Biology subjects

Suzuki, R.

Publications and source records attributed to Suzuki, R..

43 records · Page 3Linked to original sources

bioRxiv2021

Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory amino acid differences and novel oncoprotein candidates

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori, which causes gastric cancer (GC). We conducted a GWAS followed by regression-based prediction of GC and duodenal ulcer H. pylori strains. We identified 14 single nucleotide polymorphisms (11 amino acid changes) that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into GC pathogenesis and a basis for identifying a set of biomarkers for application in clinical settings.

physiology↗

bioRxiv2020

Establishment of a reverse genetics system for SARS-CoV-2 using circular polymerase extension reaction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the causative agent of coronavirus disease 2019 (COVID-19). While the development of specific treatments and a vaccine is urgently needed, functional analyses of SARS-CoV-2 have been limited by the lack of convenient mutagenesis methods. In this study, we established a PCR-based, bacterium-free method to generate SARS-CoV-2 infectious clones. Recombinant SARS-CoV-2 could be rescued at high titer with high accuracy after assembling 10 SARS-CoV-2 cDNA fragments by circular polymerase extension reaction (CPER) and transfection of the resulting circular genome into susceptible cells. Notably, the construction of infectious clones for reporter viruses and mutant viruses could be completed in two simple steps: introduction of reporter genes or mutations into the desirable DNA fragments (~5,000 base pairs) by PCR and assembly of the DNA fragments by CPER. We hope that our reverse genetics system will contribute to the further understanding of SARS-CoV-2.

microbiology↗

bioRxiv2020

Deep Texture Representations as a Universal Encoder for Pan-cancer Histology

Cancer histological images contain rich biological and clinical information, but quantitative representation can be problematic and has prevented direct comparison and accumulation of large-scale datasets. Here we show that deep texture representations (DTRs) produced by a bilinear Convolutional Neural Network, express cancer morphology well in an unsupervised manner, and work as a universal encoder for cancer histology. DTRs are useful for content-based image retrieval, enabling quick retrieval of histologically similar images from optimally area selected datasets of 7,175 cases from The Cancer Genome Atlas. Via comprehensive comparison with driver and clinically actionable gene mutations, we have successfully predicted 309 combinations of genomic features and cancer types from hematoxylin and eosin-stained images at high accuracy (AUC > 0.70 and q < 0.02). With its mounting capabilities on accessible devices such as smartphones, DTR-based encoding for cancer histology has a potentially strong impact on global equalization for cancer diagnosis and targeted therapies.

cancer biology↗

bioRxiv2020

A high fat containing chicken egg-only diet suppresses fatty liver induced by a lipid-rich methionine and choline deficient diet.

Nonalcoholic fatty liver disease (NAFLD) is a simple hepatic steatosis, which may proceed to nonalcoholic steatohepatitis (NASH) in the presence of steatosis and inflammation with hepatocyte injury. Obesity induced by a high-fat diet or high monosaccharide diet is considered a risk factor for NAFLD. A popular mouse model of NAFLD is a high-fat diet consisting of 60% energy from fat. A modified methionine and choline deficient (MCD) diet containing 60% energy from fat (CDAHFD) is a quick induction model for NAFLD. Chicken eggs also contain 60% energy from fat with very low carbohydrate. Here we compared liver pathologies in mice fed either a CDAHFD or egg-only diet. We found that a CDAHFD induced NAFLD within only two weeks.Ballooning of hepatocytes with an of immune cell appearance in the liver and high serum ALT and AST indicated that the mice fed CDAHFD developed NAFLD, which could proceed to NASH. However, mice fed an egg-only diet did not develop NAFLD even after 7 weeks. These mice showed normal liver histology with normal ALT and AST. The mice fed an egg-only diet showed high blood ketone bodies and normal blood glucose. Furthermore we found that the mice fed a combination CDAHFD /egg diet or mice fed an egg-only diet after two weeks of CDAHFD diet showed almost normal ALT and AST with reduced levels of fat bodies in the liver. These results indicate that an egg-only diet strongly inhibits high fat and carbohydrates induced NAFLD.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2019

Structural basis for ligand-induced inactivation of protein tyrosine receptor type Z (PTPRZ): Physiological relevance of head-to-toe RPTP dimerization

Protein tyrosine phosphatase receptor type Z (PTPRZ) has two receptor isoforms (PTPRZ-A and -B) containing tandem PTP-D1 and -D2 domains intracellularly, with only D1 being active. Pleiotrophin (PTN) binding to the extracellular region of PTPRZ leads to the inactivation of PTPase, thereby inducing oligodendrocyte precursor cell (OPC) differentiation and myelination in the CNS. However, the mechanisms responsible for the ligand-induced inactivation of PTPRZ remain unclear. We herein revealed that the crystal structure of the intracellular region of PTPRZ (PTPRZ-ICR) showed the \"head-to-toe\"-type dimer conformation, with D2 masking the catalytic site of D1. Mass spectrometry (MS) revealed that PTPRZ-ICR proteins remained in monomer-dimer equilibrium in aqueous solution, and a substrate-derived inhibitory peptide or competitive inhibitor (SCB4380) specifically bound to the monomer form in a 1:1 stoichiometric ratio, supporting the \"head-to-toe dimerization\" model for inactivation. A D2 deletion ({Delta}D2) or dimer interface mutation (DDKK) disrupted dimer formation, while the binding of SCB4380 was maintained. Similar to wild-type PTPRZ-B, monomer-biased PTPRZ-B-{Delta}D2 and PTPRZ-B-DDKK mutants efficiently dephosphorylated p190RhoGAP at Tyr-1105 when co-expressed in BHK-21 cells. The catalytic activities of these mutants were not suppressed by a treatment with PTN, but were inhibited by the cell-permeable PTPase inhibitor NAZ2329. The PTN treatment did not enhance OPC differentiation in primary cultured glial cells prepared from {Delta}D2 or catalytically-inactive CS mutant knock-in mice. Our results indicate that PTN-induced PTPRZ inactivation is attained by dimer formation of the intracellular tandem PTP domains in the head-to-toe configuration, which is physiologically relevant to the control of OPC differentiation in vivo.

biochemistry↗

bioRxiv2018

A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species-specificity

Hepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates from fish to human. Hepadnaviruses and their hosts have a long history of acquiring adaptive mutations. However, there are no reports providing direct molecular evidence for such a coevolutionary \"arms race\" between hepadnaviruses and their hosts. Here, we present evidence suggesting the adaptive evolution of the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, has been influenced by virus infection. Evolutionary analysis of the NTCP-encoding genes from 20 mammals showed that most NTCP residues are highly conserved among species, exhibiting evolution under negative selection (dN/dS < 1); this observation implies that the evolution of NTCP is restricted by maintaining its original protein function. However, 0.7 % of NTCP amino acid (aa) residues exhibit rapid evolution under positive selection (dN/dS > 1). Notably, a substitution at aa 158, a positively selected residue, converting the human NTCP to a monkey-type sequence abrogated the capacity to support HBV infection; conversely, a substitution at this residue converting the monkey Ntcp to the human sequence was sufficient to confer HBV susceptibility. Together, these observations suggested that positive selection at aa 158 was induced by virus infection. Moreover, the aa 158 sequence determined attachment of the HBV envelope protein to host cell, demonstrating the mechanism whereby HBV infection would create positive selection at this residue in NTCP. In summary, we provide the first evidence in agreement with the function of hepadnavirus as a driver for inducing an adaptive mutation in host receptor.\n\nImportanceHepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates, with a long infectious history (hundreds of millions of years). Such a long history generally allows adaptive mutations in hosts to escape from infection, while simultaneously allowing adaptive mutations in viruses to overcome host barriers. However, there is no published molecular evidence for such a coevolutionary \"arms race\" between hepadnaviruses and hosts. In the present study, we performed coevolutionary phylogenetic analysis between hepadnaviruses and the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, combined with virological experimental assays for investigating the biological significance of NTCP sequence variation. Our data provide the first molecular evidences supporting that HBV-related hepadnaviruses drive adaptive evolution in the NTCP sequence, including a mechanistic explanation of how NTCP mutations determine host viral susceptibility. Our novel insights enhance our understanding of how hepadnaviruses evolved with their hosts, permitting the acquisition of strong species-specificity.

evolutionary biology↗

bioRxiv2018

Luigi: Large-scale histopathological image retrieval system using deep texture representations

BackgroundAs a large number of digital histopathological images have been accumulated, there is a growing demand of content-based image retrieval (CBIR) in pathology for educational, diagnostic, or research purposes. However, no CBIR systems in digital pathology are publicly available.\n\nResultsWe developed a web application, the Luigi system, which retrieves similar histopathological images from various cancer cases. Using deep texture representations computed with a pre-trained convolutional neural network as an image feature in conjunction with an approximate nearest neighbor search method, the Luigi system provides fast and accurate results for any type of tissue or cell without the need for further training. In addition, users can easily submit query images of an appropriate scale into the Luigi system and view the retrieved results using our smartphone application. The cases stored in the Luigi database are obtained from The Cancer Genome Atlas with rich clinical, pathological, and molecular information. We tested the Luigi system by querying typical cancerous regions from four cancer types, and confirmed successful retrieval of relevant images.\n\nConclusionsThe Luigi system will help students, pathologists, and researchers easily retrieve histopathological images of various cancers similar to those of the query image.

pathology↗