Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T

Head-to-tail polymerization of tropomyosin is crucial for its actin binding, function in actin filament assembly, and the regulation of actin-myosin contraction. Here, we describe the 2.1 Å resolution structure of crystals containing overlapping tropomyosin N and C termini (TM-N and TM-C) and the 2.9 Å resolution structure of crystals containing TM-N and TM-C together with a fragment of troponin-T (TnT). At each junction, the N-terminal helices of TM-N were splayed, with only one of them packing against TM-C. In the C-terminal region of TM-C, a crucial water in the coiled-coil core broke the local 2-fold symmetry and helps generate a kink on one helix. In the presence of a TnT fragment, the asymmetry in TM-C facilitates formation of a 4-helix bundle containing two TM-C chains and one chain each of TM-N and TnT. Mutating the residues that generate the asymmetry in TM-C caused a marked decrease in the affinity of troponin for actin-tropomyosin filaments. The highly conserved region of TnT, in which most cardiomyopathy mutations reside, is crucial for interacting with tropomyosin. The structure of the ternary complex also explains why the skeletal- and cardiac-muscle specific C-terminal region is required to bind TnT and why tropomyosin homodimers bind only a single TnT. On actin filaments, the head-to-tail junction can function as a molecular swivel to accommodate irregularities in the coiled-coil path between successive tropomyosins enabling each to interact equivalently with the actin helix

Consumers' willingness to pay for alternative fuel vehicles: comparative analysis between US and Japan

Abstract This paper conducts conjoint analysis using a mixed logit model to estimate consumers' willingness to pay (WTP) for electric vehicles (EV) and plug-in hybrid electric vehicles (PHEV) on the basis of an online survey carried out in the US and Japan in 2012. We also carry out a comparative analysis across four US states. We find that on average the US consumers are more sensitive about fuel cost reduction and fuel station availability, whereas Japanese consumers are more sensitive about driving range and emissions reduction. As for the comparative analysis across the four US states, we find that WTP for fuel cost reduction varies significantly, and is the greatest in California. We use the estimates obtained in the conjoint analysis to consider EV/PHEV diffusion rates under several scenarios. In a base case scenario with relatively realistic attribute levels, conventional gasoline vehicles still dominate both in the US and Japan. However, in an innovation scenario with significant 1 Keywords: willingness to pay; conjoint analysis; discrete choice model; electric vehicles (EV); plug-in hybrid electric vehicles (PHEV) JEL Classifications: D12, O33, Q42, R40 purchase price reduction, we observe a high penetration of alternative fuel vehicles both in the US and Japan. We illustrate the potential use of conjoint analysis for forward-looking policy analysis, with the future opportunity to compare its predictions against actual revealed choices. In this case, increased purchase price subsidies are likely to have a significant impact on the diffusion rates of alternative fuel vehicles.

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation

Optimal waist circumference cut-off points and ability of different metabolic syndrome criteria for predicting diabetes in Japanese men and women: Japan Epidemiology Collaboration on Occupational Health Study

Abstract Background We sought to establish the optimal waist circumference (WC) cut-off point for predicting diabetes mellitus (DM) and to compare the predictive ability of the metabolic syndrome (MetS) criteria of the Joint Interim Statement (JIS) and the Japanese Committee of the Criteria for MetS (JCCMS) for DM in Japanese. Methods Participants of the Japan Epidemiology Collaboration on Occupational Health Study, who were aged 20–69 years and free of DM at baseline (n = 54,980), were followed-up for a maximum of 6 years. Time-dependent receiver operating characteristic analysis was used to determine the optimal cut-off points of WC for predicting DM. Time-dependent sensitivity, specificity, and positive and negative predictive values for the prediction of DM were compared between the JIS and JCCMS MetS criteria. Results During 234,926 person-years of follow-up, 3180 individuals developed DM. Receiver operating characteristic analysis suggested that the most suitable cut-off point of WC for predicting incident DM was 85 cm for men and 80 cm for women. MetS was associated with 3–4 times increased hazard for developing DM in men and 7–9 times in women. Of the MetS criteria tested, the JIS criteria using our proposed WC cut-off points (85 cm for men and 80 cm for women) had the highest sensitivity (54.5 % for men and 43.5 % for women) for predicting DM. The sensitivity and specificity of the JCCMS MetS criteria were ~37.7 and 98.9 %, respectively. Conclusion Data from the present large cohort of workers suggest that WC cut-offs of 85 cm for men and 80 cm for women may be appropriate for predicting DM for Japanese. The JIS criteria can detect more people who later develop DM than does the JCCMS criteria

A study of trends among alumni of Nayoro City College Nursing Department

本研究の目的は,市立名寄短期大学看護学科卒業生の動向と卒業生が社会で果たしている役割を明らかにすることにより,今後の名寄市立大学のあり方やその果たす役割について検討することである。市立名寄短期大学看護学科卒業生1期生〜10期生(1997年〜2006年卒)約500人を調査対象とし,2006年に自記式質問紙による留め置き調査を実施した。回答が得られた123人(回収率24.9%)について分析した。その結果,卒業時には札幌の200床以上の病院に就業していた卒業生たちが調査時点では札幌から道内各地へと広がり,都市部のみならず広く地域の保健福祉医療に従事していることがわかった。また,名寄市を含む道北地域に従事する者も卒業時点より増加していること,とりわけ名寄市内に卒業時就業した者と,調査時点で就業している者の数が等しく,名寄市に就職した後市外に転職した卒業生がいる一方で,他の地域で就業した後に名寄市内に就業する者がいることがわかった。卒業生の看護実践力の自己評価は必ずしも高くはないが,修得したい看護実践内容や自己研鑽の意欲は高く,前向きな姿勢であることが明らかとなった。卒業生がそれぞれの職場で担っている役割や,卒業生が感じている看護職としての前進・進歩の促進要因および阻害要因を分析し,教育機関としてどのような情報提供や協力体制が必要であるかについて考察した。本研究により,卒業生を輩出した地方小都市に位置する教育機関がどのような支援をしたらよいのかが今後の課題となった。This paper reviews results of a survey undertaken to clarify post-graduation trends over a 10-year period among alumini of the Nayoro City College Nursing program. Around 500 questionnaires were mailed out to graduates. Of the 123 respondents, roughly 80% were either working or studying in nursing-related fields. Immediately after graduation, the largest number of respondents found employment in Sapporo, the major centre of Hokkaido, while at the time of this survey, working alumni were spread more evenly throughout the various regions of Hokkaido. Also at graduation, respondents tended to find employment at larger institutions (>200 beds) while this percentage had decreased at the time of this survey. The number of alumni working in Nayoro has remained constant over time with some graduates moving away and others returning. Alumni did not rate their nursing skills highly, although their desire to brush up and advance their careers was high. This study reveals that graduates of Nayoro City College Nursing Department are active throughout Hokkaido

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A perspective on community development through partnerships

This thesis is about community development through partnerships in rural areas through a case study of North Sutherland in the Highlands and Islands of Scotland. It examines whether participatory and collaborative approaches benefit rural communities and enhance their quality of life. Community development begins by seeking identities through looking at the environment in which people live and the relationship between people on which social activities depend. This approach has the effect of getting people to realize their roles within social networks. At the same time, a dynamic structural change in the approach to planning has been experienced in the Highlands and Islands. Working closely with the Scottish government, and the private and voluntary sectors, the mechanism of these initiatives has structured the framework of community governance in the area. The key question is what kind of distributive patterns are associated with the outcomes being produced. To answer this, this thesis looks at how new forms of governance have emerged and what they intend to deliver. Moreover, it is important to clarify what the outcomes of community development are intended to be. This study is based on theory and practice. It defines the framework of `community development through partnership', constructed through the application of an institutionalist approach to the analysis of planning practices. The main concerns of this institutional analysis are the process, mechanism and conditions of community development, and the links between different elements such as policies, the role of actors, and the funding of community development projects. These analytical ideas are supplemented by regulation theory, urban regime theory, and intersubjectivity. The thesis outlines a wide array of policies and programmes from both European Union and the UK government / Scottish Parliament in order to understand the current picture of rural development and give a perspective on `spatial planning' for rural areas. It examines the institutional capacities of four partnerships in the case study area. Some significant findings from the case study in North Sutherland are summarised in relation to three themes: changing governance; institutional capacity; and political coherence. These findings are discussed in depth through the notions of `heuristic processes' and `potential space'.EThOS - Electronic Theses Online ServiceGBUnited Kingdo