Nature Communications

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ISSN / EISSN : 2041-1723 / 2041-1723
Current Publisher: Springer Science and Business Media LLC (10.1038)
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, Hiroki Machida, Asako Nakagawa, Kyungmin Ahn, , Kiyotoshi Sekiguchi, ,
Nature Communications, Volume 12, pp 1-18; doi:10.1038/s41467-021-22881-y

Abstract:
Inter-tissue interaction is fundamental to multicellularity. Although the basement membrane (BM) is located at tissue interfaces, its mode of action in inter-tissue interactions remains poorly understood, mainly because the molecular and structural details of the BM at distinct inter-tissue interfaces remain unclear. By combining quantitative transcriptomics and immunohistochemistry, we systematically identify the cellular origin, molecular identity and tissue distribution of extracellular matrix molecules in mouse hair follicles, and reveal that BM composition and architecture are exquisitely specialized for distinct inter-tissue interactions, including epithelial–fibroblast, epithelial–muscle and epithelial–nerve interactions. The epithelial–fibroblast interface, namely, hair germ–dermal papilla interface, makes asymmetrically organized side-specific heterogeneity in the BM, defined by the newly characterized interface, hook and mesh BMs. One component of these BMs, laminin α5, is required for hair cycle regulation and hair germ–dermal papilla anchoring. Our study highlights the significance of BM heterogeneity in distinct inter-tissue interactions.
, Lifelines Cohort Study, , Joshua Elliott, , , , Peter J. van der Most, Rui Climaco Pinto, Matthias Wielscher, et al.
Nature Communications, Volume 12, pp 1-12; doi:10.1038/s41467-021-22338-2

Abstract:
Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
Yingtong Zong, Si-Min Xu, Wenying Shi,
Nature Communications, Volume 12, pp 1-10; doi:10.1038/s41467-021-22827-4

Abstract:
The living supramolecular polymerization technique provides an exciting research avenue. However, in comparison with the thermodynamic spontaneous nucleation, using simple monomers to realize living supramolecular polymerization is hardly possible from an energy principle. This is because the activation barrier of kinetically trapped simple monomer (nucleation step) is insufficiently high to control the kinetics of subsequent elongation. Here, with the benefit of the confinement from the layered double hydroxide (LDH) nanomaterial, various simple monomers, (such as benzene, naphthalene and pyrene derivatives) successfully form living supramolecular polymer (LSP) with length control and narrow dispersity. The degree of polymerization can reach ~6000. Kinetics studies reveal LDH overcomes a huge energy barrier to inhibit undesired spontaneous nucleation of monomers and disassembly of metastable states. The universality of this strategy will usher exploration into other multifunctional molecules and promote the development of functional LSP.
Michael Tyler,
Nature Communications, Volume 12, pp 1-13; doi:10.1038/s41467-021-22800-1

Abstract:
Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.
, Sheng-Pei Wang, Yung-Chih Lai, Ben Van Handel, , Stephanie Tsai, , Arijita Sarkar, Haibin Xi, Michael Hughes, et al.
Nature Communications, Volume 12, pp 1-16; doi:10.1038/s41467-021-22822-9

Abstract:
Tissue regeneration is a process that recapitulates and restores organ structure and function. Although previous studies have demonstrated wound-induced hair neogenesis (WIHN) in laboratory mice (Mus), the regeneration is limited to the center of the wound unlike those observed in African spiny (Acomys) mice. Tissue mechanics have been implicated as an integral part of tissue morphogenesis. Here, we use the WIHN model to investigate the mechanical and molecular responses of laboratory and African spiny mice, and report these models demonstrate opposing trends in spatiotemporal morphogenetic field formation with association to wound stiffness landscapes. Transcriptome analysis and K14-Cre-Twist1 transgenic mice show the Twist1 pathway acts as a mediator for both epidermal-dermal interactions and a competence factor for periodic patterning, differing from those used in development. We propose a Turing model based on tissue stiffness that supports a two-scale tissue mechanics process: (1) establishing a morphogenetic field within the wound bed (mm scale) and (2) symmetry breaking of the epidermis and forming periodically arranged hair primordia within the morphogenetic field (μm scale). Thus, we delineate distinct chemo-mechanical events in building a Turing morphogenesis-competent field during WIHN of laboratory and African spiny mice and identify its evo-devo advantages with perspectives for regenerative medicine.
Efim A. Brener,
Nature Communications, Volume 12, pp 1-9; doi:10.1038/s41467-021-22806-9

Abstract:
A widespread framework for understanding frictional rupture, such as earthquakes along geological faults, invokes an analogy to ordinary cracks. A distinct feature of ordinary cracks is that their near edge fields are characterized by a square root singularity, which is intimately related to the existence of strict dissipation-related lengthscale separation and edge-localized energy balance. Yet, the interrelations between the singularity order, lengthscale separation and edge-localized energy balance in frictional rupture are not fully understood, even in physical situations in which the conventional square root singularity remains approximately valid. Here we develop a macroscopic theory that shows that the generic rate-dependent nature of friction leads to deviations from the conventional singularity, and that even if this deviation is small, significant non-edge-localized rupture-related dissipation emerges. The physical origin of the latter, which is predicted to vanish identically in the crack analogy, is the breakdown of scale separation that leads an accumulated spatially-extended dissipation, involving macroscopic scales. The non-edge-localized rupture-related dissipation is also predicted to be position dependent. The theoretical predictions are quantitatively supported by available numerical results, and their possible implications for earthquake physics are discussed.
, Susannah Holmes, Timothy W. Muusse, Parimala R. Vajjhala, Sara J. Thygesen, , Dominic J. B. Hunter, Tristan I. Croll, Leonie Flueckiger, , et al.
Nature Communications, Volume 12, pp 1-14; doi:10.1038/s41467-021-22590-6

Abstract:
MyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
Anastasia Gangaev, Steven L. C. Ketelaars, , Sanne Patiwael, Anna Dopler, Kelly Hoefakker, , , Cristina Mussini, , et al.
Nature Communications, Volume 12, pp 1-14; doi:10.1038/s41467-021-22811-y

Abstract:
The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.
Timothy S. Catlett, Massimo M. Onesto, Alec J. McCann, Sarah K. Rempel, Jennifer Glass, David N. Franz,
Nature Communications, Volume 12, pp 1-15; doi:10.1038/s41467-021-22770-4

Abstract:
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
Feng Wang, Kiyomi Morita, , Ken Furudate, Tomoyuki Tanaka, Yuanqing Yan, Keyur P. Patel, Kyle J. MacBeth, , Guowen Liu, et al.
Nature Communications, Volume 12, pp 1-13; doi:10.1038/s41467-021-22874-x

Abstract:
Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.
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