UTMB Health SHARED

UTMB Health SHARED is an online community space for Scholarship, Historical Archives, Repository, & Electronic Dissertations. This digital service is an important tool for preserving the organization’s legacy and facilitating scholarly communication.

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HUMAN GENETIC VARIANTS IN ESSENTIAL SPLICING FACTORS AND THEIR IMPACT ON IMMUNE PATHOLOGY
(2024-08) Nagasawa, Chloe Kazue; Garcia-Blanco, Mariano (rxh8rw@virginia.edu); Ward, Michelle (miward@utmb.edu); Lincoln, John; Abbott, Robert; Sheetz, Michael
Pre-mRNA splicing is critical for proper gene expression, and its dysregulation has been implicated in many human diseases including neurodegenerative disorders, cancers and autoimmune diseases. Splicing is a multi-step process executed by the spliceosome, which is composed of five small nuclear ribonucleoproteins (snRNPs) and hundreds of proteins that are generally referred to as splicing factors (SFs). Here we present two unique cases in which genetic variations in two essential SFs, DExD-box polypeptide 39B (DDX39B) and U2 small nuclear RNA auxiliary factor 1 (U2AF1), contribute to altered splicing of Forkhead box P3 (FOXP3) – an immunoregulatory gene critical for regulatory T (Treg) cell function and homeostasis. Mutations in FOXP3 cause immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, and aberrant expression of FOXP3 has been associated with other diseases such as multiple sclerosis (MS) and non-small cell lung cancer (NSCLC). We previously described a single nucleotide polymorphism (SNP) in DDX39B, rs2523506, which is associated with increased risk of MS. The population homozygous for the risk allele had ~50% less DDX39B protein expression. Furthermore, we demonstrated that DDX39B expression is critical for proper splicing, expression and function of FOXP3. Here we describe the mechanism underlying the exquisite dependence of FOXP3 introns on DDX39B and the potential impact of rs2523506 in DDX39B on FOXP3 expression and autoimmunity. Additionally, we highlight splicing alterations in a patient with a complex immune phenotype and a de novo in-frame deletion in U2AF1. Moreover, we discuss the potential implications of these splicing alterations in the disease pathogenesis of the patient. These two examples of genetic variations in SFs showcase the importance of splicing and how its dysregulation can contribute to immune pathology.
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The Impact of An Innovative Online Orientation Program on Graduation among Graduate Nursing Students: A Secondary Analysis
(2024-08) Letz, Lisa Kye 1978-; Nguyen, Hoang T./hnguyen@UTMB.EDU; Jupiter, Daniel/dajupite@utmb.edu; Lorenzo, Elizabeth/ellorenz@utmb.edu; Leger, Michael/jmleger@utmb.edu; Kapaale, Chaluza/chaluza.kapaale@simmons.edu
The current shortage of Advanced Practice Registered Nurses (APRN) in the United States requires innovative programs to increase on-time graduation and decrease attrition. The Master of Science in Nursing (MSN) Online Orientation for Retention Excellence (MORE) Program is one such program. However, the program’s impact on on-time graduation and attrition is not known. The purpose of this study was to examine the impact of the MORE Program on student’s on-time graduation and attrition. Tinto’s Theoretical Model of Student Departure (1993) was used as the guiding theoretical framework. A retrospective secondary analysis was conducted on all 608 MSN students who enrolled in the Fall 2016 to Fall 2018 at one nursing school located in the southern United States. Logistic regression models were used to examine the association between the MORE Program and the on-time graduation rate and the attrition rate. The models adjusted for the effect of age, sex, program track, and admission GPA. The study found no statistical difference in the odds of graduating on-time between students who did and did not participate in the MORE Program. However, age, program track, and admission GPA were significant predictors of on-time graduation. For attrition, students who never or only partially participated in the MORE Program had 2 to 3 times higher odds of attrition compared to students who fully participated. Age and program track were also significant predictors of attrition. Online orientation programs should be used in online graduate nursing programs to decrease attrition. Findings from this study could inform nursing educators about establishing online orientation programs and resources to support at-risk students to better prepare online graduate nursing students for successful graduation.
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Interferons in Influenza A Virus and Streptococcus Pneumoniae Co-Pathogenesis
(2024-08) Palani, Sunil 1992-; Sun, Keer Ph.D. (kesun@utmb.edu); Xiaoyong Bao, Ph.D.; Yingzi Cong, Ph.D.; Parimal Samir, Ph.D.; Victor Huber, Ph.D.
Secondary pneumococcal pneumonia postinfluenza significantly increases the disease burden associated with influenza A virus (IAV) infection. IAV induced interferons (IFN) play a crucial role in antiviral immunity. However, recent reports have indicated that influenza-induced IFN-I and IFN- γ signaling suppress innate antibacterial immunity by distinct mechanisms, thereby increasing host susceptibility to secondary bacterial pneumonia. Despite their detrimental role, the interplay between them remains poorly understood. In this dissertation, we have investigated the relative importance of IFN-I and IFN-γ pathways in the pathogenesis of IAV/ Streptococcus Pneumoniae (SPn) coinfection. Using gene knock-out models and neutralizing in vivo antibodies, we demonstrated that IFN-I and IFN-γ inhibit acute bacterial clearance post-IAV infection. However, IFN-γ plays a more critical role. Additionally, we found that IFN-I signaling is essential for preventing IFN-γ hyperproduction and animal death during coinfection, indicating the dual role of IFN-I, which was novel. Moreover, we show that both IFN-I and IFN-γ employ distinct mechanisms to regulate inflammatory cytokine response and immune cell recruitment during copathogenesis. Given the dominant role of IFN-γ in the progression of coinfection, we further investigated the effect of immune predisposition on susceptibility to coinfection. To that end, we demonstrated that pathogenicity to coinfection remains distinct between BALB/c and C57BL/6 (B6) mice that recapitulate Th2- and Th1-biased responses, respectively. Prior infection with a low-virulent IAV strain (X31) renders B6 mice extremely susceptible to superinfection compared to the resistant BALB/c mice. We found that neither the viral nor the bacterial infection alone induced IFN-γ response in both strains of mice. However, the coinfection resulted in a robust IFN-γ response in the B6 mice, not the BALB/c mice. Furthermore, this IFN-γ response in the B6 mice inhibited neutrophil recruitment and innate bacterial clearance. Additionally, we also demonstrated that neutrophils in BALB/c mice are required for effective bacterial control. Collectively, our results indicate that Th1-biased immune predisposition plays an important role in determining the outcome during IAV/ SPn coinfection. Altogether, our work has demonstrated the relative importance and the regulation between IFN-I and IFN-γ during the coinfection pathogenesis, which is imperative for understanding the complex pathogenic mechanisms.
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Brokaw Hospital
(Randall's Inc., Normal, Illinois; Curtiechcolor, Unknown)
Postcard of the Brokaw Hospital in Normal, Illinois. "Established in 1896 as Non-Profit Charitable Community Hospital. It has 134 beds and 21 infant Bassinets; also operates the Brokaw Nursing Home. It is affiliated with most of the Protestant Churches of McLean County, each of whom, annually appoint Trustees for the Hospital."
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Life-Space Mobility, Falls, and Healthcare Use Among Community Dwelling Mexican-American Older Adults
(2024-05) Johnson, Jason Paul 1983-; Al Snih, Soham (soalsnih@utmb.edu); Monique Pappadis; Chih-ying Li; Mukaila Raji; Kyriakos Markides; James Graham
Physical mobility affects all aspects of daily life and is a crucial part of independent living. Life-space mobility (LSM) is a valuable concept for measuring both mobility and independence of older adults in their day-to-day lives. Aims are: 1) to determine the threshold values of restricted LSM among Mexican American older adults in comparison to the original life-space assessment (LSA) validation on measures of disability, depressive symptoms, physical function, and mortality; 2) to evaluate LSM as a predictor of falls and fear of falling with and without visiting a hospital or Emergency Department (ED) among Mexican American older adults over time; and 3) to determine the association between LSM and healthcare use of Mexican American older adults over time. We included 799 respondents aged 80 and older from the Hispanic Established Population for the Epidemiologic study of the Elderly survey (2010/11-2016). The independent variable was restricted life-space mobility. Outcome variables included falls/fear of falling, and acute/post-acute healthcare use. Covariates were age, sex, education, marital status, nativity, living arrangement, pain, cognitive and physical function, comorbidities, depressive symptoms, and sensory deficits. Receiver operating characteristic curve analysis showed that the new threshold for LSM restriction in this population was a LSA of ≤35 points for disability, physical function, depressive symptoms, and mortality which was lower than the initial score of ≤60 points found in the original LSA validation cohort. Generalized Estimating Equations models showed that the new restricted LSM (LSA ≤35) is associated with falls with visits to the hospital or ED [odds ratio (OR)=1.58 95% Confidence Interval (CI)=1.03-2.44], fear of falling (OR=1.88, 95% CI=1.36-2.60), and hospital admissions (OR=1.57, 95%CI=1.13-2.19) after controlling for all covariates. No significant association was found between restricted LSM and post-acute care. In conclusion, there is a lower threshold for restricted LSM among Mexican American older adults and that the lower threshold more accurately predicts falls that required a hospital or ED visits, fear of falling, and acute healthcare use. This suggests that the new LSA threshold may be a better assessment tool for health outcomes among Mexican American older adults.