bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒05‒21
sixty-six papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.
  2. The power of outreach.
  3. The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain.
  4. DNA methylation markers for kidney function and progression of diabetic kidney disease.
  5. People.
  6. Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
  7. Subtle cell states resolved in single-cell data.
  8. Dissecting the functional organization of the C. elegans serotonergic system at whole-brain scale.
  9. Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.
  10. Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.
  11. Top Reads.
  12. Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice.
  13. Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage.
  14. Epigenetic landscape reveals MECOM as an endothelial lineage regulator.
  15. Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases.
  16. Lab-grown monkey embryos reveal in 3D how organs begin.
  17. Single cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils.
  18. An in vivo neuroimmune organoid model to study human microglia phenotypes.
  19. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.
  20. Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
  21. Lactate fuels mitosis.
  22. Microbiota-assisted iron uptake promotes immune tolerance in the intestine.
  23. GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy.
  24. Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.
  25. Spatially resolved epigenomic profiling of single cells in complex tissues.
  26. Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
  27. How one man's rare Alzheimer's mutation delayed the onset of disease.
  28. Annotating and prioritizing human non-coding variants with RegulomeDB v.2.
  29. m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.
  30. Selection by essential-gene exon knock-in for the generation of efficient cell therapies.
  31. High-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq.
  32. Quantifying tRNA abundance by sequencing.
  33. LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
  34. Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer's disease.
  35. Brain imaging: fMRI advances make scans sharper and faster.
  36. Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification.
  37. Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.
  38. Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex.
  39. Herpes simplex virus protein UL56 inhibits cGAS-Mediated DNA sensing to evade antiviral immunity.
  40. Muscle fusogens go viral for gene delivery to skeletal muscle.
  41. Conserved stromal-immune cell circuits secure B cell homeostasis and function.
  42. Nonnutritive sweeteners and glucose intolerance: Where do we go from here?
  43. Asymmetric conformations of cleaved HIV-1 envelope glycoprotein trimers in styrene-maleic acid lipid nanoparticles.
  44. Home-site advantage for host species-specific gut microbiota.
  45. Single-cell expression profiling of islets generated by the Human Pancreas Analysis Program.
  46. Cellular population dynamics shape the route to human pluripotency.
  47. Engineered allostery in light-regulated LOV-Turbo enables precise spatiotemporal control of proximity labeling in living cells.
  48. Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease.
  49. Uridine-derived ribose fuels glucose-restricted pancreatic cancer.
  50. Evolution of antibody immunity following Omicron BA.1 breakthrough infection.
  51. Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.
  52. SIRT2 regulates extracellular vesicle-mediated liver-bone communication.
  53. Immune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer.
  54. Human genomic 'bycatch' threatens privacy.
  55. Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis.
  56. Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
  57. Sites of transcription initiation drive mRNA isoform selection.
  58. Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer's disease.
  59. Cytolytic CD8+ T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes.
  60. Hexokinases in cancer and other pathologies.
  61. Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis.
  62. Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine.
  63. Multi-omics delineation of cytokine-induced endothelial inflammatory states.
  64. SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis.
  65. Oldest known 'blueprints' aided human hunters 9,000 years ago.
  66. Single-frame deep-learning super-resolution microscopy for intracellular dynamics imaging.
  1. Nat Commun. 2023 May 16. 14(1): 2803
    A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.
    Kimberly C Paul, Richard C Krolewski, Edinson Lucumi Moreno, Jack Blank, Kristina M Holton, Tim Ahfeldt, Melissa Furlong, Yu Yu, Myles Cockburn, Laura K Thompson, Alexander Kreymerman, Elisabeth M Ricci-Blair, Yu Jun Li, Heer B Patel, Richard T Lee, Jeff Bronstein, Lee L Rubin, Vikram Khurana, Beate Ritz.
      Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.
    DOI:  https://doi.org/10.1038/s41467-023-38215-z
  2. Science. 2023 May 19. 380(6646): 766
    The power of outreach.
    Claudia Fracchiolla.
      
    DOI:  https://doi.org/10.1126/science.adi7066
  3. Nat Commun. 2023 May 17. 14(1): 2833
    The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain.
    Conny Leistner, Martin Wilkinson, Ailidh Burgess, Megan Lovatt, Stanley Goodbody, Yong Xu, Susan Deuchars, Sheena E Radford, Neil A Ranson, René A W Frank.
      Amyloid plaques composed of Aβ fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the in situ molecular architecture of Aβ fibrils in the AppNL-G-F familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic Aβ fibrils. We show that in-tissue Aβ fibrils are arranged in a lattice or parallel bundles, and are interdigitated by subcellular compartments, extracellular vesicles, extracellular droplets and extracellular multilamellar bodies. The Arctic Aβ fibril differs significantly from an earlier AppNL-F fibril structure, indicating a striking effect of the Arctic mutation. These structural data also revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises β-amyloid plaque pathology.
    DOI:  https://doi.org/10.1038/s41467-023-38495-5
  4. Nat Commun. 2023 May 15. 14(1): 2543
    DNA methylation markers for kidney function and progression of diabetic kidney disease.
    TRANSCEND Consortium
      Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation markers associated with baseline estimated glomerular filtration rate (eGFR) and subsequent decline in kidney function (eGFR slope), respectively, in 1,271 type 2 diabetes subjects. Here we show 40 (30 previously unidentified) and eight (all previously unidentified) CpG sites individually reach epigenome-wide significance for baseline eGFR and eGFR slope, respectively. We also develop a multisite analysis method, which selects 64 and 37 CpG sites for baseline eGFR and eGFR slope, respectively. These models are validated in an independent cohort of Native Americans with type 2 diabetes. Our identified CpG sites are near genes enriched for functional roles in kidney diseases, and some show association with renal damage. This study highlights the potential of methylation markers in risk stratification of kidney disease among type 2 diabetes individuals.
    DOI:  https://doi.org/10.1038/s41467-023-37837-7
  5. Nat Biotechnol. 2023 May;41(5): 734
    People.
      
    DOI:  https://doi.org/10.1038/s41587-023-01785-w
  6. Sci Transl Med. 2023 May 17. 15(696): eade6509
    Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
    Tanes I Lima, Pirkka-Pekka Laurila, Martin Wohlwend, Jean David Morel, Ludger J E Goeminne, Hao Li, Mario Romani, Xiaoxu Li, Chang-Myung Oh, Dohyun Park, Sandra Rodríguez-López, Julijana Ivanisevic, Hector Gallart-Ayala, Barbara Crisol, Florence Delort, Sabrina Batonnet-Pichon, Leonardo R Silveira, Lakshmi Sankabattula Pavani Veera Venkata, Anil K Padala, Suresh Jain, Johan Auwerx.
      Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.
    DOI:  https://doi.org/10.1126/scitranslmed.ade6509
  7. Nat Biotechnol. 2023 May 17.
    Subtle cell states resolved in single-cell data.
    Caleb Lareau.
      
    DOI:  https://doi.org/10.1038/s41587-023-01797-6
  8. Cell. 2023 May 10. pii: S0092-8674(23)00419-1. [Epub ahead of print]
    Dissecting the functional organization of the C. elegans serotonergic system at whole-brain scale.
    Ugur Dag, Ijeoma Nwabudike, Di Kang, Matthew A Gomes, Jungsoo Kim, Adam A Atanas, Eric Bueno, Cassi Estrem, Sarah Pugliese, Ziyu Wang, Emma Towlson, Steven W Flavell.
      Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. Comprehensive genetic analyses identify three core serotonin receptors (MOD-1, SER-4, and LGC-50) that induce slow locomotion upon serotonin release and others (SER-1, SER-5, and SER-7) that interact with them to modulate this behavior. SER-4 induces behavioral responses to sudden increases in serotonin release, whereas MOD-1 induces responses to persistent release. Whole-brain imaging reveals widespread serotonin-associated brain dynamics, spanning many behavioral networks. We map all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict which neurons show serotonin-associated activity. These results reveal how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.
    Keywords:  C. elegans; behavior; brain-wide activity; neuromodulation; serotonin
    DOI:  https://doi.org/10.1016/j.cell.2023.04.023
  9. Nat Commun. 2023 May 13. 14(1): 2754
    Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes.
    Hyuek Jong Lee, Jueun Lee, Myung Jin Yang, Young-Chan Kim, Seon Pyo Hong, Jung Mo Kim, Geum-Sook Hwang, Gou Young Koh.
      Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.
    DOI:  https://doi.org/10.1038/s41467-023-38433-5
  10. Cell. 2023 May 11. pii: S0092-8674(23)00422-1. [Epub ahead of print]
    Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.
    Junbing Zhang, Claire M Simpson, Jacqueline Berner, Harrison B Chong, Jiafeng Fang, Zehra Ordulu, Tommy Weiss-Sadan, Anthony P Possemato, Stefan Harry, Mariko Takahashi, Tzu-Yi Yang, Marianne Richter, Himani Patel, Abby E Smith, Alexander D Carlin, Adriaan F Hubertus de Groot, Konstantin Wolf, Lei Shi, Ting-Yu Wei, Benedikt R Dürr, Nicholas J Chen, Tristan Vornbäumen, Nina O Wichmann, Mohammed S Mahamdeh, Venkatesh Pooladanda, Yusuke Matoba, Shaan Kumar, Eugene Kim, Sara Bouberhan, Esther Oliva, Bo R Rueda, Roy J Soberman, Nabeel Bardeesy, Brian B Liau, Michael Lawrence, Matt P Stokes, Sean A Beausoleil, Liron Bar-Peled.
      Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.
    Keywords:  CHK1; chemical proteomics; chemoresistance; mitochondrial translation; nuclear ROS; nucleus-to-mitochondria signaling
    DOI:  https://doi.org/10.1016/j.cell.2023.04.026
  11. J Immunol. 2023 Jun 01. 210(11): 1625
    Top Reads.
      
    DOI:  https://doi.org/10.4049/jimmunol.2390008
  12. Nat Commun. 2023 May 12. 14(1): 2748
    Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice.
    Samuel A Druzak, Matteo Tardelli, Suzanne G Mays, Mireille El Bejjani, Xulie Mo, Kristal M Maner-Smith, Thomas Bowen, Michael L Cato, Matthew C Tillman, Akiko Sugiyama, Yang Xie, Haian Fu, David E Cohen, Eric A Ortlund.
      Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp-/-) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP- PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP- PPARδ interaction that suppresses PPAR activity.
    DOI:  https://doi.org/10.1038/s41467-023-38010-w
  13. Nat Commun. 2023 May 15. 14(1): 2782
    Structural basis for breadth development in the HIV-1 V3-glycan targeting DH270 antibody clonal lineage.
    Rory Henderson, Ye Zhou, Victoria Stalls, Kevin Wiehe, Kevin O Saunders, Kshitij Wagh, Kara Anasti, Maggie Barr, Robert Parks, S Munir Alam, Bette Korber, Barton F Haynes, Alberto Bartesaghi, Priyamvada Acharya.
      Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza has therefore focused on recapitulating the natural affinity maturation process. Here, we determine structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of the broadly neutralizing HIV-1 V3-glycan targeting DH270 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination.
    DOI:  https://doi.org/10.1038/s41467-023-38108-1
  14. Nat Commun. 2023 Apr 25. 14(1): 2390
    Epigenetic landscape reveals MECOM as an endothelial lineage regulator.
    Jie Lv, Shu Meng, Qilin Gu, Rongbin Zheng, Xinlei Gao, Jun-Dae Kim, Min Chen, Bo Xia, Yihan Zuo, Sen Zhu, Dongyu Zhao, Yanqiang Li, Guangyu Wang, Xin Wang, Qingshu Meng, Qi Cao, John P Cooke, Longhou Fang, Kaifu Chen, Lili Zhang.
      A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.
    DOI:  https://doi.org/10.1038/s41467-023-38002-w
  15. Cell. 2023 May 11. pii: S0092-8674(23)00333-1. [Epub ahead of print]186(10): 2144-2159.e22
    Bat ASC2 suppresses inflammasomes and ameliorates inflammatory diseases.
    Matae Ahn, Vivian Chih-Wei Chen, Pritisha Rozario, Wei Lun Ng, Pui San Kong, Wan Rong Sia, Adrian Eng Zheng Kang, Qi Su, Lan Huong Nguyen, Feng Zhu, Wharton O Y Chan, Chee Wah Tan, Wan Shoo Cheong, Ying Ying Hey, Randy Foo, Fusheng Guo, Yan Ting Lim, Xin Li, Wan Ni Chia, Radoslaw M Sobota, Nai Yang Fu, Aaron T Irving, Lin-Fa Wang.
      Bats are special in their ability to live long and host many emerging viruses. Our previous studies showed that bats have altered inflammasomes, which are central players in aging and infection. However, the role of inflammasome signaling in combating inflammatory diseases remains poorly understood. Here, we report bat ASC2 as a potent negative regulator of inflammasomes. Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes. Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles. Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection. Importantly, it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation. Four key residues were identified for the gain of function of bat ASC2. Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.
    Keywords:  COVID-19; SARS-CoV-2; bats; disease resistance; immune complex; inflammasome; inflammation; inflammatory diseases; longevity; viral reservoir
    DOI:  https://doi.org/10.1016/j.cell.2023.03.036
  16. Nature. 2023 May 11.
    Lab-grown monkey embryos reveal in 3D how organs begin.
    Gemma Conroy.
      
    Keywords:  Biological techniques; Developmental biology
    DOI:  https://doi.org/10.1038/d41586-023-01544-6
  17. Nat Commun. 2023 May 18. 14(1): 2694
    Single cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils.
    Kensuke Miyake, Junya Ito, Jun Nakabayashi, Shigeyuki Shichino, Kenji Ishiwata, Hajime Karasuyama.
      Basophils are the rarest granulocytes and are recognized as critical cells for type 2 immune responses. However, their differentiation pathway remains to be fully elucidated. Here, we assess the ontogenetic trajectory of basophils by single-cell RNA sequence analysis. Combined with flow cytometric and functional analyses, we identify c-Kit-CLEC12Ahi pre-basophils located downstream of pre-basophil and mast cell progenitors (pre-BMPs) and upstream of CLEC12Alo mature basophils. The transcriptomic analysis predicts that the pre-basophil population includes previously-defined basophil progenitor (BaP)-like cells in terms of gene expression profile. Pre-basophils are highly proliferative and respond better to non-IgE stimuli but less to antigen plus IgE stimulation than do mature basophils. Although pre-basophils usually remain in the bone marrow, they emerge in helminth-infected tissues, probably through IL-3-mediated inhibition of their retention in the bone marrow. Thus, the present study identifies pre-basophils that bridge the gap between pre-BMPs and mature basophils during basophil ontogeny.
    DOI:  https://doi.org/10.1038/s41467-023-38356-1
  18. Cell. 2023 May 11. pii: S0092-8674(23)00418-X. [Epub ahead of print]186(10): 2111-2126.e20
    An in vivo neuroimmune organoid model to study human microglia phenotypes.
    Simon T Schafer, Abed AlFatah Mansour, Johannes C M Schlachetzki, Monique Pena, Saeed Ghassemzadeh, Lisa Mitchell, Amanda Mar, Daphne Quang, Sarah Stumpf, Irene Santisteban Ortiz, Addison J Lana, Clara Baek, Raghad Zaghal, Christopher K Glass, Axel Nimmerjahn, Fred H Gage.
      Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
    Keywords:  Human microglia; autism spectrum disorders; brain organoids; iPSCs; microglia in vivo identity; microglia surveillance; neuro-immune interactions; organoid transplantation; xenotransplantation
    DOI:  https://doi.org/10.1016/j.cell.2023.04.022
  19. Nature. 2023 May 17.
    Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.
    Nobuhiko Kayagaki, Irma B Stowe, Kamela Alegre, Ishan Deshpande, Shuang Wu, Zhonghua Lin, Opher S Kornfeld, Bettina L Lee, Juan Zhang, John Liu, Eric Suto, Wyne P Lee, Kellen Schneider, WeiYu Lin, Dhaya Seshasayee, Tushar Bhangale, Cecile Chalouni, Matthew C Johnson, Prajakta Joshi, Jan Mossemann, Sarah Zhao, Danish Ali, Neil M Goldenberg, Blayne A Sayed, Benjamin E Steinberg, Kim Newton, Joshua D Webster, Ryan L Kelly, Vishva M Dixit.
      Plasma membrane rupture (PMR) in dying cells undergoing pyroptosis or apoptosis requires the cell-surface protein NINJ11. PMR releases proinflammatory cytoplasmic molecules, collectively called damage-associated molecular patterns (DAMPs), that activate immune cells. Therefore, inhibiting NINJ1 and PMR may limit the inflammation that is associated with excessive cell death. Here we describe an anti-NINJ1 monoclonal antibody, specifically targeting murine NINJ1, that blocks oligomerization of NINJ1 and prevents PMR. By electron microscopy, this antibody prevented NINJ1 from forming oligomeric filaments. In mice, inhibition of NINJ1 or Ninj1 deficiency ameliorated hepatocellular PMR induced with TNF plus D-Galactosamine, concanavalin A, Jo2 anti-Fas agonist antibody, or ischemia-reperfusion injury (IRI). Accordingly, serum levels of lactate dehydrogenase (LDH), liver enzymes alanine aminotransaminase (ALT) and aspartate aminotransferase (AST), and DAMPs interleukin 18 (IL-18) and HMGB1 were reduced. Moreover, in the liver IRI model, there was an attendant reduction in neutrophil infiltration. These data indicate that NINJ1 mediates PMR and inflammation in diseases driven by aberrant hepatocellular death.
    DOI:  https://doi.org/10.1038/s41586-023-06191-5
  20. Nat Metab. 2023 May 15.
    Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
    Linyu Ran, Song Zhang, Guosheng Wang, Pei Zhao, Jiaxing Sun, Jiaqi Zhou, Haiyun Gan, Ryounghoon Jeon, Qiang Li, Joerg Herrmann, Feilong Wang.
      Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.
    DOI:  https://doi.org/10.1038/s42255-023-00800-3
  21. Mol Cell. 2023 May 18. pii: S1097-2765(23)00284-8. [Epub ahead of print]83(10): 1549-1551
    Lactate fuels mitosis.
    Xiaoming Dai, Wenyi Wei.
      Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al.1 reveal that glycolysis end-product lactate directly binds and inhibits the SUMO protease SENP1 to govern the E3 ligase activity of the anaphase-promoting complex, leading to efficient mitotic exit in proliferative cells.
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.013
  22. Nat Commun. 2023 May 15. 14(1): 2790
    Microbiota-assisted iron uptake promotes immune tolerance in the intestine.
    Lizhen Zhu, Geng Li, Zhixin Liang, Tuan Qi, Kui Deng, Jiancheng Yu, Yue Peng, Jusheng Zheng, Yan Song, Xing Chang.
      Iron deficiencies are the most common nonenteric syndromes observed in patients with inflammatory bowel disease, but little is known about their impacts on immune tolerance. Here we show that homeostasis of regulatory T cells in the intestine was dependent on high cellular iron levels, which were fostered by pentanoate, a short-chain fatty acid produced by intestinal microbiota. Iron deficiencies in Treg caused by the depletion of Transferrin receptor 1, a major iron transporter, result in the abrogation of Treg in the intestine and lethal autoimmune disease. Transferrin receptor 1 is required for differentiation of c-Maf+ Treg, major constituents of intestinal Treg. Mechanistically, iron enhances the translation of HIF-2α mRNA, and HIF-2α in turn induces c-Maf expression. Importantly, microbiota-produced pentanoate promotes iron uptake and Treg differentiation in the intestine. This subsequently restores immune tolerance and ameliorated iron deficiencies in mice with colitis. Our results thus reveal an association between nutrient uptake and immune tolerance in the intestine.
    DOI:  https://doi.org/10.1038/s41467-023-38444-2
  23. Nat Commun. 2023 May 15. 14(1): 2776
    GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy.
    Lisa N Kasiewicz, Souvik Biswas, Aaron Beach, Huilan Ren, Chaitali Dutta, Anne Marie Mazzola, Ellen Rohde, Alexandra Chadwick, Christopher Cheng, Sara P Garcia, Sowmya Iyer, Yuri Matsumoto, Amit V Khera, Kiran Musunuru, Sekar Kathiresan, Padma Malyala, Kallanthottathil G Rajeev, Andrew M Bellinger.
      Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.
    DOI:  https://doi.org/10.1038/s41467-023-37465-1
  24. Nat Commun. 2023 May 15. 14(1): 2779
    Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.
    Luis Filipe Costa-Machado, Esther Garcia-Dominguez, Rebecca L McIntyre, Jose Luis Lopez-Aceituno, Álvaro Ballesteros-Gonzalez, Andrea Tapia-Gonzalez, David Fabregat-Safont, Tobias Eisenberg, Jesús Gomez, Adrian Plaza, Aranzazu Sierra-Ramirez, Manuel Perez, David Villanueva-Bermejo, Tiziana Fornari, María Isabel Loza, Gonzalo Herradon, Sebastian J Hofer, Christoph Magnes, Frank Madeo, Janet S Duerr, Oscar J Pozo, Maximo-Ibo Galindo, Isabel Del Pino, Riekelt H Houtkooper, Diego Megias, Jose Viña, Mari Carmen Gomez-Cabrera, Pablo J Fernandez-Marcos.
      Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood-brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.
    DOI:  https://doi.org/10.1038/s41467-023-38410-y
  25. Cell. 2023 May 11. pii: S0092-8674(23)00402-6. [Epub ahead of print]186(10): 2275-2279
    Spatially resolved epigenomic profiling of single cells in complex tissues.
    Tian Lu, Cheen Euong Ang, Xiaowei Zhuang.
      
    DOI:  https://doi.org/10.1016/j.cell.2023.04.006
  26. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2220684120
    Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
    Wenqiang Chen, Qian Huang, Ekaterina Katie Lazdon, Antonio Gomes, Marisa Wong, Emily Stephens, Tabitha Grace Royal, Dan Frenkel, Weikang Cai, C Ronald Kahn.
      Brain insulin signaling controls peripheral energy metabolism and plays a key role in the regulation of mood and cognition. Epidemiological studies have indicated a strong connection between type 2 diabetes (T2D) and neurodegenerative disorders, especially Alzheimer's disease (AD), linked via dysregulation of insulin signaling, i.e., insulin resistance. While most studies have focused on neurons, here, we aim to understand the role of insulin signaling in astrocytes, a glial cell type highly implicated in AD pathology and AD progression. To this end, we created a mouse model by crossing 5xFAD transgenic mice, a well-recognized AD mouse model that expresses five familial AD mutations, with mice carrying a selective, inducible insulin receptor (IR) knockout in astrocytes (iGIRKO). We show that by age 6 mo, iGIRKO/5xFAD mice exhibited greater alterations in nesting, Y-maze performance, and fear response than those of mice with the 5xFAD transgenes alone. This was associated with increased Tau (T231) phosphorylation, increased Aβ plaque size, and increased association of astrocytes with plaques in the cerebral cortex as assessed using tissue CLARITY of the brain in the iGIRKO/5xFAD mice. Mechanistically, in vitro knockout of IR in primary astrocytes resulted in loss of insulin signaling, reduced ATP production and glycolic capacity, and impaired Aβ uptake both in the basal and insulin-stimulated states. Thus, insulin signaling in astrocytes plays an important role in the control of Aβ uptake, thereby contributing to AD pathology, and highlighting the potential importance of targeting insulin signaling in astrocytes as a site for therapeutics for patients with T2D and AD.
    Keywords:  Alzheimer’s disease; astrocytes; diabetes; insulin resistance; neurons
    DOI:  https://doi.org/10.1073/pnas.2220684120
  27. Nature. 2023 May 15.
    How one man's rare Alzheimer's mutation delayed the onset of disease.
    Sara Reardon.
      
    Keywords:  Brain; Genetics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-01610-z
  28. Nat Genet. 2023 05;55(5): 724-726
    Annotating and prioritizing human non-coding variants with RegulomeDB v.2.
    Shengcheng Dong, Nanxiang Zhao, Emma Spragins, Meenakshi S Kagda, Mingjie Li, Pedro Assis, Otto Jolanki, Yunhai Luo, J Michael Cherry, Alan P Boyle, Benjamin C Hitz.
      
    DOI:  https://doi.org/10.1038/s41588-023-01365-3
  29. Nat Metab. 2023 May 15.
    m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice.
    Shiguan Wang, Shanze Chen, Jianfeng Sun, Pan Han, Bowen Xu, Xinying Li, Youquan Zhong, Zaichao Xu, Peng Zhang, Ping Mi, Cuijuan Zhang, Lixiang Li, Haiyan Zhang, Yuchen Xia, Shiyang Li, Mathias Heikenwalder, Detian Yuan.
      Different organs undergo distinct transcriptional, epigenetic and physiological alterations that guarantee their functional maturation after birth. However, the roles of epitranscriptomic machineries in these processes have remained elusive. Here we demonstrate that expression of RNA methyltransferase enzymes Mettl3 and Mettl14 gradually declines during postnatal liver development in male mice. Liver-specific Mettl3 deficiency causes hepatocyte hypertrophy, liver injury and growth retardation. Transcriptomic and N6-methyl-adenosine (m6A) profiling identify the neutral sphingomyelinase, Smpd3, as a target of Mettl3. Decreased decay of Smpd3 transcripts due to Mettl3 deficiency results in sphingolipid metabolism rewiring, characterized by toxic ceramide accumulation and leading to mitochondrial damage and elevated endoplasmic reticulum stress. Pharmacological Smpd3 inhibition, Smpd3 knockdown or Sgms1 overexpression that counteracts Smpd3 can ameliorate the abnormality of Mettl3-deficent liver. Our findings demonstrate that Mettl3-N6-methyl-adenosine fine-tunes sphingolipid metabolism, highlighting the pivotal role of an epitranscriptomic machinery in coordination of organ growth and the timing of functional maturation during postnatal liver development.
    DOI:  https://doi.org/10.1038/s42255-023-00808-9
  30. Nat Biotechnol. 2023 May 17.
    Selection by essential-gene exon knock-in for the generation of efficient cell therapies.
      
    DOI:  https://doi.org/10.1038/s41587-023-01819-3
  31. Nat Commun. 2023 May 12. 14(1): 2734
    High-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq.
    Ziye Xu, Tianyu Zhang, Hongyu Chen, Yuyi Zhu, Yuexiao Lv, Shunji Zhang, Jiaye Chen, Haide Chen, Lili Yang, Weiqin Jiang, Shengyu Ni, Fangru Lu, Zhaolun Wang, Hao Yang, Ling Dong, Feng Chen, Hong Zhang, Yu Chen, Jiong Liu, Dandan Zhang, Longjiang Fan, Guoji Guo, Yongcheng Wang.
      Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank for clinical history and follow-up data. It is still challenging to achieve single cell/nucleus RNA (sc/snRNA) profile in FFPE tissues. Here, we develop a droplet-based snRNA sequencing technology (snRandom-seq) for FFPE tissues by capturing full-length total RNAs with random primers. snRandom-seq shows a minor doublet rate (0.3%), a much higher RNA coverage, and detects more non-coding RNAs and nascent RNAs, compared with state-of-art high-throughput scRNA-seq technologies. snRandom-seq detects a median of >3000 genes per nucleus and identifies 25 typical cell types. Moreover, we apply snRandom-seq on a clinical FFPE human liver cancer specimen and reveal an interesting subpopulation of nuclei with high proliferative activity. Our method provides a powerful snRNA-seq platform for clinical FFPE specimens and promises enormous applications in biomedical research.
    DOI:  https://doi.org/10.1038/s41467-023-38409-5
  32. Nat Genet. 2023 05;55(5): 727
    Quantifying tRNA abundance by sequencing.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-023-01404-z
  33. Mol Cell. 2023 May 02. pii: S1097-2765(23)00288-5. [Epub ahead of print]
    LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
    Shelby E Compton, Susan M Kitchen-Goosen, Lisa M DeCamp, Kin H Lau, Batsirai Mabvakure, Matthew Vos, Kelsey S Williams, Kwok-Kin Wong, Xiaobing Shi, Scott B Rothbart, Connie M Krawczyk, Russell G Jones.
      Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.
    Keywords:  CREB; CREB-regulated transcription coactivator 2; CRTC2; H3K27; IL-1β; IL-6; LIF; LKB1; SIKs; cAMP response element binding protein; histone acetylation; inflammation; interleukin-6; leukemia inhibitory factor; liver kinase B1; salt-inducible kinases
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.017
  34. Nat Commun. 2023 May 12. 14(1): 2747
    Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer's disease.
    Zhi Huang, Gennifer E Merrihew, Eric B Larson, Jea Park, Deanna Plubell, Edward J Fox, Kathleen S Montine, Caitlin S Latimer, C Dirk Keene, James Y Zou, Michael J MacCoss, Thomas J Montine.
      Resilience to Alzheimer's disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer's disease and 20 Alzheimer's disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer's disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer's disease continuum. The molecular basis of resilience likely holds important therapeutic insights.
    DOI:  https://doi.org/10.1038/s41467-023-38376-x
  35. Nature. 2023 May;617(7961): 640-642
    Brain imaging: fMRI advances make scans sharper and faster.
    Diana Kwon.
      
    Keywords:  Brain; Imaging; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-01616-7
  36. Nat Cell Biol. 2023 May 15.
    Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification.
    Punn Augsornworawat, Nathaniel J Hogrebe, Matthew Ishahak, Mason D Schmidt, Erica Marquez, Marlie M Maestas, Daniel A Veronese-Paniagua, Sarah E Gale, Julia R Miller, Leonardo Velazco-Cruz, Jeffrey R Millman.
      Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.
    DOI:  https://doi.org/10.1038/s41556-023-01150-8
  37. Nat Commun. 2023 May 15. 14(1): 2784
    Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.
    Liam McAllan, Damir Baranasic, Sergio Villicaña, Scarlett Brown, Weihua Zhang, Benjamin Lehne, Marco Adamo, Andrew Jenkinson, Mohamed Elkalaawy, Borzoueh Mohammadi, Majid Hashemi, Nadia Fernandes, Nathalie Lambie, Richard Williams, Colette Christiansen, Youwen Yang, Liudmila Zudina, Vasiliki Lagou, Sili Tan, Juan Castillo-Fernandez, James W D King, Richie Soong, Paul Elliott, James Scott, Inga Prokopenko, Inês Cebola, Marie Loh, Boris Lenhard, Rachel L Batterham, Jordana T Bell, John C Chambers, Jaspal S Kooner, William R Scott.
      DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.
    DOI:  https://doi.org/10.1038/s41467-023-38439-z
  38. Nat Commun. 2023 May 15. 14(1): 2783
    Structural insights into cardiolipin replacement by phosphatidylglycerol in a cardiolipin-lacking yeast respiratory supercomplex.
    Corey F Hryc, Venkata K P S Mallampalli, Evgeniy I Bovshik, Stavros Azinas, Guizhen Fan, Irina I Serysheva, Genevieve C Sparagna, Matthew L Baker, Eugenia Mileykovskaya, William Dowhan.
      Cardiolipin is a hallmark phospholipid of mitochondrial membranes. Despite established significance of cardiolipin in supporting respiratory supercomplex organization, a mechanistic understanding of this lipid-protein interaction is still lacking. To address the essential role of cardiolipin in supercomplex organization, we report cryo-EM structures of a wild type supercomplex (IV1III2IV1) and a supercomplex (III2IV1) isolated from a cardiolipin-lacking Saccharomyces cerevisiae mutant at 3.2-Å and 3.3-Å resolution, respectively, and demonstrate that phosphatidylglycerol in III2IV1 occupies similar positions as cardiolipin in IV1III2IV1. Lipid-protein interactions within these complexes differ, which conceivably underlies the reduced level of IV1III2IV1 and high levels of III2IV1 and free III2 and IV in mutant mitochondria. Here we show that anionic phospholipids interact with positive amino acids and appear to nucleate a phospholipid domain at the interface between the individual complexes, which dampen charge repulsion and further stabilize interaction, respectively, between individual complexes.
    DOI:  https://doi.org/10.1038/s41467-023-38441-5
  39. Cell Insight. 2022 Apr;1(2): 100014
    Herpes simplex virus protein UL56 inhibits cGAS-Mediated DNA sensing to evade antiviral immunity.
    Zhou-Qin Zheng, Yu-Zhi Fu, Su-Yun Wang, Zhi-Sheng Xu, Hong-Mei Zou, Yan-Yi Wang.
      After herpes simplex virus type 1 (HSV-1) infection, the cytosolic sensor cyclic GMP-AMP synthase (cGAS) recognizes DNA and catalyzes synthesis of the second messenger 2'3'-cGAMP. cGAMP binds to the ER-localized adaptor protein MITA (also known as STING) to activate downstream antiviral responses. Conversely, HSV-1-encoded proteins evade antiviral immune responses via a wide variety of delicate mechanisms, promoting viral replication and pathogenesis. Here, we identified HSV-1 envelop protein UL56 as a negative regulator of cGAS-mediated innate immune responses. Overexpression of UL56 inhibited double-stranded DNA-triggered antiviral responses, whereas UL56-deficiency increased HSV-1-triggered induction of downstream antiviral genes. UL56-deficiency inhibited HSV-1 replication in wild-type but not MITA-deficient cells. UL56-deficient HSV-1 showed reduced replication in the brain of infected mice and was less lethal to infected mice. Mechanistically, UL56 interacted with cGAS and inhibited its DNA binding and enzymatic activity. Furthermore, we found that UL56 homologous proteins from different herpesviruses had similar roles in antagonizing cGAS-mediated innate immune responses. Our findings suggest that UL56 is a component of HSV-1 evasion of host innate immune responses by antagonizing the DNA sensor cGAS, which contributes to our understanding of the comprehensive mechanisms of immune evasion by herpesviruses.
    Keywords:  Antiviral innate immunity; HSV-1; Immune evasion; UL56; cGAS
    DOI:  https://doi.org/10.1016/j.cellin.2022.100014
  40. Cell. 2023 May 11. pii: S0092-8674(23)00417-8. [Epub ahead of print]186(10): 2041-2043
    Muscle fusogens go viral for gene delivery to skeletal muscle.
    Devin E Gibbs, April D Pyle.
      Viruses and multinucleated cells rely on fusogens to facilitate the fusion of their membranes. In this issue of Cell, Millay and colleagues demonstrate that replacing viral fusogens with mammalian skeletal muscle fusogens leads to the specific transduction of skeletal muscle and the ability to deliver gene therapy constructs in a therapeutically relevant muscle disease.
    DOI:  https://doi.org/10.1016/j.cell.2023.04.021
  41. Nat Immunol. 2023 May 18.
    Conserved stromal-immune cell circuits secure B cell homeostasis and function.
    Mechthild Lütge, Angelina De Martin, Cristina Gil-Cruz, Christian Perez-Shibayama, Yves Stanossek, Lucas Onder, Hung-Wei Cheng, Lisa Kurz, Nadine Cadosch, Charlotte Soneson, Mark D Robinson, Sandro J Stoeckli, Burkhard Ludewig, Natalia B Pikor.
      B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC-immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity.
    DOI:  https://doi.org/10.1038/s41590-023-01503-3
  42. J Clin Invest. 2023 May 15. pii: e171057. [Epub ahead of print]133(10):
    Nonnutritive sweeteners and glucose intolerance: Where do we go from here?
    Samuel Philip Nobs, Eran Elinav.
      
    DOI:  https://doi.org/10.1172/JCI171057
  43. Commun Biol. 2023 May 18. 6(1): 535
    Asymmetric conformations of cleaved HIV-1 envelope glycoprotein trimers in styrene-maleic acid lipid nanoparticles.
    Kunyu Wang, Shijian Zhang, Eden P Go, Haitao Ding, Wei Li Wang, Hanh T Nguyen, John C Kappes, Heather Desaire, Joseph Sodroski, Youdong Mao.
      During virus entry, the pretriggered human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer initially transits into a default intermediate state (DIS) that remains structurally uncharacterized. Here, we present cryo-EM structures at near-atomic resolution of two cleaved full-length HIV-1 Env trimers purified from cell membranes in styrene-maleic acid lipid nanoparticles without antibodies or receptors. The cleaved Env trimers exhibited tighter subunit packing than uncleaved trimers. Cleaved and uncleaved Env trimers assumed remarkably consistent yet distinct asymmetric conformations, with one smaller and two larger opening angles. Breaking conformational symmetry is allosterically coupled with dynamic helical transformations of the gp41 N-terminal heptad repeat (HR1N) regions in two protomers and with trimer tilting in the membrane. The broken symmetry of the DIS potentially assists Env binding to two CD4 receptors-while resisting antibody binding-and promotes extension of the gp41 HR1 helical coiled-coil, which relocates the fusion peptide closer to the target cell membrane.
    DOI:  https://doi.org/10.1038/s42003-023-04916-w
  44. Sci Adv. 2023 05 12. 9(19): eadf5499
    Home-site advantage for host species-specific gut microbiota.
    Daniel D Sprockett, Jeffrey D Price, Anthony F Juritsch, Robert J Schmaltz, Madalena V F Real, Samantha L Goldman, Michael Sheehan, Amanda E Ramer-Tait, Andrew H Moeller.
      Mammalian species harbor compositionally distinct gut microbial communities, but the mechanisms that maintain specificity of symbionts to host species remain unclear. Here, we show that natural selection within house mice (Mus musculus domesticus) drives deterministic assembly of the house-mouse gut microbiota from mixtures of native and non-native microbiotas. Competing microbiotas from wild-derived lines of house mice and other mouse species (Mus and Peromyscus spp.) within germ-free wild-type (WT) and Rag1-knockout (Rag1-/-) house mice revealed widespread fitness advantages for native gut bacteria. Native bacterial lineages significantly outcompeted non-native lineages in both WT and Rag1-/- mice, indicating home-site advantage for native microbiota independent of host adaptive immunity. However, a minority of native Bacteriodetes and Firmicutes favored by selection in WT hosts were not favored or disfavored in Rag1-/- hosts, indicating that Rag1 mediates fitness advantages of these strains. This study demonstrates home-site advantage for native gut bacteria, consistent with local adaptation of gut microbiota to their mammalian species.
    DOI:  https://doi.org/10.1126/sciadv.adf5499
  45. Nat Metab. 2023 May 15.
    Single-cell expression profiling of islets generated by the Human Pancreas Analysis Program.
    Abhijeet R Patil, Jonathan Schug, Ali Naji, Klaus H Kaestner, Robert B Faryabi, Golnaz Vahedi.
      
    DOI:  https://doi.org/10.1038/s42255-023-00806-x
  46. Nat Commun. 2023 May 17. 14(1): 2829
    Cellular population dynamics shape the route to human pluripotency.
    Francesco Panariello, Onelia Gagliano, Camilla Luni, Antonio Grimaldi, Silvia Angiolillo, Wei Qin, Anna Manfredi, Patrizia Annunziata, Shaked Slovin, Lorenzo Vaccaro, Sara Riccardo, Valentina Bouche, Manuela Dionisi, Marcello Salvi, Sebastian Martewicz, Manli Hu, Meihua Cui, Hannah Stuart, Cecilia Laterza, Giacomo Baruzzo, Geoffrey Schiebinger, Barbara Di Camillo, Davide Cacchiarelli, Nicola Elvassore.
      Human cellular reprogramming to induced pluripotency is still an inefficient process, which has hindered studying the role of critical intermediate stages. Here we take advantage of high efficiency reprogramming in microfluidics and temporal multi-omics to identify and resolve distinct sub-populations and their interactions. We perform secretome analysis and single-cell transcriptomics to show functional extrinsic pathways of protein communication between reprogramming sub-populations and the re-shaping of a permissive extracellular environment. We pinpoint the HGF/MET/STAT3 axis as a potent enhancer of reprogramming, which acts via HGF accumulation within the confined system of microfluidics, and in conventional dishes needs to be supplied exogenously to enhance efficiency. Our data suggest that human cellular reprogramming is a transcription factor-driven process that it is deeply dependent on extracellular context and cell population determinants.
    DOI:  https://doi.org/10.1038/s41467-023-37270-w
  47. Nat Methods. 2023 May 15.
    Engineered allostery in light-regulated LOV-Turbo enables precise spatiotemporal control of proximity labeling in living cells.
    Song-Yi Lee, Joleen S Cheah, Boxuan Zhao, Charles Xu, Heegwang Roh, Christina K Kim, Kelvin F Cho, Namrata D Udeshi, Steven A Carr, Alice Y Ting.
      The incorporation of light-responsive domains into engineered proteins has enabled control of protein localization, interactions and function with light. We integrated optogenetic control into proximity labeling, a cornerstone technique for high-resolution proteomic mapping of organelles and interactomes in living cells. Through structure-guided screening and directed evolution, we installed the light-sensitive LOV domain into the proximity labeling enzyme TurboID to rapidly and reversibly control its labeling activity with low-power blue light. 'LOV-Turbo' works in multiple contexts and dramatically reduces background in biotin-rich environments such as neurons. We used LOV-Turbo for pulse-chase labeling to discover proteins that traffic between endoplasmic reticulum, nuclear and mitochondrial compartments under cellular stress. We also showed that instead of external light, LOV-Turbo can be activated by bioluminescence resonance energy transfer from luciferase, enabling interaction-dependent proximity labeling. Overall, LOV-Turbo increases the spatial and temporal precision of proximity labeling, expanding the scope of experimental questions that can be addressed with proximity labeling.
    DOI:  https://doi.org/10.1038/s41592-023-01880-5
  48. Nat Rev Neurol. 2023 May 17.
    Single-cell and spatial transcriptomics: deciphering brain complexity in health and disease.
    Monika Piwecka, Nikolaus Rajewsky, Agnieszka Rybak-Wolf.
      In the past decade, single-cell technologies have proliferated and improved from their technically challenging beginnings to become common laboratory methods capable of determining the expression of thousands of genes in thousands of cells simultaneously. The field has progressed by taking the CNS as a primary research subject - the cellular complexity and multiplicity of neuronal cell types provide fertile ground for the increasing power of single-cell methods. Current single-cell RNA sequencing methods can quantify gene expression with sufficient accuracy to finely resolve even subtle differences between cell types and states, thus providing a great tool for studying the molecular and cellular repertoire of the CNS and its disorders. However, single-cell RNA sequencing requires the dissociation of tissue samples, which means that the interrelationships between cells are lost. Spatial transcriptomic methods bypass tissue dissociation and retain this spatial information, thereby allowing gene expression to be assessed across thousands of cells within the context of tissue structural organization. Here, we discuss how single-cell and spatially resolved transcriptomics have been contributing to unravelling the pathomechanisms underlying brain disorders. We focus on three areas where we feel these new technologies have provided particularly useful insights: selective neuronal vulnerability, neuroimmune dysfunction and cell-type-specific treatment response. We also discuss the limitations and future directions of single-cell and spatial RNA sequencing technologies.
    DOI:  https://doi.org/10.1038/s41582-023-00809-y
  49. Nature. 2023 May 17.
    Uridine-derived ribose fuels glucose-restricted pancreatic cancer.
    Zeribe C Nwosu, Matthew H Ward, Peter Sajjakulnukit, Pawan Poudel, Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton, Rosa E Menjivar, Anthony Andren, Juan J Apiz-Saab, Zachary Tolstyka, Kristee Brown, Ho-Joon Lee, Lindsey N Dzierozynski, Xi He, Hari Ps, Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J Halbrook, Eileen S Carpenter, Jiaqi Shi, Leah P Shriver, Gary J Patti, Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.
    DOI:  https://doi.org/10.1038/s41586-023-06073-w
  50. Nat Commun. 2023 May 12. 14(1): 2751
    Evolution of antibody immunity following Omicron BA.1 breakthrough infection.
    Chengzi I Kaku, Tyler N Starr, Panpan Zhou, Haley L Dugan, Paul Khalifé, Ge Song, Elizabeth R Champney, Daniel W Mielcarz, James C Geoghegan, Dennis R Burton, Raiees Andrabi, Jesse D Bloom, Laura M Walker.
      Understanding the longitudinal dynamics of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we track SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in six mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses decline by two- to four-fold through the study period. Breakthrough infection elicits minimal de novo Omicron BA.1-specific B cell responses but drives affinity maturation of pre-existing cross-reactive MBCs toward BA.1, which translates into enhanced breadth of activity across other variants. Public clones dominate the neutralizing antibody response at both early and late time points following breakthough infection, and their escape mutation profiles predict newly emergent Omicron sublineages, suggesting that convergent antibody responses continue to shape SARS-CoV-2 evolution. While the study is limited by our relatively small cohort size, these results suggest that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory, supporting the continued development of next-generation variant-based vaccines.
    DOI:  https://doi.org/10.1038/s41467-023-38345-4
  51. Nat Commun. 2023 Apr 25. 14(1): 2367
    Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.
    Stacy A Hussong, Andy Q Banh, Candice E Van Skike, Angela O Dorigatti, Stephen F Hernandez, Matthew J Hart, Beatriz Ferran, Haneen Makhlouf, Maria Gaczynska, Pawel A Osmulski, Salome A McAllen, Kelly T Dineley, Zoltan Ungvari, Viviana I Perez, Rakez Kayed, Veronica Galvan.
      Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.
    DOI:  https://doi.org/10.1038/s41467-023-37840-y
  52. Nat Metab. 2023 May 15.
    SIRT2 regulates extracellular vesicle-mediated liver-bone communication.
    Longshuai Lin, Zengya Guo, Enjun He, Xidai Long, Difei Wang, Yingting Zhang, Weihong Guo, Qian Wei, Wei He, Wanying Wu, Jingchi Li, Lulu Wo, Dengli Hong, Junke Zheng, Ming He, Qinghua Zhao.
      The interplay between liver and bone metabolism remains largely uncharacterized. Here, we uncover a mechanism of liver-bone crosstalk regulated by hepatocyte SIRT2. We demonstrate that hepatocyte SIRT2 expression is increased in aged mice and elderly humans. Liver-specific SIRT2 deficiency inhibits osteoclastogenesis and alleviates bone loss in mouse models of osteoporosis. We identify leucine-rich α-2-glycoprotein 1 (LRG1) as a functional cargo in hepatocyte-derived small extracellular vesicles (sEVs). In SIRT2-deficient hepatocytes, LRG1 levels in sEVs are upregulated, leading to increased transfer of LRG1 to bone-marrow-derived monocytes (BMDMs), and in turn, to inhibition of osteoclast differentiation via reduced nuclear translocation of NF-κB p65. Treatment with sEVs carrying high levels of LRG1 inhibits osteoclast differentiation in human BMDMs and in mice with osteoporosis, resulting in attenuated bone loss in mice. Furthermore, the plasma level of sEVs carrying LRG1 is positively correlated with bone mineral density in humans. Thus, drugs targeting hepatocyte-osteoclast communication may constitute a promising therapeutic strategy for primary osteoporosis.
    DOI:  https://doi.org/10.1038/s42255-023-00803-0
  53. Nat Commun. 2023 Apr 25. 14(1): 2364
    Immune cellular patterns of distribution affect outcomes of patients with non-small cell lung cancer.
    Edwin Roger Parra, Jiexin Zhang, Mei Jiang, Auriole Tamegnon, Renganayaki Krishna Pandurengan, Carmen Behrens, Luisa Solis, Cara Haymaker, John Victor Heymach, Cesar Moran, Jack J Lee, Don Gibbons, Ignacio Ivan Wistuba.
      Studying the cellular geographic distribution in non-small cell lung cancer is essential to understand the roles of cell populations in this type of tumor. In this study, we characterize the spatial cellular distribution of immune cell populations using 23 makers placed in five multiplex immunofluorescence panels and their associations with clinicopathologic variables and outcomes. Our results demonstrate two cellular distribution patterns-an unmixed pattern mostly related to immunoprotective cells and a mixed pattern mostly related to immunosuppressive cells. Distance analysis shows that T-cells expressing immune checkpoints are closer to malignant cells than other cells. Combining the cellular distribution patterns with cellular distances, we can identify four groups related to inflamed and not-inflamed tumors. Cellular distribution patterns and distance are associated with survival in univariate and multivariable analyses. Spatial distribution is a tool to better understand the tumor microenvironment, predict outcomes, and may can help select therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-023-37905-y
  54. Science. 2023 May 19. 380(6646): 676-677
    Human genomic 'bycatch' threatens privacy.
    Gretchen Vogel.
      Environmental and microbe studies net human DNA that can reveal health, identity.
    DOI:  https://doi.org/10.1126/science.adi7653
  55. Nat Commun. 2023 May 13. 14(1): 2756
    Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis.
    Hao Yan, Wentong Wu, Yuhuai Hu, Jinjin Li, Jiangxin Xu, Xueqin Chen, Zhifei Xu, Xiaochun Yang, Bo Yang, Qiaojun He, Peihua Luo.
      The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.
    DOI:  https://doi.org/10.1038/s41467-023-38430-8
  56. Nat Metab. 2023 May 17.
    Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
    Owen S Skinner, Joan Blanco-Fernández, Russell P Goodman, Akinori Kawakami, Hongying Shen, Lajos V Kemény, Lena Joesch-Cohen, Matthew G Rees, Jennifer A Roth, David E Fisher, Vamsi K Mootha, Alexis A Jourdain.
      Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency1, our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s42255-023-00774-2
  57. Cell. 2023 May 08. pii: S0092-8674(23)00408-7. [Epub ahead of print]
    Sites of transcription initiation drive mRNA isoform selection.
    Carlos Alfonso-Gonzalez, Ivano Legnini, Sarah Holec, Laura Arrigoni, Hasan Can Ozbulut, Fernando Mateos, David Koppstein, Agnieszka Rybak-Wolf, Ulrike Bönisch, Nikolaus Rajewsky, Valérie Hilgers.
      The generation of distinct messenger RNA isoforms through alternative RNA processing modulates the expression and function of genes, often in a cell-type-specific manner. Here, we assess the regulatory relationships between transcription initiation, alternative splicing, and 3' end site selection. Applying long-read sequencing to accurately represent even the longest transcripts from end to end, we quantify mRNA isoforms in Drosophila tissues, including the transcriptionally complex nervous system. We find that in Drosophila heads, as well as in human cerebral organoids, 3' end site choice is globally influenced by the site of transcription initiation (TSS). "Dominant promoters," characterized by specific epigenetic signatures including p300/CBP binding, impose a transcriptional constraint to define splice and polyadenylation variants. In vivo deletion or overexpression of dominant promoters as well as p300/CBP loss disrupted the 3' end expression landscape. Our study demonstrates the crucial impact of TSS choice on the regulation of transcript diversity and tissue identity.
    Keywords:  5ʹ-3ʹ coupling; Drosophila; alternative polyadenylation; human brain organoids; long-read sequencing; mRNA isoform; nervous system; p300/CBP; transcription; transcription start site
    DOI:  https://doi.org/10.1016/j.cell.2023.04.012
  58. Commun Biol. 2023 May 15. 6(1): 503
    Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer's disease.
    Julie P Merchant, Kuixi Zhu, Marc Y R Henrion, Syed S A Zaidi, Branden Lau, Sara Moein, Melissa L Alamprese, Richard V Pearse, David A Bennett, Nilüfer Ertekin-Taner, Tracy L Young-Pearse, Rui Chang.
      Despite decades of genetic studies on late-onset Alzheimer's disease, the underlying molecular mechanisms remain unclear. To better comprehend its complex etiology, we use an integrative approach to build robust predictive (causal) network models using two large human multi-omics datasets. We delineate bulk-tissue gene expression into single cell-type gene expression and integrate clinical and pathologic traits, single nucleotide variation, and deconvoluted gene expression for the construction of cell type-specific predictive network models. Here, we focus on neuron-specific network models and prioritize 19 predicted key drivers modulating Alzheimer's pathology, which we then validate by knockdown in human induced pluripotent stem cell-derived neurons. We find that neuronal knockdown of 10 of the 19 targets significantly modulates levels of amyloid-beta and/or phosphorylated tau peptides, most notably JMJD6. We also confirm our network structure by RNA sequencing in the neurons following knockdown of each of the 10 targets, which additionally predicts that they are upstream regulators of REST and VGF. Our work thus identifies robust neuronal key drivers of the Alzheimer's-associated network state which may represent therapeutic targets with relevance to both amyloid and tau pathology in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s42003-023-04791-5
  59. Sci Immunol. 2023 May 19. 8(83): eade5872
    Cytolytic CD8+ T cells infiltrate germinal centers to limit ongoing HIV replication in spontaneous controller lymph nodes.
    David R Collins, Julia Hitschfel, Jonathan M Urbach, Geetha H Mylvaganam, Ngoc L Ly, Umar Arshad, Zachary J Racenet, Adrienne G Yanez, Thomas J Diefenbach, Bruce D Walker.
      Follicular CD8+ T cells (fCD8) mediate surveillance in lymph node (LN) germinal centers against lymphotropic infections and cancers, but the precise mechanisms by which these cells mediate immune control remain incompletely resolved. To address this, we investigated functionality, clonotypic compartmentalization, spatial localization, phenotypic characteristics, and transcriptional profiles of LN-resident virus-specific CD8+ T cells in persons who control HIV without medications. Antigen-induced proliferative and cytolytic potential consistently distinguished spontaneous controllers from noncontrollers. T cell receptor analysis revealed complete clonotypic overlap between peripheral and LN-resident HIV-specific CD8+ T cells. Transcriptional analysis of LN CD8+ T cells revealed gene signatures of inflammatory chemotaxis and antigen-induced effector function. In HIV controllers, the cytotoxic effectors perforin and granzyme B were elevated among virus-specific CXCR5+ fCD8s proximate to foci of HIV RNA within germinal centers. These results provide evidence consistent with cytolytic control of lymphotropic infection supported by inflammatory recruitment, antigen-specific proliferation, and cytotoxicity of fCD8s.
    DOI:  https://doi.org/10.1126/sciimmunol.ade5872
  60. Cell Insight. 2023 Feb;2(1): 100077
    Hexokinases in cancer and other pathologies.
    Dong Guo, Ying Meng, Xiaoming Jiang, Zhimin Lu.
      Glucose metabolism is indispensable for cell growth and survival. Hexokinases play pivotal roles in glucose metabolism through canonical functions of hexokinases as well as in immune response, cell stemness, autophagy, and other cellular activities through noncanonical functions. The aberrant regulation of hexokinases contributes to the development and progression of pathologies, including cancer and immune diseases.
    Keywords:  Cancer; Glucose metabolism; Glycolysis; Hexokinase; Immune diseases; Protein kinase
    DOI:  https://doi.org/10.1016/j.cellin.2023.100077
  61. Nat Commun. 2023 May 19. 14(1): 2875
    Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis.
    Robert E Jefferson, Aurélien Oggier, Andreas Füglistaler, Nicolas Camviel, Mahdi Hijazi, Ana Rico Villarreal, Caroline Arber, Patrick Barth.
      Engineering protein biosensors that sensitively respond to specific biomolecules by triggering precise cellular responses is a major goal of diagnostics and synthetic cell biology. Previous biosensor designs have largely relied on binding structurally well-defined molecules. In contrast, approaches that couple the sensing of flexible compounds to intended cellular responses would greatly expand potential biosensor applications. Here, to address these challenges, we develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides. To demonstrate the power of the approach, we create ultrasensitive chemotactic receptor-peptide pairs capable of eliciting potent signaling responses and strong chemotaxis in primary human T cells. Unlike traditional approaches that engineer static binding complexes, our dynamic structure design strategy optimizes contacts with multiple binding and allosteric sites accessible through dynamic conformational ensembles to achieve strongly enhanced signaling efficacy and potency. Our study suggests that a conformationally adaptable binding interface coupled to a robust allosteric transmission region is a key evolutionary determinant of peptidergic GPCR signaling systems. The approach lays a foundation for designing peptide-sensing receptors and signaling peptide ligands for basic and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-023-38491-9
  62. Commun Biol. 2023 Apr 25. 6(1): 454
    Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine.
    John V Dzimianski, Julianna Han, Giuseppe A Sautto, Sara M O'Rourke, Joseph M Cruz, Spencer R Pierce, Jeffrey W Ecker, Michael A Carlock, Kaito A Nagashima, Jarrod J Mousa, Ted M Ross, Andrew B Ward, Rebecca M DuBois.
      Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding.
    DOI:  https://doi.org/10.1038/s42003-023-04793-3
  63. Commun Biol. 2023 May 15. 6(1): 525
    Multi-omics delineation of cytokine-induced endothelial inflammatory states.
    Stijn A Groten, Eva R Smit, Esmée F J Janssen, Bart L van den Eshof, Floris P J van Alphen, Carmen van der Zwaan, Alexander B Meijer, Arie J Hoogendijk, Maartje van den Biggelaar.
      Vascular endothelial cells (ECs) form a dynamic interface between blood and tissue and play a crucial role in the progression of vascular inflammation. Here, we aim to dissect the system-wide molecular mechanisms of inflammatory endothelial-cytokine responses. Applying an unbiased cytokine library, we determined that TNFα and IFNγ induced the largest EC response resulting in distinct proteomic inflammatory signatures. Notably, combined TNFα + IFNγ stimulation induced an additional synergetic inflammatory signature. We employed a multi-omics approach to dissect these inflammatory states, combining (phospho-) proteome, transcriptome and secretome and found, depending on the stimulus, a wide-array of altered immune-modulating processes, including complement proteins, MHC complexes and distinct secretory cytokines. Synergy resulted in cooperative activation of transcript induction. This resource describes the intricate molecular mechanisms that are at the basis of endothelial inflammation and supports the adaptive immunomodulatory role of the endothelium in host defense and vascular inflammation.
    DOI:  https://doi.org/10.1038/s42003-023-04897-w
  64. iScience. 2023 May 19. 26(5): 106644
    SIRT2 inhibition by AGK2 enhances mycobacteria-specific stem cell memory responses by modulating beta-catenin and glycolysis.
    Ashima Bhaskar, Isha Pahuja, Kriti Negi, Akanksha Verma, Antara Ghoshal, Babu Mathew, Gaurav Tripathi, Jaswinder Singh Maras, Shivam Chaturvedi, Ved Prakash Dwivedi.
      Bacille Calmette-Guerin (BCG) generates limited long-lasting adaptive memory responses leading to short-lived protection against adult pulmonary tuberculosis (TB). Here, we show that host sirtuin 2 (SIRT2) inhibition by AGK2 significantly enhances the BCG vaccine efficacy during primary infection and TB recurrence through enhanced stem cell memory (TSCM) responses. SIRT2 inhibition modulated the proteome landscape of CD4+ T cells affecting pathways involved in cellular metabolism and T-cell differentiation. Precisely, AGK2 treatment enriched the IFNγ-producing TSCM cells by activating β-catenin and glycolysis. Furthermore, SIRT2 specifically targeted histone H3 and NF-κB p65 to induce proinflammatory responses. Finally, inhibition of the Wnt/β-catenin pathway abolished the protective effects of AGK2 treatment during BCG vaccination. Taken together, this study provides a direct link between BCG vaccination, epigenetics, and memory immune responses. We identify SIRT2 as a key regulator of memory T cells during BCG vaccination and project SIRT2 inhibitors as potential immunoprophylaxis against TB.
    Keywords:  Bacteriology; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2023.106644
  65. Nature. 2023 May 17.
    Oldest known 'blueprints' aided human hunters 9,000 years ago.
      
    Keywords:  Archaeology
    DOI:  https://doi.org/10.1038/d41586-023-01593-x
  66. Nat Commun. 2023 May 18. 14(1): 2854
    Single-frame deep-learning super-resolution microscopy for intracellular dynamics imaging.
    Rong Chen, Xiao Tang, Yuxuan Zhao, Zeyu Shen, Meng Zhang, Yusheng Shen, Tiantian Li, Casper Ho Yin Chung, Lijuan Zhang, Ji Wang, Binbin Cui, Peng Fei, Yusong Guo, Shengwang Du, Shuhuai Yao.
      Single-molecule localization microscopy (SMLM) can be used to resolve subcellular structures and achieve a tenfold improvement in spatial resolution compared to that obtained by conventional fluorescence microscopy. However, the separation of single-molecule fluorescence events that requires thousands of frames dramatically increases the image acquisition time and phototoxicity, impeding the observation of instantaneous intracellular dynamics. Here we develop a deep-learning based single-frame super-resolution microscopy (SFSRM) method which utilizes a subpixel edge map and a multicomponent optimization strategy to guide the neural network to reconstruct a super-resolution image from a single frame of a diffraction-limited image. Under a tolerable signal density and an affordable signal-to-noise ratio, SFSRM enables high-fidelity live-cell imaging with spatiotemporal resolutions of 30 nm and 10 ms, allowing for prolonged monitoring of subcellular dynamics such as interplays between mitochondria and endoplasmic reticulum, the vesicle transport along microtubules, and the endosome fusion and fission. Moreover, its adaptability to different microscopes and spectra makes it a useful tool for various imaging systems.
    DOI:  https://doi.org/10.1038/s41467-023-38452-2
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