ヒト及びカニクイザル胎児卵母細胞発生過程の体外再構成

京都大学新制・論文博士博士(医学)乙第13537号論医博第2277号新制||医||1065(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 篠原 隆司, 教授 近藤 玄, 教授 齋藤 潤学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

Experimental Study on Friction Properties of Rubber Material: Influence of Surface Roughness on Sliding Friction

AbstractThis study investigated the influence of the surface roughness of rubber on sliding friction. The friction was measured by using textured specimens and plain (non-textured) specimens. Under a dry condition, the textured specimens, whose contact area was smaller than that of the plain ones, showed low coefficients of friction. Under a lubricated condition, the coefficients of friction of the textured specimens were higher in a low speed region, but those were lower in a higher speed region. Therefore, the lubrication conditions should be considered in the application of the texturing on rubber surface

インシリコ及びインビトロスクリーニングによるA型インフルエンザウイルスの増殖阻害活性をもつ低分子化合物の同定

Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to identify new inhibitors of the NP using a structure-based drug discovery algorithm, named Nagasaki University Docking Engine (NUDE), which has been established especially for the Destination for GPU Intensive Machine (DEGIMA) supercomputer. The hit compounds that showed high binding scores during in silico screening were subsequently evaluated for anti-influenza virus effects using a cell-based assay. A 4-hydroxyquinolinone compound, designated as NUD-1, was found to inhibit the replication of influenza virus in cultured cells. Analysis of binding between NUD-1 and NP using surface plasmon resonance assay and fragment molecular orbital calculations confirmed that NUD-1 binds to NP and could interfere with NP-NP interactions essential for virus replication. Time-of-addition experiments showed that the compound inhibited the mid-stage of infection, corresponding to assembly of the NP and other viral proteins. Moreover, NUD-1 was also effective against various types of influenza A viruses including a clinical isolate of A(H1N1)pdm09 influenza with a 50% inhibitory concentration range of 1.8?2.1 μM. Our data demonstrate that the combined use of NUDE system followed by the cell-based assay is useful to obtain lead compounds for the development of novel anti-influenza drugs.長崎大学学位論文 学位記番号:博(医歯薬)甲第997号 学位授与年月日:平成29年9月20日Author: Juliann Nzembi Makau, Ken Watanabe, Takeshi Ishikawa, Satoshi Mizuta, Tsuyoshi Hamada, Nobuyuki Kobayashi, Noriyuki NishidaCitation: PLOS ONE, 12(3), e0173582; 2017Nagasaki University (長崎大学)課程博

A Quinolinone Compound Inhibiting the Oligomerization of Nucleoprotein of Influenza A Virus Prevents the Selection of Escape Mutants

The emergence of resistance to currently available anti-influenza drugs has heightened the need for antivirals with novel mechanisms of action. The influenza A virus (IAV) nucleoprotein (NP) is highly conserved and essential for the formation of viral ribonucleoprotein (vRNP), which serves as the template for replication and transcription. Recently, using in silico screening, we identified an antiviral compound designated NUD-1 (a 4-hydroxyquinolinone derivative) as a potential inhibitor of NP. In this study, we further analyzed the interaction between NUD-1 and NP and found that the compound interferes with the oligomerization of NP, which is required for vRNP formation, leading to the suppression of viral transcription, protein synthesis, and nuclear export of NP. We further assessed the selection of resistant variants by serially passaging a clinical isolate of the 2009 H1N1 pandemic influenza virus in the presence of NUD-1 or oseltamivir. NUD-1 did not select for resistant variants after nine passages, whereas oseltamivir selected for resistant variants after five passages. Our data demonstrate that NUD-1 interferes with the oligomerization of NP and less likely induces drug-resistant variants than oseltamivir; hence, it is a potential lead compound for the development of novel anti-influenza drugs

Adenocarcinoma of the Small Intestine in a Young Adult Diagnosed by Double-balloon Enteroscopy

A 29-year-old man presented with a 3-month history of abdominal pain and appetite loss. Superficial lymph node adenopathy was noted. Systemic computed tomography showed multiple liver and lung metastases, as well as ascites. No abnormalities were found on upper gastrointestinal endoscopy and colonoscopy; therefore, double-balloon enteroscopy was performed. A stenosis with reddish and edematous mucosal changes from the third part of the duodenum to the upper jejunum was noted; on histopathology of the biopsy specimens, adenocarcinoma was diagnosed. Thus, the patient had advanced small intestinal cancer with carcinomatous peritonitis and liver metastases. Although the patient was given chemotherapy with cisplatin and 5-fluorouracil, he died 2 months after commencing treatment. Primary small intestinal carcinoma is a rare malignancy; most cases cannot be detected on routine gastrointestinal endoscopy due to their location. Our experience suggests that double-balloon enteroscopy is useful for diagnosing small intestinal adenocarcinoma

Effects of smoking cessation on gastric emptying in smokers.

BACKGROUND: Smoking cessation can lead to changes in appetite and weight gain in some patients; thus, smoking cessation may alter gastrointestinal motility. Effects of smoking cessation on gastric emptying in smokers have not been established. AIM: This study sought to determine how smoking cessation affects gastric emptying in smokers. METHODS: Participant group comprised 53 habitual smokers and 12 healthy nonsmokers. Habitual smokers were treated for 2 months with transdermal nicotine patches. Gastric emptying was studied using C acetate breath tests at the beginning of the study, and at 1 week and 9 weeks after cessation of patch use. Maximal CO2 excretion time (Tmax), CO2 excretion half-life (T1/2), and parameters beta and kappa, representing initial and subsequent gastric-emptying phases, respectively, were determined using conventional formulae. RESULTS: Before smoking cessation, Tmax was reached significantly later in smokers (0.94+/-0.3 h, P=0.014) than in controls (0.89+/-0.1 h). At 1 week after the end of treatment, Tmax was significantly decreased (from 1.05+/-0.32 h to 0.72+/-0.64 h, P=0.003). T1/2 also tended to decrease, but not significantly. Although beta was decreased significantly (from 2.46+/-0.40 to 2.17+/-0.58, P=0.022), kappa was unchanged. However, by 9 weeks after the end of treatment, Tmax (1.28+/-0.69 h) had increased to levels seen before treatment. CONCLUSIONS: Smoking cessation temporarily accelerates gastric emptying, and decreases in beta suggest that initial-phase gastric emptying accelerates after smoking cessation. The temporary acceleration of gastric emptying after smoking cessation may be involved in the temporary increase in appetite and weight gain seen after smoking cessation

Ex vivo reconstitution of fetal oocyte development in humans and cynomolgus monkeys

ヒト・サルの胎児卵巣から原始卵胞を体外で作出することに成功. 京都大学プレスリリース. 2022-08-01.New egg recipe to boost fertility research. 京都大学プレスリリース. 2022-08-14.In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates