Le transporteur de drogues membranaire MRP1 participe à la résistance des cellules cancéreuses à la chimiothérapie lorsqu’il est surexprimé. Cette surexpression peut être exploitée afin de provoquer l’apoptose sélective de ces cellules, MRP1 devenant leur talon d’Achille : c’est l’effet de sensibilité collatérale (SC). Ainsi, le vérapamil stimule l’efflux médié par MRP1 d’un tripeptide antioxydant indispensable aux cellules, le GSH ou glutathion réduit, et provoque la mort sélective des cellules surexprimant ce transporteur. La recherche d’autres agents de SC comme le vérapamil nous a menés à l’étude de composés flavonoïdiques pouvant induire un efflux rapide et massif de GSH. Parmi ces composés, nous avons identifié un puissant agent de SC des cellules résistantes surexprimant MRP1, le dimère de flavonoïde 4e, candidat très prometteur pour de futures études in vivo. Nous avons déterminé que la surexpression de MRP1 est effectivement responsable de la SC dans les cellules cancéreuses résistantes H69AR, et que l’efflux de GSH se doit d’être massif et prolongé pour induire l’apoptose des cellules. Nous avons montré que cet efflux perturbe l’homéostasie du glutathion et l’état redox des cellules, entraînant un stress oxydatif qui participe au déclenchement de la mort cellulaire. Enfin, nous nous sommes attachés à identifier d’éventuelles cibles secondaires des agents de SC dans les cellules surexprimant MRP1, via l’initiation de l’étude de leur transcriptome et métabolome. La compréhension du mécanisme d’action de ces agents de sensibilité collatérale vise, à terme, à l’éradication des cancers résistants surexprimant MRP1 / The membrane drug transporter MRP1 is involved in the resistance of cancer cells to chemotherapy, when overexpressed. This overexpression can be exploited in order to induce the selective apoptosis of these cells, so that MRP1 becomes their Achilles’ heel: this is called Collateral Sensitivity (CS). Thus verapamil stimulates the MRP1-mediated efflux of GSH (reduced form of glutathione) that is an antioxidant tripeptide essential for cells, and induces the selective death of MRP1- overexpressing cells. Seeking for other CS agents than verapamil led to the study of flavonoid compounds able to induce a massive and rapid efflux of GSH and to the identification of a powerful CS agent of resistant cells overexpressing MRP1, i.e. flavonoid dimer 4e, which is a very promising candidate for in vivo studies. We determined that overexpression of MRP1 is indeed responsible for CS in H69AR resistant cancer cells, and that GSH efflux must be massive and protracted in order to induce cell apoptosis. We showed that this efflux disturbs glutathione homeostasis and cell redox state, which leads to an oxidative stress that is involved in triggering cell death. At last, we sought to identify possible secondary targets of CS agents in MRP1-overexpressing cells, via the initiation of transcriptomic and metabolomic studies. Understanding the mechanism of action of these Collateral Sensitivity agents aims to the eradication of resistant cancers that overexpress MRP1

According to the U.S. Small Business Administration, African Americans are the fastest growing entrepreneurial minority group in the United States. However, they suffer the highest business failure rates. The research design for this study was a multiple case study to explore the strategies small business owners used to succeed in business beyond 5 years. The conceptual framework for this study was the systems theory. The population was small business owners in the Dallas-Fort Worth metropolis, Texas. Data collection sources included semistructured interviews, company documents, company websites, and site visit observations. The data analysis process included data cleaning, uploading transcribed interviews into qualitative data analysis software, organizing and coding, and conducting methodological triangulation against company documents. The thematic analysis led to the identification of 6 major themes contributing to company sustainability. The predominate themes included entrepreneur qualities, adequacy or lack of collateral, financial planning, and market qualities. The consensus among participants denoted that in a business environment characterized by market differentiation, effective financial planning and unique entrepreneurial characteristics contributed to company sustainability. The findings revealed several features of the successful business owners such as education, professional background, motivation, creativity, negotiation skills, networking, risk-taking, and self-efficacy were critical for company sustainability. The positive social change includes increasing the rate of small business success, supporting the U.S. economy, and improving financial security for African American entrepreneurs, their families, employees, and the community.

Educators and administrators often use sub-scores derived from state accountability assessments to diagnose learning/instruction and inform curriculum planning. However, there are several psychometric limitations of observed sub-scores, two of which were the focus of the present study: (1) limited reliabilities due to short lengths, and (2) little distinct information in sub-scores for most existing assessments. The present study was conducted to evaluate the extent to which these limitations might be overcome by incorporating collateral information into sub-score estimation. The three sources of collateral information under investigation included (1) information from other sub-scores, (2) schools that students attended, and (3) school-level scores on the same test taken by previous cohorts of students in that school. Kelley's and Shin's methods were implemented in a fully Bayesian framework and were adapted to incorporate differing levels of collateral information. Results were evaluated in light of three comparison criteria, i.e., signal noise ratio, standard error of estimate, and sub-score separation index. The data came from state accountability assessments. Consistent with the literature, using information from other sub-scores produced sub-scores with enhanced precision but reduced profile variability. This finding suggests that using collateral information internal to the test has the capability of enhancing sub-score reliability, but at the expense of losing the distinctness of each individual sub-score. Using information indicating the schools that students attended led to a small gain in sub-score precision without losing sub-score distinctness. Furthermore, using such information was found to have the potential to improve sub-score validity by addressing Simpson's paradox when sub-score correlations were not invariant across schools. Using previous-year school-level sub-score information was found to have the potential to enhance both precision and distinctness for school-level sub-scores, although not for student-level sub-scores. School-level sub-scores were found to exhibit satisfactory psychometric properties and thus have value in evaluating school curricular effectiveness. Issues concerning validity, interpretability, suitability of using such collateral information are discussed in the context of state accountability assessments.

<p>This thesis consists of five chapters.</p><p><b>Chapter 1 and 2 </b>The first chapter presents the introduction and the summary and the second chapter provides details on the survey and the data collection.</p><p>Chapter 3 The demand and supply of credit in the rural finance markets are investigated in this paper using data on 989 households, in Orissa, India. The aim is to study the effects of household, farm productive characteristics and the policy variables on the demand and supply of credit. A type 3 Tobit model is estimated which corrects for sample selection and endogeniety bias. In addition, a generalised Double Hurdle model is estimated where the household's access to credit is treated distinctly from decisions about the interest rate charged. The results from the type 3 tobit model suggest that the size of the operational holdings, net-wealth, the dependency ratio, educational level of the household and the wages and output prices are important determinants of the demand and supply of credit. The Double Hurdle model suggests the important result that the size of land owned plays a crucial role in whether the household obtains a loan or not.</p><p>Chapter 4 Based on the 'Rural Credit Market Survey of the Puri district in India', this paper investigates evidence on segmentation in the rural credit markets of Puri district. It further investigates the presence of any systematic association between the type of collateral offered by the household and the rate of interest at which it borrows. The data shows differences in the loan characteristics between the households borrowing from the formal and the informal sector. The empirical results confirm the presence of segmentation in the Puri credit market. For the households borrowing from the informal sector and the moneylenders, evidence also shows that the marketability of the collateral is inversely related to the interest rate. However, no such clear relationship is found for households borrowing from the formal sector.</p><p><b>Chapter 5 </b>In the theoretical and the empirical literature on rural credit markets it is widely assumed that the households are credit rationed in the formal sector, which offers subsidised credit. This view rests on the assumptions that all households have a positive demand for formal credit and that it is the cheaper source of credit. Three different models of formal credit rationing are estimated in this paper. The first model is a conventional credit-rationing model. The second model assumes that the probability to borrow from the formal sector is jointly determined by the demand for credit and the decision of the bank on access. Finally, the third model relaxes both these assumptions and the household chooses between borrowing from the formal or the informal sector. The results confirm that the access to the formal sector in the Puri rural credit markets is limited and that there exists a high demand for credit. This suggests a high degree of effective credit rationing by the formal sector in Puri. </p>

In this work we contribute to the literature about the optimal asset allocation in continuous-time. In particular, we consider the problem of maximising the expected utility of the investor's final wealth over a finite time horizon. We develop a suitable framework in the dynamic stochastic optimal control theory in order to analyse the optimal asset allocation problem for an institutional investor like a bank, an insurance company, an investment fund, or a pension fund. Such an investor cannot control the contributions to and withdrawals from the managed wealth. In fact, while the classical consumption-portfolio problem considers consumption as a control variable, in our analysis the flows of wealth that are different from the coupons and dividends, are just state variables. We refer to them as "background variables". Furthermore, the analysis explicitly takes into account the inflation risk that is generally neglected by the asset allocation literature. In such a context we present some quasi-explicit solutions for the optimal asset allocation problem without specifying any particular functional form for the drift and diffusion terms of the stochastic differential equations describing the financial market, the background variables, and inflation. The institutional investor's attitude towards risk is supposed to be described by an increasing and concave utility function whose risk aversion is absolutely constant, relatively constant, or hyperbolic according to the problem setting that must be solved. Finally, we explicitly consider the case of a pension fund that must maximise the expected utility of its surplus. Unlike the analyses studying the problem of a non-actuarial institutional investor, the case of a pension fund requires the introduction of two new characteristics: (i) the different behaviour of the fund's wealth during the accumulation and the decumulation phases, and (ii) the mortality risk. We develop a set up aimed at finding out how and how much this mortality risk affects the optimal asset allocation./ Dans ce travail nous donnons une contribution à la litérature de l'allocation optimale du portefeuille en temps continu. En particulier, nous analysons le problème d'un investisseur qui veut maximiser la valeur espérée de l'utilité de sa richesse, avec un horizon temporel fini. En utilisant la théorie du contrôle optimal dynamique, on developpe un modèle dédié à l'analyse de l'allocation optimal de portefeuille pour un investisseur institutionnel tel qu'une banque, une compagnie d'assurance, un fond commun d'investissement ou un fond de pension. Un tel investisseur ne peut pas contrôler les contributions et les prelèvements du fond géré. En effet, même si l'approche classique optimise soit le portefeuille soit la consommation intertemporelle en considérant les prélèvements du fond dûs à la consommation comme une variable de contrôle, dans notre approche les flux de richesse qui diffèrent des coupons et dividends, sont tout simplement des variables d'état. On appellera ces variables "variables de background". De plus, notre analyse rend compte explicitement du risque d'inflation qui est généralement négligé par la literature sur l'allocation des actifs financiers. Dans ce contexte nous présentons une solution quasi-explicite pour l'investissement optimal sans spécifier acune forme fonctionnelle ni pour les dérives, ni pour les diffusions des équations stochastiques qui décrivent le marché financier, les variables de background et l'inflation. Nous supposons que l'attitude envers le risque de l'investisseur institutionnel est décrit par une fonction d'utilité croissante et concave, dont l'aversion au risque est absolument constante, relativement constante ou hyperbolique selons la structure du problème qui doit être resolu. Finalement nous analyson explicitement le cas d'un fond de pension qui veut maximiser la valeur espérée de sons surplus. Contrairement aux modèles qui étudient un investisseur qui est institutionnel mais pas actuarial, le cas d'un fond de pension requiert l'introduction de deux nouvelles characteristiques: (i) le comportement différent de la richesse du fond pendant les phases d'accumulation et de décumulation, et (ii) le risque de mortalité. Nous developpons un modèle afin de déterminer comment et combien le risque de mortalité affecte l'allocation optimale de portefeuille.

<p><font face="Times New Roman"> <p align="left">This study looks at the effect of a cross-cultural instructional approach on the learners&rsquo / conceptions of lightning and attitude towards science. It explored Basotho conceptions of lightning and thunder under the following themes: nature of lightning, protection against lightning, animalistic/humanistic behaviour of lighting and nature of wounds inflicted by lightning.</p> </font></p>

This thesis consists of five chapters. Chapter 1 and 2 The first chapter presents the introduction and the summary and the second chapter provides details on the survey and the data collection. Chapter 3 The demand and supply of credit in the rural finance markets are investigated in this paper using data on 989 households, in Orissa, India. The aim is to study the effects of household, farm productive characteristics and the policy variables on the demand and supply of credit. A type 3 Tobit model is estimated which corrects for sample selection and endogeniety bias. In addition, a generalised Double Hurdle model is estimated where the household's access to credit is treated distinctly from decisions about the interest rate charged. The results from the type 3 tobit model suggest that the size of the operational holdings, net-wealth, the dependency ratio, educational level of the household and the wages and output prices are important determinants of the demand and supply of credit. The Double Hurdle model suggests the important result that the size of land owned plays a crucial role in whether the household obtains a loan or not. Chapter 4 Based on the 'Rural Credit Market Survey of the Puri district in India', this paper investigates evidence on segmentation in the rural credit markets of Puri district. It further investigates the presence of any systematic association between the type of collateral offered by the household and the rate of interest at which it borrows. The data shows differences in the loan characteristics between the households borrowing from the formal and the informal sector. The empirical results confirm the presence of segmentation in the Puri credit market. For the households borrowing from the informal sector and the moneylenders, evidence also shows that the marketability of the collateral is inversely related to the interest rate. However, no such clear relationship is found for households borrowing from the formal sector. Chapter 5 In the theoretical and the empirical literature on rural credit markets it is widely assumed that the households are credit rationed in the formal sector, which offers subsidised credit. This view rests on the assumptions that all households have a positive demand for formal credit and that it is the cheaper source of credit. Three different models of formal credit rationing are estimated in this paper. The first model is a conventional credit-rationing model. The second model assumes that the probability to borrow from the formal sector is jointly determined by the demand for credit and the decision of the bank on access. Finally, the third model relaxes both these assumptions and the household chooses between borrowing from the formal or the informal sector. The results confirm that the access to the formal sector in the Puri rural credit markets is limited and that there exists a high demand for credit. This suggests a high degree of effective credit rationing by the formal sector in Puri.

This thesis aims to understand the role of interest rate setting behavior of the banks for the transmission of technology, monetary policy and loan rate shocks into the real economy. To this end, we introduce a monopolistically competitive banking sector into a New Keynesian model. Here, each bank can change its loan rate only infrequently in the fashion of Calvo type staggered contract. This setting implies that the adjustment of the aggregate loan rate is sticky, which is consistent with the empirical evidence. The results show that having sticky adjustment in the loan market changes the dynamics of the model significantly. Following each shock, the sluggish adjustment of the loan rate affects the amount of loan used by the borrowers considerably. This is the main reason behind the differentials across the impulse responses of the model with sticky loan rate and flexible loan rate.

This study compares the biomechanics of early cyclic valgus loading of the ulnar collateral ligament (UCL) of the elbow repaired by either the Jobe technique or the docking technique. Better understanding of the biomechanical properties of each reconstruction may help surgeons choose the optimal surgical technique, particularly in planning earlier rehabilitation programs. Sixteen fresh frozen cadaver limbs (eight pairs) were randomized to either the Jobe cohort or the docking cohort. First intact UCLs were tested, followed by the repaired constructions. A Bionix MTS apparatus applied a constant valgus load to the elbows at 70o flexion, and valgus displacement was measured and then used to calculate valgus angle displacement. The docking group had significantly less valgus angle displacement than the Jobe group at cycles 100 and 1,000 (p = 0.0189 and 0.0076, respectively). Four of the eight specimens in the Jobe group failed at the tendon-suture interface before reaching 1,000 cycles, at cycles 7, 24, 250, and 362. None of the docking specimens failed before reaching 1,000 cycles. In this cadaveric study, the docking technique resulted in less angulation of the elbow in response to cyclic valgus loading as compared to the Jobe technique. The better response to valgus loading of the docking reconstruction may translate into a better response to early rehabilitation. Further study is needed to determine if this difference translates into improved clinical outcomes.

<p><font face="Times New Roman"> <p align="left">This study looks at the effect of a cross-cultural instructional approach on the learners&rsquo / conceptions of lightning and attitude towards science. It explored Basotho conceptions of lightning and thunder under the following themes: nature of lightning, protection against lightning, animalistic/humanistic behaviour of lighting and nature of wounds inflicted by lightning.</p> </font></p>