Colorectal cancer (CRC) is a common malignancy which develops due to old age and lifestyle factors, low percent of patients afflicted by a genetic disorders. Half of all colorectal cancer patients are diagnosed after metastasis. The high rate of the late detection, emphasizes on the requirement of convenient and inexpensive diagnostic methods for comprehensive screening programs. The aim of this study was to discover proto-oncogenes mutation and assessment of tumor suppressor genes expression. Formalin fixed paraffin embedded (FFPE) histologically verified colorectal cancer samples were used. APC, KRAS and BRAF mutations were investigated using polymerase chain reaction (PCR) fragments and direct sequencing. Gene expression assessment of MLH1, MGMT and CDKN2A were achieved via quantitative polymerase chain reaction (qPCR). In the present study we could detect a novel transversion heterozygous mutation in APC gene codon 1365 in three patients. BRAF codon 600 mutation were detected in one patient. KRAS codon 12 mutation was discovered in one sample and also a novel transition mutation in codon 15 was detected in 6 patients. In 80% of cases, MLH1 and MGMT expression were undetectable, in remaining 20%, MLH1 expression were reduced, but MGMT showed both reduced and increased expression compared to control. In 100% of patients CDKN2A expression was undetectable. The rate of mutations in predetermined hotspot codons and amount of uncommon mutations into APC, BRAF and KRAS in Nepalese patients indicates the requirement of further investigation in CRC patients from that part of the world. Also, the expression rate of MLH1, MGMT, CDKN2A and deficiency of an information source emphasizes the necessity of whole genome CRC expression profiling data to comparison and conclusion. / <p>-</p> / -

La presente investigación tiene como objetivo analizar los factores que influyen en la variación de las exportaciones de café orgánico al mercado de los Estados Unidos en los años 2011-2017, determinando el precio del café orgánico, la desarticulación de los organismos competentes que impulsan el sector cafetalero y las principales carencias de los productores cafetaleros, todo esto bajo el marco de Acuerdo de Promoción Comercial (APC) con los Estados Unidos. Para empezará, se procederá a explicar los conceptos teóricos identificados para la realización de esta investigación, así también determinará las bases de las exportaciones de café orgánico al mercado estadunidense. A su vez, se detalla el tipo y diseño de investigación realizada en el presente documento. Asimismo, se establecieron 3 objetivos específicos relacionadas con identificar los factores influyentes en las fluctuaciones de las exportaciones, las cuales fueron procesadas por un software estadístico, en base a la información histórica recabada de fuentes de exportación con la finalidad de validar si las hipótesis establecidas pueden ser consideradas como los factores de las fluctuaciones de las exportaciones. De acuerdo a lo mencionado líneas arriba, se recolectó información significativa a través de diversas fuentes de acceso como: Información estadística de SUNAT, TRADEMAP, COMTRADE, WTO- Integrated Trade Intelligence Portal y de las entrevistas a los especialistas púbicos y privados conocedores de las exportaciones de café y sus implicancias. / The objective of this research is to analyze the factors that influence the variation of organic coffee exports to the U.S. market in 2011-2017, determining the price of organic coffee, the dismantling of the competent agencies that drive the coffee sector and the main deficiencies of coffee producers, all under the framework of Trade Promotion Agreement (TPA) with the United States. To begin, it will proceed to explain the theoretical concepts identified for the conduct of this research, as well as determine the basis for exports of organic coffee to the U.S. market. In turn, it details the type and design of research conducted in this document. In addition, 3 specific objectives were established to identify the factors influencing export fluctuations, which were processed by statistical software, based on historical information collected from export sources in order to validate whether established hypotheses can be considered as factors of export fluctuations. As mentioned above, significant information was collected through various sources of access such as: Statistical information from SUNAT, TRADEMAP, COMTRADE, WTO- Integrated Trade Intelligence Portal and from interviews with public and private specialists with knowledge of coffee exports and their implications. / Tesis

This diploma thesis deals with optic fiber connectors and their influence on transmissions realized via fiber optics. Optical fibers and lightguides play the key role in telecommunications because of constant demands of higher bandwidth and data rates. Original metalic wires do not meet market requirements and so the fiber optics are more and more being used. There are various types of fibers and there are also many ways of connections. This work deals with demountable way of connection – optical connectors, which have the biggest influence on a total attenuation and route length. Connector has to meet various requirements such as cleannes, quality, mechanical construction and ferrule polishing.

This study concluded that the Three Forms of Unity does not give the same meaning to the word “church” all the way through, since the word is used to describe both the visible and invisible sides of the church. When these different uses of the word “church” are left out of consideration in discussions concerning the church and only one of the two sides of the church is emphasised, it leads to the large degree of confusion and indistiction which these days is experienced in ecclesiastical debates. Before there can be any meaningful progress in these discussions, it is therefore necessary to establish which view of the Bible as well as concept of the church, is being taken as starting point of the discussion. Reformed academics have already done many studies concerning the Biblical usage of the word “church”. This study has taken the research a step further and shown that the use of the word “church” in the Three Forms of Unity agrees with the Biblical usage of the word. The Bible and the Three Forms of Unity mean, with the word “church”, both sides of the church of Christ. This church is on the one side invisible, seeing that is spans time and place and in doing so is the sum total of all the elect. On the other side, this church is made visible in a defined place and time and bears the stamp of its own time and culture in which it took its shape. Confusion arises when it is assumed that whatever the Bible and confessions state as indicative of the invisible church is necessarily indicative of the church`s visible side also. This is particularly valid, for example, in the doctrine concerning the attributes and characteristics of the church. This study has brought the old truths about the church from the Bible and confessions freshly to the fore in a time when very little attention is being paid to them. Yet it is precisely these truths concerning the concept of the church that can bring progress in ecclesiastical discussion. It was further demonstrated that the concept of the church held by the Afrikaans Protestant Churches stands on solid Biblical and confessional grounds. / Dissertation (MA (Research in Practical Theology))--University of Pretoria, 2007. / Practical Theology / MA / unrestricted

Hemostasis, thrombosis, and inflammation are tightly interconnected processes which may give rise to thrombo-inflammation, involved in infectious and non-infectious acute and chronic diseases, including cardiovascular diseases (CVD). Traditionally, due to its hemostatic role, blood coagulation is isolated from the inflammation, and its critical contribution in the progressing CVD is underrated, until the full occlusion of a critical vessel occurs. Underlying vascular injury exposes extracellular matrix to deposit platelets and inflammatory cells. Platelets being key effector cells, bridge all the three key processes (hemostasis, thrombosis, and inflammation) associated with thrombo-inflammation. Under physiological conditions, platelets remain in an inert state despite the proximity to the endothelium and other cells which are decorated with glycosaminoglycan (GAG)-rich glycocalyx (GAGs). A pathological insult to the endothelium results in an imbalanced blood coagulation system hallmarked by increased thrombin generation due to losses of anticoagulant and cytoprotective mechanisms, i.e., the endothelial GAGs enhancing antithrombin, tissue factor pathwayinhibitor (TFPI) and thrombomodulin-protein C system. Moreover, the loss of GAGs promotes the release of mediators, such as von Willebrand factor (VWF), platelet factor 4 (PF4), and P-selectin, both locally on vascular surfaces and to circulation, further enhancing the adhesion of platelets to the affected sites. Platelet-neutrophil interaction and formation of neutrophil extracellular traps foster thrombo-inflammatory mechanisms exacerbating the cardiovascular disease course. Therefore, therapies which not only target the clotting mechanisms but simultaneously or independently convey potent cytoprotective effects hemming the inflammatory mechanisms are expected to provide clinical benefits. In this regard, we review the cytoprotective protease activated protein C (aPC) and its strong anti-inflammatory effects thereby preventing the ensuing thrombotic complications in CVD. Furthermore, restoring GAGlike vasculo-protection, such as providing heparin-proteoglycan mimetics to improve regulation of platelet and coagulation activity and to suppress of endothelial perturbance and leukocyte-derived pro-inflammatory cytokines, may provide a path to alleviate thrombo-inflammatory disorders in the future. The vascular tissue-modeled heparin proteoglycan mimic, antiplatelet and anticoagulant compound (APAC), dual antiplatelet and anticoagulant, is an injury-targeting and locally acting arterial antithrombotic which downplays collagen- and thrombin-induced and complement-induced activation and protects from organ injury.

No description available.

Le virus de l’immunodéficience humaine de type 1 (VIH-1) est l’agent étiologique du SIDA, un rétrovirus complexe encodant les protéines accessoires : Nef, Vif, Vpr et Vpu. La fonction principale de ces protéines est de moduler l’environnement cellulaire afin de promouvoir la réplication virale. Les travaux présentés dans cette thèse portent sur la protéine virale Vpr, une protéine bien connue pour son activité d’arrêt du cycle cellulaire en phase G2/M dans les cellules en division et pour l’avantage réplicatif qu’elle confère au virus durant l’infection de cellules myéloïdes. Les évènements sous-jacents à ces deux activités restent pour l’heure mal compris. Le but des travaux regroupés dans cet ouvrage est d’identifier de nouveaux facteurs cellulaires pouvant éventuellement expliquer les activités de Vpr précédemment décrites. Pour ce faire, nous avons utilisé une approche d’identification des partenaires de proximité par biotinylation, appelée BioID. L’avantage du BioID est de permettre un marquage in cellulo des protéines à proximité de la protéine d’intérêt. La mise en place et la caractérisation de cette approche font l’objet de la première section de cette thèse. En utilisant cette approche, nous avons défini un réseau de 352 partenaires cellulaires de la protéine Vpr. Parmi ces partenaires de Vpr, plusieurs sont organisés sous forme de complexes ou réseaux protéiques incluant notamment le complexe promoteur de l’anaphase/cyclosome (APC/C) et les centrosomes. Étant donné que le complexe APC/C est l’un des principaux régulateurs du cycle cellulaire, nous avons décidé d’analyser sa relation avec Vpr. Nous avons découvert que Vpr formait un complexe non seulement avec APC1, une sous-unité essentielle du complexe APC/C, mais aussi avec les coactivateurs (CDH1 et CDC20) de ce complexe. Nous avons par la suite démontré que Vpr induisait la dégradation d’APC1 et que celle-ci pouvait être prévenue par une double-mutation N28S-G41N de Vpr. Cette dégradation d’APC1 ne semblerait pas être reliée aux activités précédemment décrites de Vpr. Ces travaux font l’objet de la seconde section de cette thèse. Enfin, dans une troisième section, des travaux effectués en collaboration et analysant la relation entre les centrosomes et Vpr sont présentés. Cette thèse identifie 200 nouveaux partenaires de Vpr, ouvrant la porte à l’exploration de nouvelles cibles et activités de Vpr. Elle décrit également une nouvelle cible de Vpr : le complexe APC/C. Globalement nos résultats contribuent à une meilleure compréhension de la façon dont le VIH-1 manipule l’environnement cellulaire de l’hôte à travers la protéine virale Vpr. / Human immunodeficiency virus (HIV-1) is the AIDS causal agent. This complex retrovirus encodes several accessory proteins; namely Nef, Vif, Vpr and Vpu; whose functions are to manipulate the cellular host environment in order to favor HIV-1 viral replication. This thesis focused on Vpr whose main activities are to induce a cell cycle arrest in the G2/M phase in dividing cells and to provide a replicative advantage to HIV-1 during infection of myeloid cells such as macrophages. The cellular mechanisms underlying these two activities are up to now misunderstood. The main goal of the work presented in this thesis is to identify new cellular factors that could potentially explain the previously described Vpr activities. To do so, we used the proximity labelling approach called BioID. The main strength of BioID is to tag in cellulo partners of the protein of interest. The development as well as optimization of the BioID approach is presented in the thesis first section. Using BioID, we defined a network containing 352 cellular partners in close proximity with the viral protein Vpr. Amongst these cellular partners, several were organized into protein complexes or networks such as the anaphase promoting complex/cyclosome (APC/C) or the centrosome. Given that APC/C is a cell cycle master-regulator, we analyzed the interplay governing Vpr and APC/C interactions. We first demonstrated that Vpr could form a complex containing the scaffolding subunit APC1. APC/C coactivators, namely CDH1 and CDC20, could also be found in association with Vpr. We next showed that Vpr was inducing APC1 degradation and that Vpr residues N28 and G41 were essential to this activity. Surprisingly, the APC1-Vpr interplay does not relate to previously described Vpr activities. This work is presented in the second section of this thesis. Lastly, in the third section, a work done in collaboration analyzed the interplay between Vpr and the centrosomes. In this thesis we identified 200 new potential partners of Vpr, opening the doors to discover novel Vpr targets and activities. This thesis also defined APC/C as new Vpr target. Taken together our results allow a better understanding on how HIV-1 modulates the cellular environment by using the viral accessory protein Vpr.

No description available.

20世紀以來，因為衛生醫療等因素的進步，各年齡死亡率均大幅下降，使得平均壽命大幅延長。壽命延長的效果近年逐漸顯現，其中的人口老化及其相關議題較受重視，因為人口老化已徹底改變國人的生活規劃，死亡率是否會繼續下降遂成為熱門的研究課題。描述死亡率變化的模型很多，近代發展的Age–Period–Cohort模型(簡稱APC模型)，同時考慮年齡、年代與世代三個解釋變數，是近年廣受青睞的模型之一。這個模型將死亡率分成年齡、年代與世代三個效應，常用於流行病學領域，探討疾病、死亡率是否與年齡、年代、世代三者有關，但一般僅作為資料的大致描述，本研究將評估APC模型分析死亡率的可能性。 APC模型最大的問題在於不可甄別(Non–identification)，即年齡、年代與世代三個變數存有共線性的問題，眾多的估計APC模型參數方法因應甄別問題而生。本研究預計比較七種較常見的APC模型估計方法，包括本質估計量(IE)、限制的廣義線性模型(cglim_age、cglim_period與cglim_cohort)、序列法ACP、序列法APC與自我迴歸模型(AR)，以確定哪一種估計方法較為穩定，評估包括電腦模擬與實證分析兩部份。 電腦模擬部份比較各估計方法，衡量何者有較小的年齡別死亡率及APC參數的估計誤差；實證分析則考慮交叉分析，尋找用於死亡率預測的最佳估計方法。另外，也將以蒙地卡羅檢驗APC的模型假設，以確定這個模型的可行性。初步研究發現，以台灣死亡資料做為實證，本研究考量的估計方法在估計年齡別死亡率大致相當，只是在年齡–年代–世代這三者有不同的詮釋，且模型假設並非很符合。交叉分析上，Lee–Cater模型及其延展模型相對於APC模型有較小的預測誤差，整體顯示Lee–Cater 模型較佳。 / Since the beginning of the 20th century, the human beings have been experiencing longer life expectancy and lower mortality rates, which can attributed to constant improvements of factors such as medical technology, economics, and environment. The prolonging life expectancy has dramatically changed the life planning and life style after the retirement. The change would be even more severe if the mortality rates have larger reduction, and thus the study of mortality become popular in recent years. Many methods were proposed to describe the change of mortality rates. Among all methods, the Age-Period-Cohort model (APC) is a popular method used in epidemiology to discuss the relation between diseases, mortality rate, age, period and cohort. Non-identification (i.e. collinearity) is a serious problem for APC model, and many methods used in the procedure included estimation of parameter. In the first part of this paper, we use simulation compare and evaluate popular estimation methods of APC model, such as Intrinsic Estimator (IE), constrained of age, period and cohort in the Generalized Linear Model (c–glim), sequential method, and Auto-regression (AR) Model. The simulation methods considered include Monte-Carlo and cross validation. In addition, the morality data in Taiwan (Data sources: Ministry of Interior), are used to demonstrate the validity and model assumption of these methods. In the second part of this paper, we also apply similar research method to the Lee-Carter model and compare it to the APC model. We found Lee–Carter model have smaller prediction errors than APC models in the cross–validation.

La notion de compétence et l'approche par compétences constituent une véritable préoccupation pour les différents systèmes éducatifs. L'introduction de l'enseignement et de l'apprentissage fondés sur les compétences constitue le noyau et la base des projets de réforme actuels pour adapter les écoles aux besoins de notre temps. L'APC met en relief la capacité de l'élève d'utiliser ce qu'il a appris à l'école dans des situations de la vie quotidienne. L'objectif premier de notre recherche consiste à étudier l'impact de l'introduction de l'APC sur le système éducatif libanais et la possibilité d'adapter cette approche au sein des écoles libanaises publiques. Pour ce faire, l'idée d'un projet d'un curriculum est mise en place, fondée sur une APC compatible avec les conditions d'enseignement au Liban. / The concept of competence and the approach by competence constitute a genuine preoccupation of different educatifs systems. The introduction of process teaching and learning based on competences is the core of reforming projects required by the schools to adapt to the contemporary needs. The approach by competence accentuate the skills of student to practice whatever he learned at the school in his everyday life. The essential objectif of this study is to analyze the effect of the introduction of the approach by competence on the Lebanese educatif system and the possibility to adapt this approach in the Lebanese public schools. Thus, to achieve our goal, a Curriculum based on the approach by competence compatible with the Lebanese conditions of teaching been established.