bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒04‒10
fifty-nine papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. What triggers severe COVID? Infected immune cells hold clues.
  2. Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions.
  3. Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.
  4. STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming.
  5. The PripA-TbcrA complex-centered Rab GAP cascade facilitates macropinosome maturation in Dictyostelium.
  6. Daily briefing: CRISPR-baby scientist released from prison.
  7. Your brain expands and shrinks over time - these charts show how.
  8. Tuning T cell receptor sensitivity through catch bond engineering.
  9. The miniature mice locked in an evolutionary battle of the sexes.
  10. How the antibiotic fidaxomicin targets an intestinal pathogen.
  11. Cholera-causing bacteria have defences that degrade plasmid invaders.
  12. Citrullination of glucokinase is linked to autoimmune diabetes.
  13. In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration.
  14. Structure-based design of stabilized recombinant influenza neuraminidase tetramers.
  15. Corrigendum to 'Landscape dynamic network biomarker analysis reveals the tipping point of transcriptome reprogramming to prevent skin photodamage'.
  16. Learning meaningful representations of protein sequences.
  17. The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver.
  18. Mystery space circle, coronavirus genomes and COVID antibody treatments.
  19. An unexpected protein aggregate in diseased and ageing brains.
  20. Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age.
  21. Genetic variants underlying differences in facial morphology in East Asian and European populations.
  22. Isolation of mouse pancreatic islet Procr+ progenitors and long-term expansion of islet organoids in vitro.
  23. Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery.
  24. Evidence for oxygen-conserving diamond formation in redox-buffered subducted oceanic crust sampled as eclogite.
  25. Rare coding variants in ten genes confer substantial risk for schizophrenia.
  26. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
  27. Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation.
  28. FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.
  29. Autoreactive memory Th17 cells are principally derived from T-bet+RORγt+ Th17/1 effectors.
  30. CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.
  31. Myogenesis controlled by a long non-coding RNA 1700113A16RIK and post-transcriptional regulation.
  32. Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity.
  33. Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip.
  34. Blind demixing methods for recovering dense neuronal morphology from barcode imaging data.
  35. DELE1 tracks perturbed protein import and processing in human mitochondria.
  36. CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.
  37. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
  38. Electrocorticographic evidence of a common neurocognitive sequence for mentalizing about the self and others.
  39. Creep-dilatancy development at a transform plate boundary.
  40. Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease.
  41. Glyco-Decipher enables glycan database-independent peptide matching and in-depth characterization of site-specific N-glycosylation.
  42. Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair.
  43. Introducing principles of synaptic integration in the optimization of deep neural networks.
  44. Cutting Edge: Enhanced Antitumor Immunity in ST8Sia6 Knockout Mice.
  45. Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.
  46. DNA sequence-dependent formation of heterochromatin nanodomains.
  47. FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.
  48. Unlocking the secrets to Janus kinase activation.
  49. Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation.
  50. Group testing via hypergraph factorization applied to COVID-19.
  51. Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing.
  52. In pursuit of data immortality.
  53. Zoonotic origin of the human malaria parasite Plasmodium malariae from African apes.
  54. Direct measurements of mRNA translation kinetics in living cells.
  55. High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways.
  56. Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.
  57. Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C.
  58. Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons.
  59. Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression.
  1. Nature. 2022 Apr 06.
    What triggers severe COVID? Infected immune cells hold clues.
    Smriti Mallapaty.
      
    DOI:  https://doi.org/10.1038/d41586-022-00965-z
  2. Nat Commun. 2022 Apr 04. 13(1): 1799
    Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions.
    Dheeraj S Roy, Young-Gyun Park, Minyoung E Kim, Ying Zhang, Sachie K Ogawa, Nicholas DiNapoli, Xinyi Gu, Jae H Cho, Heejin Choi, Lee Kamentsky, Jared Martin, Olivia Mosto, Tomomi Aida, Kwanghun Chung, Susumu Tonegawa.
      Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.
    DOI:  https://doi.org/10.1038/s41467-022-29384-4
  3. Science. 2022 Apr 08. 376(6589): eabf1970
    Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.
    Richard K Perez, M Grace Gordon, Meena Subramaniam, Min Cheol Kim, George C Hartoularos, Sasha Targ, Yang Sun, Anton Ogorodnikov, Raymund Bueno, Andrew Lu, Mike Thompson, Nadav Rappoport, Andrew Dahl, Cristina M Lanata, Mehrdad Matloubian, Lenka Maliskova, Serena S Kwek, Tony Li, Michal Slyper, Julia Waldman, Danielle Dionne, Orit Rozenblatt-Rosen, Lawrence Fong, Maria Dall'Era, Brunilda Balliu, Aviv Regev, Jinoos Yazdany, Lindsey A Criswell, Noah Zaitlen, Chun Jimmie Ye.
      Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.
    DOI:  https://doi.org/10.1126/science.abf1970
  4. Nat Commun. 2022 Apr 06. 13(1): 1859
    STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming.
    Zhaowei Chu, Lei Gu, Yeguang Hu, Xiaoyang Zhang, Man Li, Jiajia Chen, Da Teng, Man Huang, Che-Hung Shen, Li Cai, Toshimi Yoshida, Yifeng Qi, Zhixin Niu, Austin Feng, Songmei Geng, Dennie T Frederick, Emma Specht, Adriano Piris, Ryan J Sullivan, Keith T Flaherty, Genevieve M Boland, Katia Georgopoulos, David Liu, Yang Shi, Bin Zheng.
      The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. Stromal antigen 2 (STAG2), a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization, especially the long-range enhancer-promoter contacts and subsequent gene expression control in cancer, remains poorly understood. Here we show that depletion of STAG2 in melanoma cells leads to expansion of topologically associating domains (TADs) and enhances the formation of acetylated histone H3 lysine 27 (H3K27ac)-associated DNA loops at sites where binding of STAG2 is switched to its paralog STAG1. We further identify Interferon Regulatory Factor 9 (IRF9) as a major direct target of STAG2 in melanoma cells via integrated RNA-seq, STAG2 ChIP-seq and H3K27ac HiChIP analyses. We demonstrate that loss of STAG2 activates IRF9 through modulating the 3D genome organization, which in turn enhances type I interferon signaling and increases the expression of PD-L1. Our findings not only establish a previously unknown role of the STAG2 to STAG1 switch in 3D genome organization, but also reveal a functional link between STAG2 and interferon signaling in cancer cells, which may enhance the immune evasion potential in STAG2-mutant cancer.
    DOI:  https://doi.org/10.1038/s41467-022-29541-9
  5. Nat Commun. 2022 Apr 04. 13(1): 1787
    The PripA-TbcrA complex-centered Rab GAP cascade facilitates macropinosome maturation in Dictyostelium.
    Hui Tu, Zhimeng Wang, Ye Yuan, Xilin Miao, Dong Li, Hu Guo, Yihong Yang, Huaqing Cai.
      Macropinocytosis, an evolutionarily conserved mechanism mediating nonspecific bulk uptake of extracellular fluid, has been ascribed diverse functions. How nascent macropinosomes mature after internalization remains largely unknown. By searching for proteins that localize on macropinosomes during the Rab5-to-Rab7 transition stage in Dictyostelium, we uncover a complex composed of two proteins, which we name PripA and TbcrA. We show that the Rab5-to-Rab7 conversion involves fusion of Rab5-marked early macropinosomes with Rab7-marked late macropinosomes. PripA links the two membrane compartments by interacting with PI(3,4)P2 and Rab7. In addition, PripA recruits TbcrA, which acts as a GAP, to turn off Rab5. Thus, the conversion to Rab7 is linked to inactivation of the upstream Rab5. Consistently, disruption of either pripA or tbcrA impairs Rab5 inactivation and macropinocytic cargo processing. Therefore, the PripA-TbcrA complex is the central component of a Rab GAP cascade that facilitates programmed Rab switch and efficient cargo trafficking during macropinosome maturation.
    DOI:  https://doi.org/10.1038/s41467-022-29503-1
  6. Nature. 2022 Apr 05.
    Daily briefing: CRISPR-baby scientist released from prison.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-022-00987-7
  7. Nature. 2022 Apr 06.
    Your brain expands and shrinks over time - these charts show how.
    Max Kozlov.
      
    Keywords:  Databases; Imaging; Neuroscience; Publishing
    DOI:  https://doi.org/10.1038/d41586-022-00971-1
  8. Science. 2022 Apr 08. 376(6589): eabl5282
    Tuning T cell receptor sensitivity through catch bond engineering.
    Xiang Zhao, Elizabeth M Kolawole, Waipan Chan, Yinnian Feng, Xinbo Yang, Marvin H Gee, Kevin M Jude, Leah V Sibener, Polly M Fordyce, Ronald N Germain, Brian D Evavold, K Christopher Garcia.
      Adoptive cell therapy using engineered T cell receptors (TCRs) is a promising approach for targeting cancer antigens, but tumor-reactive TCRs are often weakly responsive to their target ligands, peptide-major histocompatibility complexes (pMHCs). Affinity-matured TCRs can enhance the efficacy of TCR-T cell therapy but can also cross-react with off-target antigens, resulting in organ immunopathology. We developed an alternative strategy to isolate TCR mutants that exhibited high activation signals coupled with low-affinity pMHC binding through the acquisition of catch bonds. Engineered analogs of a tumor antigen MAGE-A3-specific TCR maintained physiological affinities while exhibiting enhanced target killing potency and undetectable cross-reactivity, compared with a high-affinity clinically tested TCR that exhibited lethal cross-reactivity with a cardiac antigen. Catch bond engineering is a biophysically based strategy to tune high-sensitivity TCRs for T cell therapy with reduced potential for adverse cross-reactivity.
    DOI:  https://doi.org/10.1126/science.abl5282
  9. Nature. 2022 Apr;604(7905): 220
    The miniature mice locked in an evolutionary battle of the sexes.
      
    Keywords:  Genetics
    DOI:  https://doi.org/10.1038/d41586-022-00957-z
  10. Nature. 2022 Apr 06.
    How the antibiotic fidaxomicin targets an intestinal pathogen.
      
    Keywords:  Antibiotics; Microbiology
    DOI:  https://doi.org/10.1038/d41586-022-00777-1
  11. Nature. 2022 Apr 06.
    Cholera-causing bacteria have defences that degrade plasmid invaders.
    Didier Mazel.
      
    Keywords:  Cell biology; Microbiology; Virology
    DOI:  https://doi.org/10.1038/d41586-022-00871-4
  12. Nat Commun. 2022 Apr 06. 13(1): 1870
    Citrullination of glucokinase is linked to autoimmune diabetes.
    Mei-Ling Yang, Sheryl Horstman, Renelle Gee, Perrin Guyer, TuKiet T Lam, Jean Kanyo, Ana L Perdigoto, Cate Speake, Carla J Greenbaum, Aïsha Callebaut, Lut Overbergh, Richard G Kibbey, Kevan C Herold, Eddie A James, Mark J Mamula.
      Inflammation, including reactive oxygen species and inflammatory cytokines in tissues amplify various post-translational modifications of self-proteins. A number of post-translational modifications have been identified as autoimmune biomarkers in the initiation and progression of Type 1 diabetes. Here we show the citrullination of pancreatic glucokinase as a result of inflammation, triggering autoimmunity and affecting glucokinase biological functions. Glucokinase is expressed in hepatocytes to regulate glycogen synthesis, and in pancreatic beta cells as a glucose sensor to initiate glycolysis and insulin signaling. We identify autoantibodies and autoreactive CD4+ T cells to glucokinase epitopes in the circulation of Type 1 diabetes patients and NOD mice. Finally, citrullination alters glucokinase biologic activity and suppresses glucose-stimulated insulin secretion. Our study define glucokinase as a Type 1 diabetes biomarker, providing new insights of how inflammation drives post-translational modifications to create both neoautoantigens and affect beta cell metabolism.
    DOI:  https://doi.org/10.1038/s41467-022-29512-0
  13. Nat Commun. 2022 Apr 05. 13(1): 1830
    In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration.
    Elliot H Choi, Susie Suh, Andrzej T Foik, Henri Leinonen, Gregory A Newby, Xin D Gao, Samagya Banskota, Thanh Hoang, Samuel W Du, Zhiqian Dong, Aditya Raguram, Sajeev Kohli, Seth Blackshaw, David C Lyon, David R Liu, Krzysztof Palczewski.
      Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting in early visual impairment. It is therefore crucial to develop a robust therapy that not only compensates for lost RPE65 function but also protects photoreceptors from further degeneration. Here, we show that in vivo correction of an Rpe65 mutation by adenine base editor (ABE) prolongs the survival of cones in an LCA mouse model. In vitro screening of ABEs and sgRNAs enables the identification of a variant that enhances in vivo correction efficiency. Subretinal delivery of ABE and sgRNA corrects up to 40% of Rpe65 transcripts, restores cone-mediated visual function, and preserves cones in LCA mice. Single-cell RNA-seq reveals upregulation of genes associated with cone phototransduction and survival. Our findings demonstrate base editing as a potential gene therapy that confers long-lasting retinal protection.
    DOI:  https://doi.org/10.1038/s41467-022-29490-3
  14. Nat Commun. 2022 Apr 05. 13(1): 1825
    Structure-based design of stabilized recombinant influenza neuraminidase tetramers.
    Daniel Ellis, Julia Lederhofer, Oliver J Acton, Yaroslav Tsybovsky, Sally Kephart, Christina Yap, Rebecca A Gillespie, Adrian Creanga, Audrey Olshefsky, Tyler Stephens, Deleah Pettie, Michael Murphy, Claire Sydeman, Maggie Ahlrichs, Sidney Chan, Andrew J Borst, Young-Jun Park, Kelly K Lee, Barney S Graham, David Veesler, Neil P King, Masaru Kanekiyo.
      Influenza virus neuraminidase (NA) is a major antiviral drug target and has recently reemerged as a key target of antibody-mediated protective immunity. Here we show that recombinant NAs across non-bat subtypes adopt various tetrameric conformations, including an "open" state that may help explain poorly understood variations in NA stability across viral strains and subtypes. We use homology-directed protein design to uncover the structural principles underlying these distinct tetrameric conformations and stabilize multiple recombinant NAs in the "closed" state, yielding two near-atomic resolution structures of NA by cryo-EM. In addition to enhancing thermal stability, conformational stabilization improves affinity to protective antibodies elicited by viral infection, including antibodies targeting a quaternary epitope and the broadly conserved catalytic site. Stabilized NAs can also be integrated into viruses without affecting fitness. Our findings provide a deeper understanding of NA structure, stability, and antigenicity, and establish design strategies for reinforcing the conformational integrity of recombinant NA proteins.
    DOI:  https://doi.org/10.1038/s41467-022-29416-z
  15. J Mol Cell Biol. 2022 Apr 05. pii: mjac013. [Epub ahead of print]
    Corrigendum to 'Landscape dynamic network biomarker analysis reveals the tipping point of transcriptome reprogramming to prevent skin photodamage'.
    Chengming Zhang, Hong Zhang, Jing Ge, Tingyan Mi, Xiao Cui, Fengjuan Tu, Xuelan Gu, Tao Zeng, Luonan Chen.
      
    DOI:  https://doi.org/10.1093/jmcb/mjac013
  16. Nat Commun. 2022 Apr 08. 13(1): 1914
    Learning meaningful representations of protein sequences.
    Nicki Skafte Detlefsen, Søren Hauberg, Wouter Boomsma.
      How we choose to represent our data has a fundamental impact on our ability to subsequently extract information from them. Machine learning promises to automatically determine efficient representations from large unstructured datasets, such as those arising in biology. However, empirical evidence suggests that seemingly minor changes to these machine learning models yield drastically different data representations that result in different biological interpretations of data. This begs the question of what even constitutes the most meaningful representation. Here, we approach this question for representations of protein sequences, which have received considerable attention in the recent literature. We explore two key contexts in which representations naturally arise: transfer learning and interpretable learning. In the first context, we demonstrate that several contemporary practices yield suboptimal performance, and in the latter we demonstrate that taking representation geometry into account significantly improves interpretability and lets the models reveal biological information that is otherwise obscured.
    DOI:  https://doi.org/10.1038/s41467-022-29443-w
  17. Sci Transl Med. 2022 Apr 06. 14(639): eabe5795
    The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver.
    Ingmar Mederacke, Aveline Filliol, Silvia Affo, Ajay Nair, Celine Hernandez, Qiuyan Sun, Florian Hamberger, Francesco Brundu, Yu Chen, Aashreya Ravichandra, Peter Huebener, Helena Anke, Hongxue Shi, Raquel A Martínez García de la Torre, James R Smith, Neil C Henderson, Florian W R Vondran, Carla V Rothlin, Heike Baehre, Ira Tabas, Pau Sancho-Bru, Robert F Schwabe.
      Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although platelet-derived growth factor and transforming growth factor-β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5'-diphosphate (UDP)-glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal-regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.
    DOI:  https://doi.org/10.1126/scitranslmed.abe5795
  18. Nature. 2022 Apr;604(7904): 13
    Mystery space circle, coronavirus genomes and COVID antibody treatments.
      
    Keywords:  Astronomy and astrophysics; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-022-00923-9
  19. Nature. 2022 Apr 04.
    An unexpected protein aggregate in diseased and ageing brains.
    Hideyuki Takahashi, Stephen M Strittmatter.
      
    Keywords:  Neurodegeneration; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-00873-2
  20. Nat Commun. 2022 Apr 04. 13(1): 1794
    Astrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age.
    William A Mills, AnnaLin M Woo, Shan Jiang, Joelle Martin, Dayana Surendran, Matthew Bergstresser, Ian F Kimbrough, Ukpong B Eyo, Michael V Sofroniew, Harald Sontheimer.
      Astrocytes extend endfeet that enwrap the vasculature, and disruptions to this association which may occur in disease coincide with breaches in blood-brain barrier (BBB) integrity. Here we investigate if focal ablation of astrocytes is sufficient to disrupt the BBB in mice. Targeted two-photon chemical apoptotic ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. In young animals, replacement processes occur in advance of endfoot retraction, but this is delayed in aged animals. Stimulation of replacement astrocytes results in constriction of pre-capillary arterioles, suggesting that replacement astrocytes are functional. Pharmacological inhibition of pSTAT3, as well as astrocyte specific deletion of pSTAT3, reduces astrocyte replacement post-ablation, without perturbations to BBB integrity. Similar endfoot replacement occurs following astrocyte cell death due to reperfusion in a stroke model. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells.
    DOI:  https://doi.org/10.1038/s41467-022-29475-2
  21. Nat Genet. 2022 Apr 07.
    Genetic variants underlying differences in facial morphology in East Asian and European populations.
    Manfei Zhang, Sijie Wu, Siyuan Du, Wei Qian, Jieyi Chen, Lu Qiao, Yajun Yang, Jingze Tan, Ziyu Yuan, Qianqian Peng, Yu Liu, Nicolas Navarro, Kun Tang, Andrés Ruiz-Linares, Jiucun Wang, Peter Claes, Li Jin, Jiarui Li, Sijia Wang.
      Facial morphology-a conspicuous feature of human appearance-is highly heritable. Previous studies on the genetic basis of facial morphology were performed mainly in European-ancestry cohorts (EUR). Applying a data-driven phenotyping and multivariate genome-wide scanning protocol to a large collection of three-dimensional facial images of individuals with East Asian ancestry (EAS), we identified 244 variants in 166 loci (62 new) associated with typical-range facial variation. A newly proposed polygenic shape analysis indicates that the effects of the variants on facial shape in EAS can be generalized to EUR. Based on this, we further identified 13 variants related to differences between facial shape in EUR and EAS populations. Evolutionary analyses suggest that the difference in nose shape between EUR and EAS populations is caused by a directional selection, due mainly to a local adaptation in Europeans. Our results illustrate the underlying genetic basis for facial differences across populations.
    DOI:  https://doi.org/10.1038/s41588-022-01038-7
  22. Nat Protoc. 2022 Apr 08.
    Isolation of mouse pancreatic islet Procr+ progenitors and long-term expansion of islet organoids in vitro.
    Jingqiang Wang, Daisong Wang, Xinyi Chen, Shubo Yuan, Lanyue Bai, Chunye Liu, Yi Arial Zeng.
      Insulin production is required for glucose homeostasis. Pancreatic islet β cells are the only cells that produce insulin in humans; however, generation of functional β cells in vitro from embryonic or adult tissues has been challenging. Here, we describe isolation of pancreatic islet progenitors from adult mice, which enables the efficient generation and long-term expansion of functional islet organoids in vitro. This protocol starts with purification of protein C receptor (Procr)-expressing islet progenitors. Coculture with endothelial cells generates islet organoids in vitro that can be expanded by passage. Functional maturation is achieved as a consequence of a prolonged culture period and cyclic glucose stimulation. Primary islet organoids form in 7-10 days. Subsequently, each passage takes 1 week, with the final maturation step requiring 3 weeks of additional culture. The resulting organoids are predominantly composed of β cells but also contain small proportions of α, δ and pancreatic polypeptide cells. The organoids sense glucose and secrete insulin. This approach thus provides a strategy for β cell generation in vitro and an organoid system to study islet regeneration and diseases.
    DOI:  https://doi.org/10.1038/s41596-022-00683-w
  23. Nat Commun. 2022 Apr 06. 13(1): 1855
    Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery.
    Tian Zhou, Xinyi Zhu, Zhizhong Ye, Yong-Fei Wang, Chao Yao, Ning Xu, Mi Zhou, Jianyang Ma, Yuting Qin, Yiwei Shen, Yuanjia Tang, Zhihua Yin, Hong Xu, Yutong Zhang, Xiaoli Zang, Huihua Ding, Wanling Yang, Ya Guo, John B Harley, Bahram Namjou, Kenneth M Kaufman, Leah C Kottyan, Matthew T Weirauch, Guojun Hou, Nan Shen.
      Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter regulating IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to regulate AC092723.1 and IRF8 expression differentially. Our work illustrates an integrative strategy to define functional genetic variants that regulate the expression of critical genes in autoimmune diseases and decipher the mechanisms underlying the dysregulation of IRF8 expression mediated by lupus risk variants.
    DOI:  https://doi.org/10.1038/s41467-022-29514-y
  24. Nat Commun. 2022 Apr 08. 13(1): 1924
    Evidence for oxygen-conserving diamond formation in redox-buffered subducted oceanic crust sampled as eclogite.
    Sonja Aulbach, Thomas Stachel.
      Cratonic eclogite is the product of oceanic crust subduction into the subcontinental lithospheric mantle, and it also is a fertile diamond source rock. In contrast to matrix minerals in magma-borne xenoliths, inclusions in diamond are shielded from external fluids, retaining more pristine information on the state of the eclogite source at the time of encapsulation. Vanadium is a multi-valent element and a widely used elemental redox proxy. Here, we show that that xenolithic garnet has lower average V abundances than garnet inclusions. This partly reflects crystal-chemical controls, whereby higher average temperatures recorded by inclusions, accompanied by enhanced Na2O and TiO2 partitioning into garnet, facilitate V incorporation at the expense of clinopyroxene. Unexpectedly, although diamond formation is strongly linked to metasomatism and xenoliths remained open systems, V concentrations are similar for bulk eclogites reconstructed from inclusions and from xenoliths. This suggests an oxygen-conserving mechanism for eclogitic diamond formation, and implies that eclogite is an efficient system to buffer fO2 over aeons of lithospheric mantle modification by subduction-derived and other fluids.
    DOI:  https://doi.org/10.1038/s41467-022-29567-z
  25. Nature. 2022 Apr 08.
    Rare coding variants in ten genes confer substantial risk for schizophrenia.
    Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D Barchas, Nicholas Bass, Tim B Bigdeli, Gerome Breen, Evelyn J Bromet, Peter F Buckley, William E Bunney, Jonas Bybjerg-Grauholm, William F Byerley, Sinéad B Chapman, Wei J Chen, Claire Churchhouse, Nicholas Craddock, Caroline M Cusick, Lynn DeLisi, Sheila Dodge, Michael A Escamilla, Saana Eskelinen, Ayman H Fanous, Stephen V Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B Gabriel, Diane Gage, Sarah A Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C Glahn, Jakob Grove, Mei-Hua Hall, Eija Hämäläinen, Henrike O Heyne, Matti Holi, David M Hougaard, Daniel P Howrigan, Hailiang Huang, Hai-Gwo Hwu, René S Kahn, Hyun Min Kang, Konrad J Karczewski, George Kirov, James A Knowles, Francis S Lee, Douglas S Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R Marder, Steven A McCarroll, Andrew M McIntosh, Helena Medeiros, Lili Milani, Christopher P Morley, Derek W Morris, Preben Bo Mortensen, Richard M Myers, Merete Nordentoft, Niamh L O'Brien, Ana Maria Olivares, Dost Ongur, Willem H Ouwehand, Duncan S Palmer, Tiina Paunio, Digby Quested, Mark H Rapaport, Elliott Rees, Brandi Rollins, F Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura J Scott, Sally I Sharp, Pamela Sklar, Jordan W Smoller, Janet L Sobell, Matthew Solomonson, Eli A Stahl, Christine R Stevens, Jaana Suvisaari, Grace Tiao, Stanley J Watson, Nicholas A Watts, Douglas H Blackwood, Anders D Børglum, Bruce M Cohen, Aiden P Corvin, Tõnu Esko, Nelson B Freimer, Stephen J Glatt, Christina M Hultman, Andrew McQuillin, Aarno Palotie, Carlos N Pato, Michele T Pato, Ann E Pulver, David St Clair, Ming T Tsuang, Marquis P Vawter, James T Walters, Thomas M Werge, Roel A Ophoff, Patrick F Sullivan, Michael J Owen, Michael Boehnke, Michael C O'Donovan, Benjamin M Neale, Mark J Daly.
      Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.
    DOI:  https://doi.org/10.1038/s41586-022-04556-w
  26. Sci Adv. 2022 Apr 08. 8(14): eabl6579
    Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
    Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA) Group
      Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
    DOI:  https://doi.org/10.1126/sciadv.abl6579
  27. Nat Commun. 2022 Apr 06. 13(1): 1874
    Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation.
    Aleksandra Levina, Kaelin D Fleming, John E Burke, Thomas A Leonard.
      3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It is often referred to as a 'master' kinase due to its ability to activate at least 23 downstream protein kinases implicated in various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that PDK1 trans-autophosphorylation is mediated by a PIP3-mediated face-to-face dimer. We report regulatory motifs in the kinase-PH interdomain linker that allosterically activate PDK1 autophosphorylation via a linker-swapped dimer mechanism. Finally, we show that PDK1 is autoinhibited by its PH domain and that positive cooperativity of PIP3 binding drives switch-like activation of PDK1. These results imply that the PDK1-mediated activation of effector kinases, including Akt, PKC, Sgk, S6K and RSK, many of whom are not directly regulated by phosphoinositides, is also likely to be dependent on PIP3 or PI(3,4)P2.
    DOI:  https://doi.org/10.1038/s41467-022-29368-4
  28. Nature. 2022 Apr 06.
    FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.
    Caroline Junqueira, Ângela Crespo, Shahin Ranjbar, Luna B de Lacerda, Mercedes Lewandrowski, Jacob Ingber, Blair Parry, Sagi Ravid, Sarah Clark, Marie Rose Schrimpf, Felicia Ho, Caroline Beakes, Justin Margolin, Nicole Russell, Kyle Kays, Julie Boucau, Upasana Das Adhikari, Setu M Vora, Valerie Leger, Lee Gehrke, Lauren Henderson, Erin Janssen, Douglas Kwon, Chris Sander, Jonathan Abraham, Marcia B Goldberg, Hao Wu, Gautam Mehta, Steven Bell, Anne E Goldfeld, Michael R Filbin, Judy Lieberman.
      SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
    DOI:  https://doi.org/10.1038/s41586-022-04702-4
  29. J Autoimmun. 2022 Apr 05. pii: S0896-8411(22)00024-5. [Epub ahead of print]129 102816
    Autoreactive memory Th17 cells are principally derived from T-bet+RORγt+ Th17/1 effectors.
    Nai-Wen Fan, Shudan Wang, Gustavo Ortiz, Sunil K Chauhan, Yihe Chen, Reza Dana.
      Effector Th17 cells, including IFN-γ-IL-17+ (eTh17) and IFN-γ+IL-17+ (eTh17/1) subsets, play critical pathogenic functions in the induction of autoimmunity. As acute inflammation subsides, a small proportion of the effectors survive and convert to memory Th17 cells (mTh17), which sustain chronic inflammation in autoimmune diseases. Herein, we investigated the differential contributions of eTh17 versus eTh17/1 to the memory pool using an experimental model of ocular autoimmune disease. Our results show that adoptive transfer of Tbx21-/- CD4+ T cells or conditional deletion of Tbx21 in Th17 cells leads to diminished eTh17/1 in acute phase and functionally compromised mTh17 in chronic phase. Further, adoptive transfer of disease-specific eTh17/1, but not eTh17, leads to generation of mTh17 and sustained ocular inflammation. Collectively, our data demonstrate that T-bet-dependent eTh17/1 cells generated during the acute inflammation are the principal effector precursors of pathogenic mTh17 cells that sustain the chronicity of autoimmune inflammation.
    Keywords:  Effector Th17/1; Memory Th17; T-bet
    DOI:  https://doi.org/10.1016/j.jaut.2022.102816
  30. Nat Commun. 2022 Apr 07. 13(1): 1899
    CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.
    Davide Bernareggi, Qi Xie, Briana C Prager, Jiyoung Yun, Luisjesus S Cruz, Timothy V Pham, William Kim, Xiqing Lee, Michael Coffey, Cristina Zalfa, Pardis Azmoon, Huang Zhu, Pablo Tamayo, Jeremy N Rich, Dan S Kaufman.
      Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-29469-0
  31. Cell Regen. 2022 Apr 03. 11(1): 13
    Myogenesis controlled by a long non-coding RNA 1700113A16RIK and post-transcriptional regulation.
    Xin Fu, Sheng Li, Minzhi Jia, Bo Xu, Lele Yang, Ruimiao Ma, Hong Cheng, Wenjun Yang, Ping Hu.
      Long non-coding (lnc) RNA plays important roles in many cellular processes. The function of the vast majority of lncRNAs remains unknown. Here we identified that lncRNA-1700113A16RIK existed in skeletal muscle stem cells (MuSCs) and was significantly elevated during MuSC differentiation. Knockdown of 1700113A16RIK inhibits the differentiation of muscle stem cells. In contrast, overexpression of 1700113A16RIK promotes the differentiation of muscle stem cells. Further study shows the muscle specific transcription factor Myogenin (MyoG) positively regulates the expression of 1700113A16RIK by binding to the promoter region of 1700113A16RIK. Mechanistically, 1700113A16RIK may regulate the expression of myogenic genes by directly binding to 3'UTR of an important myogenic transcription factor MEF2D, which in turn promotes the translation of MEF2D. Taken together, our results defined 1700113A16RIK as a positive regulator of MuSC differentiation and elucidated a mechanism as to how 1700113A16RIK regulated MuSC differentiation.
    Keywords:  1700113A16RIK; Long non-coding RNA (lncRNA); Muscle stem cell (MuSC) differentiation; Myocyte-specific enhancer binding factor 2 (MEF2D)
    DOI:  https://doi.org/10.1186/s13619-022-00114-x
  32. Sci Immunol. 2022 Apr 08. 7(70): eabi8642
    Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity.
    Briana G Nixon, Chun Chou, Chirag Krishna, Saïda Dadi, Adam O Michel, Andrew E Cornish, Emily R Kansler, Mytrang H Do, Xinxin Wang, Kristelle J Capistrano, Alexander Y Rudensky, Christina S Leslie, Ming O Li.
      Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C-expressing ILC1s required the transcription factors T-bet and, to a lesser extent, Eomes and support from transforming growth factor-β (TGF-β) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model, depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of STAT5, a transcription factor regulated by IL-15, in granzyme C-expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond "helper-like" lymphocytes.
    DOI:  https://doi.org/10.1126/sciimmunol.abi8642
  33. Nat Commun. 2022 Apr 08. 13(1): 1928
    Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip.
    Haiqing Bai, Longlong Si, Amanda Jiang, Chaitra Belgur, Yunhao Zhai, Roberto Plebani, Crystal Yuri Oh, Melissa Rodas, Aditya Patil, Atiq Nurani, Sarah E Gilpin, Rani K Powers, Girija Goyal, Rachelle Prantil-Baun, Donald E Ingber.
      Mechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to investigate whether physical forces influence innate immune responses to viral infection. Influenza H3N2 infection of mechanically active chips induces a cascade of host responses including increased lung permeability, apoptosis, cell regeneration, cytokines production, and recruitment of circulating immune cells. Comparison with static chips reveals that breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells, which are mediated in part through activation of the mechanosensitive ion channel TRPV4 and signaling via receptor for advanced glycation end products (RAGE). RAGE inhibitors suppress cytokines induction, while TRPV4 inhibition attenuates both inflammation and viral burden, in infected chips with breathing motions. Therefore, TRPV4 and RAGE may serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
    DOI:  https://doi.org/10.1038/s41467-022-29562-4
  34. PLoS Comput Biol. 2022 Apr 08. 18(4): e1009991
    Blind demixing methods for recovering dense neuronal morphology from barcode imaging data.
    Shuonan Chen, Jackson Loper, Pengcheng Zhou, Liam Paninski.
      Cellular barcoding methods offer the exciting possibility of 'infinite-pseudocolor' anatomical reconstruction-i.e., assigning each neuron its own random unique barcoded 'pseudocolor,' and then using these pseudocolors to trace the microanatomy of each neuron. Here we use simulations, based on densely-reconstructed electron microscopy microanatomy, with signal structure matched to real barcoding data, to quantify the feasibility of this procedure. We develop a new blind demixing approach to recover the barcodes that label each neuron, and validate this method on real data with known barcodes. We also develop a neural network which uses the recovered barcodes to reconstruct the neuronal morphology from the observed fluorescence imaging data, 'connecting the dots' between discontiguous barcode amplicon signals. We find that accurate recovery should be feasible, provided that the barcode signal density is sufficiently high. This study suggests the possibility of mapping the morphology and projection pattern of many individual neurons simultaneously, at high resolution and at large scale, via conventional light microscopy.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009991
  35. Nat Commun. 2022 Apr 06. 13(1): 1853
    DELE1 tracks perturbed protein import and processing in human mitochondria.
    Evelyn Fessler, Luisa Krumwiede, Lucas T Jae.
      Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.
    DOI:  https://doi.org/10.1038/s41467-022-29479-y
  36. Nat Biotechnol. 2022 Apr 04.
    CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.
    Beverly Y Mok, Anna V Kotrys, Aditya Raguram, Tony P Huang, Vamsi K Mootha, David R Liu.
      The all-protein cytosine base editor DdCBE uses TALE proteins and a double-stranded DNA-specific cytidine deaminase (DddA) to mediate targeted C•G-to-T•A editing. To improve editing efficiency and overcome the strict TC sequence-context constraint of DddA, we used phage-assisted non-continuous and continuous evolution to evolve DddA variants with improved activity and expanded targeting scope. Compared to canonical DdCBEs, base editors with evolved DddA6 improved mitochondrial DNA (mtDNA) editing efficiencies at TC by 3.3-fold on average. DdCBEs containing evolved DddA11 offered a broadened HC (H = A, C or T) sequence compatibility for both mitochondrial and nuclear base editing, increasing average editing efficiencies at AC and CC targets from less than 10% for canonical DdCBE to 15-30% and up to 50% in cell populations sorted to express both halves of DdCBE. We used these evolved DdCBEs to efficiently install disease-associated mtDNA mutations in human cells at non-TC target sites. DddA6 and DddA11 substantially increase the effectiveness and applicability of all-protein base editing.
    DOI:  https://doi.org/10.1038/s41587-022-01256-8
  37. Nat Neurosci. 2022 Apr;25(4): 458-473
    Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
    Phan Q Duy, Stefan C Weise, Claudia Marini, Xiao-Jun Li, Dan Liang, Peter J Dahl, Shaojie Ma, Ana Spajic, Weilai Dong, Jane Juusola, Emre Kiziltug, Adam J Kundishora, Sunil Koundal, Maysam Z Pedram, Lucia A Torres-Fernández, Kristian Händler, Elena De Domenico, Matthias Becker, Thomas Ulas, Stefan A Juranek, Elisa Cuevas, Le Thi Hao, Bettina Jux, André M M Sousa, Fuchen Liu, Suel-Kee Kim, Mingfeng Li, Yiying Yang, Yutaka Takeo, Alvaro Duque, Carol Nelson-Williams, Yonghyun Ha, Kartiga Selvaganesan, Stephanie M Robert, Amrita K Singh, Garrett Allington, Charuta G Furey, Andrew T Timberlake, Benjamin C Reeves, Hannah Smith, Ashley Dunbar, Tyrone DeSpenza, June Goto, Arnaud Marlier, Andres Moreno-De-Luca, Xin Yu, William E Butler, Bob S Carter, Evelyn M R Lake, R Todd Constable, Pasko Rakic, Haifan Lin, Engin Deniz, Helene Benveniste, Nikhil S Malvankar, Juvianee I Estrada-Veras, Christopher A Walsh, Seth L Alper, Joachim L Schultze, Katrin Paeschke, Angelika Doetzlhofer, F Gregory Wulczyn, Sheng Chih Jin, Richard P Lifton, Nenad Sestan, Waldemar Kolanus, Kristopher T Kahle.
      Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.
    DOI:  https://doi.org/10.1038/s41593-022-01043-3
  38. Nat Commun. 2022 Apr 08. 13(1): 1919
    Electrocorticographic evidence of a common neurocognitive sequence for mentalizing about the self and others.
    Kevin M Tan, Amy L Daitch, Pedro Pinheiro-Chagas, Kieran C R Fox, Josef Parvizi, Matthew D Lieberman.
      Neuroimaging studies of mentalizing (i.e., theory of mind) consistently implicate the default mode network (DMN). Nevertheless, the social cognitive functions of individual DMN regions remain unclear, perhaps due to limited spatiotemporal resolution in neuroimaging. Here we use electrocorticography (ECoG) to directly record neuronal population activity while 16 human participants judge the psychological traits of themselves and others. Self- and other-mentalizing recruit near-identical cortical sites in a common spatiotemporal sequence. Activations begin in the visual cortex, followed by temporoparietal DMN regions, then finally in medial prefrontal regions. Moreover, regions with later activations exhibit stronger functional specificity for mentalizing, stronger associations with behavioral responses, and stronger self/other differentiation. Specifically, other-mentalizing evokes slower and longer activations than self-mentalizing across successive DMN regions, implying lengthier processing at higher levels of representation. Our results suggest a common neurocognitive pathway for self- and other-mentalizing that follows a complex spatiotemporal gradient of functional specialization across DMN and beyond.
    DOI:  https://doi.org/10.1038/s41467-022-29510-2
  39. Nat Commun. 2022 Apr 08. 13(1): 1913
    Creep-dilatancy development at a transform plate boundary.
    Nabil Sultan, Shane Murphy, Vincent Riboulot, Louis Géli.
      How tectonic plates slip slowly and episodically along their boundaries, is a major, open question in earthquake science. Here, we use offshore in-situ sediment pore-pressure acquired in the proximity of the active offshore Main Marmara Fault and onshore geodetic time-series data set from a single GPS station to demonstrate the pore-pressure/deformation coupling during a 10-month slow-slip event. We show that pore pressure fluctuations are the expression of hydro-mechanical process affecting the deep seismogenic zone and indicate that small disturbances in geodetic data may have important meaning in terms of transient deformations. These results have major implications in understanding the spatial impact of slow-slip processes and their role in earthquake cycles. We demonstrate that piezometers measuring along a transform fault can help define the time scale regulating the coupling between slow-slip events and earthquake nucleation process.
    DOI:  https://doi.org/10.1038/s41467-022-29558-0
  40. Science. 2022 Apr 08. 376(6589): eabf3041
    Single-cell eQTL mapping identifies cell type-specific genetic control of autoimmune disease.
    Seyhan Yazar, Jose Alquicira-Hernandez, Kristof Wing, Anne Senabouth, M Grace Gordon, Stacey Andersen, Qinyi Lu, Antonia Rowson, Thomas R P Taylor, Linda Clarke, Katia Maccora, Christine Chen, Anthony L Cook, Chun Jimmie Ye, Kirsten A Fairfax, Alex W Hewitt, Joseph E Powell.
      The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.
    DOI:  https://doi.org/10.1126/science.abf3041
  41. Nat Commun. 2022 Apr 07. 13(1): 1900
    Glyco-Decipher enables glycan database-independent peptide matching and in-depth characterization of site-specific N-glycosylation.
    Zheng Fang, Hongqiang Qin, Jiawei Mao, Zhongyu Wang, Na Zhang, Yan Wang, Luyao Liu, Yongzhan Nie, Mingming Dong, Mingliang Ye.
      Glycopeptides with unusual glycans or poor peptide backbone fragmentation in tandem mass spectrometry are unaccounted for in typical site-specific glycoproteomics analysis and thus remain unidentified. Here, we develop a glycoproteomics tool, Glyco-Decipher, to address these issues. Glyco-Decipher conducts glycan database-independent peptide matching and exploits the fragmentation pattern of shared peptide backbones in glycopeptides to improve the spectrum interpretation. We benchmark Glyco-Decipher on several large-scale datasets, demonstrating that it identifies more peptide-spectrum matches than Byonic, MSFragger-Glyco, StrucGP and pGlyco 3.0, with a 33.5%-178.5% increase in the number of identified glycopeptide spectra. The database-independent and unbiased profiling of attached glycans enables the discovery of 164 modified glycans in mouse tissues, including glycans with chemical or biological modifications. By enabling in-depth characterization of site-specific protein glycosylation, Glyco-Decipher is a promising tool for advancing glycoproteomics analysis in biological research.
    DOI:  https://doi.org/10.1038/s41467-022-29530-y
  42. Nat Commun. 2022 Apr 06. 13(1): 1875
    Ca2+-activated sphingomyelin scrambling and turnover mediate ESCRT-independent lysosomal repair.
    Patrick Niekamp, Felix Scharte, Tolulope Sokoya, Laura Vittadello, Yeongho Kim, Yongqiang Deng, Elisabeth Südhoff, Angelika Hilderink, Mirco Imlau, Christopher J Clarke, Michael Hensel, Christopher G Burd, Joost C M Holthuis.
      Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger a rapid calcium-activated scrambling and cytosolic exposure of sphingomyelin. Subsequent metabolic conversion of sphingomyelin by neutral sphingomyelinases on the cytosolic surface of injured lysosomes promotes their repair, also when ESCRT function is compromised. Conversely, blocking turnover of cytosolic sphingomyelin renders cells more sensitive to lysosome-damaging drugs. Our data indicate that calcium-activated scramblases, sphingomyelin, and neutral sphingomyelinases are core components of a previously unrecognized membrane restoration pathway by which cells preserve the functional integrity of lysosomes.
    DOI:  https://doi.org/10.1038/s41467-022-29481-4
  43. Nat Commun. 2022 Apr 07. 13(1): 1885
    Introducing principles of synaptic integration in the optimization of deep neural networks.
    Giorgia Dellaferrera, Stanisław Woźniak, Giacomo Indiveri, Angeliki Pantazi, Evangelos Eleftheriou.
      Plasticity circuits in the brain are known to be influenced by the distribution of the synaptic weights through the mechanisms of synaptic integration and local regulation of synaptic strength. However, the complex interplay of stimulation-dependent plasticity with local learning signals is disregarded by most of the artificial neural network training algorithms devised so far. Here, we propose a novel biologically inspired optimizer for artificial and spiking neural networks that incorporates key principles of synaptic plasticity observed in cortical dendrites: GRAPES (Group Responsibility for Adjusting the Propagation of Error Signals). GRAPES implements a weight-distribution-dependent modulation of the error signal at each node of the network. We show that this biologically inspired mechanism leads to a substantial improvement of the performance of artificial and spiking networks with feedforward, convolutional, and recurrent architectures, it mitigates catastrophic forgetting, and it is optimally suited for dedicated hardware implementations. Overall, our work indicates that reconciling neurophysiology insights with machine intelligence is key to boosting the performance of neural networks.
    DOI:  https://doi.org/10.1038/s41467-022-29491-2
  44. J Immunol. 2022 Apr 04. pii: ji2101165. [Epub ahead of print]
    Cutting Edge: Enhanced Antitumor Immunity in ST8Sia6 Knockout Mice.
    David J Friedman, Monika Kizerwetter, Paul Belmonte, Matthew Rajcula, Keith Theodore, Hyun Se Kim Lee, Michael J Shapiro, Haidong Dong, Virginia Smith Shapiro.
      Inhibitory receptors have a critical role in the regulation of immunity. Siglecs are a family of primarily inhibitory receptors expressed by immune cells that recognize specific sialic acid modifications on cell surface glycans. Many tumors have increased sialic acid incorporation. Overexpression of the sialyltransferase ST8Sia6 on tumors led to altered immune responses and increased tumor growth. In this study, we examined the role of ST8Sia6 on immune cells in regulating antitumor immunity. ST8Sia6 knockout mice had an enhanced immune response to tumors. The loss of ST8Sia6 promoted an enhanced intratumoral activation of macrophages and dendritic cells, including upregulation of CD40. Intratumoral regulatory T cells exhibited a more inflammatory phenotype in ST8Sia6 knockout mice. Using adoptive transfer studies, the change in regulatory T cell phenotype was not cell intrinsic and depended on the loss of ST8Sia6 expression in APCs. Thus, ST8Sia6 generates ligands for Siglecs that dampen antitumor immunity.
    DOI:  https://doi.org/10.4049/jimmunol.2101165
  45. Nat Commun. 2022 Apr 05. 13(1): 1833
    Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.
    Wenguang G Liang, Juwina Wijaya, Hui Wei, Alex J Noble, Jordan M Mancl, Swansea Mo, David Lee, John V Lin King, Man Pan, Chang Liu, Carla M Koehler, Minglei Zhao, Clinton S Potter, Bridget Carragher, Sheng Li, Wei-Jen Tang.
      Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3-4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.
    DOI:  https://doi.org/10.1038/s41467-022-29322-4
  46. Nat Commun. 2022 Apr 06. 13(1): 1861
    DNA sequence-dependent formation of heterochromatin nanodomains.
    Graeme J Thorn, Christopher T Clarkson, Anne Rademacher, Hulkar Mamayusupova, Gunnar Schotta, Karsten Rippe, Vladimir B Teif.
      The mammalian epigenome contains thousands of heterochromatin nanodomains (HNDs) marked by di- and trimethylation of histone H3 at lysine 9 (H3K9me2/3), which have a typical size of 3-10 nucleosomes. However, what governs HND location and extension is only partly understood. Here, we address this issue by introducing the chromatin hierarchical lattice framework (ChromHL) that predicts chromatin state patterns with single-nucleotide resolution. ChromHL is applied to analyse four HND types in mouse embryonic stem cells that are defined by histone methylases SUV39H1/2 or GLP, transcription factor ADNP or chromatin remodeller ATRX. We find that HND patterns can be computed from PAX3/9, ADNP and LINE1 sequence motifs as nucleation sites and boundaries that are determined by DNA sequence (e.g. CTCF binding sites), cooperative interactions between nucleosomes as well as nucleosome-HP1 interactions. Thus, ChromHL rationalizes how patterns of H3K9me2/3 are established and changed via the activity of protein factors in processes like cell differentiation.
    DOI:  https://doi.org/10.1038/s41467-022-29360-y
  47. Nat Commun. 2022 Apr 07. 13(1): 1897
    FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.
    Cristal M Hill, Diana C Albarado, Lucia G Coco, Redin A Spann, Md Shahjalal Khan, Emily Qualls-Creekmore, David H Burk, Susan J Burke, J Jason Collier, Sangho Yu, David H McDougal, Hans-Rudolf Berthoud, Heike Münzberg, Andrzej Bartke, Christopher D Morrison.
      Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice. Conversely, mice lacking FGF21 fail to exhibit metabolic responses to protein restriction in early life, and in later life exhibit early onset of age-related weight loss, reduced physical performance, increased frailty, and reduced lifespan. These data demonstrate that protein restriction in aging male mice exerts marked beneficial effects on lifespan and metabolic health and that a single metabolic hormone, FGF21, is essential for the anti-aging effect of this dietary intervention.
    DOI:  https://doi.org/10.1038/s41467-022-29499-8
  48. Science. 2022 Apr 08. 376(6589): 139-140
    Unlocking the secrets to Janus kinase activation.
    Ross L Levine, Stevan R Hubbard.
      The full-length structure of a Janus kinase provides insights for drug development.
    DOI:  https://doi.org/10.1126/science.abo7788
  49. Sci Immunol. 2022 Apr 08. 7(70): eabn6660
    Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation.
    Fatemeh Adiliaghdam, Hajera Amatullah, Sreehaas Digumarthi, Tahnee L Saunders, Raza-Ur Rahman, Lai Ping Wong, Ruslan Sadreyev, Lindsay Droit, Jean Paquette, Philippe Goyette, John D Rioux, Richard Hodin, Kathie A Mihindukulasuriya, Scott A Handley, Kate L Jeffrey.
      Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn's disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD patient-derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.
    DOI:  https://doi.org/10.1126/sciimmunol.abn6660
  50. Nat Commun. 2022 Apr 05. 13(1): 1837
    Group testing via hypergraph factorization applied to COVID-19.
    David Hong, Rounak Dey, Xihong Lin, Brian Cleary, Edgar Dobriban.
      Large scale screening is a critical tool in the life sciences, but is often limited by reagents, samples, or cost. An important recent example is the challenge of achieving widespread COVID-19 testing in the face of substantial resource constraints. To tackle this challenge, screening methods must efficiently use testing resources. However, given the global nature of the pandemic, they must also be simple (to aid implementation) and flexible (to be tailored for each setting). Here we propose HYPER, a group testing method based on hypergraph factorization. We provide theoretical characterizations under a general statistical model, and carefully evaluate HYPER with alternatives proposed for COVID-19 under realistic simulations of epidemic spread and viral kinetics. We find that HYPER matches or outperforms the alternatives across a broad range of testing-constrained environments, while also being simpler and more flexible. We provide an online tool to aid lab implementation: http://hyper.covid19-analysis.org .
    DOI:  https://doi.org/10.1038/s41467-022-29389-z
  51. Nat Commun. 2022 Apr 04. 13(1): 1804
    Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing.
    Nina Frey, Luigi Tortola, David Egli, Sharan Janjuha, Tanja Rothgangl, Kim Fabiano Marquart, Franziska Ampenberger, Manfred Kopf, Gerald Schwank.
      Pancreatic ductal adenocarcinoma (PDA) is an inherently immune cell deprived tumor, characterized by desmoplastic stroma and suppressive immune cells. Here we systematically dissect PDA intrinsic mechanisms of immune evasion by in vitro and in vivo CRISPR screening, and identify Vps4b and Rnf31 as essential factors required for escaping CD8+ T cell killing. For Vps4b we find that inactivation impairs autophagy, resulting in increased accumulation of CD8+ T cell-derived granzyme B and subsequent tumor cell lysis. For Rnf31 we demonstrate that it protects tumor cells from TNF-mediated caspase 8 cleavage and subsequent apoptosis induction, a mechanism that is conserved in human PDA organoids. Orthotopic transplantation of Vps4b- or Rnf31 deficient pancreatic tumors into immune competent mice, moreover, reveals increased CD8+ T cell infiltration and effector function, and markedly reduced tumor growth. Our work uncovers vulnerabilities in PDA that might be exploited to render these tumors more susceptible to the immune system.
    DOI:  https://doi.org/10.1038/s41467-022-29412-3
  52. Nature. 2022 Apr;604(7904): 207-208
    In pursuit of data immortality.
    Michael Eisenstein.
      
    Keywords:  Computer science; Information technology; Research data; Software
    DOI:  https://doi.org/10.1038/d41586-022-00929-3
  53. Nat Commun. 2022 Apr 06. 13(1): 1868
    Zoonotic origin of the human malaria parasite Plasmodium malariae from African apes.
    Lindsey J Plenderleith, Weimin Liu, Yingying Li, Dorothy E Loy, Ewan Mollison, Jesse Connell, Ahidjo Ayouba, Amandine Esteban, Martine Peeters, Crickette M Sanz, David B Morgan, Nathan D Wolfe, Markus Ulrich, Andreas Sachse, Sébastien Calvignac-Spencer, Fabian H Leendertz, George M Shaw, Beatrice H Hahn, Paul M Sharp.
      The human parasite Plasmodium malariae has relatives infecting African apes (Plasmodium rodhaini) and New World monkeys (Plasmodium brasilianum), but its origins remain unknown. Using a novel approach to characterise P. malariae-related sequences in wild and captive African apes, we found that this group comprises three distinct lineages, one of which represents a previously unknown, highly divergent species infecting chimpanzees, bonobos and gorillas across central Africa. A second ape-derived lineage is much more closely related to the third, human-infective lineage P. malariae, but exhibits little evidence of genetic exchange with it, and so likely represents a separate species. Moreover, the levels and nature of genetic polymorphisms in P. malariae indicate that it resulted from the zoonotic transmission of an African ape parasite, reminiscent of the origin of P. falciparum. In contrast, P. brasilianum falls within the radiation of human P. malariae, and thus reflects a recent anthroponosis.
    DOI:  https://doi.org/10.1038/s41467-022-29306-4
  54. Nat Commun. 2022 Apr 06. 13(1): 1852
    Direct measurements of mRNA translation kinetics in living cells.
    Mikhail Metelev, Erik Lundin, Ivan L Volkov, Arvid H Gynnå, Johan Elf, Magnus Johansson.
      Ribosome mediated mRNA translation is central to life. The cycle of translation, however, has been characterized mostly using reconstituted systems, with only few techniques applicable for studies in the living cell. Here we describe a live-cell ribosome-labeling method, which allows us to characterize the whole processes of finding and translating an mRNA, using single-molecule tracking techniques. We find that more than 90% of both bacterial ribosomal subunits are engaged in translation at any particular time, and that the 30S and 50S ribosomal subunits spend the same average time bound to an mRNA, revealing that 30S re-initiation on poly-cistronic mRNAs is not prevalent in E. coli. Instead, our results are best explained by substantial 70S re-initiation of translation of poly-cistronic mRNAs, which is further corroborated by experiments with translation initiation inhibitors. Finally, we find that a variety of previously described orthogonal ribosomes, with altered anti-Shine-Dalgarno sequences, show significant binding to endogenous mRNAs.
    DOI:  https://doi.org/10.1038/s41467-022-29515-x
  55. iScience. 2022 Apr 15. 25(4): 104097
    High-resolution Slide-seqV2 spatial transcriptomics enables discovery of disease-specific cell neighborhoods and pathways.
    Jamie L Marshall, Teia Noel, Qingbo S Wang, Haiqi Chen, Evan Murray, Ayshwarya Subramanian, Katherine A Vernon, Silvana Bazua-Valenti, Katie Liguori, Keith Keller, Robert R Stickels, Breanna McBean, Rowan M Heneghan, Astrid Weins, Evan Z Macosko, Fei Chen, Anna Greka.
      High-resolution spatial transcriptomics enables mapping of RNA expression directly from intact tissue sections; however, its utility for the elucidation of disease processes and therapeutically actionable pathways remains unexplored. We applied Slide-seqV2 to mouse and human kidneys, in healthy and distinct disease paradigms. First, we established the feasibility of Slide-seqV2 in tissue from nine distinct human kidneys, which revealed a cell neighborhood centered around a population of LYVE1+ macrophages. Second, in a mouse model of diabetic kidney disease, we detected changes in the cellular organization of the spatially restricted kidney filter and blood-flow-regulating apparatus. Third, in a mouse model of a toxic proteinopathy, we identified previously unknown, disease-specific cell neighborhoods centered around macrophages. In a spatially restricted subpopulation of epithelial cells, we discovered perturbations in 77 genes associated with the unfolded protein response. Our studies illustrate and experimentally validate the utility of Slide-seqV2 for the discovery of disease-specific cell neighborhoods.
    Keywords:  Cell biology; Pathophysiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104097
  56. Nat Commun. 2022 Apr 04. 13(1): 1789
    Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells.
    Davide G Franchina, Henry Kurniawan, Melanie Grusdat, Carole Binsfeld, Luana Guerra, Lynn Bonetti, Leticia Soriano-Baguet, Anouk Ewen, Takumi Kobayashi, Sophie Farinelle, Anna Rita Minafra, Niels Vandamme, Anaïs Carpentier, Felix K Borgmann, Christian Jäger, Ying Chen, Markus Kleinewietfeld, Vasilis Vasiliou, Michel Mittelbronn, Karsten Hiller, Philipp A Lang, Dirk Brenner.
      The metabolic principles underlying the differences between follicular and marginal zone B cells (FoB and MZB, respectively) are not well understood. Here we show, by studying mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that glutathione synthesis affects homeostasis and differentiation of MZB to a larger extent than FoB, while glutathione-dependent redox control contributes to the metabolic dependencies of FoB. Specifically, Gclc ablation in FoB induces metabolic features of wild-type MZB such as increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis. Furthermore, Gclc-deficient FoB have a block in the mitochondrial electron transport chain (ETC) due to diminished complex I and II activity and thereby accumulate the tricarboxylic acid cycle metabolite succinate. Finally, Gclc deficiency hampers FoB activation and antibody responses in vitro and in vivo, and induces susceptibility to viral infections. Our results thus suggest that Gclc is required to ensure the development of MZB, the mitochondrial ETC integrity in FoB, and the efficacy of antiviral humoral immunity.
    DOI:  https://doi.org/10.1038/s41467-022-29426-x
  57. Immunity. 2022 Mar 29. pii: S1074-7613(22)00132-7. [Epub ahead of print]
    Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C.
    Ming Zhao, Kaiqun Ren, Xiwen Xiong, Yue Xin, Yujie Zou, Jason C Maynard, Angela Kim, Alexander P Battist, Navya Koneripalli, Yusu Wang, Qianyue Chen, Ruyue Xin, Chenyan Yang, Rong Huang, Jiahui Yu, Zan Huang, Zengdi Zhang, Haiguang Wang, Daoyuan Wang, Yihui Xiao, Oscar C Salgado, Nicholas N Jarjour, Kristin A Hogquist, Xavier S Revelo, Alma L Burlingame, Xiang Gao, Jakob von Moltke, Zhaoyu Lin, Hai-Bin Ruan.
      The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.
    Keywords:  Gasdermin; IL-10; IL-25; IL-33; O-GlcNAc; OGT; STAT6; Tuft cell; colitis; goblet cell
    DOI:  https://doi.org/10.1016/j.immuni.2022.03.009
  58. Cell Res. 2022 Apr 04.
    Gut microbiota drives macrophage-dependent self-renewal of intestinal stem cells via niche enteric serotonergic neurons.
    Pingping Zhu, Tiankun Lu, Jiayi Wu, Dongdong Fan, Benyu Liu, Xiaoxiao Zhu, Hui Guo, Ying Du, Feng Liu, Yong Tian, Zusen Fan.
      Lgr5+ intestinal stem cells (ISCs) reside within specialized niches at the crypt base and harbor self-renewal and differentiation capacities. ISCs in the crypt base are sustained by their surrounding niche for precise modulation of self-renewal and differentiation. However, how intestinal cells in the crypt niche and microbiota in enteric cavity coordinately regulate ISC stemness remains unclear. Here, we show that ISCs are regulated by microbiota and niche enteric serotonergic neurons. The gut microbiota metabolite valeric acid promotes Tph2 expression in enteric serotonergic neurons via blocking the recruitment of the NuRD complex onto Tph2 promoter. 5-hydroxytryptamine (5-HT) in turn activates PGE2 production in a PGE2+ macrophage subset through its receptors HTR2A/3 A; and PGE2 via binding its receptors EP1/EP4, promotes Wnt/β-catenin signaling in ISCs to promote their self-renewal. Our findings illustrate a complex crosstalk among microbiota, intestinal nerve cells, intestinal immune cells and ISCs, revealing a new layer of ISC regulation by niche cells and microbiota.
    DOI:  https://doi.org/10.1038/s41422-022-00645-7
  59. Nat Commun. 2022 Apr 04. 13(1): 1808
    Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression.
    Mi-Young Song, Chang Yeob Han, Young Jae Moon, Ju Hyung Lee, Eun Ju Bae, Byung-Hyun Park.
      Expanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans, and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.
    DOI:  https://doi.org/10.1038/s41467-022-29472-5
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