Les aquifères karstiques sont associés à des enjeux importants en termes à la fois de gestion de la ressource en eau et de gestion du risque d'inondation. Ces systèmes sont caractérisés par une structure fortement hétérogène et un fonctionnement non-linéaire. Cette thèse est consacrée à l'étude de la sensibilité et de l'incertitude associés à la modélisation numérique des écoulements en milieu karstique. De façon systématique, l'analyse de sensibilité est utilisée comme outil afin de répondre aux questions suivantes: (i) la calibration est-elle possible ? (ii) la calibration est-elle robuste ? (iii) est-il possible de réduire l'équifinalité via une calibration multi-objectif ou multi-variable ?Cette contribution met en évidence le potentiel des méthodes locales d'analyse de sensibilité. En dépit des limitations inhérentes à cette approche (approximation locale et perturbation d'un facteur à la fois), l'analyse locale permet une compréhension fine du fonctionnement du modèle, pour un coût de calcul réduit.Par ailleurs, cet travail souligne l'intérêt d'une calibration multi-variable par rapport à une calibration multi-objectif, dans une optique de réduction de l'équifinalité / Karst aquifers are associated with key issues for water resource management and also for flood risk mitigation. These systems are characterized by a highly heterogeneous structure and non-linear functioning. This thesis addresses the sensitivity and uncertainty associated with the numerical modelling of groundwater flow in karst systems. As a systematic approach, sensitivity analysis has been used to answer the following questions:(i) is it possible to calibrate the model ? (ii) is the calibration robust ? (iii) is it possible to reduce equifinality, through multi-objective calibration or through multi-variable calibration ? This contribution stresses the potentialities of local sensitivity analyses. Despite their inherent limitations (local approximation), local analyses have proved to bring valuable insights into the general behaviour of complex, non-linear flow models, at little computational cost. Besides, this contribution also stresses the interest of multi-variable calibration as compared to multi-objective calibration, as regards equifinality reduction.

The fundamental need to belong is considered one of the most basic human requirements, and universally motivates human behaviour. When this need to belong is not met, it increases the risk of mental health problems like depression, which was of interest in this dissertation. Due to the psychological consequences of not being accepted by others, humans are very attuned to perceived threats to belonging and have developed types of defense mechanisms to protect themselves against social exclusion. One such defense mechanism is rejection sensitivity, and the role of rejection sensitivity as it relates to depression was the underlying theme of this dissertation. Along with rejection sensitivity, there exist external and internal factors that serve as threats to belonging, and which are associated with depression. Two of these factors, rejection (an interpersonal factor) and perfectionism (an intrapersonal factor) were examined in relation to depression. Study 1 focused on peer rejection and the developmental pathways involved in its relation to rejection sensitivity, depression, and aggression in adolescence. Results showed that rejection and rejection sensitivity were preceded by either depression or aggression across adolescence, and although depression initiated the cascade leading to rejection sensitivity, there was a bidirectional relation across late adolescence as rejection sensitivity also predicted future depression. Study 2 focused on two types of perfectionism (i.e., self-oriented and socially prescribed), including the developmental pathways associated with their relation to rejection sensitivity and depression in adolescence. Socially prescribed perfectionism was directly related to future depression and rejection sensitivity mediated the relation between self-oriented perfectionism and depression. Depression initiated the cascade leading to rejection sensitivity and supported a bidirectional relation across late adolescence. Study 3 also focused on perfectionism, but cross-sectionally in young adults, and examined three types of perfectionism (i.e., self-oriented, socially prescribed, and other-oriented). Rejection sensitivity and socially prescribed perfectionism were positively related to depression, and other-oriented perfectionism was negatively related to depression; however, self-oriented perfectionism did not contribute significantly to depression. Contrary to what was predicted, rejection sensitivity was not a significant moderator in the relation between perfectionism and depression. Overall, rejection sensitivity, a defense mechanism against threats to the need to belong, played a significant role in the development and maintenance of depression in the absence of actual rejection, as well as in conjunction with specific types of perfectionism.

OBJECTIVE: Despite advancement in targeted therapeutics, women’s cancers remain particularly deadly. The response to Poly (ADP-ribose) Polymerase (PARP) inhibitors, a prominent targeted therapy indicated for use in these cancers, is largely dictated by the cellular status of homologous recombination (HR) and varies among patients possibly due to intrinsic and acquired mechanisms of resistance. A recent effort to identify targetable pathways to enhance toxicity of PARPi identified the Snf2-like chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1), as a key determinant of PARPi sensitivity. While this discovery proposes a link between chromatin re-modeling and PARPi sensitivity, the mechanism underlying the relationship remains unclear. This study aims to validate ALC1 as a determinant of PARPi sensitivity, characterize the phenotype of ALC1 loss, investigate mechanisms of synthetic lethality and identify possibilities for future studies and clinical implementation. METHODS: UWB1.289, SUM149PT, DLD1, U-2 OS, and hTERT-RPE1 cells were cultured and used to validate ALC1-mediated PARPi sensitivity in a variety of viability assays. ALC1 depleted cells were complemented with various functional mutants to assess protein domains that were essential to PARPi-resistance. A Dual CRISPR-Cas9 system was implemented to screen BRCA1 complemented UWB1.289 cells with a sgRNA library targeting a multitude of DNA-repair associated genes in order to assess synthetic lethal/resistant relationships across different DNA-repair pathways. A MNase-sensitivity assay was developed and optimized to assess the global condensation of chromatin with combinational loss of ALC1 and PARP1. The 265-FokI system was employed to quantify the DNA damage response (DDR) to singular induced double strand breaks. Clonogenic assays were used to determine synergy with ionizing radiation. RESULTS: The loss of ALC1 significantly and selectively hypersensitized both BRCA1 and BRCA2-deficient cells to PARPi. In ALC1 depleted cells, the addition of ALC1 cDNA was able to rescue cells from PARPi hypersensitivity while cDNA with mutations in either the macro-domain or ATPase active domain remained sensitive. Screening DNA-repair pathways to assess synergy with PARPi and ALC1 loss in HR-proficient settings revealed that the loss of several HR and Alt-EJ genes selectively re-sensitized cells to PARPi. Interestingly, the loss of BER genes, including several glycosylases, were epistatic or resulted in a protective effect to PARPi. The reduction of NHEJ, NER, MMR or RER did not significantly alter cellular response to PARPi. Further, nucleosome relaxation was significantly inhibited in cells treated with PARPi, ALC1 loss or in combination via MNase assay. The recruitment of repair proteins to DSBs was significantly inhibited by PARPi as assessed by 265-FokI immunofluorescence. The addition of PARPi in the setting of ALC1 loss significantly increased the cytotoxicity of ionizing radiation. Analyzing TCGA data collected from patients’ tumors, ALC1 may be overexpressed in many cancers and alterations in ALC1 may predict patient responses to traditional and targeted cancer therapies. CONCLUSION: Using various models of BRCA1/2 deficiency we were able to validate the ability of ALC1 depletion to hypersensitize HR-deficient cells to PARPi. We provided insight into the mechanisms by which this phenomenon may be taking place, including chromatin compaction and the inhibition of DNA-damage repair. In addition, we provided therapeutic rationale that ALC1 may be targeted with PARP1 in synergy with other DNA-damaging agents. Overall, we believe that ALC1 is a prominent, viable and novel target of inducing PARP inhibitor sensitivity, that may help improve outcomes for patients with PARP inhibitor-resistant HR-deficient cancers. / 2022-06-04T00:00:00Z

Prior research suggests that rejection sensitive individuals may find it easier to express their true selves in an online environment. The purpose of the present study was to further examine the influence of true self, which is who a person believes he or she truly is, on the relationship between rejection sensitivity and online dating site usage. Additionally, the present study investigated the role of self-disclosure in online dating site usage. Five-hundred sixty one participants completed an online survey. Consistent with prior research, results indicated that rejection sensitivity and true self predicted online dating site usage. Further, true self partially mediated the relationship between rejection sensitivity and online dating site usage. Self-disclosure in online environments, however, did not influence the relationship between rejection sensitivity and online dating site use. In addition, for those who engaged in online dating, rejection sensitivity was not related to self-disclosure in online dating profiles or in communicating with individuals met through online dating sites. True self, though, was related to both self-disclosure in online dating profiles and in communication with those met through online dating sites. These findings suggest that rejection sensitive individuals are more likely to engage in online dating because it may facilitate representation of their “true” selves. Furthermore, rejection sensitivity may not facilitate individuals’ self-disclosure in online environments, whereas the desire to share one’s “true” self may facilitate self-disclosure in online environments.

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"A country's literature is its body of artistic writings. The writings are the product of its citizens who feel compelled to convey to other people their ideas, beliefs, and conviction. Excellent literature has universal appeal which will stand the test of time. The authors of this lasting and permanent literature leave records of what men, for many years, have found to be good or bad about life. A knowledge of this literature brings the reader into contact with all phases of man's life and gives him a panorama of human experiences. An understanding of literature reveals the heights, depths, and routine of living"--Introduction. / "June, 1960." / Typescript. / "Submitted to the Graduate School of Florida State University in partial fulfillment of the requirements for the degree of Master of Arts." / Advisor: Dwight L. Burton, Professor Directing Paper. / Includes bibliographical references (leaves 30-31).

Best Estimate codes are used for licensing, but with conservative assumptions. It is claimed that the uncertainties are covered by the conservatism of the calculation. As Nuclear Power Plants are applying for power up-rates and life extension, evaluation of the uncertainties could help improve the performance, while staying below the limit of the safety margins.   Given the problem of unstable behavior of Boiling Water Reactors (BWRs), which is known to occur during operation at certain power and flow conditions, it could cause SCRAM and decrease the economic performance of the plant. Performing an uncertainty analysis for BWR stability would give better understating of the phenomenon and it would help to verify and validate (V&V) the codes used to predict the NPP behavior.   This thesis reports an uncertainty study of the impact of Thermal-Hydraulic, Neutronic, and Numerical parameters on the prediction of the stability of the BWR within the framework of OECD Ringhals-1 stability benchmark. The time domain code TRACE/PARCS was used in the analysis. This thesis is divided in two parts: Sensitivity study on Numerical Discretization Parameters (Nodalization, Time Step, etc.) and Uncertainty part.   A Sensitivity study was done for the Numerical Parameters (Nodalization and Time step). This was done by refining all possible components until obtaining Space-Time Converged Solution, i.e. further refinement doesn’t change the solution. When the space-time converged solution was compared to the initial discretization, a much better solution has been obtained for both the stability measures (Decay Ratio and Frequency) with the space-time converged model.   Further on, important Neutronic and Thermal-Hydraulic Parameters were identified and the uncertainty calculation was performed using the Propagation of Input Errors (PIE) methodology. This methodology, also known as the GRS method, has been used because it has been tested and extensively verified by the industry, and because it allows identifying the most influential parameters using the Spearman Rank Correlation. / QC 20101126

An A/B test is implemented on a SaaS rm's product page to examine the dierence in conversion rates from website visitors who are randomly assigned to two dierent product-landing pages that show dierent prices. To count as a successful conversion the visitors that view a product-landing page have to click on a \Free Trial" button. Half of the group will be assigned the treatment page, which will state higher prices and the other half will be assigned the controlled page, which will state today's current price. The only variant that will dier from the two pages will be the stated price of the product and all other factors will be kept constant. The controlled experiment is executed to get a sense of customers' price sensitivity, hence this thesis contributes to microeconomic research of the private sector, more specically to the ICT industry by using a novel approach with the help of A/B testing on prices. The results showed no statistical signicance difference between the two variations, which can be translated to accepting the null hypothesis; the demand for a particular Software-As-A-Service product will hold unchanged after the proposed price increase. At first, this could be a surprising result but when looking into the industry, which the rm participates in and their early mover advantages this result could have been assumed.

SRAM-Based FPGAs provide valuable computation resources and reconfigurability; however, FPGA designs can fail during operation due to ionizing radiation. As an SRAM-based device, these FPGAs store operation-critical information in configuration RAM, or CRAM. Testing, through radiation tests, can be performed to prove the effectiveness of SEU mitigation techniques by comparing the SEU sensitivity of an FPGA design with and without the mitigation techniques applied. However, radiation testing is expensive and time-consuming. Another method for SEU sensitivity testing is through fault injection. This work describes a low-cost fault injection platform for evaluating the SEU sensitivity of an SRAM-based FPGA design by emulating faults in the device CRAM through partial reconfiguration. This fault injection platform, called the TURTLE, is designed to gather statistically significant amounts of fault injection data to test and validate SEU mitigation techniques for SRAM-based FPGAs. Across multiple fault injection campaigns, the TURTLE platform was used to inject more than 600 million faults to test SEU mitigation techniques, estimate design SEU sensitivity, and validate radiation test data through fault injection.

Magister Chirurgiae Dentium - MChD / Tooth discoloration has increased the demand by patients to pursue aesthetic treatment options. Bleaching is considered a conservative approach in performing an aesthetic treatment for discolored teeth; however colour rebound and post-operative sensitivity are among the adverse effects associated with vital bleaching. In-office bleaching systems employ the use of high hydrogen peroxide concentrations. The effects of in-office bleaching agents on the degree of colour change and the gender differences in relation to bleaching outcomes are questionable. Post-operative sensitivity can be considered a bleaching side effect and the number of patients that experience it is unknown. Aim: The aim of this study was to assess the outcome of an in-office vital bleaching technique. Objectives: The objectives of this study were to evaluate the degree of colour change after vital tooth bleaching using a 35% hydrogen peroxide gel (Yotuel® Special, Biocosmetics Laboratories, Spain), using a spectrophotometer (CM-2600d Konica, Minolta) to measure the colour change at each intervention during the bleaching process, to assess the post operative sensitivity during the first week of the intervention, to evaluate the patients' perception of the colour change and to compare it to the colour change (~E) expressed in numeric values and to investigate whether gender differences exist in relation to the outcome of the bleaching procedure. Materials and Methods: The maxillary anterior teeth of 22 patients comprising of 11 males and 11 females were. bleached with a 35% hydrogen peroxide gel (Yotuel® Special, Biocosmetics Laboratories, Spain). Pre-treatment readings of the two maxillary central incisors using a spectrophotometer (CM-2600d Konica, Minolta) were obtained. Subsequent readings were obtained after scaling and polishing, before bleaching (which was used as a baseline reading), immediately after bleaching, one week and one month postoperatively. Patients were requested to complete a form regarding postoperative tooth sensitivity and their colour perception toward the bleaching treatment. Results: The quantitative effect of the bleaching material on tooth colour showed an increase in L * values and a decrease in a* and b* values, the changes were significant (p values- 0.05) except for the mean value of b* one month after bleaching which was only significant between five and ten percent.