A cavitation model for analyzing the fuel behavior of automobile engines in Moving Particle Semi-implicit method

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 越塚 誠一, 東京大学教授 鈴木 英之, 東京大学准教授 山田 知典, 東京大学准教授 酒井 幹夫, 東京大学准教授 柴田 和也University of Tokyo(東京大学

Linkage disequilibrium of evolutionarily conserved regions in the human genome

BACKGROUND: The strong linkage disequilibrium (LD) recently found in genic or exonic regions of the human genome demonstrated that LD can be increased by evolutionary mechanisms that select for functionally important loci. This suggests that LD might be stronger in regions conserved among species than in non-conserved regions, since regions exposed to natural selection tend to be conserved. To assess this hypothesis, we used genome-wide polymorphism data from the HapMap project and investigated LD within DNA sequences conserved between the human and mouse genomes. RESULTS: Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions. CONCLUSION: Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units

Single-molecular real-time deep sequencing reveals the dynamics of multi-drug resistant haplotypes and structural variations in the hepatitis C virus genome

While direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically progressed, patients still suffer from treatment failures. For the radical eradication of HCV, a deeper understanding of multiple resistance-associated substitutions (RASs) at the single-clone level is essential. To understand HCV quasispecies and their dynamics during DAA treatment, we applied single-molecule real-time (SMRT) deep sequencing on sera from 12 patients with genotype-1b HCV infections with DAA treatment failures, both pre- and post-treatment. We identified >3.2 kbp sequences between NS3 and NS5A genes of 187, 539 clones in total, classifying into haplotype codes based on the linkage of seven RAS loci. The number of haplotype codes during the treatment, per sample, significantly decreased from 14.67 ± 9.12 to 6.58 ± 7.1, while the number of nonsynonymous codons on the seven RAS loci, per clone, significantly increased from 1.50 ± 0.92 to 3.64 ± 0.75. In five cases, the minority multi-drug resistant haplotypes at pre-treatment were identical to the major haplotypes at relapse. Moreover, various structural variations (SVs) were detected and their dynamics analysed. These results suggest that SMRT deep sequencing is useful for detecting minority haplotypes and SVs, and to evaluate the dynamics of viral genomes at the single-clone level

Increased aortic wave reflection and smaller pulse pressure amplification in smokers and passive smokers confirmed by urinary cotinine levels: The Nagahama Study.

[Background]Central blood pressure (cSBP) is suggested to be a better predictor of cardiovascular risk than brachial BP. Although brachial BP levels among smokers have been reported to be the same or somewhat lower than those in nonsmokers, it is suggested that smoking might have a substantial impact on cSBP. [Methods]We conducted a cross-sectional study to clarify the association of smoking habit with arterial tone and cSBP in a general population of 8557 participants using urinary cotinine levels as an objective marker of smoking intensity. Absolute pressure of the late systolic peak (SBP2) was obtained by calibrating the radial waveform with brachial systolic BP (bSBP) and considered to be the cSBP. [Results]Confounding factor-adjusted mean pulse pressure amplification (PPa = bSBP − cSBP) was significantly smaller in habitual smokers (current, 9.3 ± 0.15; past, 10.2 ± 0.13; never, 10.6 ± 0.10 mm Hg; p < 0.001). Further, among smokers, PPa was linearly decreased with increasing urinary cotinine quartile (Q1, 10.9 ± 0.38; Q2, 10.9 ± 0.39; Q3, 10.4 ± 0.39; Q4, 9.7 ± 0.41 mm Hg; p = 0.020). Multiple linear regression analysis identified both smoking habit (p = 0.003) and urinary cotinine levels (p = 0.008) as independent determinants of PPa. Urinary cotinine was also detected in a small fraction of never smokers (1.8%). These passive smokers showed a smaller PPa (passive smoker, 9.4 ± 0.4; never smoker, 10.4 ± 0.12 mm Hg, p = 0.020) but not bSBP (122.7 ± 0.6, 123.1 ± 0.2 mm Hg, p = 0.474). [Conclusions]Not only habitual smoking but also passive smoking had harmful effects on AIx and central BP. Our results strongly emphasize the importance of avoiding passive smoking to the prevention of cardiovascular risks of which the subject is likely unaware

Comparison of the National Early Warning Score (NEWS) and the Modified Early Warning Score (MEWS) for predicting admission and in-hospital mortality in elderly patients in the pre-hospital setting and in the emergency department

The aim of this study is to evaluate the usefulness of the pre-hospital National Early Warning Score (pNEWS) and the pre-hospital Modified Early Warning Score (pMEWS) for predicting admission and in-hospital mortality in elderly patients presenting to the emergency department (ED). We also compare the value of the pNEWS with that of the ED NEWS (eNEWS) and ED MEWS (eMEWS) for predicting admission and in-hospital mortality. This retrospective, single-centre observational study was carried out in the ED of Jikei University Kashiwa Hospital, in Chiba, Japan, from 1st April 2017 to 31st March 2018. All patients aged 65 years or older were included in this study. The pNEWS/eNEWS were derived from seven common physiological vital signs: respiratory rate, peripheral oxygen saturation, the presence of inhaled oxygen parameters, body temperature, systolic blood pressure, pulse rate and Alert, responds to Voice, responds to Pain, Unresponsive (AVPU) score, whereas the pMEWS/eMEWS were derived from six common physiological vital signs: respiratory rate, peripheral oxygen saturation, body temperature, systolic blood pressure, pulse rate and AVPU score. Discrimination was assessed by plotting the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC). The median pNEWS, pMEWS, eNEWS and eMEWS were significantly higher at admission than at discharge (p < 0.001). The median pNEWS, pMEWS, eNEWS and eMEWS of non-survivors were significantly higher than those of the survivors (p < 0.001). The AUC for predicting admission was 0.559 for the pNEWS and 0.547 for the pMEWS. There was no significant difference between the AUCs of the pNEWS and the pMEWS for predicting admission (p = 0.102). The AUCs for predicting in-hospital mortality were 0.678 for the pNEWS and 0.652 for the pMEWS. There was no significant difference between the AUCs of the pNEWS and the pMEWS for predicting in-hospital mortality (p = 0.081). The AUC for predicting admission was 0.628 for the eNEWS and 0.591 for the eMEWS. The AUC of the eNEWS was significantly greater than that of the eMEWS for predicting admission (p < 0.001). The AUC for predicting in-hospital mortality was 0.789 for the eNEWS and 0.720 for the eMEWS. The AUC of the eNEWS was significantly greater than that of the eMEWS for predicting in-hospital mortality (p < 0.001). For admission and in-hospital mortality, the AUC of the eNEWS was significantly greater than that of the pNEWS (p < 0.001, p < 0.001), and the AUC of the eMEWS was significantly greater than that of the pMEWS (p < 0.01, p < 0.05). Our single-centre study has demonstrated the low utility of the pNEWS and the pMEWS as predictors of admission and in-hospital mortality in elderly patients, whereas the eNEWS and the eMEWS predicted admission and in-hospital mortality more accurately. Evidence from multicentre studies is needed before introducing pre-hospital versions of risk-scoring systems

Mutational spectrum of hepatitis C virus in patients with chronic hepatitis C determined by single molecule real-time sequencing

The emergence of hepatitis C virus (HCV) with resistance-associated substitution (RAS), produced by mutations in the HCV genome, is a major problem in direct acting antivirals (DAA) treatment. This study aimed to clarify the mutational spectrum in HCV-RNA and the substitution pattern for the emergence of RASs in patients with chronic HCV infection. HCV-RNA from two HCV replicon cell lines and the serum HCV-RNA of four non-liver transplant and four post-liver transplant patients with unsuccessful DAA treatment were analyzed using high-accuracy single-molecule real-time long-read sequencing. Transition substitutions, especially A>G and U>C, occurred prominently under DAAs in both non-transplant and post-transplant patients, with a mutational bias identical to that occurring in HCV replicon cell lines during 10-year culturing. These mutational biases were reproduced in natural courses after DAA treatment. RASs emerged via both transition and transversion substitutions. NS3-D168 and NS5A-L31 RASs resulted from transversion mutations, while NS5A-Y93 RASs was caused by transition substitutions. The fidelity of the RNA-dependent RNA polymerase, HCV-NS5B, produces mutational bias in the HCV genome, characterized by dominant transition mutations, notably A>G and U>C substitutions. However, RASs are acquired by both transition and transversion substitutions, and the RASs-positive HCV clones are selected and proliferated under DAA treatment pressure