bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–10–16
sixty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A saturated map of common genetic variants associated with human height.
  2. Structure of the core human NADPH oxidase NOX2.
  3. The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis.
  4. Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications.
  5. Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response.
  6. Cellular barcoding to decipher clonal dynamics in disease.
  7. Mitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles.
  8. Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage.
  9. Evolution and modulation of antigen-specific T cell responses in melanoma patients.
  10. Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system.
  11. Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue.
  12. Electronic Health Record Interoperability: How Did We Get Here and How Do We Move Forward?
  13. Profiling epigenetic age in single cells.
  14. Genetic map of regional sulcal morphology in the human brain from UK biobank data.
  15. Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
  16. Maturation and circuit integration of transplanted human cortical organoids.
  17. Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes.
  18. Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.
  19. INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.
  20. Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome.
  21. A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin.
  22. Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis.
  23. Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK.
  24. Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors.
  25. Cutting Edge: Neutrophils License the Maturation of Monocytes into Effective Antifungal Effectors.
  26. CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis.
  27. The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.
  28. Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
  29. Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas.
  30. Soaring energy costs mean we are using less - but for how long?
  31. How blind fish find their way in pitch-black caves.
  32. The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis.
  33. Resident TH2 cells orchestrate adipose tissue remodeling at a site adjacent to infection.
  34. Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D.
  35. Mitochondrial network expansion and dynamic redistribution during islet morphogenesis in zebrafish larvae.
  36. An anti-influenza combined therapy assessed by single cell RNA-sequencing.
  37. Multi-omic single-cell velocity models epigenome-transcriptome interactions and improves cell fate prediction.
  38. TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis.
  39. Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.
  40. Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila.
  41. Membrane-assisted assembly and selective secretory autophagy of enteroviruses.
  42. Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis.
  43. Transcription suppression is mediated by the HDAC1-Sin3 complex in Xenopus nucleoplasmic extract.
  44. Caldesmon controls stress fiber force-balance through dynamic cross-linking of myosin II and actin-tropomyosin filaments.
  45. TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine.
  46. Quorum-sensing control of matrix protein production drives fractal wrinkling and interfacial localization of Vibrio cholerae pellicles.
  47. How do smallpox-specific memory B cells survive?
  48. Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity.
  49. The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression.
  50. A Multi-Omics Approach Reveals Features That Permit Robust and Widespread Regulation of IFN-Inducible Antiviral Effectors.
  51. Rapid fractionation of mitochondria from mouse liver and heart reveals in vivo metabolite compartmentation.
  52. CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos.
  53. Neurons that control walking go round in circles.
  54. Decoding the transcriptome of calcified atherosclerotic plaque at single-cell resolution.
  55. Our Other Epidemic: Addiction.
  56. Senescent cells in the brain and where to find them.
  57. Elucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning.
  58. CD56-negative NK cells: Frequency in peripheral blood, expansion during HIV-1 infection, functional capacity, and KIR expression.
  59. Actuating tension-loaded DNA clamps drives membrane tubulation.
  60. Enhanced mitochondrial DNA editing in mice using nuclear-exported TALE-linked deaminases and nucleases.
  61. The Role of FXR and TGR5 in Reversing and Preventing Progression of Western Diet-induced Hepatic Steatosis, Inflammation, and Fibrosis in Mice.
  62. ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress.
  63. Synaptic memory survives molecular turnover.
  64. Direct observation of ultrafast singlet exciton fission in three dimensions.
  65. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.
  66. Visualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target.
  67. Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease.
  68. Upper cortical layer-driven network impairment in schizophrenia.
  69. Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search.
  1. Nature. 2022 Oct 12.
    A saturated map of common genetic variants associated with human height.
    23andMe Research Team
      Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
    DOI:  https://doi.org/10.1038/s41586-022-05275-y
  2. Nat Commun. 2022 Oct 14. 13(1): 6079
    Structure of the core human NADPH oxidase NOX2.
    Sigrid Noreng, Naruhisa Ota, Yonglian Sun, Hoangdung Ho, Matthew Johnson, Christopher P Arthur, Kellen Schneider, Isabelle Lehoux, Christopher W Davies, Kyle Mortara, Kit Wong, Dhaya Seshasayee, Matthieu Masureel, Jian Payandeh, Tangsheng Yi, James T Koerber.
      NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O2•-), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation.
    DOI:  https://doi.org/10.1038/s41467-022-33711-0
  3. Nat Commun. 2022 Oct 13. 13(1): 6030
    The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis.
    Hongyu Shen, Xun Huang, Yiheng Zhao, Dongmei Wu, Kaili Xue, Jingfei Yao, Yushuang Wang, Nan Tang, Yifu Qiu.
      Fibrosis disrupts adipose tissue (AT) homeostasis and exacerbates metabolic dysfunction upon chronic caloric excess. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFβ signaling to orchestrate a cellular and/or functional shift of adipocytes from energy storage to extracellular matrix (ECM) remodeling in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4- myofibroblasts upon TGFβ stimulation. On the other hand, Hippo pathway inhibition during obesity impaired adipocyte identity while promoted ECM remodeling activity of adipocytes. Macrophages recruited by CCL2 produced TGFβ to accelerate AT fibrosis. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-022-33800-0
  4. Nat Commun. 2022 Oct 11. 13(1): 5998
    Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications.
    C Albert, L Bracaglia, A Koide, J DiRito, T Lysyy, L Harkins, C Edwards, O Richfield, J Grundler, K Zhou, E Denbaum, G Ketavarapu, T Hattori, S Perincheri, J Langford, A Feizi, D Haakinson, S A Hosgood, M L Nicholson, J S Pober, W M Saltzman, S Koide, G T Tietjen.
      Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.
    DOI:  https://doi.org/10.1038/s41467-022-33490-8
  5. Immunity. 2022 Oct 11. pii: S1074-7613(22)00415-0. [Epub ahead of print]55(10): 1940-1952.e5
    Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response.
    Sophia Liu, J Bryan Iorgulescu, Shuqiang Li, Mehdi Borji, Irving A Barrera-Lopez, Vignesh Shanmugam, Haoxiang Lyu, Julia W Morriss, Zoe N Garcia, Evan Murray, David A Reardon, Charles H Yoon, David A Braun, Kenneth J Livak, Catherine J Wu, Fei Chen.
      T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their clonotypic T cell receptors (TCRs). Determining the spatial distributions of T cell clonotypes in tissues is essential to understanding T cell behavior, but spatial sequencing methods remain unable to profile the TCR repertoire. Here, we developed Slide-TCR-seq, a 10-μm-resolution method, to sequence whole transcriptomes and TCRs within intact tissues. We confirmed the ability of Slide-TCR-seq to map the characteristic locations of T cells and their receptors in mouse spleen. In human lymphoid germinal centers, we identified spatially distinct TCR repertoires. Profiling T cells in renal cell carcinoma and melanoma specimens revealed heterogeneous immune responses: T cell states and infiltration differed intra- and inter-clonally, and adjacent tumor and immune cells exhibited distinct gene expression. Altogether, our method yields insights into the spatial relationships between clonality, neighboring cell types, and gene expression that drive T cell responses.
    Keywords:  T cell; T cell receptor; cell interactions; clonotype; immune niches; sequencing; spatial; tertiary lymphoid structures; transcriptomics; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.immuni.2022.09.002
  6. Science. 2022 Oct 14. 378(6616): eabm5874
    Cellular barcoding to decipher clonal dynamics in disease.
    Vijay G Sankaran, Jonathan S Weissman, Leonard I Zon.
      Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
    DOI:  https://doi.org/10.1126/science.abm5874
  7. Nat Commun. 2022 Oct 13. 13(1): 6058
    Mitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles.
    Prasanna Katti, Alexander S Hall, Hailey A Parry, Peter T Ajayi, Yuho Kim, T Bradley Willingham, Christopher K E Bleck, Han Wen, Brian Glancy.
      Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate (ATP) from nearby mitochondria. However, it remains unclear how different physical configurations between sarcomeres and mitochondria alter the energetic support for contractile function. Here, we show that sarcomere cross-sectional area (CSA) varies along its length in a cell type-dependent manner where the reduction in Z-disk CSA relative to the sarcomere center is closely coordinated with mitochondrial network configuration in flies, mice, and humans. Further, we find myosin filaments near the sarcomere periphery are curved relative to interior filaments with greater curvature for filaments near mitochondria compared to sarcoplasmic reticulum. Finally, we demonstrate variable myosin filament lattice spacing between filament ends and filament centers in a cell type-dependent manner. These data suggest both sarcomere structure and myofilament interactions are influenced by the location and orientation of mitochondria within muscle cells.
    DOI:  https://doi.org/10.1038/s41467-022-33678-y
  8. Nat Commun. 2022 Oct 10. 13(1): 5984
    Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage.
    Gayan I Balasooriya, David L Spector.
      Each mammalian autosomal gene is represented by two alleles in diploid cells. To our knowledge, no insights have been made in regard to allele-specific regulatory mechanisms of autosomes. Here we use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. We find that monoallelically expressed autosomal genes in mESCs and mouse blastocyst cells are differentially regulated based on the genetic background of the parental alleles. However, the genetic background of the allele does not affect the establishment of monoallelic genes in differentiated cardiomyocytes. Additionally, we observe epigenetic differences between deterministic and random autosomal monoallelic genes. Moreover, we also find a greater contribution of the maternal versus paternal allele to the development and homeostasis of cardiac tissue and in cardiac health, highlighting the importance of maternal influence in male cardiac tissue homeostasis. Our findings emphasize the significance of allele-specific insights into gene regulation in development, homeostasis and disease.
    DOI:  https://doi.org/10.1038/s41467-022-33722-x
  9. Nat Commun. 2022 Oct 11. 13(1): 5988
    Evolution and modulation of antigen-specific T cell responses in melanoma patients.
    Jani Huuhtanen, Liang Chen, Emmi Jokinen, Henna Kasanen, Tapio Lönnberg, Anna Kreutzman, Katriina Peltola, Micaela Hernberg, Chunlin Wang, Cassian Yee, Harri Lähdesmäki, Mark M Davis, Satu Mustjoki.
      Analyzing antigen-specific T cell responses at scale has been challenging. Here, we analyze three types of T cell receptor (TCR) repertoire data (antigen-specific TCRs, TCR-repertoire, and single-cell RNA + TCRαβ-sequencing data) from 515 patients with primary or metastatic melanoma and compare it to 783 healthy controls. Although melanoma-associated antigen (MAA) -specific TCRs are restricted to individuals, they share sequence similarities that allow us to build classifiers for predicting anti-MAA T cells. The frequency of anti-MAA T cells distinguishes melanoma patients from healthy and predicts metastatic recurrence from primary melanoma. Anti-MAA T cells have stem-like properties and frequent interactions with regulatory T cells and tumor cells via Galectin9-TIM3 and PVR-TIGIT -axes, respectively. In the responding patients, the number of expanded anti-MAA clones are higher after the anti-PD1(+anti-CTLA4) therapy and the exhaustion phenotype is rescued. Our systems immunology approach paves the way for understanding antigen-specific responses in human disorders.
    DOI:  https://doi.org/10.1038/s41467-022-33720-z
  10. Nat Commun. 2022 Oct 12. 13(1): 6004
    Targeting EGFR-dependent tumors by disrupting an ARF6-mediated sorting system.
    Huiling Guo, Juan Wang, Su Ren, Lang-Fan Zheng, Yi-Xuan Zhuang, Dong-Lin Li, Hui-Hui Sun, Li-Ying Liu, Changchuan Xie, Ya-Ying Wu, Hong-Rui Wang, Xianming Deng, Peng Li, Tong-Jin Zhao.
      Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors.
    DOI:  https://doi.org/10.1038/s41467-022-33788-7
  11. Nat Commun. 2022 Oct 13. 13(1): 6062
    Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue.
    Erin J Stephenson, Amanda S Stayton, Aarti Sethuraman, Prahlad K Rao, Alice Meyer, Charles Klazer Gomes, Molly C Mulcahy, Liam McAllan, Michelle A Puchowicz, Joseph F Pierre, Dave Bridges, Joan C Han.
      Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
    DOI:  https://doi.org/10.1038/s41467-022-33840-6
  12. JAMA Health Forum. 2021 Mar 01. 2(3): e210253
    Electronic Health Record Interoperability: How Did We Get Here and How Do We Move Forward?
    Sara Turbow, Julie R Hollberg, Mohammed K Ali.
      
    DOI:  https://doi.org/10.1001/jamahealthforum.2021.0253
  13. Nat Aging. 2021 Dec;1(12): 1189-1201
    Profiling epigenetic age in single cells.
    Alexandre Trapp, Csaba Kerepesi, Vadim N Gladyshev.
      DNA methylation dynamics emerged as a promising biomarker of mammalian aging, with multivariate machine learning models ('epigenetic clocks') enabling measurement of biological age in bulk tissue samples. However, intrinsically sparse and binarized methylation profiles of individual cells have so far precluded the assessment of aging in single-cell data. Here, we introduce scAge, a statistical framework for epigenetic age profiling at single-cell resolution, and validate our approach in mice. Our method recapitulates the chronological age of tissues, while uncovering heterogeneity among cells. We show accurate tracking of the aging process in hepatocytes, demonstrate attenuated epigenetic aging in muscle stem cells, and track age dynamics in embryonic stem cells. We also use scAge to reveal, at the single-cell level, a natural and stratified rejuvenation event occurring during early embryogenesis. We provide our framework as a resource to enable exploration of epigenetic aging trajectories at single-cell resolution.
    DOI:  https://doi.org/10.1038/s43587-021-00134-3
  14. Nat Commun. 2022 Oct 14. 13(1): 6071
    Genetic map of regional sulcal morphology in the human brain from UK biobank data.
    Biogen Biobank Team
      Genetic associations with macroscopic brain structure can provide insights into brain function and disease. However, specific associations with measures of local brain folding are largely under-explored. Here, we conducted large-scale genome- and exome-wide associations of regional cortical sulcal measures derived from magnetic resonance imaging scans of 40,169 individuals in UK Biobank. We discovered 388 regional brain folding associations across 77 genetic loci, with genes in associated loci enriched for expression in the cerebral cortex, neuronal development processes, and differential regulation during early brain development. We integrated brain eQTLs to refine genes for various loci, implicated several genes involved in neurodevelopmental disorders, and highlighted global genetic correlations with neuropsychiatric phenotypes. We provide an interactive 3D visualisation of our summary associations, emphasising added resolution of regional analyses. Our results offer new insights into the genetic architecture of brain folding and provide a resource for future studies of sulcal morphology in health and disease.
    DOI:  https://doi.org/10.1038/s41467-022-33829-1
  15. EMBO Rep. 2022 Oct 10. e54685
    Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells.
    Aleksandra Lopez Krol, Hannah P Nehring, Felix F Krause, Anne Wempe, Hartmann Raifer, Andrea Nist, Thorsten Stiewe, Wilhelm Bertrams, Bernd Schmeck, Maik Luu, Hanna Leister, Ho-Ryun Chung, Uta-Maria Bauer, Till Adhikary, Alexander Visekruna.
      Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. Here, we demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating the metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed increased levels of genome-wide histone H3K18 lactylation, a recently described marker for active chromatin in macrophages, in lactate-treated Th17 cells. In addition, we show that high lactate concentrations suppress Th17 pathogenicity during intestinal inflammation in mice. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotypes into regulatory T cells.
    Keywords:  Th17 cells; Tregs; histone lactylation; immunometabolism; lactate
    DOI:  https://doi.org/10.15252/embr.202254685
  16. Nature. 2022 Oct;610(7931): 319-326
    Maturation and circuit integration of transplanted human cortical organoids.
    Omer Revah, Felicity Gore, Kevin W Kelley, Jimena Andersen, Noriaki Sakai, Xiaoyu Chen, Min-Yin Li, Fikri Birey, Xiao Yang, Nay L Saw, Samuel W Baker, Neal D Amin, Shravanti Kulkarni, Rachana Mudipalli, Bianxiao Cui, Seiji Nishino, Gerald A Grant, Juliet K Knowles, Mehrdad Shamloo, John R Huguenard, Karl Deisseroth, Sergiu P Pașca.
      Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
    DOI:  https://doi.org/10.1038/s41586-022-05277-w
  17. Nat Commun. 2022 Oct 14. 13(1): 6090
    Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes.
    Hana Polasek-Sedlackova, Thomas C R Miller, Jana Krejci, Maj-Britt Rask, Jiri Lukas.
      Genome duplication is safeguarded by constantly adjusting the activity of the replicative CMG (CDC45-MCM2-7-GINS) helicase. However, minichromosome maintenance proteins (MCMs)-the structural core of the CMG helicase-have never been visualized at sites of DNA synthesis inside a cell (the so-called MCM paradox). Here, we solve this conundrum by showing that anti-MCM antibodies primarily detect inactive MCMs. Upon conversion of inactive MCMs to CMGs, factors that are required for replisome activity bind to the MCM scaffold and block MCM antibody binding sites. Tagging of endogenous MCMs by CRISPR-Cas9 bypasses this steric hindrance and enables MCM visualization at active replisomes. Thus, by defining conditions for detecting the structural core of the replicative CMG helicase, our results explain the MCM paradox, provide visual proof that MCMs are an integral part of active replisomes in vivo, and enable the investigation of replication dynamics in living cells exposed to a constantly changing environment.
    DOI:  https://doi.org/10.1038/s41467-022-33887-5
  18. Nat Commun. 2022 Oct 10. 13(1): 5947
    Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.
    Trevor J Gonzalez, Katherine E Simon, Leo O Blondel, Marco M Fanous, Angela L Roger, Maribel Santiago Maysonet, Garth W Devlin, Timothy J Smith, Daniel K Oh, L Patrick Havlik, Ruth M Castellanos Rivera, Jorge A Piedrahita, Mai K ElMallah, Charles A Gersbach, Aravind Asokan.
      Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies.
    DOI:  https://doi.org/10.1038/s41467-022-33745-4
  19. Nat Commun. 2022 Oct 13. 13(1): 6054
    INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex.
    Lauren G Mascibroda, Mohammad Shboul, Nathan D Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne N Jodoin, Poojitha Sitaram, Laura A Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley F Nelson, Yixuan Wu, Liang Tong, Linda J Kenney, Sudipto Roy, William K Russell, Jeanne Amiel, Bruno Reversade, Eric J Wagner.
      Oral-facial-digital (OFD) syndromes are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. Mutations within 12 cilia-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline variants in INTS13, a subunit of the Integrator complex. This multiprotein complex associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. We determined that INTS13 utilizes its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline variants p.S652L and p.K668Nfs*9. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos leads to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions between components of the Integrator complex.
    DOI:  https://doi.org/10.1038/s41467-022-33547-8
  20. Nat Biotechnol. 2022 Oct 10.
    Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome.
    Matthew G Durrant, Alison Fanton, Josh Tycko, Michaela Hinks, Sita S Chandrasekaran, Nicholas T Perry, Julia Schaepe, Peter P Du, Peter Lotfy, Michael C Bassik, Lacramioara Bintu, Ami S Bhatt, Patrick D Hsu.
      Large serine recombinases (LSRs) are DNA integrases that facilitate the site-specific integration of mobile genetic elements into bacterial genomes. Only a few LSRs, such as Bxb1 and PhiC31, have been characterized to date, with limited efficiency as tools for DNA integration in human cells. In this study, we developed a computational approach to identify thousands of LSRs and their DNA attachment sites, expanding known LSR diversity by >100-fold and enabling the prediction of their insertion site specificities. We tested their recombination activity in human cells, classifying them as landing pad, genome-targeting or multi-targeting LSRs. Overall, we achieved up to seven-fold higher recombination than Bxb1 and genome integration efficiencies of 40-75% with cargo sizes over 7 kb. We also demonstrate virus-free, direct integration of plasmid or amplicon libraries for improved functional genomics applications. This systematic discovery of recombinases directly from microbial sequencing data provides a resource of over 60 LSRs experimentally characterized in human cells for large-payload genome insertion without exposed DNA double-stranded breaks.
    DOI:  https://doi.org/10.1038/s41587-022-01494-w
  21. Science. 2022 Oct 14. 378(6616): eabq0132
    A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin.
    Qiyao Chai, Shanshan Yu, Yanzhao Zhong, Zhe Lu, Changgen Qiu, Yang Yu, Xinwen Zhang, Yong Zhang, Zehui Lei, Lihua Qiang, Bing-Xi Li, Yu Pang, Xiao-Bo Qiu, Jing Wang, Cui Hua Liu.
      The inflammasome-mediated cleavage of gasdermin D (GSDMD) causes pyroptosis and inflammatory cytokine release to control pathogen infection, but how pathogens evade this immune response remains largely unexplored. Here we identify the known protein phosphatase PtpB from Mycobacterium tuberculosis as a phospholipid phosphatase inhibiting the host inflammasome-pyroptosis pathway. Mechanistically, PtpB dephosphorylated phosphatidylinositol-4-monophosphate and phosphatidylinositol-(4,5)-bisphosphate in host cell membrane, thus disrupting the membrane localization of the cleaved GSDMD to inhibit cytokine release and pyroptosis of macrophages. Notably, this phosphatase activity requires PtpB binding to ubiquitin. Disrupting phospholipid phosphatase activity or the ubiquitin-interacting motif of PtpB enhanced host GSDMD-dependent immune responses and reduced intracellular pathogen survival. Thus, pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition.
    DOI:  https://doi.org/10.1126/science.abq0132
  22. Nat Commun. 2022 Oct 13. 13(1): 6051
    Co-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis.
    Le Qin, Yuanbin Cui, Tingjie Yuan, Dongmei Chen, Ruocong Zhao, Shanglin Li, Zhiwu Jiang, Qiting Wu, Youguo Long, Suna Wang, Zhaoyang Tang, Huixia Pan, Xiaoping Li, Wei Wei, Jie Yang, Xuequn Luo, Zhenfeng Zhang, Qiannan Tang, Pentao Liu, Robert Weinkove, Yao Yao, Dajiang Qin, Jean Paul Thiery, Peng Li.
      Co-expression of chimeric switch receptors (CSRs) specific for PD-L1 improves the antitumor effects of chimeric antigen receptor (CAR) T cells. However, the effects of trans-recognition between CSRs and PD-L1 expressed by activated CAR T cells remain unclear. Here, we design a CSR specific for PD-L1 (CARP), containing the transmembrane and cytoplasmic signaling domains of CD28 but not the CD3 ζ chain. We show that CARP T cells enhance the antitumor activity of anti-mesothelin CAR (CARMz) T cells in vitro and in vivo. In addition, confocal microscopy indicates that PD-L1 molecules on CARMz T cells accumulate at cell-cell contacts with CARP T cells. Using single-cell RNA-sequencing analysis, we reveal that CARP T cells promote CARMz T cells differentiation into central memory-like T cells, upregulate genes related to Th1 cells, and downregulate Th2-associated cytokines through the CD70-CD27 axis. Moreover, these effects are not restricted to PD-L1, as CAR19 T cells expressing anti-CD19 CSR exhibit similar effects on anti-PSCA CAR T cells with truncated CD19 expression. These findings suggest that target trans-recognition by CSRs on CAR T cells may improve the efficacy and persistence of CAR T cells via the CD70-CD27 axis.
    DOI:  https://doi.org/10.1038/s41467-022-33793-w
  23. Nat Commun. 2022 Oct 08. 13(1): 5945
    Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK.
    Chenxu Ge, Jun Tan, Xianling Dai, Qin Kuang, Shaoyu Zhong, Lili Lai, Chao Yi, Yan Sun, Jing Luo, Chufeng Zhang, Liancai Zhu, Bochu Wang, Minxuan Xu.
      Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown. Here, we find a significant decrease of DUSP22 expression in human and murine fatty liver, which is mediated by reactive oxygen species (ROS) generation. Hepatic-specific DUSP22 deletion particularly exacerbates lipid deposition, inflammatory response and fibrosis in liver, facilitating NASH and non-alcoholic fatty liver disease (NAFLD)-associated HCC progression. In contrast, transgenic over-expression, lentivirus or adeno-associated virus (AAV)-mediated DUSP22 gene therapy substantially inhibit NASH-related phenotypes and HCC development in mice. We provide mechanistic evidence that DUSP22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation at Tyr397 (Y397) and Y576 + Y577 residues, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades. The binding of DUSP22 to FAK and the dephosphorylation of FAK are indispensable for DUSP22-meliorated NASH progression. Collectively, our findings identify DUSP22 as a key suppressor of NASH-HCC, and underscore the DUSP22-FAK axis as a promising therapeutic target for treatment of the disease.
    DOI:  https://doi.org/10.1038/s41467-022-33493-5
  24. Nat Commun. 2022 Oct 12. 13(1): 6021
    Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors.
    David B Chou, Brooke A Furlong, Ryan R Posey, Christos Kyprianou, Lucy R O'Sullivan, Rhiannon David, Suzanne J Randle, Urszula M Polanska, Jon Travers, Jelena Urosevic, John N Hutchinson, Jianwei Che, Anna M Howley, Robert P Hasserjian, Rachelle Prantil-Baun, Donald E Ingber.
      Drug-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While reductions in blood cell numbers are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecules and the factors that determine the hematotoxicity profiles of oncologic drugs are not fully understood. Here, we explore why some Aurora kinase inhibitors cause preferential neutropenia. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing gene expression datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibition is caused by early developmental changes in ATP-binding cassette (ABC) transporter expression. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some Aurora kinase inhibitors affect the bone marrow.
    DOI:  https://doi.org/10.1038/s41467-022-33672-4
  25. J Immunol. 2022 Oct 10. pii: ji2200430. [Epub ahead of print]
    Cutting Edge: Neutrophils License the Maturation of Monocytes into Effective Antifungal Effectors.
    Vanessa Espinosa, Orchi Dutta, Lena J Heung, Keyi Wang, Yun-Juan Chang, Patricia Soteropoulos, Tobias M Hohl, Mark C Siracusa, Amariliz Rivera.
      Neutrophils are critical for the direct eradication of Aspergillus fumigatus conidia, but whether they mediate antifungal defense beyond their role as effectors is unclear. In this study, we demonstrate that neutrophil depletion impairs the activation of protective antifungal CCR2+ inflammatory monocytes. In the absence of neutrophils, monocytes displayed limited differentiation into monocyte-derived dendritic cells, reduced formation of reactive oxygen species, and diminished conidiacidal activity. Upstream regulator analysis of the transcriptional response in monocytes predicted a loss of STAT1-dependent signals as the potential basis for the dysfunction seen in neutrophil-depleted mice. We find that conditional removal of STAT1 on CCR2+ cells results in diminished antifungal monocyte responses, whereas exogenous administration of IFN-γ to neutrophil-depleted mice restores monocyte-derived dendritic cell maturation and reactive oxygen species production. Altogether, our findings support a critical role for neutrophils in antifungal immunity not only as effectors but also as important contributors to antifungal monocyte activation, in part by regulating STAT1-dependent functions.
    DOI:  https://doi.org/10.4049/jimmunol.2200430
  26. JCI Insight. 2022 Oct 10. pii: e159469. [Epub ahead of print]7(19):
    CD11c+ myeloid cell exosomes reduce intestinal inflammation during colitis.
    Kaylyn M Bauer, Morgan C Nelson, William W Tang, Tyson R Chiaro, D Garrett Brown, Arevik Ghazaryan, Soh-Hyun Lee, Allison M Weis, Jennifer H Hill, Kendra A Klag, Van B Tran, Jacob W Thompson, Andrew G Ramstead, Josh K Monts, James E Marvin, Margaret Alexander, Warren P Voth, W Zac Stephens, Diane M Ward, Aaron C Petrey, June L Round, Ryan M O'Connell.
      Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.
    Keywords:  Cell Biology; Immunology; Inflammatory bowel disease; Noncoding RNAs
    DOI:  https://doi.org/10.1172/jci.insight.159469
  27. Nat Commun. 2022 Oct 10. 13(1): 5973
    The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS.
    Tian-Chen Xiong, Ming-Cong Wei, Fang-Xu Li, Miao Shi, Hu Gan, Zhen Tang, Hong-Peng Dong, Tianzi Liuyu, Pu Gao, Bo Zhong, Zhi-Dong Zhang, Dandan Lin.
      The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.
    DOI:  https://doi.org/10.1038/s41467-022-33671-5
  28. Nat Commun. 2022 Oct 11. 13(1): 5995
    Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
    DOI:  https://doi.org/10.1038/s41467-022-33510-7
  29. Nat Commun. 2022 Oct 15. 13(1): 6095
    Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas.
    Paul K Paik, Jia Luo, Ni Ai, Rachel Kim, Linda Ahn, Anup Biswas, Courtney Coker, Wanchao Ma, Phillip Wong, Darren J Buonocore, W Victoria Lai, Jamie E Chaft, Swarnali Acharyya, Joan Massagué, Mark G Kris.
      We previously identified a chemotherapy-induced paracrine inflammatory loop that paradoxically mitigates the anti-tumor effect of chemotherapy and triggers metastatic propagation in breast and lung cancer models. Therefore, we sought to further validate and translate these findings into patient care by coupling the anti-TNF-α drug certolizumab pegol with standard cisplatin doublet chemotherapy. Here we first validate the anti-metastatic effect of certolizumab in a liver-metastatic Lewis Lung Carcinoma model. We then evaluate the safety, efficacy, and pharmacodynamic effects of certolizumab with cisplatin and pemetrexed in an open label Phase 1 clinical trial (NCT02120807) of eighteen adult patients with stage IV lung adenocarcinomas. The primary outcome is maximum tolerated dose. Secondary outcomes are response rate and progression-free survival (PFS); pharmacodynamic changes in blood and tumor are evaluated as a correlative outcome. There were nine partial responses among 16 patients evaluable (56%, 95% CI 30 to 80%). The median duration of response was 9.0 months (range 5.9 to 42.6 months) and median PFS was 7.1 months (95% CI 6.3 to NR). The standard 400 mg dose of certolizumab, added to cisplatin and pemetrexed, is well-tolerated and, as a correlative endpoint, demonstrates potent pharmacodynamic inhibition of peripheral cytokines associated with the paracrine inflammatory loop.
    DOI:  https://doi.org/10.1038/s41467-022-33719-6
  30. Nature. 2022 Oct 14.
    Soaring energy costs mean we are using less - but for how long?
    Heidi Ledford.
      
    DOI:  https://doi.org/10.1038/d41586-022-03261-y
  31. Nature. 2022 Oct 11.
    How blind fish find their way in pitch-black caves.
      
    Keywords:  Zoology
    DOI:  https://doi.org/10.1038/d41586-022-03227-0
  32. Nat Commun. 2022 Oct 14. 13(1): 6068
    The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis.
    Marjolein Heddes, Baraa Altaha, Yunhui Niu, Sandra Reitmeier, Karin Kleigrewe, Dirk Haller, Silke Kiessling.
      Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host's circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for microbiota composition and function, which is required to balance the host's gastrointestinal homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-33609-x
  33. Sci Immunol. 2022 Oct 21. 7(76): eadd3263
    Resident TH2 cells orchestrate adipose tissue remodeling at a site adjacent to infection.
    Agnieszka M Kabat, Alexandra Hackl, David E Sanin, Patrice Zeis, Katarzyna M Grzes, Francesc Baixauli, Ryan Kyle, George Caputa, Joy Edwards-Hicks, Matteo Villa, Nisha Rana, Jonathan D Curtis, Angela Castoldi, Jovana Cupovic, Leentje Dreesen, Maria Sibilia, J Andrew Pospisilik, Joseph F Urban, Dominic Grün, Erika L Pearce, Edward J Pearce.
      Type 2 immunity is associated with adipose tissue (AT) homeostasis and infection with parasitic helminths, but whether AT participates in immunity to these parasites is unknown. We found that the fat content of mesenteric AT (mAT) declined in mice during infection with a gut-restricted helminth. This was associated with the accumulation of metabolically activated, interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and extracellular matrix (ECM)-producing stromal cells. These cells shared transcriptional features, including the expression of Dpp4 and Pi16, with multipotent progenitor cells (MPC) that have been identified in numerous tissues and are reported to be capable of differentiating into fibroblasts and adipocytes. Concomitantly, mAT became infiltrated with resident T helper 2 (TH2) cells that responded to TSLP and IL-33 by producing stromal cell-stimulating cytokines, including transforming growth factor β1 (TGFβ1) and amphiregulin. These TH2 cells expressed genes previously associated with type 2 innate lymphoid cells (ILC2), including Nmur1, Calca, Klrg1, and Arg1, and persisted in mAT for at least 11 months after anthelmintic drug-mediated clearance of infection. We found that MPC and TH2 cells localized to ECM-rich interstitial spaces that appeared shared between mesenteric lymph node, mAT, and intestine. Stromal cell expression of epidermal growth factor receptor (EGFR), the receptor for amphiregulin, was required for immunity to infection. Our findings point to the importance of MPC and TH2 cell interactions within the interstitium in orchestrating AT remodeling and immunity to an intestinal infection.
    DOI:  https://doi.org/10.1126/sciimmunol.add3263
  34. Nat Commun. 2022 Oct 14. 13(1): 6080
    Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D.
    Yun Seok Kim, Bongsub Ko, Da Jung Kim, Jihoon Tak, Chang Yeob Han, Joo-Youn Cho, Won Kim, Sang Geon Kim.
      Disturbed lipid metabolism precedes alcoholic liver injury. Whether and how AhR alters degradation of lipids, particularly phospho-/sphingo-lipids during alcohol exposure, was not explored. Here, we show that alcohol consumption in mice results in induction and activation of aryl hydrocarbon receptor (AhR) in the liver, and changes the hepatic phospho-/sphingo-lipids content. The levels of kynurenine, an endogenous AhR ligand, are elevated with increased hepatic tryptophan metabolic enzymes in alcohol-fed mice. Either alcohol or kynurenine treatment promotes AhR activation with autophagy dysregulation via AMPK. Protein Phosphatase 2 Regulatory Subunit-Bdelta (Ppp2r2d) is identified as a transcriptional target of AhR. Consequently, PPP2R2D-dependent AMPKα dephosphorylation causes autophagy inhibition and mitochondrial dysfunction. Hepatocyte-specific AhR ablation attenuates steatosis, which is associated with recovery of phospho-/sphingo-lipids content. Changes of AhR targets are corroborated using patient specimens. Overall, AhR induction by alcohol inhibits autophagy in hepatocytes through AMPKα, which is mediated by Ppp2r2d gene transactivation, revealing an AhR-dependent metabolism of phospho-/sphingo-lipids.
    DOI:  https://doi.org/10.1038/s41467-022-33749-0
  35. FEBS Lett. 2022 Oct 10.
    Mitochondrial network expansion and dynamic redistribution during islet morphogenesis in zebrafish larvae.
    Julia Freudenblum, Dirk Meyer, Robin A Kimmel.
      Mitochondria, organelles critical for energy production, modify their shape and location in response to developmental state and metabolic demands. Mitochondria are altered in diabetes, but the mechanistic basis is poorly defined, due to difficulties in assessing mitochondria within an intact organism. Here, we use in vivo imaging in transparent zebrafish larvae to demonstrate filamentous, interconnected mitochondrial networks within islet cells. Mitochondrial movements highly resemble what has been reported for human islet cells in vitro, showing conservation in behavior across species and cellular context. During islet development, mitochondrial content increases with emergence of cell motility, and mitochondria disperse within fine protrusions. Overall, this work presents quantitative analysis of mitochondria within their native environment and provides insights into mitochondrial behavior during organogenesis.
    Keywords:  Mitochondria; image analysis; in vivo imaging; islet; pancreas; zebrafish
    DOI:  https://doi.org/10.1002/1873-3468.14508
  36. Commun Biol. 2022 Oct 10. 5(1): 1075
    An anti-influenza combined therapy assessed by single cell RNA-sequencing.
    Chiara Medaglia, Ilya Kolpakov, Arnaud Charles-Antoine Zwygart, Yong Zhu, Samuel Constant, Song Huang, Valeria Cagno, Emmanouil T Dermitzakis, Francesco Stellacci, Ioannis Xenarios, Caroline Tapparel.
      Influenza makes millions of people ill every year, placing a large burden on the healthcare system and the economy. To develop a treatment against influenza, we combined virucidal sialylated cyclodextrins with interferon lambda and demonstrated, in human airway epithelia, that the two compounds inhibit the replication of a clinical H1N1 strain more efficiently when administered together rather than alone. We investigated the mechanism of action of the combined treatment by single cell RNA-sequencing analysis and found that both the single and combined treatments impair viral replication to different extents across distinct epithelial cell types. We showed that each cell type comprises multiple sub-types, whose proportions are altered by H1N1 infection, and assessed the ability of the treatments to restore them. To the best of our knowledge this is the first study investigating the effectiveness of an antiviral therapy against influenza virus by single cell transcriptomic studies.
    DOI:  https://doi.org/10.1038/s42003-022-04013-4
  37. Nat Biotechnol. 2022 Oct 13.
    Multi-omic single-cell velocity models epigenome-transcriptome interactions and improves cell fate prediction.
    Chen Li, Maria C Virgilio, Kathleen L Collins, Joshua D Welch.
      Multi-omic single-cell datasets, in which multiple molecular modalities are profiled within the same cell, offer an opportunity to understand the temporal relationship between epigenome and transcriptome. To realize this potential, we developed MultiVelo, a differential equation model of gene expression that extends the RNA velocity framework to incorporate epigenomic data. MultiVelo uses a probabilistic latent variable model to estimate the switch time and rate parameters of chromatin accessibility and gene expression and improves the accuracy of cell fate prediction compared to velocity estimates from RNA only. Application to multi-omic single-cell datasets from brain, skin and blood cells reveals two distinct classes of genes distinguished by whether chromatin closes before or after transcription ceases. We also find four types of cell states: two states in which epigenome and transcriptome are coupled and two distinct decoupled states. Finally, we identify time lags between transcription factor expression and binding site accessibility and between disease-associated SNP accessibility and expression of the linked genes. MultiVelo is available on PyPI, Bioconda and GitHub ( https://github.com/welch-lab/MultiVelo ).
    DOI:  https://doi.org/10.1038/s41587-022-01476-y
  38. Nat Commun. 2022 Oct 14. 13(1): 6020
    TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis.
    Kasparas Petkevicius, Henrik Palmgren, Matthew S Glover, Andrea Ahnmark, Anne-Christine Andréasson, Katja Madeyski-Bengtson, Hiroki Kawana, Erik L Allman, Delaney Kaper, Martin Uhrbom, Liselotte Andersson, Leif Aasehaug, Johan Forsström, Simonetta Wallin, Ingela Ahlstedt, Renata Leke, Daniel Karlsson, Hernán González-King, Lars Löfgren, Ralf Nilsson, Giovanni Pellegrini, Nozomu Kono, Junken Aoki, Sonja Hess, Grzegorz Sienski, Marc Pilon, Mohammad Bohlooly-Y, Marcello Maresca, Xiao-Rong Peng.
      The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.
    DOI:  https://doi.org/10.1038/s41467-022-33735-6
  39. Commun Biol. 2022 Oct 08. 5(1): 1074
    Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.
    Alzheimer’s Disease Metabolomics Consortium
      Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
    DOI:  https://doi.org/10.1038/s42003-022-04011-6
  40. Nat Aging. 2022 Jun;2(6): 494-507
    Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila.
    Edward T Schmid, Jung-Hoon Pyo, David W Walker.
      The effects of aging on the brain are widespread and can have dramatic implications on the overall health of an organism. Mitochondrial dysfunction is a hallmark of brain aging, but, the interplay between mitochondrial quality control, neuronal aging, and organismal health is not well understood. Here, we show that aging leads to a decline in mitochondrial autophagy (mitophagy) in the Drosophila brain with a concomitant increase in mitochondrial content. We find that induction of BCL2-interacting protein 3 (BNIP3), a mitochondrial outer membrane protein, in the adult nervous system induces mitophagy and prevents the accumulation of dysfunctional mitochondria in the aged brain. Importantly, neuronal induction of BNIP3-mediated mitophagy increases organismal longevity and healthspan. Furthermore, BNIP3-mediated mitophagy in the nervous system improves muscle and intestinal homeostasis in aged flies, indicating cell non-autonomous effects. Our findings identify BNIP3 as a therapeutic target to counteract brain aging and prolong overall organismal health with age.
    Keywords:  Autophagy; Intestinal barrier dysfunction; Intestinal stem cell; Mito-QC; Mitophagy; Muscle aging; Neuronal aging
    DOI:  https://doi.org/10.1038/s43587-022-00214-y
  41. Nat Commun. 2022 Oct 10. 13(1): 5986
    Membrane-assisted assembly and selective secretory autophagy of enteroviruses.
    Selma Dahmane, Adeline Kerviel, Dustin R Morado, Kasturika Shankar, Björn Ahlman, Michael Lazarou, Nihal Altan-Bonnet, Lars-Anders Carlson.
      Enteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic membranes for viral genome replication. It is unknown how virions assemble around these newly synthesized genomes and how they are then loaded into autophagic membranes for release through secretory autophagy. Here, we use cryo-electron tomography of infected cells to show that poliovirus assembles directly on replication membranes. Pharmacological untethering of capsids from membranes abrogates RNA encapsidation. Our data directly visualize a membrane-bound half-capsid as a prominent virion assembly intermediate. Assembly progression past this intermediate depends on the class III phosphatidylinositol 3-kinase VPS34, a key host-cell autophagy factor. On the other hand, the canonical autophagy initiator ULK1 is shown to restrict virion production since its inhibition leads to increased accumulation of virions in vast intracellular arrays, followed by an increased vesicular release at later time points. Finally, we identify multiple layers of selectivity in virus-induced autophagy, with a strong selection for RNA-loaded virions over empty capsids and the segregation of virions from other types of autophagosome contents. These findings provide an integrated structural framework for multiple stages of the poliovirus life cycle.
    DOI:  https://doi.org/10.1038/s41467-022-33483-7
  42. Cell Metab. 2022 Oct 06. pii: S1550-4131(22)00408-9. [Epub ahead of print]
    Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis.
    Zhao Zhang, Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie Russell, Chun-Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang Qin, Tiffany Collie, Meron Tadesse, Eva Marie Y Moresco, Bruce Beutler.
      Using random germline mutagenesis in mice, we identified a viable hypomorphic allele (boh) of the transcription-factor-encoding gene Ovol2 that resulted in obesity, which initially developed with normal food intake and physical activity but decreased energy expenditure. Fat weight was dramatically increased, while lean weight was reduced in 12-week-old boh homozygous mice, culminating by 24 weeks in massive obesity, hepatosteatosis, insulin resistance, and diabetes. The Ovol2boh/boh genotype augmented obesity in Lepob/ob mice, and pair-feeding failed to normalize obesity in Ovol2boh/boh mice. OVOL2-deficient mice were extremely cold intolerant. OVOL2 is essential for brown/beige adipose tissue-mediated thermogenesis. In white adipose tissues, OVOL2 limited adipogenesis by blocking C/EBPα engagement of its transcriptional targets. Overexpression of OVOL2 in adipocytes of mice fed with a high-fat diet reduced total body and liver fat and improved insulin sensitivity. Our data reveal that OVOL2 plays dual functions in thermogenesis and adipogenesis to maintain energy balance.
    Keywords:  C/EBPα; OVOL2; UCP1; adipogenesis; brown adipose tissue; cold intolerance; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.09.018
  43. J Biol Chem. 2022 Oct 08. pii: S0021-9258(22)01022-5. [Epub ahead of print] 102578
    Transcription suppression is mediated by the HDAC1-Sin3 complex in Xenopus nucleoplasmic extract.
    Colleen E Quaas, Baicheng Lin, David T Long.
      Modification of histones provides a dynamic mechanism to regulate chromatin structure and access to DNA. Histone acetylation, in particular, plays a prominent role in controlling the interaction between DNA, histones, and other chromatin-associated proteins. Defects in histone acetylation patterns interfere with normal gene expression and underlie a wide range of human diseases. Here, we utilize Xenopus egg extracts to investigate how changes in histone acetylation influence transcription of a defined gene construct. We show that inhibition of histone deacetylase 1 and 2 (HDAC1/2) specifically counteracts transcription suppression by preventing chromatin compaction and deacetylation of histone residues H4K5 and H4K8. Acetylation of these sites supports binding of the chromatin reader and transcription regulator BRD4. We also identify HDAC1 as the primary driver of transcription suppression and show that this activity is mediated through the Sin3 histone deacetylase complex. These findings highlight functional differences between HDAC1 and HDAC2, which are often considered to be functionally redundant, and provide additional molecular context for their activity.
    Keywords:  bromodomain-containing protein-4 (BRD4); chromatin regulation; histone acetylation; histone deacetylase 1 (HDAC1); transcription regulation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102578
  44. Nat Commun. 2022 Oct 13. 13(1): 6032
    Caldesmon controls stress fiber force-balance through dynamic cross-linking of myosin II and actin-tropomyosin filaments.
    Shrikant B Kokate, Katarzyna Ciuba, Vivien D Tran, Reena Kumari, Sari Tojkander, Ulrike Engel, Konstantin Kogan, Sanjay Kumar, Pekka Lappalainen.
      Contractile actomyosin bundles are key force-producing and mechanosensing elements in muscle and non-muscle tissues. Whereas the organization of muscle myofibrils and mechanism regulating their contractility are relatively well-established, the principles by which myosin-II activity and force-balance are regulated in non-muscle cells have remained elusive. We show that Caldesmon, an important component of smooth muscle and non-muscle cell actomyosin bundles, is an elongated protein that functions as a dynamic cross-linker between myosin-II and tropomyosin-actin filaments. Depletion of Caldesmon results in aberrant lateral movement of myosin-II filaments along actin bundles, leading to irregular myosin distribution within stress fibers. This manifests as defects in stress fiber network organization and contractility, and accompanied problems in cell morphogenesis, migration, invasion, and mechanosensing. These results identify Caldesmon as critical factor that ensures regular myosin-II spacing within non-muscle cell actomyosin bundles, and reveal how stress fiber networks are controlled through dynamic cross-linking of tropomyosin-actin and myosin filaments.
    DOI:  https://doi.org/10.1038/s41467-022-33688-w
  45. Nat Commun. 2022 Oct 13. 13(1): 6043
    TGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine.
    Guo Li, Saranya Srinivasan, Liwen Wang, Chaoyu Ma, Kai Guo, Wenhao Xiao, Wei Liao, Shruti Mishra, Xin Zhang, Yuanzheng Qiu, Qianjin Lu, Yong Liu, Nu Zhang.
      TGF-β signaling is necessary for CD8+ T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+ TRM cells in the tumor microenvironment is associated with better prognosis, TGF-β-blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8+ T cells differentiate into TRMs in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8+ T cells are maintained in a stem-like state, but a proportion of cells lost TRM status and differentiate into CX3CR1+ effector CD8+ T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8+ T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent TRM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.
    DOI:  https://doi.org/10.1038/s41467-022-33768-x
  46. Nat Commun. 2022 Oct 13. 13(1): 6063
    Quorum-sensing control of matrix protein production drives fractal wrinkling and interfacial localization of Vibrio cholerae pellicles.
    Boyang Qin, Bonnie L Bassler.
      Bacterial cells at fluid interfaces can self-assemble into collective communities with stunning macroscopic morphologies. Within these soft, living materials, called pellicles, constituent cells gain group-level survival advantages including increased antibiotic resistance. However, the regulatory and structural components that drive pellicle self-patterning are not well defined. Here, using Vibrio cholerae as our model system, we report that two sets of matrix proteins and a key quorum-sensing regulator jointly orchestrate the sequential mechanical instabilities underlying pellicle morphogenesis, culminating in fractal patterning. A pair of matrix proteins, RbmC and Bap1, maintain pellicle localization at the interface and prevent self-peeling. A single matrix protein, RbmA, drives a morphogenesis program marked by a cascade of ever finer wrinkles with fractal scaling in wavelength. Artificial expression of rbmA restores fractal wrinkling to a ΔrbmA mutant and enables precise tuning of fractal dimensions. The quorum-sensing regulatory small RNAs Qrr1-4 first activate matrix synthesis to launch pellicle primary wrinkling and ridge instabilities. Subsequently, via a distinct mechanism, Qrr1-4 suppress fractal wrinkling to promote fine modulation of pellicle morphology. Our results connect cell-cell signaling and architectural components to morphogenic patterning and suggest that manipulation of quorum-sensing regulators or synthetic control of rbmA expression could underpin strategies to engineer soft biomaterial morphologies on demand.
    DOI:  https://doi.org/10.1038/s41467-022-33816-6
  47. Nat Rev Immunol. 2022 Oct 10.
    How do smallpox-specific memory B cells survive?
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-022-00794-1
  48. Sci Immunol. 2022 Oct 21. 7(76): eabo3420
    Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity.
    Simone A Minnie, Olivia G Waltner, Kathleen S Ensbey, Nicole S Nemychenkov, Christine R Schmidt, Shruti S Bhise, Samuel R W Legg, Gabriela Campoy, Luke D Samson, Rachel D Kuns, Ting Zhou, John D Huck, Slavica Vuckovic, Danniel Zamora, Albert Yeh, Andrew Spencer, Motoko Koyama, Kate A Markey, Steven W Lane, Michael Boeckh, Aaron M Ring, Scott N Furlan, Geoffrey R Hill.
      Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects. We found that CD8+ T cell exhaustion in bone marrow was primarily alloantigen-driven, with expression of inhibitory ligands present on myeloma but not AML. Because of this tumor-independent exhaustion signature, immune checkpoint inhibition (ICI) in myeloma exacerbated graft-versus-host disease (GVHD) without promoting GVT effects. Administration of post-transplant cyclophosphamide (PT-Cy) depleted donor T cells with an exhausted phenotype and spared T cells displaying a stem-like memory phenotype with chromatin accessibility present in cytokine signaling genes, including the interleukin-18 (IL-18) receptor. Whereas ICI with anti-PD-1 or anti-TIM-3 remained ineffective after PT-Cy, administration of a decoy-resistant IL-18 (DR-18) strongly enhanced GVT effects in both myeloma and leukemia models, without exacerbation of GVHD. We thus defined mechanisms of resistance to T cell-mediated antitumor effects after alloBMT and described an immunotherapy approach targeting stem-like memory T cells to enhance antitumor immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.abo3420
  49. Commun Biol. 2022 Oct 12. 5(1): 1088
    The purine metabolite inosine monophosphate accelerates myelopoiesis and acute pancreatitis progression.
    Xiao-Min Luo, Sin Man Lam, Yuan Dong, Xiao-Juan Ma, Cen Yan, Yue-Jie Zhang, Yu Cao, Li Su, Guotao Lu, Jin-Kui Yang, Guanghou Shui, Ying-Mei Feng.
      Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1+ granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.
    DOI:  https://doi.org/10.1038/s42003-022-04041-0
  50. J Immunol. 2022 Oct 12. pii: ji2200363. [Epub ahead of print]
    A Multi-Omics Approach Reveals Features That Permit Robust and Widespread Regulation of IFN-Inducible Antiviral Effectors.
    Loránd Göczi, Mária Csumita, Attila Horváth, Gergely Nagy, Szilárd Póliska, Matteo Pigni, Christoph Thelemann, Bence Dániel, Hamidreza Mianesaz, Tamás Varga, Kaushik Sen, Sunil K Raghav, John W Schoggins, Laszlo Nagy, Hans Acha-Orbea, Felix Meissner, Walter Reith, Lajos Széles.
      The antiviral state, an initial line of defense against viral infection, is established by a set of IFN-stimulated genes (ISGs) encoding antiviral effector proteins. The effector ISGs are transcriptionally regulated by type I IFNs mainly via activation of IFN-stimulated gene factor 3 (ISGF3). In this study, the regulatory elements of effector ISGs were characterized to determine the (epi)genetic features that enable their robust induction by type I IFNs in multiple cell types. We determined the location of regulatory elements, the DNA motifs, the occupancy of ISGF3 subunits (IRF9, STAT1, and STAT2) and other transcription factors, and the chromatin accessibility of 37 effector ISGs in murine dendritic cells. The IFN-stimulated response element (ISRE) and its tripartite version occurred most frequently in the regulatory elements of effector ISGs than in any other tested ISG subsets. Chromatin accessibility at their promoter regions was similar to most other ISGs but higher than at the promoters of inflammation-related cytokines, which were used as a reference gene set. Most effector ISGs (81.1%) had at least one ISGF3 binding region proximal to the transcription start site (TSS), and only a subset of effector ISGs (24.3%) was associated with three or more ISGF3 binding regions. The IRF9 signals were typically higher, and ISRE motifs were "stronger" (more similar to the canonical sequence) in TSS-proximal versus TSS-distal regulatory regions. Moreover, most TSS-proximal regulatory regions were accessible before stimulation in multiple cell types. Our results indicate that "strong" ISRE motifs and universally accessible promoter regions that permit robust, widespread induction are characteristic features of effector ISGs.
    DOI:  https://doi.org/10.4049/jimmunol.2200363
  51. FEBS Lett. 2022 Oct 11.
    Rapid fractionation of mitochondria from mouse liver and heart reveals in vivo metabolite compartmentation.
    Fay M Allen, Ana S H Costa, Anja V Gruszczyk, Georgina R Bates, Hiran A Prag, Efterpi Nikitopoulou, Carlo Viscomi, Christian Frezza, Andrew M James, Michael P Murphy.
      The compartmentation and distribution of metabolites between mitochondria and the rest of the cell is a key parameter of cell signalling and pathology. Here, we have developed a rapid fractionation procedure that enables us to take mouse heart and liver from in vivo and within ~ 30 seconds stabilise the distribution of metabolites between mitochondria and the cytosol by rapid cooling, homogenisation and dilution. This is followed by centrifugation of mitochondria through an oil layer to separate mitochondrial and cytosolic fractions for subsequent metabolic analysis. Using this procedure revealed the in vivo compartmentation of mitochondrial metabolites and will enable assessment of the distribution of metabolites between the cytosol and mitochondria during a range of situations in vivo.
    Keywords:  compartmentation; in vivo; ischemia; metabolites; mitochondria; rapid fractionation
    DOI:  https://doi.org/10.1002/1873-3468.14511
  52. EMBO J. 2022 Oct 10. e112012
    CBP/p300 and HDAC activities regulate H3K27 acetylation dynamics and zygotic genome activation in mouse preimplantation embryos.
    Meng Wang, Zhiyuan Chen, Yi Zhang.
      Epigenome reprogramming after fertilization enables transcriptionally quiescent maternal and paternal chromatin to acquire a permissive state for subsequent zygotic genome activation (ZGA). H3K27 acetylation (H3K27ac) is a well-established chromatin marker of active enhancers and promoters. However, reprogramming dynamics of H3K27ac during maternal-to-zygotic transition (MZT) in mammalian embryos are not well-studied. By profiling the allelic landscape of H3K27ac during mouse MZT, we show that H3K27ac undergoes three waves of rapid global transitions between oocyte stage and 2-cell stage. Notably, germinal vesicle oocyte and zygote chromatin are globally hyperacetylated, with noncanonical, broad H3K27ac domains that correlate with broad H3K4 trimethylation (H3K4me3) and open chromatin. H3K27ac marks genomic regions primed for activation including ZGA genes, retrotransposons, and active alleles of imprinted genes. We show that CBP/p300 and HDAC activities play important roles in regulating H3K27ac dynamics and are essential for preimplantation development. Specifically, CBP/p300 acetyltransferase broadly deposits H3K27ac in zygotes to induce the opening of condensed chromatin at putative enhancers and ensure proper ZGA. On the contrary, HDACs revert broad H3K27ac domains to canonical domains and safeguard ZGA by preventing premature expression of developmental genes. In conclusion, coordinated activities of CBP/p300 and HDACs during mouse MZT are essential for ZGA and preimplantation development.
    Keywords:  CBP/p300; H3K27ac; HDACs; MZT; ZGA
    DOI:  https://doi.org/10.15252/embj.2022112012
  53. Nature. 2022 Oct 12.
    Neurons that control walking go round in circles.
    Martha W Bagnall.
      
    Keywords:  Neuroscience; Systems biology
    DOI:  https://doi.org/10.1038/d41586-022-02238-1
  54. Commun Biol. 2022 Oct 12. 5(1): 1084
    Decoding the transcriptome of calcified atherosclerotic plaque at single-cell resolution.
    Tom Alsaigh, Doug Evans, David Frankel, Ali Torkamani.
      Atherogenesis involves an interplay of inflammation, tissue remodeling and cellular transdifferentiation (CTD), making it especially difficult to precisely delineate its pathophysiology. Here we use single-cell RNA sequencing and systems-biology approaches to analyze the transcriptional profiles of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) in calcified atherosclerotic core (AC) plaques and patient-matched proximal adjacent (PA) portions of carotid artery tissue from patients undergoing carotid endarterectomy. Our results reveal an anatomic distinction whereby PA cells express inflammatory mediators, while cells expressing matrix-secreting genes occupy a majority of the AC region. Systems biology analysis indicates that inflammation in PA ECs and VSMCs may be driven by TNFa signaling. Furthermore, we identify POSTN, SPP1 and IBSP in AC VSMCs, and ITLN1, SCX and S100A4 in AC ECs as possible candidate drivers of CTD in the atherosclerotic core. These results establish an anatomic framework for atherogenesis which forms the basis for exploration of a site-specific strategy for disruption of disease progression.
    DOI:  https://doi.org/10.1038/s42003-022-04056-7
  55. JAMA Health Forum. 2021 Mar 01. 2(3): e210273
    Our Other Epidemic: Addiction.
    Richard G Frank, Keith Humphreys, Harold Pollack.
      
    DOI:  https://doi.org/10.1001/jamahealthforum.2021.0273
  56. FEBS J. 2022 Oct 11.
    Senescent cells in the brain and where to find them.
    Noa Rachmian, Valery Krizhanovsky.
      Cellular senescence is a process in which cells change their characteristic phenotype in response to stress and enter a state of prolonged cell cycle arrest accompanied by a distinct secretory phenotype. Cellular senescence has both beneficial and detrimental outcomes. With age, senescent cells progressively accumulate in tissues and might be the bridge connecting ageing to many age-related pathologies. In recent years, evidence emerged supporting the accumulation of brain senescent cells during neurological disorders and ageing. Here, we will discuss the different brain cell populations that exhibit a senescent phenotype. Subsequently, we will explore several senolytic strategies which have been developed to eliminate senescent cells. Finally, we will examine their potential to directly eliminate these senescent brain cells.
    Keywords:  Ageing; Blood-brain barrier; Cellular Senescence; Neurodegeneration; Senolytics
    DOI:  https://doi.org/10.1111/febs.16649
  57. Nat Commun. 2022 Oct 10. 13(1): 5962
    Elucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning.
    Chunman Zuo, Yijian Zhang, Chen Cao, Jinwang Feng, Mingqi Jiao, Luonan Chen.
      Spatially resolved transcriptomics (SRT) technology enables us to gain novel insights into tissue architecture and cell development, especially in tumors. However, lacking computational exploitation of biological contexts and multi-view features severely hinders the elucidation of tissue heterogeneity. Here, we propose stMVC, a multi-view graph collaborative-learning model that integrates histology, gene expression, spatial location, and biological contexts in analyzing SRT data by attention. Specifically, stMVC adopting semi-supervised graph attention autoencoder separately learns view-specific representations of histological-similarity-graph or spatial-location-graph, and then simultaneously integrates two-view graphs for robust representations through attention under semi-supervision of biological contexts. stMVC outperforms other tools in detecting tissue structure, inferring trajectory relationships, and denoising on benchmark slices of human cortex. Particularly, stMVC identifies disease-related cell-states and their transition cell-states in breast cancer study, which are further validated by the functional and survival analysis of independent clinical data. Those results demonstrate clinical and prognostic applications from SRT data.
    DOI:  https://doi.org/10.1038/s41467-022-33619-9
  58. Front Immunol. 2022 ;13 992723
    CD56-negative NK cells: Frequency in peripheral blood, expansion during HIV-1 infection, functional capacity, and KIR expression.
    Alexander T H Cocker, Fuguo Liu, Zakia Djaoud, Lisbeth A Guethlein, Peter Parham.
      Human NK cells are usually defined as CD3-CD56+ lymphocytes. However, a CD56-CD16+ (CD56neg) lymphocyte population that displays NK-associated markers expands during chronic viral infections such as HIV-1 and HCV, and, to lesser extent, in herpesvirus infections. This CD56neg NK cell subset has been understudied because it requires the exclusion of other lymphocytes to accurately identify its presence. Many questions remain regarding the origin, development, phenotype, and function of the CD56neg NK cell population. Our objective was to determine the frequency of this NK subset in healthy controls and its alteration in viral infections by performing a meta-analysis. In addition to this, we analyzed deposited CyTOF and scRNAseq datasets to define the phenotype and subsets of the CD56neg NK cell population, as well as their functional variation. We found in 757 individuals, from a combined 28 studies and 6 datasets, that the CD56neg subset constitutes 5.67% of NK cells in healthy peripheral blood, while HIV-1 infection increases this population by a mean difference of 10.69%. Meta-analysis of surface marker expression between NK subsets showed no evidence of increased exhaustion or decreased proliferation within the CD56neg subset. CD56neg NK cells have a distinctive pattern of KIR expression, implying they have a unique potential for KIR-mediated education. A perforin-CD94-NKG2C-NKp30- CD56neg population exhibited different gene expression and degranulation responses against K562 cells compared to other CD56neg cells. This analysis distinguishes two functionally distinct subsets of CD56neg NK cells. They are phenotypically diverse and have differing capacity for education by HLA class-I interactions with KIRs.
    Keywords:  CD56neg; NK cells; chronic infection; innate immunity; meta-analysis
    DOI:  https://doi.org/10.3389/fimmu.2022.992723
  59. Sci Adv. 2022 Oct 14. 8(41): eadd1830
    Actuating tension-loaded DNA clamps drives membrane tubulation.
    Longfei Liu, Qiancheng Xiong, Chun Xie, Frederic Pincet, Chenxiang Lin.
      Membrane dynamics in living organisms can arise from proteins adhering to, assembling on, and exerting force on cell membranes. Programmable synthetic materials, such as self-assembled DNA nanostructures, offer the capability to drive membrane-remodeling events that resemble protein-mediated dynamics but with user-defined outcomes. An illustrative example is the tubular deformation of liposomes by DNA nanostructures with purposely designed shapes, surface modifications, and self-assembling properties. However, stimulus-responsive membrane tubulation mediated by DNA reconfiguration remains challenging. Here, we present the triggered formation of membrane tubes in response to specific DNA signals that actuate membrane-bound DNA clamps from an open state to various predefined closed states, releasing prestored energy to activate membrane deformation. We show that the timing and efficiency of vesicle tubulation, as well as the membrane tube widths, are modulated by the conformational change of DNA clamps, marking a solid step toward spatiotemporal control of membrane dynamics in an artificial system.
    DOI:  https://doi.org/10.1126/sciadv.add1830
  60. Genome Biol. 2022 Oct 12. 23(1): 211
    Enhanced mitochondrial DNA editing in mice using nuclear-exported TALE-linked deaminases and nucleases.
    Seonghyun Lee, Hyunji Lee, Gayoung Baek, Eunji Namgung, Joo Min Park, Sanghun Kim, Seongho Hong, Jin-Soo Kim.
      We present two methods for enhancing the efficiency of mitochondrial DNA (mtDNA) editing in mice with DddA-derived cytosine base editors (DdCBEs). First, we fused DdCBEs to a nuclear export signal (DdCBE-NES) to avoid off-target C-to-T conversions in the nuclear genome and improve editing efficiency in mtDNA. Second, mtDNA-targeted TALENs (mitoTALENs) are co-injected into mouse embryos to cleave unedited mtDNA. We generated a mouse model with the m.G12918A mutation in the MT-ND5 gene, associated with mitochondrial genetic disorders in humans. The mutant mice show hunched appearances, damaged mitochondria in kidney and brown adipose tissues, and hippocampal atrophy, resulting in premature death.
    Keywords:  DdCBE; Mitochondrial DNA editing; NES; mitoTALEN; mtDNA
    DOI:  https://doi.org/10.1186/s13059-022-02782-z
  61. J Biol Chem. 2022 Oct 06. pii: S0021-9258(22)00973-5. [Epub ahead of print] 102530
    The Role of FXR and TGR5 in Reversing and Preventing Progression of Western Diet-induced Hepatic Steatosis, Inflammation, and Fibrosis in Mice.
    Xiaoxin X Wang, Cen Xie, Andrew E Libby, Suman Ranjit, Jonathan Levi, Komuraiah Myakala, Kanchan Bhasin, Bryce A Jones, David J Orlicky, Shogo Takahashi, Alexander Dvornikov, David E Kleiner, Stephen M Hewitt, Luciano Adorini, Jeffrey B Kopp, Kristopher W Krausz, Avi Rosenberg, James L McManaman, Charles E Robertson, Diana Ir, Daniel N Frank, Yuhuan Luo, Frank J Gonzalez, Enrico Gratton, Moshe Levi.
      Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease in the US, partly due to the increasing incidence of metabolic syndrome, obesity, and type 2 diabetes. The roles of bile acids and their receptors such as the nuclear receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, on the development of NASH are not fully clear. C57BL/6J male mice fed a Western diet (WD) develop characteristics of NASH, allowing determination of the effects of FXR and TGR5 agonists on this disease. Here we show that the FXR-TGR5 dual agonist INT-767 prevents progression of WD-induced hepatic steatosis, inflammation, and fibrosis, as determined by histological and biochemical assays and novel label-free microscopy imaging techniques, including Third Harmonic Generation, Second Harmonic Generation, and Fluorescence Lifetime Imaging Microscopy. Furthermore, we show INT-767 decreases liver fatty acid synthesis and fatty acid and cholesterol uptake, as well as liver inflammation. INT-767 markedly changed bile acid composition in the liver and intestine, leading to notable decreases in the hydrophobicity index of bile acids, known to limit cholesterol and lipid absorption. In addition, INT-767 upregulated expression of liver p-AMPK, SIRT1, PGC-1α, and SIRT3, which are master regulators of mitochondrial function. Finally, we found INT-767 treatment reduced WD-induced dysbiosis of gut microbiota. Interestingly, the effects of INT-767 in attenuating NASH were absent in FXR-null mice, but still present in TGR5-null mice. Our findings support treatment and prevention protocols with the dual FXR-TGR5 agonist INT-767 arrest progression of WD-induced NASH in mice mediated by FXR-dependent, TGR5-independent mechanisms.
    Keywords:  Bile acid; FXR-TGR5; Fibrosis; Inflammation; Lipid Metabolism; NASH
    DOI:  https://doi.org/10.1016/j.jbc.2022.102530
  62. Nat Commun. 2022 Oct 10. 13(1): 5971
    ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress.
    Christopher P Wardlaw, John H J Petrini.
      The pathways involved in suppressing DNA replication stress and the associated DNA damage are critical to maintaining genome integrity. The Mre11 complex is unique among double strand break (DSB) repair proteins for its association with the DNA replication fork. Here we show that Mre11 complex inactivation causes DNA replication stress and changes in the abundance of proteins associated with nascent DNA. One of the most highly enriched proteins at the DNA replication fork upon Mre11 complex inactivation was the ubiquitin like protein ISG15. Mre11 complex deficiency and drug induced replication stress both led to the accumulation of cytoplasmic DNA and the subsequent activation of innate immune signaling via cGAS-STING-Tbk1. This led to ISG15 induction and protein ISGylation, including constituents of the replication fork. ISG15 plays a direct role in preventing replication stress. Deletion of ISG15 was associated with replication fork stalling, tonic ATR activation, genomic aberrations, and sensitivity to aphidicolin. These data reveal a previously unrecognized role for ISG15 in mitigating DNA replication stress and promoting genomic stability.
    DOI:  https://doi.org/10.1038/s41467-022-33535-y
  63. Proc Natl Acad Sci U S A. 2022 Oct 18. 119(42): e2211572119
    Synaptic memory survives molecular turnover.
    Joel Lee, Xiumin Chen, Roger A Nicoll.
      Activation of Ca2+/calmodulin-dependent kinase II (CaMKII) plays a critical role in long-term potentiation (LTP), a long accepted cellular model for learning and memory. However, how LTP and memories survive the turnover of synaptic proteins, particularly CaMKII, remains a mystery. Here, we take advantage of the finding that constitutive Ca2+-independent CaMKII activity, acquired prior to slice preparation, provides a lasting memory trace at synapses. In slice culture, this persistent CaMKII activity, in the absence of Ca2+ stimulation, remains stable over a 2-wk period, well beyond the turnover of CaMKII protein. We propose that the nascent CaMKII protein present at 2 wk acquired its activity from preexisting active CaMKII molecules, which transferred their activity to newly synthesized CaMKII molecules and thus maintain the memory in the face of protein turnover.
    Keywords:  CaMKII; memory; synapse
    DOI:  https://doi.org/10.1073/pnas.2211572119
  64. Nat Commun. 2022 Oct 10. 13(1): 5963
    Direct observation of ultrafast singlet exciton fission in three dimensions.
    Arjun Ashoka, Nicolas Gauriot, Aswathy V Girija, Nipun Sawhney, Alexander J Sneyd, Kenji Watanabe, Takashi Taniguchi, Jooyoung Sung, Christoph Schnedermann, Akshay Rao.
      We present quantitative ultrafast interferometric pump-probe microscopy capable of tracking of photoexcitations with sub-10 nm spatial precision in three dimensions with 15 fs temporal resolution, through retrieval of the full transient photoinduced complex refractive index. We use this methodology to study the spatiotemporal dynamics of the quantum coherent photophysical process of ultrafast singlet exciton fission. Measurements on microcrystalline pentacene films grown on glass (SiO2) and boron nitride (hBN) reveal a 25 nm, 70 fs expansion of the joint-density-of-states along the crystal a,c-axes accompanied by a 6 nm, 115 fs change in the exciton density along the crystal b-axis. We propose that photogenerated singlet excitons expand along the direction of maximal orbital π-overlap in the crystal a,c-plane to form correlated triplet pairs, which subsequently electronically decouples into free triplets along the crystal b-axis due to molecular sliding motion of neighbouring pentacene molecules. Our methodology lays the foundation for the study of three dimensional transport on ultrafast timescales.
    DOI:  https://doi.org/10.1038/s41467-022-33647-5
  65. Cell. 2022 Oct 10. pii: S0092-8674(22)01250-8. [Epub ahead of print]
    En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.
    Masaki Kimura, Takuma Iguchi, Kentaro Iwasawa, Andrew Dunn, Wendy L Thompson, Yosuke Yoneyama, Praneet Chaturvedi, Aaron M Zorn, Michelle Wintzinger, Mattia Quattrocelli, Miki Watanabe-Chailland, Gaohui Zhu, Masanobu Fujimoto, Meenasri Kumbaji, Asuka Kodaka, Yevgeniy Gindin, Chuhan Chung, Robert P Myers, G Mani Subramanian, Vivian Hwa, Takanori Takebe.
      Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.
    Keywords:  GCKR-rs1260326; NASH; de novo lipogenesis; genotype-phenotype association; human liver organoid; iPSC; mitochondrial dysfunction; population organoid panel
    DOI:  https://doi.org/10.1016/j.cell.2022.09.031
  66. Nat Commun. 2022 Oct 10. 13(1): 5974
    Visualizing inflammation with an M1 macrophage selective probe via GLUT1 as the gating target.
    Heewon Cho, Haw-Young Kwon, Amit Sharma, Sun Hyeok Lee, Xiao Liu, Naoki Miyamoto, Jong-Jin Kim, Sin-Hyeog Im, Nam-Young Kang, Young-Tae Chang.
      Macrophages play crucial roles in protecting our bodies from infection and cancers. As macrophages are multi-functional immune cells, they have diverse plastic subsets, such as M1 and M2, derived from naïve M0 cells. Subset-specific macrophage probes are essential for deciphering and monitoring the various activation of macrophages, but developing such probes has been challenging. Here we report a fluorescent probe, CDr17, which is selective for M1 macrophages over M2 or M0. The selective staining mechanism of CDr17 is explicated as Gating-Oriented Live-cell Distinction (GOLD) through overexpressed GLUT1 in M1 macrophages. Finally, we demonstrate the suitability of CDr17 to track M1 macrophages in vivo in a rheumatoid arthritis animal model.
    DOI:  https://doi.org/10.1038/s41467-022-33526-z
  67. Nat Commun. 2022 Oct 13. 13(1): 6036
    Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease.
    Hong Yuen Wong, Quanhu Sheng, Amanda B Hesterberg, Sarah Croessmann, Brenda L Rios, Khem Giri, Jorgen Jackson, Adam X Miranda, Evan Watkins, Kerry R Schaffer, Meredith Donahue, Elizabeth Winkler, David F Penson, Joseph A Smith, S Duke Herrell, Amy N Luckenbaugh, Daniel A Barocas, Young J Kim, Diana Graves, Giovanna A Giannico, Jeffrey C Rathmell, Ben H Park, Jennifer B Gordetsky, Paula J Hurley.
      Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal carcinoma (IDC), is an aggressive histological subtype that is associated with progression to lethal disease. To delineate the molecular and cellular underpinnings of ICC/IDC aggressiveness, this study examines paired ICC/IDC and benign prostate surgical samples by single-cell RNA-sequencing, TCR sequencing, and histology. ICC/IDC cancer cells express genes associated with metastasis and targets with potential for therapeutic intervention. Pathway analyses and ligand/receptor status model cellular interactions among ICC/IDC and the tumor microenvironment (TME) including JAG1/NOTCH. The ICC/IDC TME is hallmarked by increased angiogenesis and immunosuppressive fibroblasts (CTHRC1+ASPN+FAP+ENG+) along with fewer T cells, elevated T cell dysfunction, and increased C1QB+TREM2+APOE+-M2 macrophages. These findings support that cancer cell intrinsic pathways and a complex immunosuppressive TME contribute to the aggressive phenotype of ICC/IDC. These data highlight potential therapeutic opportunities to restore immune signaling in patients with ICC/IDC that may afford better outcomes.
    DOI:  https://doi.org/10.1038/s41467-022-33780-1
  68. Sci Adv. 2022 Oct 14. 8(41): eabn8367
    Upper cortical layer-driven network impairment in schizophrenia.
    Mykhailo Y Batiuk, Teadora Tyler, Katarina Dragicevic, Shenglin Mei, Rasmus Rydbirk, Viktor Petukhov, Ruslan Deviatiiarov, Dora Sedmak, Erzsebet Frank, Virginia Feher, Nikola Habek, Qiwen Hu, Anna Igolkina, Lilla Roszik, Ulrich Pfisterer, Diego Garcia-Gonzalez, Zdravko Petanjek, Istvan Adorjan, Peter V Kharchenko, Konstantin Khodosevich.
      Schizophrenia is one of the most widespread and complex mental disorders. To characterize the impact of schizophrenia, we performed single-nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. In addition, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most marked in upper-layer GABAergic neurons, including down-regulation in energy metabolism and up-regulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Last, Visium spatial transcriptomics further corroborated upper-layer neuron vulnerability in schizophrenia. Overall, our results point toward general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology.
    DOI:  https://doi.org/10.1126/sciadv.abn8367
  69. Nat Commun. 2022 Oct 12. 13(1): 6028
    Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search.
    Patrick Bryant, Gabriele Pozzati, Wensi Zhu, Aditi Shenoy, Petras Kundrotas, Arne Elofsson.
      AlphaFold can predict the structure of single- and multiple-chain proteins with very high accuracy. However, the accuracy decreases with the number of chains, and the available GPU memory limits the size of protein complexes which can be predicted. Here we show that one can predict the structure of large complexes starting from predictions of subcomponents. We assemble 91 out of 175 complexes with 10-30 chains from predicted subcomponents using Monte Carlo tree search, with a median TM-score of 0.51. There are 30 highly accurate complexes (TM-score ≥0.8, 33% of complete assemblies). We create a scoring function, mpDockQ, that can distinguish if assemblies are complete and predict their accuracy. We find that complexes containing symmetry are accurately assembled, while asymmetrical complexes remain challenging. The method is freely available and accesible as a Colab notebook https://colab.research.google.com/github/patrickbryant1/MoLPC/blob/master/MoLPC.ipynb .
    DOI:  https://doi.org/10.1038/s41467-022-33729-4
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