bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–03–31
fifty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Self-sustaining inflammatory cycle causes memory impairment in neuropsychiatric lupus.
  2. Shaken up by a shaker.
  3. Memories are made by breaking DNA - and fixing it.
  4. Innate immunity in neurons makes memories persist.
  5. Exit from totipotency is controlled by DUXBL in mice.
  6. Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds.
  7. Bioorthogonal photocatalytic proximity labeling in primary living samples.
  8. Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1.
  9. Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor.
  10. Protein-altering variants at copy number-variable regions influence diverse human phenotypes.
  11. TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.
  12. Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
  13. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
  14. SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.
  15. How a spreadsheet helped me to land my dream job.
  16. Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier.
  17. Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.
  18. How to make an old immune system young again.
  19. Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples.
  20. Activation of the insulin receptor by insulin-like growth factor 2.
  21. Daily briefing: Tweeting about your paper doesn't boost citations.
  22. Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche.
  23. Daily briefing: COVID 'brain fog' linked to brain inflammation.
  24. The genetic architecture of multimodal human brain age.
  25. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
  26. A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
  27. Control of cell proliferation by memories of mitosis.
  28. Partial reprogramming of the mammalian brain.
  29. Branched chemically modified poly(A) tails enhance the translation capacity of mRNA.
  30. Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.
  31. Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.
  32. Thioredoxin is a metabolic rheostat controlling regulatory B cells.
  33. Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.
  34. Niche availability and competitive loss by facilitation control proliferation of bacterial strains intended for soil microbiome interventions.
  35. Defective mitochondria remodelling in B cells leads to an aged immune response.
  36. Projective light-sheet microscopy with flexible parameter selection.
  37. Unraveling cellular complexity with transient adapters in highly multiplexed super-resolution imaging.
  38. The wearable electronic patch that's impervious to sweat.
  39. The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.
  40. T cell help induces Myc transcriptional bursts in germinal center B cells during positive selection.
  41. Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection.
  42. Journal editors are resigning en masse: what do these group exits achieve?
  43. A test for Alzheimer's-disease stage predicts dementia risk.
  44. Using rare genetic mutations to revisit structural brain asymmetry.
  45. A mitotic stopwatch determines cell fate.
  46. Structure of the human Bre1 complex bound to the nucleosome.
  47. InPACT: a computational method for accurate characterization of intronic polyadenylation from RNA sequencing data.
  48. Unsupervised ensemble-based phenotyping enhances discoverability of genes related to left-ventricular morphology.
  49. A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.
  50. Structural insights into the decoding capability of isoleucine tRNAs with lysidine and agmatidine.
  51. The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease.
  52. Architecture and activation of human muscle phosphorylase kinase.
  53. The HEAT repeat protein HPO-27 is a lysosome fission factor.
  54. Overcoming low vision to prove my abilities under pressure.
  55. The corpse of an exploded star and more - March's best science images.
  56. Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
  1. Nat Immunol. 2024 Mar 22.
    Self-sustaining inflammatory cycle causes memory impairment in neuropsychiatric lupus.
      
    DOI:  https://doi.org/10.1038/s41590-024-01786-0
  2. Science. 2024 Mar 29. 383(6690): 1506
    Shaken up by a shaker.
    Emily L Eberhardt.
      
    DOI:  https://doi.org/10.1126/science.adp4015
  3. Nature. 2024 Mar 27.
    Memories are made by breaking DNA - and fixing it.
    Max Kozlov.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00930-y
  4. Nature. 2024 Apr;628(8006): 40-42
    Innate immunity in neurons makes memories persist.
    Benjamin A Kelvington, Ted Abel.
      
    Keywords:  Brain; Immunology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00679-4
  5. Nat Genet. 2024 Mar 25.
    Exit from totipotency is controlled by DUXBL in mice.
      
    DOI:  https://doi.org/10.1038/s41588-024-01690-1
  6. Nat Commun. 2024 Mar 29. 15(1): 2760
    Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds.
    Bao-Cun Zhang, Marlene F Laursen, Lili Hu, Hossein Hazrati, Ryo Narita, Lea S Jensen, Aida S Hansen, Jinrong Huang, Yan Zhang, Xiangning Ding, Maimaitili Muyesier, Emil Nilsson, Agnieszka Banasik, Christina Zeiler, Trine H Mogensen, Anders Etzerodt, Ralf Agger, Mogens Johannsen, Emil Kofod-Olsen, Søren R Paludan, Martin R Jakobsen.
      The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-47046-5
  7. Nat Commun. 2024 Mar 28. 15(1): 2712
    Bioorthogonal photocatalytic proximity labeling in primary living samples.
    Ziqi Liu, Fuhu Guo, Yufan Zhu, Shengnan Qin, Yuchen Hou, Haotian Guo, Feng Lin, Peng R Chen, Xinyuan Fan.
      In situ profiling of subcellular proteomics in primary living systems, such as native tissues or clinic samples, is crucial for understanding life processes and diseases, yet challenging due to methodological obstacles. Here we report CAT-S, a bioorthogonal photocatalytic chemistry-enabled proximity labeling method, that expands proximity labeling to a wide range of primary living samples for in situ profiling of mitochondrial proteomes. Powered by our thioQM labeling warhead development and targeted bioorthogonal photocatalytic chemistry, CAT-S enables the labeling of mitochondrial proteins in living cells with high efficiency and specificity. We apply CAT-S to diverse cell cultures, dissociated mouse tissues as well as primary T cells from human blood, portraying the native-state mitochondrial proteomic characteristics, and unveiled hidden mitochondrial proteins (PTPN1, SLC35A4 uORF, and TRABD). Furthermore, CAT-S allows quantification of proteomic perturbations on dysfunctional tissues, exampled by diabetic mouse kidneys, revealing the alterations of lipid metabolism that may drive disease progression. Given the advantages of non-genetic operation, generality, and spatiotemporal resolution, CAT-S may open exciting avenues for subcellular proteomic investigations of primary samples that are otherwise inaccessible.
    DOI:  https://doi.org/10.1038/s41467-024-46985-3
  8. Nat Cell Biol. 2024 Mar 27.
    Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1.
    Yuanxin Yang, Jian Zhang, Mingming Lv, Na Cui, Bing Shan, Qi Sun, Lingjie Yan, Mengmeng Zhang, Chengyu Zou, Junying Yuan, Daichao Xu.
      Defects in the prelamin A processing enzyme caused by loss-of-function mutations in the ZMPSTE24 gene are responsible for a spectrum of progeroid disorders characterized by the accumulation of farnesylated prelamin A. Here we report that defective prelamin A processing triggers nuclear RIPK1-dependent signalling that leads to necroptosis and inflammation. We show that accumulated prelamin A recruits RIPK1 to the nucleus to facilitate its activation upon tumour necrosis factor stimulation in ZMPSTE24-deficient cells. Kinase-activated RIPK1 then promotes RIPK3-mediated MLKL activation in the nucleus, leading to nuclear envelope disruption and necroptosis. This signalling relies on prelamin A farnesylation, which anchors prelamin A to nuclear envelope to serve as a nucleation platform for necroptosis. Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24-/- mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders.
    DOI:  https://doi.org/10.1038/s41556-024-01374-2
  9. Nat Commun. 2024 Mar 26. 15(1): 2656
    Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor.
    Xingting Guo, Chenhui Wang, Yongchao Zhang, Ruxue Wei, Rongwen Xi.
      The manipulation of cell identity by reprograming holds immense potential in regenerative medicine, but is often limited by the inefficient acquisition of fully functional cells. This problem can potentially be resolved by better understanding the reprogramming process using in vivo genetic models, which are currently scarce. Here we report that both enterocytes (ECs) and enteroendocrine cells (EEs) in adult Drosophila midgut show a surprising degree of cell plasticity. Depleting the transcription factor Tramtrack in the differentiated ECs can initiate Prospero-mediated cell transdifferentiation, leading to EE-like cells. On the other hand, depletion of Prospero in the differentiated EEs can lead to the loss of EE-specific transcription programs and the gain of intestinal progenitor cell identity, allowing cell cycle re-entry or differentiation into ECs. We find that intestinal progenitor cells, ECs, and EEs have a similar chromatin accessibility profile, supporting the concept that cell plasticity is enabled by pre-existing chromatin accessibility with switchable transcription programs. Further genetic analysis with this system reveals that the NuRD chromatin remodeling complex, cell lineage confliction, and age act as barriers to EC-to-EE transdifferentiation. The establishment of this genetically tractable in vivo model should facilitate mechanistic investigation of cell plasticity at the molecular and genetic level.
    DOI:  https://doi.org/10.1038/s41467-024-46956-8
  10. Nat Genet. 2024 Mar 28.
    Protein-altering variants at copy number-variable regions influence diverse human phenotypes.
    Margaux L A Hujoel, Robert E Handsaker, Maxwell A Sherman, Nolan Kamitaki, Alison R Barton, Ronen E Mukamel, Chikashi Terao, Steven A McCarroll, Po-Ru Loh.
      Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most genetic association studies. Here we ascertained protein-altering CNVs from UK Biobank whole-exome sequencing data (n = 468,570) using haplotype-informed methods capable of detecting subexonic CNVs and variation within segmental duplications. Incorporating CNVs into analyses of rare variants predicted to cause gene loss of function (LOF) identified 100 associations of predicted LOF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 conferred one of the strongest protective effects of gene LOF on hypertension risk (odds ratio = 0.86 (0.82-0.90)). Protein-coding variation in rapidly evolving gene families within segmental duplications-previously invisible to most analysis methods-generated some of the human genome's largest contributions to variation in type 2 diabetes risk, chronotype and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.
    DOI:  https://doi.org/10.1038/s41588-024-01684-z
  11. Nat Neurosci. 2024 Mar 27.
    TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.
    Edward N Wilson, Congcong Wang, Michelle S Swarovski, Kristy A Zera, Hannah E Ennerfelt, Qian Wang, Aisling Chaney, Esha Gauba, Javier A Ramos Benitez, Yann Le Guen, Paras S Minhas, Maharshi Panchal, Yuting J Tan, Eran Blacher, Chinyere A Iweka, Haley Cropper, Poorva Jain, Qingkun Liu, Swapnil S Mehta, Abigail J Zuckerman, Matthew Xin, Jacob Umans, Jolie Huang, Aarooran S Durairaj, Geidy E Serrano, Thomas G Beach, Michael D Greicius, Michelle L James, Marion S Buckwalter, Melanie R McReynolds, Joshua D Rabinowitz, Katrin I Andreasson.
      Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.
    DOI:  https://doi.org/10.1038/s41593-024-01610-w
  12. Nat Commun. 2024 Mar 22. 15(1): 2598
    Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.
    Nick Huang, Thomas Winans, Brandon Wyman, Zachary Oaks, Tamas Faludi, Gourav Choudhary, Zhi-Wei Lai, Joshua Lewis, Miguel Beckford, Manuel Duarte, Daniel Krakko, Akshay Patel, Joy Park, Tiffany Caza, Mahsa Sadeghzadeh, Laurence Morel, Mark Haas, Frank Middleton, Katalin Banki, Andras Perl.
      Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-46441-2
  13. Sci Adv. 2024 Mar 29. 10(13): eadm9859
    Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
    Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.
      Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm9859
  14. Nat Commun. 2024 Mar 25. 15(1): 2635
    SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration.
    Jakob Hartmann, Thomas Bajaj, Joy Otten, Claudia Klengel, Tim Ebert, Anne-Kathrin Gellner, Ellen Junglas, Kathrin Hafner, Elmira A Anderzhanova, Fiona Tang, Galen Missig, Lindsay Rexrode, Daniel T Trussell, Katelyn X Li, Max L Pöhlmann, Sarah Mackert, Thomas M Geiger, Daniel E Heinz, Roy Lardenoije, Nina Dedic, Kenneth M McCullough, Tomasz Próchnicki, Thomas Rhomberg, Silvia Martinelli, Antony Payton, Andrew C Robinson, Valentin Stein, Eicke Latz, William A Carlezon, Felix Hausch, Mathias V Schmidt, Chris Murgatroyd, Sabina Berretta, Torsten Klengel, Harry Pantazopoulos, Kerry J Ressler, Nils C Gassen.
      High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-024-46953-x
  15. Nature. 2024 Mar 28.
    How a spreadsheet helped me to land my dream job.
    Silvia Sanasi.
      
    Keywords:  Careers; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-00950-8
  16. Nat Commun. 2024 Mar 23. 15(1): 2629
    Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier.
    Zhiqian Li, Lang You, Anita Hermann, Ethan Bier.
      DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Factors influencing the choice of particular repair pathways, however remain poorly characterized. Here we develop an Integrated Classification Pipeline (ICP) to decompose and categorize CRISPR/Cas9 generated mutations on genomic target sites in complex multicellular insects. The ICP outputs graphic rank ordered classifications of mutant alleles to visualize discriminating DSB repair fingerprints generated from different target sites and alternative inheritance patterns of CRISPR components. We uncover highly reproducible lineage-specific mutation fingerprints in individual organisms and a developmental progression wherein Microhomology-Mediated End-Joining (MMEJ) or Insertion events predominate during early rapid mitotic cell cycles, switching to distinct subsets of Non-Homologous End-Joining (NHEJ) alleles, and then to Homology-Directed Repair (HDR)-based gene conversion. These repair signatures enable marker-free tracking of specific mutations in dynamic populations, including NHEJ and HDR events within the same samples, for in-depth analysis of diverse gene editing events.
    DOI:  https://doi.org/10.1038/s41467-024-46479-2
  17. Nat Commun. 2024 Mar 29. 15(1): 2751
    Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation.
    Samuel Speaks, Matthew I McFadden, Ashley Zani, Abigail Solstad, Steve Leumi, Jack E Roettger, Adam D Kenney, Hannah Bone, Lizhi Zhang, Parker J Denz, Adrian C Eddy, Amal O Amer, Richard T Robinson, Chuanxi Cai, Jianjie Ma, Emily A Hemann, Adriana Forero, Jacob S Yount.
      Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd-/-) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd-/- mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd-/- animals, while depletion does not have additive protective effects in Gsdmd-/- mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.
    DOI:  https://doi.org/10.1038/s41467-024-47067-0
  18. Nature. 2024 Mar 27.
    How to make an old immune system young again.
    Heidi Ledford.
      
    Keywords:  Ageing; Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-00871-6
  19. Nat Commun. 2024 Mar 27. 15(1): 2679
    Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples.
    Nikita Vladimirov, Fabian F Voigt, Thomas Naert, Gabriela R Araujo, Ruiyao Cai, Anna Maria Reuss, Shan Zhao, Patricia Schmid, Sven Hildebrand, Martina Schaettin, Dominik Groos, José María Mateos, Philipp Bethge, Taiyo Yamamoto, Valentino Aerne, Alard Roebroeck, Ali Ertürk, Adriano Aguzzi, Urs Ziegler, Esther Stoeckli, Laura Baudis, Soeren S Lienkamp, Fritjof Helmchen.
      In 2015, we launched the mesoSPIM initiative, an open-source project for making light-sheet microscopy of large cleared tissues more accessible. Meanwhile, the demand for imaging larger samples at higher speed and resolution has increased, requiring major improvements in the capabilities of such microscopes. Here, we introduce the next-generation mesoSPIM ("Benchtop") with a significantly increased field of view, improved resolution, higher throughput, more affordable cost, and simpler assembly compared to the original version. We develop an optical method for testing detection objectives that enables us to select objectives optimal for light-sheet imaging with large-sensor cameras. The improved mesoSPIM achieves high spatial resolution (1.5 µm laterally, 3.3 µm axially) across the entire field of view, magnification up to 20×, and supports sample sizes ranging from sub-mm up to several centimeters while being compatible with multiple clearing techniques. The microscope serves a broad range of applications in neuroscience, developmental biology, pathology, and even physics.
    DOI:  https://doi.org/10.1038/s41467-024-46770-2
  20. Nat Commun. 2024 Mar 23. 15(1): 2609
    Activation of the insulin receptor by insulin-like growth factor 2.
    Weidong An, Catherine Hall, Jie Li, Albert Hung, Jiayi Wu, Junhee Park, Liwei Wang, Xiao-Chen Bai, Eunhee Choi.
      Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.
    DOI:  https://doi.org/10.1038/s41467-024-46990-6
  21. Nature. 2024 Mar 27.
    Daily briefing: Tweeting about your paper doesn't boost citations.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-00958-0
  22. Nat Aging. 2024 Mar 29.
    Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche.
    Lucy Xu, Julliana Ramirez-Matias, Max Hauptschein, Eric D Sun, Judith C Lunger, Matthew T Buckley, Anne Brunet.
      Partial reprogramming (pulsed expression of reprogramming transcription factors) improves the function of several tissues in old mice. However, it remains largely unknown how partial reprogramming impacts the old brain. Here we use single-cell transcriptomics to systematically examine how partial reprogramming influences the subventricular zone neurogenic niche in aged mouse brains. Whole-body partial reprogramming mainly improves neuroblasts (cells committed to give rise to new neurons) in the old neurogenic niche, restoring neuroblast proportion to more youthful levels. Interestingly, targeting partial reprogramming specifically to the neurogenic niche also boosts the proportion of neuroblasts and their precursors (neural stem cells) in old mice and improves several molecular signatures of aging, suggesting that the beneficial effects of reprogramming are niche intrinsic. In old neural stem cell cultures, partial reprogramming cell autonomously restores the proportion of neuroblasts during differentiation and blunts some age-related transcriptomic changes. Importantly, partial reprogramming improves the production of new neurons in vitro and in old brains. Our work suggests that partial reprogramming could be used to rejuvenate the neurogenic niche and counter brain decline in old individuals.
    DOI:  https://doi.org/10.1038/s43587-024-00594-3
  23. Nature. 2024 Mar 21.
    Daily briefing: COVID 'brain fog' linked to brain inflammation.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-00881-4
  24. Nat Commun. 2024 Mar 23. 15(1): 2604
    The genetic architecture of multimodal human brain age.
    Junhao Wen, Bingxin Zhao, Zhijian Yang, Guray Erus, Ioanna Skampardoni, Elizabeth Mamourian, Yuhan Cui, Gyujoon Hwang, Jingxuan Bao, Aleix Boquet-Pujadas, Zhen Zhou, Yogasudha Veturi, Marylyn D Ritchie, Haochang Shou, Paul M Thompson, Li Shen, Arthur W Toga, Christos Davatzikos.
      The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10-8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG displayed the most pronounced heritability enrichment in genetic variants within conserved regions. Oligodendrocytes and astrocytes, but not neurons, exhibited notable heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several chronic diseases on brain aging, such as type 2 diabetes on GM-BAG and AD on WM-BAG. Our results provide insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at https://labs.loni.usc.edu/medicine .
    DOI:  https://doi.org/10.1038/s41467-024-46796-6
  25. Nat Commun. 2024 Mar 28. 15(1): 2725
    Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA.
    Daan M K van Soest, Paulien E Polderman, Wytze T F den Toom, Janneke P Keijer, Markus J van Roosmalen, Tim M F Leyten, Johannes Lehmann, Susan Zwakenberg, Sasha De Henau, Ruben van Boxtel, Boudewijn M T Burgering, Tobias B Dansen.
      Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H2O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2O2. Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.
    DOI:  https://doi.org/10.1038/s41467-024-47008-x
  26. Commun Biol. 2024 Mar 28. 7(1): 377
    A semi-automatic method for extracting mitochondrial cristae characteristics from 3D focused ion beam scanning electron microscopy data.
    Chenhao Wang, Leif Østergaard, Stine Hasselholt, Jon Sporring.
      Mitochondria are the main suppliers of energy for cells and their bioenergetic function is regulated by mitochondrial dynamics: the constant changes in mitochondria size, shape, and cristae morphology to secure cell homeostasis. Although changes in mitochondrial function are implicated in a wide range of diseases, our understanding is challenged by a lack of reliable ways to extract spatial features from the cristae, the detailed visualization of which requires electron microscopy (EM). Here, we present a semi-automatic method for the segmentation, 3D reconstruction, and shape analysis of mitochondria, cristae, and intracristal spaces based on 2D EM images of the murine hippocampus. We show that our method provides a more accurate characterization of mitochondrial ultrastructure in 3D than common 2D approaches and propose an operational index of mitochondria's internal organization. With an improved consistency of 3D shape analysis and a decrease in the workload needed for large-scale analysis, we speculate that this tool will help increase our understanding of mitochondrial dynamics in health and disease.
    DOI:  https://doi.org/10.1038/s42003-024-06045-4
  27. Science. 2024 Mar 29. 383(6690): 1441-1448
    Control of cell proliferation by memories of mitosis.
    Franz Meitinger, Hazrat Belal, Robert L Davis, Mallory B Martinez, Andrew K Shiau, Karen Oegema, Arshad Desai.
      Mitotic duration is tightly constrained, and extended mitosis is characteristic of problematic cells prone to chromosome missegregation and genomic instability. We show here that mitotic extension leads to the formation of p53-binding protein 1 (53BP1)-ubiquitin-specific protease 28 (USP28)-p53 protein complexes that are transmitted to, and stably retained by, daughter cells. Complexes assembled through a Polo-like kinase 1-dependent mechanism during extended mitosis and elicited a p53 response in G1 that prevented the proliferation of the progeny of cells that experienced an approximately threefold extended mitosis or successive less extended mitoses. The ability to monitor mitotic extension was lost in p53-mutant cancers and some p53-wild-type (p53-WT) cancers, consistent with classification of TP53BP1 and USP28 as tumor suppressors. Cancers retaining the ability to monitor mitotic extension exhibited sensitivity to antimitotic agents.
    DOI:  https://doi.org/10.1126/science.add9528
  28. Nat Aging. 2024 Mar 29.
    Partial reprogramming of the mammalian brain.
    Niels C Asmussen, Marissa J Schafer.
      
    DOI:  https://doi.org/10.1038/s43587-024-00596-1
  29. Nat Biotechnol. 2024 Mar 22.
    Branched chemically modified poly(A) tails enhance the translation capacity of mRNA.
    Hongyu Chen, Dangliang Liu, Jianting Guo, Abhishek Aditham, Yiming Zhou, Jiakun Tian, Shuchen Luo, Jingyi Ren, Alvin Hsu, Jiahao Huang, Franklin Kostas, Mingrui Wu, David R Liu, Xiao Wang.
      Although messenger RNA (mRNA) has proved effective as a vaccine, its potential as a general therapeutic modality is limited by its instability and low translation capacity. To increase the duration and level of protein expression from mRNA, we designed and synthesized topologically and chemically modified mRNAs with multiple synthetic poly(A) tails. Here we demonstrate that the optimized multitailed mRNA yielded ~4.7-19.5-fold higher luminescence signals than the control mRNA from 24 to 72 h post transfection in cellulo and 14 days detectable signal versus <7 days signal from the control in vivo. We further achieve efficient multiplexed genome editing of the clinically relevant genes Pcsk9 and Angptl3 in mouse liver at a minimal mRNA dosage. Taken together, these results provide a generalizable approach to synthesize capped branched mRNA with markedly enhanced translation capacity.
    DOI:  https://doi.org/10.1038/s41587-024-02174-7
  30. Nat Commun. 2024 Mar 27. 15(1): 2542
    Regulatory T cells expressing CD19-targeted chimeric antigen receptor restore homeostasis in Systemic Lupus Erythematosus.
    M Doglio, A Ugolini, C Bercher-Brayer, B Camisa, C Toma, R Norata, S Del Rosso, R Greco, F Ciceri, F Sanvito, M Casucci, A A Manfredi, C Bonini.
      Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.
    DOI:  https://doi.org/10.1038/s41467-024-46448-9
  31. Nat Commun. 2024 Mar 27. 15(1): 2677
    Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures.
    Jinjian Hu, Wencheng Xia, Shuyi Zeng, Yeh-Jun Lim, Youqi Tao, Yunpeng Sun, Lang Zhao, Haosen Wang, Weidong Le, Dan Li, Shengnan Zhang, Cong Liu, Yan-Mei Li.
      α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained homogenous α-synuclein monomer with site-specific phosphorylation (pS87) and O-GlcNAcylation (gS87) at S87, respectively. Cryo-EM revealed that pS87 and gS87 α-synuclein form two distinct fibril structures. The GlcNAc situated at S87 establishes interactions with K80 and E61, inducing a unique iron-like fold with the GlcNAc molecule on the iron handle. Phosphorylation at the same site prevents a lengthy C-terminal region including residues 73 to 140 from incorporating into the fibril core due to electrostatic repulsion. Instead, the N-terminal half of the fibril (1-72) takes on an arch-like fibril structure. We further show that both pS87 and gS87 α-synuclein fibrils display reduced neurotoxicity and propagation activity compared with unmodified α-synuclein fibrils. Our findings demonstrate that different posttranslational modifications at the same site can produce distinct fibril structures, which emphasizes link between posttranslational modifications and amyloid fibril formation and pathology.
    DOI:  https://doi.org/10.1038/s41467-024-46898-1
  32. Nat Immunol. 2024 Mar 29.
    Thioredoxin is a metabolic rheostat controlling regulatory B cells.
    Hannah F Bradford, Thomas C R McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah Dunn-Walters, David A Isenberg, Adnan R Khan, Claudio Mauro, Claudia Mauri.
      Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by Breg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.
    DOI:  https://doi.org/10.1038/s41590-024-01798-w
  33. Nat Neurosci. 2024 Mar 25.
    Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.
    Elena Dvoretskova, May C Ho, Volker Kittke, Florian Neuhaus, Ilaria Vitali, Daniel D Lam, Irene Delgado, Chao Feng, Miguel Torres, Juliane Winkelmann, Christian Mayer.
      The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.
    DOI:  https://doi.org/10.1038/s41593-024-01611-9
  34. Nat Commun. 2024 Mar 22. 15(1): 2557
    Niche availability and competitive loss by facilitation control proliferation of bacterial strains intended for soil microbiome interventions.
    Senka Čaušević, Manupriyam Dubey, Marian Morales, Guillem Salazar, Vladimir Sentchilo, Nicolas Carraro, Hans-Joachim Ruscheweyh, Shinichi Sunagawa, Jan Roelof van der Meer.
      Microbiome engineering - the targeted manipulation of microbial communities - is considered a promising strategy to restore ecosystems, but experimental support and mechanistic understanding are required. Here, we show that bacterial inoculants for soil microbiome engineering may fail to establish because they inadvertently facilitate growth of native resident microbiomes. By generating soil microcosms in presence or absence of standardized soil resident communities, we show how different nutrient availabilities limit outgrowth of focal bacterial inoculants (three Pseudomonads), and how this might be improved by adding an artificial, inoculant-selective nutrient niche. Through random paired interaction assays in agarose micro-beads, we demonstrate that, in addition to direct competition, inoculants lose competitiveness by facilitating growth of resident soil bacteria. Metatranscriptomics experiments with toluene as selective nutrient niche for the inoculant Pseudomonas veronii indicate that this facilitation is due to loss and uptake of excreted metabolites by resident taxa. Generation of selective nutrient niches for inoculants may help to favor their proliferation for the duration of their intended action while limiting their competitive loss.
    DOI:  https://doi.org/10.1038/s41467-024-46933-1
  35. Nat Commun. 2024 Mar 22. 15(1): 2569
    Defective mitochondria remodelling in B cells leads to an aged immune response.
    Marta Iborra-Pernichi, Jonathan Ruiz García, María Velasco de la Esperanza, Belén S Estrada, Elena R Bovolenta, Claudia Cifuentes, Cristina Prieto Carro, Tamara González Martínez, José García-Consuegra, María Fernanda Rey-Stolle, Francisco Javier Rupérez, Milagros Guerra Rodriguez, Rafael J Argüello, Sara Cogliati, Fernando Martín-Belmonte, Nuria Martínez-Martín.
      The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.
    DOI:  https://doi.org/10.1038/s41467-024-46763-1
  36. Nat Commun. 2024 Mar 29. 15(1): 2755
    Projective light-sheet microscopy with flexible parameter selection.
    Bingying Chen, Bo-Jui Chang, Stephan Daetwyler, Felix Zhou, Shiv Sharma, Donghoon M Lee, Amruta Nayak, Jungsik Noh, Konstantin Dubrovinski, Elizabeth H Chen, Michael Glotzer, Reto Fiolka.
      Projection imaging accelerates volumetric interrogation in fluorescence microscopy, but for multi-cellular samples, the resulting images may lack contrast, as many structures and haze are summed up. Here, we demonstrate rapid projective light-sheet imaging with parameter selection (props) of imaging depth, position and viewing angle. This allows us to selectively image different sub-volumes of a sample, rapidly switch between them and exclude background fluorescence. Here we demonstrate the power of props by functional imaging within distinct regions of the zebrafish brain, monitoring calcium firing inside muscle cells of moving Drosophila larvae, super-resolution imaging of selected cell layers, and by optically unwrapping the curved surface of a Drosophila embryo. We anticipate that props will accelerate volumetric interrogation, ranging from subcellular to mesoscopic scales.
    DOI:  https://doi.org/10.1038/s41467-024-46693-y
  37. Cell. 2024 Mar 28. pii: S0092-8674(24)00236-8. [Epub ahead of print]187(7): 1769-1784.e18
    Unraveling cellular complexity with transient adapters in highly multiplexed super-resolution imaging.
    Florian Schueder, Felix Rivera-Molina, Maohan Su, Zach Marin, Phylicia Kidd, James E Rothman, Derek Toomre, Joerg Bewersdorf.
      Mapping the intricate spatial relationships between the many different molecules inside a cell is essential to understanding cellular functions in all their complexity. Super-resolution fluorescence microscopy offers the required spatial resolution but struggles to reveal more than four different targets simultaneously. Exchanging labels in subsequent imaging rounds for multiplexed imaging extends this number but is limited by its low throughput. Here, we present a method for rapid multiplexed super-resolution microscopy that can, in principle, be applied to a nearly unlimited number of molecular targets by leveraging fluorogenic labeling in conjunction with transient adapter-mediated switching for high-throughput DNA-PAINT (FLASH-PAINT). We demonstrate the versatility of FLASH-PAINT with four applications: mapping nine proteins in a single mammalian cell, elucidating the functional organization of primary cilia by nine-target imaging, revealing the changes in proximity of thirteen different targets in unperturbed and dissociated Golgi stacks, and investigating and quantifying inter-organelle contacts at 3D super-resolution.
    Keywords:  DNA-PAINT; FLASH-PAINT; multiplexing; nanoscopy; spatial omics; super-resolution
    DOI:  https://doi.org/10.1016/j.cell.2024.02.033
  38. Nature. 2024 Apr;628(8006): 39-40
    The wearable electronic patch that's impervious to sweat.
    Yifan Rao, Nanshu Lu.
      
    Keywords:  Engineering
    DOI:  https://doi.org/10.1038/d41586-024-00789-z
  39. Sci Immunol. 2024 Mar 26. eadn1452
    The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.
    Arumugam Balasubramanian, Alan Y Hsu, Laxman Ghimire, Muhammad Tahir, Pascal Devant, Pietro Fontana, Gang Du, Xing Liu, Dang Fabin, Hiroto Kambara, Xuemei Xie, Fei Liu, Tomoya Hasegawa, Rong Xu, Hongbo Yu, Mei Chen, Steven Kolakowski, Sunia Trauger, Martin Røssel Larsen, Wenyi Wei, Hao Wu, Jonathan C Kagan, Judy Lieberman, Hongbo R Luo.
      Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomics approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adn1452
  40. Sci Immunol. 2024 Mar 29. 9(93): eadj7124
    T cell help induces Myc transcriptional bursts in germinal center B cells during positive selection.
    Sharon Kagan Ben Tikva, Neta Gurwitz, Ehud Sivan, Dana Hirsch, Hadas Hezroni-Barvyi, Adi Biram, Lihee Moss, Noa Wigoda, Adi Egozi, Alan Monziani, Ofra Golani, Menachem Gross, Ariel Tenenbaum, Ziv Shulman.
      Antibody affinity maturation occurs in secondary lymphoid organs within germinal centers (GCs). At these sites, B cells mutate their antibody-encoding genes in the dark zone, followed by preferential selection of the high-affinity variants in the light zone by T cells. The strength of the T cell-derived selection signals is proportional to the B cell receptor affinity and to the magnitude of subsequent Myc expression. However, because the lifetime of Myc mRNA and its corresponding protein is very short, it remains unclear how T cells induce sustained Myc levels in positively selected B cells. Here, by direct visualization of mRNA and active transcription sites in situ, we found that an increase in transcriptional bursts promotes Myc expression during B cell positive selection in GCs. Elevated T cell help signals predominantly enhance the percentage of cells expressing Myc in GCs as opposed to augmenting the quantity of Myc transcripts per individual cell. Visualization of transcription start sites in situ revealed that T cell help promotes an increase in the frequency of transcriptional bursts at the Myc locus in GC B cells located primarily in the LZ apical rim. Thus, the rise in Myc, which governs positive selection of B cells in GCs, reflects an integration of transcriptional activity over time rather than an accumulation of transcripts at a specific time point.
    DOI:  https://doi.org/10.1126/sciimmunol.adj7124
  41. Nat Commun. 2024 Mar 28. 15(1): 2465
    Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection.
    Renée R C E Schreurs, Athanasios Koulis, Thijs Booiman, Brigitte Boeser-Nunnink, Alexandra P M Cloherty, Anusca G Rader, Kharishma S Patel, Neeltje A Kootstra, Carla M S Ribeiro.
      Chronic HIV-1 infection is characterized by T-cell dysregulation that is partly restored by antiretroviral therapy. Autophagy is a critical regulator of T-cell function. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis. Targeted analysis of genetic variation in core autophagy gene ATG16L1 reveals the previously unidentified rs6861 polymorphism, which correlates functionally with enhanced autophagy and clinically with improved survival of untreated HIV-1-infected individuals. T-cells carrying ATG16L1 rs6861(TT) genotype display improved antiviral immunity, evidenced by increased proliferation, revamped immune responsiveness, and suppressed exhaustion/immunosenescence features. In-depth flow-cytometric and transcriptional profiling reveal T-helper-cell-signatures unique to rs6861(TT) individuals with enriched regulation of pro-inflammatory networks and skewing towards immunoregulatory phenotype. Therapeutic enhancement of autophagy recapitulates the rs6861(TT)-associated T-cell traits in non-carriers. These data underscore the in vivo relevance of autophagy for longer-lasting T-cell-mediated HIV-1 control, with implications towards development of host-directed antivirals targeting autophagy to restore immune function in chronic HIV-1 infection.
    DOI:  https://doi.org/10.1038/s41467-024-46606-z
  42. Nature. 2024 Mar 27.
    Journal editors are resigning en masse: what do these group exits achieve?
    Katharine Sanderson.
      
    Keywords:  Publishing; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-00887-y
  43. Nature. 2024 Apr;628(8006): 11
    A test for Alzheimer's-disease stage predicts dementia risk.
      
    Keywords:  Alzheimer's disease
    DOI:  https://doi.org/10.1038/d41586-024-00860-9
  44. Nat Commun. 2024 Mar 26. 15(1): 2639
    Using rare genetic mutations to revisit structural brain asymmetry.
    Jakub Kopal, Kuldeep Kumar, Kimia Shafighi, Karin Saltoun, Claudia Modenato, Clara A Moreau, Guillaume Huguet, Martineau Jean-Louis, Charles-Olivier Martin, Zohra Saci, Nadine Younis, Elise Douard, Khadije Jizi, Alexis Beauchamp-Chatel, Leila Kushan, Ana I Silva, Marianne B M van den Bree, David E J Linden, Michael J Owen, Jeremy Hall, Sarah Lippé, Bogdan Draganski, Ida E Sønderby, Ole A Andreassen, David C Glahn, Paul M Thompson, Carrie E Bearden, Robert Zatorre, Sébastien Jacquemont, Danilo Bzdok.
      Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.
    DOI:  https://doi.org/10.1038/s41467-024-46784-w
  45. Science. 2024 Mar 29. 383(6690): 1414-1415
    A mitotic stopwatch determines cell fate.
    Agustina P Bertolin, Vanesa Gottifredi.
      Surveillance of mitotic timing prevents amplification of damaged cells.
    DOI:  https://doi.org/10.1126/science.ado5703
  46. Nat Commun. 2024 Mar 22. 15(1): 2580
    Structure of the human Bre1 complex bound to the nucleosome.
    Shuhei Onishi, Kotone Uchiyama, Ko Sato, Chikako Okada, Shunsuke Kobayashi, Keisuke Hamada, Tomohiro Nishizawa, Osamu Nureki, Kazuhiro Ogata, Toru Sengoku.
      Histone H2B monoubiquitination (at Lys120 in humans) regulates transcription elongation and DNA repair. In humans, H2B monoubiquitination is catalyzed by the heterodimeric Bre1 complex composed of Bre1A/RNF20 and Bre1B/RNF40. The Bre1 proteins generally function as tumor suppressors, while in certain cancers, they facilitate cancer cell proliferation. To obtain structural insights of H2BK120 ubiquitination and its regulation, we report the cryo-electron microscopy structure of the human Bre1 complex bound to the nucleosome. The two RING domains of Bre1A and Bre1B recognize the acidic patch and the nucleosomal DNA phosphates around SHL 6.0-6.5, which are ideally located to recruit the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. Mutational experiments suggest that the two RING domains bind in two orientations and that ubiquitination occurs when Bre1A binds to the acidic patch. Our results provide insights into the H2BK120-specific ubiquitination by the Bre1 proteins and suggest that H2B monoubiquitination can be regulated by nuclesomal DNA flexibility.
    DOI:  https://doi.org/10.1038/s41467-024-46910-8
  47. Nat Commun. 2024 Mar 22. 15(1): 2583
    InPACT: a computational method for accurate characterization of intronic polyadenylation from RNA sequencing data.
    Xiaochuan Liu, Hao Chen, Zekun Li, Xiaoxiao Yang, Wen Jin, Yuting Wang, Jian Zheng, Long Li, Chenghao Xuan, Jiapei Yuan, Yang Yang.
      Alternative polyadenylation can occur in introns, termed intronic polyadenylation (IPA), has been implicated in diverse biological processes and diseases, as it can produce noncoding transcripts or transcripts with truncated coding regions. However, a reliable method is required to accurately characterize IPA. Here, we propose a computational method called InPACT, which allows for the precise characterization of IPA from conventional RNA-seq data. InPACT successfully identifies numerous previously unannotated IPA transcripts in human cells, many of which are translated, as evidenced by ribosome profiling data. We have demonstrated that InPACT outperforms other methods in terms of IPA identification and quantification. Moreover, InPACT applied to monocyte activation reveals temporally coordinated IPA events. Further application on single-cell RNA-seq data of human fetal bone marrow reveals the expression of several IPA isoforms in a context-specific manner. Therefore, InPACT represents a powerful tool for the accurate characterization of IPA from RNA-seq data.
    DOI:  https://doi.org/10.1038/s41467-024-46875-8
  48. Nat Mach Intell. 2024 ;6(3): 291-306
    Unsupervised ensemble-based phenotyping enhances discoverability of genes related to left-ventricular morphology.
    Rodrigo Bonazzola, Enzo Ferrante, Nishant Ravikumar, Yan Xia, Bernard Keavney, Sven Plein, Tanveer Syeda-Mahmood, Alejandro F Frangi.
      Recent genome-wide association studies have successfully identified associations between genetic variants and simple cardiac morphological parameters derived from cardiac magnetic resonance images. However, the emergence of large databases, including genetic data linked to cardiac magnetic resonance facilitates the investigation of more nuanced patterns of cardiac shape variability than those studied so far. Here we propose a framework for gene discovery coined unsupervised phenotype ensembles. The unsupervised phenotype ensemble builds a redundant yet highly expressive representation by pooling a set of phenotypes learnt in an unsupervised manner, using deep learning models trained with different hyperparameters. These phenotypes are then analysed via genome-wide association studies, retaining only highly confident and stable associations across the ensemble. We applied our approach to the UK Biobank database to extract geometric features of the left ventricle from image-derived three-dimensional meshes. We demonstrate that our approach greatly improves the discoverability of genes that influence left ventricle shape, identifying 49 loci with study-wide significance and 25 with suggestive significance. We argue that our approach would enable more extensive discovery of gene associations with image-derived phenotypes for other organs or image modalities.
    Keywords:  Cardiovascular genetics; Genome-wide association studies; Machine learning; Prognostic markers
    DOI:  https://doi.org/10.1038/s42256-024-00801-1
  49. Nature. 2024 Mar 27.
    A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.
    Marco Benevento, Alán Alpár, Anna Gundacker, Leila Afjehi, Kira Balueva, Zsofia Hevesi, János Hanics, Sabah Rehman, Daniela D Pollak, Gert Lubec, Peer Wulff, Vincent Prevot, Tamas L Horvath, Tibor Harkany.
      Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.
    DOI:  https://doi.org/10.1038/s41586-024-07232-3
  50. Nat Struct Mol Biol. 2024 Mar 27.
    Structural insights into the decoding capability of isoleucine tRNAs with lysidine and agmatidine.
    Naho Akiyama, Kensuke Ishiguro, Takeshi Yokoyama, Kenjyo Miyauchi, Asuteka Nagao, Mikako Shirouzu, Tsutomu Suzuki.
      The anticodon modifications of transfer RNAs (tRNAs) finetune the codon recognition on the ribosome for accurate translation. Bacteria and archaea utilize the modified cytidines, lysidine (L) and agmatidine (agm2C), respectively, in the anticodon of tRNAIle to decipher AUA codon. L and agm2C contain long side chains with polar termini, but their functions remain elusive. Here we report the cryogenic electron microscopy structures of tRNAsIle recognizing the AUA codon on the ribosome. Both modifications interact with the third adenine of the codon via a unique C-A geometry. The side chains extend toward 3' direction of the mRNA, and the polar termini form hydrogen bonds with 2'-OH of the residue 3'-adjacent to the AUA codon. Biochemical analyses demonstrated that AUA decoding is facilitated by the additional interaction between the polar termini of the modified cytidines and 2'-OH of the fourth mRNA residue. We also visualized cyclic N6-threonylcarbamoyladenosine (ct6A), another tRNA modification, and revealed a molecular basis how ct6A contributes to efficient decoding.
    DOI:  https://doi.org/10.1038/s41594-024-01238-1
  51. Nat Commun. 2024 Mar 27. 15(1): 2576
    The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease.
    Jordi Manuello, Joosung Min, Paul McCarthy, Fidel Alfaro-Almagro, Soojin Lee, Stephen Smith, Lloyd T Elliott, Anderson M Winkler, Gwenaëlle Douaud.
      We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer's and Parkinson's disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide - a proxy for traffic-related air pollution - and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.
    DOI:  https://doi.org/10.1038/s41467-024-46344-2
  52. Nat Commun. 2024 Mar 28. 15(1): 2719
    Architecture and activation of human muscle phosphorylase kinase.
    Xiaoke Yang, Mingqi Zhu, Xue Lu, Yuxin Wang, Junyu Xiao.
      The study of phosphorylase kinase (PhK)-regulated glycogen metabolism has contributed to the fundamental understanding of protein phosphorylation; however, the molecular mechanism of PhK remains poorly understood. Here we present the high-resolution cryo-electron microscopy structures of human muscle PhK. The 1.3-megadalton PhK α4β4γ4δ4 hexadecamer consists of a tetramer of tetramer, wherein four αβγδ modules are connected by the central β4 scaffold. The α- and β-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The α-subunit serves as a bridge between the β-subunit and the γδ subcomplex, and facilitates the γ-subunit to adopt an autoinhibited state. Ca2+-free calmodulin (δ-subunit) binds to the γ-subunit in a compact conformation. Upon binding of Ca2+, a conformational change occurs, allowing for the de-inhibition of the γ-subunit through a spring-loaded mechanism. We also reveal an ADP-binding pocket in the β-subunit, which plays a role in allosterically enhancing PhK activity. These results provide molecular insights of this important kinase complex.
    DOI:  https://doi.org/10.1038/s41467-024-47049-2
  53. Nature. 2024 Mar 27.
    The HEAT repeat protein HPO-27 is a lysosome fission factor.
    Letao Li, Xilu Liu, Shanshan Yang, Meijiao Li, Yanwei Wu, Siqi Hu, Wenjuan Wang, Amin Jiang, Qianqian Zhang, Junbing Zhang, Xiaoli Ma, Junyan Hu, Qiaohong Zhao, Yubing Liu, Dong Li, Junjie Hu, Chonglin Yang, Wei Feng, Xiaochen Wang.
      Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing1. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission2,3. Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately collapses. HPO-27 and its human homologue MROH1 are recruited to lysosomes by RAB-7 and enriched at scission sites. Super-resolution imaging, negative-staining electron microscopy and in vitro reconstitution assays reveal that HPO-27 and MROH1 self-assemble to mediate the constriction and scission of lysosomal tubules in worms and mammalian cells, respectively, and assemble to sever supported membrane tubes in vitro. Loss of HPO-27 affects lysosomal morphology, integrity and degradation activity, which impairs animal development and longevity. Thus, HPO-27 and MROH1 act as self-assembling scission factors to maintain lysosomal homeostasis and function.
    DOI:  https://doi.org/10.1038/s41586-024-07249-8
  54. Nature. 2024 Mar 28.
    Overcoming low vision to prove my abilities under pressure.
    Lesley Evans Ogden.
      
    Keywords:  Careers; Lab life; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-00957-1
  55. Nature. 2024 Mar 28.
    The corpse of an exploded star and more - March's best science images.
    Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-024-00941-9
  56. Nat Commun. 2024 Mar 23. 15(1): 2615
    Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.
    Przemysław R Kac, Fernando González-Ortiz, Andreja Emeršič, Maciej Dulewicz, Srinivas Koutarapu, Michael Turton, Yang An, Denis Smirnov, Agnieszka Kulczyńska-Przybik, Vijay R Varma, Nicholas J Ashton, Laia Montoliu-Gaya, Elena Camporesi, Izabela Winkel, Bogusław Paradowski, Abhay Moghekar, Juan C Troncoso, Tammaryn Lashley, Gunnar Brinkmalm, Susan M Resnick, Barbara Mroczko, Hlin Kvartsberg, Milica Gregorič Kramberger, Jörg Hanrieder, Saša Čučnik, Peter Harrison, Henrik Zetterberg, Piotr Lewczuk, Madhav Thambisetty, Uroš Rot, Douglas Galasko, Kaj Blennow, Thomas K Karikari.
      Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
    DOI:  https://doi.org/10.1038/s41467-024-46876-7
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