bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–07–09
58 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology.
  2. Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels.
  3. Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.
  4. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
  5. Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice.
  6. The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.
  7. Causal associations between cardiorespiratory fitness and type 2 diabetes.
  8. Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.
  9. Spatial mapping of cellular senescence: emerging challenges and opportunities.
  10. A conversation with Elizabeth Jaffee.
  11. It's not just about the money.
  12. The past is key for the future of our freshwater systems.
  13. Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome.
  14. The sound of silence.
  15. Succinct discoveries that inspire.
  16. Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease.
  17. TET2 and TET3 loss disrupts small intestine differentiation and homeostasis.
  18. Detecting somatic mutations in single-cell data sets.
  19. Spatiotemporal transcriptomic maps of whole mouse embryos at the onset of organogenesis.
  20. Clonal hematopoiesis, aging and Alzheimer's disease.
  21. Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.
  22. Lab-grown meat: the science of turning cells into steaks and nuggets.
  23. Potential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans.
  24. A soft, self-sensing tensile valve for perceptive soft robots.
  25. T cell receptor signaling strength establishes the chemotactic properties of effector CD8+ T cells that control tissue-residency.
  26. STAP-2-Derived Peptide Suppresses TCR-Mediated Signals to Initiate Immune Responses.
  27. A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.
  28. Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.
  29. Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.
  30. Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus.
  31. Lactation-associated macrophages.
  32. SpatialDM for rapid identification of spatially co-expressed ligand-receptor and revealing cell-cell communication patterns.
  33. Characterizing the evolution and phenotypic impact of ampliconic Y chromosome regions.
  34. Opportunistic detection of type 2 diabetes using deep learning from frontal chest radiographs.
  35. Blood proteins control microglia.
  36. Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G.
  37. Phosphorylation by ATR triggers FANCD2 chromatin loading and activates the Fanconi anemia pathway.
  38. A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.
  39. MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development.
  40. Developing human embryos imaged at highest-ever resolution.
  41. Senolytics combat COVID-19 in aging.
  42. Extensive diversity in RNA termination and regulation revealed by transcriptome mapping for the Lyme pathogen Borrelia burgdorferi.
  43. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.
  44. Lymph node metastasis: An immunological burden.
  45. Chromatin expansion microscopy reveals nanoscale organization of transcription and chromatin.
  46. Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.
  47. Transcription factors interact with RNA to regulate genes.
  48. Plakoglobin is a mechanoresponsive regulator of naive pluripotency.
  49. Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells.
  50. Nuclear class 3 PI3K coactivates circadian clock.
  51. Principles of human pre-60S biogenesis.
  52. A microbiome exercise.
  53. Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function.
  54. Fueling the fire of B cell activation.
  55. Bacteria form unique biofilms to kill immune cells.
  56. A cellular and molecular spatial atlas of dystrophic muscle.
  57. CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
  58. 3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction.
  1. Nat Commun. 2023 Jul 07. 14(1): 4013
    Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology.
    Yunhao Bai, Bokai Zhu, John-Paul Oliveria, Bryan J Cannon, Dorien Feyaerts, Marc Bosse, Kausalia Vijayaragavan, Noah F Greenwald, Darci Phillips, Christian M Schürch, Samuel M Naik, Edward A Ganio, Brice Gaudilliere, Scott J Rodig, Michael B Miller, Michael Angelo, Sean C Bendall, Xavier Rovira-Clavé, Garry P Nolan, Sizun Jiang.
      Cellular organization and functions encompass multiple scales in vivo. Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Expansion Microscopy (ExM) and related techniques physically expand samples for enhanced spatial resolution, but are challenging to be combined with high-plex imaging technologies to enable integrative multiscaled tissue biology insights. Here, we introduce Expand and comPRESS hydrOgels (ExPRESSO), an ExM framework that allows high-plex protein staining, physical expansion, and removal of water, while retaining the lateral tissue expansion. We demonstrate ExPRESSO imaging of archival clinical tissue samples on Multiplexed Ion Beam Imaging and Imaging Mass Cytometry platforms, with detection capabilities of > 40 markers. Application of ExPRESSO on archival human lymphoid and brain tissues resolved tissue architecture at the subcellular level, particularly that of the blood-brain barrier. ExPRESSO hence provides a platform for extending the analysis compatibility of hydrogel-expanded biospecimens to mass spectrometry, with minimal modifications to protocols and instrumentation.
    DOI:  https://doi.org/10.1038/s41467-023-39616-w
  2. Nat Commun. 2023 Jul 07. 14(1): 4029
    Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels.
    V S Peche, T A Pietka, M Jacome-Sosa, D Samovski, H Palacios, G Chatterjee-Basu, A C Dudley, W Beatty, G A Meyer, I J Goldberg, N A Abumrad.
      Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80-100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36-/- mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells.
    DOI:  https://doi.org/10.1038/s41467-023-39752-3
  3. Nat Cell Biol. 2023 Jul 03.
    Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.
    Tao Zhang, Daichao Xu, Jianping Liu, Min Wang, Li-Juan Duan, Min Liu, Huyan Meng, Yuan Zhuang, Huibing Wang, Yingnan Wang, Mingming Lv, Zhengyi Zhang, Jia Hu, Linyu Shi, Rui Guo, Xingxing Xie, Hui Liu, Emily Erickson, Yaru Wang, Wenyu Yu, Fabin Dang, Dongxian Guan, Cong Jiang, Xiaoming Dai, Hiroyuki Inuzuka, Peiqiang Yan, Jingchao Wang, Mrigya Babuta, Gewei Lian, Zhenbo Tu, Ji Miao, Gyongyi Szabo, Guo-Hua Fong, Antoine E Karnoub, Yu-Ru Lee, Lifeng Pan, William G Kaelin, Junying Yuan, Wenyi Wei.
      The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.
    DOI:  https://doi.org/10.1038/s41556-023-01170-4
  4. Nature. 2023 Jul 05.
    SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity.
    Chuansheng Guo, Zhiyuan You, Hao Shi, Yu Sun, Xingrong Du, Gustavo Palacios, Cliff Guy, Sujing Yuan, Nicole M Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia, Sherri Rankin, Yogesh Dhungana, Hongbo Chi.
      Cancer cells evade T cell-mediated killing through tumour-immune interactions whose mechanisms are not well understood1,2. Dendritic cells (DCs), especially type-1 conventional DCs (cDC1s), mediate T cell priming and therapeutic efficacy against tumours3. DC functions are orchestrated by pattern recognition receptors3-5, although other signals involved remain incompletely defined. Nutrients are emerging mediators of adaptive immunity6-8, but whether nutrients affect DC function or communication between innate and adaptive immune cells is largely unresolved. Here we establish glutamine as an intercellular metabolic checkpoint that dictates tumour-cDC1 crosstalk and licenses cDC1 function in activating cytotoxic T cells. Intratumoral glutamine supplementation inhibits tumour growth by augmenting cDC1-mediated CD8+ T cell immunity, and overcomes therapeutic resistance to checkpoint blockade and T cell-mediated immunotherapies. Mechanistically, tumour cells and cDC1s compete for glutamine uptake via the transporter SLC38A2 to tune anti-tumour immunity. Nutrient screening and integrative analyses show that glutamine is the dominant amino acid in promoting cDC1 function. Further, glutamine signalling via FLCN impinges on TFEB function. Loss of FLCN in DCs selectively impairs cDC1 function in vivo in a TFEB-dependent manner and phenocopies SLC38A2 deficiency by eliminating the anti-tumour therapeutic effect of glutamine supplementation. Our findings establish glutamine-mediated intercellular metabolic crosstalk between tumour cells and cDC1s that underpins tumour immune evasion, and reveal glutamine acquisition and signalling in cDC1s as limiting events for DC activation and putative targets for cancer treatment.
    DOI:  https://doi.org/10.1038/s41586-023-06299-8
  5. Nat Commun. 2023 07 05. 14(1): 3976
    Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice.
    Joseph I Terranova, Jun Yokose, Hisayuki Osanai, Sachie K Ogawa, Takashi Kitamura.
      Observers learn to fear the context in which they witnessed a demonstrator's aversive experience, called observational contextual fear conditioning (CFC). The neural mechanisms governing whether recall of the observational CFC memory occurs from the observer's own or from the demonstrator's point of view remain unclear. Here, we show in male mice that recent observational CFC memory is recalled in the observer's context only, but remote memory is recalled in both observer and demonstrator contexts. Recall of recent memory in the observer's context requires dorsal hippocampus activity, while recall of remote memory in both contexts requires the medial prefrontal cortex (mPFC)-basolateral amygdala pathway. Although mPFC neurons activated by observational CFC are involved in remote recall in both contexts, distinct mPFC subpopulations regulate remote recall in each context. Our data provide insights into a flexible recall strategy and the functional reorganization of circuits and memory engram cells underlying observational CFC memory.
    DOI:  https://doi.org/10.1038/s41467-023-39718-5
  6. Nat Commun. 2023 07 05. 14(1): 3964
    The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.
    Thaddeus J Kunkel, Alice Townsend, Kyle A Sullivan, Jean Merlet, Edward H Schuchman, Daniel A Jacobson, Andrew P Lieberman.
      The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1-/- mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1-/- oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1-/- mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-023-39733-6
  7. Nat Commun. 2023 07 03. 14(1): 3904
    Causal associations between cardiorespiratory fitness and type 2 diabetes.
    Lina Cai, Tomas Gonzales, Eleanor Wheeler, Nicola D Kerrison, Felix R Day, Claudia Langenberg, John R B Perry, Soren Brage, Nicholas J Wareham.
      Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention.
    DOI:  https://doi.org/10.1038/s41467-023-38234-w
  8. Nat Commun. 2023 07 03. 14(1): 3902
    Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages.
    Marko Groeger, Koji Matsuo, Emad Heidary Arash, Ashley Pereira, Dounia Le Guillou, Cindy Pino, Kayque A Telles-Silva, Jacquelyn J Maher, Edward C Hsiao, Holger Willenbring.
      Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNFα and IL1β as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-κB or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver.
    DOI:  https://doi.org/10.1038/s41467-023-39311-w
  9. Nat Aging. 2023 Jul 03.
    Spatial mapping of cellular senescence: emerging challenges and opportunities.
    Aditi U Gurkar, Akos A Gerencser, Ana L Mora, Andrew C Nelson, Anru R Zhang, Anthony B Lagnado, Archibald Enninful, Christopher Benz, David Furman, Delphine Beaulieu, Diana Jurk, Elizabeth L Thompson, Fei Wu, Fernanda Rodriguez, Grant Barthel, Hao Chen, Hemali Phatnani, Indra Heckenbach, Jeffrey H Chuang, Jeremy Horrell, Joana Petrescu, Jonathan K Alder, Jun Hee Lee, Laura J Niedernhofer, Manoj Kumar, Melanie Königshoff, Marta Bueno, Miiko Sokka, Morten Scheibye-Knudsen, Nicola Neretti, Oliver Eickelberg, Peter D Adams, Qianjiang Hu, Quan Zhu, Rebecca A Porritt, Runze Dong, Samuel Peters, Stella Victorelli, Thomas Pengo, Timur Khaliullin, Vidyani Suryadevara, Xiaonan Fu, Ziv Bar-Joseph, Zhicheng Ji, João F Passos.
      Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-023-00446-6
  10. J Clin Invest. 2023 Jul 03. pii: e172246. [Epub ahead of print]133(13):
    A conversation with Elizabeth Jaffee.
    Ushma S Neill.
      
    DOI:  https://doi.org/10.1172/JCI172246
  11. Science. 2023 Jul 07. 381(6653): 102
    It's not just about the money.
    Brita Kilburg-Basnyat.
      
    DOI:  https://doi.org/10.1126/science.adj4921
  12. Nat Commun. 2023 Jul 06. 14(1): 3971
    The past is key for the future of our freshwater systems.
      
    DOI:  https://doi.org/10.1038/s41467-023-39501-6
  13. Sci Transl Med. 2023 07 05. 15(703): eade7028
    Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome.
    Andrea D Largent, Katharina Lambert, Kristy Chiang, Natali Shumlak, Denny Liggitt, Mohammed Oukka, Troy R Torgerson, Jane H Buckner, Eric J Allenspach, David J Rawlings, Shaun W Jackson.
      Heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4+ T cell and B cell activation, including expansion of TH1-skewed CXCR3+ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1GOF mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency, Stat1GOF mice and humans with STAT1 GOF syndrome exhibited normal Treg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome.
    DOI:  https://doi.org/10.1126/scitranslmed.ade7028
  14. Science. 2023 Jul 07. 381(6653): 37-38
    The sound of silence.
    Sara Clasen.
      How flagellins from commensals evade innate immunity.
    DOI:  https://doi.org/10.1126/science.adi6265
  15. Science. 2023 Jul 07. 381(6653): 24-25
    Succinct discoveries that inspire.
      
    DOI:  https://doi.org/10.1126/science.adi8737
  16. Sci Transl Med. 2023 07 05. 15(703): eabq5923
    Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease.
    Yun Ju Sung, Chengran Yang, Joanne Norton, Matt Johnson, Anne Fagan, Randall J Bateman, Richard J Perrin, John C Morris, Martin R Farlow, Jasmeer P Chhatwal, Peter R Schofield, Helena Chui, Fengxian Wang, Brenna Novotny, Abdallah Eteleeb, Celeste Karch, Suzanne E Schindler, Herve Rhinn, Erik C B Johnson, Hamilton Se-Hwee Oh, Jarod Evert Rutledge, Eric B Dammer, Nicholas T Seyfried, Tony Wyss-Coray, Oscar Harari, Carlos Cruchaga.
      Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.
    DOI:  https://doi.org/10.1126/scitranslmed.abq5923
  17. Nat Commun. 2023 Jul 06. 14(1): 4005
    TET2 and TET3 loss disrupts small intestine differentiation and homeostasis.
    Ihab Ansari, Llorenç Solé-Boldo, Meshi Ridnik, Julian Gutekunst, Oliver Gilliam, Maria Korshko, Timur Liwinski, Birgit Jickeli, Noa Weinberg-Corem, Michal Shoshkes-Carmel, Eli Pikarsky, Eran Elinav, Frank Lyko, Yehudit Bergman.
      TET2/3 play a well-known role in epigenetic regulation and mouse development. However, their function in cellular differentiation and tissue homeostasis remains poorly understood. Here we show that ablation of TET2/3 in intestinal epithelial cells results in a murine phenotype characterized by a severe homeostasis imbalance in the small intestine. Tet2/3-deleted mice show a pronounced loss of mature Paneth cells as well as fewer Tuft and more Enteroendocrine cells. Further results show major changes in DNA methylation at putative enhancers, which are associated with cell fate-determining transcription factors and functional effector genes. Notably, pharmacological inhibition of DNA methylation partially rescues the methylation and cellular defects. TET2/3 loss also alters the microbiome, predisposing the intestine to inflammation under homeostatic conditions and acute inflammation-induced death. Together, our results uncover previously unrecognized critical roles for DNA demethylation, possibly occurring subsequently to chromatin opening during intestinal development, culminating in the establishment of normal intestinal crypts.
    DOI:  https://doi.org/10.1038/s41467-023-39512-3
  18. Nat Biotechnol. 2023 Jul 06.
    Detecting somatic mutations in single-cell data sets.
      
    DOI:  https://doi.org/10.1038/s41587-023-01883-9
  19. Nat Genet. 2023 Jul 06.
    Spatiotemporal transcriptomic maps of whole mouse embryos at the onset of organogenesis.
    Abhishek Sampath Kumar, Luyi Tian, Adriano Bolondi, Amèlia Aragonés Hernández, Robert Stickels, Helene Kretzmer, Evan Murray, Lars Wittler, Maria Walther, Gabriel Barakat, Leah Haut, Yechiel Elkabetz, Evan Z Macosko, Léo Guignard, Fei Chen, Alexander Meissner.
      Spatiotemporal orchestration of gene expression is required for proper embryonic development. The use of single-cell technologies has begun to provide improved resolution of early regulatory dynamics, including detailed molecular definitions of most cell states during mouse embryogenesis. Here we used Slide-seq to build spatial transcriptomic maps of complete embryonic day (E) 8.5 and E9.0, and partial E9.5 embryos. To support their utility, we developed sc3D, a tool for reconstructing and exploring three-dimensional 'virtual embryos', which enables the quantitative investigation of regionalized gene expression patterns. Our measurements along the main embryonic axes of the developing neural tube revealed several previously unannotated genes with distinct spatial patterns. We also characterized the conflicting transcriptional identity of 'ectopic' neural tubes that emerge in Tbx6 mutant embryos. Taken together, we present an experimental and computational framework for the spatiotemporal investigation of whole embryonic structures and mutant phenotypes.
    DOI:  https://doi.org/10.1038/s41588-023-01435-6
  20. Nat Med. 2023 Jul 04.
    Clonal hematopoiesis, aging and Alzheimer's disease.
    Pablo Sánchez Vela, Jennifer J Trowbridge, Ross L Levine.
      
    DOI:  https://doi.org/10.1038/s41591-023-02406-4
  21. Nat Commun. 2023 07 04. 14(1): 3953
    Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.
    Stephen E Flaherty, Olivier Bezy, Wei Zheng, Dong Yan, Xiangping Li, Srinath Jagarlapudi, Bina Albuquerque, Ryan M Esquejo, Matthew Peloquin, Meriem Semache, Arturo Mancini, Liya Kang, Doreen Drujan, Susanne B Breitkopf, John D Griffin, Pierre M Jean Beltran, Liang Xue, John Stansfield, Evanthia Pashos, Quazi Shakey, Christian Pehmøller, Mara Monetti, Morris J Birnbaum, Jean-Philippe Fortin, Zhidan Wu.
      Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and β-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.
    DOI:  https://doi.org/10.1038/s41467-023-39597-w
  22. Nature. 2023 Jul;619(7968): 22-24
    Lab-grown meat: the science of turning cells into steaks and nuggets.
    Nicola Jones.
      
    Keywords:  Business; Cell biology; Nutrition
    DOI:  https://doi.org/10.1038/d41586-023-02095-6
  23. Nat Commun. 2023 07 04. 14(1): 3938
    Potential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans.
    Rosina Comas-Ghierra, Laura Romanelli-Cedrez, Gustavo Salinas.
      
    DOI:  https://doi.org/10.1038/s41467-023-39510-5
  24. Nat Commun. 2023 Jul 04. 14(1): 3942
    A soft, self-sensing tensile valve for perceptive soft robots.
    Jun Kyu Choe, Junsoo Kim, Hyeonseo Song, Joonbum Bae, Jiyun Kim.
      Soft inflatable robots are a promising paradigm for applications that benefit from their inherent safety and adaptability. However, for perception, complex connections of rigid electronics both in hardware and software remain the mainstay. Although recent efforts have created soft analogs of individual rigid components, the integration of sensing and control systems is challenging to achieve without compromising the complete softness, form factor, or capabilities. Here, we report a soft self-sensing tensile valve that integrates the functional capabilities of sensors and control valves to directly transform applied tensile strain into distinctive steady-state output pressure states using only a single, constant pressure source. By harnessing a unique mechanism, "helical pinching", we derive physical sharing of both sensing and control valve structures, achieving all-in-one integration in a compact form factor. We demonstrate programmability and applicability of our platform, illustrating a pathway towards fully soft, electronics-free, untethered, and autonomous robotic systems.
    DOI:  https://doi.org/10.1038/s41467-023-39691-z
  25. Nat Commun. 2023 07 04. 14(1): 3928
    T cell receptor signaling strength establishes the chemotactic properties of effector CD8+ T cells that control tissue-residency.
    Mahmoud Abdelbary, Samuel J Hobbs, James S Gibbs, Jonathan W Yewdell, Jeffrey C Nolz.
      Tissue-resident memory (TRM) CD8+ T cells are largely derived from recently activated effector T cells, but the mechanisms that control the extent of TRM differentiation within tissue microenvironments remain unresolved. Here, using an IFNγ-YFP reporter system to identify CD8+ T cells executing antigen-dependent effector functions, we define the transcriptional consequences and functional mechanisms controlled by TCR-signaling strength that occur within the skin during viral infection to promote TRM differentiation. TCR-signaling both enhances CXCR6-mediated migration and suppresses migration toward sphingosine-1-phosphate, indicating the programming of a 'chemotactic switch' following secondary antigen encounter within non-lymphoid tissues. Blimp1 was identified as the critical target of TCR re-stimulation that is necessary to establish this chemotactic switch and for TRM differentiation to efficiently occur. Collectively, our findings show that access to antigen presentation and strength of TCR-signaling required for Blimp1 expression establishes the chemotactic properties of effector CD8+ T cells to promote residency within non-lymphoid tissues.
    DOI:  https://doi.org/10.1038/s41467-023-39592-1
  26. J Immunol. 2023 Jul 07. pii: ji2200942. [Epub ahead of print]
    STAP-2-Derived Peptide Suppresses TCR-Mediated Signals to Initiate Immune Responses.
    Yuto Sasaki, Kodai Saitoh, Kota Kagohashi, Toyoyuki Ose, Shoya Kawahara, Yuichi Kitai, Ryuta Muromoto, Yuichi Sekine, Michiko Ichii, Akihiko Yoshimura, Kenji Oritani, Jun-Ichi Kashiwakura, Tadashi Matsuda.
      Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a proline-rich region in its C-terminal region. Our previous study demonstrated that STAP-2 positively regulates TCR signaling by associating with TCR-proximal CD3ζ ITAMs and the lymphocyte-specific protein tyrosine kinase. In this study, we identify the STAP-2 interacting regions of CD3ζ ITAMs and show that the STAP-2-derived synthetic peptide (iSP2) directly interacts with the ITAM sequence and blocks the interactions between STAP-2 and CD3ζ ITAMs. Cell-penetrating iSP2 was delivered into human and murine T cells. iSP2 suppressed cell proliferation and TCR-induced IL-2 production. Importantly, iSP2 treatment suppressed TCR-mediated activation of naive CD4+ T cells and decreased immune responses in CD4+ T cell-mediated experimental autoimmune encephalomyelitis. It is likely that iSP2 is a novel immunomodulatory tool that modulates STAP-2-mediated activation of TCR signaling and represses the progression of autoimmune diseases.
    DOI:  https://doi.org/10.4049/jimmunol.2200942
  27. Nat Commun. 2023 Jul 06. 14(1): 3993
    A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.
    Marta Losa, Iros Barozzi, Marco Osterwalder, Viviana Hermosilla-Aguayo, Angela Morabito, Brandon H Chacón, Peyman Zarrineh, Ausra Girdziusaite, Jean Denis Benazet, Jianjian Zhu, Susan Mackem, Terence D Capellini, Diane Dickel, Nicoletta Bobola, Aimée Zuniga, Axel Visel, Rolf Zeller, Licia Selleri.
      A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs.
    DOI:  https://doi.org/10.1038/s41467-023-39443-z
  28. Nat Commun. 2023 Jul 03. 14(1): 3923
    Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.
    DBDS Genomic Consortium
      
    DOI:  https://doi.org/10.1038/s41467-023-39492-4
  29. Proc Natl Acad Sci U S A. 2023 02 07. 120(6): e2214824120
    Inducible disruption of Tet genes results in myeloid malignancy, readthrough transcription, and a heterochromatin-to-euchromatin switch.
    Hiroshi Yuita, Isaac F López-Moyado, Hyeongmin Jeong, Arthur Xiuyuan Cheng, James Scott-Browne, Jungeun An, Toshinori Nakayama, Atsushi Onodera, Myunggon Ko, Anjana Rao.
      The three mammalian TET dioxygenases oxidize the methyl group of 5-methylcytosine in DNA, and the oxidized methylcytosines are essential intermediates in all known pathways of DNA demethylation. To define the in vivo consequences of complete TET deficiency, we inducibly deleted all three Tet genes in the mouse genome. Tet1/2/3-inducible TKO (iTKO) mice succumbed to acute myeloid leukemia (AML) by 4 to 5 wk. Single-cell RNA sequencing of Tet iTKO bone marrow cells revealed the appearance of new myeloid cell populations characterized by a striking increase in expression of all members of the stefin/cystatin gene cluster on mouse chromosome 16. In patients with AML, high stefin/cystatin gene expression correlates with poor clinical outcomes. Increased expression of the clustered stefin/cystatin genes was associated with a heterochromatin-to-euchromatin compartment switch with readthrough transcription downstream of the clustered stefin/cystatin genes as well as other highly expressed genes, but only minor changes in DNA methylation. Our data highlight roles for TET enzymes that are distinct from their established function in DNA demethylation and instead involve increased transcriptional readthrough and changes in three-dimensional genome organization.
    Keywords:  Stefins; TET proteins; heterochromatin-to-euchromatin transition; myeloid expansion; readthrough transcription
    DOI:  https://doi.org/10.1073/pnas.2214824120
  30. J Exp Med. 2023 10 02. pii: e20230461. [Epub ahead of print]220(10):
    Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus.
    Daniel A Michelson, Chong Zuo, Michael Verzi, Christophe Benoist, Diane Mathis.
      Mimetic cells are medullary thymic epithelial cells (mTECs) that mimic extra-thymic cell types to tolerize T cells to self-antigens. Here, we dissected the biology of entero-hepato mTECs, mimetic cells expressing gut- and liver-associated transcripts. Entero-hepato mTECs conserved their thymic identity yet accessed wide swaths of enterocyte chromatin and transcriptional programs via the transcription factors Hnf4α and Hnf4γ. Deletion of Hnf4α and Hnf4γ in TECs ablated entero-hepato mTECs and downregulated numerous gut- and liver-associated transcripts, with a primary contribution from Hnf4γ. Loss of Hnf4 impaired enhancer activation and CTCF redistribution in mTECs but did not impact Polycomb-mediated repression or promoter-proximal histone marks. By single-cell RNA sequencing, Hnf4 loss produced three distinct effects on mimetic cell state, fate, and accumulation. Serendipitously, a requirement for Hnf4 in microfold mTECs was discovered, which exposed a requirement for Hnf4γ in gut microfold cells and the IgA response. Study of Hnf4 in entero-hepato mTECs thus revealed mechanisms of gene control in the thymus and periphery alike.
    DOI:  https://doi.org/10.1084/jem.20230461
  31. Nat Rev Immunol. 2023 Jul 04.
    Lactation-associated macrophages.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-023-00915-4
  32. Nat Commun. 2023 Jul 06. 14(1): 3995
    SpatialDM for rapid identification of spatially co-expressed ligand-receptor and revealing cell-cell communication patterns.
    Zhuoxuan Li, Tianjie Wang, Pentao Liu, Yuanhua Huang.
      Cell-cell communication is a key aspect of dissecting the complex cellular microenvironment. Existing single-cell and spatial transcriptomics-based methods primarily focus on identifying cell-type pairs for a specific interaction, while less attention has been paid to the prioritisation of interaction features or the identification of interaction spots in the spatial context. Here, we introduce SpatialDM, a statistical model and toolbox leveraging a bivariant Moran's statistic to detect spatially co-expressed ligand and receptor pairs, their local interacting spots (single-spot resolution), and communication patterns. By deriving an analytical null distribution, this method is scalable to millions of spots and shows accurate and robust performance in various simulations. On multiple datasets including melanoma, Ventricular-Subventricular Zone, and intestine, SpatialDM reveals promising communication patterns and identifies differential interactions between conditions, hence enabling the discovery of context-specific cell cooperation and signalling.
    DOI:  https://doi.org/10.1038/s41467-023-39608-w
  33. Nat Commun. 2023 Jul 06. 14(1): 3990
    Characterizing the evolution and phenotypic impact of ampliconic Y chromosome regions.
    Elise A Lucotte, Valdís Björt Guðmundsdóttir, Jacob M Jensen, Laurits Skov, Moisès Coll Macià, Kristian Almstrup, Mikkel H Schierup, Agnar Helgason, Kari Stefansson.
      A major part of the human Y chromosome consists of palindromes with multiple copies of genes primarily expressed in testis, many of which have been claimed to affect male fertility. Here we examine copy number variation in these palindromes based on whole genome sequence data from 11,527 Icelandic men. Using a subset of 7947 men grouped into 1449 patrilineal genealogies, we infer 57 large scale de novo copy number mutations affecting palindrome 1. This corresponds to a mutation rate of 2.34 × 10-3 mutations per meiosis, which is 4.1 times larger than our phylogenetic estimate of the mutation rate (5.72 × 10-4), suggesting that de novo mutations on the Y are lost faster than expected under neutral evolution. Although simulations indicate a selection coefficient of 1.8% against non-reference copy number carriers, we do not observe differences in fertility among sequenced men associated with their copy number genotype, but we lack statistical power to detect differences resulting from weak negative selection. We also perform association testing of a diverse set of 341 traits to palindromic copy number without any significant associations. We conclude that large-scale palindrome copy number variation on the Y chromosome has little impact on human phenotype diversity.
    DOI:  https://doi.org/10.1038/s41467-023-39644-6
  34. Nat Commun. 2023 Jul 07. 14(1): 4039
    Opportunistic detection of type 2 diabetes using deep learning from frontal chest radiographs.
    Ayis Pyrros, Stephen M Borstelmann, Ramana Mantravadi, Zachary Zaiman, Kaesha Thomas, Brandon Price, Eugene Greenstein, Nasir Siddiqui, Melinda Willis, Ihar Shulhan, John Hines-Shah, Jeanne M Horowitz, Paul Nikolaidis, Matthew P Lungren, Jorge Mario Rodríguez-Fernández, Judy Wawira Gichoya, Sanmi Koyejo, Adam E Flanders, Nishith Khandwala, Amit Gupta, John W Garrett, Joseph Paul Cohen, Brian T Layden, Perry J Pickhardt, William Galanter.
      Deep learning (DL) models can harness electronic health records (EHRs) to predict diseases and extract radiologic findings for diagnosis. With ambulatory chest radiographs (CXRs) frequently ordered, we investigated detecting type 2 diabetes (T2D) by combining radiographic and EHR data using a DL model. Our model, developed from 271,065 CXRs and 160,244 patients, was tested on a prospective dataset of 9,943 CXRs. Here we show the model effectively detected T2D with a ROC AUC of 0.84 and a 16% prevalence. The algorithm flagged 1,381 cases (14%) as suspicious for T2D. External validation at a distinct institution yielded a ROC AUC of 0.77, with 5% of patients subsequently diagnosed with T2D. Explainable AI techniques revealed correlations between specific adiposity measures and high predictivity, suggesting CXRs' potential for enhanced T2D screening.
    DOI:  https://doi.org/10.1038/s41467-023-39631-x
  35. Nat Neurosci. 2023 Jul;26(7): 1139
    Blood proteins control microglia.
    Elisa Floriddia.
      
    DOI:  https://doi.org/10.1038/s41593-023-01385-6
  36. Nat Commun. 2023 Jul 07. 14(1): 4037
    Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G.
    Takahide Kouno, Satoshi Shibata, Megumi Shigematsu, Jaekyung Hyun, Tae Gyun Kim, Hiroshi Matsuo, Matthias Wolf.
      Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV's counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base preference for the interaction and a unique Vif-ribose contact. This establishes the biological significance of an RNA ligand. Further assessment of interactions between A3G, Vif, and RNA ligands show that the A3G-Vif assembly and subsequent ubiquitination can be controlled by amino acid mutations at the interface or by polynucleotide modification, suggesting that a specific chemical moiety would be a promising pharmacophore to inhibit the A3G-Vif interaction.
    DOI:  https://doi.org/10.1038/s41467-023-39796-5
  37. Cell Rep. 2023 Jun 30. pii: S2211-1247(23)00732-5. [Epub ahead of print]42(7): 112721
    Phosphorylation by ATR triggers FANCD2 chromatin loading and activates the Fanconi anemia pathway.
    Marian Kupculak, Fengxiang Bai, Qiang Luo, Yasunaga Yoshikawa, David Lopez-Martinez, Hannan Xu, Stephan Uphoff, Martin A Cohn.
      The Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICLs) in humans. Activation of the pathway relies on loading of the FANCD2/FANCI complex onto chromosomes, where it is fully activated by subsequent monoubiquitination. However, the mechanism for loading the complex onto chromosomes remains unclear. Here, we identify 10 SQ/TQ phosphorylation sites on FANCD2, which are phosphorylated by ATR in response to ICLs. Using a range of biochemical assays complemented with live-cell imaging including super-resolution single-molecule tracking, we show that these phosphorylation events are critical for loading of the complex onto chromosomes and for its subsequent monoubiquitination. We uncover how the phosphorylation events are tightly regulated in cells and that mimicking their constant phosphorylation leads to an uncontrolled active state of FANCD2, which is loaded onto chromosomes in an unrestrained fashion. Taken together, we describe a mechanism where ATR triggers FANCD2/FANCI loading onto chromosomes.
    Keywords:  ATR; CP: Molecular biology; FANCD2/FANCI; Fanconi anemia; ICL repair; cancer; genome instability; phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112721
  38. Nat Med. 2023 Jul 06.
    A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.
    Genes & Health Research Team; the Million Veteran Program
      Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P < 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P < 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.
    DOI:  https://doi.org/10.1038/s41591-023-02429-x
  39. J Clin Immunol. 2023 Jul 05.
    MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development.
    Richard A Voit, Vijay G Sankaran.
      MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.
    Keywords:  Bone marrow failure; Hematopoiesis; Hematopoietic stem cell; Human genetics; Inborn error of immunity; MECOM
    DOI:  https://doi.org/10.1007/s10875-023-01545-0
  40. Nature. 2023 Jul 06.
    Developing human embryos imaged at highest-ever resolution.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-023-02222-3
  41. Nat Aging. 2023 Jul 06.
    Senolytics combat COVID-19 in aging.
    Xu Zhang, Masayoshi Suda, Yi Zhu.
      
    DOI:  https://doi.org/10.1038/s43587-023-00450-w
  42. Nat Commun. 2023 07 04. 14(1): 3931
    Extensive diversity in RNA termination and regulation revealed by transcriptome mapping for the Lyme pathogen Borrelia burgdorferi.
    Emily Petroni, Caroline Esnault, Daniel Tetreault, Ryan K Dale, Gisela Storz, Philip P Adams.
      Transcription termination is an essential and dynamic process that can tune gene expression in response to diverse molecular signals. Yet, the genomic positions, molecular mechanisms, and regulatory consequences of termination have only been studied thoroughly in model bacteria. Here, we use several RNA-seq approaches to map RNA ends for the transcriptome of the spirochete Borrelia burgdorferi - the etiological agent of Lyme disease. We identify complex gene arrangements and operons, untranslated regions and small RNAs. We predict intrinsic terminators and experimentally test examples of Rho-dependent transcription termination. Remarkably, 63% of RNA 3' ends map upstream of or internal to open reading frames (ORFs), including genes involved in the unique infectious cycle of B. burgdorferi. We suggest these RNAs result from premature termination, processing and regulatory events such as cis-acting regulation. Furthermore, the polyamine spermidine globally influences the generation of truncated mRNAs. Collectively, our findings provide insights into transcription termination and uncover an abundance of potential RNA regulators in B. burgdorferi.
    DOI:  https://doi.org/10.1038/s41467-023-39576-1
  43. Cell. 2023 Jun 28. pii: S0092-8674(23)00642-6. [Epub ahead of print]
    Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.
    Leyuan Ma, Alexander Hostetler, Duncan M Morgan, Laura Maiorino, Ina Sulkaj, Charles A Whittaker, Alexandra Neeser, Ivan Susin Pires, Parisa Yousefpour, Justin Gregory, Kashif Qureshi, Jonathan Dye, Wuhbet Abraham, Heikyung Suh, Na Li, J Christopher Love, Darrell J Irvine.
      Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
    Keywords:  CAR T; IFN-γ; antigen loss; antigen spreading; antigenic heterogeneity; cancer; chimeric antigen receptor T cell; immunotherapy; solid tumor; tumor heterogeneity; vaccine
    DOI:  https://doi.org/10.1016/j.cell.2023.06.002
  44. J Exp Med. 2023 Sep 04. pii: e20230904. [Epub ahead of print]220(9):
    Lymph node metastasis: An immunological burden.
    Amanda W Lund.
      Lymph node metastasis in breast cancer depends in part on the acquisition of an IFN-dependent, MHC-II+ state that induces regulatory T cell expansion and local immune suppression (Lei et al. 2023. J. Exp. Med.https://doi.org/10.1084/jem.20221847).
    DOI:  https://doi.org/10.1084/jem.20230904
  45. Science. 2023 Jul 07. 381(6653): 92-100
    Chromatin expansion microscopy reveals nanoscale organization of transcription and chromatin.
    Mark E Pownall, Liyun Miao, Charles E Vejnar, Ons M'Saad, Alice Sherrard, Megan A Frederick, Maria D J Benitez, Curtis W Boswell, Kenneth S Zaret, Joerg Bewersdorf, Antonio J Giraldez.
      Nanoscale chromatin organization regulates gene expression. Although chromatin is notably reprogrammed during zygotic genome activation (ZGA), the organization of chromatin regulatory factors during this universal process remains unclear. In this work, we developed chromatin expansion microscopy (ChromExM) to visualize chromatin, transcription, and transcription factors in vivo. ChromExM of embryos during ZGA revealed how the pioneer factor Nanog interacts with nucleosomes and RNA polymerase II (Pol II), providing direct visualization of transcriptional elongation as string-like nanostructures. Blocking elongation led to more Pol II particles clustered around Nanog, with Pol II stalled at promoters and Nanog-bound enhancers. This led to a new model termed "kiss and kick", in which enhancer-promoter contacts are transient and released by transcriptional elongation. Our results demonstrate that ChromExM is broadly applicable to study nanoscale nuclear organization.
    DOI:  https://doi.org/10.1126/science.ade5308
  46. Nat Cell Biol. 2023 Jul 03.
    Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.
    Ludovic Enkler, Viktoria Szentgyörgyi, Mirjam Pennauer, Cristina Prescianotto-Baschong, Isabelle Riezman, Aneta Wiesyk, Reut Ester Avraham, Martin Spiess, Einat Zalckvar, Roza Kucharczyk, Howard Riezman, Anne Spang.
      Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts in the peroxisome from where β-oxidation products enter mitochondria and fuel the tricarboxylic acid cycle. Little is known about the physical and metabolic cooperation between these organelles. Here we found that expression of fatty acid transporters and of the rate-limiting enzyme involved in β-oxidation is decreased in cells expressing a hyperactive mutant of the small GTPase Arf1, leading to an accumulation of fatty acids in lipid droplets. Consequently, mitochondria became fragmented and ATP synthesis decreased. Genetic and pharmacological depletion of fatty acids phenocopied the arf1 mutant mitochondrial phenotype. Although β-oxidation occurs in both mitochondria and peroxisomes in mammals, Arf1's role in fatty acid metabolism is conserved. Together, our results indicate that Arf1 integrates metabolism into energy production by regulating fatty acid storage and utilization, and presumably organelle contact sites.
    DOI:  https://doi.org/10.1038/s41556-023-01180-2
  47. Mol Cell. 2023 Jun 27. pii: S1097-2765(23)00434-3. [Epub ahead of print]
    Transcription factors interact with RNA to regulate genes.
    Ozgur Oksuz, Jonathan E Henninger, Robert Warneford-Thomson, Ming M Zheng, Hailey Erb, Adrienne Vancura, Kalon J Overholt, Susana Wilson Hawken, Salman F Banani, Richard Lauman, Lauren N Reich, Anne L Robertson, Nancy M Hannett, Tong I Lee, Leonard I Zon, Roberto Bonasio, Richard A Young.
      Transcription factors (TFs) orchestrate the gene expression programs that define each cell's identity. The canonical TF accomplishes this with two domains, one that binds specific DNA sequences and the other that binds protein coactivators or corepressors. We find that at least half of TFs also bind RNA, doing so through a previously unrecognized domain with sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat. RNA binding contributes to TF function by promoting the dynamic association between DNA, RNA, and TF on chromatin. TF-RNA interactions are a conserved feature important for vertebrate development and disrupted in disease. We propose that the ability to bind DNA, RNA, and protein is a general property of many TFs and is fundamental to their gene regulatory function.
    Keywords:  RNA; RNA-binding proteins; arginine-rich motif; chromatin; development; gene regulation; single-molecule imaging; transcription factor; zebrafish
    DOI:  https://doi.org/10.1016/j.molcel.2023.06.012
  48. Nat Commun. 2023 Jul 07. 14(1): 4022
    Plakoglobin is a mechanoresponsive regulator of naive pluripotency.
    Timo N Kohler, Joachim De Jonghe, Anna L Ellermann, Ayaka Yanagida, Michael Herger, Erin M Slatery, Antonia Weberling, Clara Munger, Katrin Fischer, Carla Mulas, Alex Winkel, Connor Ross, Sophie Bergmann, Kristian Franze, Kevin Chalut, Jennifer Nichols, Thorsten E Boroviak, Florian Hollfelder.
      Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional programs will provide insight into mechanisms underlying mammalian pre-implantation development. Here, we explore this type of regulation by exerting microenvironmental control over mouse embryonic stem cells. Microfluidic encapsulation of mouse embryonic stem cells in agarose microgels stabilizes the naive pluripotency network and specifically induces expression of Plakoglobin (Jup), a vertebrate homolog of β-catenin. Overexpression of Plakoglobin is sufficient to fully re-establish the naive pluripotency gene regulatory network under metastable pluripotency conditions, as confirmed by single-cell transcriptome profiling. Finally, we find that, in the epiblast, Plakoglobin was exclusively expressed at the blastocyst stage in human and mouse embryos - further strengthening the link between Plakoglobin and naive pluripotency in vivo. Our work reveals Plakoglobin as a mechanosensitive regulator of naive pluripotency and provides a paradigm to interrogate the effects of volumetric confinement on cell-fate transitions.
    DOI:  https://doi.org/10.1038/s41467-023-39515-0
  49. Gut. 2023 Jun 30. pii: gutjnl-2022-328042. [Epub ahead of print]
    Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells.
    Alessia Potenza, Chiara Balestrieri, Martina Spiga, Luca Albarello, Federica Pedica, Francesco Manfredi, Beatrice Claudia Cianciotti, Claudia De Lalla, Oronza A Botrugno, Cristina Faccani, Lorena Stasi, Elena Tassi, Silvia Bonfiglio, Giulia Maria Scotti, Miriam Redegalli, Donatella Biancolini, Barbara Camisa, Elena Tiziano, Camilla Sirini, Monica Casucci, Chiara Iozzi, Danilo Abbati, Fabio Simeoni, Dejan Lazarevic, Ugo Elmore, Guido Fiorentini, Giulia Di Lullo, Giulia Casorati, Claudio Doglioni, Giovanni Tonon, Paolo Dellabona, Riccardo Rosati, Luca Aldrighetti, Eliana Ruggiero, Chiara Bonini.
       OBJECTIVE: Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells.
    DESIGN: We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products.
    RESULTS: We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCRED)) and the CD39 encoding gene (ENTPD1), thus generating TCREDENTPD1KOHER-2-redirected lymphocytes. We showed that the absence of CD39 confers to HER-2-specific T cells a functional advantage in eliminating HER-2+ patient-derived organoids in vitro and in vivo.
    CONCLUSION: HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC.
    Keywords:  T lymphocytes; cancer immunobiology; colorectal cancer; immunotherapy; liver metastases
    DOI:  https://doi.org/10.1136/gutjnl-2022-328042
  50. Nat Cell Biol. 2023 Jul 06.
    Nuclear class 3 PI3K coactivates circadian clock.
      
    DOI:  https://doi.org/10.1038/s41556-023-01186-w
  51. Science. 2023 Jul 07. 381(6653): eadh3892
    Principles of human pre-60S biogenesis.
    Arnaud Vanden Broeck, Sebastian Klinge.
      During the early stages of human large ribosomal subunit (60S) biogenesis, an ensemble of assembly factors establishes and fine-tunes the essential RNA functional centers of pre-60S particles by an unknown mechanism. Here, we report a series of cryo-electron microscopy structures of human nucleolar and nuclear pre-60S assembly intermediates at resolutions of 2.5 to 3.2 angstroms. These structures show how protein interaction hubs tether assembly factor complexes to nucleolar particles and how guanosine triphosphatases and adenosine triphosphatase couple irreversible nucleotide hydrolysis steps to the installation of functional centers. Nuclear stages highlight how a conserved RNA-processing complex, the rixosome, couples large-scale RNA conformational changes with pre-ribosomal RNA processing by the RNA degradation machinery. Our ensemble of human pre-60S particles provides a rich foundation with which to elucidate the molecular principles of ribosome formation.
    DOI:  https://doi.org/10.1126/science.adh3892
  52. Science. 2023 Jul 07. 381(6653): 38
    A microbiome exercise.
    Christoph A Thaiss.
      Gut-brain connections drive the motivation to work out.
    DOI:  https://doi.org/10.1126/science.adi6329
  53. Nat Commun. 2023 Jul 06. 14(1): 4007
    Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function.
    Kai Liu, Ralf Nilsson, Elisa Lázaro-Ibáñez, Hanna Duàn, Tasso Miliotis, Marie Strimfors, Michael Lerche, Ana Rita Salgado Ribeiro, Johan Ulander, Daniel Lindén, Anna Salvati, Alan Sabirsh.
      In terms of lipid nanoparticle (LNP) engineering, the relationship between particle composition, delivery efficacy, and the composition of the biocoronas that form around LNPs, is poorly understood. To explore this we analyze naturally efficacious biocorona compositions using an unbiased screening workflow. First, LNPs are complexed with plasma samples, from individual lean or obese male rats, and then functionally evaluated in vitro. Then, a fast, automated, and miniaturized method retrieves the LNPs with intact biocoronas, and multiomics analysis of the LNP-corona complexes reveals the particle corona content arising from each individual plasma sample. We find that the most efficacious LNP-corona complexes were enriched with high-density lipoprotein (HDL) and, compared to the commonly used corona-biomarker Apolipoprotein E, corona HDL content was a superior predictor of in-vivo activity. Using technically challenging and clinically relevant lipid nanoparticles, these methods reveal a previously unreported role for HDL as a source of ApoE and, form a framework for improving LNP therapeutic efficacy by controlling corona composition.
    DOI:  https://doi.org/10.1038/s41467-023-39768-9
  54. Sci Immunol. 2023 Jul 14. 8(85): eadj4913
    Fueling the fire of B cell activation.
    Patricia M Sikorski, Linda L Kusner.
      Antigen activated naïve B cells undergoing germinal center responses have distinct metabolic requirements.
    DOI:  https://doi.org/10.1126/sciimmunol.adj4913
  55. Nat Rev Immunol. 2023 Jul 04.
    Bacteria form unique biofilms to kill immune cells.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00914-5
  56. Proc Natl Acad Sci U S A. 2023 Jul 18. 120(29): e2221249120
    A cellular and molecular spatial atlas of dystrophic muscle.
    Michael J Stec, Qi Su, Christina Adler, Lance Zhang, David R Golann, Naveen P Khan, Lampros Panagis, S Armando Villalta, Min Ni, Yi Wei, Johnathon R Walls, Andrew J Murphy, George D Yancopoulos, Gurinder S Atwal, Sandra Kleiner, Gabor Halasz, Mark W Sleeman.
      Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, we generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, we found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery.
    Keywords:  Duchenne muscular dystrophy; asynchronous regeneration; skeletal muscle; spatial transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2221249120
  57. J Clin Invest. 2023 07 03. pii: e162479. [Epub ahead of print]133(13):
    CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
    Young Jae Bahn, Hariom Yadav, Paolo Piaggi, Brent S Abel, Oksana Gavrilova, Danielle A Springer, Ioannis Papazoglou, Patricia M Zerfas, Monica C Skarulis, Alexandra C McPherron, Sushil G Rane.
      Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.
    Keywords:  Metabolism; Mitochondria; Muscle Biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI162479
  58. Sci Immunol. 2023 Jul 14. 8(85): eadg3917
    3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction.
    Anne Onrust-van Schoonhoven, Marjolein J W de Bruijn, Bernard Stikker, Rutger W W Brouwer, Gert-Jan Braunstahl, Wilfred F J van IJcken, Thomas Graf, Danny Huylebroeck, Rudi W Hendriks, Grégoire Stik, Ralph Stadhouders.
      Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4+ memory T helper 2 (TH2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.
    DOI:  https://doi.org/10.1126/sciimmunol.adg3917
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