bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–08–06
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. How art improves my science.
  2. Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
  3. cGAS-STING drives ageing-related inflammation and neurodegeneration.
  4. miR-15/16 clusters restrict effector Treg cell differentiation and function.
  5. Cryo-EM structure of a RAS/RAF recruitment complex.
  6. A mother to offspring metabolic link.
  7. Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
  8. Africa-specific human genetic variation near CHD1L associates with HIV-1 load.
  9. How the cGAS-STING system links inflammation and cognitive decline.
  10. Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis.
  11. Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.
  12. Structural basis for membrane-proximal proteolysis of substrates by ADAM10.
  13. MAVS signaling is required for preventing persistent chikungunya heart infection and chronic vascular tissue inflammation.
  14. Genetic insights into resting heart rate and its role in cardiovascular disease.
  15. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
  16. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
  17. A spatiotemporal Notch interaction map from plasma membrane to nucleus.
  18. Pre-T cell receptor localization and trafficking are independent of its signaling.
  19. Energetic robustness to large scale structural fluctuations in a photosynthetic supercomplex.
  20. NIH launches trials for long COVID treatments: what scientists think.
  21. A genome-wide association study identifies 41 loci associated with eicosanoid levels.
  22. Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.
  23. Experimental insulin implant uses electricity to control genes.
  24. Naked mole-rats slay zombies.
  25. Genome-wide mutation profiles from cell-free DNA for early cancer detection.
  26. Tagging neurons with light.
  27. O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
  28. Paralysis under pressure.
  29. A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease.
  30. Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.
  31. To be (in a transcriptional complex) or not to be (promoting UBR5 ubiquitylation): That is an answer to how degradation controls gene expression.
  32. Variation in African genomes linked to control of HIV.
  33. The serotonin transporter sustains human brown adipose tissue thermogenesis.
  34. Unique functional responses differentially map onto genetic subtypes of dopamine neurons.
  35. An intestinal sphingolipid confers intergenerational neuroprotection.
  36. Epigenetics in glaucoma: a link between histone methylation and neurodegeneration.
  37. Robust phenotyping of highly multiplexed tissue imaging data using pixel-level clustering.
  38. Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
  39. A fluid biomarker accurately detects tau aggregate pathology in Alzheimer's disease.
  40. Ancient DNA reveals the living descendants of enslaved people through 23andMe.
  41. A single antibody tackles two childhood viruses.
  42. Peptide YY: A Paneth cell antimicrobial peptide that maintains Candida gut commensalism.
  43. SF3B1-mutant cells succumb to replication stress under PARP inhibition.
  44. Decoding the spermatogonial stem cell niche under physiological and recovery conditions in adult mice and humans.
  45. Scientific discovery in the age of artificial intelligence.
  46. CTCF and R-loops are boundaries of cohesin-mediated DNA looping.
  47. Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans.
  1. Science. 2023 Aug 04. 381(6657): 578
    How art improves my science.
    Amy Robison.
      
    DOI:  https://doi.org/10.1126/science.adk0183
  2. Nat Commun. 2023 07 31. 14(1): 4587
    Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.
    Madison L Doolittle, Dominik Saul, Japneet Kaur, Jennifer L Rowsey, Stephanie J Vos, Kevin D Pavelko, Joshua N Farr, David G Monroe, Sundeep Khosla.
      Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze senescent cells at single-cell resolution. We use multiple criteria to identify senescent mesenchymal cells that are growth-arrested and resistant to apoptosis. These p16 + Ki67-BCL-2+ cells are highly enriched for senescence-associated secretory phenotype and DNA damage markers, are strongly associated with age, and their percentages are increased in late osteoblasts/osteocytes and CD24high osteolineage cells. Moreover, both late osteoblasts/osteocytes and CD24high osteolineage cells are robustly cleared by genetic and pharmacologic senolytic therapies in aged mice. Following isolation, CD24+ skeletal cells exhibit growth arrest, senescence-associated β-galactosidase positivity, and impaired osteogenesis in vitro. These studies thus provide an approach using multiplexed protein profiling to define senescent mesenchymal cells in vivo and identify specific skeletal cell populations cleared by senolytics.
    DOI:  https://doi.org/10.1038/s41467-023-40393-9
  3. Nature. 2023 Aug 02.
    cGAS-STING drives ageing-related inflammation and neurodegeneration.
    Muhammet F Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V Thacker, Lucie Favre, Bastien Mangeat, Lona J Kroese, Paul Krimpenfort, Marco Prinz, Andrea Ablasser.
      Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
    DOI:  https://doi.org/10.1038/s41586-023-06373-1
  4. J Exp Med. 2023 10 02. pii: e20230321. [Epub ahead of print]220(10):
    miR-15/16 clusters restrict effector Treg cell differentiation and function.
    Jiayi Dong, William J Huth, Nimi Marcel, Ziyue Zhang, Ling-Li Lin, Li-Fan Lu.
      Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.
    DOI:  https://doi.org/10.1084/jem.20230321
  5. Nat Commun. 2023 07 29. 14(1): 4580
    Cryo-EM structure of a RAS/RAF recruitment complex.
    Eunyoung Park, Shaun Rawson, Anna Schmoker, Byeong-Won Kim, Sehee Oh, Kangkang Song, Hyesung Jeon, Michael J Eck.
      RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, whereupon they initiate signaling through the MAP kinase cascade. Prior structural studies of KRAS with RAF have focused on the isolated RAS-binding and cysteine-rich domains of RAF (RBD and CRD, respectively), which interact directly with RAS. Here we describe cryo-EM structures of a KRAS bound to intact BRAF in an autoinhibited state with MEK1 and a 14-3-3 dimer. Analysis of this KRAS/BRAF/MEK1/14-3-3 complex reveals KRAS bound to the RAS-binding domain of BRAF, captured in two orientations. Core autoinhibitory interactions in the complex are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by RAS and suggest stabilization of this pre-activation intermediate as an alternative therapeutic strategy to blocking binding of KRAS.
    DOI:  https://doi.org/10.1038/s41467-023-40299-6
  6. Nat Cell Biol. 2023 Aug 03.
    A mother to offspring metabolic link.
    Nicholas O Burton.
      
    DOI:  https://doi.org/10.1038/s41556-023-01189-7
  7. Nat Metab. 2023 Aug 03.
    Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
      
    DOI:  https://doi.org/10.1038/s42255-023-00851-6
  8. Nature. 2023 Aug 02.
    Africa-specific human genetic variation near CHD1L associates with HIV-1 load.
    Paul J McLaren, Immacolata Porreca, Gennaro Iaconis, Hoi Ping Mok, Subhankar Mukhopadhyay, Emre Karakoc, Sara Cristinelli, Cristina Pomilla, István Bartha, Christian W Thorball, Riley H Tough, Paolo Angelino, Cher S Kiar, Tommy Carstensen, Segun Fatumo, Tarryn Porter, Isobel Jarvis, William C Skarnes, Andrew Bassett, Marianne K DeGorter, Mohana Prasad Sathya Moorthy, Jeffrey F Tuff, Eun-Young Kim, Miriam Walter, Lacy M Simons, Arman Bashirova, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Andrea De Luca, James J Goedert, David B Goldstein, David W Haas, Joshua T Herbeck, Eric O Johnson, Pontiano Kaleebu, William Kilembe, Gregory D Kirk, Neeltje A Kootstra, Alex H Kral, Olivier Lambotte, Ma Luo, Simon Mallal, Javier Martinez-Picado, Laurence Meyer, José M Miro, Pravi Moodley, Ayesha A Motala, James I Mullins, Kireem Nam, Niels Obel, Fraser Pirie, Francis A Plummer, Guido Poli, Matthew A Price, Andri Rauch, Ioannis Theodorou, Alexandra Trkola, Bruce D Walker, Cheryl A Winkler, Jean-François Zagury, Stephen B Montgomery, Angela Ciuffi, Judd F Hultquist, Steven M Wolinsky, Gordon Dougan, Andrew M L Lever, Deepti Gurdasani, Harriet Groom, Manjinder S Sandhu, Jacques Fellay.
      HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.
    DOI:  https://doi.org/10.1038/s41586-023-06370-4
  9. Nature. 2023 Aug;620(7973): 280-282
    How the cGAS-STING system links inflammation and cognitive decline.
    Bart J L Eggen.
      
    Keywords:  Ageing; Immunology; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-02240-1
  10. Nat Commun. 2023 08 01. 14(1): 4601
    Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis.
    Pia Sinner, Katrin Peckert-Maier, Hashem Mohammadian, Christine Kuhnt, Christina Draßner, Vasiliki Panagiotakopoulou, Simon Rauber, Mathias Linnerbauer, Zhana Haimon, Dmytro Royzman, Deborah Kronenberg-Versteeg, Andreas Ramming, Alexander Steinkasserer, Andreas B Wild.
      Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-023-40370-2
  11. Nat Commun. 2023 Aug 03. 14(1): 4672
    Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes.
    Qiang Zhang, Sai Ma, Zhengzhi Liu, Bohan Zhu, Zirui Zhou, Gaoshan Li, J Javier Meana, Javier González-Maeso, Chang Lu.
      The genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 days. We apply the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS offers a promising solution for single-cell methylomic studies requiring examination of a large cell population.
    DOI:  https://doi.org/10.1038/s41467-023-40411-w
  12. Cell. 2023 Jul 19. pii: S0092-8674(23)00733-X. [Epub ahead of print]
    Structural basis for membrane-proximal proteolysis of substrates by ADAM10.
    Colin H Lipper, Emily D Egan, Khal-Hentz Gabriel, Stephen C Blacklow.
      The endopeptidase ADAM10 is a critical catalyst for the regulated proteolysis of key drivers of mammalian development, physiology, and non-amyloidogenic cleavage of APP as the primary α-secretase. ADAM10 function requires the formation of a complex with a C8-tetraspanin protein, but how tetraspanin binding enables positioning of the enzyme active site for membrane-proximal cleavage remains unknown. We present here a cryo-EM structure of a vFab-ADAM10-Tspan15 complex, which shows that Tspan15 binding relieves ADAM10 autoinhibition and acts as a molecular measuring stick to position the enzyme active site about 20 Å from the plasma membrane for membrane-proximal substrate cleavage. Cell-based assays of N-cadherin shedding establish that the positioning of the active site by the interface between the ADAM10 catalytic domain and the bound tetraspanin influences selection of the preferred cleavage site. Together, these studies reveal the molecular mechanism underlying ADAM10 proteolysis at membrane-proximal sites and offer a roadmap for its modulation in disease.
    Keywords:  APP; Alzheimer’s disease; Notch signaling; alpha-secretase; ectodomain shedding; metalloprotease; tetraspanin
    DOI:  https://doi.org/10.1016/j.cell.2023.06.026
  13. Nat Commun. 2023 Aug 03. 14(1): 4668
    MAVS signaling is required for preventing persistent chikungunya heart infection and chronic vascular tissue inflammation.
    Maria G Noval, Sophie N Spector, Eric Bartnicki, Franco Izzo, Navneet Narula, Stephen T Yeung, Payal Damani-Yokota, M Zahidunnabi Dewan, Valeria Mezzano, Bruno A Rodriguez-Rodriguez, Cynthia Loomis, Kamal M Khanna, Kenneth A Stapleford.
      Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in major innate immunity signaling components, we found that signaling through the mitochondrial antiviral-signaling protein (MAVS) is required for viral clearance from the heart. In the absence of MAVS signaling, persistent infection leads to focal myocarditis and vasculitis of the large vessels attached to the base of the heart. Large vessel vasculitis was observed for up to 60 days post infection, suggesting CHIKV can lead to vascular inflammation and potential long-lasting cardiovascular complications. This study provides a model of CHIKV cardiac infection and mechanistic insight into CHIKV-induced heart disease, underscoring the importance of monitoring cardiac function in patients with CHIKV infections.
    DOI:  https://doi.org/10.1038/s41467-023-40047-w
  14. Nat Commun. 2023 08 02. 14(1): 4646
    Genetic insights into resting heart rate and its role in cardiovascular disease.
    DCCT/EDIC Research Group
      Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
    DOI:  https://doi.org/10.1038/s41467-023-39521-2
  15. Nat Commun. 2023 08 01. 14(1): 4622
    Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
    Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M Camus, Harry Sokol, Hafid Ait-Oufella.
      Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
    DOI:  https://doi.org/10.1038/s41467-023-40216-x
  16. Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]
    Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
    Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.
      Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.
    Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
  17. Sci Signal. 2023 08;16(796): eadg6474
    A spatiotemporal Notch interaction map from plasma membrane to nucleus.
    Alexandre P Martin, Gary A Bradshaw, Robyn J Eisert, Emily D Egan, Lena Tveriakhina, Julia M Rogers, Andrew N Dates, Gustavo Scanavachi, Jon C Aster, Tom Kirchhausen, Marian Kalocsay, Stephen C Blacklow.
      Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor Notch to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage of Notch by the transmembrane protease ADAM10 and the intracellular protease γ-secretase releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex that induces target gene transcription. To map the location and timing of the individual steps required for the proteolysis and movement of Notch from the plasma membrane to the nucleus, we used proximity labeling with quantitative, multiplexed mass spectrometry to monitor the interaction partners of endogenous NOTCH2 after ligand stimulation in the presence of a γ-secretase inhibitor and as a function of time after inhibitor removal. Our studies showed that γ-secretase-mediated cleavage of NOTCH2 occurred in an intracellular compartment and that formation of nuclear complexes and recruitment of chromatin-modifying enzymes occurred within 45 min of inhibitor washout. These findings provide a detailed spatiotemporal map tracking the path of Notch from the plasma membrane to the nucleus and identify signaling events that are potential targets for modulating Notch activity.
    DOI:  https://doi.org/10.1126/scisignal.adg6474
  18. J Cell Biol. 2023 10 02. pii: e202212106. [Epub ahead of print]222(10):
    Pre-T cell receptor localization and trafficking are independent of its signaling.
    Andrei I Smid, Sam J Garforth, Maryam S Obaid, Hannah R Bollons, John R James.
      Expression of the pre-T cell receptor (preTCR) is an important checkpoint during the development of T cells, an essential cell type of our adaptive immune system. The preTCR complex is only transiently expressed and rapidly internalized in developing T cells and is thought to signal in a ligand-independent manner. However, identifying a mechanistic basis for these unique features of the preTCR compared with the final TCR complex has been confounded by the concomitant signaling that is normally present. Thus, we have reconstituted preTCR expression in non-immune cells to uncouple receptor trafficking dynamics from its associated signaling. We find that all the defining features of the preTCR are intrinsic properties of the receptor itself, driven by exposure of an extracellular hydrophobic region, and are not the consequence of receptor activation. Finally, we show that transitory preTCR cell surface expression can sustain tonic signaling in the absence of ligand binding, suggesting how the preTCR can nonetheless drive αβTCR lineage commitment.
    DOI:  https://doi.org/10.1083/jcb.202212106
  19. Nat Commun. 2023 08 02. 14(1): 4650
    Energetic robustness to large scale structural fluctuations in a photosynthetic supercomplex.
    Dvir Harris, Hila Toporik, Gabriela S Schlau-Cohen, Yuval Mazor.
      Photosynthetic organisms transport and convert solar energy with near-unity quantum efficiency using large protein supercomplexes held in flexible membranes. The individual proteins position chlorophylls to tight tolerances considered critical for fast and efficient energy transfer. The variability in protein organization within the supercomplexes, and how efficiency is maintained despite variability, had been unresolved. Here, we report on structural heterogeneity in the 2-MDa cyanobacterial PSI-IsiA photosynthetic supercomplex observed using Cryo-EM, revealing large-scale variances in the positions of IsiA relative to PSI. Single-molecule measurements found efficient IsiA-to-PSI energy transfer across all conformations, along with signatures of transiently decoupled IsiA. Structure based calculations showed that rapid IsiA-to-PSI energy transfer is always maintained, and even increases by three-fold in rare conformations via IsiA-specific chls. We postulate that antennae design mitigates structural fluctuations, providing a mechanism for robust energy transfer in the flexible membrane.
    DOI:  https://doi.org/10.1038/s41467-023-40146-8
  20. Nature. 2023 Aug 01.
    NIH launches trials for long COVID treatments: what scientists think.
    Max Kozlov.
      
    Keywords:  Diseases; Public health; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-023-02472-1
  21. Commun Biol. 2023 07 31. 6(1): 792
    A genome-wide association study identifies 41 loci associated with eicosanoid levels.
    Eugene P Rhee, Aditya L Surapaneni, Pascal Schlosser, Mona Alotaibi, Yueh-Ning Yang, Josef Coresh, Mohit Jain, Susan Cheng, Bing Yu, Morgan E Grams.
      Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease.
    DOI:  https://doi.org/10.1038/s42003-023-05159-5
  22. Proc Natl Acad Sci U S A. 2023 08 08. 120(32): e2309967120
    Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.
    Rene C Adam, Dwaine S Pryce, Joseph S Lee, Yuanqi Zhao, Ivory J Mintah, Soo Min, Gabor Halasz, Jason Mastaitis, Gurinder S Atwal, Senem Aykul, Vincent Idone, Aris N Economides, Luca A Lotta, Andrew J Murphy, George D Yancopoulos, Mark W Sleeman, Viktoria Gusarova.
      Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing β-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.
    Keywords:  ACVR1C; INHBE (activin E); body fat distribution; diabetes; lipolysis
    DOI:  https://doi.org/10.1073/pnas.2309967120
  23. Nature. 2023 Aug 01.
    Experimental insulin implant uses electricity to control genes.
    Lilly Tozer.
      
    Keywords:  Diabetes; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-023-02461-4
  24. Sci Signal. 2023 08;16(796): eadj8555
    Naked mole-rats slay zombies.
    Annalisa M VanHook.
      Senescent cells in naked mole-rats are eliminated by apoptosis.
    DOI:  https://doi.org/10.1126/scisignal.adj8555
  25. Nat Genet. 2023 Jul 31.
    Genome-wide mutation profiles from cell-free DNA for early cancer detection.
      
    DOI:  https://doi.org/10.1038/s41588-023-01448-1
  26. Science. 2023 Aug 04. 381(6657): 495
    Tagging neurons with light.
    Christina K Kim.
      Molecular circuits for activity-guided optogenetics.
    DOI:  https://doi.org/10.1126/science.adj1968
  27. Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]
    O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.
    Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.
      The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.
    Keywords:  O-GlcNAcylation; Raptor; glucose sensing; mTOR
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.011
  28. Science. 2023 Aug 04. 381(6657): 494-495
    Paralysis under pressure.
    Aaron Phillips.
      Treating cardiovascular paralysis with epidural electrical neuromodulation.
    DOI:  https://doi.org/10.1126/science.adj1973
  29. Cell Stem Cell. 2023 Aug 03. pii: S1934-5909(23)00251-5. [Epub ahead of print]30(8): 1043-1053.e6
    A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease.
    Yongjin Yoo, Gernot Neumayer, Yohei Shibuya, Marius Marc-Daniel Mader, Marius Wernig.
      Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.
    Keywords:  Alzheimer's disease; Trem2; circulation-derived myeloid cells; hematopoietic cell transplantation; microglia
    DOI:  https://doi.org/10.1016/j.stem.2023.07.006
  30. Nat Cardiovasc Res. 2023 Jun;2(6): 572-586
    Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis.
    Wenli Liu, Mustafa Yalcinkaya, Inés Fernández Maestre, Malgorzata Olszewska, Patrick B Ampomah, J Brett Heimlich, Ranran Wang, Pablo Sánchez Vela, Tong Xiao, Alexander G Bick, Ross Levine, Eirini P Papapetrou, Peter Libby, Ira Tabas, Nan Wang, Alan R Tall.
      Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH accelerated atherosclerosis, identifies IL-6-induced CSF1R expression as a critical mechanism and supports blockade of IL-6 signaling as a potential therapy for CH-driven cardiovascular disease.
    DOI:  https://doi.org/10.1038/s44161-023-00281-3
  31. Mol Cell. 2023 Aug 03. pii: S1097-2765(23)00524-5. [Epub ahead of print]83(15): 2616-2618
    To be (in a transcriptional complex) or not to be (promoting UBR5 ubiquitylation): That is an answer to how degradation controls gene expression.
    Laura A Hehl, Brenda A Schulman.
      Tsai et al.1 in this issue and Mark et al.2 in Cell reveal how the E3 ligase UBR5 mediates broad regulation by selectively targeting agonist-bound nuclear hormone receptors, MYC, and other transcriptional regulators not incorporated into active gene expression complexes.
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.010
  32. Nature. 2023 Aug 02.
    Variation in African genomes linked to control of HIV.
      
    Keywords:  Genetics; Genomics; Infection
    DOI:  https://doi.org/10.1038/d41586-023-02277-2
  33. Nat Metab. 2023 Aug 03.
    The serotonin transporter sustains human brown adipose tissue thermogenesis.
    Karla J Suchacki, Lynne E Ramage, T'ng Choong Kwok, Alexandra Kelman, Ben T McNeill, Stewart Rodney, Matthew Keegan, Calum Gray, Gillian MacNaught, Dilip Patel, Alison M Fletcher, Joanna P Simpson, Roderick N Carter, Robert K Semple, Natalie Z M Homer, Nicholas M Morton, Edwin J R van Beek, Sonia J Wakelin, Roland H Stimson.
      Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-023-00839-2
  34. Nat Neurosci. 2023 Aug 03.
    Unique functional responses differentially map onto genetic subtypes of dopamine neurons.
    Maite Azcorra, Zachary Gaertner, Connor Davidson, Qianzi He, Hailey Kim, Shivathmihai Nagappan, Cooper K Hayes, Charu Ramakrishnan, Lief Fenno, Yoon Seok Kim, Karl Deisseroth, Richard Longnecker, Rajeshwar Awatramani, Daniel A Dombeck.
      Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 (Vglut2), Calb1 and Anxa1, each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1+ subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.
    DOI:  https://doi.org/10.1038/s41593-023-01401-9
  35. Nat Cell Biol. 2023 Aug 03.
    An intestinal sphingolipid confers intergenerational neuroprotection.
    Wenyue Wang, Tessa Sherry, Xinran Cheng, Qi Fan, Rebecca Cornell, Jie Liu, Zhicheng Xiao, Roger Pocock.
      In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.
    DOI:  https://doi.org/10.1038/s41556-023-01195-9
  36. J Clin Invest. 2023 08 01. pii: e173784. [Epub ahead of print]133(15):
    Epigenetics in glaucoma: a link between histone methylation and neurodegeneration.
    Wendy W Liu, Yang Sun.
      
    DOI:  https://doi.org/10.1172/JCI173784
  37. Nat Commun. 2023 08 01. 14(1): 4618
    Robust phenotyping of highly multiplexed tissue imaging data using pixel-level clustering.
    Candace C Liu, Noah F Greenwald, Alex Kong, Erin F McCaffrey, Ke Xuan Leow, Dunja Mrdjen, Bryan J Cannon, Josef Lorenz Rumberger, Sricharan Reddy Varra, Michael Angelo.
      While technologies for multiplexed imaging have provided an unprecedented understanding of tissue composition in health and disease, interpreting this data remains a significant computational challenge. To understand the spatial organization of tissue and how it relates to disease processes, imaging studies typically focus on cell-level phenotypes. However, images can capture biologically important objects that are outside of cells, such as the extracellular matrix. Here, we describe a pipeline, Pixie, that achieves robust and quantitative annotation of pixel-level features using unsupervised clustering and show its application across a variety of biological contexts and multiplexed imaging platforms. Furthermore, current cell phenotyping strategies that rely on unsupervised clustering can be labor intensive and require large amounts of manual cluster adjustments. We demonstrate how pixel clusters that lie within cells can be used to improve cell annotations. We comprehensively evaluate pre-processing steps and parameter choices to optimize clustering performance and quantify the reproducibility of our method. Importantly, Pixie is open source and easily customizable through a user-friendly interface.
    DOI:  https://doi.org/10.1038/s41467-023-40068-5
  38. J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):
    Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
    Olivia M Connor, Srujan K Matta, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202303147
  39. Nat Med. 2023 Aug 02.
    A fluid biomarker accurately detects tau aggregate pathology in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41591-023-02468-4
  40. Nature. 2023 Aug 03.
    Ancient DNA reveals the living descendants of enslaved people through 23andMe.
    Ewen Callaway.
      
    Keywords:  Databases; Genetics; History
    DOI:  https://doi.org/10.1038/d41586-023-02478-9
  41. Nature. 2023 Aug 04.
    A single antibody tackles two childhood viruses.
      
    Keywords:  Virology
    DOI:  https://doi.org/10.1038/d41586-023-02428-5
  42. Science. 2023 Aug 04. 381(6657): 502-508
    Peptide YY: A Paneth cell antimicrobial peptide that maintains Candida gut commensalism.
    Joseph F Pierre, Brian M Peters, Diana La Torre, Ashley M Sidebottom, Yun Tao, Xiaorong Zhu, Candace M Cham, Ling Wang, Amal Kambal, Katharine G Harris, Julian F Silva, Olga Zaborina, John C Alverdy, Herbert Herzog, Jessica Witchley, Suzanne M Noble, Vanessa A Leone, Eugene B Chang.
      The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility whereas others regulate the microbiota. We have found that peptide YY (PYY1-36), but not endocrine PYY3-36, acts as an antimicrobial peptide (AMP) expressed by gut epithelial paneth cells (PC). PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Although PC-PYY shows some antibacterial activity, it displays selective antifungal activity against virulent Candida albicans hyphae-but not the yeast form. PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming that selects for the yeast phenotype. Hence, PC-PYY is an antifungal AMP that contributes to the maintenance of gut fungal commensalism.
    DOI:  https://doi.org/10.1126/science.abq3178
  43. Nat Genet. 2023 Aug 01.
    SF3B1-mutant cells succumb to replication stress under PARP inhibition.
      
    DOI:  https://doi.org/10.1038/s41588-023-01461-4
  44. Sci Adv. 2023 Aug 04. 9(31): eabq3173
    Decoding the spermatogonial stem cell niche under physiological and recovery conditions in adult mice and humans.
    Cheng Jin, Zhipeng Wang, Pengyu Li, Jielin Tang, Tao Jiao, Yiran Li, Jinhuan Ou, Dingfeng Zou, Mengzhen Li, Xinyu Mang, Jun Liu, Yanni Ma, Xiaolong Wu, Jie Shi, Shitao Chen, Manman He, Yan Lu, Ning Zhang, Shiying Miao, Fei Sun, Linfang Wang, Kai Li, Jia Yu, Wei Song.
      The intricate interaction between spermatogonial stem cell (SSC) and testicular niche is essential for maintaining SSC homeostasis; however, this interaction remains largely uncharacterized. In this study, to characterize the underlying signaling pathways and related paracrine factors, we delineated the intercellular interactions between SSC and niche cell in both adult mice and humans under physiological conditions and dissected the niche-derived regulation of SSC maintenance under recovery conditions, thus uncovering the essential role of C-C motif chemokine ligand 24 and insulin-like growth factor binding protein 7 in SSC maintenance. We also established the clinical relevance of specific paracrine factors in human fertility. Collectively, our work on decoding the adult SSC niche serves as a valuable reference for future studies on the aetiology, diagnosis, and treatment of male infertility.
    DOI:  https://doi.org/10.1126/sciadv.abq3173
  45. Nature. 2023 Aug;620(7972): 47-60
    Scientific discovery in the age of artificial intelligence.
    Hanchen Wang, Tianfan Fu, Yuanqi Du, Wenhao Gao, Kexin Huang, Ziming Liu, Payal Chandak, Shengchao Liu, Peter Van Katwyk, Andreea Deac, Anima Anandkumar, Karianne Bergen, Carla P Gomes, Shirley Ho, Pushmeet Kohli, Joan Lasenby, Jure Leskovec, Tie-Yan Liu, Arjun Manrai, Debora Marks, Bharath Ramsundar, Le Song, Jimeng Sun, Jian Tang, Petar Veličković, Max Welling, Linfeng Zhang, Connor W Coley, Yoshua Bengio, Marinka Zitnik.
      Artificial intelligence (AI) is being increasingly integrated into scientific discovery to augment and accelerate research, helping scientists to generate hypotheses, design experiments, collect and interpret large datasets, and gain insights that might not have been possible using traditional scientific methods alone. Here we examine breakthroughs over the past decade that include self-supervised learning, which allows models to be trained on vast amounts of unlabelled data, and geometric deep learning, which leverages knowledge about the structure of scientific data to enhance model accuracy and efficiency. Generative AI methods can create designs, such as small-molecule drugs and proteins, by analysing diverse data modalities, including images and sequences. We discuss how these methods can help scientists throughout the scientific process and the central issues that remain despite such advances. Both developers and users of AI toolsneed a better understanding of when such approaches need improvement, and challenges posed by poor data quality and stewardship remain. These issues cut across scientific disciplines and require developing foundational algorithmic approaches that can contribute to scientific understanding or acquire it autonomously, making them critical areas of focus for AI innovation.
    DOI:  https://doi.org/10.1038/s41586-023-06221-2
  46. Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00520-8. [Epub ahead of print]
    CTCF and R-loops are boundaries of cohesin-mediated DNA looping.
    Hongshan Zhang, Zhubing Shi, Edward J Banigan, Yoori Kim, Hongtao Yu, Xiao-Chen Bai, Ilya J Finkelstein.
      Cohesin and CCCTC-binding factor (CTCF) are key regulatory proteins of three-dimensional (3D) genome organization. Cohesin extrudes DNA loops that are anchored by CTCF in a polar orientation. Here, we present direct evidence that CTCF binding polarity controls cohesin-mediated DNA looping. Using single-molecule imaging, we demonstrate that a critical N-terminal motif of CTCF blocks cohesin translocation and DNA looping. The cryo-EM structure of the cohesin-CTCF complex reveals that this CTCF motif ahead of zinc fingers can only reach its binding site on the STAG1 cohesin subunit when the N terminus of CTCF faces cohesin. Remarkably, a C-terminally oriented CTCF accelerates DNA compaction by cohesin. DNA-bound Cas9 and Cas12a ribonucleoproteins are also polar cohesin barriers, indicating that stalling may be intrinsic to cohesin itself. Finally, we show that RNA-DNA hybrids (R-loops) block cohesin-mediated DNA compaction in vitro and are enriched with cohesin subunits in vivo, likely forming TAD boundaries.
    Keywords:  3D genome; CTCF; R-loop; TADs; cohesin; cryo-EM; single-molecule
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.006
  47. Sci Transl Med. 2023 08 02. 15(707): eadf2059
    Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans.
    Kenneth J Dery, Hidenobu Kojima, Shoichi Kageyama, Kentaro Kadono, Hirofumi Hirao, Brian Cheng, Yuan Zhai, Douglas G Farmer, Fady M Kaldas, Xiaoyi Yuan, Holger K Eltzschig, Jerzy W Kupiec-Weglinski.
      Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; CD66a), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of Ceacam1 affects ischemia-reperfusion injury (IRI) in mouse and human livers. We found that the short cytoplasmic isoform Ceacam1-S increased during early acute and late resolution phases of warm IRI injury in mice. Transfection of Ceacam1-deficient mouse hepatocytes with adenoviral Ceacam1-S mitigated hypoxia-induced loss of cellular adhesion by repressing the Ask1/p-p38 cell death pathway. Nucleic acid-blocking morpholinos, designed to selectively induce Ceacam1-S, protected hepatocyte cultures against temperature-induced stress in vitro. Luciferase and chromatin immunoprecipitation assays identified direct binding of hypoxia-inducible factor-1α (Hif-1α) to the mouse polypyrimidine tract binding protein 1 (Ptbp1) promoter region. Dimethyloxalylglycine protected mouse livers from warm IR stress and hepatocellular damage by inhibiting prolyl hydroxylase domain-containing protein 1 and promoting AS of Ceacam1-S. Last, analysis of 46 human donor liver grafts revealed that CEACAM1-S positively correlated with pretransplant HIF1A expression. This also correlated with better transplant outcomes, including reduced TIMP1, total bilirubin, proinflammatory MCP1, CXCL10 cytokines, immune activation markers IL17A, and incidence of delayed complications from biliary anastomosis. This translational study identified mouse Hif-1α-controlled AS of Ceacam1, through transcriptional regulation of Ptbp1 promoter region, as a functional underpinning of hepatoprotection against IR stress and tissue damage in liver transplantation.
    DOI:  https://doi.org/10.1126/scitranslmed.adf2059
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