bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒03‒17
57 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.
  2. The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression.
  3. Interrogations of single-cell RNA splicing landscapes with SCASL define new cell identities with physiological relevance.
  4. Looking towards the future of MRI in Africa.
  5. How transposable elements are spliced out.
  6. Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.
  7. The chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans.
  8. The ebbs and flows of creativity.
  9. Deciphering the genetic architecture of pain intensity.
  10. Pooling babies' saliva helps catch grave infection in newborns.
  11. An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.
  12. Deadly brain cancer shrinks after CAR-T therapy - but for how long is unclear.
  13. Quantitative proteomics reveals tissue-specific, infection-induced and species-specific neutrophil protein signatures.
  14. TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.
  15. Blockbuster obesity drug leads to better health in people with HIV.
  16. Massive public-health experiment sends vaccination rates soaring.
  17. dCas13-mediated translational repression for accurate gene silencing in mammalian cells.
  18. A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease.
  19. A multi-demand operating system underlying diverse cognitive tasks.
  20. Mechanosensing regulates tissue repair program in macrophages.
  21. AI & robotics briefing: GPT-4 can hack websites without human help.
  22. Breaking the deadlock in genetic code expansion.
  23. Researchers call for a major rethink of how Alzheimer's treatments are evaluated.
  24. Editorial expression of concern.
  25. Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.
  26. Regulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2.
  27. MYC activates transcriptional enhancers to drive cancer progression.
  28. Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.
  29. Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.
  30. Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.
  31. Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression.
  32. Mitochondrial complex I activity in microglia sustains neuroinflammation.
  33. CARD8 kills CD4+ T cells in response to HIV entry.
  34. Numerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson's disease.
  35. Genetic contribution to heterogeneity in type 2 diabetes.
  36. NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.
  37. Transcription factor binding site affinity and the link to phenotype.
  38. Inflammatory interferon response in the SARS-CoV-2-infected brain.
  39. Regulation of innate-like activities of neonatal CD8+ T cells.
  40. Identification of a cold sensor in peripheral somatosensory neurons.
  41. The eye provides an immunological gateway to the brain.
  42. AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization.
  43. De novo-designed transmembrane proteins bind and regulate a cytokine receptor.
  44. Pas de deux of NLRP3 and ASC with CD63 on mast cell granules.
  45. Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system.
  46. Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.
  47. PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.
  48. Anaphylactic degranulation by mast cells requires the mobilization of inflammasome components.
  49. Harnessing regulatory T cells to establish immune tolerance.
  50. Complement-ary protection for all ages.
  51. IL-4-ever young: Type 2 cytokine signaling in macrophages slows aging.
  52. Dysregulated cellular stress management becomes a source of stress.
  53. IgG is an early driver of aging.
  54. The neuroscientist formerly known as Prince's audio engineer.
  55. Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images.
  56. Exocytic plasma membrane flows remodel endoplasmic reticulum-plasma membrane tethering for septin collar assembly.
  57. Misconduct's forgotten victims.
  1. Nature. 2024 Mar 13.
    APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.
    Michael S Haney, Róbert Pálovics, Christy Nicole Munson, Chris Long, Patrik K Johansson, Oscar Yip, Wentao Dong, Eshaan Rawat, Elizabeth West, Johannes C M Schlachetzki, Andy Tsai, Ian Hunter Guldner, Bhawika S Lamichhane, Amanda Smith, Nicholas Schaum, Kruti Calcuttawala, Andrew Shin, Yung-Hua Wang, Chengzhong Wang, Nicole Koutsodendris, Geidy E Serrano, Thomas G Beach, Eric M Reiman, Christopher K Glass, Monther Abu-Remaileh, Annika Enejder, Yadong Huang, Tony Wyss-Coray.
      Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41586-024-07185-7
  2. Nat Commun. 2024 Mar 11. 15(1): 2194
    The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression.
    Meng Xu, Taku Ito-Kureha, Hyun-Seo Kang, Aleksandar Chernev, Timsse Raj, Kai P Hoefig, Christine Hohn, Florian Giesert, Yinhu Wang, Wenliang Pan, Natalia Ziętara, Tobias Straub, Regina Feederle, Carolin Daniel, Barbara Adler, Julian König, Stefan Feske, George C Tsokos, Wolfgang Wurst, Henning Urlaub, Michael Sattler, Jan Kisielow, F Gregory Wulczyn, Marcin Łyszkiewicz, Vigo Heissmeyer.
      The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.
    DOI:  https://doi.org/10.1038/s41467-024-46371-z
  3. Nat Commun. 2024 Mar 09. 15(1): 2164
    Interrogations of single-cell RNA splicing landscapes with SCASL define new cell identities with physiological relevance.
    Xianke Xiang, Yao He, Zemin Zhang, Xuerui Yang.
      RNA splicing shapes the gene regulatory programs that underlie various physiological and disease processes. Here, we present the SCASL (single-cell clustering based on alternative splicing landscapes) method for interrogating the heterogeneity of RNA splicing with single-cell RNA-seq data. SCASL resolves the issue of biased and sparse data coverage on single-cell RNA splicing and provides a new scheme for classifications of cell identities. With previously published datasets as examples, SCASL identifies new cell clusters indicating potentially precancerous and early-tumor stages in triple-negative breast cancer, illustrates cell lineages of embryonic liver development, and provides fine clusters of highly heterogeneous tumor-associated CD4 and CD8 T cells with functional and physiological relevance. Most of these findings are not readily available via conventional cell clustering based on single-cell gene expression data. Our study shows the potential of SCASL in revealing the intrinsic RNA splicing heterogeneity and generating biological insights into the dynamic and functional cell landscapes in complex tissues.
    DOI:  https://doi.org/10.1038/s41467-024-46480-9
  4. Nat Commun. 2024 Mar 13. 15(1): 2260
    Looking towards the future of MRI in Africa.
      
    DOI:  https://doi.org/10.1038/s41467-024-46567-3
  5. Nat Genet. 2024 Mar;56(3): 357
    How transposable elements are spliced out.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-01696-9
  6. Sci Transl Med. 2024 Mar 13. 16(738): eadk1866
    Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.
    Linkang Zhou, Xiaoxue Qiu, Ziyi Meng, Tongyu Liu, Zhimin Chen, Peng Zhang, Henry Kuang, Tong Pan, You Lu, Ling Qi, David P Olson, X Z Shawn Xu, Y Eugene Chen, Siming Li, Jiandie D Lin.
      Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.
    DOI:  https://doi.org/10.1126/scitranslmed.adk1866
  7. Nat Commun. 2024 Mar 14. 15(1): 2320
    The chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans.
    Felicity J Emerson, Caitlin Chiu, Laura Y Lin, Christian G Riedel, Ming Zhu, Siu Sylvia Lee.
      SET-26, HCF-1, and HDA-1 are highly conserved chromatin factors with key roles in development and aging. Here we present mechanistic insights into how these factors regulate gene expression and modulate longevity in C. elegans. We show that SET-26 and HCF-1 cooperate to regulate a common set of genes, and both antagonize the histone deacetylase HDA-1 to limit longevity. HCF-1 localization at chromatin is largely dependent on functional SET-26, whereas SET-26 is only minorly affected by loss of HCF-1, suggesting that SET-26 could recruit HCF-1 to chromatin. HDA-1 opposes SET-26 and HCF-1 on the regulation of a subset of their common target genes and in longevity. Our findings suggest that SET-26, HCF-1, and HDA-1 comprise a mechanism to fine-tune gene expression and longevity and likely have important implications for the mechanistic understanding of how these factors function in diverse organisms, particularly in aging biology.
    DOI:  https://doi.org/10.1038/s41467-024-46510-6
  8. Science. 2024 Mar 15. 383(6688): 1262
    The ebbs and flows of creativity.
    Jeffrey McDonnell.
      
    DOI:  https://doi.org/10.1126/science.adp1314
  9. Nat Med. 2024 Mar 14.
    Deciphering the genetic architecture of pain intensity.
      
    DOI:  https://doi.org/10.1038/s41591-024-02881-3
  10. Nature. 2024 Mar 13.
    Pooling babies' saliva helps catch grave infection in newborns.
      
    Keywords:  Public health
    DOI:  https://doi.org/10.1038/d41586-024-00733-1
  11. Nat Commun. 2024 Mar 11. 15(1): 2188
    An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome.
    Tabula Microcebus Consortium
      Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.
    DOI:  https://doi.org/10.1038/s41467-024-46070-9
  12. Nature. 2024 Mar 13.
    Deadly brain cancer shrinks after CAR-T therapy - but for how long is unclear.
    Heidi Ledford.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00704-6
  13. Sci Rep. 2024 03 12. 14(1): 5966
    Quantitative proteomics reveals tissue-specific, infection-induced and species-specific neutrophil protein signatures.
    Gabriel Sollberger, Alejandro J Brenes, Jordan Warner, J Simon C Arthur, Andrew J M Howden.
      Neutrophils are one of the first responders to infection and are a key component of the innate immune system through their ability to phagocytose and kill invading pathogens, secrete antimicrobial molecules and produce extracellular traps. Neutrophils are produced in the bone marrow, circulate within the blood and upon immune challenge migrate to the site of infection. We wanted to understand whether this transition shapes the mouse neutrophil protein landscape, how the mouse neutrophil proteome is impacted by systemic infection and perform a comparative analysis of human and mouse neutrophils. Using quantitative mass spectrometry we reveal tissue-specific, infection-induced and species-specific neutrophil protein signatures. We show a high degree of proteomic conservation between mouse bone marrow, blood and peritoneal neutrophils, but also identify key differences in the molecules that these cells express for sensing and responding to their environment. Systemic infection triggers a change in the bone marrow neutrophil population with considerable impact on the core machinery for protein synthesis and DNA replication along with environmental sensors. We also reveal profound differences in mouse and human blood neutrophils, particularly their granule contents. Our proteomics data provides a valuable resource for understanding neutrophil function and phenotypes across species and model systems.
    DOI:  https://doi.org/10.1038/s41598-024-56163-6
  14. J Clin Invest. 2024 Jan 11. pii: e172095. [Epub ahead of print]134(6):
    TGF-β controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription in mice.
    Danielle A Callaway, Ian J Penkala, Su Zhou, Jonathan J Knowlton, Fabian Cardenas-Diaz, Apoorva Babu, Michael P Morley, Mariana Lopes, Benjamin A Garcia, Edward E Morrisey.
      Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease disrupting lung health throughout the life of an individual and that is increasing in incidence. The TGF-β superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that TGFbr2 is critical for alveolar epithelial (AT1) cell fate maintenance and function. Loss of TGFbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analyses reveal the necessity of TGFbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF-β signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF-β signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.
    Keywords:  Extracellular matrix; Integrins; Pulmonology; Respiration
    DOI:  https://doi.org/10.1172/JCI172095
  15. Nature. 2024 Mar 11.
    Blockbuster obesity drug leads to better health in people with HIV.
    Mariana Lenharo.
      
    Keywords:  HIV infections; Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-00691-8
  16. Nature. 2024 Mar 13.
    Massive public-health experiment sends vaccination rates soaring.
    Max Kozlov.
      
    Keywords:  Epidemiology; Public health; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-024-00730-4
  17. Nat Commun. 2024 Mar 11. 15(1): 2205
    dCas13-mediated translational repression for accurate gene silencing in mammalian cells.
    Antonios Apostolopoulos, Naohiro Kawamoto, Siu Yu A Chow, Hitomi Tsuiji, Yoshiho Ikeuchi, Yuichi Shichino, Shintaro Iwasaki.
      Current gene silencing tools based on RNA interference (RNAi) or, more recently, clustered regularly interspaced short palindromic repeats (CRISPR)‒Cas13 systems have critical drawbacks, such as off-target effects (RNAi) or collateral mRNA cleavage (CRISPR‒Cas13). Thus, a more specific method of gene knockdown is needed. Here, we develop CRISPRδ, an approach for translational silencing, harnessing catalytically inactive Cas13 proteins (dCas13). Owing to its tight association with mRNA, dCas13 serves as a physical roadblock for scanning ribosomes during translation initiation and does not affect mRNA stability. Guide RNAs covering the start codon lead to the highest efficacy regardless of the translation initiation mechanism: cap-dependent, internal ribosome entry site (IRES)-dependent, or repeat-associated non-AUG (RAN) translation. Strikingly, genome-wide ribosome profiling reveals the ultrahigh gene silencing specificity of CRISPRδ. Moreover, the fusion of a translational repressor to dCas13 further improves the performance. Our method provides a framework for translational repression-based gene silencing in eukaryotes.
    DOI:  https://doi.org/10.1038/s41467-024-46412-7
  18. Nat Commun. 2024 Mar 12. 15(1): 2243
    A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer's disease.
    Stergios Tsartsalis, Hannah Sleven, Nurun Fancy, Frank Wessely, Amy M Smith, Nanet Willumsen, To Ka Dorcas Cheung, Michal J Rokicki, Vicky Chau, Eseoghene Ifie, Combiz Khozoie, Olaf Ansorge, Xin Yang, Marion H Jenkyns, Karen Davey, Aisling McGarry, Robert C J Muirhead, Stephanie Debette, Johanna S Jackson, Axel Montagne, David R Owen, J Scott Miners, Seth Love, Caleb Webber, M Zameel Cader, Paul M Matthews.
      Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.
    DOI:  https://doi.org/10.1038/s41467-024-46630-z
  19. Nat Commun. 2024 Mar 11. 15(1): 2185
    A multi-demand operating system underlying diverse cognitive tasks.
    Weidong Cai, Jalil Taghia, Vinod Menon.
      The existence of a multiple-demand cortical system with an adaptive, domain-general, role in cognition has been proposed, but the underlying dynamic mechanisms and their links to cognitive control abilities are poorly understood. Here we use a probabilistic generative Bayesian model of brain circuit dynamics to determine dynamic brain states across multiple cognitive domains, independent datasets, and participant groups, including task fMRI data from Human Connectome Project, Dual Mechanisms of Cognitive Control study and a neurodevelopment study. We discover a shared brain state across seven distinct cognitive tasks and found that the dynamics of this shared brain state predicted cognitive control abilities in each task. Our findings reveal the flexible engagement of dynamic brain processes across multiple cognitive domains and participant groups, and uncover the generative mechanisms underlying the functioning of a domain-general cognitive operating system. Our computational framework opens promising avenues for probing neurocognitive function and dysfunction.
    DOI:  https://doi.org/10.1038/s41467-024-46511-5
  20. Sci Adv. 2024 Mar 15. 10(11): eadk6906
    Mechanosensing regulates tissue repair program in macrophages.
    Matthew L Meizlish, Yoshitaka Kimura, Scott D Pope, Rita Matta, Catherine Kim, Naomi H Philip, Linde Meyaard, Anjelica Gonzalez, Ruslan Medzhitov.
      Tissue-resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a noncanonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by colony-stimulating factor 1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study identifies an "amoeboid" mode of ECM mechanosensing through which macrophages may regulate tissue repair and fibrosis.
    DOI:  https://doi.org/10.1126/sciadv.adk6906
  21. Nature. 2024 Mar 05.
    AI & robotics briefing: GPT-4 can hack websites without human help.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-00737-x
  22. Nat Chem Biol. 2024 Mar 11.
    Breaking the deadlock in genetic code expansion.
    Ya-Ming Hou, Yuko Nakano.
      
    DOI:  https://doi.org/10.1038/s41589-024-01579-4
  23. Nature. 2024 Mar;627(8003): S18-S20
    Researchers call for a major rethink of how Alzheimer's treatments are evaluated.
    Esther Landhuis.
      
    Keywords:  Alzheimer's disease; Diseases; Health care; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00756-8
  24. Sci Adv. 2024 Mar 15. 10(11): eadp1930
    Editorial expression of concern.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/sciadv.adp1930
  25. Nat Commun. 2024 Mar 11. 15(1): 2207
    Simultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions.
    Jordan Currie, Vyshnavi Manda, Sean K Robinson, Celine Lai, Vertica Agnihotri, Veronica Hidalgo, R W Ludwig, Kai Zhang, Jay Pavelka, Zhao V Wang, June-Wha Rhee, Maggie P Y Lam, Edward Lau.
      The spatial and temporal distributions of proteins are critical to protein function, but cannot be directly assessed by measuring protein bundance. Here we describe a mass spectrometry-based proteomics strategy, Simultaneous Proteome Localization and Turnover (SPLAT), to measure concurrently protein turnover rates and subcellular localization in the same experiment. Applying the method, we find that unfolded protein response (UPR) has different effects on protein turnover dependent on their subcellular location in human AC16 cells, with proteome-wide slowdown but acceleration among stress response proteins in the ER and Golgi. In parallel, UPR triggers broad differential localization of proteins including RNA-binding proteins and amino acid transporters. Moreover, we observe newly synthesized proteins including EGFR that show a differential localization under stress than the existing protein pools, reminiscent of protein trafficking disruptions. We next applied SPLAT to an induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) model of cancer drug cardiotoxicity upon treatment with the proteasome inhibitor carfilzomib. Paradoxically, carfilzomib has little effect on global average protein half-life, but may instead selectively disrupt sarcomere protein homeostasis. This study provides a view into the interactions of protein spatial and temporal dynamics and demonstrates a method to examine protein homeostasis regulations in stress and drug response.
    DOI:  https://doi.org/10.1038/s41467-024-46600-5
  26. Nat Commun. 2024 Mar 14. 15(1): 2315
    Regulation of meiotic telomere dynamics through membrane fluidity promoted by AdipoR2-ELOVL2.
    Jingjing Zhang, Mario Ruiz, Per-Olof Bergh, Marcus Henricsson, Nena Stojanović, Ranjan Devkota, Marius Henn, Mohammad Bohlooly-Y, Abrahan Hernández-Hernández, Manfred Alsheimer, Jan Borén, Marc Pilon, Hiroki Shibuya.
      The cellular membrane in male meiotic germ cells contains a unique class of phospholipids and sphingolipids that is required for male reproduction. Here, we show that a conserved membrane fluidity sensor, AdipoR2, regulates the meiosis-specific lipidome in mouse testes by promoting the synthesis of sphingolipids containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs). AdipoR2 upregulates the expression of a fatty acid elongase, ELOVL2, both transcriptionally and post-transcriptionally, to synthesize VLC-PUFA. The depletion of VLC-PUFAs and subsequent accumulation of palmitic acid in AdipoR2 knockout testes stiffens the cellular membrane and causes the invagination of the nuclear envelope. This condition impairs the nuclear peripheral distribution of meiotic telomeres, leading to errors in homologous synapsis and recombination. Further, the stiffened membrane impairs the formation of intercellular bridges and the germ cell syncytium, which disrupts the orderly arrangement of cell types within the seminiferous tubules. According to our findings we propose a framework in which the highly-fluid membrane microenvironment shaped by AdipoR2-ELOVL2 underpins meiosis-specific chromosome dynamics in testes.
    DOI:  https://doi.org/10.1038/s41467-024-46718-6
  27. Nat Genet. 2024 Mar 13.
    MYC activates transcriptional enhancers to drive cancer progression.
      
    DOI:  https://doi.org/10.1038/s41588-024-01677-y
  28. Nat Commun. 2024 Mar 12. 15(1): 2195
    Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.
    Naoya Yamada, Tadayoshi Karasawa, Junya Ito, Daisuke Yamamuro, Kazushi Morimoto, Toshitaka Nakamura, Takanori Komada, Chintogtokh Baatarjav, Yuma Saimoto, Yuka Jinnouchi, Kazuhisa Watanabe, Kouichi Miura, Naoya Yahagi, Kiyotaka Nakagawa, Takayoshi Matsumura, Ken-Ichi Yamada, Shun Ishibashi, Naohiro Sata, Marcus Conrad, Masafumi Takahashi.
      Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
    DOI:  https://doi.org/10.1038/s41467-024-46386-6
  29. Cell Host Microbe. 2024 Mar 08. pii: S1931-3128(24)00056-8. [Epub ahead of print]
    Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease.
    Xin Zhou, Xiaotao Shen, Jethro S Johnson, Daniel J Spakowicz, Melissa Agnello, Wenyu Zhou, Monica Avina, Alexander Honkala, Faye Chleilat, Shirley Jingyi Chen, Kexin Cha, Shana Leopold, Chenchen Zhu, Lei Chen, Lin Lyu, Daniel Hornburg, Si Wu, Xinyue Zhang, Chao Jiang, Liuyiqi Jiang, Lihua Jiang, Ruiqi Jian, Andrew W Brooks, Meng Wang, Kévin Contrepois, Peng Gao, Sophia Miryam Schüssler-Fiorenza Rose, Thi Dong Binh Tran, Hoan Nguyen, Alessandra Celli, Bo-Young Hong, Eddy J Bautista, Yair Dorsett, Paula B Kavathas, Yanjiao Zhou, Erica Sodergren, George M Weinstock, Michael P Snyder.
      To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.
    Keywords:  insulin resistance; longitudinal profiling; microbiome host interaction; microbiome stability; nasal microbiome; oral microbiome; precision medicine; prediabetes; skin microbiome; stool microbiome
    DOI:  https://doi.org/10.1016/j.chom.2024.02.012
  30. Nat Commun. 2024 Mar 12. 15(1): 2220
    Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.
    Kate E Stanley, Tatjana Jatsenko, Stefania Tuveri, Dhanya Sudhakaran, Lore Lannoo, Kristel Van Calsteren, Marie de Borre, Ilse Van Parijs, Leen Van Coillie, Kris Van Den Bogaert, Rodrigo De Almeida Toledo, Liesbeth Lenaerts, Sabine Tejpar, Kevin Punie, Laura Y Rengifo, Peter Vandenberghe, Bernard Thienpont, Joris Robert Vermeesch.
      Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.
    DOI:  https://doi.org/10.1038/s41467-024-46435-0
  31. Sci Adv. 2024 Mar 15. 10(11): eadm9518
    Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression.
    Karen G Wong, Yu-Chia F Cheng, Vincent H Wu, Anna A Kiseleva, Jun Li, Andrey Poleshko, Cheryl L Smith, Jonathan A Epstein.
      Extracellular signals are transmitted through kinase cascades to modulate gene expression, but it remains unclear how epigenetic changes regulate this response. Here, we provide evidence that growth factor-stimulated changes in the transcript levels of many responsive genes are accompanied by increases in histone phosphorylation levels, specifically at histone H3 serine-10 when the adjacent lysine-9 is dimethylated (H3K9me2S10). Imaging and proteomic approaches show that epidermal growth factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and this subset of EGF-induced genes is dependent on MSK2 for transcription. Together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes.
    DOI:  https://doi.org/10.1126/sciadv.adm9518
  32. Nature. 2024 Mar 13.
    Mitochondrial complex I activity in microglia sustains neuroinflammation.
    L Peruzzotti-Jametti, C M Willis, G Krzak, R Hamel, L Pirvan, R-B Ionescu, J A Reisz, H A Prag, M E Garcia-Segura, V Wu, Y Xiang, B Barlas, A M Casey, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, P Prasad, A E Vincent, C Frezza, C Viscomi, G Balmus, Z Takats, J C Marioni, A D'Alessandro, M P Murphy, I Mohorianu, S Pluchino.
      Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.
    DOI:  https://doi.org/10.1038/s41586-024-07167-9
  33. Nat Rev Immunol. 2024 Mar 11.
    CARD8 kills CD4+ T cells in response to HIV entry.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01021-9
  34. Nat Commun. 2024 Mar 12. 15(1): 1905
    Numerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson's disease.
    Louis Albert, Jevita Potheegadoo, Bruno Herbelin, Fosco Bernasconi, Olaf Blanke.
      Hallucinations are frequent non-motor symptoms in Parkinson's disease (PD) associated with dementia and higher mortality. Despite their high clinical relevance, current assessments of hallucinations are based on verbal self-reports and interviews that are limited by important biases. Here, we used virtual reality (VR), robotics, and digital online technology to quantify presence hallucination (vivid sensations that another person is nearby when no one is actually present and can neither be seen nor heard) in laboratory and home-based settings. We establish that elevated numerosity estimation of virtual human agents in VR is a digital marker for experimentally induced presence hallucinations in healthy participants, as confirmed across several control conditions and analyses. We translated the digital marker (numerosity estimation) to an online procedure that 170 PD patients carried out remotely at their homes, revealing that PD patients with disease-related presence hallucinations (but not control PD patients) showed higher numerosity estimation. Numerosity estimation enables quantitative monitoring of hallucinations, is an easy-to-use unobtrusive online method, reaching people far away from medical centers, translating neuroscientific findings using robotics and VR, to patients' homes without specific equipment or trained staff.
    DOI:  https://doi.org/10.1038/s41467-024-45912-w
  35. Nat Genet. 2024 Mar;56(3): 357
    Genetic contribution to heterogeneity in type 2 diabetes.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-024-01698-7
  36. Nat Commun. 2024 Mar 13. 15(1): 2264
    NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia.
    Chih-Wei Chen, Chi Su, Chang-Yu Huang, Xuan-Rong Huang, Xiaojing Cuili, Tung Chao, Chun-Hsiang Fan, Cheng-Wei Ting, Yi-Wei Tsai, Kai-Chien Yang, Ti-Yen Yeh, Sung-Tsang Hsieh, Yi-Ju Chen, Yuxi Feng, Tony Hunter, Zee-Fen Chang.
      NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.
    DOI:  https://doi.org/10.1038/s41467-024-46385-7
  37. Nat Genet. 2024 Mar;56(3): 357
    Transcription factor binding site affinity and the link to phenotype.
    Michael Fletcher.
      
    DOI:  https://doi.org/10.1038/s41588-024-01697-8
  38. Nat Aging. 2024 Mar 14.
    Inflammatory interferon response in the SARS-CoV-2-infected brain.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-024-00604-4
  39. Nat Rev Immunol. 2024 Mar 11.
    Regulation of innate-like activities of neonatal CD8+ T cells.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01020-w
  40. Nat Neurosci. 2024 Mar 11.
    Identification of a cold sensor in peripheral somatosensory neurons.
      
    DOI:  https://doi.org/10.1038/s41593-024-01606-6
  41. Nat Rev Immunol. 2024 Mar 11.
    The eye provides an immunological gateway to the brain.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-01019-3
  42. Nature. 2024 Mar 13.
    AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization.
    Yuan Fang, Kushagra Bansal, Sara Mostafavi, Christophe Benoist, Diane Mathis.
      AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells1-4. The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice5. Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.
    DOI:  https://doi.org/10.1038/s41586-024-07169-7
  43. Nat Chem Biol. 2024 Mar 13.
    De novo-designed transmembrane proteins bind and regulate a cytokine receptor.
    Marco Mravic, Li He, Huong T Kratochvil, Hailin Hu, Sarah E Nick, Weiya Bai, Anne Edwards, Hyunil Jo, Yibing Wu, Daniel DiMaio, William F DeGrado.
      Transmembrane (TM) domains as simple as a single span can perform complex biological functions using entirely lipid-embedded chemical features. Computational design has the potential to generate custom tool molecules directly targeting membrane proteins at their functional TM regions. Thus far, designed TM domain-targeting agents have been limited to mimicking the binding modes and motifs of natural TM interaction partners. Here, we demonstrate the design of de novo TM proteins targeting the erythropoietin receptor (EpoR) TM domain in a custom binding topology competitive with receptor homodimerization. The TM proteins expressed in mammalian cells complex with EpoR and inhibit erythropoietin-induced cell proliferation. In vitro, the synthetic TM domain complex outcompetes EpoR homodimerization. Structural characterization reveals that the complex involves the intended amino acids and agrees with our designed molecular model of antiparallel TM helices at 1:1 stoichiometry. Thus, membrane protein TM regions can now be targeted in custom-designed topologies.
    DOI:  https://doi.org/10.1038/s41589-024-01562-z
  44. Nat Immunol. 2024 Mar 14.
    Pas de deux of NLRP3 and ASC with CD63 on mast cell granules.
    J Magarian Blander, Yuhua Shi.
      
    DOI:  https://doi.org/10.1038/s41590-024-01791-3
  45. Nat Commun. 2024 Mar 12. 15(1): 2230
    Identifying regulators of aberrant stem cell and differentiation activity in colorectal cancer using a dual endogenous reporter system.
    Sandor Spisak, David Chen, Pornlada Likasitwatanakul, Paul Doan, Zhixin Li, Pratyusha Bala, Laura Vizkeleti, Viktoria Tisza, Pushpamali De Silva, Marios Giannakis, Brian Wolpin, Jun Qi, Nilay S Sethi.
      Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-024-46285-w
  46. Cell Rep. 2024 Mar 08. pii: S2211-1247(24)00262-6. [Epub ahead of print]43(3): 113934
    Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.
    Yi Luan, Jiajia Hu, Qijun Wang, Xujun Wang, Wenxue Li, Rihao Qu, Chuan Yang, Barani Kumar Rajendran, Hongyue Zhou, Peng Liu, Ningning Zhang, Yu Shi, Yansheng Liu, Wenwen Tang, Jun Lu, Dianqing Wu.
      Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.
    Keywords:  CD101; CP: Immunology; Wnt signaling; colitis; extramedullary hematopoiesis; granulopoiesis; immune suppression; neutrophil
    DOI:  https://doi.org/10.1016/j.celrep.2024.113934
  47. EMBO Rep. 2024 Mar 13.
    PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.
    Cheng Chen, Qianyu Liu, Wenjie Chen, Zhiyuan Gong, Bo Kang, Meihua Sui, Liming Huang, Ying-Jie Wang.
      Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.
    Keywords:  Electron Transport Chain Complex; Human Naive Pluripotency; PRODH; Reactive Oxygen Species; mtOXPHOS
    DOI:  https://doi.org/10.1038/s44319-024-00110-z
  48. Nat Immunol. 2024 Mar 14.
    Anaphylactic degranulation by mast cells requires the mobilization of inflammasome components.
    Andrea Mencarelli, Pradeep Bist, Hae Woong Choi, Hanif Javanmard Khameneh, Alessandra Mortellaro, Soman N Abraham.
      The inflammasome components NLRP3 and ASC are cytosolic proteins, which upon sensing endotoxins or danger cues, form multimeric complexes to process interleukin (IL)-1β for secretion. Here we found that antigen (Ag)-triggered degranulation of IgE-sensitized mast cells (MCs) was mediated by NLRP3 and ASC. IgE-Ag stimulated NEK7 and Pyk2 kinases in MCs to induce the deposition of NLRP3 and ASC on granules and form a distinct protein complex (granulosome) that chaperoned the granules to the cell surface. MCs deficient in NLRP3 or ASC did not form granulosomes, degranulated poorly in vitro and did not evoke systemic anaphylaxis in mice. IgE-Ag-triggered anaphylaxis was prevented by an NLRP3 inhibitor. In endotoxin-primed MCs, pro-IL-1β was rapidly packaged into granules after IgE-Ag stimulation and processed within granule remnants by proteases after degranulation, causing lethal anaphylaxis in mice. During IgE-Ag-mediated degranulation of endotoxin-primed MCs, granulosomes promoted degranulation, combined with exteriorization and processing of IL-1β, resulting in severe inflammation.
    DOI:  https://doi.org/10.1038/s41590-024-01788-y
  49. Sci Transl Med. 2024 Mar 13. 16(738): eadm8859
    Harnessing regulatory T cells to establish immune tolerance.
    Patrick Ho, Ellen Cahir-McFarland, Jason D Fontenot, Tracey Lodie, Adel Nada, Qizhi Tang, Laurence A Turka, Jeffrey A Bluestone.
      Engineered regulatory T (Treg) cells have emerged as precision therapeutics aimed at inducing immune tolerance while reducing the risks associated with generalized immunosuppression. This Viewpoint highlights the opportunities and challenges for engineered Treg cell therapies in treating autoimmune and other inflammatory diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.adm8859
  50. Immunity. 2024 Mar 12. pii: S1074-7613(24)00086-4. [Epub ahead of print]57(3): 411-413
    Complement-ary protection for all ages.
    Geongoo Han, Shipra Vaishnava.
      Complement proteins form a proteolytic cascade to clear invading microbes. In a recent issue of Cell, Wu et al. and Xu et al. demonstrate two distinct complement systems operating in the gut, independent of circulating complement, and protecting against intestinal pathogens.
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.010
  51. Immunity. 2024 Mar 12. pii: S1074-7613(24)00089-X. [Epub ahead of print]57(3): 403-406
    IL-4-ever young: Type 2 cytokine signaling in macrophages slows aging.
    Conor M Finlay, Judith E Allen.
      Macrophages activated via the IL-4 receptor possess non-immune functions that support tissue homeostasis, but their specific role in aging is unknown. In this issue of Immunity, Zhou et al. show that IL-4 extends lifespan by inducing DNA repair pathways that protect macrophages from cellular senescence.
    DOI:  https://doi.org/10.1016/j.immuni.2024.02.013
  52. Nature. 2024 Mar 11.
    Dysregulated cellular stress management becomes a source of stress.
      
    Keywords:  Biochemistry; Cell biology; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-023-04138-4
  53. Nat Aging. 2024 Mar 12.
    IgG is an early driver of aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00602-6
  54. Nature. 2024 Mar 14.
    The neuroscientist formerly known as Prince's audio engineer.
    Anne Gulland.
      
    Keywords:  Arts; Careers; Education; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00791-5
  55. Nat Commun. 2024 Mar 12. 15(1): 2221
    Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images.
    Yuchao Jiang, Wei Li, Jinmei Li, Xiuli Li, Heng Zhang, Xiutian Sima, Luying Li, Kang Wang, Qifu Li, Jiajia Fang, Lu Jin, Qiyong Gong, Dezhong Yao, Dong Zhou, Cheng Luo, Dongmei An.
      Artificial intelligence provides an opportunity to try to redefine disease subtypes based on similar pathobiology. Using a machine-learning algorithm (Subtype and Stage Inference) with cross-sectional MRI from 296 individuals with focal epilepsy originating from the temporal lobe (TLE) and 91 healthy controls, we show phenotypic heterogeneity in the pathophysiological progression of TLE. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2200062562). We identify two hippocampus-predominant phenotypes, characterized by atrophy beginning in the left or right hippocampus; a third cortex-predominant phenotype, characterized by hippocampus atrophy after the neocortex; and a fourth phenotype without atrophy but amygdala enlargement. These four subtypes are replicated in the independent validation cohort (109 individuals). These subtypes show differences in neuroanatomical signature, disease progression and epilepsy characteristics. Five-year follow-up observations of these individuals reveal differential seizure outcomes among subtypes, indicating that specific subtypes may benefit from temporal surgery or pharmacological treatment. These findings suggest a diverse pathobiological basis underlying focal epilepsy that potentially yields to stratification and prognostication - a necessary step for precise medicine.
    DOI:  https://doi.org/10.1038/s41467-024-46629-6
  56. Sci Adv. 2024 Mar 15. 10(11): eadj1512
    Exocytic plasma membrane flows remodel endoplasmic reticulum-plasma membrane tethering for septin collar assembly.
    Shinju Sugiyama, Keiko Kono.
      Endoplasmic reticulum (ER)-plasma membrane (PM) tethering is crucial for the non-vesicular lipid transport between the ER membrane and the PM. However, the PM-associated ER can impede the PM binding of cytoskeletons and other organelles. It is poorly understood how the competition between the ER and cytoskeletons/organelles on the PM is resolved. Here, we show that, upon septin collar assembly, ER-PM tethering proteins are excluded from the yeast bud sites, and the PM-associated ER is locally detached from the PM. Our results suggest that PM flows by polarized exocytosis extrude PM proteins, including ER-PM tethering proteins, from the bud sites. When the reorganization of the ER-PM tethering was inhibited by exocytosis repression, septin localization was restricted to the PM sites poor in ER-PM tethering proteins. This study proposes machinery reconciling ER-septin competition on the PM, providing mechanistic insights into the spatial organization of PM-associated organelles and cytoskeletons.
    DOI:  https://doi.org/10.1126/sciadv.adj1512
  57. Science. 2024 Mar 14. eadp2165
    Misconduct's forgotten victims.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/science.adp2165
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