupled to behavioral rhythms, we focused on delta-frequencies (1-4 Hz) that are known to occur at both the neural network and behavioral levels. We performed membrane voltage imaging of individual striatal neurons simultaneously with network-level local field potential recordings in mice during voluntary movement. We report sustained delta oscillations in the membrane potentials of many striatal neurons, particularly cholinergic interneurons, which organize spikes and network oscillations at beta-frequencies (20-40 Hz) associated with locomotion. Furthermore, the delta-frequency patterned cellular dynamics are coupled to animals' stepping cycles. Thus, delta-rhythmic cellular dynamics in cholinergic interneurons, known for their autonomous pace-making capabilities, play an important role in regulating network rhythmicity and movement patterning.
    DOI:  https://doi.org/10.1038/s41467-023-39497-z
  17. Science. 2023 Jun 30. 380(6652): 1322-1323
    Staving off cell death.
    D Grahame Hardie.
      A signaling pathway that senses energy stress opposes necroptotic cell death.
    DOI:  https://doi.org/10.1126/science.adi6827
  18. Nature. 2023 Jun 28.
    Energy burn in muscle boosted by a hormonal signalling axis.
      
    Keywords:  Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-023-01790-8
  19. Sci Adv. 2023 Jun 28. 9(26): eabq7599
    Human PBMC scRNA-seq-based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity.
    Hongming Zhu, Jiawei Chen, Kangping Liu, Lei Gao, Haiyan Wu, Liangliang Ma, Jieru Zhou, Zhongmin Liu, Jing-Dong J Han.
      Quantifying aging rate is important for evaluating age-associated decline and mortality. A blood single-cell RNA sequencing dataset for seven supercentenarians (SCs) was recently generated. Here, we generate a reference 28-sample aging cohort to compute a single-cell level aging clock and to determine the biological age of SCs. Our clock model placed the SCs at a blood biological age to between 80.43 and 102.67 years. Compared to the model-expected aging trajectory, SCs display increased naive CD8+ T cells, decreased cytotoxic CD8+ T cells, memory CD4+ T cells, and megakaryocytes. As the most prominent molecular hallmarks at the single-cell level, SCs contain more cells and cell types with high ribosome level, which is associated with and, according to Bayesian network inference, contributes to a low inflammation state and slow aging of SCs. Inhibiting ribosomal activity or translation in monocytes validates such translation against inflammation balance revealed by our single-cell aging clock.
    DOI:  https://doi.org/10.1126/sciadv.abq7599
  20. Nat Commun. 2023 Jun 24. 14(1): 3787
    Nuclear myosin VI maintains replication fork stability.
    Jie Shi, Kristine Hauschulte, Ivan Mikicic, Srijana Maharjan, Valerie Arz, Tina Strauch, Jan B Heidelberger, Jonas V Schaefer, Birgit Dreier, Andreas Plückthun, Petra Beli, Helle D Ulrich, Hans-Peter Wollscheid.
      The actin cytoskeleton is of fundamental importance for cellular structure and plasticity. However, abundance and function of filamentous actin in the nucleus are still controversial. Here we show that the actin-based molecular motor myosin VI contributes to the stabilization of stalled or reversed replication forks. In response to DNA replication stress, myosin VI associates with stalled replication intermediates and cooperates with the AAA ATPase Werner helicase interacting protein 1 (WRNIP1) in protecting these structures from DNA2-mediated nucleolytic attack. Using functionalized affinity probes to manipulate myosin VI levels in a compartment-specific manner, we provide evidence for the direct involvement of myosin VI in the nucleus and against a contribution of the abundant cytoplasmic pool during the replication stress response.
    DOI:  https://doi.org/10.1038/s41467-023-39517-y
  21. Nat Immunol. 2023 Jun 26.
    A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity.
    Joon Seok, Sung-Dong Cho, Jeongsoo Lee, Yunseo Choi, Su-Young Kim, Sung-Min Lee, Sang-Hoon Kim, Seongju Jeong, Minwoo Jeon, Hoyoung Lee, A Reum Kim, Baekgyu Choi, Sang-Jun Ha, Inkyung Jung, Ki-Jun Yoon, Jong-Eun Park, Jong Hoon Kim, Beom Joon Kim, Eui-Cheol Shin, Su-Hyung Park.
      Virtual memory T (TVM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although TVM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a TVM cell-originated CD44super-high(s-hi)CD49dlo CD8+ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8+ TVM cells and can cause alopecia areata. Mechanistically, CD44s-hiCD49dlo CD8+ T cells could be induced from conventional TVM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.
    DOI:  https://doi.org/10.1038/s41590-023-01547-5
  22. Nature. 2023 Jun 28.
    A human protein that holds bird flu viruses at bay.
    Laura Graf, Peter Staeheli.
      
    Keywords:  Immunology; Virology
    DOI:  https://doi.org/10.1038/d41586-023-01942-w
  23. Nat Cell Biol. 2023 Jun 29.
    mTORC2-NDRG1-CDC42 axis couples fasting to mitochondrial fission.
    Nuria Martinez-Lopez, Pamela Mattar, Miriam Toledo, Henrietta Bains, Manu Kalyani, Marie Louise Aoun, Mridul Sharma, Laura Beth J McIntire, Leslie Gunther-Cummins, Frank P Macaluso, Jennifer T Aguilan, Simone Sidoli, Mathieu Bourdenx, Rajat Singh.
      Fasting triggers diverse physiological adaptations including increases in circulating fatty acids and mitochondrial respiration to facilitate organismal survival. The mechanisms driving mitochondrial adaptations and respiratory sufficiency during fasting remain incompletely understood. Here we show that fasting or lipid availability stimulates mTORC2 activity. Activation of mTORC2 and phosphorylation of its downstream target NDRG1 at serine 336 sustains mitochondrial fission and respiratory sufficiency. Time-lapse imaging shows that NDRG1, but not the phosphorylation-deficient NDRG1Ser336Ala mutant, engages with mitochondria to facilitate fission in control cells, as well as in those lacking DRP1. Using proteomics, a small interfering RNA screen, and epistasis experiments, we show that mTORC2-phosphorylated NDRG1 cooperates with small GTPase CDC42 and effectors and regulators of CDC42 to orchestrate fission. Accordingly, RictorKO, NDRG1Ser336Ala mutants and Cdc42-deficient cells each display mitochondrial phenotypes reminiscent of fission failure. During nutrient surplus, mTOR complexes perform anabolic functions; however, paradoxical reactivation of mTORC2 during fasting unexpectedly drives mitochondrial fission and respiration.
    DOI:  https://doi.org/10.1038/s41556-023-01163-3
  24. Science. 2023 Jun 30. 380(6652): 1321-1322
    Mapping RNA translation.
    Rong Fan.
      A new method maps the location of thousands of translating RNAs in cells and tissues.
    DOI:  https://doi.org/10.1126/science.adi6844
  25. Nat Immunol. 2023 Jun 26.
    Distinct metabolic requirements regulate B cell activation and germinal center responses.
    Rahul Sharma, Ryan M Smolkin, Priyanka Chowdhury, Keith Conrad Fernandez, Youngjun Kim, Montserrat Cols, William Alread, Wei-Feng Yen, Wei Hu, Zhong-Min Wang, Sara Violante, Ronan Chaligné, Ming O Li, Justin R Cross, Jayanta Chaudhuri.
      Following infection or vaccination, activated B cells at extrafollicular sites or within germinal centers (GCs) undergo vigorous clonal proliferation. Proliferating lymphocytes have been shown to undertake lactate dehydrogenase A (LDHA)-dependent aerobic glycolysis; however, the specific role of this metabolic pathway in a B cell transitioning from a naïve to a highly proliferative, activated state remains poorly defined. Here, we deleted LDHA in a stage-specific and cell-specific manner. We find that ablation of LDHA in a naïve B cell did not profoundly affect its ability to undergo a bacterial lipopolysaccharide-induced extrafollicular B cell response. On the other hand, LDHA-deleted naïve B cells had a severe defect in their capacities to form GCs and mount GC-dependent antibody responses. In addition, loss of LDHA in T cells severely compromised B cell-dependent immune responses. Strikingly, when LDHA was deleted in activated, as opposed to naïve, B cells, there were only minimal effects on the GC reaction and in the generation of high-affinity antibodies. These findings strongly suggest that naïve and activated B cells have distinct metabolic requirements that are further regulated by niche and cellular interactions.
    DOI:  https://doi.org/10.1038/s41590-023-01540-y
  26. Nat Cell Biol. 2023 Jun 29.
    Fast fragmenting mitochondria by TORC2.
    Miriam Valera-Alberni, William B Mair.
      
    DOI:  https://doi.org/10.1038/s41556-023-01173-1
  27. Semin Cell Dev Biol. 2023 Jun 26. pii: S1084-9521(23)00131-3. [Epub ahead of print]
    High-resolution omics of vascular ageing and inflammatory pathways in neurodegeneration.
    Andrew J Kwok, Jianning Lu, Junzhe Huang, Bonaventure Y Ip, Vincent C T Mok, Hei Ming Lai, Ho Ko.
      High-resolution omics, particularly single-cell and spatial transcriptomic profiling, are rapidly enhancing our comprehension of the normal molecular diversity of gliovascular cells, as well as their age-related changes that contribute to neurodegeneration. With more omic profiling studies being conducted, it is becoming increasingly essential to synthesise valuable information from the rapidly accumulating findings. In this review, we present an overview of the molecular features of neurovascular and glial cells that have been recently discovered through omic profiling, with a focus on those that have potentially significant functional implications and/or show cross-species differences between human and mouse, and that are linked to vascular deficits and inflammatory pathways in ageing and neurodegenerative disorders. Additionally, we highlight the translational applications of omic profiling, and discuss omic-based strategies to accelerate biomarker discovery and facilitate disease course-modifying therapeutics development for neurodegenerative conditions.
    Keywords:  Alzheimer’s disease; Glial cells; Neurodegeneration; Neurovascular unit; Omics; Parkinson’s disease; Single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.semcdb.2023.06.005
  28. Sci Transl Med. 2023 06 28. 15(702): eabm6267
    PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis.
    Aisling M Chaney, Haley C Cropper, Poorva Jain, Edward Wilson, Federico Simonetta, Emily M Johnson, Israt S Alam, Ian T J Patterson, Michelle Swarovski, Marc Y Stevens, Qian Wang, Carmen Azevedo, Sydney C Nagy, Javier Ramos Benitez, Emily M Deal, Hannes Vogel, Katrin I Andreasson, Michelle L James.
      Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
    DOI:  https://doi.org/10.1126/scitranslmed.abm6267
  29. Nat Commun. 2023 06 26. 14(1): 3795
    The long non-coding RNA NEAT1 is a ΔNp63 target gene modulating epidermal differentiation.
    Claudia Fierro, Veronica Gatti, Veronica La Banca, Sara De Domenico, Stefano Scalera, Giacomo Corleone, Maurizio Fanciulli, Francesca De Nicola, Alessandro Mauriello, Manuela Montanaro, George A Calin, Gerry Melino, Angelo Peschiaroli.
      The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting in an increased assembly of paraspeckles foci both in vitro and in human skin tissues. RNA-seq analysis associated with global DNA binding profile (ChIRP-seq) revealed that NEAT1 associates with the promoter of key epithelial transcription factors sustaining their expression during epidermal differentiation. These molecular events might explain the inability of NEAT1-depleted keratinocytes to undergo the proper formation of epidermal layers. Collectively, these data uncover the lncRNA NEAT1 as an additional player of the intricate network orchestrating epidermal morphogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-39011-5
  30. Nat Rev Immunol. 2023 Jun 28.
    Image-seq: image-guided cell isolation for spatially resolved transcriptomic analysis.
    Christa Haase.
      
    DOI:  https://doi.org/10.1038/s41577-023-00912-7
  31. Cell Death Dis. 2023 06 26. 14(6): 376
    Myeloid-derived growth factor alleviates non-alcoholic fatty liver disease alleviates in a manner involving IKKβ/NF-κB signaling.
    Yan Ding, Xiaoli Xu, Biying Meng, Li Wang, Biao Zhu, Bei Guo, Jiajia Zhang, Lin Xiang, Jing Dong, Min Liu, Guangda Xiang.
      Whether bone marrow modulates systemic metabolism remains unknown. Our recent study suggested that myeloid-derived growth factor (MYDGF) improves insulin resistance. Here, we found that myeloid cell-specific MYDGF deficiency aggravated hepatic inflammation, lipogenesis, and steatosis, and show that myeloid cell-derived MYDGF restoration alleviated hepatic inflammation, lipogenesis, and steatosis. Additionally, recombinant MYDGF attenuated inflammation, lipogenesis, and fat deposition in primary mouse hepatocytes (PMHs). Importantly, inhibitor kappa B kinase beta/nuclear factor-kappa B (IKKβ/NF-κB) signaling is involved in protection of MYDGF on non-alcoholic fatty liver disease (NAFLD). These data revealed that myeloid cell-derived MYDGF alleviates NAFLD and inflammation in a manner involving IKKβ/NF-κB signaling, and serves as a factor involved in the crosstalk between the liver and bone marrow that regulates liver fat metabolism. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.
    DOI:  https://doi.org/10.1038/s41419-023-05904-y
  32. Nat Genet. 2023 Jun 29.
    Single-cell multiomic analyses sheds light on mitochondrial mutational selection.
    Sarah J Pickett, Gavin Hudson, Laura C Greaves.
      
    DOI:  https://doi.org/10.1038/s41588-023-01436-5
  33. Sci Adv. 2023 Jun 30. 9(26): eadf6254
    Integrating lipid metabolism, pheromone production and perception by Fruitless and Hepatocyte Nuclear Factor 4.
    Jie Sun, Wen-Kan Liu, Calder Ellsworth, Qian Sun, Yufeng Pan, Yi-Chun Huang, Wu-Min Deng.
      Sexual attraction and perception are crucial for mating and reproductive success. In Drosophila melanogaster, the male-specific isoform of Fruitless (Fru), FruM, is a known master neuro-regulator of innate courtship behavior to control the perception of sex pheromones in sensory neurons. Here, we show that the non-sex-specific Fru isoform (FruCOM) is necessary for pheromone biosynthesis in hepatocyte-like oenocytes for sexual attraction. Loss of FruCOM in oenocytes resulted in adults with reduced levels of cuticular hydrocarbons (CHCs), including sex pheromones, and show altered sexual attraction and reduced cuticular hydrophobicity. We further identify Hepatocyte nuclear factor 4 (Hnf4) as a key target of FruCOM in directing fatty acid conversion to hydrocarbons. Fru or Hnf4 depletion in oenocytes disrupts lipid homeostasis, resulting in a sex-dimorphic CHC profile that differs from doublesex- and transformer-dependent CHC dimorphism. Thus, Fru couples pheromone perception and production in separate organs to regulate chemosensory communications and ensure efficient mating behavior.
    DOI:  https://doi.org/10.1126/sciadv.adf6254
  34. Nat Rev Immunol. 2023 Jun 29.
    The kiss a cell can't forget: tracking cell-cell interactions with uLIPSTIC.
    Yavuz F Yazicioglu, Alexander J Clarke.
      
    DOI:  https://doi.org/10.1038/s41577-023-00910-9
  35. Cell Genom. 2023 Jun 14. 3(6): 100306
    Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis.
    Andrew C Brown, Carla J Cohen, Olga Mielczarek, Gabriele Migliorini, Félicie Costantino, Alice Allcock, Connor Davidson, Katherine S Elliott, Hai Fang, Alicia Lledó Lara, Alice C Martin, Julie A Osgood, Anna Sanniti, Giuseppe Scozzafava, Matteo Vecellio, Ping Zhang, Mary Helen Black, Shuwei Li, Dongnhu Truong, Julio Molineros, Trevor Howe, B Paul Wordsworth, Paul Bowness, Julian C Knight.
      Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets.
    Keywords:  ankylosing spondylitis; chromatin interactions; epigenomics; functional genomics; gene regulation; genome-wide association study; spondyloarthritis; target discovery; transcriptomics
    DOI:  https://doi.org/10.1016/j.xgen.2023.100306
  36. Nat Commun. 2023 Jun 29. 14(1): 3852
    A selective autophagy receptor VISP1 induces symptom recovery by targeting viral silencing suppressors.
    Xin Tong, Jia-Jia Zhao, Ya-Lan Feng, Jing-Ze Zou, Jian Ye, Junfeng Liu, Chenggui Han, Dawei Li, Xian-Bing Wang.
      Selective autophagy is a double-edged sword in antiviral immunity and regulated by various autophagy receptors. However, it remains unclear how to balance the opposite roles by one autophagy receptor. We previously identified a virus-induced small peptide called VISP1 as a selective autophagy receptor that facilitates virus infections by targeting components of antiviral RNA silencing. However, we show here that VISP1 can also inhibit virus infections by mediating autophagic degradation of viral suppressors of RNA silencing (VSRs). VISP1 targets the cucumber mosaic virus (CMV) 2b protein for degradation and attenuates its suppression activity on RNA silencing. Knockout and overexpression of VISP1 exhibit compromised and enhanced resistance against late infection of CMV, respectively. Consequently, VISP1 induces symptom recovery from CMV infection by triggering 2b turnover. VISP1 also targets the C2/AC2 VSRs of two geminiviruses and enhances antiviral immunity. Together, VISP1 induces symptom recovery from severe infections of plant viruses through controlling VSR accumulation.
    DOI:  https://doi.org/10.1038/s41467-023-39426-0
  37. Cell. 2023 Jun 20. pii: S0092-8674(23)00599-8. [Epub ahead of print]
    Circadian clocks are modulated by compartmentalized oscillating translation.
    Yanrong Zhuang, Zhiyuan Li, Shiyue Xiong, Chujie Sun, Boya Li, Shuangcheng Alivia Wu, Jiali Lyu, Xiang Shi, Liang Yang, Yutong Chen, Zhangbin Bao, Xi Li, Chuhanwen Sun, Yuling Chen, Haiteng Deng, Tingting Li, Qingfeng Wu, Ling Qi, Yue Huang, Xuerui Yang, Yi Lin.
      Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals.
    Keywords:  ATXN2; ATXN2L; circadian rhythm; clock genes; membrane-less organelle; neurodegeneration; phase separation; rhythmic translation; suprachiasmatic nucleus; translational regulation
    DOI:  https://doi.org/10.1016/j.cell.2023.05.045
  38. Nature. 2023 Jun 28.
    A spatially resolved single-cell genomic atlas of the adult human breast.
    Tapsi Kumar, Kevin Nee, Runmin Wei, Siyuan He, Quy H Nguyen, Shanshan Bai, Kerrigan Blake, Maren Pein, Yanwen Gong, Emi Sei, Min Hu, Anna K Casasent, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Ken Chen, Benedikt Nilges, Nachiket Kashikar, Oliver Braubach, Bassem Ben Cheikh, Nadya Nikulina, Hui Chen, Mediget Teshome, Brian Menegaz, Huma Javaid, Chandandeep Nagi, Jessica Montalvan, Tatyana Lev, Sharmila Mallya, Delia F Tifrea, Robert Edwards, Erin Lin, Ritesh Parajuli, Summer Hanson, Sebastian Winocour, Alastair Thompson, Bora Lim, Devon A Lawson, Kai Kessenbrock, Nicholas Navin.
      The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue1-3. Although most previous studies have focused on the breast epithelial system4-6, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Spatial mapping using four different technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide a reference of the adult normal breast tissue for studying mammary biology and diseases such as breast cancer.
    DOI:  https://doi.org/10.1038/s41586-023-06252-9
  39. Nature. 2023 Jun 28.
    Insights into the genetic architecture of multiple sclerosis severity.
      
    Keywords:  Brain; Genetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-01787-3
  40. Proc Natl Acad Sci U S A. 2023 07 04. 120(27): e2300204120
    Inhibition of AIM2 inflammasome activation by SOX/ORF37 promotes lytic replication of Kaposi's sarcoma-associated herpesvirus.
    Xiaolin Zhang, Qingping Lan, Mingyu Zhang, Fan Wang, Keyi Shi, Xiaojuan Li, Ersheng Kuang.
      Inflammasomes are one kind of important innate immune defense against viral and bacterial infections. Several inflammasome-forming sensors detect molecular patterns of invading pathogens and then trigger inflammasome activation and/or pyroptosis in infected cells, and viruses employ unique strategies to hijack or subvert inflammasome activation. Infection with herpesviruses induces the activation of diverse inflammasomes, including AIM2 and IFI16 inflammasomes; however, how Kaposi's sarcoma-associated herpesvirus (KSHV) counteracts inflammasome activation largely remains unclear. Here, we reveal that the KSHV ORF37-encoded SOX protein suppresses AIM2 inflammasome activation independent of its viral DNA exonuclease activity and host mRNA turnover. SOX interacts with the AIM2 HIN domain through the C-terminal Motif VII region and disrupts AIM2:dsDNA polymerization and ASC recruitment and oligomerization. The Y443A or F444A mutation of SOX abolishes the inhibition of AIM2 inflammasome without disrupting SOX nuclease activity, and a short SOX peptide is capable of inhibiting AIM2 inflammasome activation; consequently, infection with SOX-null, Y443A, or F444A Bac16 recombinant viruses results in robust inflammasome activation, suppressed lytic replication, and increased pyroptosis in human lymphatic endothelial cells in an AIM2-dependent manner. These results reveal that KSHV SOX suppresses AIM2 inflammasome activation to promote KSHV lytic replication and inhibit pyroptosis, representing a unique mechanism for evasion of inflammasome activation during KSHV lytic cycle.
    Keywords:  AIM2; KSHV lytic replication; SOX/ORF37; inflammasome; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2300204120
  41. Nat Commun. 2023 Jun 29. 14(1): 3848
    Dissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation.
    Nina Schmolka, Ino D Karemaker, Richard Cardoso da Silva, Davide C Recchia, Vincent Spegg, Jahnavi Bhaskaran, Michael Teske, Nathalie P de Wagenaar, Matthias Altmeyer, Tuncay Baubec.
      The Nucleosome Remodeling and Deacetylation (NuRD) complex is a crucial regulator of cellular differentiation. Two members of the Methyl-CpG-binding domain (MBD) protein family, MBD2 and MBD3, are known to be integral, but mutually exclusive subunits of the NuRD complex. Several MBD2 and MBD3 isoforms are present in mammalian cells, resulting in distinct MBD-NuRD complexes. Whether these different complexes serve distinct functional activities during differentiation is not fully explored. Based on the essential role of MBD3 in lineage commitment, we systematically investigated a diverse set of MBD2 and MBD3 variants for their potential to rescue the differentiation block observed for mouse embryonic stem cells (ESCs) lacking MBD3. While MBD3 is indeed crucial for ESC differentiation to neuronal cells, it functions independently of its MBD domain. We further identify that MBD2 isoforms can replace MBD3 during lineage commitment, however with different potential. Full-length MBD2a only partially rescues the differentiation block, while MBD2b, an isoform lacking an N-terminal GR-rich repeat, fully rescues the Mbd3 KO phenotype. In case of MBD2a, we further show that removing the methylated DNA binding capacity or the GR-rich repeat enables full redundancy to MBD3, highlighting the synergistic requirements for these domains in diversifying NuRD complex function.
    DOI:  https://doi.org/10.1038/s41467-023-39551-w
  42. Nat Immunol. 2023 Jun 26.
    B cells ferment sugar before they (affinity) mature.
    Rebecca J Brownlie, Ulf Klein.
      
    DOI:  https://doi.org/10.1038/s41590-023-01536-8
  43. Nat Biotechnol. 2023 Jun 26.
    Efficient A-to-C base editing with high specificity.
      
    DOI:  https://doi.org/10.1038/s41587-023-01866-w
  44. Nat Commun. 2023 Jun 28. 14(1): 3831
    T cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS.
    Tasuku Kawano, Jinyan Zhou, Shehata Anwar, Haneen Salah, Andrea H Dayal, Yuzuki Ishikawa, Katelyn Boetel, Tomoko Takahashi, Kamal Sharma, Makoto Inoue.
      Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a condition frequently occurring in immunocompromised patients receiving antiretroviral therapy. C-IRIS patients exhibit many critical symptoms, including pulmonary distress, potentially complicating the progression and recovery from this condition. Here, utilizing our previously established mouse model of unmasking C-IRIS (CnH99 preinfection and adoptive transfer of CD4+ T cells), we demonstrated that pulmonary dysfunction associated with the C-IRIS condition in mice could be attributed to the infiltration of CD4+ T cells into the brain via the CCL8-CCR5 axis, which triggers the nucleus tractus solitarius (NTS) neuronal damage and neuronal disconnection via upregulated ephrin B3 and semaphorin 6B in CD4+ T cells. Our findings provide unique insight into the mechanism behind pulmonary dysfunction in C-IRIS and nominate potential therapeutic targets for treatment.
    DOI:  https://doi.org/10.1038/s41467-023-39518-x
  45. Nature. 2023 Jun 29.
    New COVID jabs are coming - who should get them?
    Max Kozlov.
      
    Keywords:  Epidemiology; Infection; Public health; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-023-02188-2
  46. Nat Commun. 2023 Jun 29. 14(1): 3849
    Demonstration of quantum-digital payments.
    Peter Schiansky, Julia Kalb, Esther Sztatecsny, Marie-Christine Roehsner, Tobias Guggemos, Alessandro Trenti, Mathieu Bozzio, Philip Walther.
      Digital payments have replaced physical banknotes in many aspects of our daily lives. Similarly to banknotes, they should be easy to use, unique, tamper-resistant and untraceable, but additionally withstand digital attackers and data breaches. Current technology substitutes customers' sensitive data by randomized tokens, and secures the payment's uniqueness with a cryptographic function, called a cryptogram. However, computationally powerful attacks violate the security of these functions. Quantum technology comes with the potential to protect even against infinite computational power. Here, we show how quantum light can secure daily digital payments by generating inherently unforgeable quantum cryptograms. We implement the scheme over an urban optical fiber link, and show its robustness to noise and loss-dependent attacks. Unlike previously proposed protocols, our solution does not depend on long-term quantum storage or trusted agents and authenticated channels. It is practical with near-term technology and may herald an era of quantum-enabled security.
    DOI:  https://doi.org/10.1038/s41467-023-39519-w
  47. Nature. 2023 Jun 28.
    Memory Day report.
    Dominic Bock.
      
    DOI:  https://doi.org/10.1038/d41586-023-02067-w
  48. Nat Metab. 2023 Jun 26.
    Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes.
    Joseph W Beals, Brandon D Kayser, Gordon I Smith, George G Schweitzer, Kyleigh Kirbach, Monica L Kearney, Jun Yoshino, Gibraan Rahman, Rob Knight, Bruce W Patterson, Samuel Klein.
      The additional therapeutic effects of regular exercise during a dietary weight loss program in people with obesity and prediabetes are unclear. Here, we show that whole-body (primarily muscle) insulin sensitivity (primary outcome) was 2-fold greater (P = 0.006) after 10% weight loss induced by calorie restriction plus exercise training (Diet+EX; n = 8, 6 women) than 10% weight loss induced by calorie restriction alone (Diet-ONLY; n = 8, 4 women) in participants in two concurrent studies. The greater improvement in insulin sensitivity was accompanied by increased muscle expression of genes involved in mitochondrial biogenesis, energy metabolism and angiogenesis (secondary outcomes) in the Diet+EX group. There were no differences between groups in plasma branched-chain amino acids or markers of inflammation, and both interventions caused similar changes in the gut microbiome. Few adverse events were reported. These results demonstrate that regular exercise during a diet-induced weight loss program has profound additional metabolic benefits in people with obesity and prediabetes.Trial Registration: ClinicalTrials.gov (NCT02706262 and NCT02706288).
    DOI:  https://doi.org/10.1038/s42255-023-00829-4
  49. Cell Genom. 2023 Jun 14. 3(6): 100318
    Integrative dissection of gene regulatory elements at base resolution.
    Zeyu Chen, Nauman Javed, Molly Moore, Jingyi Wu, Gary Sun, Michael Vinyard, Alejandro Collins, Luca Pinello, Fadi J Najm, Bradley E Bernstein.
      Although vast numbers of putative gene regulatory elements have been cataloged, the sequence motifs and individual bases that underlie their functions remain largely unknown. Here, we combine epigenetic perturbations, base editing, and deep learning to dissect regulatory sequences within the exemplar immune locus encoding CD69. We converge on a ∼170 base interval within a differentially accessible and acetylated enhancer critical for CD69 induction in stimulated Jurkat T cells. Individual C-to-T base edits within the interval markedly reduce element accessibility and acetylation, with corresponding reduction of CD69 expression. The most potent base edits may be explained by their effect on regulatory interactions between the transcriptional activators GATA3 and TAL1 and the repressor BHLHE40. Systematic analysis suggests that the interplay between GATA3 and BHLHE40 plays a general role in rapid T cell transcriptional responses. Our study provides a framework for parsing regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants.
    Keywords:  CRISPRi; base editing; immune response; regulatory elements; transcription factor
    DOI:  https://doi.org/10.1016/j.xgen.2023.100318
  50. Nat Commun. 2023 06 27. 14(1): 3680
    In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting.
    Wen Juan Tu, Michelle Melino, Jenny Dunn, Robert D McCuaig, Helle Bielefeldt-Ohmann, Sofiya Tsimbalyuk, Jade K Forwood, Taniya Ahuja, John Vandermeide, Xiao Tan, Minh Tran, Quan Nguyen, Liang Zhang, Andy Nam, Liuliu Pan, Yan Liang, Corey Smith, Katie Lineburg, Tam H Nguyen, Julian D J Sng, Zhen Wei Marcus Tong, Keng Yih Chew, Kirsty R Short, Roger Le Grand, Nabila Seddiki, Sudha Rao.
      In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.
    DOI:  https://doi.org/10.1038/s41467-023-39341-4
  51. Science. 2023 06 30. 380(6652): 1330
    Editorial Expression of Concern.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/science.adj3306
  52. Nature. 2023 Jun 26.
    Did our human ancestors eat each other? Carved-up bone offers clues.
    Lilly Tozer.
      
    Keywords:  Evolution; Human behaviour; Palaeontology
    DOI:  https://doi.org/10.1038/d41586-023-02082-x
  53. Nat Rev Immunol. 2023 Jun 27.
    Adventitial fibroblast-ILC2 niche restrains liver fibrosis.
    Anthony Altieri, Matthew B Buechler.
      
    DOI:  https://doi.org/10.1038/s41577-023-00909-2
  54. Nat Biomed Eng. 2023 Jun 26.
    Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix.
    Kwasi Adu-Berchie, Yutong Liu, David K Y Zhang, Benjamin R Freedman, Joshua M Brockman, Kyle H Vining, Bryan A Nerger, Andrea Garmilla, David J Mooney.
      The efficacy of adoptive T-cell therapies largely depends on the generation of T-cell populations that provide rapid effector function and long-term protective immunity. Yet it is becoming clearer that the phenotypes and functions of T cells are inherently linked to their localization in tissues. Here we show that functionally distinct T-cell populations can be generated from T cells that received the same stimulation by altering the viscoelasticity of their surrounding extracellular matrix (ECM). By using a model ECM based on a norbornene-modified collagen type I whose viscoelasticity can be adjusted independently from its bulk stiffness by varying the degree of covalent crosslinking via a bioorthogonal click reaction with tetrazine moieties, we show that ECM viscoelasticity regulates T-cell phenotype and function via the activator-protein-1 signalling pathway, a critical regulator of T-cell activation and fate. Our observations are consistent with the tissue-dependent gene-expression profiles of T cells isolated from mechanically distinct tissues from patients with cancer or fibrosis, and suggest that matrix viscoelasticity could be leveraged when generating T-cell products for therapeutic applications.
    DOI:  https://doi.org/10.1038/s41551-023-01052-y
  55. Nat Commun. 2023 Jun 30. 14(1): 3877
    Ultrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity.
    Chaoyu Wang, Ruoshi Zhang, Jia He, Lvshan Yu, Xinyan Li, Junxia Zhang, Sai Li, Conggang Zhang, Jonathan C Kagan, Jeffrey M Karp, Rui Kuai.
      DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway in antigen-presenting cells (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited tumor cell killing and ineffective transfer of stable tumor DNA to APCs. Here we show that liposomes loaded with an optimized ratio of indocyanine green and doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure to ultrasound. LID plus ultrasound enhance the nuclear delivery of doxorubicin, induce tumor mitochondrial DNA oxidation, and promote oxidized tumor mitochondrial DNA transfer to APCs for effective activation of cGAS-STING signaling. Depleting tumor mitochondrial DNA or knocking out STING in APCs compromises the activation of APCs. Furthermore, systemic injection of LID plus ultrasound over the tumor lead to targeted cytotoxicity and STING activation, eliciting potent antitumor T cell immunity, which upon the combination with immune checkpoint blockade leads to regression of bilateral MC38, CT26, and orthotopic 4T1 tumors in female mice. Our study sheds light on the importance of oxidized tumor mitochondrial DNA in STING-mediated antitumor immunity and may inspire the development of more effective strategies for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-39607-x
  56. Nat Metab. 2023 Jun 26.
    Exercise increases the metabolic benefits of weight loss.
      
    DOI:  https://doi.org/10.1038/s42255-023-00842-7
  57. Cell Rep. 2023 Jun 28. pii: S2211-1247(23)00733-7. [Epub ahead of print]42(7): 112722
    Dietary restriction mitigates the age-associated decline in mouse B cell receptor repertoire diversity.
    Carolina Monzó, Lisonia Gkioni, Andreas Beyer, Dario Riccardo Valenzano, Sebastian Grönke, Linda Partridge.
      Aging impairs the capacity to respond to novel antigens, reducing immune protection against pathogens and vaccine efficacy. Dietary restriction (DR) extends life- and health span in diverse animals. However, little is known about the capacity of DR to combat the decline in immune function. Here, we study the changes in B cell receptor (BCR) repertoire during aging in DR and control mice. By sequencing the variable region of the BCR heavy chain in the spleen, we show that DR preserves diversity and attenuates the increase in clonal expansions throughout aging. Remarkably, mice starting DR in mid-life have repertoire diversity and clonal expansion rates indistinguishable from chronic DR mice. In contrast, in the intestine, these traits are unaffected by either age or DR. Reduced within-individual B cell repertoire diversity and increased clonal expansions are correlated with higher morbidity, suggesting a potential contribution of B cell repertoire dynamics to health during aging.
    Keywords:  B cell receptor repertoire; CP: Immunology; adaptive immunity; aging; dietary restriction; late onset; mice
    DOI:  https://doi.org/10.1016/j.celrep.2023.112722
  58. Immunity. 2023 Jun 20. pii: S1074-7613(23)00237-6. [Epub ahead of print]
    The nucleotide receptor STING translocates to the phagosomes to negatively regulate anti-fungal immunity.
    Tian Chen, Yiting Feng, Wanwei Sun, Guimin Zhao, Han Wu, Xiaochen Cheng, Fabao Zhao, Lei Zhang, Yi Zheng, Peng Zhan, Wei Zhao, Bingyu Liu, Chengjiang Gao.
      STING (stimulator of interferon genes) exerts protective cellular responses to viral infection via induction of interferon production and autophagy. Here, we report the role of STING in modulating the immune responses toward fungal infection. Upon Candida albicans stimulation, STING transited alongside the endoplasmic reticulum (ER) to the phagosomes. In phagosomes, STING directly bound with Src via the N-terminal 18 amino acids of STING, and this binding prevented Src from recruiting and phosphorylating Syk. Consistently, Syk-associated signaling and production of pro-inflammatory cytokines and chemokines were increased in mouse BMDCs (bone-marrow-derived dendritic cells) lacking STING with fungal treatment. STING deficiency improved anti-fungal immunity in systemic C. albicans infection. Importantly, administration of the N-terminal 18-aa (amino acid) peptide of STING improved host outcomes in disseminated fungal infection. Overall, our study identifies a previously unrecognized function of STING in negatively regulating anti-fungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infection.
    Keywords:  STING; Src; Syk; anti-fungal immunity; phagosome
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.002
  59. Cell Rep. 2023 Jun 28. pii: S2211-1247(23)00697-6. [Epub ahead of print]42(7): 112686
    Early chromosome condensation by XIST builds A-repeat RNA density that facilitates gene silencing.
    Melvys Valledor, Meg Byron, Brett Dumas, Dawn M Carone, Lisa L Hall, Jeanne B Lawrence.
      XIST RNA triggers chromosome-wide gene silencing and condenses an active chromosome into a Barr body. Here, we use inducible human XIST to examine early steps in the process, showing that XIST modifies cytoarchitecture before widespread gene silencing. In just 2-4 h, barely visible transcripts populate the large "sparse zone" surrounding the smaller "dense zone"; importantly, density zones exhibit different chromatin impacts. Sparse transcripts immediately trigger immunofluorescence for H2AK119ub and CIZ1, a matrix protein. H3K27me3 appears hours later in the dense zone, which enlarges with chromosome condensation. Genes examined are silenced after compaction of the RNA/DNA territory. Insights into this come from the findings that the A-repeat alone can silence genes and rapidly, but only where dense RNA supports sustained histone deacetylation. We propose that sparse XIST RNA quickly impacts architectural elements to condense the largely non-coding chromosome, coalescing RNA density that facilitates an unstable, A-repeat-dependent step required for gene silencing.
    Keywords:  A-Repeat; Barr body; CIZ1; CP: Molecular biology; CP: Stem cell research; H3K27; UbH2A; XIST; chromosome structure; epigenetics; heterochromatin; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2023.112686
  60. Nature. 2023 Jun 28.
    Continuous synthesis of E. coli genome sections and Mb-scale human DNA assembly.
    Jérôme F Zürcher, Askar A Kleefeldt, Louise F H Funke, Jakob Birnbaum, Julius Fredens, Simona Grazioli, Kim C Liu, Martin Spinck, Gianluca Petris, Pierre Murat, Fabian B H Rehm, Julian E Sale, Jason W Chin.
      Whole-genome synthesis provides a powerful approach for understanding and expanding organism function1-3. To build large genomes rapidly, scalably and in parallel, we need (1) methods for assembling megabases of DNA from shorter precursors and (2) strategies for rapidly and scalably replacing the genomic DNA of organisms with synthetic DNA. Here we develop bacterial artificial chromosome (BAC) stepwise insertion synthesis (BASIS)-a method for megabase-scale assembly of DNA in Escherichia coli episomes. We used BASIS to assemble 1.1 Mb of human DNA containing numerous exons, introns, repetitive sequences, G-quadruplexes, and long and short interspersed nuclear elements (LINEs and SINEs). BASIS provides a powerful platform for building synthetic genomes for diverse organisms. We also developed continuous genome synthesis (CGS)-a method for continuously replacing sequential 100 kb stretches of the E. coli genome with synthetic DNA; CGS minimizes crossovers1,4 between the synthetic DNA and the genome such that the output for each 100 kb replacement provides, without sequencing, the input for the next 100 kb replacement. Using CGS, we synthesized a 0.5 Mb section of the E. coli genome-a key intermediate in its total synthesis1-from five episomes in 10  days. By parallelizing CGS and combining it with rapid oligonucleotide synthesis and episome assembly5,6, along with rapid methods for compiling a single genome from strains bearing distinct synthetic genome sections1,7,8, we anticipate that it will be possible to synthesize entire E. coli genomes from functional designs in less than 2 months.
    DOI:  https://doi.org/10.1038/s41586-023-06268-1
  61. Nat Neurosci. 2023 Jun 26.
    Multi-level analysis of the gut-brain axis shows autism spectrum disorder-associated molecular and microbial profiles.
    James T Morton, Dong-Min Jin, Robert H Mills, Yan Shao, Gibraan Rahman, Daniel McDonald, Qiyun Zhu, Metin Balaban, Yueyu Jiang, Kalen Cantrell, Antonio Gonzalez, Julie Carmel, Linoy Mia Frankiensztajn, Sandra Martin-Brevet, Kirsten Berding, Brittany D Needham, María Fernanda Zurita, Maude David, Olga V Averina, Alexey S Kovtun, Antonio Noto, Michele Mussap, Mingbang Wang, Daniel N Frank, Ellen Li, Wenhao Zhou, Vassilios Fanos, Valery N Danilenko, Dennis P Wall, Paúl Cárdenas, Manuel E Baldeón, Sébastien Jacquemont, Omry Koren, Evan Elliott, Ramnik J Xavier, Sarkis K Mazmanian, Rob Knight, Jack A Gilbert, Sharon M Donovan, Trevor D Lawley, Bob Carpenter, Richard Bonneau, Gaspar Taroncher-Oldenburg.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by heterogeneous cognitive, behavioral and communication impairments. Disruption of the gut-brain axis (GBA) has been implicated in ASD although with limited reproducibility across studies. In this study, we developed a Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across 10 cross-sectional microbiome datasets and 15 other datasets, including dietary patterns, metabolomics, cytokine profiles and human brain gene expression profiles. We found a functional architecture along the GBA that correlates with heterogeneity of ASD phenotypes, and it is characterized by ASD-associated amino acid, carbohydrate and lipid profiles predominantly encoded by microbial species in the genera Prevotella, Bifidobacterium, Desulfovibrio and Bacteroides and correlates with brain gene expression changes, restrictive dietary patterns and pro-inflammatory cytokine profiles. The functional architecture revealed in age-matched and sex-matched cohorts is not present in sibling-matched cohorts. We also show a strong association between temporal changes in microbiome composition and ASD phenotypes. In summary, we propose a framework to leverage multi-omic datasets from well-defined cohorts and investigate how the GBA influences ASD.
    DOI:  https://doi.org/10.1038/s41593-023-01361-0
  62. Sci Immunol. 2023 Jun 30. 8(84): eade5343
    Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.
    William H Palmer, Laura Ann Leaton, Ana Campos Codo, Bergren Crute, James Roest, Shiying Zhu, Jan Petersen, Richard P Tobin, Patrick S Hume, Matthew Stone, Adrie van Bokhoven, Mark E Gerich, Martin D McCarter, Yuwen Zhu, William J Janssen, Julian P Vivian, John Trowsdale, Andrew Getahun, Jamie Rossjohn, John Cambier, Liyen Loh, Paul J Norman.
      Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.
    DOI:  https://doi.org/10.1126/sciimmunol.ade5343
  63. Nat Metab. 2023 Jun 26.
    Time-restricted feeding makes the mouse run like a pro.
    Mayer M Chalom, Chih-Hao Lee.
      
    DOI:  https://doi.org/10.1038/s42255-023-00833-8
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