Multiple sclerosis (MS) is a debilitating disease in which demyelinated lesions form in the central nervous system (CNS). A specific microRNA, miR-145-5p, is dysregulated both in blood samples from RRMS patients and in chronic lesions from progressive MS patients. In the context of remyelination, miR-145-5p regulation may be important as it exhibits strong differential regulation in oligodendrocytes (OLs), the myelinating cells of the CNS, and is also expressed in other CNS glial cell types. Dysregulation of miR-145-5p may therefore play into pathologies observed in both relapsing-remitting (RRMS) and progressive MS. Using pre-clinical rodent models, we aimed to determine how altering normal expression of miR-145-5p specifically affects OL maturation, and how the dysregulation observed in MS may affect various aspects of disease. First using a miR-145 knockdown model in primary rat OLs, we found in vitro that miR-145-5p plays a role both in maintaining oligodendrocyte progenitor cells (OPCs) in their proliferative state and preventing premature differentiation to OLs and that knockdown of miR-145 in OLs enhanced their differentiation. These effects were due at least in part to miR-145-5p regulation of a critical myelin gene transcription factor. The effects of miR-145-5p were further assessed in a miR-145 knockout mouse model in vivo. Contrary to in vitro assays, enhanced myelination was not detectable during development in these animals, nor when remyelination was assessed using the cuprizone toxic model of acute demyelination. However, chronic cuprizone exposure resulted in striking remyelination and functional recovery in miR-145 deficient animals. Sparse remyelination in wild-type animals with chronic cuprizone exposure was concomitant with upregulation of miR-145-5p, which was not the case with acute exposure, identifying miR-145-5p dysregulation as a unique feature of chronic demyelination. Specific assessment of miR-145-5p overexpression in OLs in vitro resulted in severe differentiation deficits and eventual apoptosis, driven molecularly by altered expression of multiple pathways critical to successful OL differentiation and subsequent myelination. Finally, we induced an inflammatory model of demyelination, experimental autoimmune encephalomyelitis (EAE), in our miR-145 knockout mouse to assess the role of miR-145-5p in autoimmune-mediated myelin damage. The clinical severity of EAE in miR-145 deficient animals was reduced, and this was accompanied by reduced loss of myelin and lessened immune cell infiltration in miR-145 knockout spinal cords. Alterations in both astrocytic and microglial activation were detected with loss of miR-145, suggesting that improved clinical outcomes in this model may be underpinned by changes in EAE-mediated neuroinflammation. Collectively, these data suggest that miR-145-5p plays differing roles in both progressive and inflammatory MS, affecting multiple glial cell types in the CNS. Excitingly, loss of miR-145 expression in our mouse model of chronic demyelination allowed extensive remyelination and functional recovery following chronic demyelination, and in EAE improved clinical outcomes driven by underlying improvements in myelin retention and altered neuroinflammatory reactions. Thus, miR-145-5p merits further investigation as a potential therapeutic target to help overcome both remyelination failure in all forms of progressive MS and inflammation-driven demyelination in RRMS and early secondary progressive MS (SPMS).

Includes bibliographical references (leaves 154-179). / x, 179 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Tests whether follicle shutdown affects staple strength using Merino sheep exposed to cortisol to vary wool growth rate. A correlation exists between follicle shutdown levels and staple strength. Tests also whether breed affects follicle shutdown. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1998

A key problem in multiple sclerosis (MS) is the diminished capacity for myelin repair. Although oligodendrocyte (OL) precursors can be seen at the lesion site, their ability to differentiate appears inhibited. MicroRNAs are key regulators of OL differentiation, and have been observed to be misregulated in MS lesions compared to healthy white matter. Thus, aberrant microRNA expression in MS lesions may disrupt the ability of incoming oligodendrocyte progenitor cells (OPC s) to differentiate. Specifically, a microRNA known as miR - 145 is downregulated as OPCs progress to OLs, but is found at unusually high levels in MS lesions. In this study, we investigated how misregulation of miR - 145 affects OL differentiation in vitro. Bioinformatic analysis revealed that putative targets of miR - 145 are significantly enriched for factors which promote actin cytoskeleton organization and myelination. An immortalized OL cell line was transduced with an inducible lentivirus to create stable lines that overexpress miR - 145. These stable lines were characterized while proliferating, early in differentiation and late in differentiation. Immunofluorescence was used to quantify changes in proliferation rate, apoptosis, branching ability and myelin gene expression. qPCR arrays were used to quantify changes in microRNA target expression levels between induced and uninduced cells. Two stable lines were created: ON - 145 - 1 and ON - 145 - 2, which upon induction, over - express miR - 145 ~33 - fold and ~11 - fold, respectively. When proliferating, no significant morphological differences nor target expression differences could be detected between induced and uninduced cells. Proliferation was significantly decreased in ON - 145 - 1 induced cells, but not in ON - 145 - 2. No changes in apoptosis frequency were detected. In contrast, during early and late differentiation, both induced cell lines showed significant morphological defects characterized by a reduction in both iii primary and secondary branching. Further, significant differences in branching ability were observed between induced cells of ON - 145 - 1 and ON - 145 - 2, suggesting a dose - dependent response to miR - 145 overexpression. Expression of MAG, a myelin marker, was also significantly lowered in induced cells of both cell lines. Finally, we found that multiple miR - 145 targets involved in promoting cytoskeletal organization and myelination were significantly decreased both early and late in differentiation. These results suggest that overexpression of miR - 145 during OL differentiation may disrupt actin organization and myelin gene expression required for successful process extension and subsequent myelinating ability. Thus, the increase in miR - 145 in MS lesions may be a significant contributing factor to the loss of myelin repair in MS lesions.

No description available.

Etwa 25 % der Nierenzellkarzinome (RCC) weisen bei Diagnosestellung bereits Metastasen auf. Aufgrund der schlechten Prognose des metastasierten RCC besteht ein dringender Bedarf an neuen Therapieformen sowie an prognostischen und diagnostischen Markern. microRNAs (miRNAs) bieten sich dabei als vielversprechende molekulare Biomarker an. Für den klarzelligen RCC-Subtypen (ccRCC) wurde bereits ein umfangreiches miRNA Expressionsprofil erstellt, mit dem ccRCC-relevante, vorwiegend herunterregulierte miRNAs identifiziert werden konnten. In der vorliegenden Arbeit wurde gezeigt, dass die Expression der miR-141 und miR-145 in RCC-Zelllinien durch epigenetische Mechanismen gehemmt ist und die Promotorbereiche dieser miRNAs stark methyliert vorliegen. In RCC-Zellen konnte eine tumorsuppressive Wirkung dieser miRNAs durch Hemmung der Migration (beide) und Invasion (miR-141) nachgewiesen werden. Durch die gleichzeitige Überexpression der beiden miRNAs kam es zu einer kooperativen Wirkung und so zu einer verstärkten Hemmung der Zellmigration. Weitere Untersuchungen konnten eine Reihe neuer onkogener Targets der miR 141 und miR 145 identifizieren. Dabei zeigte sich ein kooperativer Effekt durch Kombination beider miRNAs auf die Expression der Targets HS6ST2 und LOX. Die Targets LOX und MAP4K4 waren in ccRCC Gewebe auf mRNA-Ebene stark überexprimiert im Vergleich zum umliegenden Normalgewebe. Bei der anschließenden Tissue-Mikroarray-Analyse der Expression auf Proteinebene zeigte sich zudem ein prognostisches Potenzial der Targets LOX und MAP4K4 für das Gesamtüberleben von ccRCC Patienten. Diese Daten verdeutlichen den enormen Einfluss von epigenetisch dysregulierten miRNAs und deren spezifischen Targets auf tumorassoziierte Prozesse. Zudem bietet das Netzwerk aus Epigenetik, miRNAs und deren jeweiligen Targets nicht nur eine Reihe von diagnostischen und prognostischen Möglichkeiten, sondern liefert auch viele Ansatzpunkte für die Entwicklung von neuen therapeutischen Strategien. / Approximately 25 % of diagnosed renal cell carcinoma (RCC) have already metastasized. Due to poor prognosis of metastatic RCC, there is an urgent need for new therapies and prognostic and diagnostic markers to identify high-risk patients. Here microRNAs (miRNAs) might be promising new molecular biomarkers. For the clear cell RCC subtype (ccRCC) a comprehensive miRNA expression profile was already established. In this profiling several ccRCC-associated, predominantly down-regulated miRNAs were identified. In the present study, epigenetic mechanisms were identified to play a significant role in the down regulation of miR-141 and miR-145 in RCC cell lines. In addition, a strong methylation of the corresponding promoter regions was detected at molecular level. In RCC cells a tumor suppressive effect of these miRNAs was shown by decreasing migration (both) and invasion (miR-141) and furthermore, co overexpression of both miRNAs resulted in a cooperative effect with increased inhibition of cell migration. Several new oncogenic targets of miR-141 and miR-145 were identified by further investigations. Here the two miRNAs again showed a cooperative effect, as demonstrated by a significantly increased inhibition of HS6ST2 and LOX expression. In ccRCC tissue the expression of LOX and MAP4K4 was strongly enhanced on mRNA level compared to normal tissue. In the subsequent tissue microarray analysis of protein expression, LOX and MAP4K4 showed a prognostic impact for the overall survival of patients with ccRCC. These results illustrate a huge impact of epigenetically dysregulated miRNAs and of their specific targets on tumor-associated processes. Furthermore, the network of epigenetics, miRNAs and their respective targets will offer a number of diagnostic and prognostic capabilities, but will also provide many opportunities for the development of new therapeutic strategies.

黃學明. / 據稿本複印 / 論文(哲學碩士)--香港中文大學中國文學系,1992. / 參考文獻: leaves 394-414 / Huang Xueming. / 前言 --- p.1 / 前言註釋 --- p.5 / Chapter 一 --- «史記» 單用« 國語» 之部分 --- p.7 / 第一部分註釋 --- p.156 / Chapter 二 --- « 史記» 兼用« 國語» 、« 左傳» 之部分 --- p.175 / 第二部分註釋 --- p.355 / 結論 --- p.386 / 引用書目 --- p.394

J.G. Linvill. / "March 14, 1950." / Bibliography: p. 28. / Army Signal Corps Contract No. W36-039 sc-32037 Project No. 102B. Dept. of the Army Project No. 3-99-10-022.

The changes in the behaviour of the innovating firm that would not have been the case in the absence of the public support, behavioural additionality, is investigated in this thesis. The theoretical foundations of the concept along with the existing evaluation attempts worldwide are analysed. The need for evaluation in Turkey is established. The design of the T&Uuml / BiTAK-TEYDEB programme in question along with the related policy context is described to form a basis for the evaluation of the behavioural additionality. It is revealed that the need for an evaluation of behavioural additionality for the legitimacy of the programme from the data analysis. Finally, given such inputs, the thesis develops a methodological proposal for a framework to evaluate the behavioural additionality of the public support to private R&amp / D in Turkey.

Sveriges apoteksmarknad omreglerades år 2009 från ett statligt monopol till en konkurrensutsatt marknad. Orsaken till reformen var liberaliseringsinfluenser inom ekonomin från 90-talet, utifrån teori såväl som medlemskapet i Europeiska Unionen. Reformen mottogs med blandade känslor vilket reflekteras väl i de många motsägande utvärderingarna av reformen de efterföljande åren. Bristen av konsensus om målens uppfyllelse samt de många opartiska granskningarna leder till uppsatsens syfte att granska om målen med reformen är uppfyllda nu nio år senare eller ej. Målen med omregleringen presenteras i proposition 2008/09:145 och är övergripande: ökad tillgänglighet, förbättrad service och låga kostnader för konsumenter och staten. Metoden i uppsatsen är måluppfyllelseanalys med stöd i ett kontrafaktiskt scenario, Sverige utan omregleringen vilket baseras på en applikation av Finlands utveckling efter 2009. Analysen granskar målet utifrån nio aspekter och kommer fram till att marknaden med omreglering uppvisar bättre resultat i åtta av dem jämfört med resultatet på marknaden som inte omreglerades. Den omreglerade marknaden genererade 434 fler apotek och antalet ökade i nio utav tio områden med mellan 18,9 och 80,7 procent mer än den icke reglerade. Öppettiderna var även 11,2 timmar längre per vecka på den omreglerade marknaden. Totalt tillkom det 956 fler farmaceuter när marknaden omreglerades, antal apotek ökade dock snabbare och förhållandet mellan farmaceuter och apotek försämrades mer med omregleringen än utan. På den omreglerade marknaden gick det fem farmaceuter per apotek istället för sex, direktexpedieringen ökade dock med 1,6 procent mer. De totala kostnaderna ökade med 0,289 miljoner euro mindre och kostnaderna per person sjönk istället för att stiga, även priserna i detaljhandel föll mer med omregleringen än utan. Målet om ökad tillgänglighet och låga kostnader är således uppfyllt, målet om förbättrad service är uppfyllt till viss grad. Den totala bedömningen av omregleringen är att den varit lyckad. / Sweden's pharmacy market underwent a reregulation year 2009 from a public monopoly to a market exposed to competition. The reason for the reform was liberalization influences in the economy during the nineties, in economic theory aswell as from becoming a member of the European Union. The reform was received with mixed feelings which was well reflected in the many contradictory assessment reports of the reregulation the following years. The lack of consensus about the goal fulfillment and the many impartial reviews leads to the purpose of this essay, to examine if the goals of the reform are fulfilled now nine years later or not. The goals of the reform are presented in proposition 2008/09:145 as following: increased accessibility, improved service and low costs for consumers and the government. The method is goal fulfillment with support in a counterfactual analysis, Sweden without reregulation, that is based upon Sweden before the reregulation with the application of Finland's development after 2009. The analyze examines the goal from nine aspects and lands in the fact that the market with reregulation shows a better result in eight out of nine of them compared with the result of the market without a reregulation. The reregulated market generated 434 more pharmacies and the number increased in nine out of ten areas with between 18,9 and 80,7 percent more than the non-reregulated market. The open hours were also 11,2 hours longer per week in the reregulated market. The total added number of pharmacist increased by 956 workers with the reregulation, however, the number of pharmacies increased at a greater rate and the relation between pharmacists and pharmacies worsened, more with the reregulation than without. On the reregulated market there were five pharmacists per pharmacy instead of six, however directly dispensed medicine increased with 1,6 percent more. Total governmental costs increased with 0,289 million euro less and the cost per person decreased instead of increased, also the prices in retail dropped more with the reregulation than without. The goal of increased accessibility and low costs are therefore fulfilled, the goal of improved service is fulfilled to a certain degree. The total assessment of the reregulation is that it has been successful.

Denna litteraturstudie behandlar Safety Managment System (SMS), ett relativt nytt begrepp och arbetssätt inom flygindustrin för att arbeta med flygsäkerhet och som initierades av det som idag är International Civil Aviation Organization (ICAO), ett organ inom Förenta Nationen (FN). SMS utvecklades eftersom det i flygsäkerhetsarbetet har blivit allt svårare att utpeka enskilda faktorer som orsakar olyckor, utan är i större grad en kedja av faktorer när en olycka inträffat. SMS är en systematisk metod för att hantera säkerhet, inklusive de nödvändiga organisatoriska strukturer, ansvarsområden, riktlinjer och rutiner. SMS omfattar säkerhetspolicy och mål, riskhantering, säkerhetsförsäkran samt säkerhetsfrämjande. Transportstyrelsen publicerade 2013 ett svenskt State Safety Program (SSP) med krav på SMS inom andra verksamhetsområden inom flyget. European Aviation Safety Agency (EASA) publicerade 2013 ett förslag där SMS skulle krävas hos flygunderhållorganisationer (Part-145), vilket ej än har fastställts och publicerats. Syftet var att tydliggöra hur implementeringsarbetet fortgår för SMS inom svenska Part-145 organisationer, vilka faktorer som kan försvåra arbetet, samt att belysa möjligheter och utmaningar vid implementering av SMS. Även att få en förståelse i skillnaden mellan dagens säkerhetsarbete i förhållande till vid implementerat SMS inom flygunderhåll. Arbetet begränsades till SMS i Svenska flygindustrin och inom flygunderhåll Part-145 och arbetet baseras på källor från ICAO, EASA, Transportstyrelsen, relevant litteratur och forskning samt en kvalitativ intervju med representant på Transportstyrelsen. Slutsatsen är att det finns i dagsläget starka indicier på att EASA kommer att publicera ett lagförslag sommaren 2018 som gäller för underhålls-organisationer (Part-145) och att dessa organisationer då kommer att ha en tvåårsperiod för implementering. Vidare krav på rapportering, riskbedömning och tydligt krav på dokumentering är viktiga skillnader mellan dagens krav och de nya kraven i och med SMS. Vidare kan man konstatera att risken vid implementering av SMS är att man överkomplicerar implementeringen, inte anpassar systemet till egna organisationen, att rutiner sedan inte används alternativt otillräckligt med resurser eller att man efter implementering inte kontinuerligt arbetar med SMS. Vi kan även slå fast att framgångsfaktorer för att erhålla ett fungerande SMS inkluderar utbildning och engagerad ledning samt att SMS anpassas för organisationens verksamhet och blir väl integrerat i de dagliga aktiviteterna. / This literature study covers the Safety Management System (SMS), a relatively new concept and working method within the aviation industry to work with flight safety and initiated by what is now the International Civil Aviation Organization (ICAO), a United Nation (UN) specialized agency. SMS was developed since work with flight safety has become increasingly difficult to identify individual factors that cause accidents, but to a greater extent a chain of factors when an accident occurred. SMS is a systematic approach to managing safety, including the necessary organizational structures, responsibilities, policies and procedures. SMS includes safety policy and objectives, risk management, safety assurance and safety promotion. The Swedish Transport Agency published in 2013 a Swedish State Safety Program (SSP) with requirements for SMS in other areas in aviation. European Aviation Safety Agency (EASA) published in 2013, a proposal with requirements of SMS to the maintenance organizations (Part-145), which has not yet been established and published. The objective was to clarify how the implementation work continues for SMS in Swedish Part-145 organizations, the factors that can complicate the work, as well as highlighting opportunities and challenges in the implementation of the SMS. Also to get an understanding of the difference between today's safety work in relation to the implemented SMS in aviation maintenance. The work was limited to SMS within Swedish aviation industry and maintenance Part-145 and the work is based on sources from ICAO, EASA, Swedish Transport Agency, relevant literature and research as well as a qualitative interview with a representative of the Swedish Transport Agency. The conclusion is that there is at today strong indications that EASA will publish a legislative proposal the summer of 2018, which applies to maintenance organizations (Part-145), and that these organizations will then have two years to implement the new requirements. Further reporting requirements, risk assessment and clear demands on documentation are important differences between today's requirements and the new requirements of the SMS. Furthermore, it can be stated that the risk in the implementation of SMS is that it complicates implementation more than needed, do not customize the system to their own organization, the routines then will not be use alternative insufficient resources, or that after the implementation the organization do not continuously work with the SMS. We can also conclude that the success factors to obtain effective SMS includes education and management commitment and that the SMS adapts to the organization's operations and is well integrated in the daily activities.