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Training through a Novel Community-Engaged Research Project to Reduce Pregnancy-Associated Morbidity and Mortality from Maternal Sepsis in New York City
Get PDFThe 62nd Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 30, 2024, 3-6 p.m., D1.700 Lecture Hall)Maternal sepsis is the second-leading cause of maternal mortality in the U.S., with a disproportionate impact among racial and ethnic minorities. Although maternal sepsis is largely preventable, there remains little evidence concerning the management of risk factors to ensure safe and equitable maternal care during delivery and transition to postpartum. The EnCoRe MoMS study (Engaging Communities to Reduce Morbidity from Maternal Sepsis) is a comprehensive, community-engaged project focused on reducing pregnancy-associated sepsis risk and promoting maternal health equity in NYC. Community stakeholders are integrated in the community research design process through the Community Organization Leadership Advisory Board (CoLAB).
I aimed to contribute to the qualitative portion of the ongoing EnCoRe MoMS study to better understand how the social determinants of health impact the lived experiences of patients and how qualitative interviewing can uncover specific barriers and proposed solutions that may be implemented across the pregnancy continuum. We developed an efficient workflow for the recruitment, consent, and enrollment of patients, then conducted qualitative in-depth interviews (IDIs) with postpartum patients and community focus group discussions (FGDs). Major themes explored during IDIs included prenatal and labor/delivery experiences, facilitators/barriers to accessing quality maternal care, respectful care, community-based resources and solutions, etc. (see table). Ultimately, qualitative data collection through IDIs and the FGD allowed us to observe the lived experiences of patients at high risk of pregnancy and postpartum complications, including sepsis.Southwestern Medical Foundatio
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Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.A dystopian vision that came to mind while running around White Rock Lake
Breaking barriers: pioneering home dialysis for undocumented immigrants
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
Colonocyte-Derived Lactate Promotes Enterobacteriaceae Fitness During Non-Infectious Colitis
Get PDFThe interface of the gut microbiota and the host intestine presents ample opportunities for interactions between host and microbe. In homeostatic conditions, these interactions are often beneficial, such as exchange of metabolites or resistance to gastrointestinal pathogens. In disease, however, the perturbation of these complex interactions can exacerbate pathogenesis. In this study, we examine the mechanisms promoting the disruption of normal host-microbe interactions after perturbances induced by helminth infection, antibiotics, and non-infectious colitis. We specifically probe the contribution of metabolism by members of the Enterobacteriaceae family of bacteria, a group known to commonly outgrow during intestinal inflammation. In the example of non-infectious colitis, we further explore metabolic interactions between host and microbe by manipulating host factors that produce metabolites which can be used by the gut microbiota.
In our studies with the murine intestinal helminth parasite H. polygyrus, we found that helminth infection exacerbated colitis-associated and antibiotic-associated gut microbiota dysbiosis and worsened disease severity of chemically-induced murine colitis. Though we did not identify the molecular mechanisms underlying the helminth-associated exacerbation, we further explored how Enterobacteriaceae metabolism contributes generally to dysbiosis associated with antibiotic treatment and non-infectious colitis.
Using comparative metagenomics, we observed that microbial lactate utilization is elevated during non-infectious chemically-induced colitis. We recapitulated these findings in a genetic model of colitis and found that lactate utilization via the respiratory lactate dehydrogenase LldD enhanced E. coli fitness during intestinal inflammation. We then were able to separate the contributing factors of dysbiosis and inflammation by administering either the antibiotic streptomycin, a low dose of dextran sulfate sodium (DSS), or both together. In this way, we demonstrated that both inflammation and dysbiosis together were required to induce a maximal production of lactate and for E. coli to utilize lactate. With a genetic mouse model lacking lactate dehydrogenase subunit A (LDHA, encoded by Ldha) in its intestinal epithelium, we illustrated that epithelial-derived lactate contributes to the accumulation of lactate during non-infectious colitis, and that epithelial-produced lactate is utilized by the gastrointestinal pathogen Salmonella enterica subspecies Typhimurium during Salmonella infection, another model of intestinal inflammation accompanied by dysbiosis.
In all, this study illustrates how metabolic changes in the intestinal epithelium can support the fitness of Enterobacteriaceae during intestinal inflammation and dysbiosis
Combining Chemical Biology and Forward Genetics to Identify the Target of Anticancer Small Molecules
No full textOxaboroles exhibit diverse biological activity, including antimalarial and anti-parasitic activity. A benzoxaborole compound was found to exhibit potent anticancer activity, and my work discovered the anticancer mechanism of this compound. To tackle this question, two approaches were employed: chemical biology and forward genetics. The chemical biology approach revealed several binding partners of unknown consequences, but no clear cytotoxic targets. In the forward genetics approach, drug-resistant clones were generated in a mutagenic colorectal cancer cell line. Whole exome sequencing revealed mutations in CPSF3, a pre-mRNA 3'-end-processing endonuclease. Knock-in CRISPR/Cas9 experiments recapitulated resistance to the compound, increasing confidence that CPSF3 is the direct target of the benzoxaboroles. Recombinant CPSF3 initially appeared to cleave pre-mRNA in vitro, but non-specific RNAse activity made it difficult to interpret results. Click chemistry was employed to demonstrate direct binding of benzoxaboroles to CPSF3; competition experiments using this method served as evidence of a structure-activity relationship between the benzoxaboroles' CPSF3 binding and biological activity. Finally, transcription analyses show that CPSF3 inhibition by the benzoxaboroles results in mRNA read-through, and that this inhibition is significantly milder in clones exhibiting CPSF3 mutations. Overall, my work demonstrates that the anticancer benzoxaboroles cause cell death due to mRNA read-through induced by CPSF3 inhibition
This Wondrous World
No full textThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.As a chaplain, we often share in others' experience most difficult experiences. So, I wanted to reflect the beauty and wonder in the interconnectedness of the natural world all around us. And in honoring this beauty, we can find some peace and hope
Optimizing Glucose Meter Downloads at Parkland Diabetes Clinic
Get PDFBACKGROUND: Diabetes is a common chronic condition that has vast health and economic consequences. Diabetes requires constant monitoring and attention to various metabolic variables. Self-monitoring of blood glucose (SMBG) levels has been shown to reduce microvascular and macrovascular disease complications.
LOCAL PROBLEM: The Parkland Diabetes Clinic (PDC) encourages patients to take an active role in their health through SMBG, which requires them to check their blood sugar at home and then share this data with their provider to create personalized treatment plans. Currently, only about 50% of patients at this clinic bring their meter to their appointments. Thus, the provider struggles to provide personalized, effective care due to lack of blood sugar history.
METHODS: This project began by obtaining a benchmark for the current percentage of patients at the PDC that bring their glucose meters to their appointments. Provider and patient surveys were created to better understand beliefs and habits regarding SMBG and utility of bringing glucometers to clinic appointments. The survey results were obtained and analyzed.
PLANNED OR ACTUAL INTERVENTIONS: The intervention implemented for this project was determined based on analysis of the survey results as well as discussion with clinic staff and providers. A staff education session was conducted every 3 months during the intervention period and small glucometer messaging reminder posters were hung to improve communication between staff/providers and patients. The percentage of patients that brought their glucometers improved from 50.71% to 57.76%. This showed a statistically significantly increase following the intervention period, indicating a successful and reproducible intervention
Cohesin Promotes the Myelination Transcriptional Program in Oligodendrocytes
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.The cohesin complex is crucial for sister-chromatid cohesion and chromatin spatial organization in the interphase nucleus. Cohesin-extruded DNA loops have regulatory functions in gene expression. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathies. The vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. STAG1-cohesin and STAG2-cohesin are redundant in sister-chromatid cohesion, but appear to exert specific functions in gene regulation. How they achieve their functions in gene expression is poorly understood. I characterized the outcomes of Stag2 loss in the mouse nervous system. Conditional knockout (CKO) of Stag2 in the nervous system causes severe growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Expression profiling reveals that myelination-related genes are downregulated in oligodendrocytes of Stag2 CKO mice. Chromatin conformational capture experiments (Hi-C) reveal that Stag2-deficient oligodendrocytes contain fewer DNA loops than wild-type cells do. In particular, promoter-anchored DNA loops at downregulated genes are significantly reduced by Stag2 loss. Interestingly, downregulated genes exhibit promoter-anchored "stripes", indicative of strong loop extrusion. We propose that STAG2-cohesin generated promoter-anchored loops at myelination-promoting genes are critical for the proper gene expression during oligodendrocyte differentiation and brain development. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanism by which cohesin regulates transcription
Bird in a Cage
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This was inspired from a watching a beautiful bird in cage, looking happy, singing, dancing, amusing people, yet no freedom. Poem was inspired when I saw similarity in lives of people, who are living life yet like this bird oppressed with no free will
Elucidating the Secreted Bacterial Kinome
Get PDFPages vi-x are misnumbered as pages v-ix.In the post-genomic era, millions of amino acid sequences have been acquired and revealed a remarkable diversity among protein families. This is especially apparent in pathogenic species where host and pathogen participate in an intense evolutionary arms race, and horizontal gene transfer is common. We have taken a bioinformatic approach to identify and characterize distant members of the protein kinase superfamily that share little sequence similarity, yet retain a kinase fold, and possibly catalytic activity. Using this approach, we identified the uncharacterized HopBF1and MavQ families of bacterial type III and type IV secretion system effectors, respectively, as remote members of the eukaryotic protein kinase superfamily. We demonstrate that the HopBF1 kinases are eukaryotic-specific HSP90 kinases. HopBF1 phosphorylates HSP90 on a strictly conserved serine that potently inactivates its ATPase activity, and inactivation by phosphorylation prevents the maturation or folding of various HSP90 clients, including immune receptors necessary for the activation of the hypersensitive response in plants. Consequently, HopBF1 kinase activity is sufficient to induce severe disease symptoms in plants infected with the bacterial plant pathogen, Pseudomonas syringae. Moreover, we show that MavQ is a phosphatidylinositol (PI) 3-kinase required for full Legionella virulence in a eukaryotic host. MavQ and the Legionella PI 3-phosphatase SidP drive rapid PI 3-phosphate turnover on the ER and spontaneously form traveling waves that spread along ER subdomains and induce vesicle/tubule budding. Our results reveal a novel mechanism by which self-organizing bacterial effectors remodel host cellular membranes for survival and uncover a family of bacterial effector kinases which act to compromise the host immune response through a "betrayal-like" mechanism