bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒01‒14
seventy papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Missing the signs.
  2. High-dimensional phenotyping to define the genetic basis of cellular morphology.
  3. Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.
  4. TIMely connections: APOE4, aging, and Alzheimer's.
  5. Prediction of single-cell RNA expression profiles in live cells by Raman microscopy with Raman2RNA.
  6. Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
  7. CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.
  8. The selection landscape and genetic legacy of ancient Eurasians.
  9. Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol.
  10. TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.
  11. Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension.
  12. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.
  13. MarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer.
  14. Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response.
  15. Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents.
  16. Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila.
  17. Protein interaction networks in the vasculature prioritize genes and pathways underlying coronary artery disease.
  18. A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding.
  19. Unanswered questions following reports of secondary malignancies after CAR-T cell therapy.
  20. Functional neuronal circuits emerge in the absence of developmental activity.
  21. Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.
  22. EPAC1 boosts thermogenic adipocyte formation.
  23. tRNA flux and consistency in differentiation.
  24. Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.
  25. Squeeze to arm.
  26. Local and dynamic regulation of neuronal glycolysis in vivo.
  27. The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34.
  28. Sequencing of N6-methyl-deoxyadenosine at single-base resolution across the mammalian genome.
  29. Integrated organ immunity: a path to a universal vaccine.
  30. The CRISPR effector Cam1 mediates membrane depolarization for phage defence.
  31. Pioneer and PRDM transcription factors coordinate bivalent epigenetic states to safeguard cell fate.
  32. 100 ancient genomes show repeated population turnovers in Neolithic Denmark.
  33. Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils.
  34. Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.
  35. Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.
  36. Computational prediction and experimental validation identify functionally conserved lncRNAs from zebrafish to human.
  37. Targeting COPIng liabilities of senescent cells.
  38. The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
  39. Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.
  40. Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.
  41. A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
  42. LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.
  43. Identifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies.
  44. Tissues of origin matter to plasma cell longevity.
  45. PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity.
  46. Profiling of RNA-binding protein binding sites by in situ reverse transcription-based sequencing.
  47. A global analysis of how human infrastructure squeezes sandy coasts.
  48. Economists are crucial for solving public health challenges.
  49. Why have T cell-inducing vaccines for HIV failed so far?
  50. Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
  51. A plasma proteome measure of organ aging.
  52. How we remember the dead by their digital afterlives.
  53. Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.
  54. S1PR1 inhibition induces pro-apoptotic signaling in T cells and limits humoral responses within lymph nodes.
  55. Selective gene expression maintains human tRNA anticodon pools during differentiation.
  56. Single-cell mapping of lipid metabolites using an infrared probe in human-derived model systems.
  57. Conformational transitions and activation of the adhesion receptor CD97.
  58. On blood and tissue-resident natural killer cells.
  59. Natural killer cells that target autoimmune cells linked with protection against multiple sclerosis.
  60. Ancient DNA reveals origins of multiple sclerosis in Europe.
  61. Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
  62. TRIM56 protects against non-alcoholic fatty liver disease via promoting the degradation of fatty acid synthase.
  63. OXR1 maintains the retromer to delay brain aging under dietary restriction.
  64. EPAC1 enhances brown fat growth and beige adipogenesis.
  65. Decoding the language of immunity.
  66. Hormonal basis of sex differences in anesthetic sensitivity.
  67. Slow and steady lives the longest.
  68. How does the microbiota control systemic innate immunity?
  69. Overcoming resolution attenuation during tilted cryo-EM data collection.
  70. Deterministic reprogramming of neutrophils within tumors.
  1. Science. 2024 Jan 12. 383(6679): 234
    Missing the signs.
    Joe Higham.
      
    DOI:  https://doi.org/10.1126/science.adn8957
  2. Nat Commun. 2024 Jan 06. 15(1): 347
    High-dimensional phenotyping to define the genetic basis of cellular morphology.
    Matthew Tegtmeyer, Jatin Arora, Samira Asgari, Beth A Cimini, Ajay Nadig, Emily Peirent, Dhara Liyanage, Gregory P Way, Erin Weisbart, Aparna Nathan, Tiffany Amariuta, Kevin Eggan, Marzieh Haghighi, Steven A McCarroll, Luke O'Connor, Anne E Carpenter, Shantanu Singh, Ralda Nehme, Soumya Raychaudhuri.
      The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identify novel associations between rare protein altering variants in WASF2, TSPAN15, and PRLR with several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirms their role in cell morphology. Analysis of common variants yields one significant association and nominate over 300 variants with suggestive evidence (P < 10-6) of association with one or more morphology traits. We then use these data to make predictions about sample size requirements for increasing discovery in cellular genetic studies. We conclude that, similar to molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.
    DOI:  https://doi.org/10.1038/s41467-023-44045-w
  3. Nat Commun. 2024 Jan 09. 15(1): 410
    Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.
    J Josephine Botsch, Roswitha Junker, Michèle Sorgenfrei, Patricia P Ogger, Luca Stier, Susanne von Gronau, Peter J Murray, Markus A Seeger, Brenda A Schulman, Bastian Bräuning.
      Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, and metabolic regulation, are determined by ER-resident MARCH6 E3 ligases, including Doa10 in yeast. Here, we present Doa10/MARCH6 structural analysis by cryo-EM and AlphaFold predictions, and a structure-based mutagenesis campaign. The majority of Doa10/MARCH6 adopts a unique circular structure within the membrane. This channel is established by a lipid-binding scaffold, and gated by a flexible helical bundle. The ubiquitylation active site is positioned over the channel by connections between the cytosolic E3 ligase RING domain and the membrane-spanning scaffold and gate. Here, by assaying 95 MARCH6 variants for effects on stability of the well-characterized substrate SQLE, which regulates cholesterol levels, we reveal crucial roles of the gated channel and RING domain consistent with AlphaFold-models of substrate-engaged and ubiquitylation complexes. SQLE degradation further depends on connections between the channel and RING domain, and lipid binding sites, revealing how interconnected Doa10/MARCH6 elements could orchestrate metabolic signals, substrate binding, and E3 ligase activity.
    DOI:  https://doi.org/10.1038/s41467-023-44670-5
  4. Immunity. 2024 Jan 09. pii: S1074-7613(23)00546-0. [Epub ahead of print]57(1): 8-10
    TIMely connections: APOE4, aging, and Alzheimer's.
    Qingyun Li.
      How do APOE4 and aging, two of the strongest risk factors for late-onset Alzheimer's disease (AD), promote disease progression? In this issue of Immunity, Millet et al. examine microglia in AD mice bearing different APOE alleles at distinct ages and identify a conserved exhausted-like microglial state enriched in very elderly and APOE4 AD brains.
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.015
  5. Nat Biotechnol. 2024 Jan 10.
    Prediction of single-cell RNA expression profiles in live cells by Raman microscopy with Raman2RNA.
    Koseki J Kobayashi-Kirschvink, Charles S Comiter, Shreya Gaddam, Taylor Joren, Emanuelle I Grody, Johain R Ounadjela, Ke Zhang, Baoliang Ge, Jeon Woong Kang, Ramnik J Xavier, Peter T C So, Tommaso Biancalani, Jian Shu, Aviv Regev.
      Single-cell RNA sequencing and other profiling assays have helped interrogate cells at unprecedented resolution and scale, but are inherently destructive. Raman microscopy reports on the vibrational energy levels of proteins and metabolites in a label-free and nondestructive manner at subcellular spatial resolution, but it lacks genetic and molecular interpretability. Here we present Raman2RNA (R2R), a method to infer single-cell expression profiles in live cells through label-free hyperspectral Raman microscopy images and domain translation. We predict single-cell RNA sequencing profiles nondestructively from Raman images using either anchor-based integration with single molecule fluorescence in situ hybridization, or anchor-free generation with adversarial autoencoders. R2R outperformed inference from brightfield images (cosine similarities: R2R >0.85 and brightfield <0.15). In reprogramming of mouse fibroblasts into induced pluripotent stem cells, R2R inferred the expression profiles of various cell states. With live-cell tracking of mouse embryonic stem cell differentiation, R2R traced the early emergence of lineage divergence and differentiation trajectories, overcoming discontinuities in expression space. R2R lays a foundation for future exploration of live genomic dynamics.
    DOI:  https://doi.org/10.1038/s41587-023-02082-2
  6. Nat Commun. 2024 Jan 11. 15(1): 451
    Prostaglandin E2 controls the metabolic adaptation of T cells to the intestinal microenvironment.
    Matteo Villa, David E Sanin, Petya Apostolova, Mauro Corrado, Agnieszka M Kabat, Carmine Cristinzio, Annamaria Regina, Gustavo E Carrizo, Nisha Rana, Michal A Stanczak, Francesc Baixauli, Katarzyna M Grzes, Jovana Cupovic, Francesca Solagna, Alexandra Hackl, Anna-Maria Globig, Fabian Hässler, Daniel J Puleston, Beth Kelly, Nina Cabezas-Wallscheid, Peter Hasselblatt, Bertram Bengsch, Robert Zeiser, Sagar, Joerg M Buescher, Edward J Pearce, Erika L Pearce.
      Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8+ T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8+ T cell pool. CD8+ T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8+ T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E2 (PGE2), which drives mitochondrial depolarization in CD8+ T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE2 sensing promotes CD8+ T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE2-autophagy-glutathione axis defines the metabolic adaptation of CD8+ T cells to the intestinal microenvironment, to ultimately influence the T cell pool.
    DOI:  https://doi.org/10.1038/s41467-024-44689-2
  7. Sci Transl Med. 2024 Jan 10. 16(729): eadi1572
    CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.
    Francesco Andreata, Kelly D Moynihan, Valeria Fumagalli, Pietro Di Lucia, Danielle C Pappas, Keigo Kawashima, Irene Ni, Paul H Bessette, Chiara Perucchini, Elisa Bono, Leonardo Giustini, Henry C Nguyen, S Michael Chin, Yik Andy Yeung, Craig S Gibbs, Ivana Djuretic, Matteo Iannacone.
      CD8+ T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8+ T cell dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (Treg) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8+ T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8+ T cells in the liver without substantially altering Treg or NK cell counts. These expanded CD8+ T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen-positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8+ T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8+ T cells without affecting NK or Treg cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.
    DOI:  https://doi.org/10.1126/scitranslmed.adi1572
  8. Nature. 2024 Jan;625(7994): 312-320
    The selection landscape and genetic legacy of ancient Eurasians.
    Evan K Irving-Pease, Alba Refoyo-Martínez, William Barrie, Andrés Ingason, Alice Pearson, Anders Fischer, Karl-Göran Sjögren, Alma S Halgren, Ruairidh Macleod, Fabrice Demeter, Rasmus A Henriksen, Tharsika Vimala, Hugh McColl, Andrew H Vaughn, Leo Speidel, Aaron J Stern, Gabriele Scorrano, Abigail Ramsøe, Andrew J Schork, Anders Rosengren, Lei Zhao, Kristian Kristiansen, Astrid K N Iversen, Lars Fugger, Peter H Sudmant, Daniel J Lawson, Richard Durbin, Thorfinn Korneliussen, Thomas Werge, Morten E Allentoft, Martin Sikora, Rasmus Nielsen, Fernando Racimo, Eske Willerslev.
      The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.
    DOI:  https://doi.org/10.1038/s41586-023-06705-1
  9. Nat Commun. 2024 Jan 11. 15(1): 220
    Single-molecule localization microscopy reveals STING clustering at the trans-Golgi network through palmitoylation-dependent accumulation of cholesterol.
    Haruka Kemmoku, Kanoko Takahashi, Kojiro Mukai, Toshiki Mori, Koichiro M Hirosawa, Fumika Kiku, Yasunori Uchida, Yoshihiko Kuchitsu, Yu Nishioka, Masaaki Sawa, Takuma Kishimoto, Kazuma Tanaka, Yasunari Yokota, Hiroyuki Arai, Kenichi G N Suzuki, Tomohiko Taguchi.
      Stimulator of interferon genes (STING) is critical for the type I interferon response to pathogen- or self-derived DNA in the cytosol. STING may function as a scaffold to activate TANK-binding kinase 1 (TBK1), but direct cellular evidence remains lacking. Here we show, using single-molecule imaging of STING with enhanced time resolutions down to 5 ms, that STING becomes clustered at the trans-Golgi network (about 20 STING molecules per cluster). The clustering requires STING palmitoylation and the Golgi lipid order defined by cholesterol. Single-molecule imaging of TBK1 reveals that STING clustering enhances the association with TBK1. We thus provide quantitative proof-of-principle for the signaling STING scaffold, reveal the mechanistic role of STING palmitoylation in the STING activation, and resolve the long-standing question of the requirement of STING translocation for triggering the innate immune signaling.
    DOI:  https://doi.org/10.1038/s41467-023-44317-5
  10. Nat Aging. 2024 Jan 10.
    TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.
    Patrick T Griffin, Alice E Kane, Alexandre Trapp, Jien Li, Matthew Arnold, Jesse R Poganik, Ryan J Conway, Maeve S McNamara, Margarita V Meer, Noah Hoffman, João A Amorim, Xiao Tian, Michael R MacArthur, Sarah J Mitchell, Amber L Mueller, Colleen Carmody, Daniel L Vera, Csaba Kerepesi, Kejun Ying, Nicole Noren Hooten, James R Mitchell, Michele K Evans, Vadim N Gladyshev, David A Sinclair.
      Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.
    DOI:  https://doi.org/10.1038/s43587-023-00555-2
  11. Nat Commun. 2024 Jan 06. 15(1): 330
    Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension.
    Anna Ulrich, Yukyee Wu, Harmen Draisma, John Wharton, Emilia M Swietlik, Inês Cebola, Eleni Vasilaki, Zhanna Balkhiyarova, Marjo-Riitta Jarvelin, Juha Auvinen, Karl-Heinz Herzig, J Gerry Coghlan, James Lordan, Colin Church, Luke S Howard, Joanna Pepke-Zaba, Mark Toshner, Stephen J Wort, David G Kiely, Robin Condliffe, Allan Lawrie, Stefan Gräf, Nicholas W Morrell, Martin R Wilkins, Inga Prokopenko, Christopher J Rhodes.
      Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10-7) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10-4). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.
    DOI:  https://doi.org/10.1038/s41467-023-44683-0
  12. Nature. 2024 Jan;625(7994): 321-328
    Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.
    William Barrie, Yaoling Yang, Evan K Irving-Pease, Kathrine E Attfield, Gabriele Scorrano, Lise Torp Jensen, Angelos P Armen, Evangelos Antonios Dimopoulos, Aaron Stern, Alba Refoyo-Martinez, Alice Pearson, Abigail Ramsøe, Charleen Gaunitz, Fabrice Demeter, Marie Louise S Jørkov, Stig Bermann Møller, Bente Springborg, Lutz Klassen, Inger Marie Hyldgård, Niels Wickmann, Lasse Vinner, Thorfinn Sand Korneliussen, Morten E Allentoft, Martin Sikora, Kristian Kristiansen, Santiago Rodriguez, Rasmus Nielsen, Astrid K N Iversen, Daniel J Lawson, Lars Fugger, Eske Willerslev.
      Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.
    DOI:  https://doi.org/10.1038/s41586-023-06618-z
  13. Nat Commun. 2024 Jan 06. 15(1): 338
    MarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer.
    Xiaoying Wang, Maoteng Duan, Jingxian Li, Anjun Ma, Gang Xin, Dong Xu, Zihai Li, Bingqiang Liu, Qin Ma.
      Rare cell populations are key in neoplastic progression and therapeutic response, offering potential intervention targets. However, their computational identification and analysis often lag behind major cell types. To fill this gap, we introduce MarsGT: Multi-omics Analysis for Rare population inference using a Single-cell Graph Transformer. It identifies rare cell populations using a probability-based heterogeneous graph transformer on single-cell multi-omics data. MarsGT outperforms existing tools in identifying rare cells across 550 simulated and four real human datasets. In mouse retina data, it reveals unique subpopulations of rare bipolar cells and a Müller glia cell subpopulation. In human lymph node data, MarsGT detects an intermediate B cell population potentially acting as lymphoma precursors. In human melanoma data, it identifies a rare MAIT-like population impacted by a high IFN-I response and reveals the mechanism of immunotherapy. Hence, MarsGT offers biological insights and suggests potential strategies for early detection and therapeutic intervention of disease.
    DOI:  https://doi.org/10.1038/s41467-023-44570-8
  14. Sci Immunol. 2024 Jan 12. 9(91): eabq6930
    Tuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response.
    Shir Nevo, Noga Frenkel, Noam Kadouri, Tom Gome, Noa Rosenthal, Tal Givony, Ayelet Avin, Cristina Peligero Cruz, Merav Kedmi, Moshit Lindzen, Shifra Ben Dor, Golda Damari, Ziv Porat, Rebecca Haffner-Krausz, Hadas Keren-Shaul, Yosef Yarden, Ariel Munitz, Dena Leshkowitz, Yael Goldfarb, Jakub Abramson.
      The thymus is a primary lymphoid organ that is essential for the establishment of adaptive immunity through generation of immunocompetent T cells. In response to various stress signals, the thymus undergoes acute but reversible involution. However, the mechanisms governing its recovery are incompletely understood. Here, we used a dexamethasone-induced acute thymic involution mouse model to investigate how thymic hematopoietic cells (excluding T cells) contribute to thymic regeneration. scRNA-seq analysis revealed marked transcriptional and cellular changes in various thymic populations and highlighted thymus-resident innate lymphoid cells type 2 (ILC2) as a key cell type involved in the response to damage. We identified that ILC2 are activated by the alarmins IL-25 and IL-33 produced in response to tissue damage by thymic tuft cells and fibroblasts, respectively. Moreover, using mouse models deficient in either tuft cells and/or IL-33, we found that these alarmins are required for effective thymus regeneration after dexamethasone-induced damage. We also demonstrate that upon their damage-dependent activation, thymic ILC2 produce several effector molecules linked to tissue regeneration, such as amphiregulin and IL-13, which in turn promote thymic epithelial cell differentiation. Collectively, our study elucidates a previously undescribed role for thymic tuft cells and fibroblasts in thymus regeneration through activation of the type 2 immune response.
    DOI:  https://doi.org/10.1126/sciimmunol.abq6930
  15. Nat Commun. 2024 Jan 10. 15(1): 438
    Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents.
    Hongwei Ma, Yongheng Yang, Tiejian Nie, Rong Yan, Yue Si, Jing Wei, Mengyun Li, He Liu, Wei Ye, Hui Zhang, Linfeng Cheng, Liang Zhang, Xin Lv, Limin Luo, Zhikai Xu, Xijing Zhang, Yingfeng Lei, Fanglin Zhang.
      Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
    DOI:  https://doi.org/10.1038/s41467-024-44687-4
  16. Nat Commun. 2024 Jan 11. 15(1): 468
    Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila.
    Daewon Lee, Eunju Yoon, Su Jin Ham, Kunwoo Lee, Hansaem Jang, Daihn Woo, Da Hyun Lee, Sehyeon Kim, Sekyu Choi, Jongkyeong Chung.
      Diabetic sensory neuropathy (DSN) is one of the most common complications of type 2 diabetes (T2D), however the molecular mechanistic association between T2D and DSN remains elusive. Here we identify ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinase highly expressed in neurons, as a key molecule underlying T2D and DSN. Genetic ablation of UCHL1 leads to neuronal insulin resistance and T2D-related symptoms in Drosophila. Furthermore, loss of UCHL1 induces DSN-like phenotypes, including numbness to external noxious stimuli and axonal degeneration of sensory neurons in flies' legs. Conversely, UCHL1 overexpression improves DSN-like defects of T2D model flies. UCHL1 governs insulin signaling by deubiquitinating insulin receptor substrate 1 (IRS1) and antagonizes an E3 ligase of IRS1, Cullin 1 (CUL1). Consistent with these results, genetic and pharmacological suppression of CUL1 activity rescues T2D- and DSN-associated phenotypes. Therefore, our findings suggest a complete set of genetic factors explaining T2D and DSN, together with potential remedies for the diseases.
    DOI:  https://doi.org/10.1038/s41467-024-44747-9
  17. Commun Biol. 2024 Jan 12. 7(1): 87
    Protein interaction networks in the vasculature prioritize genes and pathways underlying coronary artery disease.
    Qiuyu Martin Zhu, Yu-Han H Hsu, Frederik H Lassen, Bryan T MacDonald, Stephanie Stead, Edyta Malolepsza, April Kim, Taibo Li, Taiji Mizoguchi, Monica Schenone, Gaelen Guzman, Benjamin Tanenbaum, Nadine Fornelos, Steven A Carr, Rajat M Gupta, Patrick T Ellinor, Kasper Lage.
      Population-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we perform interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their roles in CAD. The resulting PPI networks contain interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms. Several PPI networks derived from smooth muscle cells are significantly enriched for genetic variants associated with CAD and related vascular phenotypes. Furthermore, the networks identify 61 genes that are found in genetic loci associated with risk of CAD, prioritizing them as the causal candidates within these loci. These findings indicate that the PPI networks we have generated are a rich resource for guiding future research into the molecular pathogenesis of CAD.
    DOI:  https://doi.org/10.1038/s42003-023-05705-1
  18. Nat Commun. 2024 Jan 06. 15(1): 334
    A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding.
    Haopeng Lin, Kunimasa Suzuki, Nancy Smith, Xi Li, Lisa Nalbach, Sonia Fuentes, Aliya F Spigelman, Xiao-Qing Dai, Austin Bautista, Mourad Ferdaoussi, Saloni Aggarwal, Andrew R Pepper, Leticia P Roma, Emmanuel Ampofo, Wen-Hong Li, Patrick E MacDonald.
      Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in β-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. RNA-seq of sorted β-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state. Increased β-cell exocytosis after 2-day high fat diet is dependent on this reduced intracellular redox state and requires the sentrin-specific SUMO-protease-1. Mice with either pancreas- or β-cell-specific deletion of this fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day high fat diet. Mechanistically, redox-sensing by the SUMO-protease requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained β-cell exocytosis, and increases enzyme sensitivity to regulation by redox signals.
    DOI:  https://doi.org/10.1038/s41467-023-44589-x
  19. Nat Med. 2024 Jan 09.
    Unanswered questions following reports of secondary malignancies after CAR-T cell therapy.
    Bruce L Levine, Marcelo C Pasquini, John E Connolly, David L Porter, Michael P Gustafson, Jaap J Boelens, Edwin M Horwitz, Stephan A Grupp, Marcela V Maus, Frederick L Locke, Fabio Ciceri, Annalisa Ruggeri, John Snowden, Helen E Heslop, Crystal L Mackall, Carl H June, Anna M Sureda, Miguel-Angel Perales.
      
    DOI:  https://doi.org/10.1038/s41591-023-02767-w
  20. Nat Commun. 2024 Jan 08. 15(1): 364
    Functional neuronal circuits emerge in the absence of developmental activity.
    Dániel L Barabási, Gregor F P Schuhknecht, Florian Engert.
      The complex neuronal circuitry of the brain develops from limited information contained in the genome. After the genetic code instructs the birth of neurons, the emergence of brain regions, and the formation of axon tracts, it is believed that temporally structured spiking activity shapes circuits for behavior. Here, we challenge the learning-dominated assumption that spiking activity is required for circuit formation by quantifying its contribution to the development of visually-guided swimming in the larval zebrafish. We found that visual experience had no effect on the emergence of the optomotor response (OMR) in dark-reared zebrafish. We then raised animals while pharmacologically silencing action potentials with the sodium channel blocker tricaine. After washout of the anesthetic, fish could swim and performed with 75-90% accuracy in the OMR paradigm. Brain-wide imaging confirmed that neuronal circuits came 'online' fully tuned, without requiring activity-dependent plasticity. Thus, complex sensory-guided behaviors can emerge through activity-independent developmental mechanisms.
    DOI:  https://doi.org/10.1038/s41467-023-44681-2
  21. Immunity. 2024 Jan 09. pii: S1074-7613(23)00540-X. [Epub ahead of print]57(1): 14-27
    Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation.
    Mohammad Arifuzzaman, Nicholas Collins, Chun-Jun Guo, David Artis.
      Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently alter immune responses in health and disease. We discuss how specific dietary components and metabolites can be either pro-inflammatory or anti-inflammatory in a context- and tissue-dependent manner during infection, chronic inflammation, and cancer. Together, these studies emphasize the influence of diet-microbiota crosstalk on immune regulation that will have a significant impact on precision nutrition approaches and therapeutic interventions for managing inflammation, infection, and cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.009
  22. Nat Cell Biol. 2024 Jan 09.
    EPAC1 boosts thermogenic adipocyte formation.
    Evan D Rosen.
      
    DOI:  https://doi.org/10.1038/s41556-023-01304-8
  23. Nat Cell Biol. 2024 Jan 08.
    tRNA flux and consistency in differentiation.
    Yichen Hou, Tao Pan.
      
    DOI:  https://doi.org/10.1038/s41556-023-01323-5
  24. Nat Commun. 2024 Jan 09. 15(1): 386
    Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.
    Fengxia Ma, Laxman Ghimire, Qian Ren, Yuping Fan, Tong Chen, Arumugam Balasubramanian, Alan Hsu, Fei Liu, Hongbo Yu, Xuemei Xie, Rong Xu, Hongbo R Luo.
      Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-023-44669-y
  25. Nat Rev Immunol. 2024 Jan 09.
    Squeeze to arm.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-024-00987-w
  26. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2314699121
    Local and dynamic regulation of neuronal glycolysis in vivo.
    Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Ian J Gonzalez, Marc Hammarlund, Anthony A Hyman, Philip J S Stork, Richard H Goodman, Daniel A Colón-Ramos.
      Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.
    Keywords:  C. elegans; biosensor; energy metabolism; glycolysis; neurons
    DOI:  https://doi.org/10.1073/pnas.2314699121
  27. Nat Commun. 2024 Jan 09. 15(1): 383
    The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34.
    Rasmus Berglund, Yufei Cheng, Eliane Piket, Milena Z Adzemovic, Manuel Zeitelhofer, Tomas Olsson, Andre Ortlieb Guerreiro-Cacais, Maja Jagodic.
      Microglia harness an unutilized health-promoting potential in age-related neurodegenerative and neuroinflammatory diseases, conditions like progressive multiple sclerosis (MS). Our research unveils an microglia population emerging in the cortical brain regions of aging mice, marked by ERK1/2, Akt, and AMPK phosphorylation patterns and a transcriptome indicative of activated autophagy - a process critical for cellular adaptability. By deleting the core autophagy gene Ulk1 in microglia, we reduce this population in the central nervous system of aged mice. Notably, this population is found dependent on IL-34, rather than CSF1, although both are ligands for CSF1R. When aging mice are exposed to autoimmune neuroinflammation, the loss of autophagy-dependent microglia leads to neural and glial cell death and increased mortality. Conversely, microglial expansion mediated by IL-34 exhibits a protective effect. These findings shed light on an autophagy-dependent neuroprotective microglia population as a potential target for treating age-related neuroinflammatory conditions, including progressive MS.
    DOI:  https://doi.org/10.1038/s41467-023-44556-6
  28. Mol Cell. 2024 Jan 06. pii: S1097-2765(23)01040-7. [Epub ahead of print]
    Sequencing of N6-methyl-deoxyadenosine at single-base resolution across the mammalian genome.
    Xinran Feng, Xiaolong Cui, Li-Sheng Zhang, Chang Ye, Pingluan Wang, Yuhao Zhong, Tong Wu, Zhong Zheng, Chuan He.
      Although DNA N6-methyl-deoxyadenosine (6mA) is abundant in bacteria and protists, its presence and function in mammalian genomes have been less clear. We present Direct-Read 6mA sequencing (DR-6mA-seq), an antibody-independent method, to measure 6mA at base resolution. DR-6mA-seq employs a unique mutation-based strategy to reveal 6mA sites as misincorporation signatures without any chemical or enzymatic modulation of 6mA. We validated DR-6mA-seq through the successful mapping of the well-characterized G(6mA)TC motif in the E. coli DNA. As expected, when applying DR-6mA-seq to mammalian systems, we found that genomic DNA (gDNA) 6mA abundance is generally low in most mammalian tissues and cells; however, we did observe distinct gDNA 6mA sites in mouse testis and glioblastoma cells. DR-6mA-seq provides an enabling tool to detect 6mA at single-base resolution for a comprehensive understanding of DNA 6mA in eukaryotes.
    Keywords:  DNA modification; N(6)-methyl-deoxyadenosine; epigenetics; glioblastoma; single-base resolution sequencing
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.021
  29. Nat Rev Immunol. 2024 Jan 11.
    Integrated organ immunity: a path to a universal vaccine.
    Bali Pulendran.
      
    DOI:  https://doi.org/10.1038/s41577-024-00990-1
  30. Nature. 2024 Jan 10.
    The CRISPR effector Cam1 mediates membrane depolarization for phage defence.
    Christian F Baca, You Yu, Jakob T Rostøl, Puja Majumder, Dinshaw J Patel, Luciano A Marraffini.
      Prokaryotic type III CRISPR-Cas systems provide immunity against viruses and plasmids using CRISPR-associated Rossman fold (CARF) protein effectors1-5. Recognition of transcripts of these invaders with sequences that are complementary to CRISPR RNA guides leads to the production of cyclic oligoadenylate second messengers, which bind CARF domains and trigger the activity of an effector domain6,7. Whereas most effectors degrade host and invader nucleic acids, some are predicted to contain transmembrane helices without an enzymatic function. Whether and how these CARF-transmembrane helix fusion proteins facilitate the type III CRISPR-Cas immune response remains unknown. Here we investigate the role of cyclic oligoadenylate-activated membrane protein 1 (Cam1) during type III CRISPR immunity. Structural and biochemical analyses reveal that the CARF domains of a Cam1 dimer bind cyclic tetra-adenylate second messengers. In vivo, Cam1 localizes to the membrane, is predicted to form a tetrameric transmembrane pore, and provides defence against viral infection through the induction of membrane depolarization and growth arrest. These results reveal that CRISPR immunity does not always operate through the degradation of nucleic acids, but is instead mediated via a wider range of cellular responses.
    DOI:  https://doi.org/10.1038/s41586-023-06902-y
  31. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01026-2. [Epub ahead of print]
    Pioneer and PRDM transcription factors coordinate bivalent epigenetic states to safeguard cell fate.
    Satoshi Matsui, Marissa Granitto, Morgan Buckley, Katie Ludwig, Sandra Koigi, Joseph Shiley, William J Zacharias, Christopher N Mayhew, Hee-Woong Lim, Makiko Iwafuchi.
      Pioneer transcription factors (TFs) regulate cell fate by establishing transcriptionally primed and active states. However, cell fate control requires the coordination of both lineage-specific gene activation and repression of alternative-lineage programs, a process that is poorly understood. Here, we demonstrate that the pioneer TF FOXA coordinates with PRDM1 TF to recruit nucleosome remodeling and deacetylation (NuRD) complexes and Polycomb repressive complexes (PRCs), which establish highly occupied, accessible nucleosome conformation with bivalent epigenetic states, thereby preventing precocious and alternative-lineage gene expression during human endoderm differentiation. Similarly, the pioneer TF OCT4 coordinates with PRDM14 to form bivalent enhancers and repress cell differentiation programs in human pluripotent stem cells, suggesting that this may be a common and critical function of pioneer TFs. We propose that pioneer and PRDM TFs coordinate to safeguard cell fate through epigenetic repression mechanisms.
    Keywords:  FOXA; NuRD; OCT4; PRC; PRDM1; PRDM14; Polycomb repressive complex; bivalent epigenetic state; cell fate control; complex; nucleosome remodeling and deacetylation; pioneer transcription factor
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.007
  32. Nature. 2024 Jan;625(7994): 329-337
    100 ancient genomes show repeated population turnovers in Neolithic Denmark.
    Morten E Allentoft, Martin Sikora, Anders Fischer, Karl-Göran Sjögren, Andrés Ingason, Ruairidh Macleod, Anders Rosengren, Bettina Schulz Paulsson, Marie Louise Schjellerup Jørkov, Maria Novosolov, Jesper Stenderup, T Douglas Price, Morten Fischer Mortensen, Anne Birgitte Nielsen, Mikkel Ulfeldt Hede, Lasse Sørensen, Poul Otto Nielsen, Peter Rasmussen, Theis Zetner Trolle Jensen, Alba Refoyo-Martínez, Evan K Irving-Pease, William Barrie, Alice Pearson, Bárbara Sousa da Mota, Fabrice Demeter, Rasmus A Henriksen, Tharsika Vimala, Hugh McColl, Andrew Vaughn, Lasse Vinner, Gabriel Renaud, Aaron Stern, Niels Nørkjær Johannsen, Abigail Daisy Ramsøe, Andrew Joseph Schork, Anthony Ruter, Anne Birgitte Gotfredsen, Bjarne Henning Nielsen, Erik Brinch Petersen, Esben Kannegaard, Jesper Hansen, Kristoffer Buck Pedersen, Lisbeth Pedersen, Lutz Klassen, Morten Meldgaard, Morten Johansen, Otto Christian Uldum, Per Lotz, Per Lysdahl, Pernille Bangsgaard, Peter Vang Petersen, Rikke Maring, Rune Iversen, Sidsel Wåhlin, Søren Anker Sørensen, Søren H Andersen, Thomas Jørgensen, Niels Lynnerup, Daniel J Lawson, Simon Rasmussen, Thorfinn Sand Korneliussen, Kurt H Kjær, Richard Durbin, Rasmus Nielsen, Olivier Delaneau, Thomas Werge, Kristian Kristiansen, Eske Willerslev.
      Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
    DOI:  https://doi.org/10.1038/s41586-023-06862-3
  33. Nat Commun. 2024 Jan 12. 15(1): 486
    Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils.
    Kartikay Sharma, Fabian Stockert, Jayakrishna Shenoy, Mélanie Berbon, Muhammed Bilal Abdul-Shukkoor, Birgit Habenstein, Antoine Loquet, Matthias Schmidt, Marcus Fändrich.
      The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.
    DOI:  https://doi.org/10.1038/s41467-023-44489-0
  34. Nat Metab. 2024 Jan 08.
    Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.
    Xing Zhang, Xiaofeng Ding, Chunqing Wang, Que Le, Dandan Wu, Anying Song, Guixiang Huang, Liping Luo, Yan Luo, Xin Yang, Aleyah E Goins, Sharina P Desai, Chengrui Qiu, Floyd D Silva, Lily Elizabeth Feldman, Jianlin Zhou, Michael F Spafford, Nathan H Boyd, Eric R Prossnitz, Xuexian O Yang, Qiong A Wang, Meilian Liu.
      The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB+) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB+ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.
    DOI:  https://doi.org/10.1038/s42255-023-00945-1
  35. Cell. 2024 Jan 05. pii: S0092-8674(23)01347-8. [Epub ahead of print]
    Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.
    Zhenlong Li, Rui Ma, Hejun Tang, Jiamin Guo, Zahir Shah, Jianying Zhang, Ningyuan Liu, Shuai Cao, Guido Marcucci, David Artis, Michael A Caligiuri, Jianhua Yu.
      The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.
    Keywords:  DNAM-1; GZMB; ILC2s; apoptosis; cancer immunotherapy; cell therapy; innate lymphoid cells; leukemia; pyroptosis; solid tumors
    DOI:  https://doi.org/10.1016/j.cell.2023.12.015
  36. Nat Genet. 2024 Jan;56(1): 124-135
    Computational prediction and experimental validation identify functionally conserved lncRNAs from zebrafish to human.
    Wenze Huang, Tuanlin Xiong, Yuting Zhao, Jian Heng, Ge Han, Pengfei Wang, Zhihua Zhao, Ming Shi, Juan Li, Jiazhen Wang, Yixia Wu, Feng Liu, Jianzhong Jeff Xi, Yangming Wang, Qiangfeng Cliff Zhang.
      Functional studies of long noncoding RNAs (lncRNAs) have been hindered by the lack of methods to assess their evolution. Here we present lncRNA Homology Explorer (lncHOME), a computational pipeline that identifies a unique class of long noncoding RNAs (lncRNAs) with conserved genomic locations and patterns of RNA-binding protein (RBP) binding sites (coPARSE-lncRNAs). Remarkably, several hundred human coPARSE-lncRNAs can be evolutionarily traced to zebrafish. Using CRISPR-Cas12a knockout and rescue assays, we found that knocking out many human coPARSE-lncRNAs led to cell proliferation defects, which were subsequently rescued by predicted zebrafish homologs. Knocking down coPARSE-lncRNAs in zebrafish embryos caused severe developmental delays that were rescued by human homologs. Furthermore, we verified that human, mouse and zebrafish coPARSE-lncRNA homologs tend to bind similar RBPs with their conserved functions relying on specific RBP-binding sites. Overall, our study demonstrates a comprehensive approach for studying the functional conservation of lncRNAs and implicates numerous lncRNAs in regulating vertebrate physiology.
    DOI:  https://doi.org/10.1038/s41588-023-01620-7
  37. Nat Aging. 2024 Jan 12.
    Targeting COPIng liabilities of senescent cells.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-024-00567-6
  38. Cell Rep. 2024 Jan 10. pii: S2211-1247(23)01599-1. [Epub ahead of print]43(1): 113587
    The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
    Huanyu Lu, Linni Fan, Wenli Zhang, Guo Chen, An Xiang, Li Wang, Zifan Lu, Yue Zhai.
      Nonalcoholic steatohepatitis (NASH) is a metabolism-associated fatty liver disease with accumulated mitochondrial stress, and targeting mitochondrial function is a potential therapy. The mitochondrial genome-encoded bioactive peptide MOTS-c plays broad physiological roles, but its effectiveness and direct targets in NASH treatment are still unclear. Here, we show that long-term preventive and short-term therapeutic effects of MOTS-c treatments alleviate NASH-diet-induced liver steatosis, cellular apoptosis, inflammation, and fibrosis. Mitochondrial oxidative capacity and metabolites profiling analysis show that MOTS-c significantly reverses NASH-induced mitochondrial metabolic deficiency. Moreover, we identify that MOTS-c directly interacts with the BH3 domain of antiapoptotic B cell lymphoma-2 (Bcl-2), increases Bcl-2 protein stability, and suppresses Bcl-2 ubiquitination. By using a Bcl-2 inhibitor or adeno-associated virus (AAV)-mediated Bcl-2 knockdown, we further confirm that MOTS-c improves NASH-induced mitochondrial dysfunction, inflammation, and fibrosis, which are dependent on Bcl-2 function. Therefore, our findings show that MOTS-c is a potential therapeutic agent to inhibit the progression of NASH.
    Keywords:  Bcl-2; CP: Metabolism; CP: Molecular biology; MOTS-c; apoptosis; mitochondrial dysfunction; nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113587
  39. Nat Commun. 2024 Jan 08. 15(1): 354
    Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.
    Zhijian Yang, Junhao Wen, Ahmed Abdulkadir, Yuhan Cui, Guray Erus, Elizabeth Mamourian, Randa Melhem, Dhivya Srinivasan, Sindhuja T Govindarajan, Jiong Chen, Mohamad Habes, Colin L Masters, Paul Maruff, Jurgen Fripp, Luigi Ferrucci, Marilyn S Albert, Sterling C Johnson, John C Morris, Pamela LaMontagne, Daniel S Marcus, Tammie L S Benzinger, David A Wolk, Li Shen, Jingxuan Bao, Susan M Resnick, Haochang Shou, Ilya M Nasrallah, Christos Davatzikos.
      Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes.
    DOI:  https://doi.org/10.1038/s41467-023-44271-2
  40. Mol Cell. 2024 Jan 01. pii: S1097-2765(23)01032-8. [Epub ahead of print]
    Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.
    Iqbal Dulloo, Michael Tellier, Clémence Levet, Anissa Chikh, Boyan Zhang, Diana C Blaydon, Catherine M Webb, David P Kelsell, Matthew Freeman.
      iRhoms are pseudoprotease members of the rhomboid-like superfamily and are cardinal regulators of inflammatory and growth factor signaling; they function primarily by recognizing transmembrane domains of their clients. Here, we report a mechanistically distinct nuclear function of iRhoms, showing that both human and mouse iRhom2 are non-canonical substrates of signal peptidase complex (SPC), the protease that removes signal peptides from secreted proteins. Cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus and modifies the transcriptome, in part by binding C-terminal binding proteins (CtBPs). The biological significance of nuclear iRhom2 is indicated by elevated levels in skin biopsies of patients with psoriasis, tylosis with oesophageal cancer (TOC), and non-epidermolytic palmoplantar keratoderma (NEPPK); increased iRhom2 cleavage in a keratinocyte model of psoriasis; and nuclear iRhom2 promoting proliferation of keratinocytes. Overall, this work identifies an unexpected SPC-dependent ER-to-nucleus signaling pathway and demonstrates that iRhoms can mediate nuclear signaling.
    Keywords:  CtBP1; CtBP2; RHBDF1; RHBDF2; RNA-seq; TOC; psoriasis; rhomboid; skin
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.012
  41. Mol Cell. 2024 Jan 04. pii: S1097-2765(23)01034-1. [Epub ahead of print]
    A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.
    Xu Wang, Sheng-Qiao Fu, Xiao Yuan, Feng Yu, Qian Ji, Hao-Wen Tang, Rong-Kun Li, Shan Huang, Pei-Qi Huang, Wei-Ting Qin, Hao Zuo, Chang Du, Lin-Li Yao, Hui Li, Jun Li, Dong-Xue Li, Yan Yang, Shu-Yu Xiao, Aziguli Tulamaiti, Xue-Feng Wang, Chun-Hua Dai, Xu Zhang, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Zhi-Gang Zhang.
      Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.
    Keywords:  5-HT; CD8(+) T cell; GAPDH; glycolysis; post-translational modification; serotonin; serotonylation; tumor immunity
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.015
  42. Nat Cancer. 2024 Jan 09.
    LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells.
    Dhiraj Kumar, Sreeharsha Gurrapu, Yan Wang, Seong-Yeon Bae, Poonam R Pandey, Hong Chen, Jayanta Mondal, Hyunho Han, Chang-Jiun Wu, Spyros Karaiskos, Fei Yang, Aysegul Sahin, Ignacio I Wistuba, Jianjun Gao, Debasish Tripathy, Hua Gao, Benjamin Izar, Filippo G Giancotti.
      The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.
    DOI:  https://doi.org/10.1038/s43018-023-00695-9
  43. Nat Commun. 2024 Jan 09. 15(1): 388
    Identifying immune signatures of sepsis to increase diagnostic accuracy in very preterm babies.
    A Das, G Ariyakumar, N Gupta, S Kamdar, A Barugahare, D Deveson-Lucas, S Gee, K Costeloe, M S Davey, P Fleming, D L Gibbons.
      Bacterial infections are a major cause of mortality in preterm babies, yet our understanding of early-life disease-associated immune dysregulation remains limited. Here, we combine multi-parameter flow cytometry, single-cell RNA sequencing and plasma analysis to longitudinally profile blood from very preterm babies (<32 weeks gestation) across episodes of invasive bacterial infection (sepsis). We identify a dynamically changing blood immune signature of sepsis, including lymphopenia, reduced dendritic cell frequencies and myeloid cell HLA-DR expression, which characterizes sepsis even when the common clinical marker of inflammation, C-reactive protein, is not elevated. Furthermore, single-cell RNA sequencing identifies upregulation of amphiregulin in leukocyte populations during sepsis, which we validate as a plasma analyte that correlates with clinical signs of disease, even when C-reactive protein is normal. This study provides insights into immune pathways associated with early-life sepsis and identifies immune analytes as potential diagnostic adjuncts to standard tests to guide targeted antibiotic prescribing.
    DOI:  https://doi.org/10.1038/s41467-023-44387-5
  44. Nat Immunol. 2024 Jan 08.
    Tissues of origin matter to plasma cell longevity.
    Wataru Ise, Tomohiro Kurosaki.
      
    DOI:  https://doi.org/10.1038/s41590-023-01731-7
  45. Nat Commun. 2024 Jan 08. 15(1): 361
    PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity.
    Sundarraj Jayakumar, Manthan Patel, Fanny Boulet, Hadicha Aziz, Greg N Brooke, Hemanth Tummala, Madapura M Pradeepa.
      R-loops that accumulate at transcription sites pose a persistent threat to genome integrity. PSIP1 is a chromatin protein associated with transcriptional elongation complex, possesses histone chaperone activity, and is implicated in recruiting RNA processing and DNA repair factors to transcription sites. Here, we show that PSIP1 interacts with R-loops and other proteins involved in R-loop homeostasis, including PARP1. Genome-wide mapping of PSIP1, R-loops and γ-H2AX in PSIP1-depleted human and mouse cell lines revealed an accumulation of R-loops and DNA damage at gene promoters in the absence of PSIP1. R-loop accumulation causes local transcriptional arrest and transcription-replication conflict, leading to DNA damage. PSIP1 depletion increases 53BP1 foci and reduces RAD51 foci, suggesting altered DNA repair choice. Furthermore, PSIP1 depletion increases the sensitivity of cancer cells to PARP1 inhibitors and DNA-damaging agents that induce R-loop-induced DNA damage. These findings provide insights into the mechanism through which PSIP1 maintains genome integrity at the site of transcription.
    DOI:  https://doi.org/10.1038/s41467-023-44544-w
  46. Nat Methods. 2024 Jan 10.
    Profiling of RNA-binding protein binding sites by in situ reverse transcription-based sequencing.
    Yu Xiao, Yan-Ming Chen, Zhongyu Zou, Chang Ye, Xiaoyang Dou, Jinjun Wu, Chang Liu, Shun Liu, Hao Yan, Pingluan Wang, Tie-Bo Zeng, Qinzhe Liu, Jingyi Fei, Weixin Tang, Chuan He.
      RNA-binding proteins (RBPs) regulate diverse cellular processes by dynamically interacting with RNA targets. However, effective methods to capture both stable and transient interactions between RBPs and their RNA targets are still lacking, especially when the interaction is dynamic or samples are limited. Here we present an assay of reverse transcription-based RBP binding site sequencing (ARTR-seq), which relies on in situ reverse transcription of RBP-bound RNAs guided by antibodies to identify RBP binding sites. ARTR-seq avoids ultraviolet crosslinking and immunoprecipitation, allowing for efficient and specific identification of RBP binding sites from as few as 20 cells or a tissue section. Taking advantage of rapid formaldehyde fixation, ARTR-seq enables capturing the dynamic RNA binding by RBPs over a short period of time, as demonstrated by the profiling of dynamic RNA binding of G3BP1 during stress granule assembly on a timescale as short as 10 minutes.
    DOI:  https://doi.org/10.1038/s41592-023-02146-w
  47. Nat Commun. 2024 Jan 10. 15(1): 432
    A global analysis of how human infrastructure squeezes sandy coasts.
    Eva M Lansu, Valérie C Reijers, Solveig Höfer, Arjen Luijendijk, Max Rietkerk, Martin J Wassen, Evert Jan Lammerts, Tjisse van der Heide.
      Coastal ecosystems provide vital services, but human disturbance causes massive losses. Remaining ecosystems are squeezed between rising seas and human infrastructure development. While shoreline retreat is intensively studied, coastal congestion through infrastructure remains unquantified. Here we analyse 235,469 transects worldwide to show that infrastructure occurs at a median distance of 392 meter from sandy shorelines. Moreover, we find that 33% of sandy shores harbour less than 100 m of infrastructure-free space, and that 23-30% of this space may be lost by 2100 due to rising sea levels. Further analyses show that population density and gross domestic product explain 35-39% of observed squeeze variation, emphasizing the intensifying pressure imposed as countries develop and populations grow. Encouragingly, we find that nature reserves relieve squeezing by 4-7 times. Yet, at present only 16% of world's sandy shores have a protected status. We therefore advocate the incorporation of nature protection into spatial planning policies.
    DOI:  https://doi.org/10.1038/s41467-023-44659-0
  48. Nat Med. 2024 Jan 09.
    Economists are crucial for solving public health challenges.
    Ximena P Garzon-Villalba.
      
    DOI:  https://doi.org/10.1038/s41591-023-02657-1
  49. Nat Rev Immunol. 2024 Jan 10.
    Why have T cell-inducing vaccines for HIV failed so far?
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-024-00989-8
  50. EMBO J. 2024 Jan 11.
    Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
    Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.
      Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.
    Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis
    DOI:  https://doi.org/10.1038/s44318-023-00008-x
  51. Nat Aging. 2024 Jan 09.
    A plasma proteome measure of organ aging.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00568-5
  52. Nature. 2024 Jan;625(7994): 233-234
    How we remember the dead by their digital afterlives.
    Margaret Gibson.
      
    Keywords:  Culture; Society; Sociology
    DOI:  https://doi.org/10.1038/d41586-024-00016-9
  53. Immunity. 2024 Jan 09. pii: S1074-7613(23)00545-9. [Epub ahead of print]57(1): 188-192
    Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB-CD8+ memory T cells and accumulation of type 2 memory T cells.
    Marina Terekhova, Amanda Swain, Pavla Bohacova, Ekaterina Aladyeva, Laura Arthur, Anwesha Laha, Denis A Mogilenko, Samantha Burdess, Vladimir Sukhov, Denis Kleverov, Barbora Echalar, Petr Tsurinov, Roman Chernyatchik, Kamila Husarcikova, Maxim N Artyomov.
      
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.014
  54. J Clin Invest. 2024 Jan 09. pii: e174984. [Epub ahead of print]
    S1PR1 inhibition induces pro-apoptotic signaling in T cells and limits humoral responses within lymph nodes.
    Dhaval Dixit, Victoria M Hallisey, Ethan Ys Zhu, Martyna Okuniewska, Ken Cadwell, Jerry E Chipuk, Jordan E Axelrad, Susan R Schwab.
      Effective immunity requires a large, diverse naïve T cell repertoire circulating among lymphoid organs in search of antigen. Sphingosine 1-phosphate (S1P) and its receptor S1PR1 contribute by both directing T cell migration and supporting T cell survival. Here, we addressed how S1P enables T cell survival, and the implications for patients treated with S1PR1 antagonists. We found that S1PR1 limited apoptosis by maintaining the appropriate balance of BCL2 family members via restraint of JNK activity. Interestingly, the same residues of S1PR1 that enable receptor internalization were required to prevent this pro-apoptotic cascade. Findings in mice were recapitulated in ulcerative colitis patients treated with the S1PR1 antagonist ozanimod, and the loss of naïve T cells limited B cell responses. Our findings highlighted an effect of S1PR1 antagonists on the ability to mount immune responses within lymph nodes, beyond their effect on lymph node egress, and suggested both limitations and additional uses of this important class of drugs.
    Keywords:  Adaptive immunity; Apoptosis; Cell migration/adhesion; Immunology
    DOI:  https://doi.org/10.1172/JCI174984
  55. Nat Cell Biol. 2024 Jan 08.
    Selective gene expression maintains human tRNA anticodon pools during differentiation.
    Lexi Gao, Andrew Behrens, Geraldine Rodschinka, Sergio Forcelloni, Sascha Wani, Katrin Strasser, Danny D Nedialkova.
      Transfer RNAs are essential for translating genetic information into proteins. The human genome contains hundreds of predicted tRNA genes, many in multiple copies. How their expression is regulated to control tRNA repertoires is unknown. Here we combined quantitative tRNA profiling and chromatin immunoprecipitation with sequencing to measure tRNA expression following the differentiation of human induced pluripotent stem cells into neuronal and cardiac cells. We find that tRNA transcript levels vary substantially, whereas tRNA anticodon pools, which govern decoding rates, are more stable among cell types. Mechanistically, RNA polymerase III transcribes a wide range of tRNA genes in human induced pluripotent stem cells but on differentiation becomes constrained to a subset we define as housekeeping tRNAs. This shift is mediated by decreased mTORC1 signalling, which activates the RNA polymerase III repressor MAF1. Our data explain how tRNA anticodon pools are buffered to maintain decoding speed across cell types and reveal that mTORC1 drives selective tRNA expression during differentiation.
    DOI:  https://doi.org/10.1038/s41556-023-01317-3
  56. Nat Commun. 2024 Jan 08. 15(1): 350
    Single-cell mapping of lipid metabolites using an infrared probe in human-derived model systems.
    Yeran Bai, Carolina M Camargo, Stella M K Glasauer, Raymond Gifford, Xinran Tian, Andrew P Longhini, Kenneth S Kosik.
      Understanding metabolic heterogeneity is the key to uncovering the underlying mechanisms of metabolic-related diseases. Current metabolic imaging studies suffer from limitations including low resolution and specificity, and the model systems utilized often lack human relevance. Here, we present a single-cell metabolic imaging platform to enable direct imaging of lipid metabolism with high specificity in various human-derived 2D and 3D culture systems. Through the incorporation of an azide-tagged infrared probe, selective detection of newly synthesized lipids in cells and tissue became possible, while simultaneous fluorescence imaging enabled cell-type identification in complex tissues. In proof-of-concept experiments, newly synthesized lipids were directly visualized in human-relevant model systems among different cell types, mutation status, differentiation stages, and over time. We identified upregulated lipid metabolism in progranulin-knockdown human induced pluripotent stem cells and in their differentiated microglia cells. Furthermore, we observed that neurons in brain organoids exhibited a significantly lower lipid metabolism compared to astrocytes.
    DOI:  https://doi.org/10.1038/s41467-023-44675-0
  57. Mol Cell. 2024 Jan 09. pii: S1097-2765(23)01039-0. [Epub ahead of print]
    Conformational transitions and activation of the adhesion receptor CD97.
    Chunyou Mao, Ru-Jia Zhao, Ying-Jun Dong, Mingxin Gao, Li-Nan Chen, Chao Zhang, Peng Xiao, Jia Guo, Jiao Qin, Dan-Dan Shen, Su-Yu Ji, Shao-Kun Zang, Huibing Zhang, Wei-Wei Wang, Qingya Shen, Jin-Peng Sun, Yan Zhang.
      Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.
    Keywords:  CD97; Cryo-EM; adhesion GPCR; conformational transition; inactive structure; tethered agonism
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.020
  58. Immunity. 2024 Jan 09. pii: S1074-7613(23)00544-7. [Epub ahead of print]57(1): 6-8
    On blood and tissue-resident natural killer cells.
    Emilie Narni-Mancinelli, Carole Berruyer, Eric Vivier.
      Conventional natural killer (cNK) cells patrol the organism via circulation and invade tissues in response to infection or inflammation. In this issue of Immunity, Torcellan et al. report that circulating cNK cells are recruited into infected skin and differentiate into long-lived tissue-resident NK cells capable of mediating an accelerated response upon reinfection.
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.013
  59. Nat Rev Immunol. 2024 Jan 09.
    Natural killer cells that target autoimmune cells linked with protection against multiple sclerosis.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-00988-9
  60. Nature. 2024 Jan 10.
    Ancient DNA reveals origins of multiple sclerosis in Europe.
    Sara Reardon.
      
    Keywords:  Archaeology; Genomics; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-024-00024-9
  61. Cell. 2024 Jan 05. pii: S0092-8674(23)01342-9. [Epub ahead of print]
    Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.
    Joshua D Meisel, Maria Miranda, Owen S Skinner, Presli P Wiesenthal, Sandra M Wellner, Alexis A Jourdain, Gary Ruvkun, Vamsi K Mootha.
      The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
    Keywords:  C. elegans; NADH:ubiquinone oxidoreductase; NDUFA6; NDUFS4; complex I; electron transport chain; hyperoxia; hypoxia; mitochondria; oxygen
    DOI:  https://doi.org/10.1016/j.cell.2023.12.010
  62. J Clin Invest. 2024 Jan 11. pii: e166149. [Epub ahead of print]
    TRIM56 protects against non-alcoholic fatty liver disease via promoting the degradation of fatty acid synthase.
    Suowen Xu, Xiumei Wu, Sichen Wang, Mengyun Xu, Tingyu Fang, Xiaoxuan Ma, Meijie Chen, Jiajun Fu, Juan Guo, Song Tian, Tian Tian, Xu Cheng, Hailong Yang, Junjie Zhou, Zhenya Wang, Yanjun Yin, Wen Xu, Fen Xu, Jinhua Yan, Zhihua Wang, Sihui Luo, Xiao-Jing Zhang, Yan-Xiao Ji, Jianping Weng.
      Nonalcoholic liver disease (NAFLD) encompasses a disease continuum from simple steatosis, to non-alcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NALFD, identification of potential therapeutic targets is clinically important. Here, we demonstrated that TRIM56 protein abundance is markedly downregulated in the livers of individuals with NAFLD and mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactomic and transcriptomic profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified lipogenesis factor FASN as a direct binding partner of TRIM56. TRIM56 directly interacts with FASN and triggers its K48-linked ubiquitination-dependent degradation. Finally, by using AI-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) which potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with optimal safety, tolerability and pharmacokinetic profile. Our findings provide the proof-of-concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.
    Keywords:  Hepatology; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI166149
  63. Nat Commun. 2024 Jan 11. 15(1): 467
    OXR1 maintains the retromer to delay brain aging under dietary restriction.
    Kenneth A Wilson, Sudipta Bar, Eric B Dammer, Enrique M Carrera, Brian A Hodge, Tyler A U Hilsabeck, Joanna Bons, George W Brownridge, Jennifer N Beck, Jacob Rose, Melia Granath-Panelo, Christopher S Nelson, Grace Qi, Akos A Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B Brem, Philippe M Campeau, Hugo J Bellen, Birgit Schilling, Nicholas T Seyfried, Lisa M Ellerby, Pankaj Kapahi.
      Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects. Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.
    DOI:  https://doi.org/10.1038/s41467-023-44343-3
  64. Nat Cell Biol. 2024 Jan 09.
    EPAC1 enhances brown fat growth and beige adipogenesis.
    Laia Reverte-Salisa, Sana Siddig, Staffan Hildebrand, Xi Yao, Jelena Zurkovic, Michelle Y Jaeckstein, Joerg Heeren, Frank Lezoualc'h, Natalie Krahmer, Alexander Pfeifer.
      Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.
    DOI:  https://doi.org/10.1038/s41556-023-01311-9
  65. Science. 2024 Jan 12. 383(6679): 146-147
    Decoding the language of immunity.
    Raymond A Alvarez, Louisa K James.
      Optimized transfer RNA (tRNA) codon use can speed up antibody generation.
    DOI:  https://doi.org/10.1126/science.adn1067
  66. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2312913120
    Hormonal basis of sex differences in anesthetic sensitivity.
    ReCCognition Study Group
      General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.
    Keywords:  EEG; behavior; hormones; sex differences; whole brain c-Fos imaging
    DOI:  https://doi.org/10.1073/pnas.2312913120
  67. Nat Aging. 2024 Jan 08.
    Slow and steady lives the longest.
    Francesco Morandini, Andrei Seluanov, Vera Gorbunova.
      
    DOI:  https://doi.org/10.1038/s43587-023-00554-3
  68. Trends Immunol. 2024 Jan 11. pii: S1471-4906(23)00262-4. [Epub ahead of print]
    How does the microbiota control systemic innate immunity?
    Christine K I Jordan, Thomas B Clarke.
      The intestinal microbiota has a pervasive influence on mammalian innate immunity fortifying defenses to infection in tissues throughout the host. How intestinal microbes control innate defenses in systemic tissues is, however, poorly defined. In our opinion, there are three core challenges that need addressing to advance our understanding of how the intestinal microbiota controls innate immunity systemically: first, deciphering how signals from intestinal microbes are transmitted to distal tissues; second, unraveling how intestinal microbes prime systemic innate immunity without inducing widespread immunopathology; and third, identifying which intestinal microbes control systemic immunity. Here, we propose answers to these problems which provide a framework for understanding how microbes in the intestine can regulate innate immunity systemically.
    Keywords:  infection; microbiota; systemic innate immunity
    DOI:  https://doi.org/10.1016/j.it.2023.12.002
  69. Nat Commun. 2024 Jan 09. 15(1): 389
    Overcoming resolution attenuation during tilted cryo-EM data collection.
    Sriram Aiyer, Philip R Baldwin, Shi Min Tan, Zelin Shan, Juntaek Oh, Atousa Mehrani, Marianne E Bowman, Gordon Louie, Dario Oliveira Passos, Selena Đorđević-Marquardt, Mario Mietzsch, Joshua A Hull, Shuichi Hoshika, Benjamin A Barad, Danielle A Grotjahn, Robert McKenna, Mavis Agbandje-McKenna, Steven A Benner, Joseph A P Noel, Dong Wang, Yong Zi Tan, Dmitry Lyumkis.
      Structural biology efforts using cryogenic electron microscopy are frequently stifled by specimens adopting "preferred orientations" on grids, leading to anisotropic map resolution and impeding structure determination. Tilting the specimen stage during data collection is a generalizable solution but has historically led to substantial resolution attenuation. Here, we develop updated data collection and image processing workflows and demonstrate, using multiple specimens, that resolution attenuation is negligible or significantly reduced across tilt angles. Reconstructions with and without the stage tilted as high as 60° are virtually indistinguishable. These strategies allowed the reconstruction to 3 Å resolution of a bacterial RNA polymerase with preferred orientation, containing an unnatural nucleotide for studying novel base pair recognition. Furthermore, we present a quantitative framework that allows cryo-EM practitioners to define an optimal tilt angle during data acquisition. These results reinforce the utility of employing stage tilt for data collection and provide quantitative metrics to obtain isotropic maps.
    DOI:  https://doi.org/10.1038/s41467-023-44555-7
  70. Science. 2024 Jan 12. 383(6679): eadf6493
    Deterministic reprogramming of neutrophils within tumors.
    Melissa S F Ng, Immanuel Kwok, Leonard Tan, Changming Shi, Daniela Cerezo-Wallis, Yingrou Tan, Keith Leong, Gabriel F Calvo, Katharine Yang, Yuning Zhang, Jingsi Jin, Ka Hang Liong, Dandan Wu, Rui He, Dehua Liu, Ye Chean Teh, Camille Bleriot, Nicoletta Caronni, Zhaoyuan Liu, Kaibo Duan, Vipin Narang, Iván Ballesteros, Federica Moalli, Mengwei Li, Jinmiao Chen, Yao Liu, Lianxin Liu, Jingjing Qi, Yingbin Liu, Lingxi Jiang, Baiyong Shen, Hui Cheng, Tao Cheng, Veronique Angeli, Ankur Sharma, Yuin-Han Loh, Hong Liang Tey, Shu Zhen Chong, Matteo Iannacone, Renato Ostuni, Andrés Hidalgo, Florent Ginhoux, Lai Guan Ng.
      Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.
    DOI:  https://doi.org/10.1126/science.adf6493
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