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Structural and functional studies of cysteine-rich proteomimetic scaffolds
No full textLinear chains of covalently connected amino acids direct the proteins to fold into specific three-dimensional shapes and thereby control the function of proteins. Altering the backbone connectivity in natural proteins by blending natural with artificial building blocks is a powerful approach to generate proteomimetic scaffolds. Though significant advancements have been made in the field of proteomimetics, a generalizable set of design principles for developing such artificial molecules still remain elusive. A main focus of this dissertation is understanding the structural and functional consequences of modifying the backbone composition in cysteine-rich proteomimetic scaffolds. Chapter 2 of this dissertation sheds light on modifying metal-binding β-turns found in zinc finger domains without compromising folded structure or stability. In chapters 4 and 5, we describe our rational approach to develop structural and functional mimics of a multidomain zinc finger protein and a disulfide-rich antimicrobial peptide. Additionally, in chapter 3, we document our efforts to advance the use of proton chemical shift information obtained by NMR methods to understand folding behavior in protein-like artificial backbones. Collectively, the body of work presented in this dissertation aims to provide more insights into the impacts of backbone modifications on folded structure and function of proteomimetic scaffolds
Human Rights Writing: Activist Composition in a Global World
No full textThis dissertation explores the intersection of human rights and writing in global contexts, emphasizing the link between rhetoric, genre theory, and the shaping of human rights discourse. It argues that written documents play a pivotal role in human rights action. The failure to integrate human rights discourse into composition studies is a missed opportunity, limiting discussions of social justice to local and national issues and neglecting their global impact. Working within a theoretical framework that positions genres as dynamic and context-driven social actions, I demonstrate how genres play a significant role in shaping human rights realities. I begin by analyzing the United Nations Charter and the Universal Declaration of Human Rights, showing how they construct a collective humanity with moral authority over nation-states, while also reinforcing state sovereignty. The tension between the idealized moral concept of human rights and their manifestation as law is explored, exemplified by the UN Charter's dual characterization as a charter and a treaty. This tension persists in subsequent human rights writing as a gap between human rights ideals and practical effects. Texts such as human rights reports, and demonstrations of grassroots activism, like Amnesty International's letter campaigns, are caught between asserting humanity's authority over States while grappling with the State autonomy imposed by the charter and treaty genres. Having identified these dynamics of human rights writing through the constitutive and epistemic act of composing human rights genres, I turn to a case study of the Tumaini Festival and Homestay Program at the Dzaleka Refugee Camp in Malawi to explore the ways refugee activists deploy genres of the hospitality industry to reposition refugees as individuals with agency and economic value. This reframing offers refugees access to essential resources and opportunities, challenging the “rhetoric of illegibility” defining protracted encampment. This dissertation concludes by encouraging compositionists to engage critically but generatively with the intersections of human rights and writing studies to improve the work and impact of both in global issues of social justice
Identifying Novel Cardiovascular Biomarkers for Cognitive Performance Across the Menopause Transition
No full textBackground: Women are disproportionally affected by Alzheimer’s disease (AD). The menopause transition may be a stage with increased AD susceptibility, due to its association with accelerated cardiovascular risks, the most common modifiable risk factors of AD. While traditional cardiovascular risk factors have been associated with processing speed and working memory, we aimed to identify novel cardiovascular biomarkers with potential to link to episodic memory loss, the initial and predominant symptom of AD.
Objectives: To assess the associations of cardiovascular fat [epicardial (EAT), paracardial (PAT), and thoracic perivascular adipose tissue (PVAT)] volume and radiodensity (paper 1), serum high-density lipoprotein (HDL) metrics (paper 2), and immune/inflammatory biomarkers [serum complement factor 3 (C3) and 4 (C4) and Glycoprotein acetylation (GlycA)] (paper 3) at and/or over midlife with future cognitive performance.
Methods: Participants from the Study of Women’s Health Across the Nation (SWAN) cardiovascular fat ancillary study (paper 1, n=531, age: 50.9±2.9 years) with cognitive performance assessed repeatedly after the cardiovascular fat scan (the baseline) over 13.4 years of median follow up and HDL ancillary study (paper 2 and 3, n=503, age: 50.2±2.7 years) with repeated measurements of HDL and immune/inflammatory biomarkers assessed 1.5±1 years before subsequent cognitive measures over 7.7±4.1 years of follow up. We applied mixed models with multiple imputation (paper 1) and joint models (paper 2 and 3).
Results: Greater volume and radiodensity of thoracic PVAT, but not of EAT and PAT, at midlife were associated with higher future delayed recall and lower future working memory and delayed recall levels over time, respectively. Greater increases in HDL phospholipid, apolipoprotein A-1, medium HDL particles, and total HDL particles and less increase in HDL size over midlife, instead of their levels at midlife, were associated with higher subsequent immediate and/or delayed recall. Higher serum C4 and lower C3/C4 ratio and GlycA at midlife, instead of their changes over midlife, were associated with higher subsequent immediate recall and/or working memory.
Conclusions: Novel cardiovascular biomarkers distinctively associated with future episodic memory immediate and delayed recall in midlife women implicated their special relationship with AD and potential application in AD prevention and treatment at younger age
One Caring Person: The Impact of Student-Staff Casual Interaction on International Students’ Sense of Belonging
No full textOver the last 10 years, undergraduate international student enrollment at the University of Pittsburgh (Pitt) has increased by 175%. However, international students still face unique challenges and experience low sense of belonging. With the aim of increasing students’ sense of belonging, I created and implemented the staff-student mentoring program called One Caring Person (OCP) program where students can meet staff informally who are not in their academic or professional setting.
I recruited 23 staff and 23 students who are diverse in their country of origin, gender, area of study, school year, academic background, cultural experience, interest, personalities, etc. During the program, I facilitated training sessions separately for students and staff which were intentionally designed and tailored to the needs and situations of each group. International students were paired with staff who were recruited and trained to serve as a One Caring Person (mentor) and they were encouraged to meet 2-3 times in a semester to build the relationship and share their experiences and cultures. This program ended with an end-of-program celebration.
I used the qualitative study method to test the impact of the One Caring Person (OCP) program on undergraduate international students’ sense of belonging at Pitt. I purposefully selected 11 students to share their perspectives, thoughts, and feelings about their experiences with their staff OCP for data collection and analysis.
My findings indicated that all 11 students who were interviewed expressed that they felt cared about, accepted, respected, or valued by their staff OCP (mentor), which are all necessary steps toward achieving or increasing a sense of belonging. The study revealed several key findings. First, students felt that their OCP was an emotional support pillar. Second, they saw their OCP as a friend and mentor. Third, they considered the OCP program as an opportunity for cultural exploration. Lastly, they relied on their OCP to help them overcome challenges such as cultural adjustment and language barriers. Recommendations, limitations, and considerations for future study concluded the dissertation. In the future, senior leadership and institutional support will be necessary especially if the program is expanding to a larger scale
Mutual Benefits of Caregiver Implemented Music Interventions Among Persons with Dementia and their Caregivers: A Scoping Review
No full textBackground: Dementia is an umbrella term that describes several diseases that impact memory, thinking, behavior, and daily activities. With the aging population, it is estimated that by 2030, 78 million people will be living globally with dementia (Shin, 2022). Caring for persons with dementia can carry a physical and emotional burden (Wang et al., 2022). Music therapy has shown to be an effective tool in managing the symptoms of dementia. A comprehensive review exploring the dyadic effects of caregiver implemented music interventions is essential to understand how the use of music interventions may positively influence both the caregiver and persons with dementia. Objective: The primary objective of this scoping review is to examine studies that explore caregiver implemented music interventions among persons with dementia to assess if there are mutual benefits. These benefits include the reduction of dementia symptoms and the reduction of the negative consequences of the burden of care. Other mutual outcomes such as engagement and
communication were also explored.
Methods: A search strategy was developed to identify literature exploring dual outcomes of caregiver implemented music interventions and their care receivers with dementia. The search interface Ovid-Medline was used.
Results: A total of seven papers were extracted for this review. There were mixed results found in quantitative measures; however, qualitative measures show that caregiver implemented music interventions are effective at reducing symptoms of dementia and the negative consequences of caregiver burden. Results showed improvements in engagement and communication between caregivers and people living with dementia. Major limitations of the studies reviewed included the small sample sizes and the lack of randomized controlled trials.
Conclusion: This review demonstrates that the use of music interventions implemented by caregivers of those with dementia may serve as a positive tool for both the caregiver and person with dementia. To best understand the effects of caregiver implemented music interventions, larger, higher quality studies need to be conducted, specifically randomized controlled trials. Given the increasing prevalence of dementia, it is of public health significance to develop novel tools to support dementia care, such as caregiver implemented music interventions
Estimating the Prevalence of HHT Using Variant Effect Predictions
No full textHereditary Hemorrhagic Telangiectasia (HHT) is currently classified as a rare genetic condition that is characterized by potentially fatal blood vessel malformations. Upwards of 90% of HHT cases are caused by a pathogenic genetic variant in the ENG or ACVRL1 gene. Current estimates, based on case counting methods, calculate the prevalence of HHT to be between 1 in 5,000 and 1 in 10,000 people worldwide (0.01% - 0.02%). Due to variable HHT symptom presentation and severity, along with physician unfamiliarity, HHT is likely underdiagnosed by providers and therefore past prevalence measures may be inaccurate. In this study I (1) gathered variant data from gnomAD, (2) predicted variant pathogenicity using a variant effect predictor (VEP) from Ensembl, and (3) calculated the prevalence of HHT pathogenic variants at different levels of restrictiveness using allele frequencies. Without excluding any variants from the VEP software, a prevalence of 2.75% was calculated. After adjusting for homozygous variants, variants with large individual allele frequencies, and variants reliably labeled benign via clinical observations, a prevalence of 0.3203% was calculated. Finally, I adjusted the calculation for all clinically benign variant annotations. The calculated prevalence of HHT is then 0.2945%, 14.7-fold higher than currently accepted values. While there are notable limitations to the variant database, VEP, and datapoints used, an increased prevalence value holds great public health significance for the HHT and medical communities. This increased prevalence estimate suggests that HHT may indeed be more common in the population than currently reported
Reviewing Appropriateness of C. difficile Testing and Ordering Practices: An Approach to Reduce Pediatric C. difficile Infections
No full textBackground: Hospital-acquired infections (HAIs), including Clostridioides difficile (C. difficile) infections, pose significant threats to patient safety, healthcare economics, and public health. C. difficile, a Gram-positive, spore-forming bacillus, can be acquired in both community and hospital settings. Children exhibit higher colonization rates during their first two years of life, with a subsequent decrease to 3-5% in those aged two and older. Accurate identification of C. difficile infections in children is challenging due to these elevated colonization rates during early development.
Methods: Infection preventionists at the University of Pittsburgh Medical Center (UPMC) Children’s Hospital of Pittsburgh (CHP) implemented a surveillance and feedback strategy for C. difficile testing. This involved reviewing all C. difficile orders that could result in an HAI upon lab confirmation of a positive result. Pilot data from the project, gathered between March 15 and July 31, 2023, were compared with data from the same period in 2022, before the project's initiation.
Results: In 2023, out of 99 C. difficile orders, 67 (67.7%) were reviewed by infection preventionists. Following review, 22 orders (32%) were deemed inappropriate and suggested to be canceled, 8 (12%) resulted in positive infections, and 27 (40%) were negative. The proportion of C. difficile orders in 2023 was higher among patients with a recent infection history (31%), compared to zero orders in 2022 among such patients. Additionally, more patients in 2023 had recent antibiotic exposure (95%) within the past seven days compared to 2022 (70%).
Discussion: The project's impact on reducing inappropriate test orders and the significance of accurate HAI diagnosis. Although the results suggest progress, a yearly analysis is recommended to determine sustained improvements. The review of orders not only enhances C. difficile infection confirmation but also contributes to appropriate treatment, reducing unnecessary antibiotic distribution and healthcare costs. The findings underscore the broader implications of C. difficile infections on healthcare systems and the importance of ongoing efforts to mitigate the impact in public health
Evaluating the association between socio-demographic variables and place of delivery in Nepal: A Review of the Literature
No full textNepal is a multi-ethnic, multilinguistic, and landlocked country where one third of its population lives below the multidimensional poverty level. In 2020, Nepal’s maternal mortality ratio (MMR), or the number of maternal deaths during a given period per 100,000 live births during the period, was 174. This is higher than other Southeast Asian Region neighboring countries like India (103), Bangladesh (123), and Bhutan (60). The higher MMR in Nepal may stem from the wide disparity in the utilization of maternal health services, which varies by one’s socio-economic status. The World Health Organization (WHO) also suggests the presence of skilled health professionals to assist in delivery that mothers to visit a health facility within 2 hours of delivery. Therefore, it is essential to evaluate the effect of women’s socio-economic status on access to institutional delivery. To gain a better understanding of this issue in Nepal, a search of the relevant literature was conducted on Ovid-Medline related to maternal health and factors affecting the place of delivery accessible by women in Nepal resulting in 16 studies which met the inclusion criteria. Most of the studies showed an association between the place of delivery (Health institution or home) and three socio-demographic variables: mother’s education (n=8), household wealth index (n=7), mother’s ethnicity (n=4). The association with institutional delivery was positive for women with higher education, the advantaged ethnicities such as Brahmin/Chhetri whereas the association was mostly negative for Dalit and for Janajati subgroups which are the lower caste group in the social class system and indigenous groups of Nepal. Mothers who belonged to a wealthy household had higher likelihood of giving birth in a health institution with skilled health professionals. Collectively, these findings provide insights into how different socio-demographic factors influence the ability of mothers to utilize maternal-health services for delivery. Negative perceptions about institutional delivery among mothers may escalate the issue of MMR which is already a persistent public health issue. Therefore, lower use of institutional delivery services by women in Nepal remains an important public health issue which should be addressed to reduce the maternal deaths and MMR
Assessing SARS-CoV-2 Disease Morbidity within the Navajo Tribal Nation in relation to the Reduced Access to Equitable Water Infrastructure and Health Policy
No full textPublic health is defined as the science of protecting and improving the health of people and their communities (Prevention, 2023). The access to clean water is and basic sanitation infrastructure is critical to public health and the health of a community. Lack of or limited access to uncontaminated water and associated waterway infrastructure within the Navajo (Dine) Nation is resulting in higher rates of infectious disease morbidity among indigenous community members.
The Navajo Nation is a federally recognized tribe with over 200,000 enrolled members, making it one of the largest in North America. The treaties of 1849 and 1868, signed by both the Navajo and the U.S (United States) federal government, ensured the U.S. recognized the Navajo Nation as a self-governing entity and were supplied with the adequate resources to be self-sufficient from the U.S federal government. The Navajo tribal reservation land spans across areas of Arizona, New Mexico, Utah, and is entirely situated within the lower portions of the Colorado River Basin. Due to extreme climatic conditions, water scarcity is resulting in increased water competition. The effects of reduced water access and associated resources exacerbated the threat of Sars-CoV-2 (Covid-19) on the Navajo reservation.
The main aims of this paper include addressing the water crisis faced by the Navajo and how the reduced access to potable water increases the burden of infectious diseases, referencing Covid-19 and Hantavirus events on Navajo Nation as framework. Additionally, discussing the relationship between tribal and federal government entities and how that has led to gaps in the current public health policies. The intended outcomes of this essay are to address the adverse public health impacts associated with the lack of access to clean water on Navajo Nation in relation to government-to-government (i.e., U.S. Federal Government and Tribal Governments) policy interactions
Transcriptional dysregulation associated with pathologic development and maintenance of myofibroblasts in systemic sclerosis
No full textSystemic sclerosis (SSc) is rare disease that is both complex and heterogenous. It can affect multiple organ systems and varies greatly in severity. The leading cause of SSc-related mortality is lung fibrosis, i.e., interstitial lung disease (ILD). Patients with SSc-ILD have an expanded population of myofibroblasts in their lungs. Myofibroblasts contribute to pathogenicity through their ability to increase extracellular matrix and the formation of fibrotic foci. In end-stage lung disease, there is a major distortion of the pulmonary architecture and diminished gas exchange. The transcriptional drivers of myofibroblasts are incompletely understood, particularly in the direct context of the human disease. My research has focused on two areas of dysregulation.
In the first, I used single cell data collected from control and SSc-ILD lungs, to identify upregulated expression of transcription factor 12 (TCF12), along with downstream target genes, within the myofibroblast population using pySCENIC. Perturbation of TCF12 in vitro identified altered gene expression implicating pathways associated with actin regulation, TGF- signaling, and cell cycle interruption. Overexpression of TCF12 led to upregulation of SSc associated genes. TCF12 overexpression was also associated with differentially accessible regions in chromatin compared to baseline TCF12 expression. These data support the role of aberrant TCF12 activity in SSc-ILD myofibroblasts.
My second focus was to associate skewing of chromatin accessibility and transcription factor binding site access with single nucleotide variants (SNVs) that have been associated by GWAS with SSc. I found that nearly 20% of the investigated SNVs were enriched for SMAD2 binding motifs, noteworthy because of the role TGF- is thought to play in SSc. Though none of the SMAD2 sites are altered by the index SNV, these data suggest that these loci are important in pathogenesis. Determining dysregulation in gene expression of the myofibroblast can provide insight into the disease progression and potentially allow for the development of new therapeutics. These projects have helped define the roles of TGF- and TCF12 in myofibroblast differentiation and may provide insight into treatment plans for SSc-ILD patients.
Public Health Significance: Pulmonary fibrosis is a life-threatening disease. Understanding the regulation of myofibroblasts can aid the development of new treatment options