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Molecular Dissection of Bsc2: A Novel Negative Regulator of Triglyceride Lipolysis for a Lipid Droplet Subpopulation
Get PDFEukaryotic cells store lipids in the form of triglyceride (TG) and sterol-ester (SE) in cytoplasmic organelles called lipid droplets (LDs). Distinct pools of LDs with unique surface proteomes exist in cells, but a pervasive question is how proteins localize to and convey functions to specific LD subsets. Here, we show the yeast protein Bsc2 localizes to a specific subset of TG-containing LDs, and reveal it negatively regulates TG lipolysis. Mechanistically, Bsc2 LD targeting requires TG, and LD targeting is mediated by specific N-terminal hydrophobic regions (HRs) sufficient for Bsc2 function. Molecular dynamics simulations reveal these Bsc2 HRs interact extensively with TG on modeled LDs, and adopt a specific conformation on TG-rich LDs versus SE-rich LDs or a modeled ER bilayer. Bsc2-deficient yeast display no defect in LD biogenesis, but exhibit enhanced TG lipolysis dependent on the major TG lipase Tgl3. Remarkably, over-expression of Bsc2, but not LD protein Pln1, causes TG accumulation without altering SE levels. Finally, we find that Bsc2-deficient cells display altered LD accumulation during stationary phase growth. We propose that Bsc2 is a novel regulator of TG lipolysis that localizes to a subset of TG-enriched LDs and locally regulates TG lipolysis
Bynar
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.Bynar was a cross between an old Star Trek episode and my experience with medicolegal consulting, where yin or yang were the only possible answers. James Berry is a professor and Vice-Chair in the Department of Anesthesiology and Pain Management at UT Southwestern. He serves as the Section Editor of "Mind to Mind", a creative writing section of the journal "Anesthesiology". His work has been published in the journals "Anesthesiology" and "Chest", as well as in online poetry venues
Who Gets Sent?
Get PDFThe author submitted this entry in the AI Literature category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This work received a First Place Award in the "AI Literature" category in the 2024 On My Own Time show.This piece was inspired by all those drafted to fight and die in wars that could have been avoided. I used AI assistance for language and editing
Bioethics and COVID-19: lessons for a post-pandemic future
Get PDF[Note: The slide presentation is not available from this event.] Tuesday, March 12, 2024; noon to 1 p.m. (Central Time); Room NB2.100A or via Zoom. "Bioethics and COVID-19: Lessons for a Post-Pandemic Future". Rebecca Weintraub Brendel, M.D., J.D.; Director of the Center for Bioethics and Associate Professor of Psychiatry at Harvard Medical School; Director of Law and Ethics at the Center for Law, Brain, and Behavior in the Department of Psychiatry at Massachusetts General Hospital; and Immediate Past-President of the American Psychiatric Association.[Note: The slide presentation is not available from this event.] The COVID-19 pandemic presented a critical need for bioethics engagement as the U.S. (and the world) faced the stark reality that the demand for critical care resources would exceed supply. This session begins by reviewing general approaches to bioethical challenges through an overview of major philosophical approaches with attention to Beauchamp and Childress' (Four) Principles of Biomedical Ethics. Using the COVID-19 pandemic as a paradigm, it will explore the successes and lessons learned from the work of bioethics in the pandemic context. The experience of COVID-19 and the disparities laid bare will serve as an introduction to a variety of lenses, strategies, and opportunities through which bioethics can strive to chart a path forward to achieve health care justice in its broadest forms. The presentation concludes with practical guidance regarding both identifying ethical challenges and approaches in health care generally and candidate opportunities for progress in the future.UT Southwestern--Program in Ethic
Munc18-1 Is a Master Orchestrator of Synaptic SNARE Assembly
Get PDFPages 114-185 are misnumbered as pages 115-186.Neurotransmitters are released by tightly controlled synaptic vesicle exocytosis at the active zone of presynaptic nerve terminals. This process requires primed fusion-competent vesicles and coordinated calcium-secretion coupling, and all these steps are governed by a sophisticated protein apparatus. SNAREs and Munc18-1 are the core components of this apparatus: SNAREs form SNARE complexes that bridge the vesicle and plasma membranes and Munc18-1 coordinates SNARE assembly. Productive formation of SNARE complexes is topologically complicated and requires overcoming multiple energy barriers. This work elucidates distinctive molecular mechanisms of how Munc18-1 orchestrates SNARE assembly.
Reproducing the steps that lead to neuronal exocytosis with purified proteins and synthetic lipid vesicles has become an irreplaceable tool to decipher mechanistic details underlying synaptic membrane fusion. In one project, I created a new, much slower system by reconstituting a limited number of SNAREs. This new tool not only allowed to study the activity of the calcium sensor, synaptotagmin-1, showing its stimulatory function, but also provided a way to control the number of SNARE complexes. The latter is important as emerging evidence suggests that the number of primed SNARE complexes in neurons is small. My study shows that liposome fusion with few SNAREs requires Munc18-1, synaptotagmin-1, and Munc13-1. While the requirement of Munc13-1 for synaptic fusion can be partially bypassed by SNARE or Munc18-1 mutations, the absence of Munc18-1 has not been rescued by any means so far. In my next project, I elucidated the fundamental mechanism that completely prevents synaptic vesicle fusion unless Munc18-1 is present. Using fluorescence and nuclear resonance spectroscopy, I showed that another protein, αSNAP, completely blocks SNARE-dependent liposome fusion through diverse interactions with SNAREs and that such inhibition can only be overcome by Munc18-1 upon binding to closed syntaxin-1, which in turns initiates SNARE assembly. My third study described another mechanism underlying the essential role of Munc18-1 in SNARE assembly. I solved cryo-electron microscope structures of Munc18-1 bound simultaneously to its two cognate SNAREs, showing structural details of how Munc18-1 organizes formation of productive SNARE complexes. Overall, I described multiple mechanisms of how Munc18-1 functions at virtually every step of SNARE assembly
Choice of Anesthetic Induction Drugs for Tracheal Intubation in Critically Ill Patients and Impact on Outcomes: A Systematic Review
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)BACKGROUND: Airway management in critically ill patients can significantly impact patient outcomes, and the choice of induction drugs used for endotracheal intubation (TI) is key for a successful and safe airway management. However, critically ill patients often have physiologic derangements leading to complications such as hypoxemia, hypotension, arrythmias, and cardiac arrest.
HYPOTHESIS: This review aims to analyze the usage and outcomes of induction drugs used for airway management in critically ill adult patients to determine if there are select induction drugs that have better success rates and patient outcomes.
METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE for randomized controlled trials published since January 1, 2003, on critically ill adult patients who underwent TI in an emergency, ICU, or trauma setting. Our search yielded 1526 results, of which 18 were chosen.
FINDINGS: These 18 studies include 15 randomized control trials, 2 ongoing phase 4 clinical trials, and 1 single blinded randomized study, for a total of 3142 patients. Etomidate and ketamine were the two most common drugs used, with 13 studies involving the use of etomidate, for a total of 1470 patients, and 7 studies involving the use of ketamine, for a total of 1082 patients. Etomidate and ketamine were compared the most frequently (n = 7), followed by etomidate and midazolam (n = 4). Most studies were performed in either the ICU (n = 6) or the ED/ER (n = 5). Hospital mortality (n = 10) and peri-intubation hypotension (n = 11) were also the most common outcomes studied.
CONCLUSIONS: In general, there was no major trend that could be identified regarding patient outcomes when two induction drugs were compared with each other. This was due to the variability in the use of induction drugs for TI in critically ill patients and their patient outcomes. Comparing findings of different studies was limited by the heterogeneity of the studies. Further research is needed to identify the impact of the choice of induction drugs for TI in critically ill patients.Southwestern Medical Foundatio
Bonds
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.My immediate family has all moved far away from Texas. Though we are still close, the distance can be a challenge to our relationships. Despite our distance, though, we still find ways to love and support one another
Exploiting Multi-Cell Type Cultures to Elucidate Tumor Cell Features That Impact Macrophage Phenotype
Get PDFLung cancer is expected to kill ~150,000 people this year, encompassing 25% of all cancer related deaths making lung cancer the leading cause of cancer-related mortality in men and women. Lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) which represent 80-85% and 15-20% of cases, respectively. My dissertation project focused on understanding how to model the interactions between lung cancer cells, fibroblasts and immune cells. Immune cells are critical components of the tumor microenvironment (TME) that contribute to tumorigenesis, angiogenesis and metastasis. Macrophages are key regulators of the immune landscape within the TME. The plasticity of macrophage phenotypes in the TME correlates with prognosis of NSCLC. Depending on their phenotype, macrophages in the TME can secrete pro-tumor cytokines and chemokines, ultimately suppressing the function of anti-tumor immune cells in the TME. The purpose of my project was to investigate if and how NSCLC cells alter macrophage phenotype in multi-cellular co-cultures and to relate effects on macrophages to the molecular characteristics of different NSCLCs. The central hypothesis of the project is, tumor cell characteristics drive macrophage polarization in the TME, and this can be captured using a multicellular co-culture model. Given the central importance of macrophages to the TME and the immune landscape of NSCLC, an understanding of the tumor cell characteristics associated with immune suppressive or immune stimulatory macrophage phenotype could be exploited from a therapy perspective in the future. To address this hypothesis, an in vitro co-culture system (NSCLC tumor cells, human cancer associated fibroblasts (CAFs), and mouse macrophages) was developed to interrogate cancer cell features driving heterogeneity of macrophage phenotypes across a panel of NSCLCs. We measured: mRNA expression in mouse macrophages with a panel of qPCR probes for genes associated with distinct macrophage phenotypes (Arg1, iNOS, Il-1β, Il-6, Ym-1, Socs3). This system was validated by comparison of macrophage phenotypes represented in the TME of lung cancer xenografts grown in athymic nude mice. Using our platform, we evaluated ~80 NSCLC patient derived lines for their effect on mouse macrophage phenotype. We identified three main macrophage phenotypes across this panel of NSCLCs. To identify cancer cell biomarkers for macrophage polarization, we interrogated molecular characteristics of the cancer lines. Additionally, we expanded the functionality of the platform to assess the effects of pharmacologic agents on macrophage phenotype. As a proof of principle, a small panel of known immune stimulating compounds was tested in the in vitro co-culture platform and validated in human tumor xenografts. Finally, we identified a few novel compounds that show selective cancer cell toxicity and reprogram macrophage phenotype. In conclusion, we built a reproducible in vitro platform to interrogate macrophage polarization in the TME. We leveraged this platform to identify three dominant macrophage phenotypes induced by NSCLC cells and CAFs. We found that no cancer cell molecular characteristic alone drives macrophage polarization. Finally, we illustrate the significance of this platform for immune stimulating drug identification; we identified two novel chemicals that repolarize macrophages and kill cancer cells simultaneously
Medical futility: what a long, strange trip it's been
Get PDFTuesday, May 14, 2024; noon to 1 p.m. (Central Time), Room NB2.100A or via Zoom. "Medical Futility: What a Long, Strange Trip It's Been". Thomas W. Mayo, J.D., Senior Associate Dean for Academic Affairs, Altschuler Distinguished Teaching Professor, and Professor of Law at the Dedman School of Law at Southern Methodist University and Adjunct Professor in the Department of Internal Medicine at UT Southwestern.In medical terms, "futility" results from the inevitable playing out of illness, trauma, and advanced age. In ethical terms, however, it represents a serious ethical dilemma. Texas unexpectedly broke new ground in 1999 with a law that attempted to map out an approach to resolving the dilemma. Subsequent developments have been even more unexpected.UT Southwestern--Program in Ethic
More Punk than Steam
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Professional division) for the 2024 On My Own Time (OMOT) Art Show.Steampunk played a huge role in my 20s, as I found community and a form of self-expression. However, in exploring my identity through it, I wound up realizing that I didn't fit in and learned about the historical baggage that many tried to push under the rug. The essay is about outgrowing something that was important in your life and what it means to be a fashion rebel of sorts