4,162 research outputs found

    Totally normal cellular stratified spaces and applications to the configuration space of graphs

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    The notion of regular cell complexes plays a central role in topological combinatorics because of its close relationship with posets. A generalization, called totally normal cellular stratified spaces, was introduced by the third author by relaxing two conditions; face posets are replaced by acyclic categories and cells with incomplete boundaries are allowed. The aim of this article is to demonstrate the usefulness of totally normal cellular stratified spaces by constructing a combinatorial model for the configuration space of graphs. As an application, we obtain a simpler proof of Ghrist's theorem on the homotopy dimension of the configuration space of graphs. We also make sample calculations of the fundamental group of ordered and unordered configuration spaces of two points for small graphs.Comment: 44 pages. v2. Typos fixed. Accepted for publication by Topological Methods in Nonlinear Analysi

    Knockout animals and natural mutations as experimental and diagnostic tool for studying tight junction functions in vivo

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    AbstractTwo sides of functions of tight junctions; the barrier and the channel in the paracellular pathway are believed to be essential for the development and physiological functions of organs. Recent identification of molecular components of tight junctions has enabled us to analyze their functions by generating knockout mice of the corresponding genes. In addition, positional cloning has identified mutations in the genes of several components of tight junctions in hereditary diseases. These studies have highlighted in vivo functions of tight junctions

    Molecular Targeted Therapy for Growth Factors in Hepatocellular Carcinoma

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    Identifying Potentially Beneficial Genetic Mutations Associated with Monophyletic Selective Sweep and a Proof-of-Concept Study with Viral Genetic Data

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    Genetic mutations play a central role in evolution. For a significantly beneficial mutation, a one-time mutation event suffices for the species to prosper and predominate through the process called "monophyletic selective sweep." However, existing methods that rely on counting the number of mutation events to detect selection are unable to find such a mutation in selective sweep. We here introduce a method to detect mutations at the single amino acid/nucleotide level that could be responsible for monophyletic selective sweep evolution. The method identifies a genetic signature associated with selective sweep using the population genetic test statistic Tajima's D We applied the algorithm to ebolavirus, influenza A virus, and severe acute respiratory syndrome coronavirus 2 to identify known biologically significant mutations and unrecognized mutations associated with potential selective sweep. The method can detect beneficial mutations, possibly leading to discovery of previously unknown biological functions and mechanisms related to those mutations.IMPORTANCE In biology, research on evolution is important to understand the significance of genetic mutation. When there is a significantly beneficial mutation, a population of species with the mutation prospers and predominates, in a process called "selective sweep." However, there are few methods that can find such a mutation causing selective sweep from genetic data. We here introduce a novel method to detect such mutations. Applying the method to the genomes of ebolavirus, influenza viruses, and the novel coronavirus, we detected known biologically significant mutations and identified mutations the importance of which is previously unrecognized. The method can deepen our understanding of molecular and evolutionary biology

    Sorafenib for the treatment of unresectable hepatocellular carcinoma

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    Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-β). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients

    Fluvoxamine for blonanserin-associated akathisia in patients with schizophrenia: report of five cases

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    BACKGROUND: Atypical antipsychotic drugs have been reported to cause fewer incidences of extrapyramidal side effects (EPS) than typical antipsychotic drugs, but adverse events such as akathisia have been observed even with atypical antipsychotic drugs. Although understanding of the pathophysiology of akathisia remains limited, it seems that a complex interaction of several neurotransmitter systems plays a role in its pathophysiology. The endoplasmic reticulum protein sigma-1 receptors have been shown to regulate a number of neurotransmitter systems in the brain. METHODS: We report on five cases in which monotherapy of the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the akathisia of patients with schizophrenia treated with the new atypical antipsychotic drug blonanserin. RESULTS: The global score on the Barnes Akathisia Scale in five patients with schizophrenia treated with blonanserin rapidly decreased after fluvoxamine treatment. CONCLUSION: Doctors should consider that fluvoxamine may be an alternative approach in treating akathisia associated with atypical antipsychotic drugs

    Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells

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    For epithelia to function as barriers, the intercellular space must be sealed. Sealing two adjacent cells at bicellular tight junctions (bTJs) is well described with the discovery of the claudins. Yet, there are still barrier weak points at tricellular contacts, where three cells join together. In this study, we identify tricellulin, the first integral membrane protein that is concentrated at the vertically oriented TJ strands of tricellular contacts. When tricellulin expression was suppressed with RNA interference, the epithelial barrier was compromised, and tricellular contacts and bTJs were disorganized. These findings indicate the critical function of tricellulin for formation of the epithelial barrier
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