Structures and Mechanisms of Lysosomal Transporters

Lysosomal membrane transporters are indispensable for maintaining lysosomal homeostasis and proper function. Indeed, mutations in these key proteins can lead to debilitating disorders known as lysosomal storage diseases. Cystinosin and Sialin are two such transporters. Both proteins utilize the low pH environment to transport their main substrates of interest from the lumen to the cytosol where they can be reused by the cell. Understanding how these proteins work at an atomic level can help us understand their overall function, the roles they play in lysosomal signaling pathways, and may enable the future development of therapeutics to treat their associated disorders. Mutations in Cystinosin cause Cystinosis, a neurodegenerative disorder that occurs when Cystinosin's substrate, the dimeric form of cysteine called cystine, builds up in the lysosome. While there currently is a treatment for this disorder, how mutations disrupt this transport and how the protein utilizes the proton gradient remain a mystery. Similarly, Sialin causes a variety of free sialic acid storage diseases that result in developmental delays as well as neurodegeneration. Unlike Cystinosis, there is currently no approved treatment for these disorders. Like Cystinosin, the structure and mechanism of transport remain unknown. The work presented herein reveals the cryo-EM structures of Cystinosin and Sialin at near atomic level resolution. These structures, captured in both cytosol- and lumen-open conformations as well as substrate bound states, reveal not only the mechanisms of conformational changes but also the residues involved in the substrate binding pocket(s). Along with the accompanying functional assays, I demonstrate that the majority of disease-causing mutations in both Cystinosin and Sialin center around their ability to bind their respective substrates. Additionally, I reveal the potential proton sensors of both proteins involved in their substrate symport. In the case of Sialin, I also hypothesize that its proton sensor could potentially double as a membrane potential sensor for its transport of neurotransmitters into synaptic vesicles. This work paves the way for understanding the greater PQ-loop family (Cystinosin) and SLC17 family (Sialin) of transporters. It also builds a foundation upon which future therapeutics can be designed to treat their associated disorders

From Stem Cells to Blastoids: Unraveling the Mechanisms of Early Embryonic Development and Gene Silencing

Understanding the mechanisms of early embryonic development is essential for understanding the origins of aging and disease. Advancements in the culture of embryonic stem cells have opened new avenues for modeling critical timepoints of early development in vitro, such as blastocyst formation, implantation, and gastrulation. The work presented here shows the development of stem cell derived blastocyst like structures, termed blastoids, from pluripotent stem cell cultures in both humans and animals. Blastoids have increased our understanding of the signaling, genetic and epigenetic requirements for the formation of the early embryo. Finally, our work helps to uncover the critical epigenetic interplay that happens in the epiblast of the blastocyst before and after implantation, by using naïve and primed embryonic stem cells to respectively model these stages. We show that TASOR (transcription activator suppressor), part of the Human Silencing Hub (HUSH) complex, is a co-transcriptional platform for epigenetic and epitranscriptomic silencing. We show how the H3K9me3 deposition in naïve cells is essential for the proper establishment of long-term silencing via DNA methylation in primed or differentiated cells. Moreover, our work uncovers an innate immune checkpoint that is activated upon the exit of naïve pluripotency against endogenous retroviral LINE-1 elements and repeats. Overall, this dissertation provides significant insights into the genetic, epigenetic, immunological and signaling mechanisms of the early embryo, offering new perspectives on the intricate biological processes that govern the earliest stage of mammalian life

Pre- and Postsynaptic MEF2C Promote Experience-Dependent, Input-Specific Development of Local Cortical Excitatory Synapses

Complex and specific neocortical circuits mature postnatally through a combination of genetic factors and sensory experience-driven neural activity. Experience- and activity-dependent transcriptional factor activation is a candidate mechanism for the development and refinement of these circuits. Synapses form the basis of neurons. Robust synapse proliferation during development is closely followed by experience-dependent pruning and modification to preserve and strengthen circuits. Neurodevelopmental disorders, including Autism Spectrum Disorder, are characterized by synaptic and circuit properties that give rise to behavioral and cognitive deficits and symptoms. Transcription factor Myocyte Enhancer Factor 2 C (MEF2C) is highly expressed in the cortex during development and into adulthood and has been identified as a regulator of synaptic strength and transmission in a sensory experience-dependent manner. MEF2C has been shown to function in both repressive and activator roles in postsynaptic compartments; however, little is known about presynaptic regulation by MEF2C. Additionally, the mechanisms by which MEF2C regulates synapses in an activity- and input-specific manner are still largely unknown. My work provides evidence that the activity-dependent transcription factor MEF2C is required for experience-dependent development of inputs from Layer (L) 4 to L2/3 neurons in the mouse primary somatosensory barrel cortex (S1). Importantly, MEF2C is required in both presynaptic L4 and postsynaptic L2/3 neurons during the first two postnatal weeks for L4–L2/3 synapse development. MEF2C plays a local L4 input-specific role in postsynaptic L2/3 cells through the mechanism of reduced probability of presynaptic neurotransmitter release for L4 presynaptic MEF2C. Constitutively active MEF2C-VP16 can rescue the lack of whisker sensory input but does not rescue the loss of MEF2C in presynaptic neurons. Together, these results suggest that the activity-dependent transcriptional activation of MEF2C promotes the development of L4–L2/3 synapses. MEF2C is necessary for the activity-dependent expression of genes encoding pre-, post-, and transsynaptic proteins in cortical neurons. I examined the protein tyrosine kinase PYK2, which was found to be elevated in the cortex of MEF2C KO mice but appeared to be insufficient in affecting or regulating synaptic strength, like MEF2C. Altogether, this work provides insights into the mechanisms of MEF2C-mediatied, experience-dependent development of specific cortical circuits

Visual Quality After LASIK: A Comparative Study of Topography-Guided and Wavefront-Optimized Treatments

The 64th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 27, 2026, 3-6 p.m., D1.700)PURPOSE: Two major methods of LASIK surgery, Topography-guided LASIK (TG-LASIK) and Wavefront-optimized LASIK (WFO-LASIK), use different optimization approaches. Both have been shown to be safe procedures that improve visual outcomes. The aim of this study is to investigate whether aberrations and visual disturbances differ significantly between the two LASIK treatment methods. PATIENTS AND METHODS: This was a retrospective clinical study that utilized chart review of patients who underwent TG-LASIK or WFO-LASIK at Laser Center for Vision Care at UT Southwestern between 2010 and 2024. A total of 161 eyes were analyzed, with 58 undergoing TG-LASIK and 103 undergoing WFO-LASIK. The measured outcomes included best-corrected visual acuity (BCVA), higher-order aberrations (HOAs), and self-reported visual symptoms. RESULTS: At 1-month post-op, TG-LASIK resulted in significantly better visual improvement compared to WFO-LASIK. While both treatment methods showed postoperative improvement in visual acuity, TG-LASIK was associated with more favorable 1-month visual outcomes. The WFO group had a higher percentage of eyes associated with reported postoperative visual symptoms or complications when compared to the TG group (52.5% vs. 29.3%, respectively; p = 0.0077). Ocular dryness was the most commonly reported symptom in both groups. CONCLUSIONS: TG-LASIK was found to have better 1-month visual outcomes and fewer postoperative symptoms compared to WFO-LASIK. Although both methods remain safe and effective options, TG-LASIK may provide better short-term improvements in visual quality and patient comfort in appropriately selected cases.Southwestern Medical Foundatio

Mechanistic Basis of Skeletal Muscle Wasting Diseases

Skeletal muscle is the largest tissue in the human body by biomass and it is essential for life. Impaired skeletal muscle function can negatively impact one's quality of life but in the case of diseases like cancer cachexia, it can directly contribute to death of patients. Skeletal muscle wasting is a key feature of many monogenic muscle diseases such as Duchenne muscular dystrophy (DMD) and Emery-Dreifuss muscular dystrophy (EDMD) but also more complex conditions such as cancer cachexia, starvation, and various neuromuscular diseases. Throughout this thesis, I focus on two muscle wasting diseases, cancer cachexia and EDMD. While these diseases have been studied for decades, with the disease-causing genes being identified for EDMD, the mechanistic basis has not been elucidated for either disease. Here we propose that downregulation of the nuclear envelope protein, Net39, contributes to EDMD pathogenesis. Adult deletion of Net39 in mice recapitulates many of the key features of EDMD, including nuclear envelope deformations, dysregulated gene expression, altered metabolism, and muscle wasting. Mechanistically, Net39 protects myonuclear envelopes from mechanical stretch and nuclear envelopes deficient of Net39 are structurally compromised, leading to DNA damage. Cancer cachexia on the other hand, is a highly prevalent and systemic wasting condition characterized by skeletal muscle wasting. We profiled the molecular changes at play in mouse and human cachexic muscle at single nuclear resolution, identifying the conserved activation of a denervation gene program. Mechanistically, we discovered that myogenin regulates myostatin during cancer cachexia and the inhibition of myostatin via AAV-Follistatin gene therapy rescues cancer cachexia and prolongs survival in preclinical models of cancer. Overall, our findings here highlight the importance of Net39 to EDMD pathogenesis and the myogenin-myostatin axis to cancer cachexia-induced muscle atrophy

When GERD is more than just heartburn: how reflux impacts airway and lung disease

Detailed 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

Evaluating Near-Infrared Imaging as a Screening Tool for Diabetic Retinopathy

The 64th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 27, 2026, 3-6 p.m., D1.700)BACKGROUND/HYPOTHESIS: Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and early detection enables timely intervention. Optical coherence tomography (OCT) imaging for staging and evaluation of DR is often acquired alongside near-infrared (NIR) reflectance imaging, though NIR is rarely used. We hypothesized that NIR will detect subtle DR changes earlier than OCT and show greater concordance with the clinician's exam-based grading, particularly in mild or subclinical DR stages. METHODS: Charts from 6/2020-6/2025 of adults with diabetes who underwent same-day macula-centered OCT and NIR imaging were screened, excluding eyes treated with anti-VEGF agents for macular edema within the past 12 months. Eyes were excluded for poor quality (n=70), miscoding (n=173), media opacity (n=13), confounding disease/treatment (n=64), or stratum quota being met (n=12,567). Thirty-three mild, moderate, and severe DR eyes and 102 diabetic eyes without DR were analyzed. Two masked retina fellows graded presence of DR via REDCap; 93 discrepancies were adjudicated by a senior specialist. The clinical exam DR grade served as reference. Agreement was assessed with Cohen's κ (95% CI), paired modality comparisons with McNemar tests, and accuracy modeled by generalized estimating equations (GEE). RESULTS: NIR showed higher inter-grader agreement than OCT (NIR κ=0.585, 95% CI 0.461-0.709 vs OCT κ=0.239, 95% CI 0.138-0.340; difference z=4.25, p=2.2×10⁻⁵). Of 204 eyes, 9 NIR and 1 OCT images were ungradable. Among gradable eyes, accuracy was 80.6% for NIR and 75.2% for OCT (Δ = +5.4%, p = 0.206). For NIR and OCT, sensitivity was respectively 67.0% vs 52.4% (Δ=+14.6%, p=0.016) and specificity was respectively 94.0% vs 99.0% (Δ=-5.0%, p=0.014). When stratified by clinical grade, NIR outperformed OCT for detecting mild DR (19/33 = 0.58, 95 % CI 0.41-0.73 vs 9/34 = 0.27, 0.15-0.43); discordant cases favored NIR, with 12 eyes positive on NIR and 2 positive on OCT (McNemar p = 0.008). Performance was similar in moderate DR (NIR 21/31=0.68 vs OCT 21/34=0.62; p=0.48) and severe DR (NIR 24/31=0.77 vs OCT 24/34=0.71; p=0.56). CONCLUSIONS: NIR was more sensitive than OCT for detecting DR, particularly in mild disease, with higher grader agreement. Incorporating NIR review alongside OCT in the clinical DR evaluation workflow may improve early DR detection, though external validation is warranted.Southwestern Medical Foundatio

Not just drugs: clinical ethics and the health-system pharmacist

Tuesday, February 10, 2026; noon to 1 p.m. (Central Time); via Zoom. "Not Just Drugs: Clinical Ethics and The Health-System Pharmacist". Linda B. Uchal, Pharm.D., M.S., BCPS, BCCCP, Clinical Pharmacist - Critical Care, The University of Texas Southwestern Medical Center.Health-system pharmacists have taken on a more visible team-based role with providers to serve the needs of patients and their families. Being a part of team-based patient care combined with complex drug therapy choices and issues involving medication access and payment make understanding the values of the patient, members of the health care team, and the organization necessary to inform decisions that provide effective and ethical patient care. The ability to process the nuances found in ethical dilemmas can be essential for professional success and resilience, and at times as important as the science and pharmacotherapy. Although universities, organizations, and employers have begun to reflect the importance of this more human-values side of pharmacy practice, there needs to be an increase in systems and educational opportunities to support clinical ethics decision making for health-system pharmacists.UT Southwestern--Program in Ethic

Preoperative Brain MRI Does Not Reduce Neurologic Injury in Neonates Undergoing Cardiac Surgery

The 64th Annual Medical Student Research Forum at UT Southwestern Medical Center (Tuesday, January 27, 2026, 3-6 p.m., D1.700)BACKGROUND: Neonates with congenital heart disease (CHD) are vulnerable to central nervous system (CNS) injury, and cardiac surgery with cardiopulmonary bypass (CPB) adds further risk. Since 2017, our institution has implemented a routine preoperative brain MRI screening protocol to identify unrecognized CNS injury that might alter the timing of surgical intervention. This study evaluates whether MRI findings altered surgical timing or impacted postoperative CNS outcomes. METHODS: We retrospectively reviewed 397 neonates with CHD who underwent surgery with CPB within 30 days of life (2017-2025). Patients were grouped by whether they received preoperative MRI (pre-MRI vs. no-MRI). Clinical, imaging, and surgical data were analyzed using chi-square, Fisher's exact, and two-sample t-tests, with the primary outcomes being changes in surgical timing and postoperative CNS injury. RESULTS: Of 397 patients, 339 (85%) had preoperative brain MRI. Patients who did not receive MRI were more likely to present with emergent or salvage-level acuity, including emergent (no-MRI: 21% vs. pre-MRI: 5%), salvage (9% vs. 0%), and ECMO-supported (3% vs. 0%) cases (all p ≤ 0.02). These patients were also more likely to have diagnoses associated with hemodynamic instability such as obstructed total anomalous pulmonary venous return (no-MRI: 34% vs. pre-MRI: 3%, p=0.0001), likely precluding the opportunity for imaging prior to surgery. Preoperative MRI detected abnormalities in 47% of cases; however, only two patients (0.6%) had surgical delays due to low-grade screening MRI findings (grade II IVH and large cephalohematoma). Surgery was delayed by two weeks and then proceeded uneventfully for both. Postoperative neurologic outcomes were similar between groups (seizure, stroke, hemorrhage; all p>0.05). CONCLUSION: Our preoperative brain MRI screening protocol revealed that nearly half of neonates with CHD harbor abnormal findings. However, surgical timing was rarely influenced as only two patients (0.6%) experienced a documented change in surgical management out of an abundance of caution due to low-grade MRI findings. Additionally, preoperative brain MRI did not reduce incidence of postoperative CNS injury, with similar rates of seizure, stroke, or hemorrhage observed between groups. Nonetheless, preoperative MRI may serve an important role in multidisciplinary care by guiding neurodevelopmental counseling, establishing a baseline for longitudinal follow-up, and assisting in the interpretation of postoperative events.Southwestern Medical Foundatio

The Role of Target-Directed MicroRNA Degradation in Mammalian Development

Pages vi-xvi are misnumbered as pages vii-xvii.MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. In animals, miRNAs canonically bind to partially complementary sites in messenger RNA 3′ untranslated regions, resulting in target repression. However, specialized targets, typically exhibiting extensive complementarity to the miRNA, can invert the regulatory logic and trigger degradation of the miRNA. Although this pathway, known as target-directed miRNA degradation (TDMD), has emerged as a potent mechanism of controlling miRNA levels, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of ZSWIM8 resulted in developmental defects in heart and lung, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD and greatly expanded the known catalog of miRNAs regulated by this pathway. These experiments also uncovered novel features of TDMD-regulated miRNAs, including their enrichment in co-transcribed clusters and examples in which TDMD underlies 'arm switching', a phenomenon wherein the dominant strand of a miRNA precursor changes in different tissues or conditions. Importantly, deletion of two TDMD-regulated miRNAs, miR-322 and miR-503, rescued growth of Zswim8 null embryos, directly implicating the TDMD pathway as a regulator of mammalian body size. Together, these data reveal the broad landscape of TDMD in mammals and demonstrate that regulation of miRNA abundance by this pathway is essential for normal mammalian development