連鎖解析と全エキソン配列決定による家族性甲状腺腫に関連する新規遺伝子の同定

京都大学0048新制・課程博士博士(医学)甲第18142号医博第3862号新制||医||1002(附属図書館)31000京都大学大学院医学研究科医学専攻(主査)教授 山田 亮, 教授 小杉 眞司, 教授 松田 文彦学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

THE CORRELATIONS BETWEEN DYNAMIC WALKING STABILITY AND PERCEPTION-MOTOR ABILITIES OF HUMANS

External perturbations can challenge a person’s walking stability, and people will autonomously make a series of responses to regain the balance of walking, which includes two periods: perturbation-perception (reaction time, RT) and posture-adjustment (motion time, MT). The purpose of this paper was to investigate the correlations between the dynamic walking stability and perception-motor abilities. During the 30 level walking trials preformed by sixteen healthy participants, perturbations were applied at random. The fall probability (FP) during the walking with perturbations was calculated to evaluate the dynamic walking stability of each participant. Furthermore, the ground reaction force (GRF) of each participant during walking with perturbations was recorded and analyzed. The experimental results show that the RT had a significant positive-correlation with FP, while MT had no correlation with FP

Association between organic cation transporter genetic polymorphisms and metformin response and intolerance in T2DM individuals: a systematic review and meta-analysis

BackgroundVariants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies investigating the effect of OCT genetic polymorphisms on metformin response have reported inconsistent results. This review and meta-analysis aimed to evaluate the associations between OCT genetic polymorphisms and metformin response and intolerance in individuals with type 2 diabetes mellitus (T2DM).MethodA systematic search was conducted on PubMed, EMBASE, CNKI, WANFANG DATA, and VIP database for identifying potential studies up to 10 November 2022. The Q-Genie tool was used to evaluate the quality of included studies. Pooled odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated to determine the associations between OCT genetic polymorphisms and metformin response and intolerance that were reflected by glycemic response indexes, such as glycated hemoglobin level (HbA1c%) or change in glycated hemoglobin level (ΔHbA1c%), fasting plasma level (FPG) or change in fasting plasma glucose level (ΔFPG), the effectiveness rate of metformin treatment, and the rate of metformin intolerance. A qualitative review was performed for the variants identified just in one study and those that could not undergo pooling analysis.ResultsA total of 30 related eligible studies about OCT genes (SLC22A1, SLC22A2, and SLC22A3) and metformin pharmacogenetics were identified, and 14, 3, and 6 single nucleotide polymorphisms (SNPs) in SLC22A1, SLC22A2, and SLC22A3, respectively, were investigated. Meta-analysis showed that the SLC22A1 rs622342 polymorphism was associated with a reduction in HbA1c level (AA vs. AC: SMD [95% CI] = −0.45 [−0.73–−0.18]; p = 0.001). The GG genotype of the SLC22A1 rs628031 polymorphism was associated with a reduction in FPG level (GG vs. AA: SMD [95 %CI] = −0.60 [−1.04–0.16], p = 0.007; GG vs. AG: −0.45 [−0.67–0.20], p < 0.001). No statistical association was found between the remaining variants and metformin response and intolerance.ConclusionSLC22A1 rs622342 and rs628031 polymorphisms were potentially associated with glycemic response to metformin. This evidence may provide novel insight into gene-oriented personalized medicine for diabetes

Analysis on the status quo of construction industry and workers’ professional literacy

Under the background of the new building industrialization in China, the traditional cast-in-place construction mode begins to change to assembly construction mode. Such subversive changes make all regions face various assembly construction quality problems caused by traditional workers’ lack of assembly construction knowledge, low awareness and unskilled operation. Therefore, improving workers’ professional quality is very important to improve the quality of assembly construction. Through the analysis of a large number of domestic and foreign literature, this paper found that when studying prefabricated buildings from different dimensions such as quality, cost, schedule and safety, Will involve the “operation proficiency", “education level”, “professional skills”, “vocational training”, “qualification”, “working years”, “professional experience”, “lack of knowledge”, “reputation”, “professional pride”, “mobile operation”, “work attitude” and other aspects of the workers, These factors focus on safety awareness, operation norms, vocational training, work experience, professional knowledge, cultural level, quality awareness, technical skill level. All these factors will affect the quality of assembly construction, and the quality of workers is one of the reasons for poor construction performance, frequent safety accidents and low construction quality

Blood arsenic exposure levels of preschool children and dietary factors analysis

Objective To explore the blood arsenic exposure levels of preschool children and analyze the factors of blood arsenic. Methods By the multi-stage cluster and simple randomized method, six districts of Shanghai City was chosen and the preschool children in the selected village were asked to fill in the questionnaire and have blood sampling. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect blood arsenic, of which the data was analyzed by multiple linear regression models. Marine fish, freshwater fish, freshwater shrimp and shellfish were grouped as follows: ≤3 times per month, 1-3 times per week, and 4-6 times per week. Rice, noodles and milk were grouped as <50, 50-100, and ≥100 g/d. Results 2 263 preschool children were recruited. The range of blood arsenic was 0.12-27.94 μg/L. The median (P25, P75) were 2.26 (1.63, 3.09) μg/L. Statistical analysis showed that the more intake of rice, wheaten food, and sea fish and shrimp, the more arsenic in children’s blood (P<0.05). Whereas highter intake of freshwater fish and shrimp group showed decreased blood arsenic (P<0.05). Conclusion Most preschool children’s blood arsenic levels (92.4%, 2 091/2 263) were at normal level (<5 μg/L). There was a positive correlation between blood arsenic concentration and the intake of rice, wheaten food, and sea fish and shrimp, while negative correlation with high freshwater fish and shrimp consumption

Salvianolic Acid B Attenuates Rat Hepatic Fibrosis via Downregulating Angiotensin II Signaling

The renin-angiotensin system (RAS) plays an important role in hepatic fibrosis. Salvianolic acid B (Sal B), one of the water-soluble components from Radix Salviae miltiorrhizae, has been used to treat hepatic fibrosis, but it is still not clear whether the effect of Sal B is related to angiotensin II (Ang II) signaling pathway. In the present study, we studied Sal B effect on rat liver fibrosis and Ang-II related signaling mediators in dimethylnitrosamine-(DMN-) induced rat fibrotic model in vivo and Ang-II stimulated hepatic stellate cells (HSCs) in vitro, with perindopril or losartan as control drug, respectively. The results showed that Sal B and perindopril inhibited rat hepatic fibrosis and reduced expression of Ang II receptor type 1 (AT1R) and ERK activation in fibrotic liver. Sal B and losartan also inhibited Ang II-stimulated HSC activation including cell proliferation and expression of type I collagen I (Col-I) and α-smooth muscle actin (α-SMA) production in vitro, reduced the gene expression of transforming growth factor beta (TGF-β), and downregulated AT1R expression and ERK and c-Jun phosphorylation. In conclusion, our results indicate that Sal B may exert an antihepatic fibrosis effect via downregulating Ang II signaling in HSC activation

Use of PETRA-MRA to assess intracranial arterial stenosis: Comparison with TOF-MRA, CTA, and DSA

Background and purposeNon-invasive and accurate assessment of intracranial arterial stenosis (ICAS) is important for the evaluation of intracranial atherosclerotic disease. This study aimed to evaluate the performance of 3D pointwise encoding time reduction magnetic resonance angiography (PETRA-MRA) and compare its performance with that of 3D time-of-flight (TOF) MRA and computed tomography angiography (CTA), using digital subtraction angiography (DSA) as the reference standard in measuring the degree of stenosis and lesion length.Materials and methodsThis single-center, prospective study included a total of 52 patients (mean age 57 ± 11 years, 27 men, 25 women) with 90 intracranial arterial stenoses who underwent PETRA-MRA, TOF-MRA, CTA, and DSA within 1 month. The degree of stenosis and lesion length were measured independently by two radiologists on these four datasets. The degree of stenosis was classified according to DSA measurement. Severe stenosis was defined as a single lesion with &gt;70% diameter stenosis. The smaller artery stenosis referred to the stenosis, which occurred at the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery, except for the first segment of them. The continuous variables were compared using paired t-test or Wilcoxon signed rank test. The intraclass correlation coefficients (ICCs) were used to assess the agreement between MRAs/CTA and DSA as well as inter-reader variabilities. The ICC value &gt;0.80 indicated excellent agreement. The agreement of data was assessed further by Bland–Altman analysis and Spearman's correlation coefficients. When the difference between MRAs/CTA and DSA was statistically significant in the degree of stenosis, the measurement of MRAs/CTA was larger than that of DSA, which referred to the overestimation of MRAs/CTA for the degree of stenosis.ResultsThe four imaging methods exhibited excellent inter-reader agreement [intraclass correlation coefficients (ICCs) &gt; 0.80]. PETRA-MRA was more consistent with DSA than with TOF-MRA and CTA in measuring the degree of stenosis (ICC = 0.94 vs. 0.79 and 0.89) and lesion length (ICC = 0.99 vs. 0.97 and 0.73). PETRA-MRA obtained the highest specificity and positive predictive value (PPV) than TOF-MRA and CTA for detecting stenosis of &gt;50% and stenosis of &gt;75%. TOF-MRA and CTA overestimated considerably the degree of stenosis compared with DSA (63.0% ± 15.8% and 61.0% ± 18.6% vs. 54.0% ± 18.6%, P &lt; 0.01, respectively), whereas PETRA-MRA did not overestimate (P = 0.13). The degree of stenosis acquired on PETRA-MRA was also more consistent with that on DSA than with that on TOF-MRA and CTA in severe stenosis (ICC = 0.78 vs. 0.30 and 0.57) and smaller artery stenosis (ICC = 0.95 vs. 0.70 and 0.80). In anterior artery circulation stenosis, PETRA-MRA also achieved a little bigger ICC than TOF-MRA and CTA in measuring the degree of stenosis (0.93 vs. 0.78 and 0.88). In posterior artery circulation stenosis, PETRA-MRA had a bigger ICC than TOF-MRA (0.94 vs. 0.71) and a comparable ICC to CTA (0.94 vs. 0.91) in measuring the degree of stenosis.ConclusionPETRA-MRA is more accurate than TOF-MRA and CTA for the evaluation of intracranial stenosis and lesion length when using DSA as a reference standard. PETRA-MRA is a promising non-invasive tool for ICAS assessment

PKM2 promotes glucose metabolism and cell growth in gliomas through a mechanism involving a let-7a/c-Myc/hnRNPA1 feedback loop

AbstrAct Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than non-tumor cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let-7a/c-Myc/hnRNPA1/PKM2 signaling in glioma cell glucose metabolism. PKM2 depletion via siRNA inhibits cell proliferation and aerobic glycolysis in glioma cells. C-Myc promotes up-regulation of hnRNPA1 expression, hnRNPA1 binding to PKM pre-mRNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let-7a, which functionally targets c-Myc, whereas hnRNPA1 blocks the biogenesis of let-7a to counteract its ability to downregulate the c-Myc/hnRNPA1/PKM2 signaling pathway. The down-regulation of c-Myc/ hnRNPA1/PKM2 by let-7a is verified using a glioma xenograft model. These results suggest that let-7a, c-Myc and hnRNPA1 from a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of glioma cells. These findings elucidate a new pathway mediating aerobic glycolysis in gliomas and provide an attractive potential target for therapeutic intervention

Upregulation of miR-196b Confers a Poor Prognosis in Glioblastoma Patients via Inducing a Proliferative Phenotype

PURPOSE: To explore the expression pattern, prognostic value and functional role of miR-196b in glioblastoma (GBM) patients using large cohorts. EXPERIMENTAL DESIGN: MiR-196b expression was measured using the Human v2.0 miRNA Expression BeadChip (Illumina) in 198 frozen glioma tissues. The expression levels of miR-196b were also validated in an independent cohort containing 128 formalin-fixed paraffin-embedded (FFPE) glioma samples using qRT-PCR. The presence of other molecular prognostic indicators was assessed centrally in the glioma samples. Whole genome gene profiling was performed to investigate the underlying biological behavior. MiR-196b functional analyses were performed in U87 and U251 cell lines. RESULTS: The expression levels of miR-196b were inversely correlated with overall survival in GBM patients. Gene set enrichment analysis (GSEA) showed that the gene sets relating to cell cycle were significantly enriched in the cases with miR-196b overexpression. Functional analyses in U87 and U251 cells revealed that miR-196b was involved in cell proliferation. CONCLUSIONS: MiR-196b is overexpressed and confers a poor prognosis via promoting cellular proliferation in GBM patients