ミトコンドリア品質管理におけるパーキンソン病の原因遺伝子産物PINK1と Parkinの解析

学位の種別:課程博士University of Tokyo(東京大学

Analysis of both the envelope sequence and the complete genome of a HIV-1 subtype f cluster of rapid expansion in Galicia: coreceptor use prediction and phylogeny

La epidemia por VIH-1 en España, al igual que en el resto de Europa occidental, está dominada por el subtipo B. Sin embargo, recientemente se ha descrito la rápida expansión de un cluster de subsubtipo F1 entre hombres que tienen relaciones sexuales con hombres en Galicia. Los objetivos de este trabajo son analizar la secuencia de la envoltura de los virus del mencionado cluster para predicción de utilización de correceptores y presencia de aminoácidos característicos, así como caracterizar secuencias de genomas completos, determinando las relaciones filogenéticas con virus de subtipo F de otros países. Los análisis filogenéticos permitieron determinar relaciones del cluster F con virus de Brasil, Suiza, Bélgica, Francia y Gran Bretaña. Por otra parte, se han encontrado posiciones características del cluster en la región V3, diferentes de otras cepas F1, así como en otras regiones de la envoltura. Aparte, se han identificado mutaciones características asociadas a tropismo X4. El cluster de VIH-1 de subtipo F recientemente expandido en Galicia procede de una variante ampliamente diseminada en Europa occidental. Los virus de dicho cluster presentan aminoácidos característicos en la envoltura, identificándose en algunos de ellos mutaciones asociadas a tropismo X4, de potencial relevancia biológicaThe HIV-1 epidemic in Spain, as in the rest of Western Europe, is dominated by subtype B. However, it has recently been reported that a subsubtype F1 cluster has rapidly expanded among men who have sex with men in Galicia. The objectives of this work are to analyze the virus envelope sequence of the aforementioned cluster to predict the use of coreceptors and to examine the presence of characteristic amino acids, as well as to characterize full-length genome sequences, determining the phylogenetic relations with subtype F viruses from other countries. The phylogenetic analyses allowed to determine the relation of the Galician F cluster with viruses from Brazil, Switzerland, Belgium, France and Great Britain. On the other hand, characteristic amino acid residues were found in the V3 loop of viruses of the cluster, differing from other F1 strains, as well as in other regions of the envelope. Additionally, characteristic mutations associated with X4 tropism were identified. The HIV-1 subtype F cluster recently expanded in Galicia derives from a variant widely disseminated in Western Europe. The viruses of the mentioned cluster show characteristic amino acids in the envelope, with mutations associated with X4 tropism having been identified in some of them, which are of potential biological relevance

成人の運動・スポーツ実施促進条件に関する社会学的研究 ―実施経験のジェンダー差に着目して―

Chukyo University （中京大学

High Strength Linepipe with Excellent HAZ toughness

Abstract The API 5L-X65 steel plates for low temperature service were produced using the thermo-mechanical control process (TMCP) with the optimum micro-alloying addition. Featuring of the additions are as low amount of titanium, calcium, niobium, and vanadium as possible, for high heat affected zone (HAZ) toughness and strength. Controlling titanium and nitrogen and the Ti / N ratio, a large number of TiN dispersed finely are formed in steel and the austenite grain size near a weld fusion line is refined remarkably owing to strong pinning effect of TiN. Calcium addition promotes ferrite nucleation, so that increase in fine polygonal ferrites makes microstructure of HAZ much finer. Niobium and vanadium content are reduced, because carbide precipitates are formed when the coarse grain HAZ is reheated around 700 degree C and the precipitation hardening deteriorates HAZ toughness. The trial manufacturing of the 19.5mm, 26.9mm and 31.4mm thick X65 grade UOE pipes was finalized with the satisfactory results. The toughness of longitudinal submerged-arc welds was more than 50 J in Charpy V-notch impact test at -30°C. Introduction As the exploration of oil and gas fields are expanding toward severe environment regions, requirements for the performance of linepipes has been diversified and has become stringent. Recent study indicated the significant advantages of using higher strength linepipes in constructing long distance pipelines [1], because it can improve transportation efficiency of gas and oil pipelines by increasing internal pressure, and material cost can be saved by reducing wall thickness of pipe body and consumable of weldment. Another severe requirement for the pipes these days is to ensure low temperature toughness of welded region, such as Heat Affected Zone (HAZ) and weld metal, as well as parent material. The parent material of linepipe is usually manufactured by using TMCP (Thermo-Mechanical Controlling Process) technique. Accelerated cooling techniques gives significant advantages in improving strength and toughness of parent materials through controlling their microstructure to be fine shape, and this led to a considerable increase in the number of applications for manufacturing the higher strength linepipes in this decade. However, the fine microstructure that has been developed by TMCP can not exist in HAZ, because HAZ is exposed in high temperature during welding. This microstructural change often brings deterioration effects in toughness of HAZ. In case of heavier wall linepipes than 20mm, testing temperature reduction rule is often applied. This means testing temperature for Charpy V test should be -20 to -30 degree C for the heavier wall linepipes even when their service temperature is -10 degree C. In this sense, importance to ensure superior HAZ toughness for the heavier wall materials is highlighted. To ensure the superior toughness of HAZ, the effects of alloying elements, such as Ti, N, Ca, Nb V and Oxygen on microstructure of HAZ in terms of suppressing grain coarsening in HAZ, introducing ferrite nucleation sites and suppressing formation of M-A constituents in HAZ have been investigated

TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1

The Seepage Control of the Tunnel Excavated in High-Pressure Water Condition Using Multiple Times Grouting Method

Groundwater can cause many hazardous problems when a tunnel is excavating. Seepage force acting on the support structure and the tunnel surface cannot be negligible. Under high groundwater table condition, the seepage situation becomes more complex and it is more difficult to control the leakage of groundwater to flow into a tunnel. In the paper, a multiple times grouting method is proposed, and the mechanical deformation behavior of surrounding rock is analyzed using the FLAC3D (Fast Lagrangian Analysis of Continua in 3 Dimensions) software according to the high groundwater table condition of the Hokusatsu tunnel. The results present that multiple times grouting can control leakage and the rock deformation well, compared with one-time grouting condition in rock breaking and high water pressure area. The seepage force decrease around the tunnel and the displacement is controlled effectively. The pore pressure reduces inside the grouting zone using a new kind of grouting material, which is high permeability ultramicro particle cement (average particle size 1.5 μm). In the test fieldwork, the grouting scheme reduces the maximum discharge from 300 t/h to 40 t/h, and there is not obvious deformation and abnormal stress in the tunnel. The multiple times grouting method proposed in this research is verified effectively and can supply a positive experience to on-site construction

Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy

Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates

高齢者の友人関係 : 交流館の自主グループ活動者の調査から

The purpose of this study is to clarify friendships among the elderly. A survey was conducted by questionnaires on elderly people active at a community center in Toyota City. The subjects of this study were a total of 1,901 (men=538, women=1363) elderly people over the age of sixty years. The results of this study clarified the characteristics of best friends and the structure of close friends. Characteristics of best friend were as follows: (1) a person of the same sex and ages; (2) got to know each others through a hobby or sport; (3) male friends live in the same citys; (4) female friends live in the same neighborhood. Structures close friends are characterized as follows: (1) a high rate friends of the same sex the women; (2) a low rate of friends of the same age; (3) a high rate of close friends living in the same community. A hobby and/or sports activity are important to make friends. Because their friendships developed from ways for eldery people a hobby and/or sports activity in a given neighborhood, it is suggested that such relationships may well have a certain influence upon the local community

14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice

新たなてんかん治療戦略を提案 --脳の過剰興奮を阻止するタンパク質ADAM22の量が鍵--. 京都大学プレスリリース. 2021-12-15.What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that ∼50% of LGI1 and ∼10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment