Au cours de ce travail de thèse, nous avons abordé l’étude des gènes BTBD6 et Dmrt5 au cours du développement embryonnaire en utilisant les avantages complémentaires de plusieurs organismes modèles.<p>\ / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Indiana University-Purdue University Indianapolis (IUPUI) / The addition and removal of phosphate groups is a key regulatory mechanism for many cellular processes. The balance between phosphorylation and dephosphorylation is delicate and must be maintained in order for proper cell functions to be carried out. Protein kinases and phosphatases are the keepers of this balance with kinases adding phosphate groups and phosphatases removing them. As such, mutation and/or altered regulation of these proteins can be the driving factor in disease. Phosphatase of Regenerating Liver (PRL) is a family novel of three dual specificity phosphatases (DSPs) first discovered in the regenerating liver tissue of rats. PRLs have also been shown to act as oncogenes in cell culture and in animal models. However, the physiological substrate and mechanisms of the PRLs are not yet known. Recently, our lab has developed a PRL 2 knockout mouse and found several striking phenotypes all of which correspond to a significant increase in PTEN. We also found that PRL 2 is targetable by small molecular inhibitors that can potentially be used to disrupt tumor growth and spermatogenesis. Furthermore, a PTEN heterozygous mouse model crossed into our PRL 2 knockout line was generated to investigate the relevance of PRL interaction with PTEN in cancer.

Indiana University-Purdue University Indianapolis (IUPUI) / Non-alcoholic steatohepatitis (NASH), which is characterized by the induction of hepatocellular death and inflammation, is associated with the activation of cellular stress pathways such as the Unfolded Protein Response (UPR), an adaptive response to disruptions in endoplasmic reticulum (ER) homeostasis. Because the role of the UPR in the progression of liver disease is not well understood, we established an in vitro model to evaluate the role of the UPR in NASH and translated results to clarify disease progression in human liver biopsy samples. Treating HepG2 cells and primary human hepatocytes with saturated, but not unsaturated free fatty acids (FFAs), at physiologic concentrations induced hepatotoxicity by inhibiting autophagic flux. Saturated FFA treatment activated the UPR, including the transcription factors CHOP (GADD153/DDIT3) and NF-κB, leading to increased expression and secretion of cytokines such as TNFα and IL-8 that contributed to hepatic cell death and inflammation. Depletion of either CHOP or the RELA subunit of NF-κB in hepatocytes alleviated autophagy and cytokine secretion, resulting in enhanced cell viability and lowered inflammatory responses during exposure to saturated FFAs. We carried out next generation sequencing on cells deleted for either CHOP or RELA and identified IBTKα as a novel UPR member directly regulated by CHOP and NF-κB. In response to saturated FFAs, loss of IBTKα increased cell survival through lowered phagophore formation and reduced cytokine secretion. We also identified binding partners of IBTKα by immunoprecipitation and LC/MS, indicating that that IBTKα is part of a protein complex which functions at ER exit sites to facilitate initiation of autophagy and protein secretion. Furthermore, we discovered that CHOP and RELA coordinately regulate proteasome activity through NRF2 as an adaptive response to an inhibition of autophagic flux following palmitate exposure. To validate our model, we utilized human liver biopsy samples and demonstrated up-regulation of the UPR coincident with accumulation of autophagy markers, as well as secretion of cytokines IL 8 and TNFα in serum of NASH patients. Our study provides a mechanistic understanding of the roles of the UPR and autophagy in regulating saturated FFA induced hepatotoxicity at the cellular level.

Currently, researchers are more likely to use mindfulness techniques. These practices have a beneficial effect on anger perception, experience, understanding, expression, and anger control. There has not yet been research on the influence of mindfulness on anger management in the Czech Republic. This thesis concerns the question, of whether it is possible to better manage and understand anger with the help of an 8week mindfulness course (MBSR). The literature-overview part summarizes current knowledge about mindfulness and anger, possible mechanisms of mindfulness on anger and methods of measuring anger. The research part includes the translation of the self-assessment inventory of anger STAXI-2 into the Czech language and the verification of its psychometric properties. It also covers the pilot use of STAXI-2 supplemented by FFMQ-15 in quantitatively focused research. The research design consists of a pretest-posttest control-group design plus a third measurement after one month. The experimental group participates in the eight-week mindfulness course, whereas the active control group participates in walks. The research is complemented by a qualitative analysis using semi-structured interviews. The main result of the research part is that completing an eight-week mindfulness course can lead to a...

Indiana University-Purdue University Indianapolis (IUPUI) / Patients with the genetic disorder tuberous sclerosis complex (TSC) suffer from neoplastic growths in multiple organ systems. These growths are the result of inactivating mutations in either the TSC1 or TSC2 tumor suppressor genes, which negatively regulate the activity of mammalian target of rapamycin complex 1(mTORC1). There is currently no cure for this disease; however, my research has found that cells harboring TSC2-inactivating mutations derived from a rat model of TSC are sensitive to apoptosis induced by the clinically approved proteasome inhibitor, bortezomib, in a manner dependent on their high levels of mTORC1 activation. We see that bortezomib induces the unfolded protein response (UPR) in our cell model of TSC, resulting in cell death via apoptosis. The UPR is induced by accumulation of unfolded protein in the endoplasmic reticulum (ER) which activates the three branches of this pathway: Activating transcription factor 6 (ATF6) cleavage, phosphorylation of eukaryotic initiation factor 2α (eIF2α), and the splicing of X-box binding protein1 (XBP1) mRNA. Phosphorylation of eIF2α leads to global inhibition of protein synthesis, preventing more unfolded protein from accumulating in the ER. This phosphorylation also induces the transcription and translation of ATF4 and CCAAT-enhancer binding protein homologous protein (CHOP). Blocking mTORC1 activity in these cells using the mTORC1 inhibitor, rapamycin, prevented the expression of ATF4 and CHOP at both the mRNA and protein level during bortezomib treatment. Rapamycin treatment also reduced apoptosis induced by bortezomib; however, it did not affect bortezomib-induced eIF2α phosphorylation or ATF6 cleavage. These data indicate that rapamycin can repress the induction of UPR-dependent apoptosis by suppressing the transcription of ATF4 and CHOP mRNAs. In addition to these findings, we find that a TSC2-null angiomyolipoma cell line forms vacuoles when treated with the proteasome inhibitor MG-132. We found these vacuoles to be derived from the ER and that rapamycin blocked their formation. Rapamycin also enhanced expansion of the ER during MG-132 stress and restored its degradation by autophagy. Taken together these findings suggest that bortezomib might be used to treat neoplastic growths associated with TSC. However, they also caution against combining specific cell death inducing agents with rapamycin during chemotherapy.

No / People, systems, and things in the cities generate large amount of data which is considered to be the most scalable asset of any smart city. Linux users are rapidly increased in last few years, and many large multinational organizations are deploying long distance high bandwidth (LDHB) cloud networks for centralizing the data from various smart cities on a central location. TCP is responsible for reliable communication of data in these cloud networks. For reliability communication among various smart cities, a number of TCP congestion control mechanisms have been developed in the past. TCP Compound, TCP Fusion, and TCP CUBIC are the default TCP congestion control mechanisms for Microsoft Windows, Sun Solaris, and Linux operating systems respectively. The response function of TCP CUBIC is higher than the response function of Standard TCP, which is a trademark congestion control mechanism. As a result, TCP CUBIC does not behave friendly with Standard TCP in LDHB cloud networks. The Congestion Window (cwnd) reduction and growth of TCP CUBIC is very aggressive, which causes high packet loss rate and unfair share of available link bandwidth among competing flows from various smart cities. The aim of this research is to design a new TCP congestion control mechanism for Linux operating system to achieve maximum performance in LDHB cloud networks being used by smart cities. In this paper, congestion control module for slow start (CCM-SS) is designed by increasing the lower boundary limit of cwnd size in slow start phase of communication. Congestion control module for loss event (CCM-LE) is designed by increasing the cwnd reduction rate at each packet loss event and finally Advance Response Function for TCP CUBIC (ARFC) is proposed to design a new congestion control mechanism for Linux operating system. NS-2 is used to compare the performance of TCP CUBIC* with TCP CUBIC in short distance high bandwidth (SDHB) and long distance high bandwidth (LDHB) cloud networks. Results show that TCP CUBIC* has outperformed in LDHB networks, at least by a factor of 18% as compared to TCP CUBIC.

Este trabalho estuda o instituto das medidas compensatórias como uma nova obrigação imposta pelo direito aos empreendimentos com potencial de causar impactos negativos ao meio ambiente. A pesquisa do tema se deu de forma crítica, enfrentando as contradições do sistema econômico vigente. Verificou-se que as medidas compensatórias emergiram da mais evidente crise ambiental ou à crescente escassez dos recursos naturais, buscando, ao mesmo tempo, a proteção ambiental e a manutenção do sistema de mercado. Procurando a melhor funcionalidade das medidas, pretendeu-se demonstrar que elas não se equiparam a uma forma de reparação por dano futuro, tampouco se enquadram necessariamente em uma espécie tributária; podem, como quis o Supremo Tribunal Federal, ser chamadas de compartilhamento de despesas entre o Poder Público e os empreendedores pelos custos da utilização dos recursos naturais no processo produtivo. Na verdade, em razão de serem dotadas das características da transversalidade e da interdisciplinaridade, as medidas compensatórias apresentam-se com diversas facetas, podendo mostrar características predominantes de mecanismos de comando e controle, como também de instrumentos econômicos. Assim, concluiu-se nesta tese ser um instituto híbrido, não enquadrável em uma categoria jurídica estanque. Verificou-se, ainda, ser necessária uma análise estrutural a fim de serem eficazes. Nesse sentido, propôs-se a sua instituição por normas primárias, nas quais se fixem padrões mínimos e com critérios objetivos de aplicação. Para tanto concluir, o estudo partiu dos debates já travados, tanto pela jurisprudência quanto pela doutrina, acerca da constitucionalidade, metodologia de cálculo e natureza jurídica de uma das medidas compensatórias, chamada compensação ambiental, instituída pela Lei nº 9.985/2000 (Lei do Sistema Nacional de Unidades de Conservação-SNUC). A partir daí, buscou-se demonstrar o processo subjacente à edição de normas ambientais, recaindo nos princípios do Direito Ambiental, dentre eles o importante princípio do poluidor-pagador, cuja premissa é internalizar os custos pela utilização dos recursos naturais no processo produtivo, para não serem assumidos pelo Poder Público e por toda a coletividade. Ainda, buscou-se diferenciar os conceitos de dano ambiental e de impacto negativo ao meio ambiente, porquanto as medidas compensatórias visam a compensar o meio ambiente pelos impactos negativos, significando uma perda aceita, prevista e gerenciada; o dano ambiental, por sua vez, é algo intolerável, indesejado e, por isso, objeto de reparação civil objetiva, de responsabilidade administrativa e, ainda, da penalização criminal / This paper studies the institution of compensatory measures, considered as a new obligation imposed by law for projects with the potential to cause adverse environmental impacts. The theme was investigated critically, facing the contradictions of the current economic system. In this regard, we verified compensatory measures instituted to cope with an increasingly apparent environmental crisis and the growing shortage of natural resources, while seeking environmental protection and maintenance of the market. In the search for a better functionality of the measures, we sought to demonstrate that they do not represent a form of compensation for future damages, nor do they necessarily fall within the range of any legitimate taxation. In fact, these measures were adopted by the Supreme Court more as a sharing of costs between government and entrepreneurs for the use of natural resources in the production process. Fundamentally, the compensatory measures of this instrument, equipped with characteristics of transversality and interdisciplinarity, present different aspects, which can deploy features to carry out command and control mechanisms, as well as economic instruments. Our thesis has therefore led us to the conclusion that this instrument is not readily classifiable under any isolated legal category, and should be looked upon as a hybrid mechanism. Nevertheless, we considered that a structural analysis was necessary to ensure the effectiveness of the measures. In this respect, we proposed it be instituted on primary norms, with the establishment of minimum standards and objective application criteria. This required starting with debates conducted in jurisprudence and doctrine over the constitutionality, method of calculation, and legal nature of a compensatory measure called environmental compensation, established by Law No. 9.985/2000 (Law of the National System of Conservation Units, SNUC). From there, we sought to demonstrate the process behind the issuing of environmental standards falling within the principles of environmental law; among which the important polluter pays principle, which is premised on the environmental externalities of economic activities that use natural resources, and prevents that pollution costs be borne by Government and, ultimately, by the whole community. We went on by delimiting the concepts of environmental damage and negative environmental impact, considering that compensatory measures aim at providing compensation for adverse impacts, which signify accepted, provided and managed losses. Environmental damage, in turn, is something unacceptable and undesirable, and must therefore be subject to civil liability, as well as criminal penalties.

Made available in DSpace on 2016-04-26T20:22:25Z (GMT). No. of bitstreams: 1 Livia Gaigher Bosio Campello.pdf: 14428380 bytes, checksum: 25b599490f25334aec981859c64ae994 (MD5) Previous issue date: 2013-06-10 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / This study aims at the international mechanisms instituted for the control implementation and compliance of multilateral international Treaties on environment protection prevailing in the international order. The interest in this investigation is justit1ed by the need to find the basis of and to give answers to difficulties on the integration, implementation and compliance of environment protection rules by the States. On the other hand, the prevention and the promotion of compliance are identified as primary purposes herein. Thus, the assistance mechanisms provided in the Treaties form part of a strategy destined to promote a new culture of environmental protection necessary for damage prevention and compliance with the environmental protection rules. The valorative basis of such international practice, which is pragmatically verified by means of cooperation, s the principle of solidarity, a fundamental value of the International Law and, in particular, the Environmental International Law. The principle of solidarity, in this study, figures as a landmark and a pillar to the operation and control of compliance with the States' obligations in two dimensions: international solidarity among States in order to defend the common interests of humankind; and intergenerational solidarity in order to ensure the environment preservation for present and future generations. In this perspective, solidarity is conceived as more than a general concept of neighborliness or good faith, bl.1t a structurally regulated legal value that generates rights and duties / Este estudo tem por objeto os mecanismos internacionais instituídos para o controle da aplicação e cumprimento dos Tratados internacionais multilaterais de proteção ambiental vigentes no ordenamento internacional. O interesse nesta investigação se justifica pela necessidade de encontrar os fundamentos e dar respostas às dificuldades de integração, aplicação e cumprimento das normas internacionais de proteção do meio ambiente pelos Estados. De outro lado, a prevenção e a promoção do cumprimento são identificadas nesta pesquisa como finalidades primordiais. Assim, os mecanismos assistenciais previstos nos Tratados formam parte da estratégia destinada a fomentar uma cultura de proteção do meio ambiente, necessária para prevenir os danos e favorecer o cumprimento das normas jurídicas protetoras do meio ambiente pelos Estados. O alicerce valorativo dessa prática internacional, a qual se verifica pragmaticamente por intermédio da cooperação, é o princípio da solidariedade, valor fundamental do Direito Internacional e, em especial, do Direito Internacional Ambiental. O princípio da solidariedade, nesta tese, é apresentado 'como marco e alicerce para atuação e controle do cumprimento das obrigações dos Estados em duas dimensões: solidariedade' internacional entre os Estados para defesa dos interesses comuns da humanidade e solidariedade intergeracional para garantir a preservação do meio ambiente para as gerações presentes e futuras. Nessa perspectiva, a solidariedade é concebida como mais do que uma noção geral de boa vizinhança ou boa-fé, como valor jurídico estruturante positivado que cria direitos e obrigações

醫院屬於非營利性機構，不以追求最大利潤為其績效標準，故醫院管理與一般企業管理在本質上便有所不同。在長期觀察醫院的經營情況中，醫院內部長久以來存在於醫療體系與行政體系之間的衝突，成為當今醫院內部重要的管理問題。因此，本研究擬根據醫療體系與行政體系之間的互動情形，歸納出醫院類型的區分構面，希望對於醫院的經營與管理能提供正面而積極的建議。此外，全民健康保險已於民國84年3月1日起正式實施，此一政策對於醫療院所的影響極為深遠，造成台灣醫療生態環境以及醫院管理方式大幅度的改變，並使得業者殷切期盼新的醫院管理之道。 本研究以醫院評鑑等級在地區教學醫院（含）以上的醫院為研究對象。首先透過個案研究，尋找醫院內部互動類型的適當分類構面以及控制機制的選用情形，並提出研究假設。接著再以實證方式，驗證研究假設。經篩選醫院名單後，合格樣本數為112家，回收有效問卷為47份，而檢定結果支持大部分的假設。本研究的具體發現分述如下： 1.醫院可以根據「專業取向」與「行政取向」兩個分類構面，將醫院區分成專業取向較高的「專業取向型」、行政取向較高的「行政取向型」、以及兩者皆高的「互動協調型」三類。 2.互動關係偏向專業取向的「專業取向型」，在全民健康保險實施前，其選用的控制機制，由最高至最低依次為官僚控制機制、文化控制機制、市場控制機制。然而專業取向型醫院在三種控制機制選用之間並無顯著差異，但與其他類型醫院比較，其選用控制機制的絕對值均小於互動協調型。在全民健康保險實施後，其選用的控制機制，由最高至最低依次為官僚控制機制、市場控制機制、文化控制機制。然而專業取向型醫院在三種控制機制選用之間並無顯著差異，但與其他類型醫院比較，其選用控制機制的絕對值亦均小於互動協調型。 3.互動關係最複雜的「互動協調型」，在全民健康保險實施前，其選用的控制機制，由最高至最低依次為官僚控制機制、文化控制機制、市場控制機制，且三種控制機制之間有顯著差異。在全民健康保險實施後，其選用的控制機制，由最高至最低依次為官僚控制機制、市場控制機制、文化控制機制，且三種控制機制之間亦有顯著差異。 4.互動關係偏向行政取向的「行政取向型」，在全民健康保險實施前，其選用的控制機制，以市場控制機制與官僚控制機制同高，其次為文化控制機制，且三種控制機制之間有顯著差異。在全民健康保險實施後，其選用的控制機制，由最高至最低依次為市場控制機制、官僚控制機制、文化控制機制，且三種控制機制之間亦有顯著差異。 由上述研究結果可知，醫院混合採用不同的控制機制。當醫院內部互動關係偏向專業取向時，醫院使用的三種控制機制雖有差異，然其三種控制機制之間的差異並未達顯著水準。當醫院內部互動類型偏向互動協調型時，醫院相對地高度使用標準化的規定與程序，所以互動協調型醫院在官僚控制機制的選用程度上最高。當醫院內部互動類型偏向行政取向時，醫院相對地高度使用可明確衡量的產出，所以行政取向型醫院在市場控制機制的選用程度上最高。 第一章 緒論 第一節 研究動機 第二節 研究問題與研究目的 第三節 研究假定與研究限制 第二章 文獻探討 第一節 醫院概論 第二節 醫院內部互動類型 第三節 控制機制 第四節 醫院內部互動類型與控制機制間的關係 第五節 醫療政策與全民健康保險 第三章 個案分析 第一節 個案研究方法說明 第二節 個案一：甲醫院 第三節 個案二：乙醫院 第四節 個案三：丙醫院 第五節 個案比較分析 第四章 研究方法 第一節 研究架構的建立 第二節 研究變數定義與衡量 第三節 研究假設 第四節 樣本選擇與資料蒐集 第五節 資料分析方法 第六節 問卷的效度與信度 第五章 結果與討論 第一節 樣本描述 第二節 醫院內部互動類型 第三節 醫院內部控制機制 第四節 醫院內部互動類型與控制機制間的關係 第五節 全民健保實施的影響 第六節 假設驗證 第六章 結論與建議 第一節 研究結論 第二節 理論與實務涵義 第三節 後續研究建議 參考文獻 一、中文部份 二、英文部份 附錄 附錄一：醫院起源 附錄二：醫院產品 附錄三：醫院通路 附錄四：醫療品質 附錄五：傳統的醫院分類方法 附錄六：策略觀點的醫院分類方法 附錄七：研究問卷 附錄八：互動類型與權屬別、評鑑等級的關係 附錄九：互動類型與醫院產出的關係 附錄十：控制機制的因素分析 附錄十一：控制機制組合的變化 附錄十二：控制機制的其他影響因素 附錄十三：問卷個別項目分析結果 / Applying control theory, this paper examines the relationship between types of interaction and adoption of control mechanism. After investigating 47 hospitals in Taiwan, we found that there exists strong relationship as described by four hypotheses. Based on “professional orientation” and “administrative orientation”, the hospitals can be classified into three types of interaction, namely, “professional orientation”, “interaction harmony”, and “administrative orientation”. The literature review suggests three types of mechanisms. These mechanisms are market, bureaucratic, and culture control. After empirical survey, this research has three major findings. First, for interaction harmony hospitals, they prefer to adopt bureaucratic control mechanisms, while administrative orientation hospitals prefer to adopt market control mechanisms. As to professional orientation hospitals, there is no significant difference on adoption of three control mechanisms. Second, to compare the intensities of various control mechanisms adopted by different types of hospitals, this study finds that administrative orientation hospital has the highest intensities both on market control and bureaucratic control. As to the adoption of cultural control, there is no significant difference among three kinds of hospitals. Finally, the research finds that the implementation of National Health Insurance has significant impact on the intention of adopting various control mechanisms.

本研究的主要目的是在於了解台灣企業母公司內與大陸子公司的內部網路 關係，在結合代理理論之下，期望能提出一個適合的海外單位管理模式。 經過對相關文獻的歸納之後，本研究認為多國籍企業母子公司的網路關係 會影響代理型態，由於必須管理不同的代理型態，企業會有較適的內部控 制機制。經過歸納整理後，本研究以「網路間母子公司互動程度」及「子 公司相對重要程度」來區分母子以司網路關係，而「互動程度」與「資訊 不對稱」呈反向關聯；「相對重要程度」與「任務風險性」呈正向關聯， 而在其交互影響下區分代理型態。本研究係屬於探索性之研究，採取個案 研究法進行資料的收集與分析。試圖結合網路理論與代理理論而能對多國 籍企業之內部控制機制有更進一步了解。主要的研究對象是在大陸投資經 營的本國企業。研究結果發現，在由資訊不對稱與任務風險性所構成的四 種代理型態中，其所著重的問題都不太相同，在資訊不對稱高且任務風險 性高的代理型態型Ⅰ中面臨的是雙重的壓力，母公司會傾向採用「掌控代 理」型管理方式。此時公司會有較多的正式化機制；適度中等的授權；採 用社會化機制維持員工的忠誠度；選擇行為統治的績效制度，使員工的作 為能符合公司的目標。在資訊不對稱高但任務風險性低的代理型態型Ⅱ中 ，公司對子公司的控制是設法突破分離可能帶來的問題，母公司會傾向採 用「監控代理」型管理方式。因此公司會有較多的正式化機制；對於子公 司給予相當的授權；透過社會化機制的採行與產出的績效制度，以維持員 工的向心力與激勵員工。在資訊不對稱低但任務風險性高的代理型態型Ⅲ 中公司對子公司的控制應是使子公司能夠正確有效的運作以配合公司的策 略，母公司會傾向採用「主理掌控」型管理方式。因此公司會有較多的正 式化機制；較高的集權掌握子公司的運作；並有社會化機制維持子公司幹 部的向心力，能按步就班完成任務；選擇行為的績效制度來評定員工的貢 獻。在資訊不對稱低且任務風險性低的代理型態型Ⅳ中對子公司的控制應 是如何激勵小兵，使其充分發揮效能，母公司會傾向採用「代理自主」型 管理方式。因此公司並不需投入太多的正式機制；並會給予較高的授權； 主要是透過產出統治的績效制度來加以管理。