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Shto?
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Amateur division) for the 2023 On My Own Time (OMOT) Art Show.This work is inspired by the time I spent translating for my Grandparents in medical settings. Reflecting on these experiences, I try to comfort and relate to the patients I encounter now in the hospital
STK25 and TAO Regulate Muscle-Specific Transcription and Muscle Function in the Parasitic Flatworm Schistosoma Mansoni
Get PDFSchistosomiasis, a disease caused by parasitic flatworms called schistosomes, affects 240 million people in developing regions, including large parts of Africa, Asia, and South America. In some of these areas, the disease affects over 50% of the population, making Schistosomiasis second only to Malaria in parasite devastation. To look for functionally important schistosome genes, we performed a large-scale RNAi screen in adult Schistosoma mansoni, and discovered 3 genes that produce an identical type of sickness in the worm. Disruption of the genes thousand-and-one kinase (TAO), serine threonine kinase 25 (STK25), or cerebral cavernous malformations 3 (CCM3) by RNAi in these worms produces a rapid and consistent deterioration consisting of detachment from the culture dish, drastic length reduction, selective paralysis in the worm body, and a distinctive "banana"-shaped morphology. Transplantation of stk25(RNAi) or tao(RNAi)- treated worms into a mouse host results in a significant reduction of worm eggs, and associated liver pathology, compared to healthy worm transplantations. RNA sequencing of stk25(RNAi) and tao(RNAi) worms uncovered that not only do both stk25 and tao cause significant transcriptional changes, but those changes are unusually similar, supporting the model that these genes are interacting as part of a signaling pathway in the worm. RNAi-induced transcriptional changes were heavily biased to worm muscle, a clue to explain loss of movement in these worms. By visualizing gene expression as well as muscle structure in whole worms, we concluded that these worms undergo specific loss of gene expression in the muscle cells of the body, but without significant loss of muscle cells or structure. Additionally, we find that schistosome TAO kinase can directly phosphorylate schistosome STK25 in vitro, and that this phosphorylation occurs at an amino acid (T173) which is known to be required for activation of all homologous STK25 kinases in other organisms. Using a yeast 2-hybrid system, we find that schistosome STK25 and CCM3 can physically interact, in agreement with literature reporting this interaction in other organisms. Altogether, our data supports a model that these genes work together in the parasite to control a muscle-specific transcriptional program that is essential for worm health both in culture and in the host
Delineating the Mechanisms Through Which ZNF165 Supports Growth and Survival of Triple-Negative Breast Cancer
Get PDFCancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. The transcription factor ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), was previously identified as essential for the growth and survival of TNBC and sustained transforming growth factor beta (TGFβ) signaling. However, the mechanisms through which ZNF165 functions in this context to regulate both TGFβ signaling and survival were poorly understood. To investigate its mechanism of action, I first sought to determine how ZNF165 interfaces with the TGFβ pathway in TNBC using a combination of genomics and biochemical approaches. I found that ZNF165 associates with SMAD3, a key signal transducing factor in the TGFβ pathway, to modulate transcription of TGFβ-dependent genes and thereby promote growth and survival of human TNBC cells. Importantly, my data demonstrate that through functioning as a cofactor for SMAD3, ZNF165 is able to specify a TGFβ-dependent gene expression program that promotes oncogenic phenotypes while repressing tumor-suppressive functions. In addition, I identified the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. I found that while ZNF446 is bound to chromatin with the ZNF165-SMAD3 complex, TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Moreover, my data also suggest that ZNF165 is SUMOylated by TRIM27 to enhance its protein stability, providing further insight into the mechanisms that regulate ZNF165 activity in TNBC. Together, my findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC
Equity teaching rounds
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
SAM Homeostasis Is Regulated by CFIm-Mediated Splicing of MAT2A
Get PDFS-adenosylmethionine (SAM) is the methyl donor for nearly all cellular methylation events. Cells regulate intracellular SAM levels through intron detention of MAT2A, the only SAM synthetase expressed in most cells. The N6-adenosine methyltransferase METTL16 promotes splicing of the MAT2A detained intron by an unknown mechanism. Using an unbiased CRISPR knock-out screen, we identified CFIm25 (NUDT21) as a regulator of MAT2A intron detention and intracellular SAM levels. CFIm25 is a component of the cleavage factor Im (CFIm) complex that regulates poly(A) site selection, but we show it promotes MAT2A splicing independent of poly(A) site selection. CFIm25-mediated MAT2A splicing induction requires the RS domains of its binding partners, CFIm68 and CFIm59 as well as binding sites in the detained intron and 3´ UTR. These studies uncover mechanisms that regulate MAT2A intron detention and reveal a previously undescribed role for CFIm in splicing and SAM metabolism
The Effects of Chromatin Remodeling and Pseudokinase Activity on Liver Pathophysiology
Get PDFThe liver exhibits a remarkable capability to regenerate itself in the face of injury; however, in the setting of sustained damage, this capability can be overwhelmed and eventually lead to chronic liver diseases such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Although these processes are complex and not completely understood, specific genetic and epigenetic factors that drive aspects of this pathophysiology can shed further light on both how these diseases develop and on how normal, healthy regeneration differs from liver disease. In this body of work, we show that loss of Arid1a, a DNA-binding component of the SWI/SNF chromatin remodeling complex, shifts hepatocyte metabolism to promote lipid accumulation in a manner similar to that seen in non-alcoholic fatty liver disease. We further explore the dynamics of the SWI/SNF complex by examining a mutually exclusive homolog of Arid1a, Arid1b, and provide evidence to suggest that its role is to stabilize the hepatocyte SWI/SNF complex in the absence of Arid1a seen in regeneration and hepatocellular carcinoma. Finally, we harness the power of in vivo CRISPR screening within the liver to identify the pseudokinase STK31 as a positive regulator of hepatocyte proliferation and liver oncogenesis. Our findings underscore the important role that chromatin remodeling has in enforcing hepatocyte identity and functionality as well as allowing for plasticity. Additionally, our work with STK31 highlights the power of in vivo screening within the liver to identify new potential therapeutic targets not only for hepatocellular carcinoma, but other tumor types as well
Demographics, Clinical Presentation, and Outcomes of HIV Infected and Uninfected Patients with Hepatocellular Carcinoma
Get PDFThe 61st Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 31, 2023, 3-6 p.m., D1.600)With highly active antiretroviral therapy (HAART), HIV infected individuals have seen longer survival, which is associated with increased mortality and morbidity from chronic liver diseases (CLD). Patients with HIV are 7 times more likely to develop HCC. To date, the clinical course and outcomes of patients with HIV and HCC is not well defined. We compared the survival of HCC patients with and without HIV infection, and we expected demographic factors, clinical presentation, and treatment patterns to impact survival differently between the two groups.
We performed a retrospective cohort study of HCC patients at two hospitals within the same system in Dallas between January 2010 and June 2022. We excluded patients without a known HIV diagnosis status. Demographics, prognostic measures, tumor characteristics, treatment modalities, and survival were compared between patients with and without HIV infection. Survival curves were generated using Kaplan- Meier plots and compared with the log rank test.
Of the 1,391 patients with HCC, 43 (3.1%) were HIV infected. HIV infected patients were more likely to have Medicare (51% vs 29%; P=0.012) and less likely to be uninsured (0% vs 9.9%; P=0.012). CLD etiologies differed between the groups with HIV infected patients less likely to have alcohol-related liver disease (4.7% vs 17.6%; P=2 (HR 1.331, 95% CI 1.0-1.7), Child Pugh class B (HR 1.278, 95% CI 1.1-1.5), and having multiple lesions at time of diagnosis (HR 1.213, 95% CI 1.1-1.4) were also associated with worse survival. HIV infection was not independently associated with worse survival (HR 1.295, 95% CI .858-1.955).
The relationship between HIV infection and HCC in affecting clinical outcomes remains complex. HIV infected patients present with different underlying liver disease but similar prognostic and tumor characteristics. Overall survival was ultimately found to be similar between HIV infected and uninfected patients with HCC.Southwestern Medical Foundatio
The triumph of Bacchus: the alcohol-associated liver disease epidemic
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
Bayesian Spatial Analysis of High Throughput Sequencing Data
Get PDFThe past decade has witnessed the development and wide use of high-throughput sequencing data in biology. The recent advancement of RNA Sequencing (RNA-Seq) coupled with other molecular technologies such as methylated RNA immunoprecipitation (MeRIP) and spatial barcoding has delivered more specialized platform to investigate certain cellular process and spatial molecular profiling. However, the development of associated analysis tools capable of accommodating the unique features of these new sequencing technologies is still lacking or unsatisfied. For the past few years, I have been devoting to the methodology development of MeRIP-Seq and spatial molecular profiling data. The proposed BaySeqPeak and BOOST-GP methods demonstrated good accuracy, sensitivity and robustness in identifying methylated RNA region and spatial variable genes in both the simulation study and real data analysis
Effects of Alcohol Use on Cognition During Later Adulthood
No full textPages vi-xi are misnumbered as pages iv-ix.Alcohol is one of the most widely used psychoactive substance in the world, yet there are conflicting findings related to its long-term effect on cognition. Some research has identified a U-shaped relationship between alcohol consumption and cognition, while negative relationships have been identified in other studies. Methodological issues, particularly the time at which alcohol consumption was measured relative to when cognition was measured, wide variability in definitions of "moderate" alcohol consumption, and selecting appropriate comparison groups, have made exploring the effects of alcohol on cognition during aging difficult. The current study examined the relationship between drinking at three separate time points (between the ages of 50 and 74) and cognition in older adulthood. Results revealed that the quantity of self-reported drinks over the three time points was a significant predictor of cognition in older adulthood (b=0.001; p0.05). Overall, the results suggest no that there is not a meaningful relationship between alcohol consumption and cognitive functioning in older adulthood in this sample. There were few consistent heavy drinkers (n=71), but a large number of consistent moderate drinkers (n=1,847), although even the moderate drinkers did not consume much alcohol (mean alcohol consumption = 15.3 drinks/month; median alcohol consumption = 5.0 drinks/month). This may have limited the ability to detect clinically meaningful differences. Future studies should rely on more standardized alcohol measures, large, diverse samples, and inclusion of cognitive measures assessing visuospatial abilities and executive functioning, in order to better explore the relationship of alcohol in the aging brain