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Transcription Factor Dynamics Investigated through Single-Molecule Imaging, High-Throughput Sequencing, and Neural Networks
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Recent chromatin characterization and sequencing technologies, paired with growing power in computational and bioinformatic analysis, have enabled a deeper understanding of the highly sequence-dependent nature of protein-DNA interactions. Further, these tools have brought to the forefront gaps in our understanding of how changing chromatin landscapes shape cell and tissue identity, and particularly how proteins with stable and transient DNA associations provide feedback to this process. Chromatin remodeling and reorganization serve as umbrella terms to describe diverse mechanisms altering cell epigenetic identity. Transcription factors interacting with chromatin can be influenced by chromatin remodeling processes specifically through cognate sites modifications or generally through a variety of mechanisms, but the degree to which chromatin remodeling alters transcription factor dynamics and activity through general or specific mechanisms is poorly understood. We applied the techniques of Single-Molecule Tracking (SMT) to study the changing dynamics of transcription factors through a B cell activation process marked by widespread chromatin reorganization. First, we identified that during B cell activation, and specifically by the process of nanodomain decompaction, residence time for transcription factors is decreased, suggesting an increased efficiency in transcription. Further studies will be needed to determine if this association between transcription factor residence time and gene transcription is reproducible, and the mechanism underlying it. Second, we identified that the process by which transcription factors scan DNA to identify cognate binding sites, measured by transcription factor random collisions and search time, occurred more rapidly in activated B cells. Given that our work gave additional evidence of the effect of chromatin organization on transcription factor residence time and transcription, we aimed to systematically identify proteins that work upstream to influence the accessibility of chromatin. We generated datasets measuring chromatin accessibility in a variety of mouse tissues and cells, with significant contribution of immune cell subsets. Our accessibility data showed patterns for regulatory elements that fall in line with literature describing significant regions of the genome dedicated to cell-specific regulation, rather than universal regulation. Using a neural network tool known as DeepLIFT with motif identification tools TF-MoDISco and HOMER, we tracked patterns of transcription factor contributions to accessibility across these cell and tissue types, and especially through cell lineages. We identified orphan motifs with no assigned transcription factor, and further identified pleiotropic transcription factors predicting overlooked immune cell functions. Our work stands as a valuable resource for connecting chromatin reorganization and transcription factor dynamics, as well as for testing limits for systematic approaches to predicting contributions of transcription factors to chromatin accessibility
Predicting Heart Disease Through Supervised Machine Learning Algorithms
No full textLightning talk presentation at Texas Health Informatics Alliance (THIA) 2022.The 2022 Texas Health Informatics Alliance Conference was held at the University of Texas at Arlington on September 9, 2022.INTRODUCTION: Heart disease may present in a variety of forms including rhythm-disturbances, pump-failure, silent ischemia, angina, and sudden death among others. Early diagnosis is a crucial step to decrease serious cardiac events. Machine Learning (ML) is a promising tool to improve healthcare diagnostics and risk prediction in highly relevant and common illnesses such as cardiovascular disease.
OBJECTIVE: To develop and evaluate three effective machine learning-supervised models to diagnose heart disease based on individual features.
METHODS: We developed three machine learning models (Elastic net, logistic regression, and random forest) to identify individuals with heart disease. The discovery dataset used for model development included 303 subjects (138 with heart disease and 165 controls) and 14 predictor variables (including traditional cardiovascular risk factors). The outcome variable was the diagnosis of heart disease. The discovery dataset was split into training (70%), validation (10%), and testing (20%) subsets. Model development for elastic net and random forest was accomplished using the training and validation splits, whereas logistic regression was fit using only the training split. We selected hyperparameters for the elastic net model through cross validation and selected the predictors for logistic regression by backward stepwise selection. We calculated predictions using the testing split and evaluated the performance of the classifier based on the area under the receiver-operating-characteristic curve (AUC). Lastly, we used an external validation dataset (n=295, 107 cases and 188 controls) to make predictions.
RESULTS: In the testing dataset, the elastic net model achieved AUC of 90% and accuracy of 86%; the logistic regression AUC was 95% and accuracy of 90%. For the random forest model, the Out-of-Box error was 25.21%; the number of variables used at each split were 3 and the accuracy in the testing test was 83%. When the model was confronted with an external validation dataset, the accuracy was 77%.
CONCLUSION: We developed three models to evaluate ML performance with a discrete dataset. The logistic regression model outperformed the other models with an accuracy of 90% and an AUC of 95%. The final model included 6 variables: Sex, heart rate, exercise induced ST depression, and typical and atypical anginal pain and non-anginal pain. Future work on boosting techniques is required to improve the accuracy of the predictive model. Additionally, developing a comparison analysis between these ML models and conventional clinical approaches may help elucidate the net benefit
The Psychosocial Impact of a Social Interaction Skills Training (SIST) Workshop for Vitiligo Patients
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.BACKGROUND: Vitiligo may cause substantial psychosocial burden on affected individuals, particularly affecting social and interpersonal interactions. Psychosocial interventions remain scarce.
OBJECTIVE: To develop and implement a Social Interaction Skills Training (SIST) workshop for vitiligo patients.
METHODS: A workshop was developed and facilitated using Social Interaction Skills Training principles. The Social Avoidance and Distress Scale, Brief Fear of Negative Evaluation-II Scale, visual analog scales, and open-ended workshop questionnaire were administered to participants before and after the workshop to determine its impact.
RESULTS: Of 17 participants, 11 completed all assessments; 6 completed at all but the penultimate and/or last assessment. Statistically significant improvement in the Social Avoidance and Distress Scale and visual analog scales were seen up to 8 weeks after the workshop. The Brief Fear of Negative Evaluation-II Scale showed a statistically significant decrease immediately after the workshop that was not maintained at follow up. Workshop questionnaires revealed themes regarding motivations to attend, impact on quality of life, and implementation of newly-learned strategies.
LIMITATIONS: Single-arm pilot study with small sample size and lack of randomization to non-intervention group.
CONCLUSION: Social Interaction Skills Training may potentially be a useful intervention for vitiligo patients to reduce psychosocial burden and warrants further study
Association Between Posttraumatic Growth, Medication Adherence, and Barriers to Adherence in Pediatric Solid Organ Transplant Patients and Their Caregivers
Get PDFLiving with a chronic illness can be a traumatic experience, yet there is also evidence that adverse experiences may facilitate positive psychological changes, such as posttraumatic growth (PTG). Little is known about PTG in pediatric solid organ transplant (SOT) patients and their caregivers or PTG's relationship with health behaviors. Study aims were to longitudinally evaluate 1) the role of medication nonadherence and BTA on PTG, and 2) PTG's influence on medication nonadherence and barriers to adherence (BTA). It was hypothesized that 1) Greater baseline medication nonadherence and BTA would predict greater follow-up PTG, and 2) greater baseline PTG would predict lower follow-up medication nonadherence and fewer BTA. Participants included 43 pediatric SOT patient-caregiver dyads at baseline (range: .11-17.09 years post SOT) and follow-up (range: .87-3.37 years post baseline). Baseline measures of PTG, medication nonadherence, BTA, and psychosocial factors were obtained. Follow-up measures of primary outcomes were also collected. Baseline medication nonadherence (β = -.05, SE = .87), patient-rated BTA (β = -.17, SE = .10), and caregiver-rated BTA (β = -.24, SE = .12), did not predict follow-up patient PTG. More baseline caregiver-rated BTA (β = .29, SE = .30), but not medication nonadherence (β = .07, SE = 3.02) or patient-rated BTA (β = .20, SE = .20), predicted greater follow-up caregiver PTG. Baseline patient PTG (β = -.01, SE = .04) and caregiver PTG (β = -.25, SE = .01) did not predict follow-up medication nonadherence. Higher baseline caregiver PTG (β = -.25, SE = .08), but not patient PTG (β = -.07, SE = .26), predicted fewer follow-up patient-rated BTA. Greater baseline patient PTG (β = -.01, SE = .21), but not caregiver PTG (β = -.04, SE = .06), predicted more follow-up caregiver-rated BTA. Exploratory analyses were also conducted to identify psychosocial predictors of primary outcomes. Results suggest that strengthening PTG in caregivers of pediatric SOT patients may be important for reducing BTA. Further research needed to determine whether specific domains of PTG and BTA are associated. Findings have the potential to inform strength-based interventions focused on decreasing BTA for pediatric SOT patients
Phosphatase Regulation of Mechanical Stress and Aging in C. elegans
Get PDFStress and aging embody two related processes driving cellular dysfunction. In either case, environmental stimuli and genetically encoded regulatory mechanisms affect cellular homeostasis and influence adaptation. Phosphatases represent master regulators of stress signaling and modulate cellular responses and fate during stress and aging. Yet, physiologically relevant mechanisms by which these phosphatases are regulated or orchestrate stress response and lifespan are incompletely understood. Herein, I present two scenarios, mechanical trauma and intestinal aging, both of which involve regulation by phosphatases. Mechanical stimuli initiate adaptive signal transduction pathways, but exceeding cell tolerance for physical stress results in degeneration and death via unclear mechanisms. In the nematode C. elegans, I developed a model to study cellular degeneration in response to mechanical stress caused by blunt force trauma. I identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and itself is dually regulated by its target, KGB-1. KGB-1 both activates VHP-1 via a negative feedback loop and represses via inhibition of a deubiquitinase, MATH-33, affecting proteasomal degradation. Thus, I describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity.
Like stress, aging challenges cell tolerances, instigating death upon inadequacy of homeostatic regulation. Intestinal cells form a vital barrier separating environment from organism. Age impairs intercellular interactions and the cells' capacity to tightly associate within tissues and form an effective barrier necessary for normal systemic function. In particular, the actin cytoskeleton represents a key determinant in maintaining tissue architecture; how age disrupts the actin cytoskeleton, and, in turn, promotes mortality remains unclear. Herein, I show that phosphorylation of ACT-5 compromises C. elegans intestinal barrier integrity and accelerates pathogenesis. Age-related loss of the heat shock transcription factor, HSF-1, disrupts the Jun kinase/Protein Phosphatase I equilibrium, increasing ACT-5 phosphorylation within a troponin-binding site. Phosphorylated ACT-5 accelerates decay of the intestinal terminal web and impairs cell junctions. Therefore, age-associated dysregulation of phosphatase/kinase activity contributes to intestinal dysmorphogenesis and organism death
Understanding and improving inflammatory bowel disease care in 2022: the gut and beyond
Get PDFDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.UT Southwestern--Internal Medicin
Ethics large and small: moral considerations in response to childhood obesity
Get PDFTuesday, March 8, 2022; noon to 1 p.m. (Central Time); via Zoom. "Ethics Large and Small: Moral Considerations in Response to Childhood Obesity". D. Micah Hester, Ph.D., Chair, Department of Medical Humanities and Bioethics, Professor of Medical Humanities and Pediatrics, College of Medicine at the University of Arkansas for Medical Sciences and Clinical Ethicist, Arkansas Children's Hospital.Obesity in the U.S. has been described as an epidemic, and in response to such rhetoric, individuals, healthcare providers, public health officials, even state legislatures, and courts have proposed initiatives or enacted consequences either to encourage better eating habits, discourage poor eating habits, or even punish poor nutritional practices. All these actions raise ethical concerns for public health and individual patient care. This talk will explore a number of these issues and will suggest that certain state-based responses do not merit ethical scrutiny, but individual provider directiveness in regards to nutritional counseling, especially with parents of overweight children, is warranted.UT Southwestern--Program in Ethic
An Examination of GME Funding: A Critical Look at Non-ACGME Surgical Fellowships
No full textThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.BACKGROUND: Since 1997, the Fellowship Council (FC) has evolved into a robust organization that is responsible for the advanced training of nearly half of the U.S. residency graduates entering general surgery practice. While FC fellowships are competitive (55% match rate) and offer outstanding educational experiences, funding is arguably vulnerable as external support has diminished.
OBJECTIVE: The aim of this study was to investigate the current funding models of FC fellowships.
METHODS: Under an IRB-approved protocol, an electronic survey was administered to 167 FC programs with subsequent phone interview follow-ups to collect data on total cost and sources of funding. De-identified data were also obtained via 2020-2021 Foundation for Surgical Fellowships (FSF) grant applications. Means and ranges are reported.
RESULTS: Data were obtained from 59 programs (35% response rate) via the FC survey and 116 programs via FSF applications. The results from the FC and FSF data sets indicated that the average cost to train one fellow per year was USD 107,957 and USD 110,816, respectively. Similar averages were reported for the four components of cost. Programs received an average funding of USD 109,118 and USD 110,816, respectively. Most programs utilized departmental and grants funds. Additionally, 36% (FC data) to 39% (FSF data) of programs indicated that they billed for their fellow, generating USD 74,824 (range USD 15,000-USD 200,000) and USD 33,281 on average (range USD 11,500 - 66,259), respectively. 14% of programs via FC survey reported generating net positive revenue whereas 100% of programs from FSF application declared budget neutral.
CONCLUSIONS: Our results indicated similar findings in support of the overall accuracy of these data. Most programs seemed to rely heavily on subsidies from both internal and external sources, although some programs were able to generate a positive revenue stream. The most notable difference was the revenue amount generated from billing. Programs that generated a positive revenue often billed for fellows. Given the value of these fellowships and the inherent vulnerabilities associated with graduate medical education funding, new alternative grant funding models are encouraged. In addition, standardization of annual cost and funding reports would provide greater insights into funding models
Tap Dance
Get PDFThis work received a Third Place Award in the "Fictional Short Story" category from all literary works submitted in the 2022 On My Own Time show.This work of fiction is loosely based on experiences I had in residency supervising an intern, and wanting to impress my attending
The relationship between socioeconomic status, coronary artery calcium and atherosclerotic cardiovascular disease: the Dallas Heart Study
No full textDetailed formal protocol with illustrations and extensive bibliography.A recording of the protocol presentation is available on UT Southwestern's Mediasite. Note: Access to the video is restricted to authorized UT Southwestern users only.This edition of the UT Southwestern Internal Medicine Grand Rounds features presentations by the six Foster Fellows selected as finalists from the Seventh Annual Donald W. Seldin, M.D. Research Symposium, which was held on April 21, 2022. These Foster Fellows presented work that spanned the breadth and depth of scholarly activity across the department, and at the close of Grand Rounds, one will be selected as the 2022 Seldin Scholar, in honor of Dr. Donald W. Seldin. The Grand Rounds presentation includes additional award presentations recognizing Clinical Vignettes, as well as the Award for Research in Quality and Education at Parkland Hospital and the Social Impact Award.UT Southwestern--Internal MedicineOnline and Simulation Based Cardiac Point of Care Ultrasound Training for Residents: A Randomized Pilot Study / Matthew Almonte --
"Doctor" Badge Intervention to Mitigate Provider Level Risk Associated with Housestaff Role Misrepresentation / Angela Duvalyan --
Risk Prediction for Acute Kidney Injury in Patients Hospitalized with COVID-19: Withstanding Variants over Time / Meredith McAdams --
Clinical Outcomes of Patients with Suspicious (LI-RADS 4) Liver Observations / Kristeen Onyirioha --
Profiling Tau Pathology in Essential Tremor / Nil Saez-Calveras --
The Relationship Between Socioeconomic Status, Coronary Artery Calcium and Atherosclerotic Cardiovascular Disease: The Dallas Heart Study / Taylor Triana