マイクロRNA-33bの阻害は、炎症経路の抑制を介して腹部大動脈瘤形成を特異的に改善する

京都大学新制・課程博士博士(医学)甲第24484号医博第4926号新制||医||1063(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 森信 暁雄, 教授 YOUSSEFIAN Shohab, 教授 齊藤 博英学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Analysis of Absorbing Times of Quantum Walks

Quantum walks are expected to provide useful algorithmic tools for quantum computation. This paper introduces absorbing probability and time of quantum walks and gives both numerical simulation results and theoretical analyses on Hadamard walks on the line and symmetric walks on the hypercube from the viewpoint of absorbing probability and time.Comment: LaTeX2e, 14 pages, 6 figures, 1 table, figures revised, references added, to appear in Physical Review

Human Molecular Chaperone Hsp60 and Its Apical Domain Suppress Amyloid Fibril Formation of α-Synuclein

Heat shock proteins play roles in assisting other proteins to fold correctly and in preventing the aggregation and accumulation of proteins in misfolded conformations. However, the process of aging significantly degrades this ability to maintain protein homeostasis. Consequently, proteins with incorrect conformations are prone to aggregate and accumulate in cells, and this aberrant aggregation of misfolded proteins may trigger various neurodegenerative diseases, such as Parkinson’s disease. Here, we investigated the possibilities of suppressing α-synuclein aggregation by using a mutant form of human chaperonin Hsp60, and a derivative of the isolated apical domain of Hsp60 (Hsp60 AD(Cys)). In vitro measurements were used to detect the effects of chaperonin on amyloid fibril formation, and interactions between Hsp60 proteins and α-synuclein were probed by quartz crystal microbalance analysis. The ability of Hsp60 AD(Cys) to suppress α-synuclein intracellular aggregation and cytotoxicity was also demonstrated. We show that Hsp60 mutant and Hsp60 AD(Cys) both effectively suppress α-synuclein amyloid fibril formation, and also demonstrate for the first time the ability of Hsp60 AD(Cys) to function as a mini-chaperone inside cells. These results highlight the possibility of using Hsp60 AD as a method of prevention and treatment of neurodegenerative diseases

Zinc is a novel intracellular second messenger

Zinc is an essential trace element required for enzymatic activity and for maintaining the conformation of many transcription factors; thus, zinc homeostasis is tightly regulated. Although zinc affects several signaling molecules and may act as a neurotransmitter, it remains unknown whether zinc acts as an intracellular second messenger capable of transducing extracellular stimuli into intracellular signaling events. In this study, we report that the cross-linking of the high affinity immunoglobin E receptor (Fcɛ receptor I [FcɛRI]) induced a release of free zinc from the perinuclear area, including the endoplasmic reticulum in mast cells, a phenomenon we call the zinc wave. The zinc wave was dependent on calcium influx and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation. The results suggest that the zinc wave is involved in intracellular signaling events, at least in part by modulating the duration and strength of FcɛRI-mediated signaling. Collectively, our findings indicate that zinc is a novel intracellular second messenger

Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1

Thymic selection shapes an appropriate T cell antigen receptor (TCR) repertoire during T cell development. Here, we show that a serine/threonine kinase, protein kinase D (PKD), is crucial for thymocyte positive selection. In T cell-specific PKD-deficient (PKD2/PKD3 double-deficient) mice, the generation of CD4 single positive thymocytes is abrogated. This defect is likely caused by attenuated TCR signalling during positive selection and incomplete CD4 lineage specification in PKD-deficient thymocytes; however, TCR-proximal tyrosine phosphorylation is not affected. PKD is activated in CD4+CD8+ double positive (DP) thymocytes on stimulation with positively selecting peptides. By phosphoproteomic analysis, we identify SH2-containing protein tyrosine phosphatase-1 (SHP-1) as a direct substrate of PKD. Substitution of wild-type SHP-1 by phosphorylation-defective mutant (SHP-1S557A) impairs generation of CD4+ thymocytes. These results suggest that the PKD–SHP-1 axis positively regulates TCR signalling to promote CD4+ T cell development

Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis

マイクロRNA-33bの阻害は非アルコール性脂肪肝炎を改善する --核酸医薬による治療応用へ--. 京都大学プレスリリース. 2023-06-13.Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element–binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element–binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism–related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH

Successful Resection of locally infiltrative Glomus Tumor without pulmonary resection

Introduction: Extracutaneous glomus tumors occurring in the bronchus is very rare. Complete resection is basic procedure for treatment of glomus tumor. We present a glomus tumor of the left main bronchus that was successfully treated with rigid bronchoscopy followed by sleeve resection of the left main bronchus. Presentation of case: A 56-year-old man underwent two term resections to glomus tumor that originated from the left main bronchus. Firstly, we performed palliative resection with rigid bronchoscopy to make the correct diagnosis and evaluate the extent of the tumor. We subsequently performed curative resection. No complications or recurrence has occurred since the operation took place one year ago. Discussion: Before curative resection, it is important to confirm the diagnosis and spread of the tumor. Therefore, palliative tumor resection by rigid bronchoscopy was useful to make the correct diagnosis, evaluate the extent of the tumor and open the bronchial lumen. After bronchoscopic treatment, curative pulmonary resection was performed and preservation of lung function was successful. Conclusion: Two term resections enabled us to make an accurate diagnosis and evaluation, thereby preserving respiratory function without pulmonary resection

CD4+CD25(high)CD127(low/-) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis.

To investigate whether the frequency of peripheral blood (PB) regulatory T cells (Treg) correlates with the clinical disease activity of rheumatoid arthritis (RA)