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Molecular Basis of Coupling Calcium Sensing to Fast Membrane Fusion by Synaptotagmin-1 in Neurotransmitter Release
Get PDFThe content of this work is based on the previously published articles that are cited below.Neuronal communication depends on the rapid release of neurotransmitters through Ca2+-triggered synaptic vesicle exocytosis. Synaptotagmin-1 (Syt1) acts as the Ca2+ sensor for fast, synchronous neurotransmitter release. Despite decades of research, the precise molecular mechanism of Syt1 action and the coupling of Ca2+ sensing to membrane fusion remains elusive. Addressing these questions requires an understanding of the cooperation between Syt1 and the SNARE complex, which drives membrane fusion. The SNARE proteins anchored on opposing membranes bring them together by forming a tight four-helix bundle, a process referred to as zippering. A recent molecular model of SNARE-mediated membrane fusion has revealed that the zippering of the SNARE motifs into the juxta-membrane linkers, which catalyzes encounters of acyl chains from opposing bilayers, is the key event leading to membrane fusion.
The work presented in this thesis provides a thorough analysis of the interactions between Syt1 and the SNARE complex in solution and on membranes. Leveraging NMR and fluorescence spectroscopy, the included studies systematize the often-contradictory data and present a comprehensive model illustrating how Ca2+ signaling is coupled to SNARE-mediated fusion. In our model, in the primed state of synaptic vesicles Syt1 binds the SNARE complex through a primary interface and the plasma membrane through a polybasic region. In the absence of Ca2+, Syt1 both enables the formation of a partially assembled SNARE complex yet strongly inhibits complete helical zippering and hence membrane fusion. Upon Ca2+ influx, Ca2+ binding by Syt1 induces its membrane insertion, leading to reorientation of the Syt1-SNARE complex on the plasma membrane. The reorientation generates a lever-like action of Syt1 that pulls the SNARE complex, facilitating the zippering of the linkers that induces fast membrane fusion and subsequent neurotransmitter release
Harnessing the microbiome for understanding inflammatory arthritis
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
Having difficult conversations with patients with chronic disabilities: mitigating disability bias in prognostication and resource allocation
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
Predicting Neurologic Disease Progression Using Machine Learning and Causal Inference
Get PDFPages vi-xv are misnumbered as pages vii-xvi.Quantifying communication between different brain regions allows us insight into one of the most complex emergent properties of biological systems. Fundamental properties about cognition, health, and disease can be gleaned from this immensely complicated biologic communication web. One of the best, noninvasive ways for analyzing brain connectivity is functional magnetic resonance imaging (fMRI) - which provides a noninvasive way to look at healthy and diseased individuals' neural communication. Starting with existing means of quantifying neural connectivity, this work performs an in-depth cross-analysis of their capabilities before proposing, testing, and applying novel connectivity measures, including both nonlinear machine learning approaches and prior-knowledge informed causal approaches. These measures are tested in healthy individuals before being applied to clinically-relevant use cases across multiple neurodegenerative diseases. This work finds neuroimaging connectivity biomarkers for the diagnosis of Autism spectrum disorder, the diagnosis of Parkinson's disease, and Parkinson's disease progression. The new measures of connectivity prove invaluable for these diagnostic and prognostic models, providing insights into pathophysiology of the disease and generating clinically-relevant models that meet patient needs
Staying afloat in a sea of pain
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
Development of an IL12 Prodrug to Treat Solid Tumors with Minimal Toxicity
No full textCytokines are secreted molecules that guide the immune system to respond correctly to various challenges. Among all cytokines, IL12 is perhaps the most powerful at polarizing the immune response into a Type 1, cell-mediated phenotype. Cell-mediated immunity plays a critical role in cancer immunoediting, allowing CTLs to recognize and kill aberrant cells. Because of this, IL12 has been tested in many different preclinical and clinical studies for its potential use as an anti-tumor therapeutic agent. However, IL12 also causes severe, dose-limiting systemic toxicity due to on-target, off-tumor activation of peripheral immune cells. Newer attempts at IL12-mediated delivery focus on restricting IL12 activity to within the tumor as much as possible, but they each have their own limitations. To address these problems, we developed a novel IL12 prodrug, pro-IL12, that is actively blocked until it is preferentially activated within the TME. We achieved this by using portions of the IL12 receptor attached with a flexible linker to sterically block the active site of IL12. The linker contains a substrate site that can be cleaved by tumor-specific proteinases, thereby releasing the blocker and activating the prodrug. Pro-IL12 successfully maintained anti-tumor efficacy with reduced toxicity compared to its non-prodrug counterpart. We determined that the mechanism of anti-tumor immunity was predominantly through pre-existing, intratumor CD8+ T cells that produce IFNγ after direct binding of the prodrug to cell surface IL12 receptor complexes. Pro-IL12 also worked in combination with TKI and ICB to achieve even more potent tumor control. In a follow up study, I propose that a higher dose of pro-IL12 might use distinct cellular and molecular mechanisms. Indeed, high dose pro-IL12 more effectively controls large tumors at the cost of reintroducing systemic toxicity. Mechanistically, this dose used a broader, T cell-dependent mechanism that was independent of IFNγ. Further analysis determined that IFNγ was responsible for all manifestations of toxicity and that IFNγ blockade given concurrently with pro-IL12 could limit toxicity with no effect on efficacy. Additionally, the absence of IFNγ signaling on T cells had no effect on their phenotype or ability to control the tumor. As a whole, these studies document the development of a next generation, IL12 immunotherapy for the treatment of solid tumors with an emphasis on its mechanisms of tumor control that are distinct from toxicity
Creating and Implementing Collection Development Policies
No full textJoin us for an open discussion about collection development policies in libraries. Why are collection development policies important? What elements make up a successful or clear policy? If your library has adopted its own collection development policy, what is it, how is it implemented, and has it helped your library? Everyone is welcome, regardless of collection development or policy-making experience
Assessing the Success of a Research Data Lifecycle Email Course
Get PDFBACKGROUND: This institution piloted an email course for librarians and early career researchers to explore freely available tools and resources that support biomedical research. Email courses are on-demand, provide bite-sized chunks of information, and are a great way to teach resource heavy content. This instruction format is helpful for busy professionals who may want to brush on their skills, but don't have the time for longer, more structured learning environment. DESCRIPTION: The email course comprises of six lessons, a welcome and a farewell email. Each lesson covers a phase of the research data lifecycle, points to open tools and describes how the tools support different phases of the research lifecycle. Once learners sign up, they receive an email every few days until the course is completed. CONCLUSION: The email course officially launched in July 2024. Assessment of the email course will include reviewing the number of subscribers, email opens, clicks, and survey feedback. Initial feedback and engagement data will be shared
Dreams to Reality: Insights into Onboarding Experiences of Early Career Health Sciences Librarians
Get PDFAs health sciences libraries look to the future, one area of focus should be the onboarding of new hires. Onboarding includes not only basic orientation, but other knowledge needed to succeed in their positions. This project investigates the onboarding experiences of newly hired health sciences librarians through use of a survey and personal interviews. This study will use a mixed method design to analyze the attitudes and perceptions of new health sciences librarians towards their most recent onboarding experiences. The researchers designed a survey and interviews focused on onboarding experiences of health sciences librarians and how these experiences have affected their careers. The majority of survey respondents had been in librarianship for over five years, but about a quarter were still in their first professional position. Analysis of interviews with early career librarians showed information around the themes of preparation, communication, relationships, and reflection with subthemes of opportunities, materials, colleagues, and mentors. Overall, only half of librarians felt that their onboarding experience was comprehensive. Key areas of onboarding such as orientation, job duties and expectations, and meeting library staff were included, but the area of relationship building was found to be problematic, especially for virtual librarians. Libraries need to explore more connections for new hires both inside and outside of the library
Innovating Library Services: Exploring the Potential of ChatGPT 4.0
Get PDFOBJECTIVES: This study assessed the utility of ChatGPT 4.0 in an academic health sciences library, focusing on its potential to support staff, enhance workflow efficiency, and foster innovation. METHODS: A pre- and post-test survey evaluated user experiences over six months with 15 employees. The pre-test was administered in the first four weeks, and the post-test followed six months later. Investigator responses were separated to ensure data integrity. All responses were anonymous. RESULTS: Initial survey showed most participants were slightly to moderately familiar with ChatGPT 4.0, primarily as novices or advanced beginners. They used it for writing, project management, instructional practices, and research. Participants found it effective for brainstorming, writing assistance, and project planning but noted challenges with accuracy and privacy. The evolving nature of ChatGPT during the study required continual adaptation, presenting challenges for both participants and the investigators. By the study's end, familiarity and expertise increased, with most finding it useful and expressing interest in continued use, particularly for improving workflow efficiency and task integration. CONCLUSIONS: ChatGPT 4.0 shows strong potential for boosting productivity in an academic health sciences library. Continued exploration and training are needed to maximize its benefits. Future studies can help refine best practices for integrating AI tools like ChatGPT into library workflows