UTMB Health SHARED (Univ. of Texas Medical Branch at Galveston)
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Efficient Identification and Comprehension of Molecular Pathways Associated with Irradiation Induced Hepatic Carcinogenesis
No full textAs human exploration into deep space continues to expand in the future, risk prediction for irradiation-induced diseases will become an increasingly important task. It will be critical to identify the biological effects of high-charge, high energy (HZE) and low energy 137Cs γ rays, which are the major components of space irradiation on the human body during longer stay in deep space, including a mission to Mars. It has been shown that there is a significant increase in incidence of Hepatocellular carcinoma (HCC), after exposure to low dose HZE. There is, however, limited knowledge of the effects of low dose irradiation on the formation of HCC. To address this gap in knowledge, RNA-Seq and MALDI-MSI were used to assess the effects of space irradiation on the pathogenesis of HCC. In particular, RNA-seq was used to determine transcriptional changes, and MALDI-MSI to determine lipid changes, in the hepatic microenvironment of ion irradiated compared to non-irradiated controls, in two different strains of mice, at five different time points post-irradiation. For our RNA-Seq datasets, we first present a novel pipeline to perform gene co-expression network analysis, and use this to show that mitochondrial pathways are dysregulated in response to 56Fe irradiation compared to non-irradiated control, in the wildtype mouse strain (C57BL/6NCrl.) Next we performed a comparative transcriptomic analysis in a mouse model for irradiation-induced HCC (C3H/HeNCrl), in order to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy), compared to non-irradiated control. Our data demonstrated a clear difference in the effects of these HZE ions, particularly immunological, suggesting different molecular mechanisms of tumorigenesis for each ion. Additionally, we observed novel, functionally unannotated transcripts that were significantly affected by HZE. The biological functions of these transcripts were investigated using Self-Organizing Maps (SOMs). Finally, we used MALDI-MSI to identify lipid changes 12 months post-exposure to low dose 28Si and 137Cs γ rays’ irradiation. We identified a number of lipid species; in particular, we have confirmed the identity of GSL; which is of special interest because its up-regulation have been reported in patients with HCC
Profiling the Serotonin2 Receptor System Functional Capacity: Towards Identification of a Cocaine Use Disorder Biosignature
No full textVulnerability to developing a cocaine use disorder (CUD) starts with a background of genetics and environment and results in changes in neuroplasticity that leads to a greater drive to take cocaine. The intricate interplay between these variables differs for each individual, presenting a barrier to understanding the origin of the disorder as well as the development of treatments. Characterization of a CUD biosignature through the use of defining biological markers will greatly improve our ability to predict patient response, disease risk, accurate CUD diagnosis and potentially even identify novel targets for medications development, all the while moving CUD treatment towards an age of precision medicine. The cycling progressive nature of CUD stymies efforts to stay abstinent with vulnerability to abuse and relapse during abstinence often precipitated by impulsive behavior. The loss of impulse control has been particularly noted in cocaine-dependent subjects who also express high reactivity to cocaine-associated cues (“cue reactivity”) suggesting that impulsivity and cue reactivity are interlocked contributors to relapse, a cardinal facet of addiction. Serotonin (5-HT) neurotransmission through the 5-HT2C receptor (5-HT2CR) and 5-HT2A receptor (5-HT2AR) within the central nervous system is a critical driver of the cognitive and/or behavioral dimensions underlying impulsivity and cue reactivity. Characterization of how these receptors are regulated or altered by genetic and epigenetic means will lead to the identification of a 5-HT2R-mediate biosignature for CUD. To bridge this gap in knowledge, we first investigated the functional effects of a single nucleotide polymorphism (SNP) of the 5-HT2CR that converts a cysteine (Cys) to a serine (Ser) at amino acid codon 23 in the N-terminal extracellular domain (Cys23Ser; rs6318). We established that the Cys23Ser SNP dramatically reduces efficacy of 5-HT at the 5-HT2CR with a decrease in potency as a result of reduced plasma membrane expression from altered localization through the secretory and recycling pathway. We also demonstrate in vivo, that overexpressing the human Ser23 5-HT2CR in the medial prefrontal cortex, a key region implicated in relapse-like behaviors, of rodents exhibit dampened cocaine-seeking behavior accompanied by greater plasma membrane expression of the 5-HT2CR versus rodents expressing the Cys23 5-HT2CR. Finally, we characterized methylation patterns of the HTR2A, 5-HT2AR human gene, promoter that correlated with relapse-related behavior in cocaine-dependent participants. Taken together, we have identified genetic and epigenetic makers of the 5-HT2R system with great potential to define a high-risk relapse biosignature of CUD
Primary Care Nurse Practitioners Perceptions of Facilitators and Barriers to Encounters with Transgender Patients
No full textTransgender persons in the United States number are estimated to number 1.4 million. These patients are seeking care in primary clinics for not only preventative services, but for acute and chronic conditions as well. Often these patients are met with discrimination, a lack of knowledge regarding transgender care needs and may delay care resulting in poor health outcomes. Little nursing research exists in literature relating to facilitators and barriers to providing care to transgender persons. The purpose of this study was to evaluate primary care nurse practitioners’ perceptions relating to facilitators and barriers to healthcare encounters with transgender patients
A Naturalistic Inquiry Into the Lived Experience of Nurse Practitioners Who Have Full Practice Authority
No full textFull Practice Authority (FPA) is one of three types of practice authority that a nurse practitioner (NP) can obtain through state licensure, depending on the state where the NP plans to practice. The American Academy of Nurse Practitioners (AANP) explains that FPA entails “…the authorization of nurse practitioners to evaluate patients, diagnose, order, and interpret diagnostic tests, initiate, and manage treatments - including prescribing medications – under the exclusive licensure authority of the state board of nursing” (AANP, 2022, Policy Briefs section). To date, there are 29 FPA states and territories, 16 reduced practice states, and 11 restricted practice states. The purpose of the study, “A Naturalistic Inquiry Into the Lived Experiences of Nurse Practitioners with Full Practice Authority,” was to explore the everyday experience of the FPA NP using Naturalistic Inquiry (NI). NPs were recruited through electronic mail (e-mail) requests using e-mail addresses obtained from the state Board of Nursing in FPA states. Eleven NPs were interviewed, and data collection followed a semi-structured interview format, with analysis resulting in the emergence of the following themes: (a) autonomy, (b) confidence, (c) collaboration/support system (d) standard credentialing/licensure process, (e) legislation, (f) accessibility and flexibility in patient care, (g) new FPA NP education and research, (h) limitations, (i) reimbursement. The participants indicated FPA is a positive experience in their practices, but limitations to practice and inconsistencies in regulation still exist as the United States, including the District of Columbia and U.S. territories. This study can offer information and insights about the experience of practicing with FPA to the NP who has yet to obtain FPA as all states progress towards FPA for NPs
Pediatric Nurses' Perceptions of Bedside Shift Report
No full textNursing bedside shift report (BSR) is a form of nursing shift report that may be used to involve pediatric patients and their families in discussions about their plan of care. According to Healthy People.gov (Office of Disease Prevention and Health Promotion, 2020) in the ten years between 2007 and 2017, there has only been a 1.2% increase in the number of people who reported that health care providers included them in decisions about their health care, to the extent they wanted to be involved. The bulk of research focusing on BSR has been conducted on adult patient units or with nurses who care for adult patients. Adult patient care nurses’ perceptions of the benefits and challenges of using BSR have been explored (Jeffs, Cardoso, et al., 2013), in addition to issues that may have contributed to nurses’ not fully implementing BSR (Small & Fitzpatrick, 2017). There is a significant gap in the literature that looks at BSR’s utilization on pediatric nursing units and there is a lack of studies that aim to understand the perceptions of pediatric nurses who use BSR for nursing shift report. This study utilized Naturalistic Inquiry (NI), first introduced by Lincoln and Guba (1985) and further developed by Erlandson et al. (1993), to explore and describe pediatric nurses’ perceptions of BSR. Participants were recruited using purposive and snowball sampling resulting in a total of twelve pediatric nurses who worked on pediatric general medicine nursing units. Data collection and analysis for this study was ongoing and iterative beginning with the first participant interview utilizing a bio-demographic questionnaire and semi-structured interviews. Rigor was established by using Lincoln and Guba’s criteria as described by Erlandson et al.
Findings from the study raised the question of whether BSR is the right form of nursing shift report for all patient populations. While nurses in the current study agreed with the underlying principles of BSR they also identified some issues with utilizing BSR on their pediatric units that frequently required them to modify BSR practices. Repeated modifications of BSR practices could easily lead to an erosion of those practices
Psychological Safety and Inclusive Teaching Practices: Occupational Therapy Faculty's Perception for Student Success
No full textIntroduction: Psychological safety (PS) is the belief that it is safe to freely voice concerns and ideas, with little or no fear of reprimand, or belittlement. Currently, there is a gap in the literature about the construct of PS within U.S. Occupational Therapy (OT) educational programs related to faculty leadership and student engagement.
Objectives: This capstone explored faculty's perception of PS within their program and highlighted the need to 1) introduce the concept of PS in OT education 2) call to action the use of PS practices in OT academics to support diversity, equity, and inclusion (DEI) initiatives in OT education and 3) utilize inclusive instructional design in OT curriculum to foster PS.
Methods: An exploratory, cross-sectional online survey design consisting of 44 closed-ended questions was distributed through virtual platforms and email Listserves to OT/OTA faculty in the U.S. Questions explored PS on a Likert scale ranking and inclusive teaching practices (ITP) through dichotomous yes/no responses. By the response deadline, 85 valid responses were received.
Results: Descriptive statistics results of this capstone indicated faculty report a perception of PS when working in teams. On average, participants fell between “sometimes” and “often” for overall PS (M= 3.61) and ITP (M=3.86). For ITP practices, transparency (M= 4.11) and academic belonging (M= 4.04) were the most used strategies. Correlational statistics results indicated no significant association between PS and ITP strategies (r=.091), program cohort size to PS (r= .050), and faculty team size to PS (r= .050). There was a significant association observed between overall PS and ITP subscale critical engagement (CE) (r= .235).
Discussion: The findings indicated that there is no strong association between the overall PS and ITP within OT education; however, the results do indicate the presence of both constructs within OTA/OTA programs. Faculty team size and program cohort size are not mediating factors affecting PS or ITP use. Therefore, all OT/ OTA programs could consider utilizing PS and ITP strategies in their program curriculum. Faculty who perceive greater overall PS in their teams are also more likely to use specific critical engagement strategies in their courses.
Conclusion: This capstone adds to the body of OT literature to introduce the construct of PS in OT education and highlights faculty’s use of ITP strategies in OT education. Additionally, OT/OTA faculty could benefit from continuing education regarding PS leadership practices, utilization of ITP strategies in the classroom to support DEI in OT curriculum and continuing ongoing research toward trauma-informed approaches as an educational framework in OT education to support critical student engagement
Investigating the Potential Role of α-Synuclein in Tau Aggregation and Toxicity
No full textA group of neurodegenerative diseases that are pathologically characterized by the presence of intracellular abnormal aggregation of α-Synuclein (α-Syn) in Lewy bodies (LBs) and Lewy neurites (LNs), are collectively known as synucleinopathies. Even so, tau protein pathology is abundantly found in these diseases. Apart from Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), LBs and LNs have been reported in Alzheimer’s disease (AD) patients as well. Both α-Syn and tau can exist as polymorphic aggregates, and this phenomenon has been widely studied, mostly in their fibrillar assemblies. Growing evidence suggests that intermediate metastable oligomeric assemblies of several amyloidogenic proteins, including α-Syn and tau are actual neurotoxic species. However, little is known about the structural and functional heterogeneity among α-Syn oligomers occurring in different diseases. Moreover, the functional crosstalk between these toxic oligomers has not been scrupulously studied. Here, by using biochemical, biophysical and cell-based techniques, I have studied the structural and functional diversity of distinct recombinant α-Syn oligomers, prepared by modifying the protein with two physiological inducers, dopamine (DA) and docosahexaenoic acid (DHA). The two recombinant α-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion and toxicity, suggesting them as distinct α-Syn oligomeric strains. I have also analyzed brain-derived α-Syn oligomers (BDSOs) from AD, DLB and PD brain tissues. I observed that disease associated BDSOs were diverse in their functional properties. Notably, they can be uptaken via gap junction protein Cx50 in the primary neurons, thus suggesting a unique mechanism that might be involved in the oligomers mediated toxicity. Additionally, both recombinant and brain-derived α-Syn oligomeric strains effectively cross-seeded tau aggregates with diverse biochemical, biophysical and biological properties. Interestingly, BDSOs cross-seeded tau aggregates were more potent seeds causing cellular tau aggregation than the ones cross-seeded with recombinant α-Syn oligomeric strains. The findings here represent a significant step to elucidate the toxic interplay between α-Syn oligomeric strains and tau, altering the aggregation profiles and nature of the amyloid deposits. This will lay the groundwork for more successful therapeutic interventions by targeting multiple candidate molecules, such as α-Syn and tau in diseases
Vector Competence of Aedes aegypti for Zika Virus and Effects of Colonization
No full textThe following dissertation aims to determine how vector colonization of influences the vector competence of Aedes aegypti for Zika virus (ZIKV) as well as the microbiome as a correlating factor. Ae. aegypti is the vector of multiple arthropod-borne viruses including dengue, yellow fever, and Zika virus, making it one of the most globally significant disease vectors and is studied in laboratories world-wide with significant research focus on vector competence studies. Many of these studies, however, utilize strains of Ae. aegypti that have been colonized in insectaries for laboratory use and may not reflect the phenotype of wild mosquitoes. While studies have shown differences lab adaptation of mosquitoes resulting in an altered phenotype compared to field mosquitoes, a comprehensive study examining the process of adaptation and effects on vector competence has not been conducted. I hypothesize that the colonization of Ae. aegypti results in an increase in vector competence for ZIKV, correlated with a change in microbiome diversity and composition. First, the vector competence of multiple species of mosquitoes (Ae. aegypti, Ae. albopictus, and Culex quinquefasciatus) was determined for ZIKV, using various strains of both virus and each vector species. A field-collected population of Ae. aegypti was then colonized and experimentally examined for vector competence for ZIKV and microbiome over the course of ten generations. I found that the vector competence of this population did increase over the course of the study and that this change occurred abruptly after multiple generations, resulting in two distinct groups of low and high competence. I then identified a number of bacteria that exhibited different levels of abundance between the low and high competence groups, many of which remain uncharacterized in the mosquito microbiome. Further studies to elucidate the role of these bacteria in determining vector competence as well as the development methods to minimize the effects of colonization could lead to better standardization across vector competence studies and increased relevance to field mosquitoes. These findings are incorporated into the existing literature with recommendations on the design of vector competence studies
HCV Core Protein affects Lipid Metabolism in a Genotype-Dependent Manner
No full textChronic HCV infection is the leading cause of steatosis (fatty liver disease) and hepatocellular carcinoma (HCC). The virus establishes a chronic infection in 70% of patients and infects approximately 71 million people worldwide. Genotypes (gt) 1 and 3 are the most prevalent, with gt3 HCV being associated with more severe disease. It is known that core protein plays a role in the development of steatosis, but the precise mechanism is not yet understood. In this study, we investigate the role of genotypes in core-mediated differential regulation of lipid metabolism. Prior studies described the lipid induction by HCV infection or ectopic expression of core derived from gt1a and 3a HCV qualitatively. The goal of this thesis is to define the gt1a and 3a HCV core-mediated lipid regulation in a quantitative manner. Using FACS analysis, and immunofluorescence analysis by using confocal microscope, we found that gt3a core protein induces larger lipid droplet formation, although the quantity of lipids remains similar to that induced by gt1a core protein. We then attempted to determine the difference in fatty liver-associated gene expression levels induced by gt1a and gt3a core proteins. To do this, we utilized microarray to analyze the gene expression in cells transfected with different HCV core proteins. The analysis showed that both gt1a and gt3a core upregulated SOCS3; this upregulation has been shown to influence the liver response to previously used antiviral therapies, as well as the induction of insulin resistance. Additionally, genes that were downregulated by gt1a and gt3a core are largely associated with insulin resistance, which plays a role in the development of diabetes. Interestingly, more genes appear to be downregulated by gt3a than gt1a core protein, which could suggest that gt3a core protein induces insulin resistance and steatosis in a different manner, or to a more severe degree. Overall, these results present a potential mechanism for the relationship between insulin resistance and lipid metabolism deregulation induced by gt1a and gt3a core proteins
Subversion of innate antiviral immunity by SARS-CoV-2: An example from the study of nonstructural protein 16.
No full textUnderstanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein (NSP) 16 of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2’-O methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process. Based on observations with other CoVs, we hypothesized that NSP16 2’-O MTase function protects SARS-CoV-2 from cap-sensing host restriction. Therefore, we engineered SARS-CoV-2 with a mutation that disrupts a conserved residue in the active site of NSP16. We subsequently show that this mutant is attenuated both in vitro and in vivo, using a hamster model of SARS-CoV-2 infection. Mechanistically, we confirm that the NSP16 mutant is more sensitive to type I interferon (IFN-I) in vitro. Furthermore, silencing IFIT1 or IFIT3, IFN-stimulated genes that sense a lack of 2’-O methylation, partially restores fitness to the NSP16 mutant. Conversely, overexpressing IFIT1 either alone or in combination with IFIT3 attenuates the NSP16 mutant relative to wild-type. Finally, we demonstrate that sinefungin, a MTase inhibitor that binds the catalytic site of NSP16, sensitizes wild-type SARS-CoV-2 to IFN-I treatment and attenuates viral replication in IFN-I competent cells. Overall, our findings highlight the importance of SARS-CoV-2 NSP16 to evading host innate immunity and suggest a possible target for future antiviral therapies