bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–08–27
79 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Restriction factor.
  2. lnc(RNA)-ing myeloid metabolism.
  3. Modulating RNF41.
  4. Small does not mean less.
  5. Single-cell diversity and functional plasticity of human MAIT cells.
  6. Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.
  7. Environmental and genetic predictors of human cardiovascular ageing.
  8. Expanding Vδ1 T cells.
  9. The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation.
  10. Erythropoietin re-wires cognition-associated transcriptional networks.
  11. Cell type-specific delivery by modular envelope design.
  12. Editorial Expression of Concern.
  13. Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations.
  14. Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.
  15. Trim33 masks a non-transcriptional function of E2f4 in replication fork progression.
  16. Next-generation proteomics for quantitative Jumbophage-bacteria interaction mapping.
  17. Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13.
  18. PINK1 and Parkin regulate IP3R-mediated ER calcium release.
  19. Assembly of 43 human Y chromosomes reveals extensive complexity and variation.
  20. A high-performance speech neuroprosthesis.
  21. Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis.
  22. O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function.
  23. Single-cell lipidomics enabled by dual-polarity ionization and ion mobility-mass spectrometry imaging.
  24. Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
  25. Structural and functional insights into the modulation of T cell costimulation by monkeypox virus protein M2.
  26. NFIB facilitates replication licensing by acting as a genome organizer.
  27. PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.
  28. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
  29. At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.
  30. An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells.
  31. A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.
  32. Long-read whole-genome analysis of human single cells.
  33. T cell-microglia signaling exacerbates neuropathology in an Alzheimer's disease model.
  34. Architecture of the Heme-translocating CcmABCD/E complex required for Cytochrome c maturation.
  35. Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.
  36. RNAPII-dependent ATM signaling at collisions with replication forks.
  37. Droplet-based high-throughput single microbe RNA sequencing by smRandom-seq.
  38. Structural mechanism of mitochondrial membrane remodelling by human OPA1.
  39. Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development.
  40. John B. Goodenough (1922-2023).
  41. OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection.
  42. A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels.
  43. CD36 mediates SARS-CoV-2-envelope-protein-induced platelet activation and thrombosis.
  44. Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides.
  45. Cryopreservation and revival of Hawaiian stony corals using isochoric vitrification.
  46. A pan-cancer single-cell panorama of human natural killer cells.
  47. Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress.
  48. Sphagnum increases soil's sequestration capacity of mineral-associated organic carbon via activating metal oxides.
  49. Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites.
  50. Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.
  51. The gut microbiota reprograms intestinal lipid metabolism through long noncoding RNA Snhg9.
  52. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
  53. Forest carbon offsets are failing.
  54. Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.
  55. Europe spent €600 million to recreate the human brain in a computer. How did it go?
  56. In-memory mechanical computing.
  57. CD98hc is a target for brain delivery of biotherapeutics.
  58. Targeted sequencing of the 9p21.3 region reveals association with reduced disease risks in Ashkenazi Jewish centenarians.
  59. Antibody-mediated NK cell activation as a correlate of immunity against influenza infection.
  60. Brain-wide representations of behavior spanning multiple timescales and states in C. elegans.
  61. Principles and methods for transferring polygenic risk scores across global populations.
  62. Author Correction: Demonstration of quantum-digital payments.
  63. Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing.
  64. Molecular architecture and conservation of an immature human endogenous retrovirus.
  65. The complete sequence of a human Y chromosome.
  66. Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
  67. Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model.
  68. APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
  69. Thin jets underlie the solar wind.
  70. Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins.
  71. Zero-shot visual reasoning through probabilistic analogical mapping.
  72. Omicron infection following vaccination enhances a broad spectrum of immune responses dependent on infection history.
  73. Convergent somatic evolution commences in utero in a germline ribosomopathy.
  74. Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.
  75. Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.
  76. Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity.
  77. Brain implants that enable speech pass performance milestones.
  78. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  79. Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons.
  1. Nat Immunol. 2023 Sep;24(9): 1396
    Restriction factor.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-023-01616-9
  2. Nat Immunol. 2023 Sep;24(9): 1396
    lnc(RNA)-ing myeloid metabolism.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01615-w
  3. Nat Immunol. 2023 Sep;24(9): 1396
    Modulating RNF41.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-023-01618-7
  4. Science. 2023 Aug 25. 381(6660): 914
    Small does not mean less.
    Zheng Li.
      
    DOI:  https://doi.org/10.1126/science.adk3901
  5. Nat Immunol. 2023 Sep;24(9): 1409-1410
    Single-cell diversity and functional plasticity of human MAIT cells.
      
    DOI:  https://doi.org/10.1038/s41590-023-01600-3
  6. Nat Commun. 2023 Aug 25. 14(1): 5197
    Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.
    Jiyeon Lee, Julie M Dimitry, Jong Hee Song, Minsoo Son, Patrick W Sheehan, Melvin W King, G Travis Tabor, Young Ah Goo, Mitchell A Lazar, Leonard Petrucelli, Erik S Musiek.
      Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
    DOI:  https://doi.org/10.1038/s41467-023-40927-1
  7. Nat Commun. 2023 Aug 21. 14(1): 4941
    Environmental and genetic predictors of human cardiovascular ageing.
    Mit Shah, Marco H de A Inácio, Chang Lu, Pierre-Raphaël Schiratti, Sean L Zheng, Adam Clement, Antonio de Marvao, Wenjia Bai, Andrew P King, James S Ware, Martin R Wilkins, Johanna Mielke, Eren Elci, Ivan Kryukov, Kathryn A McGurk, Christian Bender, Daniel F Freitag, Declan P O'Regan.
      Cardiovascular ageing is a process that begins early in life and leads to a progressive change in structure and decline in function due to accumulated damage across diverse cell types, tissues and organs contributing to multi-morbidity. Damaging biophysical, metabolic and immunological factors exceed endogenous repair mechanisms resulting in a pro-fibrotic state, cellular senescence and end-organ damage, however the genetic architecture of cardiovascular ageing is not known. Here we use machine learning approaches to quantify cardiovascular age from image-derived traits of vascular function, cardiac motion and myocardial fibrosis, as well as conduction traits from electrocardiograms, in 39,559 participants of UK Biobank. Cardiovascular ageing is found to be significantly associated with common or rare variants in genes regulating sarcomere homeostasis, myocardial immunomodulation, and tissue responses to biophysical stress. Ageing is accelerated by cardiometabolic risk factors and we also identify prescribed medications that are potential modifiers of ageing. Through large-scale modelling of ageing across multiple traits our results reveal insights into the mechanisms driving premature cardiovascular ageing and reveal potential molecular targets to attenuate age-related processes.
    DOI:  https://doi.org/10.1038/s41467-023-40566-6
  8. Nat Immunol. 2023 Sep;24(9): 1396
    Expanding Vδ1 T cells.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-023-01617-8
  9. Science. 2023 Aug 25. 381(6660): eadh5021
    The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation.
    Xin Gu, Christopher Nardone, Nolan Kamitaki, Aoyue Mao, Stephen J Elledge, Michael E Greenberg.
      Cells use ubiquitin to mark proteins for proteasomal degradation. Although the proteasome also eliminates proteins that are not ubiquitinated, how this occurs mechanistically is unclear. Here, we found that midnolin promoted the destruction of many nuclear proteins, including transcription factors encoded by the immediate-early genes. Diverse stimuli induced midnolin, and its overexpression was sufficient to cause the degradation of its targets by a mechanism that did not require ubiquitination. Instead, midnolin associated with the proteasome via an α helix, used its Catch domain to bind a region within substrates that can form a β strand, and used a ubiquitin-like domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation.
    DOI:  https://doi.org/10.1126/science.adh5021
  10. Nat Commun. 2023 Aug 21. 14(1): 4777
    Erythropoietin re-wires cognition-associated transcriptional networks.
    Manvendra Singh, Ying Zhao, Vinicius Daguano Gastaldi, Sonja M Wojcik, Yasmina Curto, Riki Kawaguchi, Ricardo M Merino, Laura Fernandez Garcia-Agudo, Holger Taschenberger, Nils Brose, Daniel Geschwind, Klaus-Armin Nave, Hannelore Ehrenreich.
      Recombinant human erythropoietin (rhEPO) has potent procognitive effects, likely hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO remained obscure. Here, we provide transcriptional hippocampal profiling of male mice treated with rhEPO. Based on ~108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as 'tool', we discover populations of newly differentiating pyramidal neurons, overpopulating to ~200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.
    DOI:  https://doi.org/10.1038/s41467-023-40332-8
  11. Nat Commun. 2023 Aug 23. 14(1): 5141
    Cell type-specific delivery by modular envelope design.
    Daniel Strebinger, Chris J Frangieh, Mirco J Friedrich, Guilhem Faure, Rhiannon K Macrae, Feng Zhang.
      The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.
    DOI:  https://doi.org/10.1038/s41467-023-40788-8
  12. Science. 2023 Aug 24. eadk4448
    Editorial Expression of Concern.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/science.adk4448
  13. Nat Commun. 2023 Aug 23. 14(1): 5137
    Type-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations.
    Esmee K van der Ploeg, Lisette Krabbendam, Heleen Vroman, Menno van Nimwegen, Marjolein J W de Bruijn, Geertje M de Boer, Ingrid M Bergen, Mirjam Kool, Gerdien A Tramper-Standers, Gert-Jan Braunstahl, Danny Huylebroeck, Rudi W Hendriks, Ralph Stadhouders.
      CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells are considered the main producers of type-2 cytokines that fuel chronic airway inflammation in allergic asthma. However, CD8+ cytotoxic T (Tc) cells - critical for anti-viral defense - can also produce type-2 cytokines (referred to as 'Tc2' cells). The role of Tc cells in asthma and virus-induced disease exacerbations remains poorly understood, including which micro-environmental signals and cell types promote Tc2 cell formation. Here we show increased circulating Tc2 cell abundance in severe asthma patients, reaching peak levels during exacerbations and likely emerging from canonical IFNγ+ Tc cells through plasticity. Tc2 cell abundance is associated with increased disease burden, higher exacerbations rates and steroid insensitivity. Mouse models of asthma recapitulate the human disease by showing extensive type-2 skewing of lung Tc cells, which is controlled by conventional type-1 dendritic cells and IFNγ. Importantly, we demonstrate that the alarmin interleukin-33 (IL-33) critically promotes type-2 cytokine production by lung Tc cells in experimental allergic airway inflammation. Our data identify Tc cells as major producers of type-2 cytokines in severe asthma and during exacerbations that are remarkably sensitive to alterations in their inflammatory tissue micro-environment, with IL-33 emerging as an important regulator of Tc2 formation.
    DOI:  https://doi.org/10.1038/s41467-023-40820-x
  14. Cell. 2023 Aug 15. pii: S0092-8674(23)00796-1. [Epub ahead of print]
    Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.
    Jin-Gyu Cheong, Arjun Ravishankar, Siddhartha Sharma, Christopher N Parkhurst, Simon A Grassmann, Claire K Wingert, Paoline Laurent, Sai Ma, Lucinda Paddock, Isabella C Miranda, Emin Onur Karakaslar, Djamel Nehar-Belaid, Asa Thibodeau, Michael J Bale, Vinay K Kartha, Jim K Yee, Minh Y Mays, Chenyang Jiang, Andrew W Daman, Alexia Martinez de Paz, Dughan Ahimovic, Victor Ramos, Alexander Lercher, Erik Nielsen, Sergio Alvarez-Mulett, Ling Zheng, Andrew Earl, Alisha Yallowitz, Lexi Robbins, Elyse LaFond, Karissa L Weidman, Sabrina Racine-Brzostek, He S Yang, David R Price, Louise Leyre, André F Rendeiro, Hiranmayi Ravichandran, Junbum Kim, Alain C Borczuk, Charles M Rice, R Brad Jones, Edward J Schenck, Robert J Kaner, Amy Chadburn, Zhen Zhao, Virginia Pascual, Olivier Elemento, Robert E Schwartz, Jason D Buenrostro, Rachel E Niec, Franck J Barrat, Lindsay Lief, Joseph C Sun, Duygu Ucar, Steven Z Josefowicz.
      Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.
    Keywords:  COVID-19; IL-6; PASC; epigenetic memory; epigenome; hematopoietic stem and progenitor cells; monocytes; peripheral blood mononuclear cell progenitor input enrichment; post-acute sequelae SARS-CoV-2 infection; single-cell; trained immunity; transcriptome
    DOI:  https://doi.org/10.1016/j.cell.2023.07.019
  15. Nat Commun. 2023 Aug 23. 14(1): 5143
    Trim33 masks a non-transcriptional function of E2f4 in replication fork progression.
    Vanessa Rousseau, Elias Einig, Chao Jin, Julia Horn, Mathias Riebold, Tanja Poth, Mohamed-Ali Jarboui, Michael Flentje, Nikita Popov.
      Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.
    DOI:  https://doi.org/10.1038/s41467-023-40847-0
  16. Nat Commun. 2023 Aug 24. 14(1): 5156
    Next-generation proteomics for quantitative Jumbophage-bacteria interaction mapping.
    Andrea Fossati, Deepto Mozumdar, Claire Kokontis, Melissa Mèndez-Moran, Eliza Nieweglowska, Adrian Pelin, Yuping Li, Baron Guo, Nevan J Krogan, David A Agard, Joseph Bondy-Denomy, Danielle L Swaney.
      Host-pathogen interactions are pivotal in regulating establishment, progression, and outcome of an infection. While affinity-purification mass spectrometry has become instrumental in characterizing such interactions, it suffers from limitations in scalability and biological authenticity. Here we present the use of co-fractionation mass spectrometry for high throughput analysis of host-pathogen interactions from native viral infections of two jumbophages (ϕKZ and ϕPA3) in Pseudomonas aeruginosa. This approach enabled the detection of > 6000 unique host-pathogen interactions for each phage, encompassing > 50% of their respective proteomes. This deep coverage provided evidence for interactions between KZ-like phage proteins and the host ribosome, and revealed protein complexes for previously undescribed phage ORFs, including a ϕPA3 complex showing strong structural and sequence similarity to ϕKZ non-virion RNA polymerase. Interactome-wide comparison across phages showed similar perturbed protein interactions suggesting fundamentally conserved mechanisms of phage predation within the KZ-like phage family. To enable accessibility to this data, we developed PhageMAP, an online resource for network query, visualization, and interaction prediction ( https://phagemap.ucsf.edu/ ). We anticipate this study will lay the foundation for the application of co-fractionation mass spectrometry for the scalable profiling of host-pathogen interactomes and protein complex dynamics upon infection.
    DOI:  https://doi.org/10.1038/s41467-023-40724-w
  17. Nat Commun. 2023 Aug 24. 14(1): 5158
    Structural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13.
    Shenping Liu, Ruth F Sommese, Nicole L Nedoma, Lucy Mae Stevens, Jason K Dutra, Liying Zhang, David J Edmonds, Yang Wang, Michelle Garnsey, Michelle F Clasquin.
      Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports that predicted loss of function variants in HSD17B13 protect against the progression of steatosis to non-alcoholic steatohepatitis with fibrosis and hepatocellular carcinoma. Here we report crystal structures of full length HSD17B13 in complex with its NAD+ cofactor, and with lipid/detergent molecules and small molecule inhibitors from two distinct series in the ligand binding pocket. These structures provide insights into a mechanism for lipid droplet-associated proteins anchoring to membranes as well as a basis for HSD17B13 variants disrupting function. Two series of inhibitors interact with the active site residues and the bound cofactor similarly, yet they occupy different paths leading to the active site. These structures provide ideas for structure-based design of inhibitors that may be used in the treatment of liver disease.
    DOI:  https://doi.org/10.1038/s41467-023-40766-0
  18. Nat Commun. 2023 Aug 25. 14(1): 5202
    PINK1 and Parkin regulate IP3R-mediated ER calcium release.
    Su Jin Ham, Heesuk Yoo, Daihn Woo, Da Hyun Lee, Kyu-Sang Park, Jongkyeong Chung.
      Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson's disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-40929-z
  19. Nature. 2023 Aug 23.
    Assembly of 43 human Y chromosomes reveals extensive complexity and variation.
    Human Genome Structural Variation Consortium (HGSVC)
      The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date1 and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes2. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established1 boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.
    DOI:  https://doi.org/10.1038/s41586-023-06425-6
  20. Nature. 2023 Aug 23.
    A high-performance speech neuroprosthesis.
    Francis R Willett, Erin M Kunz, Chaofei Fan, Donald T Avansino, Guy H Wilson, Eun Young Choi, Foram Kamdar, Matthew F Glasser, Leigh R Hochberg, Shaul Druckmann, Krishna V Shenoy, Jaimie M Henderson.
      Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text1,2 or sound3,4. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary1-7. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant-who can no longer speak intelligibly owing to amyotrophic lateral sclerosis-achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI2) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant's attempted speech was decoded  at 62 words per minute, which is 3.4 times as fast as the previous record8 and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.
    DOI:  https://doi.org/10.1038/s41586-023-06377-x
  21. Nat Commun. 2023 Aug 24. 14(1): 4960
    Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis.
    Yibing Han, Takeshi Tomita, Masayoshi Kato, Norihiro Ashihara, Yumiko Higuchi, Hisanori Matoba, Weiyi Wang, Hikaru Hayashi, Yuji Itoh, Satoshi Takahashi, Hiroshi Kurita, Jun Nakayama, Nobuo Okumura, Sachie Hiratsuka.
      Primary tumor cells metastasize to a distant preferred organ. However, the most decisive host factors that determine the precise locations of metastases in cancer patients remain unknown. We have demonstrated that post-translational citrullination of fibrinogen creates a metastatic niche in the vulnerable spots. Pulmonary endothelial cells mediate the citrullination of fibrinogen, changing its conformation, surface charge, and binding properties with serum amyloid A proteins (SAAs), to make it a host tissue-derived metastatic pathogen. The human-specific SAAs-citrullinated fibrinogen (CitFbg) complex recruits cancer cells to form a protein-metastatic cell aggregation in humanized SAA cluster mice. Furthermore, a CitFbg peptide works as a competitive inhibitor to block the homing of metastatic cells into the SAAs-CitFbg sites. The potential metastatic sites in the lungs of patients are clearly visualized by our specific antibody for CitFbg. Thus, CitFbg deposition displays metastatic risks for cancer patients, and the citrullinated peptide is a new type of metastasis inhibitor.
    DOI:  https://doi.org/10.1038/s41467-023-40371-1
  22. Commun Biol. 2023 Aug 25. 6(1): 877
    O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function.
    Stefan Norlin, Jan Axelsson, Madelene Ericsson, Helena Edlund.
      Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.
    DOI:  https://doi.org/10.1038/s42003-023-05255-6
  23. Nat Commun. 2023 Aug 25. 14(1): 5185
    Single-cell lipidomics enabled by dual-polarity ionization and ion mobility-mass spectrometry imaging.
    Hua Zhang, Yuan Liu, Lauren Fields, Xudong Shi, Penghsuan Huang, Haiyan Lu, Andrew J Schneider, Xindi Tang, Luigi Puglielli, Nathan V Welham, Lingjun Li.
      Single-cell (SC) analysis provides unique insight into individual cell dynamics and cell-to-cell heterogeneity. Here, we utilize trapped ion mobility separation coupled with dual-polarity ionization mass spectrometry imaging (MSI) to enable high-throughput in situ profiling of the SC lipidome. Multimodal SC imaging, in which dual-polarity-mode MSI is used to perform serial data acquisition runs on individual cells, significantly enhanced SC lipidome coverage. High-spatial resolution SC-MSI identifies both inter- and intracellular lipid heterogeneity; this heterogeneity is further explicated by Uniform Manifold Approximation and Projection and machine learning-driven classifications. We characterize SC lipidome alteration in response to stearoyl-CoA desaturase 1 inhibition and, additionally, identify cell-layer specific lipid distribution patterns in mouse cerebellar cortex. This integrated multimodal SC-MSI technology enables high-resolution spatial mapping of intercellular and cell-to-cell lipidome heterogeneity, SC lipidome remodeling induced by pharmacological intervention, and region-specific lipid diversity within tissue.
    DOI:  https://doi.org/10.1038/s41467-023-40512-6
  24. Nat Commun. 2023 Aug 22. 14(1): 5114
    Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
    Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.
      M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.
    DOI:  https://doi.org/10.1038/s41467-023-40738-4
  25. Nat Commun. 2023 Aug 25. 14(1): 5186
    Structural and functional insights into the modulation of T cell costimulation by monkeypox virus protein M2.
    Shangyu Yang, Yong Wang, Feiyang Yu, Rao Cheng, Yiwei Zhang, Dan Zhou, Xuanxiu Ren, Zengqin Deng, Haiyan Zhao.
      The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the poxvirus immune evasion family and plays roles in host immunomodulation via the regulation of innate immune response mediated by the NF-κB pathway and adaptive immune response mediated by B7 ligands. However, the interaction of monkeypox virus (MPXV) M2 with B7 ligands and structural insight into poxviral M2 function have remained elusive. Here we reveal that MPXV M2, co-existing as a hexamer and a heptamer, recognizes human B7.1 and B7.2 (hB7.1/2) with high avidities. The binding of oligomeric MPXV M2 interrupts the interactions of hB7.1/2 with CD28 and CTLA4 and subverts T cell activation mediated by B7.1/2 costimulatory signals. Cryo-EM structures of M2 in complex with hB7.1/2 show that M2 binds to the shallow concave face of hB7.1/2 and displays sterically competition with CD28 and CTLA4 for the binding to hB7.1/2. Our findings provide structural mechanisms of poxviral M2 function and immune evasion deployed by poxviruses.
    DOI:  https://doi.org/10.1038/s41467-023-40748-2
  26. Nat Commun. 2023 Aug 21. 14(1): 5076
    NFIB facilitates replication licensing by acting as a genome organizer.
    Wenting Zhang, Yue Wang, Yongjie Liu, Cuifang Liu, Yizhou Wang, Lin He, Xiao Cheng, Yani Peng, Lu Xia, Xiaodi Wu, Jiajing Wu, Yu Zhang, Luyang Sun, Ping Chen, Guohong Li, Qiang Tu, Jing Liang, Yongfeng Shang.
      The chromatin-based rule governing the selection and activation of replication origins in metazoans remains to be investigated. Here we report that NFIB, a member of Nuclear Factor I (NFI) family that was initially purified in host cells to promote adenoviral DNA replication but has since mainly been investigated in transcription regulation, is physically associated with the pre-replication complex (pre-RC) in mammalian cells. Genomic analyses reveal that NFIB facilitates the assembly of the pre-RC by increasing chromatin accessibility. Nucleosome binding and single-molecule magnetic tweezers shows that NFIB binds to and opens up nucleosomes. Transmission electron microscopy indicates that NFIB promotes nucleosome eviction on parental chromatin. NFIB deficiency leads to alterations of chromosome contacts/compartments in both G1 and S phase and affects the firing of a subset of origins at early-replication domains. Significantly, cancer-associated NFIB overexpression provokes gene duplication and genomic alterations recapitulating the genetic aberrance in clinical breast cancer and empowering cancer cells to dynamically evolve growth advantage and drug resistance. Together, these results point a role for NFIB in facilitating replication licensing by acting as a genome organizer, shedding new lights on the biological function of NFIB and on the replication origin selection in eukaryotes.
    DOI:  https://doi.org/10.1038/s41467-023-40846-1
  27. Sci Immunol. 2023 Aug 04. 8(86): eadg0539
    PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.
    Amanda L Gill, Peter H Wang, Judong Lee, William H Hudson, Satomi Ando, Koichi Araki, Yinghong Hu, Andreas Wieland, Sejin Im, Autumn Gavora, Christopher B Medina, Gordon J Freeman, Masao Hashimoto, Steven L Reiner, Rafi Ahmed.
      PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1- daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1-directed immunotherapy in humans.
    DOI:  https://doi.org/10.1126/sciimmunol.adg0539
  28. Nat Commun. 2023 Aug 25. 14(1): 5208
    MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.
    Nicholas T Crump, Alastair L Smith, Laura Godfrey, Ana M Dopico-Fernandez, Nicholas Denny, Joe R Harman, Joseph C Hamley, Nicole E Jackson, Catherine Chahrour, Simone Riva, Siobhan Rice, Jaehoon Kim, Venkatesha Basrur, Damian Fermin, Kojo Elenitoba-Johnson, Robert G Roeder, C David Allis, Irene Roberts, Anindita Roy, Huimin Geng, James O J Davies, Thomas A Milne.
      Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.
    DOI:  https://doi.org/10.1038/s41467-023-40981-9
  29. Nat Commun. 2023 Aug 21. 14(1): 5080
    At-home wearables and machine learning sensitively capture disease progression in amyotrophic lateral sclerosis.
    Anoopum S Gupta, Siddharth Patel, Alan Premasiri, Fernando Vieira.
      Amyotrophic lateral sclerosis causes degeneration of motor neurons, resulting in progressive muscle weakness and impairment in motor function. Promising drug development efforts have accelerated in amyotrophic lateral sclerosis, but are constrained by a lack of objective, sensitive, and accessible outcome measures. Here we investigate the use of wearable sensors, worn on four limbs at home during natural behavior, to quantify motor function and disease progression in 376 individuals with amyotrophic lateral sclerosis. We use an analysis approach that automatically detects and characterizes submovements from passively collected accelerometer data and produces a machine-learned severity score for each limb that is independent of clinical ratings. We show that this approach produces scores that progress faster than the gold standard Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (-0.86 ± 0.70 SD/year versus -0.73 ± 0.74 SD/year), resulting in smaller clinical trial sample size estimates (N = 76 versus N = 121). This method offers an ecologically valid and scalable measure for potential use in amyotrophic lateral sclerosis trials and clinical care.
    DOI:  https://doi.org/10.1038/s41467-023-40917-3
  30. Nat Commun. 2023 Aug 23. 14(1): 5116
    An integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells.
    Fiamma Salerno, Andrew J M Howden, Louise S Matheson, Özge Gizlenci, Michael Screen, Holger Lingel, Monika C Brunner-Weinzierl, Martin Turner.
      During B cell maturation, transitional and mature B cells acquire cell-intrinsic features that determine their ability to exit quiescence and mount effective immune responses. Here we use label-free proteomics to quantify the proteome of B cell subsets from the mouse spleen and map the differential expression of environmental sensing, transcription, and translation initiation factors that define cellular identity and function. Cross-examination of the full-length transcriptome and proteome identifies mRNAs related to B cell activation and antibody secretion that are not accompanied by detection of the encoded proteins. In addition, proteomic data further suggests that the translational repressor PDCD4 restrains B cell responses, in particular those from marginal zone B cells, to a T-cell independent antigen. In summary, our molecular characterization of B cell maturation presents a valuable resource to further explore the mechanisms underpinning the specialized functions of B cell subsets, and suggest the presence of 'poised' mRNAs that enable expedited B cell responses.
    DOI:  https://doi.org/10.1038/s41467-023-40621-2
  31. Mol Cell. 2023 Aug 18. pii: S1097-2765(23)00601-9. [Epub ahead of print]
    A Zpr1 co-chaperone mediates folding of eukaryotic translation elongation factor 1A via a GTPase cycle.
    Alexander J McQuown, Anjali R Nelliat, Dvir Reif, Ibrahim M Sabbarini, Britnie Santiago Membreno, Colin Chih-Chien Wu, Vladimir Denic.
      General protein folding is mediated by chaperones that utilize ATP hydrolysis to regulate client binding and release. Zinc-finger protein 1 (Zpr1) is an essential ATP-independent chaperone dedicated to the biogenesis of eukaryotic translation elongation factor 1A (eEF1A), a highly abundant GTP-binding protein. How Zpr1-mediated folding is regulated to ensure rapid Zpr1 recycling remains an unanswered question. Here, we use yeast genetics and microscopy analysis, biochemical reconstitution, and structural modeling to reveal that folding of eEF1A by Zpr1 requires GTP hydrolysis. Furthermore, we identify the highly conserved altered inheritance of mitochondria 29 (Aim29) protein as a Zpr1 co-chaperone that recognizes eEF1A in the GTP-bound, pre-hydrolysis conformation. This interaction dampens Zpr1⋅eEF1A GTPase activity and facilitates client exit from the folding cycle. Our work reveals that a bespoke ATP-independent chaperone system has mechanistic similarity to ATPase chaperones but unexpectedly relies on client GTP hydrolysis to regulate the chaperone-client interaction.
    Keywords:  chaperones; eEF1A; heat-shock response; integrated stress response; protein folding; protein homeostasis; proteostasis; translation elongation factors
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.028
  32. Nat Commun. 2023 Aug 24. 14(1): 5164
    Long-read whole-genome analysis of human single cells.
    Joanna Hård, Jeff E Mold, Jesper Eisfeldt, Christian Tellgren-Roth, Susana Häggqvist, Ignas Bunikis, Orlando Contreras-Lopez, Chen-Shan Chin, Jessica Nordlund, Carl-Johan Rubin, Lars Feuk, Jakob Michaëlsson, Adam Ameur.
      Long-read sequencing has dramatically increased our understanding of human genome variation. Here, we demonstrate that long-read technology can give new insights into the genomic architecture of individual cells. Clonally expanded CD8+ T-cells from a human donor were subjected to droplet-based multiple displacement amplification (dMDA) to generate long molecules with reduced bias. PacBio sequencing generated up to 40% genome coverage per single-cell, enabling detection of single nucleotide variants (SNVs), structural variants (SVs), and tandem repeats, also in regions inaccessible by short reads. 28 somatic SNVs were detected, including one case of mitochondrial heteroplasmy. 5473 high-confidence SVs/cell were discovered, a sixteen-fold increase compared to Illumina-based results from clonally related cells. Single-cell de novo assembly generated a genome size of up to 598 Mb and 1762 (12.8%) complete gene models. In summary, our work shows the promise of long-read sequencing toward characterization of the full spectrum of genetic variation in single cells.
    DOI:  https://doi.org/10.1038/s41467-023-40898-3
  33. Nat Neurosci. 2023 Aug 24.
    T cell-microglia signaling exacerbates neuropathology in an Alzheimer's disease model.
      
    DOI:  https://doi.org/10.1038/s41593-023-01417-1
  34. Nat Commun. 2023 Aug 25. 14(1): 5190
    Architecture of the Heme-translocating CcmABCD/E complex required for Cytochrome c maturation.
    Lorena Ilcu, Lukas Denkhaus, Anton Brausemann, Lin Zhang, Oliver Einsle.
      Mono- and multiheme cytochromes c are post-translationally matured by the covalent attachment of heme. For this, Escherichia coli employs the most complex type of maturation machineries, the Ccm-system (for cytochrome c maturation). It consists of two membrane protein complexes, one of which shuttles heme across the membrane to a mobile chaperone that then delivers the cofactor to the second complex, an apoprotein:heme lyase, for covalent attachment. Here we report cryo-electron microscopic structures of the heme translocation complex CcmABCD from E. coli, alone and bound to the heme chaperone CcmE. CcmABCD forms a heterooctameric complex centered around the ABC transporter CcmAB that does not by itself transport heme. Our data suggest that the complex flops a heme group from the inner to the outer leaflet at its CcmBC interfaces, driven by ATP hydrolysis at CcmA. A conserved heme-handling motif (WxWD) at the periplasmic side of CcmC rotates the heme by 90° for covalent attachment to the heme chaperone CcmE that we find interacting exclusively with the CcmB subunit.
    DOI:  https://doi.org/10.1038/s41467-023-40881-y
  35. Nat Commun. 2023 Aug 22. 14(1): 4944
    Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.
    Cheng Zeng, Jiwei Chen, Emmalee W Cooke, Arijita Subuddhi, Eliana T Roodman, Fei Xavier Chen, Kaixiang Cao.
      The major enhancer regulator lysine-specific histone demethylase 1A (LSD1) is required for mammalian embryogenesis and is implicated in human congenital diseases and multiple types of cancer; however, the underlying mechanisms remain enigmatic. Here, we dissect the role of LSD1 and its demethylase activity in gene regulation and cell fate transition. Surprisingly, the catalytic inactivation of LSD1 has a mild impact on gene expression and cellular differentiation whereas the loss of LSD1 protein de-represses enhancers globally and impairs cell fate transition. LSD1 deletion increases H3K27ac levels and P300 occupancy at LSD1-targeted enhancers. The gain of H3K27ac catalyzed by P300/CBP, not the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss. Together, our study demonstrates a demethylase-independent role of LSD1 in regulating enhancers and cell fate transition, providing insight into treating diseases driven by LSD1 mutations and misregulation.
    DOI:  https://doi.org/10.1038/s41467-023-40606-1
  36. Nat Commun. 2023 Aug 24. 14(1): 5147
    RNAPII-dependent ATM signaling at collisions with replication forks.
    Elias Einig, Chao Jin, Valentina Andrioletti, Boris Macek, Nikita Popov.
      Deregulation of RNA Polymerase II (RNAPII) by oncogenic signaling leads to collisions of RNAPII with DNA synthesis machinery (transcription-replication conflicts, TRCs). TRCs can result in DNA damage and are thought to underlie genomic instability in tumor cells. Here we provide evidence that elongating RNAPII nucleates activation of the ATM kinase at TRCs to stimulate DNA repair. We show the ATPase WRNIP1 associates with RNAPII and limits ATM activation during unperturbed cell cycle. WRNIP1 binding to elongating RNAPII requires catalytic activity of the ubiquitin ligase HUWE1. Mutation of HUWE1 induces TRCs, promotes WRNIP1 dissociation from RNAPII and binding to the replisome, stimulating ATM recruitment and activation at RNAPII. TRCs and translocation of WRNIP1 are rapidly induced in response to hydroxyurea treatment to activate ATM and facilitate subsequent DNA repair. We propose that TRCs can provide a controlled mechanism for stalling of replication forks and ATM activation, instrumental in cellular response to replicative stress.
    DOI:  https://doi.org/10.1038/s41467-023-40924-4
  37. Nat Commun. 2023 Aug 23. 14(1): 5130
    Droplet-based high-throughput single microbe RNA sequencing by smRandom-seq.
    Ziye Xu, Yuting Wang, Kuanwei Sheng, Raoul Rosenthal, Nan Liu, Xiaoting Hua, Tianyu Zhang, Jiaye Chen, Mengdi Song, Yuexiao Lv, Shunji Zhang, Yingjuan Huang, Zhaolun Wang, Ting Cao, Yifei Shen, Yan Jiang, Yunsong Yu, Yu Chen, Guoji Guo, Peng Yin, David A Weitz, Yongcheng Wang.
      Bacteria colonize almost all parts of the human body and can differ significantly. However, the population level transcriptomics measurements can only describe the average bacteria population behaviors, ignoring the heterogeneity among bacteria. Here, we report a droplet-based high-throughput single-microbe RNA-seq assay (smRandom-seq), using random primers for in situ cDNA generation, droplets for single-microbe barcoding, and CRISPR-based rRNA depletion for mRNA enrichment. smRandom-seq showed a high species specificity (99%), a minor doublet rate (1.6%), a reduced rRNA percentage (32%), and a sensitive gene detection (a median of ~1000 genes per single E. coli). Furthermore, smRandom-seq successfully captured transcriptome changes of thousands of individual E. coli and discovered a few antibiotic resistant subpopulations displaying distinct gene expression patterns of SOS response and metabolic pathways in E. coli population upon antibiotic stress. smRandom-seq provides a high-throughput single-microbe transcriptome profiling tool that will facilitate future discoveries in microbial resistance, persistence, microbe-host interaction, and microbiome research.
    DOI:  https://doi.org/10.1038/s41467-023-40137-9
  38. Nature. 2023 Aug 23.
    Structural mechanism of mitochondrial membrane remodelling by human OPA1.
    Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.
      Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
    DOI:  https://doi.org/10.1038/s41586-023-06441-6
  39. Nat Commun. 2023 Aug 24. 14(1): 5152
    Downregulation of chemokine receptor 9 facilitates CD4+CD8αα+ intraepithelial lymphocyte development.
    Keiko Ono, Tomohisa Sujino, Kentaro Miyamoto, Yosuke Harada, Satoshi Kojo, Yusuke Yoshimatsu, Shun Tanemoto, Yuzo Koda, Jiawen Zheng, Kazutoshi Sayama, Tsuyoshi Koide, Toshiaki Teratani, Yohei Mikami, Kaoru Takabayashi, Nobuhiro Nakamoto, Naoki Hosoe, Mariya London, Haruhiko Ogata, Daniel Mucida, Ichiro Taniuchi, Takanori Kanai.
      Intestinal intraepithelial lymphocytes (IELs) reside in the gut epithelial layer, where they help in maintaining intestinal homeostasis. Peripheral CD4+ T cells can develop into CD4+CD8αα+ IELs upon arrival at the gut epithelium via the lamina propria (LP). Although this specific differentiation of T cells is well established, the mechanisms preventing it from occurring in the LP remain unclear. Here, we show that chemokine receptor 9 (CCR9) expression is low in epithelial CD4+CD8αα+ IELs, but CCR9 deficiency results in CD4+CD8αα+ over-differentiation in both the epithelium and the LP. Single-cell RNA sequencing shows an enriched precursor cell cluster for CD4+CD8αα+ IELs in Ccr9-/- mice. CD4+ T cells isolated from the epithelium of Ccr9-/- mice also display increased expression of Cbfβ2, and the genomic occupancy modification of Cbfβ2 expression reveals its important function in CD4+CD8αα+ differentiation. These results implicate a link between CCR9 downregulation and Cbfb2 splicing upregulation to enhance CD4+CD8αα+ IEL differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-40950-2
  40. Science. 2023 Aug 25. 381(6660): 836
    John B. Goodenough (1922-2023).
    Clare P Grey, Laura H Lewis.
      A giant in the fields of solid-state chemistry and physics.
    DOI:  https://doi.org/10.1126/science.adj9263
  41. Cell Death Dis. 2023 08 19. 14(8): 534
    OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection.
    Lien Verboom, Christopher J Anderson, Maude Jans, Ioanna Petta, Gillian Blancke, Arne Martens, Mozes Sze, Tino Hochepied, Kodi S Ravichandran, Lars Vereecke, Geert van Loo.
      The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients.
    DOI:  https://doi.org/10.1038/s41419-023-06058-7
  42. Nat Commun. 2023 Aug 21. 14(1): 5072
    A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels.
    Yichen Liu, Carlos A Z Bassetto, Bernardo I Pinto, Francisco Bezanilla.
      The hinged-lid model was long accepted as the canonical model for fast inactivation in Nav channels. It predicts that the hydrophobic IFM motif acts intracellularly as the gating particle that binds and occludes the pore during fast inactivation. However, the observation in recent high-resolution structures that the bound IFM motif is located far from the pore, contradicts this preconception. Here, we provide a mechanistic reinterpretation of fast inactivation based on structural analysis and ionic/gating current measurements. We demonstrate that in Nav1.4 the final inactivation gate is comprised of two hydrophobic rings at the bottom of S6 helices. These rings function in series and close downstream of IFM binding. Reducing the volume of the sidechain in both rings leads to a partially conductive, leaky inactivated state and decreases the selectivity for Na+ ion. Altogether, we present an alternative molecular framework to describe fast inactivation.
    DOI:  https://doi.org/10.1038/s41467-023-40514-4
  43. Nat Commun. 2023 Aug 21. 14(1): 5077
    CD36 mediates SARS-CoV-2-envelope-protein-induced platelet activation and thrombosis.
    Zihan Tang, Yanyan Xu, Yun Tan, Hui Shi, Peipei Jin, Yunqi Li, Jialin Teng, Honglei Liu, Haoyu Pan, Qiongyi Hu, Xiaobing Cheng, Junna Ye, Yutong Su, Yue Sun, Jianfen Meng, Zhuochao Zhou, Huihui Chi, Xuefeng Wang, Junling Liu, Yong Lu, Feng Liu, Jing Dai, Chengde Yang, Saijuan Chen, Tingting Liu.
      Aberrant coagulation and thrombosis are associated with severe COVID-19 post-SARS-CoV-2 infection, yet the underlying mechanism remains obscure. Here we show that serum levels of SARS-CoV-2 envelope (E) protein are associated with coagulation disorders of COVID-19 patients, and intravenous administration of the E protein is able to potentiate thrombosis in mice. Through protein pull-down and mass spectrometry, we find that CD36, a transmembrane glycoprotein, directly binds with E protein and mediates hyperactivation of human and mouse platelets through the p38 MAPK-NF-κB signaling pathway. Conversely, the pharmacological blockade of CD36 or p38 notably attenuates human platelet activation induced by the E protein. Similarly, the genetic deficiency of CD36, as well as the pharmacological inhibition of p38 in mice, significantly diminishes E protein-induced platelet activation and thrombotic events. Together, our study reveals a critical role for the CD36-p38 axis in E protein-induced platelet hyperactivity, which could serve as an actionable target for developing therapies against aberrant thrombotic events related to the severity and mortality of COVID-19.
    DOI:  https://doi.org/10.1038/s41467-023-40824-7
  44. Nat Commun. 2023 Aug 22. 14(1): 5093
    Bile acid-dependent transcription factors and chromatin accessibility determine regional heterogeneity of intestinal antimicrobial peptides.
    Yue Wang, Yanbo Yu, Lixiang Li, Mengqi Zheng, Jiawei Zhou, Haifan Gong, Bingcheng Feng, Xiao Wang, Xuanlin Meng, Yanyan Cui, Yanan Xia, Shuzheng Chu, Lin Lin, Huijun Chang, Ruchen Zhou, Mingjun Ma, Zhen Li, Rui Ji, Ming Lu, Xiaoyun Yang, Xiuli Zuo, Shiyang Li, Yanqing Li.
      Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn's disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.
    DOI:  https://doi.org/10.1038/s41467-023-40565-7
  45. Nat Commun. 2023 Aug 23. 14(1): 4859
    Cryopreservation and revival of Hawaiian stony corals using isochoric vitrification.
    Matthew J Powell-Palm, E Michael Henley, Anthony N Consiglio, Claire Lager, Brooke Chang, Riley Perry, Kendall Fitzgerald, Jonathan Daly, Boris Rubinsky, Mary Hagedorn.
      Corals are under siege by both local and global threats, creating a worldwide reef crisis. Cryopreservation is an important intervention measure and a vital component of the modern coral conservation toolkit, but preservation techniques are currently limited to sensitive reproductive materials that can only be obtained a few nights per year during spawning. Here, we report the successful cryopreservation and revival of cm-scale coral fragments via mL-scale isochoric vitrification. We demonstrate coral viability at 24 h post-thaw using a calibrated oxygen-uptake respirometry technique, and further show that the method can be applied in a passive, electronics-free configuration. Finally, we detail a complete prototype coral cryopreservation pipeline, which provides a platform for essential next steps in modulating post-thaw stress and initiating long-term growth. These findings pave the way towards an approach that can be rapidly deployed around the world to secure the biological genetic diversity of our vanishing coral reefs.
    DOI:  https://doi.org/10.1038/s41467-023-40500-w
  46. Cell. 2023 Aug 15. pii: S0092-8674(23)00849-8. [Epub ahead of print]
    A pan-cancer single-cell panorama of human natural killer cells.
    Fei Tang, Jinhu Li, Lu Qi, Dongfang Liu, Yufei Bo, Shishang Qin, Yuhui Miao, Kezhuo Yu, Wenhong Hou, Jianan Li, Jirun Peng, Zhigang Tian, Linnan Zhu, Hui Peng, Dongfang Wang, Zemin Zhang.
      Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3+ dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets.
    DOI:  https://doi.org/10.1016/j.cell.2023.07.034
  47. J Clin Invest. 2023 Aug 22. pii: e159860. [Epub ahead of print]
    Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress.
    Zi-Yan Yang, Xian-Chun Yan, Jia-Yu-Lin Zhang, Liang Liang, Chun-Chen Gao, Pei-Ran Zhang, Yuan Liu, Jia-Xing Sun, Bai Ruan, Juan-Li Duan, Ruo-Nan Wang, Xing-Xing Feng, Bo Che, Tian Xiao, Hua Han.
      Human cancers induce a chaotic, dysfunctional vasculature that promotes tumor growth and dampens most current therapies, but the underlying mechanism has been unclear. Here we show that SPEN (split end), a transcription repressor, coordinates ribosome RNA (rRNA) synthesis in endothelial cells (ECs) and is required for physiological and tumor angiogenesis. SPEN deficiency attenuated EC proliferation and blunted retinal angiogenesis, which was attributed to p53 activation. Furthermore, SPEN knockdown activated p53 by upregulating the noncoding promoter RNA (pRNA), which represses rRNA transcription and triggers p53-mediated nucleolar stress. In human cancer biopsies, low endothelial SPEN level correlated with extended overall survival. Consistently in mice, endothelial SPEN deficiency compromised rRNA expression and repressed tumor growth and metastasis by normalizing tumor vessels, which was abrogated by p53 haploinsufficiency. rRNA gene transcription is driven by RNA polymerase I (RNPI). We found that CX-5461, an RNPI inhibitor, recapitulated the effect of Spen ablation on tumor vessel normalization, and combining CX-5461 with cisplatin substantially improved the efficacy on treating tumors in mice. Together, these results demonstrate that SPEN is required for angiogenesis by repressing pRNA to enable rRNA gene transcription and ribosomal biogenesis, and that RNPI represents a target for tumor vessel normalization therapy of cancer.
    Keywords:  Cell stress; Endothelial cells; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI159860
  48. Nat Commun. 2023 Aug 19. 14(1): 5052
    Sphagnum increases soil's sequestration capacity of mineral-associated organic carbon via activating metal oxides.
    Yunpeng Zhao, Chengzhu Liu, Xingqi Li, Lixiao Ma, Guoqing Zhai, Xiaojuan Feng.
      Sphagnum wetlands are global hotspots for carbon storage, conventionally attributed to the accumulation of decay-resistant litter. However, the buildup of mineral-associated organic carbon (MAOC) with relatively slow turnover has rarely been examined therein. Here, employing both large-scale comparisons across major terrestrial ecosystems and soil survey along Sphagnum gradients in distinct wetlands, we show that Sphagnum fosters a notable accumulation of metal-bound organic carbon (OC) via activating iron and aluminum (hydr)oxides in the soil. The unique phenolic and acidic metabolites of Sphagnum further strengthen metal-organic associations, leading to the dominance of metal-bound OC in soil MAOC. Importantly, in contrast with limited MAOC sequestration potentials elsewhere, MAOC increases linearly with soil OC accrual without signs of saturation in Sphagnum wetlands. These findings collectively demonstrate that Sphagnum acts as an efficient 'rust engineer' that largely boosts the rusty carbon sink in wetlands, potentially increasing long-term soil carbon sequestration.
    DOI:  https://doi.org/10.1038/s41467-023-40863-0
  49. Nat Commun. 2023 Aug 22. 14(1): 5094
    Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites.
    Alexander Y G Yip, Olivia G King, Oleksii Omelchenko, Sanjana Kurkimat, Victoria Horrocks, Phoebe Mostyn, Nathan Danckert, Rohma Ghani, Giovanni Satta, Elita Jauneikaite, Frances J Davies, Thomas B Clarke, Benjamin H Mullish, Julian R Marchesi, Julie A K McDonald.
      The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Broad-spectrum antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. Here, we show that antibiotic-induced reduction of gut microbial populations leads to an enrichment of nutrients and depletion of inhibitory metabolites, which enhances CRE growth. Antibiotics decrease the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in ex vivo cultures of human faecal microbiota; this is accompanied by depletion of microbial metabolites and enrichment of nutrients. We measure the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several CRE strains. We find that CRE can use the nutrients (enriched after antibiotic treatment) as carbon and nitrogen sources for growth. These nutrients also increase in faeces from antibiotic-treated mice and decrease following intestinal colonisation with carbapenem-resistant Escherichia coli. Furthermore, certain microbial metabolites (depleted upon antibiotic treatment) inhibit CRE growth. Our results show that killing gut commensals with antibiotics facilitates CRE colonisation by enriching nutrients and depleting inhibitory microbial metabolites.
    DOI:  https://doi.org/10.1038/s41467-023-40872-z
  50. Nat Commun. 2023 Aug 23. 14(1): 4863
    Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.
    BioBank Japan Project
      Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.
    DOI:  https://doi.org/10.1038/s41467-023-39858-8
  51. Science. 2023 Aug 25. 381(6660): 851-857
    The gut microbiota reprograms intestinal lipid metabolism through long noncoding RNA Snhg9.
    Yuhao Wang, Meng Wang, Jiaxin Chen, Yun Li, Zheng Kuang, Chaitanya Dende, Prithvi Raj, Gabriella Quinn, Zehan Hu, Tarun Srinivasan, Brian Hassell, Kelly A Ruhn, Cassie L Behrendt, Tingbo Liang, Xiaobing Dou, Zhangfa Song, Lora V Hooper.
      The intestinal microbiota regulates mammalian lipid absorption, metabolism, and storage. We report that the microbiota reprograms intestinal lipid metabolism in mice by repressing the expression of long noncoding RNA (lncRNA) Snhg9 (small nucleolar RNA host gene 9) in small intestinal epithelial cells. Snhg9 suppressed the activity of peroxisome proliferator-activated receptor γ (PPARγ)-a central regulator of lipid metabolism-by dissociating the PPARγ inhibitor sirtuin 1 from cell cycle and apoptosis protein 2 (CCAR2). Forced expression of Snhg9 in the intestinal epithelium of conventional mice impaired lipid absorption, reduced body fat, and protected against diet-induced obesity. The microbiota repressed Snhg9 expression through an immune relay encompassing myeloid cells and group 3 innate lymphoid cells. Our findings thus identify an unanticipated role for a lncRNA in microbial control of host metabolism.
    DOI:  https://doi.org/10.1126/science.ade0522
  52. Nat Commun. 2023 Aug 25. 14(1): 5211
    Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
    Peter Bailey, Rachel A Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D Campbell, Emmanouil Dimonitsas, Alexander J Stratigos, Sarah T Arron, Jun Wang, Karen Blyth, Charlotte M Proby, Catherine A Harwood, Owen J Sansom, Irene M Leigh, Gareth J Inman.
      The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.
    DOI:  https://doi.org/10.1038/s41467-023-40822-9
  53. Science. 2023 Aug 25. 381(6660): 830-831
    Forest carbon offsets are failing.
    Julia P G Jones, Simon L Lewis.
      Analysis reveals emission reductions from forest conservation have been overestimated.
    DOI:  https://doi.org/10.1126/science.adj6951
  54. Nat Commun. 2023 Aug 21. 14(1): 5062
    Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.
    DIRECT Consortium
      We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
    DOI:  https://doi.org/10.1038/s41467-023-40569-3
  55. Nature. 2023 Aug;620(7975): 718-720
    Europe spent €600 million to recreate the human brain in a computer. How did it go?
    Miryam Naddaf.
      
    Keywords:  Brain; Computational biology and bioinformatics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02600-x
  56. Nat Commun. 2023 Aug 25. 14(1): 5204
    In-memory mechanical computing.
    Tie Mei, Chang Qing Chen.
      Mechanical computing requires matter to adapt behavior according to retained knowledge, often through integrated sensing, actuation, and control of deformation. However, inefficient access to mechanical memory and signal propagation limit mechanical computing modules. To overcome this, we developed an in-memory mechanical computing architecture where computing occurs within the interaction network of mechanical memory units. Interactions embedded within data read-write interfaces provided function-complete and neuromorphic computing while reducing data traffic and simplifying data exchange. A reprogrammable mechanical binary neural network and a mechanical self-learning perceptron were demonstrated experimentally in 3D printed mechanical computers, as were all 16 logic gates and truth-table entries that are possible with two inputs and one output. The in-memory mechanical computing architecture enables the design and fabrication of intelligent mechanical systems.
    DOI:  https://doi.org/10.1038/s41467-023-40989-1
  57. Nat Commun. 2023 Aug 19. 14(1): 5053
    CD98hc is a target for brain delivery of biotherapeutics.
    Kylie S Chew, Robert C Wells, Arash Moshkforoush, Darren Chan, Kendra J Lechtenberg, Hai L Tran, Johann Chow, Do Jin Kim, Yaneth Robles-Colmenares, Devendra B Srivastava, Raymond K Tong, Mabel Tong, Kaitlin Xa, Alexander Yang, Yinhan Zhou, Padma Akkapeddi, Lakshman Annamalai, Kaja Bajc, Marie Blanchette, Gerald Maxwell Cherf, Timothy K Earr, Audrey Gill, David Huynh, David Joy, Kristen N Knight, Diana Lac, Amy Wing-Sze Leung, Katrina W Lexa, Nicholas P D Liau, Isabel Becerra, Mario Malfavon, Joseph McInnes, Hoang N Nguyen, Edwin I Lozano, Michelle E Pizzo, Elysia Roche, Patricia Sacayon, Meredith E K Calvert, Richard Daneman, Mark S Dennis, Joseph Duque, Kapil Gadkar, Joseph W Lewcock, Cathal S Mahon, René Meisner, Hilda Solanoy, Robert G Thorne, Ryan J Watts, Y Joy Yu Zuchero, Mihalis S Kariolis.
      Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
    DOI:  https://doi.org/10.1038/s41467-023-40681-4
  58. Aging Cell. 2023 Aug 22. e13962
    Targeted sequencing of the 9p21.3 region reveals association with reduced disease risks in Ashkenazi Jewish centenarians.
    Yizhou Zhu, Seungjin Ryu, Archana Tare, Nir Barzilai, Gil Atzmon, Yousin Suh.
      Genome-wide association studies (GWAS) have pinpointed the chromosomal locus 9p21.3 as a genetic hotspot for various age-related disorders. Common genetic variants in this locus are linked to multiple traits, including coronary artery diseases, cancers, and diabetes. Centenarians are known for their reduced risk and delayed onset of these conditions. To investigate whether this evasion of disease risks involves diminished genetic risks in the 9p21.3 locus, we sequenced this region in an Ashkenazi Jewish centenarian cohort (centenarians: n = 450, healthy controls: n = 500). Risk alleles associated with cancers, glaucoma, CAD, and T2D showed a significant depletion in centenarians. Furthermore, the risk and non-risk genotypes are linked to two distinct low-frequency variant profiles, enriched in controls and centenarians, respectively. Our findings provide evidence that the extreme longevity cohort is associated with collectively lower risks of multiple age-related diseases in the 9p21.3 locus.
    Keywords:  9p21; age-related disease; aging; centenarians; longevity; population genomics
    DOI:  https://doi.org/10.1111/acel.13962
  59. Nat Commun. 2023 Aug 24. 14(1): 5170
    Antibody-mediated NK cell activation as a correlate of immunity against influenza infection.
    Carolyn M Boudreau, John S Burke, Ashraf S Yousif, Maya Sangesland, Sandra Jastrzebski, Chris Verschoor, George Kuchel, Daniel Lingwood, Harry Kleanthous, Iris De Bruijn, Victoria Landolfi, Saranya Sridhar, Galit Alter.
      Antibodies play a critical role in protection against influenza; yet titers and viral neutralization represent incomplete correlates of immunity. Instead, the ability of antibodies to leverage the antiviral power of the innate immune system has been implicated in protection from and clearance of influenza infection. Here, post-hoc analysis of the humoral immune response to influenza is comprehensively profiled in a cohort of vaccinated older adults (65 + ) monitored for influenza infection during the 2012/2013 season in the United States (NCT: 01427309). While robust humoral immune responses arose against the vaccine and circulating strains, influenza-specific antibody effector profiles differed in individuals that later became infected with influenza, who are deficient in NK cell activating antibodies to both hemagglutinin and neuraminidase, compared to individuals who remained uninfected. Furthermore, NK cell activation was strongly associated with the NK cell senescence marker CD57, arguing for the need for selective induction of influenza-specific afucosylated NK activating antibodies in older adults to achieve protection. High dose vaccination, currently used for older adults, was insufficient to generate this NK cell-activating humoral response. Next generation vaccines able to selectively bolster NK cell activating antibodies may be required to achieve protection in the setting of progressively senescent NK cells.
    DOI:  https://doi.org/10.1038/s41467-023-40699-8
  60. Cell. 2023 Aug 14. pii: S0092-8674(23)00850-4. [Epub ahead of print]
    Brain-wide representations of behavior spanning multiple timescales and states in C. elegans.
    Adam A Atanas, Jungsoo Kim, Ziyu Wang, Eric Bueno, McCoy Becker, Di Kang, Jungyeon Park, Talya S Kramer, Flossie K Wan, Saba Baskoylu, Ugur Dag, Elpiniki Kalogeropoulou, Matthew A Gomes, Cassi Estrem, Netta Cohen, Vikash K Mansinghka, Steven W Flavell.
      Changes in an animal's behavior and internal state are accompanied by widespread changes in activity across its brain. However, how neurons across the brain encode behavior and how this is impacted by state is poorly understood. We recorded brain-wide activity and the diverse motor programs of freely moving C. elegans and built probabilistic models that explain how each neuron encodes quantitative behavioral features. By determining the identities of the recorded neurons, we created an atlas of how the defined neuron classes in the C. elegans connectome encode behavior. Many neuron classes have conjunctive representations of multiple behaviors. Moreover, although many neurons encode current motor actions, others integrate recent actions. Changes in behavioral state are accompanied by widespread changes in how neurons encode behavior, and we identify these flexible nodes in the connectome. Our results provide a global map of how the cell types across an animal's brain encode its behavior.
    Keywords:  C. elegans; behavior; brain-wide activity; cell atlas; internal states; neural circuits
    DOI:  https://doi.org/10.1016/j.cell.2023.07.035
  61. Nat Rev Genet. 2023 Aug 24.
    Principles and methods for transferring polygenic risk scores across global populations.
    Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium Methods Working Group
      Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.
    DOI:  https://doi.org/10.1038/s41576-023-00637-2
  62. Nat Commun. 2023 Aug 21. 14(1): 5059
    Author Correction: Demonstration of quantum-digital payments.
    Peter Schiansky, Julia Kalb, Esther Sztatecsny, Marie-Christine Roehsner, Tobias Guggemos, Alessandro Trenti, Mathieu Bozzio, Philip Walther.
      
    DOI:  https://doi.org/10.1038/s41467-023-40866-x
  63. Nat Commun. 2023 Aug 25. 14(1): 5183
    Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing.
    Hsiu-Hui Tsai, Hsiao-Jung Kao, Ming-Wei Kuo, Chin-Hsien Lin, Chun-Min Chang, Yi-Yin Chen, Hsiao-Huei Chen, Pui-Yan Kwok, Alice L Yu, John Yu.
      CRISPR-Cas9 genome editing has promising therapeutic potential for genetic diseases and cancers, but safety could be a concern. Here we use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing and in comparison to four parental cell lines. In addition to the previously reported large structural variants at on-target sites, we identify heretofore unexpected large chromosomal deletions (91.2 and 136 Kb) at atypical non-homologous off-target sites without sequence similarity to the sgRNA in two edited lines. The observed large structural variants induced by CRISPR-Cas9 editing in dividing cells may result in pathogenic consequences and thus limit the usefulness of the CRISPR-Cas9 editing system for disease modeling and gene therapy. In this work, our whole genomic analysis may provide a valuable strategy to ensure genome integrity after genomic editing to minimize the risk of unintended effects in research and clinical applications.
    DOI:  https://doi.org/10.1038/s41467-023-40901-x
  64. Nat Commun. 2023 Aug 24. 14(1): 5149
    Molecular architecture and conservation of an immature human endogenous retrovirus.
    Anna-Sophia Krebs, Hsuan-Fu Liu, Ye Zhou, Juan S Rey, Lev Levintov, Juan Shen, Andrew Howe, Juan R Perilla, Alberto Bartesaghi, Peijun Zhang.
      The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.
    DOI:  https://doi.org/10.1038/s41467-023-40786-w
  65. Nature. 2023 Aug 23.
    The complete sequence of a human Y chromosome.
    Arang Rhie, Sergey Nurk, Monika Cechova, Savannah J Hoyt, Dylan J Taylor, Nicolas Altemose, Paul W Hook, Sergey Koren, Mikko Rautiainen, Ivan A Alexandrov, Jamie Allen, Mobin Asri, Andrey V Bzikadze, Nae-Chyun Chen, Chen-Shan Chin, Mark Diekhans, Paul Flicek, Giulio Formenti, Arkarachai Fungtammasan, Carlos Garcia Giron, Erik Garrison, Ariel Gershman, Jennifer L Gerton, Patrick G S Grady, Andrea Guarracino, Leanne Haggerty, Reza Halabian, Nancy F Hansen, Robert Harris, Gabrielle A Hartley, William T Harvey, Marina Haukness, Jakob Heinz, Thibaut Hourlier, Robert M Hubley, Sarah E Hunt, Stephen Hwang, Miten Jain, Rupesh K Kesharwani, Alexandra P Lewis, Heng Li, Glennis A Logsdon, Julian K Lucas, Wojciech Makalowski, Christopher Markovic, Fergal J Martin, Ann M Mc Cartney, Rajiv C McCoy, Jennifer McDaniel, Brandy M McNulty, Paul Medvedev, Alla Mikheenko, Katherine M Munson, Terence D Murphy, Hugh E Olsen, Nathan D Olson, Luis F Paulin, David Porubsky, Tamara Potapova, Fedor Ryabov, Steven L Salzberg, Michael E G Sauria, Fritz J Sedlazeck, Kishwar Shafin, Valery A Shepelev, Alaina Shumate, Jessica M Storer, Likhitha Surapaneni, Angela M Taravella Oill, Françoise Thibaud-Nissen, Winston Timp, Marta Tomaszkiewicz, Mitchell R Vollger, Brian P Walenz, Allison C Watwood, Matthias H Weissensteiner, Aaron M Wenger, Melissa A Wilson, Samantha Zarate, Yiming Zhu, Justin M Zook, Evan E Eichler, Rachel J O'Neill, Michael C Schatz, Karen H Miga, Kateryna D Makova, Adam M Phillippy.
      The human Y chromosome has been notoriously difficult to sequence and assemble because of its complex repeat structure that includes long palindromes, tandem repeats and segmental duplications1-3. As a result, more than half of the Y chromosome is missing from the GRCh38 reference sequence and it remains the last human chromosome to be finished4,5. Here, the Telomere-to-Telomere (T2T) consortium presents the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference, showing the complete ampliconic structures of gene families TSPY, DAZ and RBMY; 41 additional protein-coding genes, mostly from the TSPY family; and an alternating pattern of human satellite 1 and 3 blocks in the heterochromatic Yq12 region. We have combined T2T-Y with a previous assembly of the CHM13 genome4 and mapped available population variation, clinical variants and functional genomics data to produce a complete and comprehensive reference sequence for all 24 human chromosomes.
    DOI:  https://doi.org/10.1038/s41586-023-06457-y
  66. Nat Chem Biol. 2023 Aug 24.
    Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
    Laura A Hehl, Daniel Horn-Ghetko, J Rajan Prabu, Ronnald Vollrath, D Tung Vu, David A Pérez Berrocal, Monique P C Mulder, Gerbrand J van der Heden van Noort, Brenda A Schulman.
      Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron microscopy (cryo-EM) to visualize stable mimics of the intermediates along K48-linked Ub chain formation by the human E3, UBR5. The structural data reveal a ≈ 620 kDa UBR5 dimer as the functional unit, comprising a scaffold with flexibly tethered Ub-associated (UBA) domains, and elaborately arranged HECT domains. Chains are forged by a UBA domain capturing an acceptor Ub, with its K48 lured into the active site by numerous interactions between the acceptor Ub, manifold UBR5 elements and the donor Ub. The cryo-EM reconstructions allow defining conserved HECT domain conformations catalyzing Ub transfer from E2 to E3 and from E3. Our data show how a full-length E3, ubiquitins to be adjoined, E2 and intermediary products guide a feed-forward HECT domain conformational cycle establishing a highly efficient, broadly targeting, K48-linked Ub chain forging machine.
    DOI:  https://doi.org/10.1038/s41589-023-01414-2
  67. Nat Neurosci. 2023 Aug 24.
    Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model.
    Mehdi Jorfi, Joseph Park, Clare K Hall, Chih-Chung Jerry Lin, Meng Chen, Djuna von Maydell, Jane M Kruskop, Byunghoon Kang, Younjung Choi, Dmitry Prokopenko, Daniel Irimia, Doo Yeon Kim, Rudolph E Tanzi.
      Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.
    DOI:  https://doi.org/10.1038/s41593-023-01415-3
  68. Nat Commun. 2023 Aug 19. 14(1): 5058
    APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants.
    Salvatore Daniele Bianco, Luca Parca, Francesco Petrizzelli, Tommaso Biagini, Agnese Giovannetti, Niccolò Liorni, Alessandro Napoli, Massimo Carella, Vincent Procaccio, Marie T Lott, Shiping Zhang, Angelo Luigi Vescovi, Douglas C Wallace, Viviana Caputo, Tommaso Mazza.
      Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.
    DOI:  https://doi.org/10.1038/s41467-023-40797-7
  69. Science. 2023 Aug 25. 381(6660): 833-834
    Thin jets underlie the solar wind.
    Ignacio Ugarte-Urra, Yi-Ming Wang.
      Solar Orbiter images reveal widespread magnetic plasma jets at the roots of the solar wind.
    DOI:  https://doi.org/10.1126/science.adj8002
  70. Nat Commun. 2023 Aug 25. 14(1): 5203
    Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins.
    Wenzhe Liu, Limin Chen, Dongbao Yin, Zhiheng Yang, Jianfei Feng, Qi Sun, Luhua Lai, Xuefeng Guo.
      Intrinsically disordered proteins (IDPs) play crucial roles in cellular processes and hold promise as drug targets. However, the dynamic nature of IDPs remains poorly understood. Here, we construct a single-molecule electrical nanocircuit based on silicon nanowire field-effect transistors (SiNW-FETs) and functionalize it with an individual disordered c-Myc bHLH-LZ domain to enable label-free, in situ, and long-term measurements at the single-molecule level. We use the device to study c-Myc interaction with Max and/or small molecule inhibitors. We observe the self-folding/unfolding process of c-Myc and reveal its interaction mechanism with Max and inhibitors through ultrasensitive real-time monitoring. We capture a relatively stable encounter intermediate ensemble of c-Myc during its transition from the unbound state to the fully folded state. The c-Myc/Max and c-Myc/inhibitor dissociation constants derived are consistent with other ensemble experiments. These proof-of-concept results provide an understanding of the IDP-binding/folding mechanism and represent a promising nanotechnology for IDP conformation/interaction studies and drug discovery.
    DOI:  https://doi.org/10.1038/s41467-023-41018-x
  71. Nat Commun. 2023 Aug 24. 14(1): 5144
    Zero-shot visual reasoning through probabilistic analogical mapping.
    Taylor Webb, Shuhao Fu, Trevor Bihl, Keith J Holyoak, Hongjing Lu.
      Human reasoning is grounded in an ability to identify highly abstract commonalities governing superficially dissimilar visual inputs. Recent efforts to develop algorithms with this capacity have largely focused on approaches that require extensive direct training on visual reasoning tasks, and yield limited generalization to problems with novel content. In contrast, a long tradition of research in cognitive science has focused on elucidating the computational principles underlying human analogical reasoning; however, this work has generally relied on manually constructed representations. Here we present visiPAM (visual Probabilistic Analogical Mapping), a model of visual reasoning that synthesizes these two approaches. VisiPAM employs learned representations derived directly from naturalistic visual inputs, coupled with a similarity-based mapping operation derived from cognitive theories of human reasoning. We show that without any direct training, visiPAM outperforms a state-of-the-art deep learning model on an analogical mapping task. In addition, visiPAM closely matches the pattern of human performance on a novel task involving mapping of 3D objects across disparate categories.
    DOI:  https://doi.org/10.1038/s41467-023-40804-x
  72. Nat Commun. 2023 Aug 21. 14(1): 5065
    Omicron infection following vaccination enhances a broad spectrum of immune responses dependent on infection history.
    PITCH Consortium
      Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without prior SARS-CoV-2 infection. We find that most individuals increase BA.1/BA.2/BA.5-specific neutralizing antibodies following infection, but confirm that the magnitude of increase and post-omicron titres are higher in the infection-naive. In contrast, significant increases in nasal responses, including neutralizing activity against BA.5 spike, are seen regardless of infection history. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are significantly higher in the previously-infected, who display a maximally induced response with a highly cytotoxic CD8+ phenotype following their 3rd mRNA vaccine dose. Responses to non-spike antigens increase significantly regardless of prior infection status. These findings suggest that hybrid immunity induced by omicron breakthrough infections is characterized by significant immune enhancement that can help protect against future omicron variants.
    DOI:  https://doi.org/10.1038/s41467-023-40592-4
  73. Nat Commun. 2023 Aug 22. 14(1): 5092
    Convergent somatic evolution commences in utero in a germline ribosomopathy.
    Heather E Machado, Nina F Øbro, Nicholas Williams, Shengjiang Tan, Ahmed Z Boukerrou, Megan Davies, Miriam Belmonte, Emily Mitchell, E Joanna Baxter, Nicole Mende, Anna Clay, Philip Ancliff, Jutta Köglmeier, Sally B Killick, Austin Kulasekararaj, Stefan Meyer, Elisa Laurenti, Peter J Campbell, David G Kent, Jyoti Nangalia, Alan J Warren.
      Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
    DOI:  https://doi.org/10.1038/s41467-023-40896-5
  74. JCI Insight. 2023 Aug 22. pii: e168102. [Epub ahead of print]8(16):
    Prior cycles of anti-CD20 antibodies affect antibody responses after repeated SARS-CoV-2 mRNA vaccination.
    Hiromitsu Asashima, Dongjoo Kim, Kaicheng Wang, Nikhil Lele, Nicholas C Buitrago-Pocasangre, Rachel Lutz, Isabella Cruz, Khadir Raddassi, William E Ruff, Michael K Racke, JoDell E Wilson, Tara S Givens, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Steven H Kleinstein, Ruth R Montgomery, Albert C Shaw, Fangyong Li, Rong Fan, David A Hafler, Mary M Tomayko, Erin E Longbrake.
      BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).
    Keywords:  Autoimmune diseases; Autoimmunity; COVID-19; Multiple sclerosis
    DOI:  https://doi.org/10.1172/jci.insight.168102
  75. JCI Insight. 2023 Aug 22. pii: e166386. [Epub ahead of print]8(16):
    Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity.
    Jeeyeon Cha, Xin Tong, Emily M Walker, Tehila Dahan, Veronica A Cochrane, Sudipta Ashe, Ronan Russell, Anna B Osipovich, Alex M Mawla, Min Guo, Jin-Hua Liu, Zachary A Loyd, Mark O Huising, Mark A Magnuson, Matthias Hebrok, Yuval Dor, Roland Stein.
      Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell-enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin+ (Gast+) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST+ gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non-β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.
    Keywords:  Beta cells; Cell Biology; Diabetes; Endocrinology; Islet cells
    DOI:  https://doi.org/10.1172/jci.insight.166386
  76. Diabetes. 2023 Aug 25. pii: db230317. [Epub ahead of print]
    Inhibiting phosphatidylcholine remodeling in adipose tissue increases insulin sensitivity.
    Mulin He, Zhiqiang Li, Victoria Sook Keng Tung, Meixia Pan, Xianlin Han, Oleg Evgrafov, Xian-Cheng Jiang.
      Cell membrane phosphatidylcholine composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane phosphatidylcholine saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissues and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated phosphatidylcholines in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissues from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated phosphatidylcholines to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissues to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.
    DOI:  https://doi.org/10.2337/db23-0317
  77. Nature. 2023 Aug;620(7976): 954-955
    Brain implants that enable speech pass performance milestones.
    Nick F Ramsey, Nathan E Crone.
      
    Keywords:  Engineering; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02546-0
  78. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  79. Nat Commun. 2023 Aug 24. 14(1): 5165
    Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons.
    Dalia Halawani, Yiqun Wang, Aarthi Ramakrishnan, Molly Estill, Xijing He, Li Shen, Roland H Friedel, Hongyan Zou.
      Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.
    DOI:  https://doi.org/10.1038/s41467-023-40816-7
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