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Development and Application of Chemoenzymatic Tools to Investigate Site-Specific Protein ADP-Ribosylation
Get PDFHerein I have developed the first technologies to install mono- and poly-ADP-ribosylation at specific sites on synthetic peptides and full-length proteins. Historically, chemical and topological complexities associated with ADP-ribosylation have stymied progress in this area. To overcome this, I have identified enzymes capable of: (i) installing ADP-ribose specific side chain functionalities on synthetic peptides, and (ii) elongating ADP-ribose chains from mono-ADP-ribosylated substrate peptides. These enzymes are highly efficient and promiscuous in regard to substrate peptide amino acid sequence. ADP-ribosylated peptides are compatible with N-terminal and C-terminal protein ligation technologies to afford assembly of homogenous, full-length proteins bearing ADP-ribosylation at user-defined sites. These reagents were then employed to address fundamental questions regarding the structure, function, and regulation of different ADP-ribose:protein linkage types and specific ADP-ribosylation sites on chromatin and chromatin associated proteins. Overall, the work discussed here reveals basic chemical and biological principles of arginine, aspartate, glutamate, and serine ADP-ribosylation and enables new strategies to interrogate the biochemical consequences of this widespread protein modification in human physiology and disease
The role of race in lung function interpretation: a modern view
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.UT Southwestern--Internal Medicin
My First Patient's Final Gift
No full textThe author submitted this entry in the Fictional Short Story category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.Written from the perspective of a first-year medical school, this is a short story about what I imagine the experience of dissecting a cadaver would feel like
Cultural competence in the care of Muslim patients and their families
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
Guarding your gut: understanding colon cancer screening
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
Barriers to Cochlear Implantation
Get PDFThe file named "BALACHANDRA-PRIMARY-2022-1.pdf" is the primary dissertation file. One (1) supplemental file -- i.e., a Microsoft Word document (DOCX) -- is also available and may be viewed individually.INTRODUCTION: Cochlear implantation (CI) is the most effective treatment for profound sensorineural hearing loss, despite the low utilization of CI in the United States. Only about 5-7% of CI-eligible adults pursue CI, for reasons which remain unclear.
OBJECTIVE: Our research has two primary aims: 1) to identify sociodemographic disparities in CI in Texas and explore trends using an all-payer database from 2010-2017; and 2) to investigate patient-reported barriers to, and motivators for, pursuing CI.
METHODS: Aim 1) The publicly available Texas Outpatient Surgical and Radiological Procedure Data was accessed to analyze outpatient CI cases in the entire state of Texas. Variables analyzed include patient age, sex, race/ethnicity, and insurance status. Population data from the American Community Survey were utilized to generate CI utilization rates by patient demographic characteristics. Insurance data was obtained from the Kaiser Family Foundation.
Aim 2) A single-institutional review of CI candidates between December 2010 and December 2018 was performed to identify patients who did not pursue surgery, as well as those who pursued surgery after a delayed time period or at a different institution. A 21-question survey was developed internally, aimed at identifying and ranking patients' concerns regarding surgical risks, adaptation to the CI, time commitment to adapt, costs, loss of residual hearing, and lack of benefit. Current hearing aid usage and familiarity with other CI users were also analyzed. The survey was administered via email or telephone.
RESULTS: Aim 1) 6,158 CI cases were identified during the study period. The number of CI per year nearly doubled from 497 in 2010 to 961 in 2017. The majority of CI recipients were white (59.5%), male (51.9%), and privately insured (47.9%). Patients over 75 demonstrated the greatest increase in the CI rate per 100,000 population, increasing from 4.60 in 2010 to 14.30 in 2017. All racial/ethnic groups noted an increase in the CI per 100,000 population, with white patients demonstrating the highest rate in 2017, at 4.36 CI per 100,000 population. Asian patients had a 502% increase in the CI rate (from 0.42 to 2.53), compared with 87.9%, 84.4%, and 69.2% increases for White, Black, and Hispanic populations, respectively. Medicaid recipients were the only insurance group that did not experience a statistically significant growth from 2010-2017 (3.27 to 3.49, p=0.26).
Aim 2) Fifty-two survey responses were received, comprised of 27 patients who did not pursue CI and 25 patients who did. The most commonly reported barrier was a belief that CI would not significantly improve the ability to communicate, followed by concerns over the post-operative recovery process, risks of surgery, and risks of losing music appreciation. Anesthetic risk and cost were the least important reasons not to pursue CI. The most commonly reported facilitator was a belief that hearing loss was affecting job performance.
CONCLUSIONS: CI became more widespread between 2010-2017; however, vast disparities exist in who benefitted most from this growth in CI. Black and Hispanic populations had lower CI per 100,000 population than their white peers, while patients >65 years of age accounted for the greatest increase in CI. Moreover, the decision not to pursue CI despite eligibility is multifactorial and includes concern for minimal hearing benefit and perioperative risks. These factors should be taken into consideration when counseling patients on CI surgery. Resources should be devoted to promote CI to disadvantaged groups as identified in our research
What Is a Mother?
No full textThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.Written for Mother's Day, this poem is inspired by the various qualities my mom displayed throughout my life
ER-PM Junction Proteins and Their Roles in Regulating Cell Homeostasis and Signaling
No full textPages x-xiii are misnumbered as pages xi-xiv, page xiv is misnumbered as page 1, and pages 1-96 are misnumbered as pages 2-97.Homeostatic regulation of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2) in receptor-stimulated cells is a critical step in the phosphoinositide cycle (PI-Cycle). This regulatory feedback mechanism is mediated by the lipid transfer protein (LTP) Nir2. Nir2 is dynamically recruited to endoplasmic reticulum-plasma membrane (ER-PM) junctions to facilitate replenishment of PM PIP2 hydrolyzed during receptor-mediated signaling. However, our knowledge regarding the activation and sustainment of Nir2-mediated replenishment of PM PIP2 is limited. The work presented in this dissertation, describes the functions of Nir1, a previously unidentified ER-PM junction tether and regulator of Nir2 and PM PIP2 replenishment. Manipulation of Nir1 levels in live cells via overexpression or transient knockdown drives remodeling of ER-PM junction properties. Additionally, Nir1 potentiates Nir2 targeting to ER-PM junctions during receptor-mediated signaling and is required for efficient PM PIP2 replenishment. Importantly, I found that Nir1 localization at ER-PM junctions is a requirement for Nir2 potentiation, highlighting the importance of this subcellular site in regulating the PI-Cycle. The Live-cell and biochemical analysis revealed that Nir1 interacts with Nir2 via a region between the FFAT motif and the DDHD domain. Lastly, I describe a novel localization of Nir proteins near the nucleus and demonstrate the requirement of the minimally characterized domain, DDHD. In summary, the results from these studies identify Nir1 as a novel ER-PM junction tether as well as a positive regulator of the PI-Cycle and of the LTP, Nir2. My observations of Nir proteins near the nucleus implicate a novel subcellular site for phosphoinositide metabolic regulation beyond ER-PM junctions
Modulation of Nocturnin Phosphatase Activity through the Disordered Amino Terminus
Get PDFThe endogenous circadian clock controls the rhythmicity of behavioral and physiological processes and this is entrained by the daily fluctuations in light and dark. Nocturnin (Noct) is a rhythmically expressed gene regulated by the circadian clock that belongs to the CCR4 family of endonuclease-exonuclease-phosphatase (EEP) enzymes. Its expression is induced by acute stimuli and loss of Nocturnin (Noct-/-) in mice results in resistance to diet-induced obesity on a high fat diet and confers a protective effect to oxidative stress in HEK cells. Modeling of full-length Nocturnin reveals a partially structured amino terminus that is disparate from its CCR4 family members. I show that Nocturnin functions as a phosphatase, catalyzing the removal of the 2′-phosphate from NADP(H). High sequence conservation of the leucine zipper (LZ)-like motif, the only structural element in the amino terminus, highlights the potential importance of this domain in modulating phosphatase activity. I use in vitro biochemical and biophysical techniques to demonstrate that the amino terminus and the LZ-like domain are necessary for preserving the active site cleft in an optimal conformation to promote efficient turnover of the substrate. This modulation occurs in cis and is additionally pivotal in maintaining the stability and conformational integrity of the enzyme. These new findings suggest an additional layer of modulating the activity of Nocturnin in addition to its rhythmicity in order to provide fine-tuned control over cellular levels of NADPH. This lays the essential groundwork necessary to further understand the role of the partially structured amino terminus in metabolism and the oxidative stress response through regulation of NADP(H) and NAD(H) levels
Barriers to population-wide lipid management and new tools for success
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