bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–01–28
fifty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mucosal boosting.
  2. In the right place.
  3. Deciphering cell states and genealogies of human hematopoiesis.
  4. CTLA-4 nanobody stops colitis.
  5. JAK1 hits a nerve.
  6. SiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data.
  7. AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
  8. A bumpy road ahead for genetic biocontainment.
  9. Genetic architecture and biology of youth-onset type 2 diabetes.
  10. Segment anything in medical images.
  11. A developmental increase of inhibition promotes the emergence of hippocampal ripples.
  12. Obesity drugs have another superpower: taming inflammation.
  13. An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life.
  14. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
  15. Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin.
  16. Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.
  17. Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health.
  18. Deploying blood-based cancer screening.
  19. Inosine induces stemness features in CAR-T cells and enhances potency.
  20. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
  21. CD8+ TRM cells in perpetual motion.
  22. Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging.
  23. LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing.
  24. Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.
  25. Trial-history biases in evidence accumulation can give rise to apparent lapses in decision-making.
  26. The nucleolar shell provides anchoring sites for DNA untwisting.
  27. A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.
  28. Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.
  29. The HIV capsid mimics karyopherin engagement of FG-nucleoporins.
  30. The pathogenesis of Parkinson's disease.
  31. When ceramides meet immune senescence, a GIMAP5 connection.
  32. Cortical regulation of helping behaviour towards others in pain.
  33. Cell surface RNAs control neutrophil recruitment.
  34. Computationally designed sensors detect endogenous Ras activity and signaling effectors at subcellular resolution.
  35. UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.
  36. Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.
  37. A cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis.
  38. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
  39. Structural and functional insights into the lipid regulation of human anion exchanger 2.
  40. A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.
  41. Anti-correlated feature selection prevents false discovery of subpopulations in scRNAseq.
  42. Tracking down tuberculosis.
  43. Audio long read: Long COVID is a double curse in low-income nations - here's why.
  44. A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer's disease.
  45. Dual phosphorylation of DGK5-mediated PA burst regulates ROS in plant immunity.
  46. Thinking outside the chromosome: epigenetic mechanisms in non-canonical chromatin species.
  47. HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III.
  48. Receptor-associated kinases control the lipid provisioning program in plant-fungal symbiosis.
  49. Connectome-based reservoir computing with the conn2res toolbox.
  50. Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.
  51. Computer-based design of sensors that can monitor endogenous Ras activity.
  52. MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.
  53. Functionally heterogeneous β cells regulate biphasic insulin secretion.
  54. HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor.
  55. Conditional transcriptome-wide association study for fine-mapping candidate causal genes.
  56. The hagfish genome and the evolution of vertebrates.
  1. Nat Immunol. 2024 Jan 23.
    Mucosal boosting.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-024-01751-x
  2. Science. 2024 Jan 26. 383(6681): 450
    In the right place.
    Rebecca Lengnick-Hall.
      
    DOI:  https://doi.org/10.1126/science.ado1708
  3. Nature. 2024 Jan 22.
    Deciphering cell states and genealogies of human hematopoiesis.
    Chen Weng, Fulong Yu, Dian Yang, Michael Poeschla, L Alexander Liggett, Matthew G Jones, Xiaojie Qiu, Lara Wahlster, Alexis Caulier, Jeffrey A Hussmann, Alexandra Schnell, Kathryn E Yost, Luke Koblan, Jorge D Martin-Rufino, Joseph Min, Alessandro Hammond, Daniel Ssozi, Raphael Bueno, Hari Mallidi, Antonia Kreso, Javier Escabi, William M Rideout, Tyler Jacks, Sahand Hormoz, Peter van Galen, Jonathan S Weissman, Vijay G Sankaran.
      The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived hematopoietic stem cells (HSCs)1. Perturbations to this process underlie diverse diseases, but the clonal contributions to human hematopoiesis and how this changes with age remain incompletely understood. While recent insights have emerged from barcoding studies in model systems4,5,16,17, simultaneous detection of cell states and phylogenies from natural barcodes in humans has been challenging. Here, we introduce an improved single-cell lineage tracing system based on deep detection of naturally-occurring mitochondrial DNA (mtDNA) mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as differences in total HSC output as well as biases toward the production of different mature cell types. We also find that the diversity of HSC clones decreases dramatically with age leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides the first clonally-resolved and cell-state aware atlas of human hematopoiesis at single-cell resolution revealing an unappreciated functional diversity of human HSC clones and more broadly paves the way for refined studies of clonal dynamics across a range of tissues in human health and disease.
    DOI:  https://doi.org/10.1038/s41586-024-07066-z
  4. Nat Immunol. 2024 Jan 23.
    CTLA-4 nanobody stops colitis.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-024-01749-5
  5. Nat Immunol. 2024 Jan 23.
    JAK1 hits a nerve.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-024-01752-w
  6. Nat Commun. 2024 Jan 26. 15(1): 760
    SiFT: uncovering hidden biological processes by probabilistic filtering of single-cell data.
    Zoe Piran, Mor Nitzan.
      Cellular populations simultaneously encode multiple biological attributes, including spatial configuration, temporal trajectories, and cell-cell interactions. Some of these signals may be overshadowed by others and harder to recover, despite the great progress made to computationally reconstruct biological processes from single-cell data. To address this, we present SiFT, a kernel-based projection method for filtering biological signals in single-cell data, thus uncovering underlying biological processes. SiFT applies to a wide range of tasks, from the removal of unwanted variation in the data to revealing hidden biological structures. We demonstrate how SiFT enhances the liver circadian signal by filtering spatial zonation, recovers regenerative cell subpopulations in spatially-resolved liver data, and exposes COVID-19 disease-related cells, pathways, and dynamics by filtering healthy reference signals. SiFT performs the correction at the gene expression level, can scale to large datasets, and compares favorably to state-of-the-art methods.
    DOI:  https://doi.org/10.1038/s41467-024-44757-7
  7. Nat Commun. 2024 Jan 23. 15(1): 686
    AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis.
    Taiqi Chen, Siyi Xie, Jie Cheng, Qiao Zhao, Hong Wu, Peng Jiang, Wenjing Du.
      Many types of tumors feature aerobic glycolysis for meeting their increased energetic and biosynthetic demands. However, it remains still unclear how this glycolytic phenomenon is achieved and coordinated with other metabolic pathways in tumor cells in response to growth stimuli. Here we report that activation of AKT1 induces a metabolic switch to glycolysis from the mitochondrial metabolism via phosphorylation of cytoplasmic malic enzyme 2 (ME2), named ME2fl (fl means full length), favoring an enhanced glycolytic phenotype. Mechanistically, in the cytoplasm, AKT1 phosphorylates ME2fl at serine 9 in the mitochondrial localization signal peptide at the N-terminus, preventing its mitochondrial translocation. Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.
    DOI:  https://doi.org/10.1038/s41467-024-44772-8
  8. Nat Commun. 2024 Jan 20. 15(1): 650
    A bumpy road ahead for genetic biocontainment.
    Dalton R George, Mark Danciu, Peter W Davenport, Matthew R Lakin, James Chappell, Emma K Frow.
      
    DOI:  https://doi.org/10.1038/s41467-023-44531-1
  9. Nat Metab. 2024 Jan 26.
    Genetic architecture and biology of youth-onset type 2 diabetes.
    Progress in Diabetes Genetics in Youth (ProDiGY) consortium
      The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10-6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies-and rare variants in particular-are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.
    DOI:  https://doi.org/10.1038/s42255-023-00970-0
  10. Nat Commun. 2024 Jan 22. 15(1): 654
    Segment anything in medical images.
    Jun Ma, Yuting He, Feifei Li, Lin Han, Chenyu You, Bo Wang.
      Medical image segmentation is a critical component in clinical practice, facilitating accurate diagnosis, treatment planning, and disease monitoring. However, existing methods, often tailored to specific modalities or disease types, lack generalizability across the diverse spectrum of medical image segmentation tasks. Here we present MedSAM, a foundation model designed for bridging this gap by enabling universal medical image segmentation. The model is developed on a large-scale medical image dataset with 1,570,263 image-mask pairs, covering 10 imaging modalities and over 30 cancer types. We conduct a comprehensive evaluation on 86 internal validation tasks and 60 external validation tasks, demonstrating better accuracy and robustness than modality-wise specialist models. By delivering accurate and efficient segmentation across a wide spectrum of tasks, MedSAM holds significant potential to expedite the evolution of diagnostic tools and the personalization of treatment plans.
    DOI:  https://doi.org/10.1038/s41467-024-44824-z
  11. Nat Commun. 2024 Jan 25. 15(1): 738
    A developmental increase of inhibition promotes the emergence of hippocampal ripples.
    Irina Pochinok, Tristan M Stöber, Jochen Triesch, Mattia Chini, Ileana L Hanganu-Opatz.
      Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12-day-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of channelrhodopsin-2-transfected CA1 pyramidal neurons only from postnatal day 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response than SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.
    DOI:  https://doi.org/10.1038/s41467-024-44983-z
  12. Nature. 2024 Jan 26.
    Obesity drugs have another superpower: taming inflammation.
    Mariana Lenharo.
      
    Keywords:  Brain; Immunology; Neurodegeneration; Neuroscience; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-00118-4
  13. Nat Commun. 2024 Jan 23. 15(1): 680
    An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life.
    Eleni Vergadi, Ourania Kolliniati, Ioanna Lapi, Eleftheria Ieronymaki, Konstantina Lyroni, Vasileia Ismini Alexaki, Eleni Diamantaki, Katerina Vaporidi, Eleftheria Hatzidaki, Helen A Papadaki, Emmanouil Galanakis, George Hajishengallis, Triantafyllos Chavakis, Christos Tsatsanis.
      The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.
    DOI:  https://doi.org/10.1038/s41467-023-44178-y
  14. Nat Aging. 2024 Jan 24.
    Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
    Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe.
      Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.
    DOI:  https://doi.org/10.1038/s43587-023-00560-5
  15. Sci Adv. 2024 Jan 26. 10(4): eadj3880
    Early-life stress triggers long-lasting organismal resilience and longevity via tetraspanin.
    Wei I Jiang, Henry De Belly, Bingying Wang, Andrew Wong, Minseo Kim, Fiona Oh, Jason DeGeorge, Xinya Huang, Shouhong Guang, Orion D Weiner, Dengke K Ma.
      Early-life stress experiences can produce lasting impacts on organismal adaptation and fitness. How transient stress elicits memory-like physiological effects is largely unknown. Here, we show that early-life thermal stress strongly up-regulates tsp-1, a gene encoding the conserved transmembrane tetraspanin in C. elegans. TSP-1 forms prominent multimers and stable web-like structures critical for membrane barrier functions in adults and during aging. Increased TSP-1 abundance persists even after transient early-life heat stress. Such regulation requires CBP-1, a histone acetyltransferase that facilitates initial tsp-1 transcription. Tetraspanin webs form regular membrane structures and mediate resilience-promoting effects of early-life thermal stress. Gain-of-function TSP-1 confers marked C. elegans longevity extension and thermal resilience in human cells. Together, our results reveal a cellular mechanism by which early-life thermal stress produces long-lasting memory-like impact on organismal resilience and longevity.
    DOI:  https://doi.org/10.1126/sciadv.adj3880
  16. Genes Immun. 2024 Jan 22.
    Take my breath away-mitochondrial dysfunction drives CD8+ T cell exhaustion.
    Felix Clemens Richter, Mariia Saliutina, Ahmed N Hegazy, Andreas Bergthaler.
      
    DOI:  https://doi.org/10.1038/s41435-023-00233-8
  17. Nat Neurosci. 2024 Jan 24.
    Oligodendrocyte-axon metabolic coupling is mediated by extracellular K+ and maintains axonal health.
    Zoe J Looser, Zainab Faik, Luca Ravotto, Henri S Zanker, Ramona B Jung, Hauke B Werner, Torben Ruhwedel, Wiebke Möbius, Dwight E Bergles, L Felipe Barros, Klaus-Armin Nave, Bruno Weber, Aiman S Saab.
      The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon-OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca2+) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K+) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K+ signaling, making acute metabolic coupling possible and adjusting the axon-OL metabolic unit to promote axonal health.
    DOI:  https://doi.org/10.1038/s41593-023-01558-3
  18. Science. 2024 Jan 26. 383(6681): 368-370
    Deploying blood-based cancer screening.
    Douglas S Micalizzi, Lecia V Sequist, Daniel A Haber.
      AI-based risk assessment may enable personalized blood-based multicancer screening.
    DOI:  https://doi.org/10.1126/science.adk1213
  19. Cancer Cell. 2024 Jan 17. pii: S1535-6108(24)00008-4. [Epub ahead of print]
    Inosine induces stemness features in CAR-T cells and enhances potency.
    Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Yiyun Chen, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Vimal Keerthi, Amaury Leruste, Malek Bashti, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
    DOI:  https://doi.org/10.1016/j.ccell.2024.01.002
  20. Nat Immunol. 2024 Jan 23.
    Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.
    Jingwei Ma, Liang Tang, Yaoyao Tan, Jingxuan Xiao, Keke Wei, Xin Zhang, Yuan Ma, Shuai Tong, Jie Chen, Nannan Zhou, Li Yang, Zhang Lei, Yonggang Li, Jiadi Lv, Junwei Liu, Huafeng Zhang, Ke Tang, Yi Zhang, Bo Huang.
      The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-023-01738-0
  21. Nat Immunol. 2024 Jan 23.
    CD8+ TRM cells in perpetual motion.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-024-01750-y
  22. Immunity. 2024 Jan 17. pii: S1074-7613(24)00026-8. [Epub ahead of print]
    Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging.
    Zhao Zhou, Jingfei Yao, Dongmei Wu, Xun Huang, Yushuang Wang, Xinmeng Li, Qiang Lu, Yifu Qiu.
      Accumulation of senescent cells in organs and tissues is a hallmark of aging and known to contribute to age-related diseases. Although aging-associated immune dysfunction, or immunosenescence, is known to contribute to this process, the underlying mechanism remains elusive. Here, we report that type 2 cytokine signaling deficiency accelerated aging and, conversely, that the interleukin-4 (IL-4)-STAT6 pathway protected macrophages from senescence. Mechanistically, activated STAT6 promoted the expression of genes involved in DNA repair both via homologous recombination and Fanconi anemia pathways. Conversely, STAT6 deficiency induced release of nuclear DNA into the cytoplasm to promote tissue inflammation and organismal aging. Importantly, we demonstrate that IL-4 treatment prevented macrophage senescence and improved the health span of aged mice to an extent comparable to senolytic treatment, with further additive effects when combined. Together, our findings support that type 2 cytokine signaling protects macrophages from immunosenescence and thus hold therapeutic potential for improving healthy aging.
    Keywords:  DNA repair; IL-4; STAT6; aging; immunosenescence; inflammaging; macrophage; type 2 cytokine
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.001
  23. Nat Commun. 2024 Jan 25. 15(1): 739
    LNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing.
    Yonger Xue, Yuebao Zhang, Yichen Zhong, Shi Du, Xucheng Hou, Wenqing Li, Haoyuan Li, Siyu Wang, Chang Wang, Jingyue Yan, Diana D Kang, Binbin Deng, David W McComb, Darrell J Irvine, Ron Weiss, Yizhou Dong.
      Adipose stem cells (ASCs) have attracted considerable attention as potential therapeutic agents due to their ability to promote tissue regeneration. However, their limited tissue repair capability has posed a challenge in achieving optimal therapeutic outcomes. Herein, we conceive a series of lipid nanoparticles to reprogram ASCs with durable protein secretion capacity for enhanced tissue engineering and regeneration. In vitro studies identify that the isomannide-derived lipid nanoparticles (DIM1T LNP) efficiently deliver RNAs to ASCs. Co-delivery of self-amplifying RNA (saRNA) and E3 mRNA complex (the combination of saRNA and E3 mRNA is named SEC) using DIM1T LNP modulates host immune responses against saRNAs and facilitates the durable production of proteins of interest in ASCs. The DIM1T LNP-SEC engineered ASCs (DS-ASCs) prolong expression of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 12 (CXCL12), which show superior wound healing efficacy over their wild-type and DIM1T LNP-mRNA counterparts in the diabetic cutaneous wound model. Overall, this work suggests LNPs as an effective platform to engineer ASCs with enhanced protein generation ability, expediting the development of ASCs-based cell therapies.
    DOI:  https://doi.org/10.1038/s41467-024-45094-5
  24. Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2314627121
    Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.
    Xaria X Li, Jenny N Fung, Richard J Clark, John D Lee, Trent M Woodruff.
      The complement factor C5a is a core effector product of complement activation. C5a, acting through its receptors C5aR1 and C5aR2, exerts pleiotropic immunomodulatory functions in myeloid cells, which is vital for host defense against pathogens. Pattern-recognition receptors (PRRs) are similarly expressed by immune cells as detectors of pathogen-associated molecular patterns. Although there is evidence of cross talk between complement and PRR signaling pathways, knowledge of the full potential for C5a-PRR interaction is limited. In this study, we comprehensively investigated how C5a signaling through C5a receptors can modulate diverse PRR-mediated cytokine responses in human primary monocyte-derived macrophages and observed a powerful, concentration-dependent bidirectional effect of C5a on PRR activities. Unexpectedly, C5a synergized with Dectin-1, Mincle, and STING in macrophages to a much greater extent than TLRs. Notably, we also identified that selective Dectin-1 activation using depleted zymosan triggered macrophages to generate cell-intrinsic C5a, which acted on intracellular and cell surface C5aR1, to help sustain mitochondrial ROS generation, up-regulate TNFα production, and enhance fungal killing. This study adds further evidence to the holistic functions of C5a as a central immunomodulator and important orchestrator of pathogen sensing and killing by phagocytes.
    Keywords:  C5a; Dectin-1; complement; cytokine; macrophage
    DOI:  https://doi.org/10.1073/pnas.2314627121
  25. Nat Commun. 2024 Jan 22. 15(1): 662
    Trial-history biases in evidence accumulation can give rise to apparent lapses in decision-making.
    Diksha Gupta, Brian DePasquale, Charles D Kopec, Carlos D Brody.
      Trial history biases and lapses are two of the most common suboptimalities observed during perceptual decision-making. These suboptimalities are routinely assumed to arise from distinct processes. However, previous work has suggested that they covary in their prevalence and that their proposed neural substrates overlap. Here we demonstrate that during decision-making, history biases and apparent lapses can both arise from a common cognitive process that is optimal under mistaken beliefs that the world is changing i.e. nonstationary. This corresponds to an accumulation-to-bound model with history-dependent updates to the initial state of the accumulator. We test our model's predictions about the relative prevalence of history biases and lapses, and show that they are robustly borne out in two distinct decision-making datasets of male rats, including data from a novel reaction time task. Our model improves the ability to precisely predict decision-making dynamics within and across trials, by positing a process through which agents can generate quasi-stochastic choices.
    DOI:  https://doi.org/10.1038/s41467-024-44880-5
  26. Commun Biol. 2024 Jan 23. 7(1): 83
    The nucleolar shell provides anchoring sites for DNA untwisting.
    Jumpei Fukute, Koichiro Maki, Taiji Adachi.
      DNA underwinding (untwisting) is a crucial step in transcriptional activation. DNA underwinding occurs between the site where torque is generated by RNA polymerase (RNAP) and the site where the axial rotation of DNA is constrained. However, what constrains DNA axial rotation in the nucleus is yet unknown. Here, we show that the anchorage to the nuclear protein condensates constrains DNA axial rotation for DNA underwinding in the nucleolus. In situ super-resolution imaging of underwound DNA reveal that underwound DNA accumulates in the nucleolus, a nuclear condensate with a core-shell structure. Specifically, underwound DNA is distributed in the nucleolar core owing to RNA polymerase I (RNAPI) activities. Furthermore, underwound DNA in the core decreases when nucleolar shell components are prevented from binding to their recognition structure, G-quadruplex (G4). Taken together, these results suggest that the nucleolar shell provides anchoring sites that constrain DNA axial rotation for RNAPI-driven DNA underwinding in the core. Our findings will contribute to understanding how nuclear protein condensates make up constraints for the site-specific regulation of DNA underwinding and transcription.
    DOI:  https://doi.org/10.1038/s42003-023-05750-w
  27. Nat Commun. 2024 Jan 25. 15(1): 735
    A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues.
    Haoshuang Wu, Li Yang, Rifang Luo, Li Li, Tiantian Zheng, Kaiyang Huang, Yumei Qin, Xia Yang, Xingdong Zhang, Yunbing Wang.
      Drug-eluting stent implantation suppresses the excessive proliferation of smooth muscle cells to reduce in-stent restenosis. However, the efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here, we show that a drug-free coating formulation functionalized with tailored recombinant humanized type III collagen exerts one-produces-multi effects in response to injured tissue following stent implantation. We demonstrate that the one-produces-multi coating possesses anticoagulation, anti-inflammatory, and intimal hyperplasia suppression properties. We perform transcriptome analysis to indicate that the drug-free coating favors the endothelialization process and induces the conversion of smooth muscle cells to a contractile phenotype. We find that compared to drug-eluting stents, our drug-free stent reduces in-stent restenosis in rabbit and porcine models and improves vascular neointimal healing in a rabbit model. Collectively, the one-produces-multi drug-free system represents a promising strategy for the next-generation of stents.
    DOI:  https://doi.org/10.1038/s41467-024-44902-2
  28. Nat Commun. 2024 Jan 25. 15(1): 749
    Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.
    Nikolaos M R Lykoskoufis, Evarist Planet, Halit Ongen, Didier Trono, Emmanouil T Dermitzakis.
      Transposable elements (TEs) are prevalent repeats in the human genome, play a significant role in the regulome, and their disruption can contribute to tumorigenesis. However, TE influence on gene expression in cancer remains unclear. Here, we analyze 275 normal colon and 276 colorectal cancer samples from the SYSCOL cohort, discovering 10,231 and 5,199 TE-expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively, of which 376 are colorectal cancer specific eQTLs, likely due to methylation changes. Tumor-specific TE-eQTLs show greater enrichment of transcription factors, compared to shared TE-eQTLs suggesting specific regulation of their expression in tumor. Bayesian networks reveal 1,766 TEs as mediators of genetic effects, altering the expression of 1,558 genes, including 55 known cancer driver genes and show that tumor-specific TE-eQTLs trigger the driver capability of TEs. These insights expand our knowledge of cancer drivers, deepening our understanding of tumorigenesis and presenting potential avenues for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-023-42405-0
  29. Nature. 2024 Jan 24.
    The HIV capsid mimics karyopherin engagement of FG-nucleoporins.
    C F Dickson, S Hertel, A J Tuckwell, N Li, J Ruan, S C Al-Izzi, N Ariotti, E Sierecki, Y Gambin, R G Morris, G J Towers, T Böcking, D A Jacques.
      HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus1,2. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore3. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport4. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.
    DOI:  https://doi.org/10.1038/s41586-023-06969-7
  30. Lancet. 2024 Jan 20. pii: S0140-6736(23)01478-2. [Epub ahead of print]403(10423): 293-304
    The pathogenesis of Parkinson's disease.
    Huw R Morris, Maria Grazia Spillantini, Carolyn M Sue, Caroline H Williams-Gray.
      Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.
    DOI:  https://doi.org/10.1016/S0140-6736(23)01478-2
  31. Nat Immunol. 2024 Jan 23.
    When ceramides meet immune senescence, a GIMAP5 connection.
    Atrayee Gope, Claudio Mauro.
      
    DOI:  https://doi.org/10.1038/s41590-023-01736-2
  32. Nature. 2024 Jan 24.
    Cortical regulation of helping behaviour towards others in pain.
    Mingmin Zhang, Ye Emily Wu, Mengping Jiang, Weizhe Hong.
      Humans and animals exhibit various forms of prosocial helping behaviour towards others in need1-3. Although previous research has investigated how individuals may perceive others' states4,5, the neural mechanisms of how they respond to others' needs and goals with helping behaviour remain largely unknown. Here we show that mice engage in a form of helping behaviour towards other individuals experiencing physical pain and injury-they exhibit allolicking (social licking) behaviour specifically towards the injury site, which aids the recipients in coping with pain. Using microendoscopic imaging, we found that single-neuron and ensemble activity in the anterior cingulate cortex (ACC) encodes others' state of pain and that this representation is different from that of general stress in others. Furthermore, functional manipulations demonstrate a causal role of the ACC in bidirectionally controlling targeted allolicking. Notably, this behaviour is represented in a population code in the ACC that differs from that of general allogrooming, a distinct type of prosocial behaviour elicited by others' emotional stress. These findings advance our understanding of the neural coding and regulation of helping behaviour.
    DOI:  https://doi.org/10.1038/s41586-023-06973-x
  33. Cell. 2024 Jan 17. pii: S0092-8674(23)01443-5. [Epub ahead of print]
    Cell surface RNAs control neutrophil recruitment.
    Ningning Zhang, Wenwen Tang, Lidiane Torres, Xujun Wang, Yasmeen Ajaj, Li Zhu, Yi Luan, Hongyue Zhou, Yadong Wang, Dingyao Zhang, Vadim Kurbatov, Sajid A Khan, Priti Kumar, Andres Hidalgo, Dianqing Wu, Jun Lu.
      RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.
    Keywords:  45S rRNA; E-selectin; Sidt1; Sidt2; peritonitis; snoRNA; tRNA
    DOI:  https://doi.org/10.1016/j.cell.2023.12.033
  34. Nat Biotechnol. 2024 Jan 25.
    Computationally designed sensors detect endogenous Ras activity and signaling effectors at subcellular resolution.
    Jason Z Zhang, William H Nguyen, Nathan Greenwood, John C Rose, Shao-En Ong, Dustin J Maly, David Baker.
      The utility of genetically encoded biosensors for sensing the activity of signaling proteins has been hampered by a lack of strategies for matching sensor sensitivity to the physiological concentration range of the target. Here we used computational protein design to generate intracellular sensors of Ras activity (LOCKR-based Sensor for Ras activity (Ras-LOCKR-S)) and proximity labelers of the Ras signaling environment (LOCKR-based, Ras activity-dependent Proximity Labeler (Ras-LOCKR-PL)). These tools allow the detection of endogenous Ras activity and labeling of the surrounding environment at subcellular resolution. Using these sensors in human cancer cell lines, we identified Ras-interacting proteins in oncogenic EML4-Alk granules and found that Src-Associated in Mitosis 68-kDa (SAM68) protein specifically enhances Ras activity in the granules. The ability to subcellularly localize endogenous Ras activity should deepen our understanding of Ras function in health and disease and may suggest potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41587-023-02107-w
  35. Nat Commun. 2024 Jan 26. 15(1): 780
    UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors.
    Duomeng Yang, Tingting Geng, Andrew G Harrison, Jason G Cahoon, Jian Xing, Baihai Jiao, Mark Wang, Chao Cheng, Robert E Hill, Huadong Wang, Anthony T Vella, Gong Cheng, Yanlin Wang, Penghua Wang.
      The Retinoic acid-Inducible Gene I (RIG-I) like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we screen 375 definite ubiquitin ligase knockout cell lines and identify Ubiquitin Protein Ligase E3 Component N-Recognin 5 (UBR5) as a positive regulator of RLR transcription. UBR5 deficiency reduces antiviral immune responses to RNA viruses, while increases viral replication in primary cells and mice. Ubr5 knockout mice are more susceptible to lethal RNA virus infection than wild type littermates. Mechanistically, UBR5 mediates the Lysine 63-linked ubiquitination of Tripartite Motif Protein 28 (TRIM28), an epigenetic repressor of RLRs. This modification prevents intramolecular SUMOylation of TRIM28, thus disengages the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
    DOI:  https://doi.org/10.1038/s41467-024-45141-1
  36. Nat Metab. 2024 Jan 23.
    Liver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication.
    Paula M Miotto, Chieh-Hsin Yang, Stacey N Keenan, William De Nardo, Cait A Beddows, Gio Fidelito, Garron T Dodd, Benjamin L Parker, Andrew F Hill, Paul R Burton, Kim Loh, Matthew J Watt.
      Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.
    DOI:  https://doi.org/10.1038/s42255-023-00971-z
  37. Nat Commun. 2024 Jan 26. 15(1): 786
    A cytomegalovirus inflammasome inhibitor reduces proinflammatory cytokine release and pyroptosis.
    Yingqi Deng, Eleonore Ostermann, Wolfram Brune.
      In response to viral infection, cells can initiate programmed cell death (PCD), leading to a reduction in the release of viral progeny. Viruses have therefore evolved specific mechanisms to curb PCD. Cytomegaloviruses (CMVs) are sophisticated manipulators of cellular defenses and encode potent inhibitors of apoptosis and necroptosis. However, a CMV inhibitor of pyroptosis has not been clearly identified and characterized. Here we identify the mouse cytomegalovirus M84 protein as an inhibitor of pyroptosis and proinflammatory cytokine release. M84 interacts with the pyrin domain of AIM2 and ASC to inhibit inflammasome assembly. It thereby prevents Caspase-1-mediated activation of interleukin 1β (IL-1β), IL-18, and Gasdermin D. Growth attenuation of an M84-deficient MCMV in macrophages is rescued by knockout of either Aim2 or Asc or by treatment with a Caspase-1 inhibitor, and its attenuation in infected mice is partially rescued in Asc knockout mice. Thus, viral inhibition of the inflammasome-pyroptosis pathway is important to promote viral replication in vivo.
    DOI:  https://doi.org/10.1038/s41467-024-45151-z
  38. Nat Aging. 2024 Jan 24.
    TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation.
    Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang.
      Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1-cGAS interaction is a relevant target for selectively suppressing inflammaging.
    DOI:  https://doi.org/10.1038/s43587-023-00564-1
  39. Nat Commun. 2024 Jan 26. 15(1): 759
    Structural and functional insights into the lipid regulation of human anion exchanger 2.
    Weiqi Zhang, Dian Ding, Yishuo Lu, Hongyi Chen, Peijun Jiang, Peng Zuo, Guangxi Wang, Juan Luo, Yue Yin, Jianyuan Luo, Yuxin Yin.
      Anion exchanger 2 (AE2) is an electroneutral Na+-independent Cl-/HCO3- exchanger belongs to the SLC4 transporter family. The widely expressed AE2 participates in a variety of physiological processes, including transepithelial acid-base secretion and osteoclastogenesis. Both the transmembrane domains (TMDs) and the N-terminal cytoplasmic domain (NTD) are involved in regulation of AE2 activity. However, the regulatory mechanism remains unclear. Here, we report a 3.2 Å cryo-EM structure of the AE2 TMDs in complex with PIP2 and a 3.3 Å full-length mutant AE2 structure in the resting state without PIP2. We demonstrate that PIP2 at the TMD dimer interface is involved in the substrate exchange process. Mutation in the PIP2 binding site leads to the displacement of TM7 and further stabilizes the interaction between the TMD and the NTD. Reduced substrate transport activity and conformation similar to AE2 in acidic pH indicating the central contribution of PIP2 to the function of AE2.
    DOI:  https://doi.org/10.1038/s41467-024-44966-0
  40. Sci Immunol. 2024 Jan 26. 9(91): eadi2848
    A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.
    David Wu, Ashley A Hailer, Sijia Wang, Michelle Yuan, Jamie Chan, Abdullah El Kurdi, David Han, Hira Ali, Blaize D'Angio, Aaron Mayer, Maha Rahim, Ayano Kondo, Daniel Klufas, Esther Kim, A Hunter Shain, Jaehyuk Choi, Tina Bhutani, Gregory Simpson, Roy C Grekin, Roberto Ricardo-Gonzalez, Elizabeth Purdom, Jeffrey P North, Jeffrey B Cheng, Raymond J Cho.
      Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.
    DOI:  https://doi.org/10.1126/sciimmunol.adi2848
  41. Nat Commun. 2024 Jan 24. 15(1): 699
    Anti-correlated feature selection prevents false discovery of subpopulations in scRNAseq.
    Scott R Tyler, Daniel Lozano-Ojalvo, Ernesto Guccione, Eric E Schadt.
      While sub-clustering cell-populations has become popular in single cell-omics, negative controls for this process are lacking. Popular feature-selection/clustering algorithms fail the null-dataset problem, allowing erroneous subdivisions of homogenous clusters until nearly each cell is called its own cluster. Using real and synthetic datasets, we find that anti-correlated gene selection reduces or eliminates erroneous subdivisions, increases marker-gene selection efficacy, and efficiently scales to millions of cells.
    DOI:  https://doi.org/10.1038/s41467-023-43406-9
  42. Nature. 2024 Jan 25.
    Tracking down tuberculosis.
    Neil Savage.
      
    Keywords:  Diseases; Imaging; Machine learning; Public health
    DOI:  https://doi.org/10.1038/d41586-024-00087-8
  43. Nature. 2024 Jan 26.
    Audio long read: Long COVID is a double curse in low-income nations - here's why.
    Heidi Ledford, Benjamin Thompson.
      
    Keywords:  Diseases; Public health; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-024-00224-3
  44. Nat Commun. 2024 Jan 24. 15(1): 705
    A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer's disease.
    Jiefei Wang, Ping Shangguan, Xiaoyu Chen, Yong Zhong, Ming Lin, Mu He, Yisheng Liu, Yuan Zhou, Xiaobin Pang, Lulu Han, Mengya Lu, Xiao Wang, Yang Liu, Huiqing Yang, Jingyun Chen, Chenhui Song, Jing Zhang, Xin Wang, Bingyang Shi, Ben Zhong Tang.
      Toxic amyloid-beta (Aβ) plaque and harmful inflammation are two leading symptoms of Alzheimer's disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aβ fibrils formation, degrades Aβ fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model.
    DOI:  https://doi.org/10.1038/s41467-024-44737-x
  45. Cell. 2024 Jan 11. pii: S0092-8674(23)01404-6. [Epub ahead of print]
    Dual phosphorylation of DGK5-mediated PA burst regulates ROS in plant immunity.
    Liang Kong, Xiyu Ma, Chao Zhang, Sung-Il Kim, Bo Li, Yingpeng Xie, In-Cheol Yeo, Hem Thapa, Sixue Chen, Timothy P Devarenne, Teun Munnik, Ping He, Libo Shan.
      Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA homeostasis is tightly regulated and intertwined with ROS signaling upon immune elicitation remains elusive. We report here that Arabidopsis diacylglycerol kinase 5 (DGK5) regulates plant pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). The pattern recognition receptor (PRR)-associated kinase BIK1 phosphorylates DGK5 at Ser-506, leading to a rapid PA burst and activation of plant immunity, whereas PRR-activated intracellular MPK4 phosphorylates DGK5 at Thr-446, which subsequently suppresses DGK5 activity and PA production, resulting in attenuated plant immunity. PA binds and stabilizes the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD), regulating ROS production in plant PTI and ETI, and their potentiation. Our data indicate that distinct phosphorylation of DGK5 by PRR-activated BIK1 and MPK4 balances the homeostasis of cellular PA burst that regulates ROS generation in coordinating two branches of plant immunity.
    Keywords:  effector-triggered immunity; pattern-triggered immunity; phosphatidic acid; phosphorylation; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cell.2023.12.030
  46. Nat Struct Mol Biol. 2024 Jan;31(1): 8-10
    Thinking outside the chromosome: epigenetic mechanisms in non-canonical chromatin species.
    Albert S Agustinus, Yael David.
      
    DOI:  https://doi.org/10.1038/s41594-023-01200-7
  47. Mol Cell. 2024 Jan 19. pii: S1097-2765(24)00002-9. [Epub ahead of print]
    HSP70 binds to specific non-coding RNA and regulates human RNA polymerase III.
    Sergio Leone, Avinash Srivastava, Andrés Herrero-Ruiz, Barbara Hummel, Lena Tittel, Roberto Campalastri, Fernando Aprile-Garcia, Jun Hao Tan, Prashant Rawat, Patrik Andersson, Anne E Willis, Ritwick Sawarkar.
      Molecular chaperones are critical for protein homeostasis and are implicated in several human pathologies such as neurodegeneration and cancer. While the binding of chaperones to nascent and misfolded proteins has been studied in great detail, the direct interaction between chaperones and RNA has not been systematically investigated. Here, we provide the evidence for widespread interaction between chaperones and RNA in human cells. We show that the major chaperone heat shock protein 70 (HSP70) binds to non-coding RNA transcribed by RNA polymerase III (RNA Pol III) such as tRNA and 5S rRNA. Global chromatin profiling revealed that HSP70 binds genomic sites of transcription by RNA Pol III. Detailed biochemical analyses showed that HSP70 alleviates the inhibitory effect of cognate tRNA transcript on tRNA gene transcription. Thus, our study uncovers an unexpected role of HSP70-RNA interaction in the biogenesis of a specific class of non-coding RNA with wider implications in cancer therapeutics.
    Keywords:  HSP70; RNA polymerase III; RNA-binding proteome; RNA-protein interaction; heat-shock proteins; molecular chaperones; non-coding RNA; proteostasis; tRNA; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.001
  48. Science. 2024 Jan 26. 383(6681): 443-448
    Receptor-associated kinases control the lipid provisioning program in plant-fungal symbiosis.
    Sergey Ivanov, Maria J Harrison.
      The mutualistic association between plants and arbuscular mycorrhizal (AM) fungi requires intracellular accommodation of the fungal symbiont and maintenance by means of lipid provisioning. Symbiosis signaling through lysin motif (LysM) receptor-like kinases and a leucine-rich repeat receptor-like kinase DOES NOT MAKE INFECTIONS 2 (DMI2) activates transcriptional programs that underlie fungal passage through the epidermis and accommodation in cortical cells. We show that two Medicago truncatula cortical cell-specific, membrane-bound proteins of a CYCLIN-DEPENDENT KINASE-LIKE (CKL) family associate with, and are phosphorylation substrates of, DMI2 and a subset of the LysM receptor kinases. CKL1 and CKL2 are required for AM symbiosis and control expression of transcription factors that regulate part of the lipid provisioning program. Onset of lipid provisioning is coupled with arbuscule branching and with the REDUCED ARBUSCULAR MYCORRHIZA 1 (RAM1) regulon for complete endosymbiont accommodation.
    DOI:  https://doi.org/10.1126/science.ade1124
  49. Nat Commun. 2024 Jan 22. 15(1): 656
    Connectome-based reservoir computing with the conn2res toolbox.
    Laura E Suárez, Agoston Mihalik, Filip Milisav, Kenji Marshall, Mingze Li, Petra E Vértes, Guillaume Lajoie, Bratislav Misic.
      The connection patterns of neural circuits form a complex network. How signaling in these circuits manifests as complex cognition and adaptive behaviour remains the central question in neuroscience. Concomitant advances in connectomics and artificial intelligence open fundamentally new opportunities to understand how connection patterns shape computational capacity in biological brain networks. Reservoir computing is a versatile paradigm that uses high-dimensional, nonlinear dynamical systems to perform computations and approximate cognitive functions. Here we present conn2res: an open-source Python toolbox for implementing biological neural networks as artificial neural networks. conn2res is modular, allowing arbitrary network architecture and dynamics to be imposed. The toolbox allows researchers to input connectomes reconstructed using multiple techniques, from tract tracing to noninvasive diffusion imaging, and to impose multiple dynamical systems, from spiking neurons to memristive dynamics. The versatility of the conn2res toolbox allows us to ask new questions at the confluence of neuroscience and artificial intelligence. By reconceptualizing function as computation, conn2res sets the stage for a more mechanistic understanding of structure-function relationships in brain networks.
    DOI:  https://doi.org/10.1038/s41467-024-44900-4
  50. Cell Rep Med. 2024 Jan 18. pii: S2666-3791(23)00616-X. [Epub ahead of print] 101387
    Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.
    Lucas Jurado-Fasoli, Guillermo Sanchez-Delgado, Xinyu Di, Wei Yang, Isabelle Kohler, Francesc Villarroya, Concepcion M Aguilera, Thomas Hankemeier, Jonatan R Ruiz, Borja Martinez-Tellez.
      Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.
    Keywords:  adiposity; bioactive lipids; brown adipose tissue; cardiometabolic health; cold; endocannabinoids; lipidomics; obesity; oxylipins; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101387
  51. Nat Biotechnol. 2024 Jan 25.
    Computer-based design of sensors that can monitor endogenous Ras activity.
      
    DOI:  https://doi.org/10.1038/s41587-023-02108-9
  52. Nat Commun. 2024 Jan 22. 15(1): 661
    MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.
    Hanqing Liao, Carolina Barra, Zhicheng Zhou, Xu Peng, Isaac Woodhouse, Arun Tailor, Robert Parker, Alexia Carré, Persephone Borrow, Michael J Hogan, Wayne Paes, Laurence C Eisenlohr, Roberto Mallone, Morten Nielsen, Nicola Ternette.
      Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue.
    DOI:  https://doi.org/10.1038/s41467-023-44460-z
  53. Nat Metab. 2024 Jan 26.
    Functionally heterogeneous β cells regulate biphasic insulin secretion.
      
    DOI:  https://doi.org/10.1038/s42255-023-00964-y
  54. Nature. 2024 Jan 24.
    HIV-1 capsids enter the FG phase of nuclear pores like a transport receptor.
    Liran Fu, Erika N Weiskopf, Onno Akkermans, Nicholas A Swanson, Shiya Cheng, Thomas U Schwartz, Dirk Görlich.
      HIV-1 infection requires nuclear entry of the viral genome. Previous evidence suggests that this entry proceeds through nuclear pore complexes (NPCs), with the 120 × 60 nm capsid squeezing through an approximately 60-nm-wide central channel1 and crossing the permeability barrier of the NPC. This barrier can be described as an FG phase2 that is assembled from cohesively interacting phenylalanine-glycine (FG) repeats3 and is selectively permeable to cargo captured by nuclear transport receptors (NTRs). Here we show that HIV-1 capsid assemblies can target NPCs efficiently in an NTR-independent manner and bind directly to several types of FG repeats, including barrier-forming cohesive repeats. Like NTRs, the capsid readily partitions into an in vitro assembled cohesive FG phase that can serve as an NPC mimic and excludes much smaller inert probes such as mCherry. Indeed, entry of the capsid protein into such an FG phase is greatly enhanced by capsid assembly, which also allows the encapsulated clients to enter. Thus, our data indicate that the HIV-1 capsid behaves like an NTR, with its interior serving as a cargo container. Because capsid-coating with trans-acting NTRs would increase the diameter by 10 nm or more, we suggest that such a 'self-translocating' capsid undermines the size restrictions imposed by the NPC scaffold, thereby bypassing an otherwise effective barrier to viral infection.
    DOI:  https://doi.org/10.1038/s41586-023-06966-w
  55. Nat Genet. 2024 Jan 26.
    Conditional transcriptome-wide association study for fine-mapping candidate causal genes.
    Lu Liu, Ran Yan, Ping Guo, Jiadong Ji, Weiming Gong, Fuzhong Xue, Zhongshang Yuan, Xiang Zhou.
      Transcriptome-wide association studies (TWASs) aim to integrate genome-wide association studies with expression-mapping studies to identify genes with genetically predicted expression (GReX) associated with a complex trait. In the present report, we develop a method, GIFT (gene-based integrative fine-mapping through conditional TWAS), that performs conditional TWAS analysis by explicitly controlling for GReX of all other genes residing in a local region to fine-map putatively causal genes. GIFT is frequentist in nature, explicitly models both expression correlation and cis-single nucleotide polymorphism linkage disequilibrium across multiple genes and uses a likelihood framework to account for expression prediction uncertainty. As a result, GIFT produces calibrated P values and is effective for fine-mapping. We apply GIFT to analyze six traits in the UK Biobank, where GIFT narrows down the set size of putatively causal genes by 32.16-91.32% compared with existing TWAS fine-mapping approaches. The genes identified by GIFT highlight the importance of vessel regulation in determining blood pressures and lipid metabolism for regulating lipid levels.
    DOI:  https://doi.org/10.1038/s41588-023-01645-y
  56. Nature. 2024 Jan 23.
    The hagfish genome and the evolution of vertebrates.
    Ferdinand Marlétaz, Nataliya Timoshevskaya, Vladimir A Timoshevskiy, Elise Parey, Oleg Simakov, Daria Gavriouchkina, Masakazu Suzuki, Kaoru Kubokawa, Sydney Brenner, Jeramiah J Smith, Daniel S Rokhsar.
      As the only surviving lineages of jawless fishes, hagfishes and lampreys provide a critical window into early vertebrate evolution1-3. Here, we investigate the complex history, timing, and functional role of genome-wide duplications4-7 and programmed DNA elimination8,9 in vertebrates in the light of a chromosome-scale genome sequence for the brown hagfish Eptatretus atami. Combining evidence from syntenic and phylogenetic analyses, we establish a comprehensive picture of vertebrate genome evolution including an auto-tetraploidisation (1RV) predating the Early Cambrian cyclostome-gnathostome split, followed by a Mid-Late Cambrian allo-tetraploidisation (2RJV) in gnathostomes and a prolonged Cambrian-Ordovician hexaploidisation (2RCY) in cyclostomes. Subsequently, hagfishes underwent extensive genomic changes with chromosomal fusions accompanied by the loss of genes essential for organ systems (eyes, osteoclasts), accounting in part for the simplification of their body plan1,2. Finally, we characterise programmed DNA elimination in hagfish, identifying protein-coding genes and repetitive elements that are deleted from somatic cell lineages during early development. The elimination of these germline-specific genes provides a mechanism for resolving genetic conflict between soma and germline by repressing germline/pluripotency functions, paralleling findings in lampreys10,11. Reconstruction of the early genomic history of vertebrates provides a valuable framework for further exploration of cyclostome and jawed vertebrate evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07070-3
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