窒化物半導体成長における構造制御と発光素子への応用

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 藤岡 洋, 東京大学教授 尾張 眞則, 東京大学教授 立間 徹, 東京大学教授 石井 和之, 東京大学講師 徳本 有紀University of Tokyo(東京大学

Gut taste receptor type 1 member 3 is an intrinsic regulator of Western diet-induced intestinal inflammation

Background Long-term intake of a Western diet (WD), characterized by a high-fat content and sugary drinks, is hypothesized to contribute to the development of inflammatory bowel disease (IBD). Despite the identified clinical association, the molecular mechanisms by which dietary changes contribute to IBD development remain unknown. Therefore, we examined the influence of long-term intake of a WD on intestinal inflammation and the mechanisms by which WD intake affects IBD development. Methods Mice fed normal diet or WD for 10weeks, and bowel inflammation was evaluated through pathohistological and infiltrated inflammatory cell assessments. To understand the role of intestinal taste receptor type 1 member 3 (TAS1R3) in WD-induced intestinal inflammation, cultured enteroendocrine cells harboring TAS1R3, subjected to RNA interference or antagonist treatment, and Tas1r3-deficient mice were used. RNA-sequencing, flow cytometry, 16S metagenomic sequencing, and bioinformatics analyses were performed to examine the involved mechanisms. To demonstrate their clinical relevance, intestinal biopsies from patients with IBD and mice with dextran sulfate sodium-induced colitis were analyzed. Results Our study revealed for the first time that intestinal TAS1R3 is a critical mediator of WD-induced intestinal inflammation. WD-fed mice showed marked TAS1R3 overexpression with hallmarks of serious bowel inflammation. Conversely, mice lacking TAS1R3 failed to exhibit inflammatory responses to WD. Mechanistically, intestinal transcriptome analysis revealed that Tas1r3 deficiency suppressed mTOR signaling, significantly increasing the expression of PPARγ (a major mucosal defense enhancer) and upregulating the expression of PPARγ target-gene (tight junction protein and antimicrobial peptide). The gut microbiota of Tas1r3-deficient mice showed expansion of butyrate-producing Clostridia. Moreover, an increased expression of host PPARγ-signaling pathway proteins was positively correlated with butyrate-producing microbes, suggesting that intestinal TAS1R3 regulates the relationship between host metabolism and gut microflora in response to dietary factors. In cultured intestinal cells, regulation of the TAS1R3–mTOR–PPARγ axis was critical for triggering an inflammatory response via proinflammatory cytokine production and secretion. Abnormal regulation of the axis was observed in patients with IBD. Conclusions Our findings suggest that the TAS1R3–mTOR–PPARγ axis in the gut links Western diet consumption with intestinal inflammation and is a potential therapeutic target for IBD.This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (Grant NRF-2021R1A2C3010280), and the Korea Mouse Phenotyping Project through the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant NRF-2013M3A9D5072550). The funding sources had no role in the design of the study, in the collection, analysis, and interpretation of data, or in the writing of the manuscrip

Efficacy and Tolerability of Peginterferon Alpha Plus Ribavirin in the Routine Daily Treatment of Chronic Hepatitis C Patients in Korea: A Multi-Center, Retrospective Observational Study

Background/Aims: We aimed to evaluate the efficacy and safety of peginterferon plus ribavirin for chronic hepatitis C (CHC) patients under real life setting in Korea. Methods: We retrospectively analyzed the medical records of 758 CHC patients treated with peginterferon plus ribavirin between 2000 and 2008 from 14 university hospitals in the Gyeonggi-Incheon area in Korea. Results: Hepatitis C virus (HCV) genotype 1 was detected in 61.2% of patients, while genotype 2 was detected in 35.5%. Baseline HCV RNA level was >= 6x10(5) IU/mL in 51.6% of patients. The sustained virological response (SVR) rate was 59.6% regardless of genotype; 53.6% in genotype 1 and 71.4% in genotype 2/3. On multivariate analysis, male gender (p=0.011), early virological response (p<0.001), genotype 2/3 (p<0.001), HCV RNA <6x10(5) IU/mL (p=0.005) and adherence to the drug >80% of the planned dose (p<0.001) were associated with SVR. The rate of premature discontinuation was 35.7%. The main reason for withdrawal was intolerance to the drug due to common adverse events or cytopenia (48.2%). Conclusions: Our data suggest that the efficacy of peginterferon and ribavirin therapy in Koreans is better in Koreans than in Caucasians for the treatment of CHC, corroborating previous studies that have shown the superior therapeutic efficacy of this regimen in Asians.This study was supported by the Korean Association for the Study of the Liver in 2009

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia

IntroductionDespite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. MethodsHere, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. ResultsDifferential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. DiscussionAberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Taste receptor type 1 member 3 is required for the fertility of male mice

Male infertility is a global health concern. However, its underlying pathophysiology remains unclear. Taste receptor type 1 member 3 (TAS1R3) is highly expressed in the testes, indicating its potential involvement in male fertility. Using wild-type and Tas1r3 knockout (KO) mice, we investigated whether TAS1R3 modulates male reproductive function. Tas1r3 KO mice exhibited reduced male fertility compared to WT mice, with fewer live pups per litter and a delayed first litter. Testicular transcriptome analysis indicated suppressed PKA/CREB/StAR signaling–mediated testosterone synthesis in Tas1r3 KO mice. In silico single-cell RNA sequencing revealed considerably higher Tas1r3 expression in Leydig cells than in other testicular cell subtypes. An in vitro study validated that Tas1r3 knockdown downregulated the expression of Creb1 and steroidogenic genes in Leydig cells. Our results suggest that testicular TAS1R3 is intricately involved in male reproduction via the PKA/CREB/StAR signaling pathway, highlighting its potential as a promising target for addressing male infertility

Molecular Imaging of Cathepsin B Proteolytic Enzyme Activity Reflects the Inflammatory Component of Atherosclerotic Pathology and Can Quantitatively Demonstrate the Antiatherosclerotic Therapeutic Effects of Atorvastatin and Glucosamine

Inflammation in atherosclerotic plaques causes plaque vulnerability and rupture, leading to thromboembolic complications. Cathepsin B (CatB) proteases secreted by macrophages play a major role in plaque inflammation. We used a CatB-activatable near-infrared fluorescence (NIRF) imaging agent to demonstrate the inflammatory component in mice atheromata and the atherosclerosis-modulating effects of atorvastatin or glucosamine treatments. Apolipoprotein E knockout mice (n = 35) were fed normal chow, a Western diet, a Western diet + atorvastatin, a Western diet + glucosamine, or a Western diet + atorvastatin + glucosamine for 14 weeks. Twenty-four hours after the intravenous injection of a CatB-activatable probe, ex vivo NIRF imaging of the aortas and brains was performed, followed by histology. The CatB-related signal, observed in the aortas but not in the cerebral arteries, correlated very well with protease activity and the presence of macrophages on histology. Animals on Western diets could be distinguished from animals on a normal diet. The antiatherosclerotic effects of atorvastatin and glucosamine could be demonstrated, with reduced CatB-related signal compared with untreated animals. Plaque populations were heterogeneous within individuals, with some plaques showing a high and others a lower CatB-related signal. These differences in signal intensity could not be predicted by visual inspection of the plaques but did correlate with histologic evidence of inflammation in every case. This suggests that vulnerable inflamed plaques can be identified by optical molecular imaging

Altered white matter connectivity in patients with schizophrenia: An investigation using public neuroimaging data from SchizConnect.

Several studies have produced extensive evidence on white matter abnormalities in schizophrenia (SZ). However, optimum consistency and reproducibility have not been achieved, and reported low white matter tract integrity in patients with SZ varies between studies. A whole-brain imaging study with a large sample size is needed. This study aimed to investigate white matter integrity in the corpus callosum and connections between regions of interests (ROIs) in the same hemisphere in 122 patients with SZ and 129 healthy controls with public neuroimaging data from SchizConnect. For each diffusion-weighted image (DWI), two-tensor full-brain tractography was performed; DWIs were parcellated by processing and registering T1 images with FreeSurfer and Advanced Normalization Tools. White matter query language was used to extract white matter fiber tracts. We evaluated group differences in means of diffusion measures between the patients and controls, and correlations of diffusion measures with the severity of clinical symptoms and cognitive impairment in the patients using the Positive and Negative Syndrome Scale (PANSS), a letter-number sequencing (LNS) test, vocabulary test, letter fluency test, category fluency test, and trail-making test, part A. To correct for multiple comparisons, a false discovery rate of q < 0.05 was applied. In patients with SZ, we observed significant radial diffusivity (RD) and trace (TR) increases in left thalamo-occipital tracts and the right uncinate fascicle, and a significant RD increase in the right middle longitudinal fascicle (MDLF) and the right superior longitudinal fascicle ii. Correlations were present between TR of left thalamo-occipital tracts, and the letter fluency test and the LNS test, and RD in the right MDLF and PANSS positive subscale score. However, these correlations were not significant after correction for multiple comparisons. These results indicated widespread white matter fiber tract abnormalities in patients with SZ, contributing to SZ pathophysiology