Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo

Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC(50) ≈ 1.5 µM. Using an imaging probe we demonstrated that compound n = 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n = 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination

Linguagem, tecnologia e corporeidade: produção de significados para o tempo em gráficos cartesianos

Este artigo discute a produção de significados para gráficos cartesianos por alunos do ensino médio. Em particular, trata do papel da tecnologia na emergência da compreensão dos alunos de gráficos de distância versus tempo, onde o tempo é um eixo componente do gráfico. Vinte e oito alunos do primeiro ano do ensino médio foram filmados enquanto resolviam uma atividade de esboçar um gráfico cartesiano para uma situação de movimento dividida em três momentos: 1- lendo uma estória e usando lápis e papel; 2 - trabalhando com calculadora gráfica e sensores de movimento; 3 - revisitando o gráfico esboçado em 1. A teoria da cognição corporificada foi utilizada como fundamentação para analisar as produções de significado pelos estudantes sobre o produzido durante essa atividade. Os resultados mostram mudanças na percepção e na construção do eixo tempo, transformando o que antes era abstrato em algo palpável

Municipal service delivery: the role of transaction costs in the choice between alternative governance mechanisms

Service provision by local governments can be delivered using in-house bureaucracies, private firms, and partnerships with other governments or the not-for-profit sector. This production decision has been a major focus of discussion among scholars, practitioners and political agents for the last quarter of a century. The transaction costs framework is an important tool to analyse decisions regarding the production of local services. In this paper, the authors employ this framework to analyse service delivery in Portugal and find that service characteristics and the local political environment play a key role in local officials’ choice among the three governance mechanisms to deliver public service

Design of price incentives for adjunct policy goals in formula funding for hospitals and health services

Background. Hospital policy involves multiple objectives: efficiency of service delivery, pursuit of high quality care, promoting access. Funding policy based on hospital casemix has traditionally been considered to be only about promoting efficiency. Discussion. Formula-based funding policy can be (and has been) used to pursue a range of policy objectives, not only efficiency. These are termed 'adjunct' goals. Strategies to incorporate adjunct goals into funding design must, implicitly or explicitly, address key decision choices outlined in this paper. Summary. Policy must be clear and explicit about the behaviour to be rewarded; incentives must be designed so that all facilities with an opportunity to improve have an opportunity to benefit; the reward structure is stable and meaningful; and the funder monitors performance and gaming

Short Telomeres Compromise β-Cell Signaling and Survival

The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca2+ influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16INK4a. Specifically, we identified gene expression changes in pathways which are essential for Ca2+-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis

Numerical verification of icing hypotheses of the inlet of aircraft turbine engine TW2-117A

Numerical analysis of the inlet flow of aircraft turbine powerplant has been performed. The analysis has been focused on thermal conditions in view of the expected inlet icing phenomena. A commercial CFD Fluent package has been utilized in developing the model and solving the stated problem. The modelled system was a TW2-117A engine inlet of Mi-8P helicopter. Calculations of 2-D axisymmetric compressible viscous flow have been conducted. The modelled medium has been assumed of the air thermophysical properties. At the present stage effects the moist content and two-phase flow have been neglected. The calculations complemented results of previous theoretical analyses and experimental measurements with images of the temperature and the flow velocity distribution. The maximum temperature drop has been estimated to be at last -4 K close to the external inlet wall and about -5 K close to the central body. The boundary layer parameters have been identified applying several standard models of turbulence. The qualitative image of icing flow conditions has been verified and confirmed.Praca dotyczy analizy numerycznej termicznych warunków przepływu powietrza we wlocie lotniczego silnika turbinowego. Do analizy wykorzystano pakiet numerycznych obliczeń przepływowych FLUENT. Modelowano ściśliwy przepływ powietrza we wlocie silnika TW2-117A śmigłowca Mi-8P. Obliczenia wykonano w wariancie dwuwymiarowym osiowosymetrycznym dla założonych charakterystycznych warunków brzegowych przepływu. Kontekst analizy stanowiły zjawiska oblodzeniowe uwzględnione głównie w warunkach termicznych i w opisie właściwości modelowanego medium - powietrza. Ze względu na skupienie uwagi na zagadnieniach zmian temperatury uwarunkowanych kinetyką przepływu pominięto w obecnym etapie pracy zjawiska związane z efektami przepływu dwufazowego, uwzględniono natomiast lepkość powietrza. Wyniki obliczeń, w tym rezultaty otrzymane dla różnych modeli turbulencji, porównano z rezultatami wcześniej przeprowadzonej analizy teoretycznej i wynikami pomiarów zmian temperatury w trakcie prób silnika na hamowni. Uzyskano potwierdzenie hipotez oblodzeniowych oraz potwierdzono poprawność zastosowanych procedur badań doświadczalnych. Analiza wyników obliczeń numerycznych pozwoliła na odtworzenie obrazu przestrzennego pól parametrów przepływu. Maksymalny spadek temperatury w pobliżu ścianek zewnętrznych kanału określono jako nie mniejszy od -4 K, a w pobliżu ciała centralnego -5 K. Porównując wyniki obliczeń z wykorzystaniem kilku modeli turbulencji zidentyfikowano również parametry warstwy przyścienne

[[alternative]]The study of public-private partnership in BOT from the perspective of relational contract : the case study of Taipei transfer station

碩士[[abstract]]壹、研究背景：我國政府以「公私部門夥伴關係」(public-private partnerships)模式推動公共建設的發展已行之有年，其主要目的是為了利用民間的資金與專業以紓緩窘迫的財政，並且創造額外財政收入同時增加就業機會，而推行公共建設的方式又以BOT（Build-Operate-Transfer）模式為大宗。BOT模式乃是公部門藉由契約的簽訂將特許權授予私部門，公私雙方在契約的架構之下共同合作開發公共建設，但是卻發現在這類以公私夥伴關係經營BOT的諸多案例之中不乏失敗的個案，由此可見契約的簽訂並無法保證契約目標得以實現，因此如何經營公私夥伴之間的「關係契約」（relational contract），藉此達成契約目標實為本研究焦點。 貳、理論基礎：本文以Macneil在1960年代首次提出的關係契約理論為基礎，此理論強調任何的契約不僅存在著財貨的交易同時包含了雙方之間關係的交流，Macneil認為關係交流幾乎無處不在，因此關係契約理論可以說是描述社會秩序的通用理論。 參、研究方法：本文首先透過文獻分析法整理出各領域學者對於關係契約的理論論述與看法，歸納出關係契約的三項特徵，包括：長期合作、條款開放以及自行履約。接著藉由深入訪談瞭解本研究個案的實務工作者對於關係契約的認知以及關係契約在實務中的呈現方式。 肆、研究發現：關係契約的三項特徵在本個案中各自扮演不同的角色與功能： 一、長期合作特徵：本特徵以各種不確定因素呈現在本個案中，是造成合作過程容易產生問題與爭議的主要因素； 二、條款開放特徵：本特徵能夠讓合作夥伴建立彼此之間的信任以及合作情感，有利於夥伴關係的穩定發展；同時提供契約內部的爭議處裡機制讓夥伴得以尋求雙方都能夠接受的爭議處理方式，契約內部的爭議協調機制有效的避免法律強制力在爭議產生時的直接介入，間接確保了合作關係的和諧。 三、自我履行特徵：在個案中本特徵扮演著「胡蘿蔔與棒子」的角色，以誘因與壓力兩中方式呈現於本個案中，確保法律強制力難以介入合作關係。[[abstract]]I. Background: Our government use public-private partnerships mode to promoted the development of public construction has been several years.The main purpose is to ease the relief of financial distress, and create additional revenue while increasing employment opportunities, and the main way of implementation of public construction is BOT (Build-Operate-Transfer). The meaning of BOT model is the public sector granted concession to the private sector by signing contract. Then the public and private sector cooperation to develop public construction under the framework of the contract. But found that there are many failure cases, among many other cases of operating BOT by public-private partnerships mode. Shows that signing contract can not guarantee that the contract targets can be achieved, and how to operate relational contract between public and private sector, to achieve contract targets is the focus of this article. II. Theoretical Foundations: Relational contract theory was first proposed by Macneil in the 1960s, this theory stressed that any contract not only exists goods trading but also relations exchanges between both sides. Macneil thinks that the relation exchanges are almost unbitquious, so relational contract theory is the general theory to description of social order. III. Methods: Firstly, discourse and perspectives of scholars in various fields for the relational contract theory are sorted by literature analysis，and we conclude the following three features about relational contract：long-term cooperation、the opening of terms and self-enforcing.Then we can understand practitioners’ cognition for relational contract and the presentation of relational contract in practice in this case by in-depth interview. IV. Conclusions: The three features of relational contract play different roles and have important function individually in this case. 1.Long-term cooperation：It’s main factor to cause problems and disputes easily in process of cooperation, and thus it unsure factor in this case. 2.The opening of terms：It enables to establish trust and cooperation among partners, and it''s conducive to the stable development of the partnership.At the same time, it provide a mechanism that deal with controversy in contract for partners, and it will help partners search for the way that each other can accept. If there are controversy among partners, the mechanism of coordinating controversy in the contract can avoid interference of legal force directly, and indirectly ensure cooperation relationship. 3.Self-enforcing：It plays a role just like carrot-and-stick in this case, and it’s presentation of incentive and pressure to ensure that the force of law can’t intrude into the relationship of cooperation.[[tableofcontents]]目次 第一章　緒論 1 第一節 　研究背景與動機 1 第二節　研究目的與問題 5 第三節　研究流程 6 第二章　文獻回顧 7 第一節　「公私部門夥伴關係」之興起與定義 7 第二節　關係契約理論 12 第三節　我國促參法與施行現況 19 第三章　研究方法與架構 24 第一節 研究架構 24 第二節　研究個案 25 第三節　資料蒐集方法 27 第四節　資料分析方法 31 第四章　研究分析 32 第一節　長期合作特徵與挑戰之分析 33 第二節　條款開放特徵與挑戰之分析 43 第三節　自我履行特徵與挑戰之分析 59 第五章　結論 71 第一節　研究發現 71 第二節　研究建議 78 第三節　研究限制 81 參考書目 82 附件一　深度訪談資料 86 表次 表2-1 關係契約整理 17 表2-2 國內公共建設運作方式演變歷程 20 表2-3 2002至2012已簽約案件簽約件數及效益(截至101.03.31止) 21 表2-4 政府執行機關推動促参事務遭遇之困難 22 表2-5 相關產業界執行促参事務遭遇之困難 22 表3-1 受訪者列表 29 表3-2 訪談題綱表 30 表4-1 關係契約特徵於本個案中的呈現方式 70 圖次 圖1-1 研究流程圖 6 圖2-1 夥伴關係特徵分類圖 11 圖2-2 長期合作建立信任關係 14 圖2-3 契約光譜 18 圖3-1 研究架構 24 圖4-1 合作時期之劃分 32[[note]]學號: 698640447, 學年度: 10

Neuartige Konstruktions- und Funktionswerkstoffe aus gentechnisch synthetisierten und durch Biofarming hergestellten fibrillaeren Proteinen. Teilvorhaben 4: Applikationsuntersuchungen zur Biofunktionalitaet und zur Biokompatibilitaet neuartiger Konstruktions- und Funktionswerkstoffe aus fibrillaeren Proteinen Schlussbericht

SIGLEAvailable from TIB Hannover: F04B279 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Verbraucherschutz, Ernaehrung und Landwirtschaft (BMVEL), Berlin (Germany)DEGerman