Jump-type Hunt processes generated by lower bounded semi-Dirichlet forms

Let $E$ be a locally compact separable metric space and $m$ be a positive Radon measure on it. Given a nonnegative function $k$ defined on $E\times E$ off the diagonal whose anti-symmetric part is assumed to be less singular than the symmetric part, we construct an associated regular lower bounded semi-Dirichlet form $\eta$ on $L^2(E;m)$ producing a Hunt process $X^0$ on $E$ whose jump behaviours are governed by $k$. For an arbitrary open subset $D\subset E$, we also construct a Hunt process $X^{D,0}$ on $D$ in an analogous manner. When $D$ is relatively compact, we show that $X^{D,0}$ is censored in the sense that it admits no killing inside $D$ and killed only when the path approaches to the boundary. When $E$ is a $d$-dimensional Euclidean space and $m$ is the Lebesgue measure, a typical example of $X^0$ is the stable-like process that will be also identified with the solution of a martingale problem up to an $\eta$-polar set of starting points. Approachability to the boundary $\partial D$ in finite time of its censored process $X^{D,0}$ on a bounded open subset $D$ will be examined in terms of the polarity of $\partial D$ for the symmetric stable processes with indices that bound the variable exponent $\alpha(x)$.Comment: Published in at http://dx.doi.org/10.1214/10-AOP633 the Annals of Probability (http://www.imstat.org/aop/) by the Institute of Mathematical Statistics (http://www.imstat.org

Trends in the incidence and mortality of legionellosis in Japan: a nationwide observational study, 1999-2017

This study examined temporal trend, seasonality, and geographical variations of legionellosis incidence and mortality in Japan. This nationwide observational study used the Japanese Vital Statistics and Infectious Diseases Weekly Report (1999-2017) data to calculate legionellosis crude and age-adjusted incidence and mortality rates per 100,000 population by age and sex. Incidence was compared among the 4 seasons and regional incidence among 47 prefectures. Of 13,613 (11,194 men) people with legionellosis in Japan, 725 (569 men) were fatal. Increasing incidence trend occurred from 0.0004 (1999) to 1.37 (2017) per 100,000 population. People aged >= 70 years accounted for 43.1% overall; men's age-adjusted incidence rate was consistently approximately five times higher than for women. Significantly higher incidence occurred in summer than in winter (p=0.013). Geographically, highest incidence (>= 2.0 per 100,000 population) occurred in Hokuriku District, with increasing trends in Hokkaido and middle-part of Japan. Estimated fatality rates decreased consistently at 5.9% (95% confidence interval: - 8.1, - 3.5) annually, from 1999 to 2017, with no trend change point. Increasing legionellosis incidence occurred in Japan during 1999-2017, with declining estimated fatality rates. In this aging society and warming world, disease clinical burden may further deteriorate in future due to increasing incidence trends

Induced-fit expansion and contraction of a self-assembled nanocube finely responding to neutral and anionic guests

Induced-fit or conformational selection is of profound significance in biological regulation. Biological receptors alter their conformation to respond to the shape and electrostatic surfaces of guest molecules. Here we report a water-soluble artificial molecular host that can sensitively respond to the size, shape, and charged state of guest molecules. The molecular host, i.e. nanocube, is an assembled structure consisting of six gear-shaped amphiphiles (GSAs). This nanocube can expand or contract its size upon the encapsulation of neutral and anionic guest molecules with a volume ranging from 74 to 535 Å3 by induced-fit. The responding property of this nanocube, reminiscent of a feature of biological molecules, arises from the fact that the GSAs in the nanocubes are connected to each other only through the hydrophobic effect and very weak intermolecular interactions such as van der Waals and cation-π interactions

Genome-Scale CRISPR/Cas9 Screening Reveals Squalene Epoxidase as a Susceptibility Factor for Cytotoxicity of Malformin A1

Malformin A1 (MA1) is a fungus-produced cyclic pentapeptide. MA1 exhibits teratogenicity to plants, fibrinolysis-enhancing activity, and cytotoxicity to mammalian cells. To clarify the cytotoxic mechanism of MA1, we screened for the genes involved in the cytotoxicity of MA1 in monocytoid U937 cells by using a CRISPR/Cas9-based genome-wide knockout library. Screening was performed by positive selection for cells that were resistant to MA1 treatment, and single guide RNAs (sgRNAs) integrated into MA1-resistant cells were analyzed by high-throughput sequencing. As a result of the evaluation of sgRNAs that were enriched in MA1-resistant cells, SQLE, which encodes squalene epoxidase, was identified as a candidate gene. SQLE-depleted U937 cells were viable in the presence of MA1, and squalene epoxidase inhibitor conferred MA1 resistance to wild-type cells. These results indicate that squalene epoxidase is implicated in the cytotoxicity of MA1. This finding represents a new insight into applications of MA1 for treating ischemic diseases

Calibration of Photomultiplier Tubes for the Fluorescence Detector of Telescope Array Experiment using a Rayleigh Scattered Laser Beam

We performed photometric calibration of the PhotoMultiplier Tube (PMT) and readout electronics used for the new fluorescence detectors of the Telescope Array (TA) experiment using Rayleigh scattered photons from a pulsed nitrogen laser beam. The experimental setup, measurement procedure, and results of calibration are described. The total systematic uncertainty of the calibration is estimated to be 7.2%. An additional uncertainty of 3.7% is introduced by the transport of the calibrated PMTs from the laboratory to the TA experimental site.Comment: 43 pages, 15 figure

Induced-fit expansion and contraction of a self-assembled nanocube finely responding to neutral and anionic guests

Induced-fit or conformational selection is of profound significance in biological regulation. Biological receptors alter their conformation to respond to the shape and electrostatic surfaces of guest molecules. Here we report a water-soluble artificial molecular host that can sensitively respond to the size, shape, and charged state of guest molecules. The molecular host, i.e. nanocube, is an assembled structure consisting of six gear-shaped amphiphiles (GSAs). This nanocube can expand or contract its size upon the encapsulation of neutral and anionic guest molecules with a volume ranging from 74 to 535 Å3 by induced-fit. The responding property of this nanocube, reminiscent of a feature of biological molecules, arises from the fact that the GSAs in the nanocubes are connected to each other only through the hydrophobic effect and very weak intermolecular interactions such as van der Waals and cation-π interactions.UTokyo FOCUS Press releases掲載「取り込む分子の大きさ・形・電荷に応答して膨らんだり縮んだりする分子カプセル」＜研究成果＞ URI: https://www.u-tokyo.ac.jp/focus/ja/press/z0109_00048.htmlUTokyo FOCUS Press releases "Don’t underestimate the Force Researchers discover weak chemical interactions hold together box of infinite possibilities" URI: https://www.u-tokyo.ac.jp/focus/en/press/z0508_00014.htm

Identification of prophylactic drugs for oxaliplatin-induced peripheral neuropathy using big data

Background: Drug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. Methods: Herein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA’s database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague–Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. Results: Simvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. Conclusion and relevance: Thus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed