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Experience-Dependent and Input-Specific Regulation of Neocortical Circuit Development by Genes Linked to Neurodevelopmental Disorders
Get PDFAbnormal structural and functional brain connectivity has been widely observed in human neuropsychiatric diseases. Specifically, patients with neurodevelopmental disorders like autism often show an imbalance in the local versus long-range connectivity for cerebral cortex. Whether and how genes implicated in neurodevelopmental disorders regulate development of cortical synaptic connectivity in a pathway-specific manner remain largely unknown. Furthermore, environmental sensory experience can determine or significantly remodel the postnatal development of synaptic connections and neural circuits in sensory cortices. Knowledge on what intracellular proteins or mechanisms can mediate experience-dependent development of specific cortical synaptic connections is also lacking. In this work, I studied the roles of two neurodevelopment disease implicated genes, namely, fragile X mental retardation 1 (Fmr1) and myocyte enhancer factor 2c (Mef2c) in the postnatal experience-dependent development of input-specific synaptic connections.
I report that postnatal, cell-autonomous deletion of Fmr1 in postsynaptic L2/3 or L5 neurons results in a selective weakening of AMPA receptor-, but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. Unlike callosal inputs, synapses originating from local L4 and L2/3 circuits are normal with postsynaptic Fmr1 deletion, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. Opposite to Fmr1 KO, postnatal deletion of Mef2c in L2/3 neurons leads to a cell autonomous and selective weakening of excitatory synapses from L4, whereas ipsilateral or contralateral long-range excitatory synaptic inputs are unaffected. Postsynaptic Mef2c only promotes the development but not the maintenance of L4-to-L2/3 excitatory synaptic connections and Fmr1 is not required for this process, in contrast to predictions from work in CA1 hippocampal neurons. Weakening of L4-L2/3 synaptic strength by sensory deprivation can be rescued by postnatal postsynaptic expression of a transcriptionally active form of MEF2C (MEF2-VP16), suggesting that MEF2C transcriptional activation drives experience-dependent development of L4-L2/3 synapses. Together, my findings on Fmr1 and Mef2c demonstrate an interaction of experience and gene functions in regulation of specific synaptic connections with important implications for neurodevelopmental disorders
Structural and Molecular Mechanisms of Centrosome Assembly and Strength
Get PDFThe outermost layer of centrosomes, called pericentriolar material (PCM), organizes microtubules for mitotic spindle assembly. The molecular interactions that enable PCM to assemble and resist external forces are poorly understood. To answer such question, we use cross-linking mass spectrometry (XL-MS) to analyze PLK-1-potentiated multimerization of SPD-5, the main PCM scaffold protein in C. elegans. In the unassembled state, SPD-5 exhibits numerous intramolecular interactions that are eliminated after phosphorylation by PLK-1. Thus, phosphorylation induces a structural opening of SPD-5 that primes it for assembly. Multimerization of SPD-5 is driven by interactions between multiple dispersed coiled-coil domains. Structural analyses of a phosphorylated region (PReM) in SPD-5 revealed a helical hairpin that dimerizes to form a tetrameric coiled-coil. Mutations within this structure and other interacting regions cause PCM assembly defects that are partly rescued by eliminating microtubule-mediated forces, revealing that PCM assembly and strength are interdependent. We propose that PCM size and strength emerge from specific, multivalent coiled-coil interactions between SPD-5 proteins
Comfort
Get PDFThe author submitted this entry in the 10-Word Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This work received a First Place Award in the "10-Word Story" category in the 2024 On My Own Time show.As a hospital chaplain, I have witnessed many people caring for loved ones as they come near to death and pass away. It is a powerful moment, and one that is worthy of remembering
Decreased Emergency Department Utilization by Lower Socioeconomic Status Population as a Result of the COVID-19 Pandemic
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.BACKGROUND: The SARS-CoV-2 (virus which causes COVID-19) pandemic has resulted in lower emergency department (ED) volumes. It precipitated business and school closures along with the implementation of physical distancing measures, which culminated in a Shelter-in-Place Order (SIPO) issued for a major urban area county in March 2020.
OBJECTIVE: The objective of this study was to determine the effect of the COVID-19 pandemic on access to health care by patients of different socioeconomic status by examining differences in ED volume by zip code stratified by the SocioNeeds Index, a measure of socioeconomic need correlated with poor health outcomes. Our hypothesis was that decrease in patient visits due to the SIPO was not uniform across Dallas County but was based on socioeconomic need and proximity to Parkland's ED.
METHODS: This retrospective chart review examines whether there was a quantitative change in patient visits to an urban, tertiary county hospital (Parkland or PMH) ED from 2019-2020 by zip code. The inclusion criterion was any ED visit from a patient with a zip code within Dallas County, and the exclusion criterion was any blank, alphanumeric, or PO box zip codes including zip codes located outside of Dallas County. The SocioNeeds Index, which rates each zip code by demographic factors relative to others in the county, was used as a proxy for the socioeconomic status of residents of each zip code. We mapped daily patient visits by zip code for four phases: Phase 1 was the three months preceding the first COVID-19 case's announcement in Dallas, Phase 2 began with the first COVID case, Phase 3 encompassed when the SIPO was in effect for Dallas County, and Phase 4 comprised the three months following the expiration of the SIPO. We compared this data to records over the same time period from the previous year to control for seasonal variation in the absence of a pandemic.
RESULTS: There were 275,756 ED patient visits included in this study. We identified a statistically significant decrease in ED visits among patients from all zip codes during the pandemic: 24% between Phase 1 and 4 (p<0.0001) in 2020. Additionally, there was a decrease in visits after the first case in Dallas: Phase 2 (-14%, p<0.0001), Phase 3 (-41%, p<0.0001) and Phase 4 (-25%, p<0.0001) when compared to 2019 but an increase in visits (36%, p< 0.0001) in 2020 once the SIPO expired. Zip codes with highest SNI ranks (highest needs communities) were found to have greater reductions in visits during the SIPO and more sluggish recoveries after the expiration of the SIPO in comparison to those zip codes with the lowest needs. An examination of the geographic distribution of self-reported zip codes indicated that most communities in Dallas County saw a reduction in patient visits over Phases 2 and 3 (especially zip codes further from the ED) and an increase in visits during Phase 4 although not to pre-pandemic values. These changes, however, were not uniform across the county and were tied to socioeconomic factors and proximity of residence to PMH.
CONCLUSION: Our hypothesis was supported by the results obtained: a significant decrease in ED visits was observed during the pandemic relative to a non-pandemic year among patients in most zip codes except those with the highest socioeconomic status, suggesting that the threat of the virus and SIPO deterred patients disproportionately from the higher socioeconomic needs communities from accessing healthcare. These results could have implications for future pandemic public health messaging and targeted outreach to communities with barriers to healthcare access
Wake Up! Wake Up! Wake Up!
Get PDFThe author submitted this entry in the Fictional Short Story category (Amateur division) for the 2024 On My Own Time (OMOT) Art Show.This piece was inspired by an object that I've had with me for over a decade now. It's usually the first entity I interact with every day, and we have a love-hate relationship. Curious? Read on to see what I'm referring to
Quantitative Non-Contrast Perfusion Imaging Using Arterial Spin Labeled MRI
Get PDFArterial Spin Labeled (ASL) magnetic resonance imaging (MRI) is a promising non-contrast perfusion imaging method. ASL has been widely used in brains and has seen emerging applications in kidneys, lungs, and placentas. This work is focused on glioblastoma (GBM), a highly vascularized tumor, with median survival of less than a year and poor prognosis. Elevation of tumor perfusion is often seen in patients with GBM and perfusion may change in response to treatment. ASL-measured perfusion can be an early biomarker of treatment response in GBM patients and can assist in the assessment of their treatment responses. This work is focused on the technical developments of robust perfusion MRI method and its clinical applications in GBM. A k-space filtering approach was proposed and optimized to deblur the brain ASL images acquired with a previously developed 3D Cartesian TSE approach called CASPR, which is Cartesian Acquisition with Spiral Profile Recording. Significant deblurring effect was achieved in brain ASL images with this approach. To further improve the robustness and SNR, a novel ASL acquisition approach called VD-CASPR, which is Variable-Density sampling of CASPR, was proposed and optimized. VD-CASPR showed improved robustness and SNR in both brain and kidney ASL MRI and was combined with CS-SENSE to achieve improved spatial resolution in clinically feasible scan times. These techniques can also be potentially applied in GBM patients. A study was initiated and underway to evaluate treatment response using ASL measured perfusion in patients with GBM. So far, this study has recruited 14 patients with GBM and performed over 60 imaging sessions before, during, and after treatment. Preliminary results showed that perfusion reduction measured by ASL could be seen as early as the 3rd week after treatment initiation in treatment-responding patients, indicating ASL measured perfusion can act as an early biomarker to evaluate treatment response in GBM patients. In addition, we also performed intra-session reproducibility tests of ASL measured perfusion in GBM patients and healthy volunteers, and results showed good reproducibility. Reproducibility tests were also performed in a previously developed 3D-printed perfusion phantom over a 16-week period to demonstrate the reliability of ASL, which also showed good reproducibility
Hybrid Enzyme-Loaded Silica Nanoparticles for Potential Therapeutic Applications
Get PDFPages 24-131 are misnumbered as pages 23-130.Enzymes are powerful biological catalysts that enable selective chemical reactions. Their ability to convert substrates to products at physiological pH and temperature have made them attractive as potential therapeutic agents. Since most enzymes are non-humanderived, their clinical use faces two main challenges: short functional half-life and immunogenicity. To address these limitations, there is a need for a versatile strategy that increases the functional half-life and safety profile of enzymes while preserving their efficacy. In this dissertation, I will report the design, syntheses, and applications of a Hybrid Enzyme-Loaded silica nanoParticle (HELP) platform used for therapeutic purposes. In this platform, enzymes are embedded inside nanoporous silica nanoparticles that prevent their interaction with large biomacromolecules but allow them to interact with small molecule substrates. This versatile encapsulation method has the potential to improve the stability of enzymes in circulation, eliminate immune responses, and prolong their functional half-life.
First, I used catalase as a model enzyme because it has oxygen-generating properties that can be used for potential hypoxia relief and radiosensitization of tumors. Catalase was encapsulated in silica nanoparticles by modifying surface lysines to introduce a silica precursor, followed by silication in mild, aqueous phase conditions. These nanoparticles had high enzyme activity, optimal protection from proteases, and excellent stability over time. An in vivo pilot study demonstrated the ability of these particles to oxygenate tissues upon hydrogen peroxide infusion. Additionally, targeting moieties and radiotracers could be conjugated to the surface of these particles post-formulation.
The HELP platform was also applied to asparaginase, a therapeutic enzyme used as first-line treatment to treat acute lymphoblastic leukemia (ALL), the most common childhood cancer. Unfortunately, it is bacterially derived and can elicit immune responses in pediatric patients. Asparaginase-loaded silica nanoparticles were formulated using a direct modification method and subsequent reverse emulsion conditions. These particles were monodisperse, had a mean diameter less than 50 nm, and demonstrated excellent protection from proteases and antibodies in vitro. Both immunogenicity and functional half-life of these particles are currently being investigated in vivo. Future studies will look at the therapeutic potential of these nanoparticles in an animal model of ALL
Toward a Better Understanding of Racial and Ethnic Differences in Cognitive Function in MDD
Get PDFMajor Depressive Disorder (MDD) is a highly pervasive and disabling disease that is characterized by persistent sadness and loss of interest. It creates a host of complications for the individual and affects various domains of functioning and quality of life. Although the prevalence for MDD is estimated to be higher in the white, non-Hispanic population, MDD still has a significant prevalence among other races and ethnicities. Due to the disparities in diagnosis and treatment in MDD, the burden of disability is increased in minority populations. To begin understanding what factors could possibly contribute to disparities in MDD, it is important to examine key players in MDD such as cognitive functioning. One increasingly recognized impact of depression that can be seen across all populations and ages is cognitive dysfunction, which plays a role in depression severity and recurrence. The examination of potential differences in cognitive function associated with race and ethnicity in depressive disorders has been underexplored. Apart from race/ethnicity itself, there are independent factors highly prevalent in minority populations including social determinants of health (SDOH) such as age and education, and medical or metabolic comorbidities, that independently impact cognitive functioning and depression.
This broad investigation was broken into two parts. Part One focused on understanding the current knowledge and findings of racial and ethnic differences in cognitive performance in adults with MDD and possible contributors to those differences. This literature review found associations between race/ethnicity and cognitive functioning as well as other possible contributors to cognitive performance such as age, education, and presence of medical comorbidities such as HIV, metabolic syndrome, and obesity.
Part Two of the investigation was a secondary analysis that compared group differences (between Black/non-Hispanic, White/non-Hispanic, and White/Hispanic participants) on measures of cognitive functioning using the National Institute of Health (NIH) Toolbox - Cognition Battery (NIHTB-CB). Significant mean group differences were observed across the Fluid and Total NIHTB-CB cognitive composite scores, with Black participants scoring lower than White, non-Hispanic/Latinx participants. Several differences remained significant when controlling for depressive symptomatology, metabolic function, and medical comorbidity burden. These results indicate that Black, non-Hispanic/Latinx race is a possible contributor to differences in cognitive performance in depression that is independent of depression, metabolic factors, and medical comorbidity burden, although the size of the noted differences may not be clinically meaningful. Future studies are needed to better understand contributors to such differences in cognitive performance and further expand our understanding of depression and development of precision medicine
Senses at Sunset
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 work received a First Place Award in the "Open Verse Poetry" category in the 2024 On My Own Time show. It was also honored with the Best in Show Award.This piece was inspired by my experiences with young cancer patients
The role of inflammation and infection in neurodegeneration
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