バキュロウイルスにおける長鎖非コードRNAの機能解析

学位の種別: 課程博士審査委員会委員 : (主査)東京大学准教授 勝間 進, 東京大学教授 宇垣 正志, 東京大学教授 嶋田 透, 東京大学准教授 山次 康幸, 宇都宮大学准教授 岩永 将司University of Tokyo(東京大学

Corrigendum: Retrospective cohort study to determine the effect of preinjury antiplatelet or anticoagulant therapy on mortality in patients with major trauma

OBJECTIVE: This study aimed to compare outcomes among patients who sustained major trauma from injury with and without receiving antiplatelet therapy (APT) or anticoagulant therapy (ACT) to test the hypothesis that APT does not increase the risk of mortality. However, ACT increases the mortality risk in the acute phase of trauma. METHODS: Patients registered in the Japanese Observational body for Coagulation and Thrombolysis in Early Trauma 2 between April 2017 and March 2018 who had sustained a severe injury in any anatomic region of the body, as determined using an injury severity score (ISS) ≥ 16 were included in this retrospective cohort study. We analyzed the mortality within 24 h from the arrival using a multivariable linear regression analysis adjusted for several confounding variables. RESULTS: We identified 1,186 eligible participants who met the inclusion criteria for this study: 105 in the APT (cases), 1,081 in the non-antiplatelet therapy (nAPT) group (controls), 65 in the ACT (cases), and 1,121 in the non-anticoagulant therapy (nACT) group (controls). The mortality within 24 h in the ACT group was significantly higher than in the nACT group (odds ratio 4.5; 95%CI: 1.2–16.79; p = 0.025); however, there was no significant difference between the two groups with or without the antiplatelet drug (odds ratio 0.32; 95%CI: 0.04–2.79; p = 0.3) administration. Other outcomes, like the 28-day mortality, mortality at discharge, and surgery for hemostasis, were not significantly different between regular users and non-users of either antiplatelet or anticoagulant drugs. CONCLUSION: Regular antiplatelet medications did not increase mortality within 24 h, 28 days, or at discharge in patients with major trauma, suggesting that standard treatment, including surgery, is sufficient

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

Genetic dissection of behavioral traits related to successful training of drug detection dogs

Abstract Drug detection dogs play integral roles in society. However, the interplay between their behaviors and genetic characteristics underlying their performance remains uninvestigated. Herein, more than 120,000 genetic variants were evaluated in 326 German Shepherd or Labrador Retriever dogs to profile the genetic traits associated with various behavioral traits related to the successful training of drug detection dogs. Behavioral breed differences were observed in ‘friendliness to humans’ and ‘tolerance to dogs.’ A genome-wide association study within both breeds identified 11 regions potentially associated with drug detection dog characteristics as well as ‘interest in the target’ and ‘friendliness to humans,’ which are related to drug detection abilities. Among them, 63 protein-coding genes, including Atat1 and Pfn2 known to be associated with anxiety-related or exploration behavior in mice, respectively, were located surrounding the identified candidate polymorphisms. This study highlights genetic characteristics associated with behavioral traits that are important for the successful training of drug detection dogs. Thus, these findings may facilitate improved breeding and training of these dogs

Urinary Pharmacokinetic and Pharmacodynamic Profiles of Fosfomycin against Extended-Spectrum β-Lactamase-Producing Escherichia coli with Canine Ex Vivo Modeling: A Pilot Study

Fosfomycin is a candidate drug for extended-spectrum β-lactamase (ESBL)-producing bacteria, but its efficacy is yet to be investigated in dogs. This study investigated the urinary pharmacokinetic/pharmacodynamic (PK/PD) profile of fosfomycin orally administered at 80 mg/kg to six healthy dogs to assess its efficacy for canine urinary tract infections (UTIs) caused by ESBL-producing bacteria. Four strains of ESBL-producing Escherichia coli (ESBL-EC) characterized by fosfomycin minimum inhibitory concentrations (MICs) of 0.5, 1, 2, and 32 µg/mL were used. Urine samples for the measurement of urinary drug concentrations and urinary bactericidal titers (UBTs) were obtained after drug administration. The urinary concentrations (µg/mL, mean ± SE) were 1348.2 ± 163.5, 1191.6 ± 260.2, and 661.1 ± 190.4 at 0–4, 4–8, and 8–12 h, respectively, after drug administration. The mean urinary area under the curve during the test period (AUC0–12) of fosfomycin was estimated to be 12,803.8 µg·h/mL. The UBTs for all tested strains fluctuated closely with urine concentration during the test period (r = 0.944–1.000), and the area under the UBT-versus-time curve correlated with the urinary AUC/MIC of each strain (r = 0.991). According to the optimal urinary PK/PD target value, fosfomycin at 80 mg/kg twice daily may be suitable for the treatment of canine UTIs caused by ESBL-EC presenting MIC ≤ 128 µg/mL

Peripheral endothelial function can be improved by daily consumption of water containing over 7 ppm of dissolved hydrogen: A randomized controlled trial.

BACKGROUND:Measurement of the reactive hyperemia index (RHI) using peripheral arterial tonometry (PAT) has shown benefits in the evaluation of vascular endothelial function and prediction of cardiovascular disease prognosis. Thus, it is important to examine the factors that promote the RHI. In this study, we aimed to investigate the effect of molecular hydrogen (H2) on reactive hyperemia-PAT of the small arteries of fingers in healthy people. METHODS:To determine the efficacy of H2 for improving peripheral vascular endothelial function, water containing high H2 concentrations was administered to participants, and the Ln_RHI was measured in the finger vasculature. Sixty-eight volunteers were randomly divided into two groups: a placebo group (n = 34) that drank molecular nitrogen (N2)-containing water and a high H2 group (n = 34) that drank high H2 water (containing 7 ppm of H2: 3.5 mg H2 in 500-mL water). The Ln_RHI was measured before ingesting the placebo or high H2 water, 1 h and 24 h after the first ingestion, and 14 days after daily ingestion of high H2 water or the placebo. The mixed effects model for repeated measures was used in data analysis. RESULTS:The high H2 group had a significantly greater improvement in Ln_RHI than the placebo group. Ln_RHI improved by 22.2% (p<0.05) at 24 h after the first ingestion of high H2 water and by 25.4% (p<0.05) after the daily consumption of high H2 water for 2 weeks. CONCLUSIONS:Daily consumption of high H2 water improved the endothelial function of the arteries or arterioles assessed by the PAT test. The results suggest that the continuous consumption of high H2 water contributes to improved cardiovascular health

Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines.

Exosomes are small extracellular vesicles released from almost all cell types, which play roles in cell-cell communication. Recent studies have suggested that microenvironmental crosstalk mediated by exosomes is an important factor in the escape of tumour cells from the anti-tumour immune system in human haematopoietic malignancies. Here, we conducted comprehensive analysis of the miRNA and protein profiles within the exosomes released from four canine lymphoid tumour cell lines as a model of human lymphoid tumours. The results showed that the major miRNAs and proteins extracted from the exosomes were similar among the four cell lines. However, the miRNA profiles differed among the exosomes of each cell line, which corresponded to the expression patterns of the parent cells. In the comparison of the amounts of miRNAs and proteins among the cell lines, those of three miRNAs (miR-151, miR-8908a-3p, and miR-486) and CD82 protein differed between exosomes derived from vincristine-sensitive and resistant cell lines. Further investigations are needed to elucidate the biological functions of the exosomal contents in the microenvironmental crosstalk of lymphoid tumours

Effect of sevoflurane anesthesia on neuromuscular blockade produced by rocuronium infusion in dogs

This study evaluated the effect of sevoflurane anesthesia on neuromuscular blockade with rocuronium in dogs. Six healthy beagle dogs were anesthetized four times with a minimum 14-day washout period. On each occasion, the dogs were administered 1.25-, 1.5-, 1.75-, or 2.0-fold of the individualized minimum alveolar concentration (MAC) of sevoflurane and received an infusion of rocuronium (0.5 mg/kg followed by 0.2 mg/kg/hr) for 120 min. Neuromuscular function was monitored with acceleromyography and train-of-four (TOF) stimulation of the left hind limb. Time to achieve TOF count 0 (onset time), time from the onset of neuromuscular blockade to the reappearance of TOF count 4 (blockade period), and time from the onset of rocuronium infusion to attaining a 70 or 90% TOF ratio (TOFR70 or TOFR90) were recorded. There were no significant differences in the onset time, blockade period, and plasma rocuronium concentration between the sevoflurane MAC multiples. The TOFR70 and TOFR90 were dose-dependently prolonged with the sevoflurane MAC multiples. There were significant differences in the TOFR70 and TOFR90 between the 1.25 sevoflurane MAC (median: 55 and 77.5 min, respectively) and 1.75 sevoflurane MAC (122.0 and 122.6 min; P=0.020 and P=0.020, respectively), 1.25 sevoflurane MAC and 2.0 sevoflurane MAC (126.0 and 131.4 min; P=0.020 and P=0.020), and 1.5 sevoflurane MAC (97.5 and 121.3 min) and 2.0 sevoflurane MAC (P=0.033 and P=0.032). In dogs, sevoflurane anesthesia produced dose-dependent prolongation of recovery from neuromuscular blockade produced by rocuronium

DNA methylation landscape of 16 canine somatic tissues by methylation-sensitive restriction enzyme-based next generation sequencing

DNA methylation plays important functions in gene expression regulation that is involved in individual development and various diseases. DNA methylation has been well studied in human and model organisms, but only limited data exist in companion animals like dog. Using methylation-sensitive restriction enzyme-based next generation sequencing (Canine DREAM), we obtained canine DNA methylation maps of 16 somatic tissues from two dogs. In total, we evaluated 130,861 CpG sites. The majority of CpG sites were either highly methylated (>70%, 52.5-64.6% of all CpG sites analyzed) or unmethylated (<30%, 22.5-28.0% of all CpG sites analyzed) which are methylation patterns similar to other species. The overall methylation status of CpG sites across the 32 methylomes were remarkably similar. However, the tissue types were clearly defined by principle component analysis and hierarchical clustering analysis with DNA methylome. We found 6416 CpG sites located closely at promoter region of genes and inverse correlation between DNA methylation and gene expression of these genes. Our study provides basic dataset for DNA methylation profiles in dogs