MEDICA@MUSC (Medical University of South Carolina)
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A Connecting Link Between Sphingolipid Metabolism and the Complement System in Cancer Metastasis
No full textThe tumor microenvironment (TME) is composed of complex constituents that consistently change to support tumor escape from anti-tumor immune surveillance, thus promoting cancer progression and negatively impacting patient survival. Components of the tumor microenvironment must have a reciprocal relationship with the cancer cells to allow tumors to escape the immune system. The functional roles of sphingolipid metabolism and the activating components of the complement system sustained in the tumor microenvironments represent an intricate mechanism that favors tumor growth and survival. Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-a’2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/ inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-a’2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, the S1PR1/C3/PPIL1/NLRP3 axis activation is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using wild-type and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis
Virtual Visits in Routine Prenatal Care
Get PDFProblem
One million pregnant persons in the United States do not receive early prenatal care or the recommended number of prenatal visits each year, and this gap in care access disproportionately affects people of color, those with lower incomes, and those living in rural communities. Telemedicine was widely utilized in prenatal care during the COVID-19 pandemic, and optimizing prenatal telemedicine has the potential to improve prenatal care access beyond the pandemic.
Purpose
This dissertation focused on examining the integration of virtual visits in routine prenatal care during the COVID-19 pandemic. The purpose of this dissertation was to:
Aim 1. Explore the needs, experiences, and preferences of perinatal providers and patients participating in routine prenatal care during the COVID-19 pandemic.
Aim 2. Identify facilitators and barriers to implementing virtual visits into routine prenatal care through the lens of the normalization process theory’s four core constructs: coherence, cognitive participation, collective action, and reflexive monitoring.
Aim 3. Examine patient demographic characteristics and motivators for utilizing or declining a virtual care model.
Design
This dissertation includes an integrative review that used the social ecological model to analyze factors impacting virtual prenatal visits in original research. In addition, a convergent mixed methods study was conducted with a national sample of pregnant/postpartum patients and perinatal providers from July to December, 2021. Researchers explored participant experiences with telemedicine use in routine prenatal care using the Telehealth Usability Questionnaire, and also analyzed barriers and facilitators that affect the implementation and normalization of prenatal telemedicine using the Normalization Process Theory as a guiding framework.
Findings
The integrative review identified 12 studies and 1 quality improvement project on virtual visits in routine prenatal care. Reviewers found that patient and provider satisfaction were moderate to high using prenatal telemedicine and that there were two comprehensive virtual prenatal care models established prior to the pandemic. They also outlined factors impacting prenatal telemedicine across the five levels of the social ecological model.
The mixed methods dissertation study included 946 survey responses (750 patients, 196 providers) and 30 interviews (15 patients, 15 providers) across 48 states. The primary reasons given for not using telemedicine were that it was not offered, concerns for care quality, and concerns for establishing a patient-provider relationship. Telemedicine utilization was not impacted by parity or income, however urban residents, Black pregnant patients, those planning community births, and those with a graduate degree all had statistically higher usage rates. Researchers identified mild to moderate general satisfaction for patients and providers across the following telehealth usability domains: usefulness, ease of use and learnability, interface quality, interaction quality, reliability, and satisfaction and future use. Barriers and facilitators for normalization of virtual prenatal care were identified across the following Normalization Process Theory constructs: coherence, cognitive participation, collective action, and reflexive monitoring.
Conclusion
An informed understanding of patient and provider experiences along with barriers and facilitators to telemedicine normalization for virtual visits with routine prenatal care can inform and optimize telemedicine delivery. Future research is warranted on how the use and acceptance of prenatal telemedicine will evolve beyond the COVID-19 pandemic
The Genomics of Autism-Related Genes IL1RAPL1 and IL1RAPL2: Insights into Their Cortical Distribution, Cell-Type Specificity, and Developmental Trajectories
Get PDFNeuropsychiatric disorders have a significant impact on modern society. These disorders affect a large percentage of the population: schizophrenia has a world-wide prevalence of 1% and autism spectrum disorders (ASD) affects 1 in 59 school-aged children in the US. There is substantial evidence that most neuropsychiatric disorders have a genetic component. Thus, with the advent of high throughput sequencing much effort has gone into identifying genetic variants associated with these disorders. The emerging picture from these studies is a complex one where hundreds of genes with small effects interact with a varied landscape of common variants to result in disease. Despite this complexity, individual disease-associated genes have been identified but studies of the functional role of each of these genes in brain development and function have only just begun. In addition to efforts designed to identify disease-relevant genetic variants, large consortia have been formed to generate other genomic datasets (e.g., bulk, or single cell RNA expression) to uncover both cell-type specific and tissue-specific transcriptional networks where disease-associated genes are involved.
This study integrated several types of bulk tissue datasets with single-cell datasets to investigate the cortical distribution, cell-type specificity, and developmental trajectories of two ASD-linked genes: IL1RAPL1 and its paralog IL1RAPL2. Genetics studies linked IL1RAPL1 and IL1RAPL2 with ASD and intellectual disabilities (ID) and both are strong ASD risk gene candidates with a SFARI score of two. Even though IL1RAPL1 has been shown to have a role in synaptic development and synaptic strength, little is known about IL1RAPL2. Therefore, whether or how IL1RAPL2 functions in synapse development is a significant gap in knowledge and given the role of cortical excitatory neurons in ASD and intellectual ability, IL1RAPL2 is highly likely to serve a critical role. Recently, IL1RAPL2 has been identified as a hub gene in an ASD module associated with memory oscillations and it is strongly co-expressed with other ASD-risk genes. These data further confirm the potential role of IL1RAPL2 in neuronal etiology and ASD.
To further gain insights into the role of these genes in the human brain and ASD, we analyzed the transcriptomic landscapes of IL1RAPL1 and IL1RAPL2 in cortical region and cell types of the human brain. We hypothesized that IL1RAPL1 and IL1RAPL2 gene expression significantly differs within cortical regions involved in higher order cognitive function, both at cell-type level and during development.
This project took advantage of publicly available genomic data from PsychENCODE, Allen Institute, and Lister Lab. We analyzed bulk RNA-seq from neurotypical and ASD patients (N = 103) identifying gene expression and co-expression differences between IL1RAPL2 and IL1RAPL1 in 11 cortical regions. We next used a time series bulk RNA-seq data from neurotypical subjects (N = 39) to infer the developmental trajectories of IL1RAPL2 and IL1RAPL1 in 11 cortical regions. Finally, by using single cell RNA-seq data, we uncovered the cell-type gene expression distribution differences between IL1RAPL2 and IL1RAPL1 in multiple regions and cortical-layers in human and mice samples, and to find differences in expression across development.
In summary, this comprehensive genomic project highlighted significant differences between IL1RAPL1 and IL1RAPL2 in specific brain regions, cell-types, and developmental trajectories across the human lifespan. The identified differences provide preliminary evidence that IL1RAPL1 and IL1RAPL2 might play a different role in human cortical development and cell-type
Novel Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis
No full textSystemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Currently, only two drugs are approved by the Food and Drug Administration (FDA) for SSc, but these merely reduce progression of ILD rather than stop or reverse it. Thus, there is a need to investigate novel molecular pathways involved in fibrosis, especially lung fibrosis in the context of SSc, to find potential therapeutic treatments.
The presented thesis describes two novel mechanisms that are interrelated and implicated in SSc lung fibrosis. The 1st identifies Cathepsin L (CTSL) as a protein protective against lung fibrosis, whose expression and secretion into the extracellular milieu is suppressed in SSc lung tissue and fibroblasts. Cathepsin L is the main enzyme that cleaves endostatin from the c-terminus of Collagen XVIII, activating its potent antifibrotic activity. We further show that reduced secretion of CTSL is partly due to its packaging into extracellular vesicles (EVs) in its inactive form. This finding prompted us to explore another mechanism of lung fibrosis that hasn’t been thoroughly studied, investigating the role of EVs in the progressive nature of SSc-related lung fibrosis. While most SSc research has focused on the pathology of the fibrosis itself, the mechanism mediating the fibrotic spread remains unclear. Our findings show that EVs from experimentally activated or SSc fibroblasts and lung tissues carry an active fibrotic cargo capable of transmitting a potent fibrotic response to healthy fibroblasts in-vitro, human lung tissue ex-vivo, and mice lungs in-vivo. Moreover, reducing EV release systemically ameliorated the lung fibrosis in-vivo. We thus show that EVs play a crucial role in the spread of lung fibrosis in SSc.
In conclusion, our findings suggest that identifying therapies to boost CTSL endogenous levels in SSc patients, or suppress EV release, activity, and/or fibrotic cargo, could serve as viable therapeutic strategies to halt lung fibrosis and its progression, improving SSc mortality
MEF2C Hypofunction in GABAergic Cells Alters Sociability and Prefrontal Cortex Inhibitory Synaptic Transmission in a Sex-dependent Manner
No full textThe MEF2 (Myocyte Enhancer Factor 2) family of transcription factors regulate gene expression controlling cell differentiation and synapse development. Loss-of-function mutations or deletions of the MEF2C gene cause a neurodevelopmental disorder, termed MEF2C Haploinsufficiency Syndrome (MCHS). MEF2C is highly expressed in excitatory forebrain neurons, microglia, and GABAergic neurons, but the effects of MEF2C hypofunction in GABAergic cells on MCHS-like phenotypes is not known. To study the role of MEF2C in GABAergic cell populations during mouse development, we generated mice that are GABAergic cell-specific Mef2c heterozygous mutants (Mef2cfl/+;Vgat-Cre or Mef2c cHetVgat). The Mef2c cHetVgat and littermate control mice underwent a battery of tests measuring MCHS-relevant phenotypes, including learning and memory, approach avoidance, and social preference. Mef2c cHetVgat mice exhibited altered spatial working memory. Interestingly, Mef2c cHetVgat female, but not male, mice displayed significant alterations in approach-avoidance and sociability. Using additional cell type-specific Cre driver lines, we found that MEF2C hypofunction in inhibitory neuron subtypes SST (somatostatin) and VIP (vasoactive intestinal peptide) populations alone cannot account for the behavioral phenotypes observed in Mef2c cHetVgat mice. Female Mef2c cHetVgat mice displayed social-related frontocortical network activity measured by electroencephalography. Using a single nucleus RNA-Seq approach, we found significant differentially expressed genes in PV-expressing cells with enrichment for risk genes linked to ASD, schizophrenia, and intellectual disability. Moreover, in female, but not male, mice, we observed that developmental, GABAergic-specific Mef2c heterozygosity produced significant alterations in excitatory/inhibitory balance and physiological properties of a GABAergic interneuron subtype, PV (parvalbumin) cells, in the prefrontal cortex (PFC), a brain region linked to social behavior deficits in multiple mouse models of ASD. Collectively, we find that MEFC hypofunction in female, but not male, developing GABAergic cells is important for sociability and approach-avoidance behaviors and PV inhibitory neuron function in the PFC of mice. While there is no apparent sex bias in ASD symptoms of MCHS, our new findings suggest that GABAergic cell-specific dysfunction in females with MCHS might contribute disproportionately to sociability symptoms
Pathogenicity of Acinetobacter calcoaceticus
Get PDFAcinetobacter is a genus of gram-negative bacteria that have been appearing frequently in hospitals contributing to infections in the blood, lungs, urinary tract, and other parts of the body. It infects patients with weakened immune systems that are placed on ventilators, after the use of catheters, or have any other open wounds produced by prolonged hospital stays. This genus of bacteria is problematic due to its high probability of becoming resistant to multiple classes of antibiotics. Thus, we are determining the pathogenicity of clinical isolates of Acinetobacter calcoaceticus using the organism Caenorhabditis elegans as a model.
We are testing this using the following methods, a plate survival assay using eight strains of bacteria, including two laboratory-adapted strains and four clinical isolates of Acinetobacter calcoaceticus, Acinetobacter baumannii as a negative control, and Escherichia coli OP50 as a positive control, the second method being a worm microtracker assay using the same strains cultured in brain-heart infusion or ZMB1, and methods pertaining to identifying what is causing virulence such as methanol extraction, proteinase K treatment, and centrifuge filtering. Our hypotheses for each are: On the plates and in liquid, wild type, N2 strain worms will expire faster on/in the clinical isolates of Acinetobacter.
Our hypothesis for the microtracker analyses states that Acinetobacter calcoaceticus is pathogenic due to the decreased motility in the wells over time. Pertaining to what causes virulence in the nematodes, we hypothesize that it’s a protein.
Our results on plates indicate that after ingesting Acinetobacter, nematodes live for the same amount of time and in some cases longer than the nematodes plated on OP50. However, when placed in the liquid culture the nematodes in the BHI solution expire within twenty-four hours. When treated with proteinase K or filtered we observed protection from lethality. In future experiments we plan to send samples off to partner labs to perform proteomics to search for possible virulence proteins. The findings of this project will help lead us to a better understanding of the pathogenicity of this strain of Acinetobacter and its effects on the innate immune system
A Multi-Modal Imaging Analysis of Inter-Community Hub Nodes in Subjective Cognitive Decline Linking Longitudinal Hub Function Disruption to White Matter Integrity Kurtosis
Get PDFSubjective Cognitive Decline (SCD) has garnered much interest as a potential identifiable preclinical stage and indicator of risk for cognitive decline in Alzheimer’s Disease and related dementias (ADRD). Identification of individuals in this stage though is difficult, as they present with objectively normal cognitive evaluation scores, relying instead upon self-report of concern about decline in cognitive abilities. The use of non-invasive in-vivo imaging methods like BOLD functional imaging and diffusion tensor have allowed for complex mapping of both the functional and structural network features unique to this condition. This study furthers this network biomarker map of SCD by investigating the link between Mean Kurtosis integrity metric of white matter fibers and functional network changes, specifically focusing on the vulnerable inter-community hubs of the functional connectome. In the first chapter we investigate baseline differences between SCD and healthy subjects by first identifying five major functional hubs, then analyzing white matter tractography associated with these hubs. We find that there is a disparity in the group differences of the two modalities, with hubness of all five hubs being lower in SCD as measured by diversity coefficient (DC), while in several of the hubs, associated white matter had significantly higher integrity metrics as measured by mean kurtosis (MK). In SCD, these metrics were related such that a higher MK was necessary to achieve healthy control-like levels of hub DC. In chapter 2, we analyze longitudinal follow-up scans of the same subjects, finding that fewer of the hubs in SCD have significantly lower DC hubness, and fewer fibers are identified in which MK integrity is significantly higher in SCD. In the left insular cortex, baseline MK in SCD was predictive of the degree of hubness decline, with higher baseline MK resulting in a healthy control-like longitudinal change pattern. These observations provide evidence supporting a mix of existing SCD-ADRD models, with functional results matching existing progressive decline, while white matter results match paradoxical increase hypotheses of hub vulnerability. In conclusion, we have identified a unique multi-modal model of SCD, emphasizin
Tips and Tricks for Customizing Exhibits in DCX
No full textDCX provides users an easily navigable platform with seemingly static design options for digital exhibit development. Our lightning talk will focus on leveraging the features within DCX to create more customizable options that can be implemented within the design of digital exhibits. We will explore lessons learned through the creation of our virtual exhibit, ‘“Men of Unsullied Reputation:’ The Founders of the Medical College.” Key insights will include using HTML for formatting, importing items from Digital Commons to increase page hierarchy capacity, and utilizing Canva to enhance branding capabilities
Trends in Primary Care Visits and Diabetes Control for Type 2 Diabetics before and during the COVID-19 Pandemic
Get PDFCommunity health worker interventions have shown potential to improve health outcomes and reduce inequities particularly for patients with chronic diseases such as type 2 diabetes (T2D). However, there is a lack of support for CHW integration in the delivery of health care. The recent COVID pandemic may have affected outcomes for T2D patients and exacerbated existing inequities in care. This dissertation aimed to address three broad questions through three separate manuscripts. The first one was a systematic literature review to examine the impact of community health workers on health outcomes for rural US populations. The second and third papers used electronic health record data from the Medical University of South Carolina primary care clinics to assess the impact of the COVID interruption on monthly diabetes visits and HbgA1c measures on T2D patients, including analyses by high-risk subgroups based on age, race, ethnicity, rurality, and insurance status. The systematic review provided evidence that CHW can improve access to care in rural settings and may represent a cost-effective investment for the healthcare system. After the onset of the COVID-19 pandemic in South Carolina in March 2020, the overall rate outpatient visits for type 2 diabetes (T2D) patients did not significantly drop thanks to the implementation of telehealth services. Nonetheless, glycemic control was negatively impacted by the COVID-19 interruption, especially for older patients and those covered by Medicaid or without insurance. Taken together these results can inform future research and interventions leveraging CHW and telehealth modalities to better address equitable T2D management