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The Role of the Digestive Vacuole Redox Homeostasis on Drug Resistance in Plasmodium falciparum
No full textPh.D.The recent emergence of artemisinin (ART) resistance in Plasmodium falciparum malarial parasites is of major concern and has focused attention on the mechanism of action of ART - based drugs. During the intraerythrocytic stage of parasite development, copious amounts of free ferriprotoporphyrin IX (FPIX) heme is released upon hemoglobin catabolism within the parasite digestive vacuole (DV). Recently, we have shown that ART-FPIX adducts are formed within ART treated parasites, and that the abundance of these toxic adducts is altered for ART resistant P. falciparum. Adduct formation is dependent upon glutathione (GSH) balance within the DV. Herein, I test the abilities of ART and related endoperoxide compounds to inhibit the formation of Hz. I also develop the complete synthesis of a set of DV and cytosolically localizing probes to measure GSH concentrations, in the presence and absence of drug pressure. I have also done an extensive analysis of the P. falciparum chloroquine resistance transporter (PfCRT) protein structure based on important intramolecular interactions through computational modelling. I docked chloroquine (CQ) to the protein in silico and analyzed the binding sites. In the course of this work, we identified a putative redox active region of PfCRT on the DV disposed side. Lastly, I developed a fluorescent piperaquine (PPQ) probe to probe altered drug transport in PPQ resistant vs sensitive P. falciparum strains
The Role of HAI-2 in the Intestine Depends on Its Correct Subcellular Targeting
No full textPh.D.The hepatocyte growth factor activator inhibitor 1 (HAI-1) and HAI-2 are two closely related type I transmembrane Kunitz type serine protease inhibitors, that consist of two homologous extracellular Kunitz-type protease inhibitor domains. They are widely co-expressed in most epithelial cells and inhibit a broad range of trypsin-like serine proteases with similar potency and specificity. However, they have distinct functions that cannot be replaced by the other. The different functions of HAIs are due to their accessibility to different proteases caused by their differential subcellular localization. HAI-1 proteins are mainly on the cell surface, while HAI-2 proteins stay inside cell in polarized vesicles. Studying the intracellular transportation of HAIs can help us to understand the differences between these two homologous proteins during physiological and pathological processes. This work proved that the intracellular domains of HAIs are responsible for their subcellular localization. Particularly, the putative ER retention signals and the incomplete plasma membrane exportation motif contribute to the dominantly intracellular localization of HAI-2. And the complex N-glycan on the Asn-57 site is required for the correct HAI-2 protein folding and protease inhibitory activity. A lethal inherited disease of infancy called Syndromic Congenital Sodium Diarrhea (SCSD) is only caused by the loss-of-function mutation of HAI-2, but not HAI-1. Among all the mutations found in SCSD, the single amino acid substitutions that occur in the functional less important Kunitz domain 2, are the most common ones. The expression of three of these mutants by using doxycycline-inducible system in HAI-2-knockout Caco-2 cells reveals that roughly 50% of the proteins are synthesized as disulfide-linked oligomers that lose protease inhibitory activity due to the distortion of the Kunitz domains by disarrayed disulfide bonding. Although the remaining proteins are synthesized as monomers, their glycosylation status suggest these monomers remain in the immature, lightly glycosylated form, and are not converted to the heavily glycosylated mature form with full anti-protease activity. As predicted, these HAI-2 mutants cannot suppress the excessive prostasin proteolysis caused by HAI-2 deletion. Our study reveals that abnormal protein folding and N-glycosylation can cause widespread HAI-2 inactivation in SCSD patents
Acceptability of smart locker technology for dispensing chronic disease medication among patients and healthcare providers in Nigeria
No full textCenter for Global Health Practice and ImpactSmart lockers are automated delivery machines. They have been used in dispensing ARVs and Tuberculosis medication to chronically ill patients in South Africa, Kenya, and Eswatini. However, there is no evidence of smart lockers in dispensing chronic disease medication in Nigeria. This study aimed to assess the acceptability of smart lockers in dispensing chronic disease medication and to describe the barriers to accessing care among patients with chronic diseases medication in 5 states in Nigeria. We conducted a cross-sectional study among healthcare workers and patients living with chronic diseases in five Nigerian states of Adamawa, Akwa Ibom, Cross River, Benue, and Niger between November and December 2021. A total of 1,133 participants were recruited (728 patients and 405 healthcare workers). The results revealed that most patients and healthcare workers agreed that using smart lockers for drug dispensing will lead to reduced transportation costs, hospital waiting times, the workload of healthcare workers, and decongestion of health facilities. The majority of the patients living with chronic diseases (43%) and healthcare workers (51%) showed high acceptability for the use of smart lockers. The use of smart lockers in dispensing chronic disease medication in Nigeria is feasible, and patients and healthcare workers are willing to accept the smart lockers, provided that a patient-centred implementation strategy is developed
Tightening the Screws: Examining the Efficacy of U.S. Sanctions Against Russia Amid the Russo-Ukrainian War
No full textU.S. Foreign Military Aid and Combating Terrorism: Has Increased Aid Given Humanity the Upper Hand on Terrorism?
No full textM.P.P.As terrorism continues to put a strain on the daily lives of many people around the globe, the United States seeks to eliminate terrorism and build a safer global community. The United States has allocated tremendous amounts of money to countries around the world to help them fight terrorism and insulate themselves and their institutions from the effects of terrorism. The trend of increasing foreign military aid has led to questions surrounding the effectiveness that increased foreign military aid has in combating terrorism. This thesis analyzes the relationship between U.S. foreign military aid and global terrorism levels. Building on existing literature, we present a nuanced approach to looking at foreign military aid, its relationship to global terrorism levels, and various economic indicators' role in changing this relationship using several empirical models. We find that there is a positive correlation between U.S. foreign military aid and global terrorism levels, and it does not necessarily seem to help countries reduce potential terrorism threats
A Non-Weight Centered Approach to Modifying Eating Attitudes in Polycystic Ovarian Syndrome
No full textD.N.P.Polycystic Ovarian Syndrome (PCOS) is an anovulatory disorder characterized by insulin resistance and endocrine dysfunction. Infertility and abnormal weight gain in women of childbearing age are often a result of PCOS, impacting quality of life and posing potential long-term health sequelae. Prescribing weight loss has been adopted by clinicians as an effective intervention to improve insulin resistance. For some patients, this practice has led to the negative effects of weight cycling and disordered eating attitudes which can result in long term adverse cardiometabolic outcomes. A quasi-experimental pre-and-post-test study was conducted to evaluate how a non-weight centered program influences eating attitudes in patients with PCOS. Four individuals assigned female at birth (AFAB) between ages 31-40 with a known diagnosis of PCOS enrolled in a pilot program that consisted of six bi-weekly visits with a dietician, food logging, and participation in a private online support group. Participants completed the Disordered Eating Attitudes Scale (DEAS) assessment before and after completing the program. Waist circumference was measured at visits one, three, and six. The support group activity was tracked based on the participants’ ability to interact three times weekly.
DEAS scores decreased for 75% of the sample with an average reduction of 13 points. All participants experienced at minimum a one-inch reduction in waist circumference with an average decrease of 2.5 inches. Fifty percent of the sample made nutrient rich (green) food choices less than 50% of the time at baseline (visit two). By visit five, 100% of the sample made green food choices greater than 50% of the time. Majority of participants completed support group interaction only two out of ten weeks. The relationship between group support and eating attitudes remains unclear. Results suggest that a non-weight centered approach to modifying eating attitudes in clients with PCOS may be effective in helping patients achieve more sustainable lifestyle changes. Further research is indicated to explore the impact of non-weight centered approaches for the management of PCOS symptoms and reducing risk of long term sequelae
Tearing Down Tent Cities: Does Encampment Clearance Reduce Crime?
No full textM.P.P.The dismantlement of unsheltered homeless encampments has become a common local government policy in the United States. It is often framed as a measure to reduce crime. However, there is no consensus in the current quantitative research literature about the effectiveness of encampment clearance as crime reduction policy. This thesis uses data from Washington, D.C., between 2019 and 2023 to examine the relationship between encampment clearance and the incidence of crime in the surrounding census tract during the following calendar month. I observe a statistically insignificant result, suggesting encampment clearance may not be an effective policy for crime reduction
Comparative Historical Analysis of Language Legislation in Québec and New Orleans from the Era of French Colonisation to the Present Day
No full textM.A.The provinces of Québec in Canada and the city of New Orleans in the United States are iconically rooted in French language and culture. Both communities originated as colonies of the French Empire in the 17th century, but over five centuries underwent social and cultural evolutions that waxed and waned in similarity. A major element of these evolutionary periods was the pieces of language legislation that altered the usage of the French language, and as a result the culture and identity of these communities as a whole. Legislation reflects society and society, in turn, reflects legislation. This relationship is laid clear to see through the implementation of socio-legal methodology within a greater comparative historical analysis that maps comprehensive timelines of these communities. Five centuries of legal, social, and linguistic evolution creates a holistic image of the patterns and practices of these communities, especially when directly compared to one another. From these understandings, it is possible to understand and anticipate how the language legislation in these communities will continue to evolve. Language is the very essence of a social reality; it is the means through which all interpersonal and official connections occur. A thorough understanding of the legislation that dictates such a major element of life is essential to understanding the very same reality that language permits society as a whole to connect
Votando En Una Pandemia: The Impact of Vote-By-Mail Policy Changes on Latino Participation in the 2020 Presidential Election
No full textM.P.P.As a presidential, general election approached in the wake of the COVID-19 pandemic, states scrambled to ensure that their constituents could safety and securely cast their ballots. Each state, having autonomy over their election laws, sought individual approaches based on preference; many notably enacting policies expanding access to voting by mail. This paper examines the impact that changes in vote-by-mail (VBM) policies had on Latino voter participation in 2020. It seeks to understand the effects of the different approaches and determine whether these changes hurt or helped Latino voters. Using individual-level data from National Opinion Research Center’s (NORC) 2018 and 2020 AP VoteCast surveys, I categorize the changes into three levels of intervention: automatically sending voters VBM ballots, automatically sending VBM applications, or making other, smaller changes to VBM policies. My study finds that Latino voters who lived instates that made “other changes” to their VBM were 4.3% points (