Saudi Cultural Missions Theses & Dissertations
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Item Restricted Intracellular and extracellular immunisation for HIV(The University of Manchester, 2024-11) Alatiq, Abdulrahman; Klapper, Paul; Valley, Pamela; Faqih, LaylaThe prevalence of HIV infection remains a serious challenge for public health. HIV infection results in considerable mortality and morbidity, as well as imposing a substantial financial burden on healthcare systems globally. Despite the availability of effective antiretroviral treatments to control infection, an effective protective vaccine remains elusive. This project aimed to develop a practical, affordable, and effective combined vaccine and treatment by combining intracellular antibodies and extracellular immunisation to prevent or reduce HIV viraemia. Specifically, an approach in which DNA-encoding N49P7 broadly neutralising antibodies against the HIV-1 envelope glycoprotein 120 is delivered to cells using recombinant baculovirus or lipid nanoparticle (LNP) transfection. Extracellular antibodies were anticipated to prevent gp120 from attaching to cells, and intracellular antibodies were intended to inhibit the genesis of virions. The expression of N49P7, either as a human IgG antibody or as human Fab, was attempted. The expression of the N49P7 IgG antibody was not achieved in HEK 293 cells despite employing three delivery models for transfections: recombinant baculovirus, MC3-based LNP, or lipofectamine 2000 LNP. While transfection was successfully achieved (monitored via an eGFP gene included within the plasmid design), functional antibody was not achieved. The most likely explanation for the failure was thought to be the use of dual promoters within the expression cassette. Redesign of the plasmid to create a bicistronic vector including the N49P7 Fab region and signal peptide sequences of murine IgG and IL-2 allowed successful expression of N49P7 Fab through recombinant baculovirus or lipofectamine 2000 reagent transfection of HEK 293 cells. However, the expressed N49P7 Fab region was predominantly accumulated intracellularly. A further redesign was implemented to incorporate homogenous signal peptides H7 and L1 into the N49P7 Fab gene, which significantly enhanced the secretion of the antibody fragment. This design maintained functional intracellular and extracellular antibody activity. Lower cellular cytotoxicity was seen with recombinant baculovirus transfection compared to lipofectamine 2000 LNP mediated transfection although both were equally efficient. The selection of an optimum method for transfection will form part of future investigations progressing to animal model testing. This proof of principle study showed that recombinant baculovirus or lipofectamine 2000-mediated transfection systems allowed efficient N49P7 Fab expression both intracellularly and extracellularly in mammalian cells, suggesting that this approach indicates potential for providing a vaccine against HIV infection in addition to a therapeutic intervention for those who already have HIV infection.12 0Item Restricted Neurocognitive Impairment and Oral Health Outcomes in Patients with HIV (PWH) On Antiretroviral Therapy (ART)(The University of Pennsylvania, School of Dental Medicine, 2024-08) Alamodi, Eman; Omolehinwa, Temitope; Akay-Espinoza, Cagla; Jordan-Sciutto, Kelly; Akintoye, SundayBackground The advent of antiretroviral medication (ART) led to a significant decline in HIV associated morbidity, including the more severe presentations of HIV-associated neurocognitive disorders (HAND). However, milder forms of neurocognitive impairment (NCI) persist. Neurocognitive deficits have also been independently associated with poor dental outcomes, especially in the elderly population. However, there is limited, if any, reports of dental health outcomes in people with HIV (PWH) with NCI. This study was designed to better understand oral health outcomes in PWH with NCI. Methods A cross-sectional pilot study was conducted on 40 participants, comprising 10 healthy controls and 30 PWH. Neurocognition and dental outcomes were assessed in all participants. Neurocognition was evaluated using a computerized neurobehavioral battery (CNB) test. Dental caries was assessed using the Decayed, Missing, and Filled Teeth (DMFT) index, the Decayed and Filled Teeth (DFT) index, and the Missing Teeth (MT) index. Periodontal status was measured through clinical attachment loss, periodontal pocket depth, and the percentage of sites with bleeding on probing (%BOP). Results Mean DMFT, DFT and MT were significantly higher among PWH (p < 0.001, p = 0.02, p = 0.048, respectively) than in control subjects. NCI was present in 4 PWH and 1 control subject. We also noted that among PWH, those with NCI had a higher DMFT index (20.8 versus 18.5) and a significantly higher mean DFT (12.3 versus 8.0) compared to PWH without NCI (p = 0.048). Conclusion Poor oral health, especially dental caries, is a challenge among PWH and moreso among PWH with NCI.51 0Item Restricted THE EFFECT OF ANTIRETROVIRAL THERAPY ON THE INTEGRATED STRESS RESPONSE IN THE CENTRAL NERVOUS SYSTEM: IN VIVO ASSESSMENT IN SIV-INFECTED RHESUS MACAQUES(University of Pennsylvania, 2024) AbedAlthaqafi, Razan; Jordan-Sciutto, Kelly; Akay-Espinoza, CaglaDespite the benefits of antiretroviral therapy (ART) in people with HIV (PWH), a large percentage of PWH still suffer from some form of neurocognitive impairment. Studies have shown that high degree of oxidative stress and inflammation remain present in the central nervous system of PWH, which can activate the integrated stress response (ISR) pathway. In our lab, studies showed that the levels of several markers for ISR activation, like phosphorylated eukaryotic initiation factor 2α (P-eIF2α), were elevated in neurons and astrocytes in the cortex in autopsy brain tissue of PWH. Phosphorylation of eIF2α is mediated by four kinases, which will result in ISR activation, which is reported in neurodegenerative conditions. In general, ISR is an adaptive pathway; however, chronically activated ISR may contribute to neuronal damage or death and to neurocognitive impairment in PWH. Recently, several studies showed that certain ART drugs contribute to the persistence of HIV-associated neurocognitive disorders and can induce ISR. The aim of the present study was to assess ISR activation in neurons, astrocytes, and oligodendrocytes in brain tissue samples of SIV-infected rhesus macaques. Methods We examined necropsy brain tissue specimens of 11 rhesus macaques, including SIV-infected/ART-untreated macaques (n = 3), SIV-infected/ART-treated macaques (n = 4), and uninfected/untreated (n = 4) macaques to determine if ART aggravated ISR activation in the CNS. Formalin-fixed/paraffin-embedded sections of cortical tissue were immunofluorescently stained using an antibody to p-eIF2α to detect the activation of ISR and antibodies against MAP2, GFAP, and ASPA to label neurons, astrocytes, and oligodendrocytes, respectively. Results By semiquantitative analysis of images of stained specimens obtained from the cortex of the frontal lobes of the treated rhesus macaques, we found that ISR activation in neurons was higher in the SIV-infected/ART-treated group compared to the SIV-infected/ART-untreated group, which was statistically significant. However, we did not observe differences in ISR activation in astrocytes and oligodendrocytes among the three groups. Conclusion In our study, we observed a significant increase in ISR activation in neurons in the gray matter of SIV-infected/ART-treated rhesus macaques compared to SIV-infected/ART-untreated rhesus macaques, which we did not observe in astrocytes and oligodendrocytes.11 0Item Restricted Optimal control frameworks for a class of epidemiological and oncological models(University of Texas at Arlington, 2024-05) Alghamdi, Asma; Roy, SouvikIn this thesis, we employ optimal control frameworks in two distinct contexts: Human immunodeficiency virus (HIV) and esophageal cancer. For HIV, we introduce a comprehensive data-driven nonlinear optimization framework designed for personalized therapies. This framework utilizes a deterministic in-host nonlinear ordinary differential equation (ODE) model and formulates two optimization problems using individual patient data. The first problem focuses on estimating patient-specific parameters through constrained optimization, while the second problem determines optimal combination therapies to reduce viral load to undetectable levels. Several numerical experiments suggest that our framework can provide robust and effective optimal dosages with lower toxicity levels to control HIV. In esophageal cancer, we present an innovative approach to model and control aberrant signaling pathways. This involves leveraging an It\^o stochastic process to capture signaling pathway dynamics governed by a degenerate Fokker-Planck partial differential equation. Our study proposes a refined treatment strategy targeting aberrant signaling pathways, specifically focusing on epidermal growth factor (EGF) pathways. This strategy includes developing a pharmacokinetic model considering pathway heterogeneities, preceded by constrained optimization to obtain model parameters from patient data. Subsequently, we propose a personalized optimal treatment strategy targeting aberrant EGF using a non-smooth open-loop control for a stochastic process modeled by the Fokker-Planck equation. The solution to these problems is characterized within the framework of Pontryagin's minimum principle (PMP), and the optimization problem is solved using a sequential quadratic Hamiltonian (SQH) method. Experimental results are presented to validate the proposed framework successfully.21 0Item Restricted An exploration of the knowledge and attitudes of Saudi occupational therapists (OTs) regarding people living with HIV\AIDS in Saudi Arabia(Saudi Digital Library, 2023-01-20) Bin Numay, Abdulelah; Sakellariou, DikaiosIntroduction: Relatively 38 million people are living with the acquired immunodeficiency syndrome (AIDS) in addition to the virus which causes AIDS, the human immunodeficiency virus (HIV). AIDS-related complications were responsible for the deaths of 35 million people globally between the beginning of the pandemic and the end of 2020, with the disease's prevalence continuing to rise across the Middle East and North Africa. Due to an early misunderstanding of HIV transmission patterns, many Muslims incorrectly think that only "sinners" may get HIV/AIDS. Consequently, stigma and prejudice are seen as the greatest challenges for persons with HIV/AIDS in Saudi Arabia. Therefore, the purpose of this research is to get an understanding of and investigate the experience and knowledge of Saudi Arabian Occupational Therapists. Methodology: The researcher selected the framework qualitative design as the research's methodology to collect data from six participants, 4 male and 2 female Occupational Therapy practitioners. Semi-structured audio recorded interviews were conducted, recordings were transcribed digitally for data analysis. Then, the qualitative data were thematically analysed. Result: The analysis concluded four main themes and eight subthemes. Proceeded with the participants' general perception of HIV/AIDS, then move on to their knowledge development in relation to the virus, their clinical practise in the context of working with a person living with HIV/AIDS, and finally, the socio-cultural obstacles and future prospects from the perspective of the participants. Conclusion: Participants mentioned they lacked significant understanding about HIV/AIDS and the occupational therapy role with HIV+ patients. Their collective understanding of HIV/AIDS was derived from the theory they studied, movies, television programmes, chats with others, and books or articles, owing their lack of understanding to the incomplete HIV/AIDS education incorporated in the curriculum. In addition, while they would not mind working with an HIV- positive client, HIV/AIDS related discrimination in the study population was presented by altering the treatment approach, take extra contact precautions, minimize interaction between HIV positive patients with other patients9 0Item Restricted Role of HIV-1 Nef in reduced migration of Macrophages in the Lung of HIV-Tg Mice(Saudi Digital Library, 2022-12) Alrajhi, Yousef; Jerebtsova, MarinaBackground: Past studies have shown that antiretroviral therapy significantly improved the longevity of HIV-infected patients. However, chronic long-term HIV-1 infection is complicated by the increased rates of age-associated chronic diseases, particularly non-infectious respiratory disorders. The mechanism of increased lung non-infectious lung diseases in people living with HIV is poorly understood. An HIV-transgenic mouse model was used to study LPS-induced lung injury. Reduced lung macrophage infiltration and increased lung neutrophil infiltrations with increased lung injury after LPS injection was demonstrated in HIV-transgenic (HIV-Tg) compared to wild-type mice (WT). Activated macrophages accumulated in the capillaries of HIV-Tg mice after LPS injection. The results further showed that Inhibition of HIV-1 transcription significantly increased macrophages' lung infiltration and reduced lung injury in HIV-Tg mice. Hypothesis: We, therefore, hypothesize that reduced LPS-induced lung macrophage migration in HIV-Tg mice is associated with the activation of Src kinase by HIV-1 Nef. We further hypothesize that inhibition of Src activation by PPi inhibitor will restore regular lung macrophage migration and reduces lung injury. Methods: HIV Tg mice and wild-type littermates (WT) were injected with LPS, and blood and lungs were collected 24h after injection. RT-PCR was used to detect the expression of proinflammatory cytokines (IL-1β and IL-18) and Nef in the lung. ELISAs were used to detect the plasma levels of pro-inflammatory cytokines (IL-6 and TNF-α). Levels of Src kinase and phosphorylated Src were determined by Western Blot and flow cytometry. Hematoxylin and eosin staining was used to evaluate lung injury—immunohistochemistry and immunofluorescence staining were used to assess lung macrophage infiltration. Results: Our results demonstrate higher levels of LPS-induced inflammation in HIV-Tg mice. Nef was not expressed in the lung of HIV-Tg mice but was detected in the infiltrated immune cells after LPS injection. Src was expressed and was highly phosphorylated in the lungs of both HIVTg and WT mice. LPS injection significantly reduced lung Src phosphorylation, but Src was highly phosphorylated in the capillary macrophages of HIV-Tg mice. PPI inhibitor of Src significantly reduces lung injury and increases macrophage migration in the lung of HIV Tg mice. Conclusion: Inhibition of Src with PPi improves migration of macrophages and reduces lung injury of HIV-Tg mice.13 0Item Restricted Synthesis and biological evaluation of novel borono-nucleoside analogs as anti- HIV agents(2023-03-21) Alhthlol, Latifah; Tomsho, JohnThe human immunodeficiency virus (HIV) has infected millions of people worldwide. This virus is still a global pandemic due to the continued emergence of viral resistance to current drugs. The nucleoside reverse transcriptase inhibitors (NRTIs) are one of the most used classes of drugs in antiretroviral therapy (ART). These NRTIs analogs can inhibit HIV replication since they are competitive inhibitors of the native nucleotide triphosphate (NTP) substrates of reverse transcriptase (RT). Because of the lack of 3’-hydroxyl group in the nucleoside reverse transcriptase inhibitors, incorporation causes termination of DNA chain elongation. Although these drugs have been proven effective clinically, they have several drawbacks when used in long-term treatment regimes. These drugs have relatively low bioavailability and require phosphorylation by human and/or viral kinases to become activated. Boronic acids and their derivatives have recently emerged as biologically interesting moieties, with increased attention in their use as pharmaceutical agents. It is hypothesized that the incorporation of the boronic acid moiety will improve cellular permeability and pharmacological properties due to their lower negative charge compared to the current nucleoside analogs which incorporate phosphonate moieties, e.g., tenofovir. In this research, we investigate nucleoside boronic acids and their derivatives as potential NRTIs useful for HIV treatment. Herein, we report on the synthesis of a novel borono-nucleoside analogs compounds that are rationally designed analog of Adefovir and tenofovir. Novel borono-nucleoside analogs compounds exhibit an anti- HIV activity when they evaluated against HIV replication. Moreover, structure activity relationship studies indicate that changing boron warhead, increasing carbon chain length, and including ether linker on the alkyl chain backbone, have importance effect on the borononucleoside analogs activity against HIV replication. In addition, cytotoxicity analysis also shows that the borono-nucleoside analogs are not toxic to the mammalian cells. However, the mechanism of action is still unclear although we suggest that borono-nucleoside analogs may act as competitive inhibition, metal chelator, and act as Lewis’s acids and bind to Lewis basic amino acids in the active side. These data will then be utilized in ongoing drug design efforts and allow us to further probe the structure activity relationships of this class compounds.26 0