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.

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

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.

The cyclical behaviour of sector and regional diversification benefits: 1987-2002

This paper investigates the time series behaviour of the relative benefits of sector and regional diversification strategies, using the notion of cross-sectional dispersion introduced by Solnik and Roulet (2000). Using monthly data over the period 1987:1 to 2002:12, four sector and four regional classifications are examined in the UK. The results indicate that sector and regional dispersion indices are highly time varying and so dwarf any lower frequency cyclical components that may be present. Nonetheless, periods of high dispersion are closely followed by periods of low dispersion, suggestive of cyclical behaviour of sector and regional diversification benefits. Then, using the HP-filter we isolated the cyclical component of the various dispersion indices and found that the sector dispersion indices are generally above the regional dispersion indices. This implies that a sector diversification strategy is likely to offer greater risk reduction benefits than a regional diversification approach. Nonetheless, we find that in some periods, certain regional diversification strategies are of equal or greater benefit than certain sector approaches. The results also appear to be quite sensitive to the classifications of sectors and regions. Hence, the appropriate definition of sectors and regions can have important implications for sector and regional diversification strategies.

The relationship between size, diversification and risk

Property portfolio diversification takes many forms, most of which can be associated with asset size. In other words larger property portfolios are assumed to have greater diversification potential than small portfolios. In addition, since greater diversification is generally associated with lower risk it is assumed that larger property portfolios will also have reduced return variability compared with smaller portfolios. If large property portfolios can simply be regarded as scaled-up, better-diversified versions of small property portfolios, then the greater a portfolio’s asset size, the lower its risk. This suggests a negative relationship between asset size and risk. However, if large property portfolios are not simply scaled-up versions of small portfolios, the relationship between asset size and risk may be unclear. For instance, if large portfolios hold riskier assets or pursue more volatile investment strategies, it may be that a positive relationship between asset size and risk would be observed, even if large property portfolios are more diversified. This paper tests the empirical relationship between property portfolio size, diversification and risk, in Institutional portfolios in the UK, during the period from 1989 to 1999 to determine which of these two characterisations is more appropriate.

The adjustment strategies of Mexican ejidatarios in the face of neoliberal reform

Includes bibliography

Free trade agreements in Latin America since 1990: an evaluation of export diversification

Includes bibliography

Bridging innovation, nature and tradition: assessment of strategies for rural tourism development in Maramureş (Romania)

In the frame of EU rural policy, always more oriented towards environmental concerns and green livelihoods, Romania stands out for the predominance of rural areas and high nature value farming. The country has to face the challenge of joining the modernization process of rural farming systems with the valorization of local assets. Tourism has emerged as one of the main drivers of change and contributors for a sustainable exploitation of local resources. Rural tourism (RT) can foster the enhancement of the territorial capital (TC), the preservation of public goods (PGs) and the promotion of a more environmental oriented livelihood. The research focuses on a case study area, two valleys from Maramureş, where environmental approaches as diversification strategies are partially explored. The work investigates the role of tourism initiatives for the promotion of green oriented practices. The first part of the work is based on a literature review and interdisciplinary analysis of secondary data to identify the key issues: from rural development policy, to the concept of TC, of PGs and RT. The Romanian development programmes and related strategies are investigated; afterwards the characteristics of the County and the role of RT as diversification and valorisation policies is considered. The second part is based on the collection of primary data through interviews to different local stakeholders (farmers owners of rural guesthouses, local administrators, networks and artisans). The main frequencies are analyzed, a cluster analysis is computed to evaluate the similarities within the most representative groups and a comparative analysis is carried out between the two Valleys. The frame of the analysis is based on a set of indicators following the dimensions of the TC, to assess the characteristics of the local stakeholders and to outline the perception about the local PGs and on the adopted strategies to manage the territory. Final considerations are elaborated and few scenarios are outlined, giving relevance to the importance of improving awareness and creating embeddedness among public-private local stakeholders and resources as a tool for a socio-economic and environmental development of the area.

Rural governance and livelihoods systems diversification in the Western Balkans: comparative case studies of Bosnia and Herzegovina, Montenegro and Serbia

Agriculture is still important for socio-economic development in rural areas of Bosnia, Montenegro and Serbia (BMS). However, for sustainable rural development rural economies should be diversified so attention should be paid also to off-farm and non-farm income-generating activities. Agricultural and rural development (ARD) processes and farm activity diversification initiatives should be well governed. The ultimate objective of this work is to explore linkages between ARD governance and rural livelihoods diversification in BMS. The thesis is based on an extended secondary data analysis and surveys. Questionnaires for ARD governance and coordination were sent via email to public, civil society and international organizations. Concerning rural livelihood diversification, the field questionnaire surveys were carried out in three rural regions of BMS. Results show that local rural livelihoods are increasingly diversified but a significant share of households are still engaged in agriculture. Diversification strategies have a chance to succeed taking into consideration the three rural regions’ assets. However, rural households have to tackle many problems for developing new income-generating activities such as the lack of financial resources. Weak business skills are also a limiting factor. Fully exploiting rural economy diversification potential in BMS requires many interventions including improving rural governance, enhancing service delivery in rural areas, upgrading rural people’s human capital, strengthening rural social capital and improving physical capital, access of the rural population to finance as well as creating a favourable and enabling legal and legislative environment fostering diversification. Governance and coordination of ARD policy design, implementation and evaluation is still challenging in the three Balkan countries and this has repercussions also on the pace of rural livelihoods diversification. Therefore, there is a strong and urgent need for mobilization of all rural stakeholders and actors through appropriate governance arrangements in order to foster rural livelihoods diversification and quality of life improvement.

Productive Diversification and Sustainable Use of Complex Social-Ecological Systems: A Comparative Study of Indigenous and Settler Communities in the Bolivian Amazon

Agricultural and forest productive diversification depends on multiple socioeconomic drivers—like knowledge, migration, productive capacity, and market—that shape productive strategies and influence their ecological impacts. Our comparison of indigenous and settlers allows a better understanding of how societies develop different diversification strategies in similar ecological contexts and how the related socioeconomic aspects of diversification are associated with land cover change. Our results suggest that although indigenous people cause less deforestation and diversify more, diversification is not a direct driver of deforestation reduction. A multidimensional approach linking sociocognitive, economic, and ecological patterns of diversification helps explain this contradiction.

Food crop diversification as a risk mitigating strategy during conflict : evidence from Cote d'Ivoire

This study examines the significance of food crop diversification as a household risk mitigating strategy to achieve "self-sufficiency" to ensure food security during the civil conflict in Cote d’Ivoire. The main motivation for seeking self-sufficiency stems from the fact that during the period of heightened tension due to conflict, the north–south divide set by the UN peacekeeping line disrupted the agricultural supply chain from the food surplus zone, Savane in the north. While we theoretically predict a positive effect on crop diversification because of interrupted food supply chain, we also consider a negative effect due to the covariate shocks. We find robust and statistically significant empirical outcomes supporting such claims. The baseline outcomes withstand a series of robustness checks. The net effect of conflict on crop diversification is positive but not statistically significant. In addition, we find that increasing vulnerability to poverty and food insecurity during conflict seems to be the underlying factors that motivate farm households to adopt such coping strategies.

Returns from Income Strategies in Rural Poland. Factor Markets Working Document No. 64, August 2013

In order to stabilise and improve their income situation, rural households are strongly encouraged to diversify their activities both within and outside the agricultural sector. Often, however, this advice is only moderately pursued. This paper addresses issues of rural household income diversification in the case of Poland. It investigates returns from rural household income strategies using propensity score matching methods and extensive datasets spanning 1998-2008. Results suggest that returns from combining farm and off-farm activities were lower than returns from concentrating on farming or on self-employment outside agriculture. This differential is stable over time although returns from diversification have relatively improved after Poland’s accession to the EU. This is also visible in the fact that since 2006 returns from combining farm and off-farm activities have evened with returns from relying solely on hired off-farm labour, thus smoothing the difference observed before the accession. Further, over the analysed period, households pursuing the diversification strategy performed better than those relying solely on unearned income. Finally, in general, the income in households combining farm and off-farm activities was higher than in those combining two off-farm income sources.

Climate change adaptation strategies of maize producers of the Central Rift Valley of Ethiopia

The impacts of climate change are considered to be strong in countries located in tropical Africa that depend on agriculture for their food, income and livelihood. Therefore, a better understanding of the local dimensions of adaptation strategies is essential to develop appropriate measures that will mitigate adverse consequences. Hence, this study was conducted to identify the most commonly used adaptation strategies that farm households practice among a set of options to withstand the effects of climate change and to identify factors that affect the choice of climate change adaptation strategies in the Central Rift Valley of Ethiopia. To address this objective, Multivariate Probit model was used. The results of the model indicated that the likelihood of households to adapt improved varieties of crops, adjust planting date, crop diversification and soil conservation practices were 58.73%, 57.72%, 35.61% and 41.15%, respectively. The Simulated Maximum Likelihood estimation of the Multivariate Probit model results suggested that there was positive and significant interdependence between household decisions to adapt crop diversification and using improved varieties of crops; and between adjusting planting date and using improved varieties of crops. The results also showed that there was a negative and significant relationship between household decisions to adapt crop diversification and soil conservation practices. The paper also recommended household, socioeconomic, institutional and plot characteristics that facilitate and impede the probability of choosing those adaptation strategies.

Fishers’ perception on livelihood strategies, adaptation and mitigation measures to cope with changes in climate variables around Lake Wamala, Uganda

Fisheries support livelihoods but are threatened by climate variability and change which intensified since the 1970s. This study used quantitative and qualitative methods to determine the extent to which fishers around Lake Wamala in Uganda were copying with perceived changes in climate variables and the impacts on their livelihoods, to generate knowledge to enable the fishers increase resilience and sustain their livelihoods. Fishers were aware of changes in climate manifested by unpredictable seasons, floods and droughts. Fishing was the main livelihood activity. The African catfish had replaced Nile tilapia as the dominant fish species. There was damage and loss of gear, boats, landing sites and lives, and changes in fish catches and sizes, income and fish consumption during the perceived floods and droughts. The fishers adapted to the changes through increasing time on fishing grounds and changing target species and fishing gears but innovative ones diversified to high value crops and livestock which increased their income beyond what was earned from fishing thus acting as an incentive for some of them to quit fishing. Diversification to non-fishery activities as a form of adaptation was enhanced by membership to social groups, weekly fishing days, fishing experience and age of fishers but its benefits were not equally shared among men and women. Mitigation measures included planting trees, mulching gardens and protecting wetlands. Adaptation and mitigation measures were constrained by limited credit, awareness and land. The required interventions included improving access to credit, irrigation facilities and appropriate planting materials and raising awareness. The study showed that the fishers were aware of changes in climatic variables and the impacts on their livelihoods. There were also adaptation and mitigation measures practiced by the fishers which if promoted and their constraints addressed, could increase resilience of fishers to climatic change and sustain their livelihoods.

[strategies For Integration Of Health Care Practices And Sanitary Surveillance In The Context Of The Implementation Of Rede Cegonha - A Brazilian Mother And Infant Health Care Network].

Mother and infant mortality has been the scope of analysis throughout the history of public health in Brazil and various strategies to tackle the issue have been proposed to date. The Ministry of Health has been working on this and the Rede Cegonha strategy is the most recent policy in this context. Given the principle of comprehensive health care and the structure of the Unified Health System in care networks, it is necessary to ensure the integration of health care practices, among which are the sanitary surveillance actions (SSA). Considering that the integration of health care practices and SSA can contribute to reduce mother and infant mortality rates, this article is a result of qualitative research that analyzed the integration of these actions in four cities in the State of São Paulo/Brazil: Campinas, Indaiatuba, Jaguariúna and Santa Bárbara D'Oeste. The research was conducted through interviews with SSA and maternal health managers, and the data were evaluated using thematic analysis. The results converge with other studies, identifying the isolation of health care practices and SSA. The insertion of SSA in collectively-managed areas appears to be a potential strategy for health planning and implementation of actions in the context under scrutiny.