Neste trabalho propomos a distribuição Weibull-Binomial-Negativa (WBN) considerando uma estrutura de ativação latente para explicar a ocorrência do evento de interesse, em que o número de causas competitivas é modelado pela distribuição Binomial Negativa, e os tempos não observados devido às causas seguem a distribuição Weibull. Em geral, as causas competitivas podem ter diferentes mecanismos de ativação, sendo assim os casos de primeira ativação, última ativação e ativação aleatória foram considerados no estudo. Desse modo o modelo proposto inclui uma ampla distribuição, tais como Weibull-Geométrico (WG) e Exponencial-Poisson Complementar (EPC), introduzidas por Barreto-Souza et al. (2011) e G. et al. (2011), respectivamente. Baseando-nos na mesma estrutura, consideramos o modelo de regressão locação-escala baseado na distribuição proposta (WBN) e o modelo para dados de sobrevivência com fração de cura. Os principais objetivos deste trabalho é estudar as propriedades matemáticas dos modelos propostos e desenvolver procedimentos de inferências desde uma perspectiva clássica e Bayesiana. Além disso, as medidas de diagnóstico Bayesiana baseadas na \'psi\'-divergência (Peng & Dey, 1995; Weiss, 1996), que inclui como caso particular a medida de divergência Kullback-Leibler (K-L), foram consideradas para detectar observações influentes / In this work we propose the Weibull-Negative-Binomial (WNB) considering a latent activation structure to explain the occurrence of an event of interest, where the number of competing causes are modeled by the Negative Binomial distribution and the no observed time due to the causes following the Weibull distribution. In general, the competitive causes may have different activation mechanisms, cases of first, last and random activation were considered in the study. Thus, the proposed model includes a wide distribution such as Weibull-Geometric distribution (WG) and Exponential-Poisson complementary (EPC) introduced by (Barreto-Souza et al., 2011) and (G. et al., 2011) respectively. Based on the same structure, we propose a location-scale regression model based on the proposed distribution (WNB) and the model for survival data with cure fraction. The main objectives of this work is to study the mathematical properties of the proposed models and develop procedures inferences from a classical and Bayesian perspective. Moreover, the Bayesian diagnostic measures based on the \'psi\'-divergence (Peng & Dey, 1995; Weiss, 1996), which includes Kullback-Leibler (K-L) divergence measure as a particular case, were considered to detect influential observations

Dans le cadre des analyses des données de survie, la comparaison de plusieurs groupes d’individus, où l'événement d'intérêt est censuré par intervalle, représente un défi méthodologique. Lorsque le suivi des patients au cours de l'étude n'est pas continu, l'événement d'intérêt pourra survenir entre deux dates d'observation; il est dit censuré par intervalle. Des tests de comparaisons des distributions des temps de survie pour plusieurs groupes, adaptés à la censure par intervalle, ont été développés (tests du score, tests de pseudo log-rank pondérés, tests des rangs). C’est dans ce contexte que nous avons proposé deux nouveaux tests de comparaisons de groupes adaptés à des situations particulières de censure par intervalle. Le premier test concerne une situation où l’hypothèse alternative considère que les fonctions de risque instantané se croisent. Le second test concerne une situation où la population étudiée comporte une fraction non à risque pour l’événement d’intérêt. Ces deux tests ont fait l'objet d'une application sur des données réelles d'immunologie clinique. / In the context of analysis of survival data, the comparison of several groups of individuals, where the event of interest is interval censored, represents a methodological challenge. When the monitoring of patients during the study is not continuous, the event of interest may occur between two observation dates; it is said "interval censored". Tests of comparisons of survival time distributions for several groups, adapted for interval censoring, have been developed (score tests, weighted pseudo log-rank tests, rank tests). In this context, we have developped two new group comparison tests adapted to the particular situations of interval censoring. The first test apply to a situation where the alternative hypothesis considers that the hazard functions cross. The second test concerns a situation where the study population has a fraction not at risk for the event of interest. Both of these tests have been applied to real clinical immunology dataset.

Farmer suicide is at crisis levels in the United States and India. This crisis is both a problem of experiential knowledge within infrastructure as well as a problem of discourse power. I argue that the logical abstraction required to conceptualize and evaluate farmer suicide cannot be separated from the overall experience of farmer suicide. Rather than existing as distinctly separate phenomena, these elements are co-constitutive. Despite the Centers' for Disease Control identification and designation of farmer suicide as complex, statistically relevant, and elevated, nearly all the policy efforts addressing farmer suicide focus on narrow economic impact and narrow economic relief. While these economic vectors are important, the problem is multifaceted and requires a broadening of policy discourse to include additional factors (e.g. philosophical, existential, psychological, etc.). Using Hannah Arendt's work on politics and the human condition, I connect the conditionality of homo faber (human fabricator/maker), animal laborans (laboring animal), and vita activa (active life) with farmer struggle and suicide. Through the work of Georges Canguilhem and Achille Mbembe, I critique and analyze the predominant discourse and framing of suicide as a disease. Last, but not least, I propose decolonial theory and degrowth theory as viable critical pathways to shift the scale of farming infrastructure towards a more equitable and just future.

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Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this study is to further investigate the effect of using six different light source types with different light output intensities on the parameters of a mathematical model that predicts the DOC in VLDC’s. In this equation: D = Dp In(E0/Ec), D is the depth of cure in millimeters, E is the curing energy in J/cm2, Ec is the critical curing energy for the composite to reach a gel layer, and Dp is a characteristic coefficient. Three LED and three halogen dental curing units with different light output intensities were used to cure three shades (B1, A3, D3) of a hybrid resin composite. The exposure duration was at the intervals of 10, 20, 30, and 40 seconds for each sample setting. ISO scraping technique was performed to measure the depth of cure of each sample. Regression analysis was used to assess the fit of the proposed mathematical model D = Dp In(E0/Ec) to the experimental data obtained in this study. 72 For all the shade-light combinations; A3, B1, and D3 had significantly different regression lines (P < 0.05) with significantly higher Dp and Ec for B1 than A3 and D3. The only exceptions were for the Ec values between B1 and D3 in Allegro, Astralis 5, and Visilux 2 groups; and the Ec between A3 and B1 in Allegro group. The Dp and Ec parameters didn’t show significant differences between A3 and D3 shades in all the groups. Also, most of the significant differences for Dp values occurred in the B1 shade-light combinations; however, none of the D3 shade-light combinations showed significant differences for Dp. Several factors play combined influential effects on the kinetics of polymerization and depth of cure in VLDC’s. The shade has a more dominant effect on both parameters Dp and Ec than the curing light type or source output intensity. As we cure lighter shades “B1,” the effect of using different lights with different output intensities on the two parameters Dp and Ec will be greater and more significant than for darker shades “A3 or D3.” The clinical significance drawn from this study is that clinicians should recognize that using curing lights w/ increased output intensities doesn’t absolutely increase the DOC of VLDC’s especially with the darker shades.

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an associated telomeric DNA damage, DNA damage repair signaling, and the apoptotic pathways in CD4 T cells during HIV infection with or without ART treatment. Our data support a DNA damage accumulation, and impaired DNA damage repair in chromosome ends via recruitment of 53BP1 protein to the damaged foci. We found that a key player of DNA damage and repair enzyme, ATM, and its associated checkpoint proteins (CHK1, CKH2) are affected by HIV infection. HIV infection also altered another multifunctional master regulator protein AKT that is crucial in maintaining cellular homeostasis. Curing HIV is the ultimate redemption against HIV-associated complications. To explore the possibility of a functional cure, we investigated the use of a transient and a non-viral CRISPR/Cas9-based gene editing technology targeting the latently incorporated HIV provirus. After performing a nucleofection/electroporation using an in vitro formulated ribonucleoprotein (RNP) constituting a synthetic guide RNA (gRNA) and Cas9 nuclease protein, we demonstrated a significant (maximum 97%) reduction of HIV-mRNA and p24-capsid protein expression, upon stimulation (using PMA) and latency reactivation of latently HIV-infected CD4 T cells and latent-monocytes. Notably, the RNP treatment did not induce any cytotoxic effects, without affecting the abilility of cell proliferation. A sequence specific cleavage of HIV-provirus in two crucial gene locations (targeting vpr/tat genes) showed the most significant suppression of HIV reactivation or latency reversal. We have used DNA sequencing, and T7EI assay to confirm the target-site-specific cleavage of the HIV-proviral genome. Our data confirm the activation of non- homologous end joining (NHEJ) pathway to repair the double-stranded DNA break created by the CRISPR/Cas9 treatment. Taken together, this study provides a new gene therapeutic approach using synthetic gRNA/Cas9 targeting HIV genome, which warrant further in vivo animal and human studies.

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