Saudi Cultural Missions Theses & Dissertations
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Item Restricted Efficiency of Nitric Oxide and Peroxynitrite Release by Endothelial Nitric Oxide Synthase Variants - Implications for Cardiovascular Disease and Aging(Ohio University, 2024-05) Alsulami, Seham; Malinski, Tadeusz; Dewald, HowardThe cardiovascular system is mainly regulated by nitric oxide (NO). A reduction in its synthesis or bioavailability might underlie the impaired endothelium-dependent vasodilatation, which is observed in the blood vessels of individuals with cardiovascular disease (CVD). The dysfunction of endothelium, which is a main characteristic of vascular aging, has been associated with low NO production and high production of cytotoxic peroxynitrite (ONOO-). Thus, the ratio of NO to ONOO- is an indicator of endothelial dysfunction. Moreover, vascular NO is produced by an enzyme called (endothelial nitric oxide synthase (eNOS), and its gene exhibits high polymorphism. However, it is unclear whether polymorphisms or haplotypes in the eNOS gene affect the NO production, ONOO- production, and eNOS coupling, as well as how aging impacts these haplotypes. The influence of the eNOS haplotype (consisting of single nucleotide polymorphisms (SNP) in the promoter region (T-786C) and (C-665T) and exon 7 (Glu298Asp) and a variable number of tandem repeats (VNTR) in intron 4 (4a/4b/4c)) on the production of NO and ONOO- and eNOS coupling was investigated. Sanger sequencing and DNA electrophoresis were used to detect SNPs and VNTRs in the samples, respectively. To evaluate the production of NO and ONOO-, nanosensors were used to determine the maximal concentrations of NO and ONOO- and traditional and low-temperature SDS-PAGE to evaluate the expression of eNOS and the eNOS dimer/monomer ratio, respectively. Interestingly, these results indicated that the eNOS haplotype (H5) combining the “T T/C C 4b” of the G894T, T-786C, C-665T, and 27 bp VNTR a/b/c is more susceptible to endothelial dysfunction. Compared with other haplotype samples, it had lower [NO]/[ONOO-] and higher eNOS expression with reduced eNOS dimer/monomer (P < 0.005). These findings have important implications for understanding the genetic basis of cardiovascular disease and aging and may lead to new therapeutic approaches to these diseases.37 0Item Restricted The effect of dual task training on postural control of young and older adults(Loughborough University, 2024-03) Alqurafi, Alaa; Blenkinsop, Glen; Pain, MatthewResearch has shown that a lack of postural control during standing, particularly a failure to use the reactive balance strategy to regain equilibrium, is a leading cause of falls for older individuals. However, most previous fall prevention research has focused solely on the motor aspect of the balance system while ignoring cognitive influence. Thus, the current thesis highlights and provides novel evidence by addressing essential gaps and limitations in the literature related to dual task assessment and training and how they influence postural control in different age ranges. This thesis aimed to examine the effect of novel dual task training on different age groups postural control and dual task cost. In order to achieve this aim, three studies were conducted. The first study was a systematic review and meta-analysis aimed at reviewing the effect of a specific or general exergame DT training on postural control among older adults over 65 (Chapter 3). Both DT training has been shown to enhance cognitive, balance, and dual task performance in most of the studies. The study concluded no significant difference between the specific and general exergame training for these performances. The other two studies were conducted to measure the effect of novel interventions on young and older adults (Chapters 5 and 6). Both studies were a quasi-experimental design with pre-and post-testing. The studies compared two types of DT training with different goals: Cognitive Dual task Training (CDT) and Balance Dual task Training (BDT). Both DT training were unsupervised and used exergames three times a week for two months. The BDT focused on training and enhancing the ankle strategy. In contrast, CDT aimed to improve specific cognitive domains such as working memory, reaction time, mental tracking and decision-making under the dual task paradigm. These studies found that the BDT was more effective in enhancing hand reaching activity, balance stability and limit (LOS) of stability in young and older adults. Conversely, the CDT group showed better cognitive task outcomes for both younger and older participants. Also, BDT resulted in an overall reduction in dual task cost in static balance and LOS for younger and older participants, respectively. In contrast, CDT resulted in an overall increase in DTC. In addition, CDT and BDT decreased walking time in Time Up and Go test by 0.5 seconds, indicating that DT training assisted to reduce the walking time factor of risk of falls among older adults over 65.Finally, both DT training showed a high adherence rate of over 93% of training sessions among young and older participants. In conclusion, completing the current thesis has resulted in new knowledge about the effect of different types of DT training on individual responses to dual task elements (i.e. a cognitive or balance task) and postural control. In addition, selecting a proper assessment tool can help objectively measure DT training’s influence on postural control. Using unsupervised exergame DT training is feasible to reduce the risk factors for falls among older adults.12 0Item Restricted The Effects of Dosage Compensation on Aging(Saudi Digital Library, 2023-08-20) Almuanidi, Hend; Csankovszki, GyörgyiThis comprehensive investigation explores the intricate relationship between the X chromosome, aging, and dosage compensation in hermaphrodite C. elegans. The study sheds light on the dynamic changes in X chromosome structure and condensation as hermaphrodites age, providing insights into the role of the dosage compensation complex (DCC) and its accessory protein, DPY-21, in maintaining X chromosome integrity. Notably, mutations in DPY-21 and CEC-4, involved in dosage compensation, result in embryonic lethality and significant changes in X chromosome condensation. A longevity assay highlights the role of DPY-21 in regulating lifespan, with the double mutant (cec-4, dpy-21) exhibiting intriguing variations. Furthermore, the study explores the impact of dauer arrest on X chromosome condensation and localization, revealing distinctive changes on x chromosome condensation as a result of going through the dauer stage. These findings underscore the multifaceted interplay between dosage compensation, aging, and X chromosome dynamics, laying the groundwork for further research to address technical limitations and gain deeper insights into these complex mechanisms.28 0Item Restricted Three Essays on the Impacts of Immigrants on Natives(University of Connecticut, 2023-08) Almuhaisen, Abdulmohsen; Furtado, Delia; Agüero, Jorge; Amuedo-Dorantes, Catalina; Cesur, ResulThis dissertation explores the impacts of refugee and immigrant inflows on natives in the context of developing (Jordan) and developed (United States) countries. The first chapter investigates whether the sudden influx of Syrian refugees into Jordan starting in 2011 induced a reduction in healthcare utilization among native Jordanians, perhaps especially in terms of routine care. Exploiting variation in the share of refugees across time and space and using an instrumented difference-in-differences identification strategy, this chapter examines the impact of Syrian refugees on childhood immunization rates of native Jordanians. I find that the influx delayed natives’ receipt of childhood vaccines, suggesting some congestion in the healthcare sector. However, I find no effect on the likelihood of eventually receiving the vaccines, pointing to the short-term nature of the impacts of such events. The second chapter investigates another potential impact of the same influx –namely the impact on school enrollment among youth Jordanians. Using a similar identification strategy, I show that the influx reduced school enrollment, primarily among males and youths with less educated parents. Next, I show that the effect would have been larger in the absence of post-influx investments in educational infrastructure in the most impacted areas. Finally, I show an increase in employment among Jordanian youths, pointing to a potential labor market mechanism for the estimated effect. The third chapter examines the relationship between immigration enforcement and the institutionalization rates of the elderly. Exploiting the staggered implementation of the Secure Communities (SC) immigration enforcement program across U.S. counties from 2008 through 2014, we show that SC increased the likelihood that Americans aged 65 and above live in an institution. Supportive of supply shocks in the household services market as a central mechanism, we find that the elderly who are most likely to purchase domestic worker services are also the most likely to move into nursing homes following the implementation of SC. Additionally, we find suggestive evidence of significant reductions in the work hours of housekeepers, personal care aides, and home health workers hinting at the critical role of negative supply shocks in occupations that facilitate aging in community.23 0Item Restricted Insights into the Roles of Aging and Chemokine Signaling During Neuromuscular Regeneration(2023-07-09) Furati, Esraa; Chakkalakal, JoeAging is associated with delayed skeletal muscle recovery from injury leading to increased morbidity in the elderly population. Inefficiency of aged muscle regenerative capacity is primarily attributed to the decline in numbers and functionality of the muscle stem cells (MuSCs) with aging. The identification of abnormalities in the aged regenerative environment which impair MuSCs regenerative capacity, and targeting them to develop therapeutic strategies has become a focus of the field. Various studies have observed that myofiber degeneration after injury was associated with loss of innervation. However, whether age-related differences exist in the rate or extent of reinnervation has not been explored. Here we identify a novel anomaly in the aged regenerating environment, where aged regenerating muscle show more extensive and prolonged denervation. Consistent with the crucial role of neuromuscular junction (NMJ) integrity in proper myofiber regeneration, we find that denervated regenerating myofibers in aged muscle are smaller in diameter than innervated myofibers. On the other hand, our lab has recently identified persistent elevated expression of C-C chemokine receptor type 2 (Ccr2) ligands in aged regenerating muscle and that timely pharmacologic inhibition of Ccr2 signaling significantly improves aged muscle regeneration. Moreover, our lab discovers MuSC-derived progenitor (MP) expression of Ccr2 and the inhibitory effect of Ccr2 signaling on MP differentiation and fusion. Here we develop and characterize a MuSC-targeted conditional Ccr2 knockout mouse to prospectively utilize to examine the role of Ccr2 signaling in MPs during various stages of aged muscle regeneration. Collectively our work sheds the light on MuSC Ccr2 signaling and myofiber denervation as causative factors in aged regenerative impairment which may become future therapeutic targets to improve aged muscle regeneration.15 0Item Restricted OSTERIX - POSITIVE CELL-INTRINSIC IRE1α /XBP1 SIGNALING REGULATES THE POSTNATAL BONE DEVELOPMENT AND BONE MARROW HOMEOSTASIS(Saudi Digital Library, 2022) Alshalawy, Faisal; Ouyang, HongjiaoX-box binding protein-1 (XBP1) is a transcription factor that plays a critical role in managing cellular responses to endoplasmic reticulum (ER) stress. Under stress conditions, the transcriptionally active form of XBP1 is generated from unspliced Xbp1 by the inositol-requiring enzyme-1 (IRE1), an endoplasmic reticulum (ER) stress sensor and an ER-membrane residing endoribonuclease and kinase. The IRE1/XBP1s signaling is implicated in the development and homeostasis of many professional secretory cells and organs. Herein, In the second chapter of the dissertation, we demonstrate that deficiency of IRE1α, an IRE1 isoform that is expressed by osteoblast-lineage cells (Osterix-expressing cells), e.g., osteoblasts and skeletal progenitor cells, leads to osteoporosis/osteopenia with reduced bone formation/osteoblastogenesis and bone resorption/osteoclastogenesis, as well as enhanced bone marrow adipogenesis, in vivo. IRE1 deficiency results in compromised XBP1s signaling in osteolineage cells. In order to determine whether XBP1 is an important biological mediator of IRE1α in regulating postnatal bone development and bone hemostasis. In the third chapter of the dissertation, we showed that functional deficiency of XBP1 in Osterix-expressing cells, e.g., osteoblasts and skeletal progenitor cells, leads to osteoporosis/osteopenia with a significant compromised osteoblastogenesis and osteoclastogenesis, and increased bone marrow adipogenesis, in vivo. XBP1 deficiency results in both direct reduction in mRNA levels of XBP1 spliced and XBP1 total. Our study provides mouse genetic evidence demonstrating that Osx+ cell-intrinsic IRE1α/XBP1 is a physiological regulator for the postnatal bone development and bone marrow homeostasis.28 0