Diversification Limited by Absence of Short Sales: the Chinese Case.

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Importance of the HSP90 molecular chaperoning pathway for antibody diversification by determining AID stability

La protéine AID (déaminase induite par l’activation) joue un rôle central dans la réponse immunitaire adaptative. En désaminant des désoxycytidines en désoxyuridines au niveau des gènes immunoglobulines, elle initie l’hypermutation somatique (SHM), la conversion génique (iGC) et la commutation isotypique (CSR). Elle est essentielle à une réponse humorale efficace en contribuant à la maturation de l’affinité des anticorps et au changement de classe isotypique. Cependant, son activité mutagénique peut être oncogénique et causer une instabilité génomique propice au développement de cancers et de maladies autoimmunes. Il est donc critique de réguler AID, en particulier ses niveaux protéiques, pour générer une réponse immunitaire efficace tout en minimisant les risques de cancer et d’autoimmunité. Un élément de régulation est le fait qu’AID transite du cytoplasme vers le noyau mais reste majoritairement cytoplasmique à l’équilibre. AID est par ailleurs plus stable dans le cytoplasme que dans le noyau, ce qui contribue à réduire sa présence à proximité de l’ADN. Le but de cette thèse était d’identifier de nouveaux partenaires et déterminants d’AID régulant sa stabilité et ses fonctions biologiques. Dans un premier temps, nous avons identifié AID comme une nouvelle protéine cliente d’HSP90. Nous avons montré qu’HSP90 interagit avec AID dans le cytoplasme, ce qui empêche la poly-ubiquitination d’AID et sa dégradation par le protéasome. En conséquence, l’inhibition d’HSP90 résulte en une diminution significative des niveaux endogènes d’AID et corrèle avec une réduction proportionnelle de ses fonctions biologiques dans la diversification des anticorps mais aussi dans l’introduction de mutations aberrantes. Dans un second temps, nous avons montré que l’étape initiale dans la stabilisation d’AID par la voie de chaperonnage d’HSP90 dépend d’HSP40 et d’HSP70. En particulier, la protéine DnaJa1, qui fait partie de la famille des protéines HSP40s, limite la stabilisation d’AID dans le cytoplasme. La farnésylation de DnaJa1 est importante pour l’interaction entre DnaJa1 et AID et moduler les niveaux de DnaJa1 ou son état de farnésylation impacte à la fois les niveaux endogènes d’AID mais aussi la diversification des anticorps. Les souris DNAJA1-/- présentent une réponse immunitaire compromise en cas d’immunisation, qui est dûe à des niveaux réduits d’AID et un défaut de commutation de classe. Dans un troisième temps, nous avons montré que la protéine AID est intrinsèquement plus instable que sesprotéines paralogues APOBEC. Nous avons identifié l’acide aspartique en seconde position d’AID ainsi qu’un motif semblable au PEST comme des modulateurs de la stabilité d’AID. La modification de ces motifs augmente la stabilité d’AID et résulte en une diversification des anticorps plus efficace. En conclusion, l’instabilité intrinsèque d’AID est un élément de régulation de la diversification des anticorps. Cette instabilité est en partie compensée dans le cytoplasme par l’action protective de la voie de chaperonnage DnaJa1-HSP90. Par ailleurs, l’utilisation d’inhibiteurs d’HSP90 ou de farnésyltransférases pourrait être un outil intéressant pour la modulation indirecte des niveaux d’AID et le traitement de lymphomes/leucémies et de maladies auto-immunes causés par AID.

Conception, synthèse et diversification de l'azaGly-Pro : un mime de tour beta, outil d'étude structure-activité : application au développement d'un nouvel agent tocolytique

Les accouchements prématurés constituent un problème médical majeur en constante augmentation et ce, malgré tous les efforts mis en œuvre afin de contrer le déclenchement des contractions avant terme. Cette thèse relate du ''design'' rationnel d'un nouvel agent thérapeutique (i.e., tocolytique) qui serait capable de 1) arrêter les contractions, et 2) prolonger la gestation. Pour ce faire, une nouvelle cible, la prostaglandine F2α et son récepteur ont été sélectionnés et le peptidomimétisme a été choisi afin de résoudre cette problématique. L'introduction contient un historique rapide de la conception à la synthèse (''drug design'') du peptide parent, le PDC113, premier peptide a avoir démontré des aptitudes tocolytiques suffisantes pour faire du peptidomimétisme. La deuxième partie de l'introduction présente les concepts du peptidomimétisme appliqués au PDC113 qui ont permis d'accéder au PDC113.824, inhibiteur allostérique du récepteur de la prostaglandine F2α, et explique comment ce mime nous a permis d'élucider les mécanismes de signalisation intracellulaire impliqués dans la contraction musculaire lisse. Cette thèse présente la conception, la synthèse et l'étude structure-activité de mimes de repliement de tour β au sein du mime peptidique original (PDC113.824) dans lequel nous avons remplacé l'azabicycloalkane central (l'indolizidin-2-one) par une série d'autres azabicycloalcanes connus et des acides aza-aminés dont nous avons élaboré la synthèse. Dans un premier temps, une nouvelle stratégie de synthèse en solution de l'aza-glycyl-proline à partir de la diphényle hydrazone et du chloroformate de p-nitrophényle a été réalisée. Cette stratégie a permis d'éliminer les réactions secondaires de cyclisation intramoléculaires communément obtenues lors de l'introduction d'acides aza-aminés avec les protections traditionnelles de type carbamate en présence de phosgène, mais aussi de faciliter l'accès en une étape à des dérivés peptidiques du type aza-glycyle. L'élongation de l'aza-glycyl-proline en solution nous a permis d'accéder à un nouveau mime tetrapeptidique du Smac, un activateur potentiel de l'apoptose au sein de cellules cancéreuses. Par la suite, nous avons développé une stratégie de diversification sélective de l'azote α du résidu azaglycine en utilisant différents types d'halogénures d'alkyle en présence de tert-butoxyde de potassium. Afin de valider le protocole d'alkylation de l'aza-dipeptide, différents halogénures d'alkyle ont été testés. Nous avons également démontré l'utilité des aza-dipeptides résultants en tant que ''building block'' afin d'accéder à une variété d'azapeptides. En effet, l'aza-dipeptide a été déprotégée sélectivement soit en N-terminal soit en C-terminal, respectivement. D'autre part, la libération de l'amine de l'ester méthylique de l'aza-alkylglycyl-proline a conduit à une catégorie de composés à potentiel thérapeutique, les azadicétopipérazines (aza-DKP) par cyclisation intramoléculaire. Enfin, notre intérêt quant au développement d'un nouvel agent tocolytique nous a amené à développer une nouvelle voie de synthèse en solution du PDC113.824 permettant ainsi d'élucider les voies de signalisation intracellulaires du récepteur de la prostaglandine F2α. Afin de valider l'importance de la stéréochimie et d'étudier la relation structure/ activité du mime, nous avons remplacé l'indolizidin-2-one (I2aa) centrale du PDC113.824 par une série d'autres azabicycloalcanes et azadipeptides. Les azabicycloalcanes D-I2aa, quinolizidinone, et indolizidin-9-one ont été synthétisés et incorporés au sein du dit peptide ne donnant aucune activité ni in vitro ni ex vivo, validant ainsi l'importance du tour β de type II' pour le maintien de l'activité biologique du PDC113.824. Finalement, l'insertion d'une série de dérivés aza(alkyl)glycyl-prolyles a mené à de nouveaux inhibiteurs allostériques du récepteur de la PGF2α, l'un contenant l'azaglycine et l'autre, l'azaphénylalanine. Cette thèse a ainsi contribué, grâce à la conception et l'application de nouvelles méthodes de synthèse d'aza-peptides, au développement de nouveaux composés à potentiel thérapeutique afin d'inhiber le travail prématuré.

Diversification In Employment Structure And Status Of Rural Women Workers In Ernakulam District

The basic objective of the present study has been to observe the process and pattern of employment diversification among the rural women workers in Ernakulam district. The evidences are that the women workers in the rural areas of the state are being increasingly diversified into the tertiary sector. The clear cut evidence for the fact that in Kerala non-agricultural employment of rural women is increasing with more and more of them getting diversified into the tertiary sector. The women get more self esteem and recognition in terms of the work being done by them. In the urban areas of the state as a poverty eradicating measure the Kerala government has already introduced a new scheme under the banner of Kudumbasree. Another fact noticed in the study that the sectoral shift of women workers has posed a grave problem to the agricultural sector. The reluctance of workers to do manual jobs on land and the prevalence of high wages among the agricultural labours has left many a cultivable area fallow or has induced farmers to shift to less labour –intensive crops. The situation is expected to worsen in future as even the high wages fail to attract the young generation to this sector. To conclude the study has fulfilled all its objectives, viz; highlighting the rural employment structure in Kerala, examining the process, pattern, determinants and consequences of diversification among rural women workers in the sample villages. Being the first of its kind at the micro level in the state it contributes to the available literature in the area enriching the database that is crucially lacking for devising projects at the village and block-level. There exists ample scope for future research of similar nature in an urban background where the secondary data-sources are hinding towards a reversal of trends from non-agriculture to agriculture.

India's Engineering Exports: Growth, Concentration and Diversification

The unprecedented increase in competition as well as protectionism in world markets makes it imperative for a country like India to get much more energetically involved in the export business and make the dictum "export and flourish" a really true proposition, as against a somewhat passive "export and perish" approach followed during the last three and a half decades. At present, India needs to evolve new export strategies to cope with the changing international scenario and to ensure a steady improvement in the otherwise sagging export performance. A search for such strategic measures becomes all the more important in view of the all-out efforts of the government for expanding the country's exports to tide over the crippling balance of payment deficits and to generate necessary foreign exchange to meet the import requirements for accelerating the tempo of economic development. The present study is an endeavour in this direction. Taking engineering exports as an example, the study demonstrates alternative ways of understanding indepth export performance analysis and learning lessons for better performance in future

From Market Concentration to Market Diversification: WTO and the Marine Products Exports from Kerala- Using ARIMA

Marine product export does something pivotal in the fish export economy of Kerala. The post WTO period has witnessed a strengthening of food safety and quality standards applied on food products in the developed countries. In the case of the primary importers, like the EU, the US and Japan, market actions will have far reaching reverberations and implications for the marine product exports from developing nations. The article focuses on Kerala’s marine product exports that had been targeting the markets of the EU, the US and Japan, and the concomitant shift in markets owing to the stringent stipulations under the WTO regime. Despite the overwhelming importance of the EU in the marine product exports of the state, the pronounced influence of irregular components on the quantity and value of marine product exports to the EU in the post WTO period raises concern. However, the tendencies of market diversification validated by the forecast generated for the emerging markets of the SEA, the MEA and others, to an extent, allay the pressures on the marine product export sector of the state which had hitherto relied heavily on the markets of the EU, the US and Japan

Improving food and nutritional security of small and marginal coconut growers through diversification of crops and enterprises

This paper presents the impact of integrating interventions like nutrition gardening, livestock rearing, product diversification and allied income generation activities in small and marginal coconut homesteads along with nutrition education in improving the food and nutritional security as well as the income of the family members. The activities were carried out through registered Community Based Organizations (CBOs) in three locations in Kerala, India during 2005-2008. Data was collected before and after the project periods through interviews using a pre-tested questionnaire containing statements indicating the adequacy, quality and diversity of food materials. Fifty respondents each were randomly selected from the three communities, thereby resulting in a total sample size of 150. The data was analysed using SPSS by adopting statistical tools like frequency, average, percentage analysis, t – test and regression. Participatory planning and implementation of diverse interventions notably intercropping and off-farm activities along with nutrition education brought out significant improvements in the food and nutritional security, in terms of frequency and quantity of consumption as well as diet diversity. At the end of the project, 96%of the members became completely food secure and 72% nutritionally secure. The overall consumption of fruits, vegetables and milk by both children and adults and egg by children recorded increase over the project period. Consumption of fish was more than the Recommended Dietary Intake (RDI) level during pre and post project periods. Project interventions like nutrition gardening could bring in surplus consumption of vegetables (35%) and fruits (10%) than RDI. In spite of the increased consumption of green leafy vegetables and milk and milk products over the project period, the levels of consumption were still below the RDI levels. CBO-wise analysis of the consumption patterns revealed the need for location-specific interventions matching to the needs and preferences of the communities.

Trade diversification in Colombia, 1991-2011

We describe the evolution of international trade and the behavior of export diversification in Colombia during the period 1991-2011. For measuring trade diversification and following up its behavior along the period, we employ alternative ways of decomposing trade flows along its intensive and extensive margins, using the latter as a measure of diversification. Results indicate that, in the short run, trade diversification in Colombia can be characterized as weak but that there is a modest trend for an increase in its importance. With some differences in degree, for both exports and imports, the number of partner countries increases faster than the number of products contained in the average basket traded and, simultaneously, the number of traded products increases faster than the average number of countries with which they are traded. Hence, trade diversification in Colombia seems to follow a pattern that implies that trade with new partners tends to be relatively slowly populated in terms of products or, from the opposite point of view, trade of new products is relatively sluggish in extending to new partner countries

Risk, ambiguity, and diversification

Attitudes toward risk influence the decision to diversify among uncertain options. Yet, because in most situations the options are ambiguous, attitudes toward ambiguity may also play an important role. I conduct a laboratory experiment to investigate the effect of ambiguity on the decision to diversify. I find that diversification is more prevalent and more persistent under ambiguity than under risk. Moreover, excess diversification under ambiguity is driven by participants who stick with a status quo gamble when diversification among gambles is not feasible. This behavioral pattern cannot be accommodated by major theories of choice under ambiguity.

Extractivism, economic diversification and prospects for sustainable development in Ecuador

The objectives of this paper are first, evaluating economic, social and environmental effects on oil extraction in Ecuador during the last 41 years, and second, discussing prospects to achieving a sustainable and equitable development path in the future, in the context of declining oil reserves. The current government is pursuing an extractivist policy, based on expanding oil extraction in formerly unexploited fields -including those inside the Yasuni National Park- and starting largescale mining exploitation. Two future options will be evaluated, first, an expansion of extractive activities, and second an alternative based on conservation, with sustainable use of natural resources (e.g. ecotourism, agroforestry, bio-knowledge), without expansion of oil field expansion and mining.

Microbial relatives of the seed storage proteins of higher plants: conservation of structure and diversification of function during evolution of the cupin superfamily.

This review summarizes the recent discovery of the cupin superfamily (from the Latin term "cupa," a small barrel) of functionally diverse proteins that initially were limited to several higher plant proteins such as seed storage proteins, germin (an oxalate oxidase), germin-like proteins, and auxin-binding protein. Knowledge of the three-dimensional structure of two vicilins, seed proteins with a characteristic beta-barrel core, led to the identification of a small number of conserved residues and thence to the discovery of several microbial proteins which share these key amino acids. In particular, there is a highly conserved pattern of two histidine-containing motifs with a varied intermotif spacing. This cupin signature is found as a central component of many microbial proteins including certain types of phosphomannose isomerase, polyketide synthase, epimerase, and dioxygenase. In addition, the signature has been identified within the N-terminal effector domain in a subgroup of bacterial AraC transcription factors. As well as these single-domain cupins, this survey has identified other classes of two-domain bicupins including bacterial gentisate 1, 2-dioxygenases and 1-hydroxy-2-naphthoate dioxygenases, fungal oxalate decarboxylases, and legume sucrose-binding proteins. Cupin evolution is discussed from the perspective of the structure-function relationships, using data from the genomes of several prokaryotes, especially Bacillus subtilis. Many of these functions involve aspects of sugar metabolism and cell wall synthesis and are concerned with responses to abiotic stress such as heat, desiccation, or starvation. Particular emphasis is also given to the oxalate-degrading enzymes from microbes, their biological significance, and their value in a range of medical and other applications.