UTMB Health SHARED (Univ. of Texas Medical Branch at Galveston)
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Characterization of Flavivirus-Infected Neurons
No full textPowassan virus (POWV) is a tick-borne flavivirus (TBFV) that can cause severe encephalitis in humans with a case fatality rate as high as 15%. Patients who survived severe encephalitic disease can develop long-term sequelae that can be debilitating and life-long. In this dissertation, a primary human fetal brain neural stem cell system (hNSC) was characterized, which can be differentiated into neuron and astrocyte co-cultures to serve as a translational in vitro system for infection with POWV and a comparative mosquito-borne flavivirus (MBFV), West Nile virus (WNV). It was found that both viruses were able to infect both cell types in the co-culture and that WNV elicited a strong inflammatory response characterized by increased cytokines IL-4, IL-6, IL-8, TNF-α, IL-1β and apoptosis. POWV infection resulted in fewer cytokine responses, as well as less apoptosis, while neurons infected with POWV exhibited aberrations forming in the dendrites. These anomalies were consistent with previous findings using tick-borne encephalitis virus (TBEV) infected murine primary neurons and the formation of laminal membrane structures (LMS). Tissue clearing protocols for infected tissues were established and optimized and applied to prove that structural aberrations were also recapitulated in tissue samples from virus-infected mice. Overall, the studies showed that POWV was capable of infecting human primary neurons and astrocytes without causing widespread apoptosis, while forming punctate structures consistent with LMS in primary neurons and in vivo. This is significant as it is the first time that LMS formation has been indicated in human cells and in animal models. The findings will contribute to the knowledge of TBFV neuropathogenesis by defining the inflammatory response in human neuronal cells and indicating structural changes that could contribute to long-term sequelae
The Impact of Powassan Virus and Borrelia burgdorferi Coinfection in Ixodes scapularis Ticks
No full textTicks (Order: Ixodida) are hematophagous arthropods that transmit a number of medically significant pathogens. Two of these include Powassan virus (POWV) and the spirochete Borrelia burgdorferi, both of which are transmitted by Ixodes scapularis in the northern parts of the United States. Powassan virus can lead to neuroinvasive illness with a high fatality rate. B. burgdorferi causes Lyme disease, a potentially long-term infection of the joints, heart and brain. B. burgdorferi is present in 20-70% of ticks, while POWV is present in less than 5%. This suggests the possibility that most ticks capable of transmitting POWV are coinfected with B. burgdorferi. The existence of negative or synergistic interactions between ticks are unknown, though, as are unique consequences of dual disease. Field surveillance was conducted in endemic areas to ascertain the baseline rates of both pathogens and the rate of coinfection, and to gain an insight into the environment where the pathogens are present. B. burgdorferi was common in New York and Connecticut, while POWV was detected at a low rate, primarily in the form of Deer Tick virus (POWV Lineage II) but also in I. scapularis as a non-Lineage II strain. Coinfection was limited by the rate of POWV. Laboratory analysis of the pathogen interaction was performed to assess possible inhibition or synergistic effects that could influence their shared sylvatic cycles and to assess the risk of human co-exposure. It was determined that ticks can harbor both pathogens, and that the presence of B. burgdorferi enhances viral replication in the midgut and accelerates dissemination to the salivary glands. Transcriptome analysis suggests this response is caused by enhancement of anti-Borrelia responses in the midgut and suppression of POWV-induced metabolic changes in the salivary glands. No change was noted in the microbiome. Dual infection was studied in a murine model. A lethal model of POWV infection was developed for C3H mice, the primary model of Lyme disease. Dual infection did not attenuate the response to POWV, although the expression of some cytokines was enhanced by dual infection. Additionally, Powassan virus replication was noted in the heart, suggesting a potential interaction role in Lyme carditis
Characterization of the Increased Risk of Attention Deficit Hyperactivity Disorder Following Early-Life Exposure to Deltamethrin
No full textUnmasking the mechanistic etiology of neurodevelopmental disorders remains at the forefront of neuroscience research. To this end, epidemiological studies have sought to identify key risk factors driving these disorders. Unsurprisingly, early-life exposure to ubiquitous pesticides which target the central nervous system has been identified as one such risk factor. Pyrethroids, a popular class of insecticides, have been directly correlated with an increased risk in Attention Deficit Hyperactivity Disorder (ADHD). The focus of this thesis is to elucidate the mechanism through which the pyrethroid deltamethrin (DM) contributes to the development of ADHD. Our studies identify perturbations in voltage-gated sodium (Nav) channel 1.6 and medium spiny neurons which highly express Nav1.6- both of which are key components of reward circuitry. These studies are further complemented by identification of behavioral aberrations that typify the human pathophysiology of ADHD. Together, this data identifies a possible mechanism through which early-life exposure to DM disrupts reward circuitry contributing to the etiology of ADHD
Proviral Roles of Ebola virus VP35 Ubiquitination
No full textEbola virus’ structural protein VP35 is polyfunctional and plays vital roles in Ebola’s life cycle from antagonizing the host’s type I interferon pathway to acting as the polymerase co-factor. The mechanisms that regulate which function any given VP35 molecule engages remains unknown. Previously, we observed the host E3 ubiquitin ligase TRIM6 conjugates ubiquitin onto VP35 at lysine (K) 309. This post-translational modification was found to be proviral, but we did not know which VP35 role(s) ubiquitination regulated. We generated recombinant EBOVs encoding glycine (G) or arginine (R) mutations at VP35/K309 (rEBOV-VP35/K309G/-R) and show that both mutations prohibit VP35/K309 ubiquitination. The rEBOV-VP35/K309G mutant loses the ability to efficiently antagonize the IFN-I response, while the rEBOV-VP35/K309R mutant’s suppression is enhanced. The replication of both mutants was significantly attenuated in both IFN-competent and -deficient cells due to impaired interactions with the viral polymerase. The lack of ubiquitination on VP35/K309 or TRIM6 deficiency disrupts viral transcription with increasing severity along the transcriptional gradient. This dysregulation of the transcriptional gradient results in unbalanced viral protein production, including reduced synthesis of the viral transcription factor VP30. Blocking VP35/K309 ubiquitination enhanced interaction with the viral nucleoprotein and may trigger premature nucleocapsid packaging. Prior work also showed that at least one lysine residue other than K309 is ubiquitinated and that VP35 non-covalently interacts with ubiquitin. We observed that multiple residues in VP35’s N-terminus can receive covalent ubiquitin, including K119, 126, and 141. Substitution of K119-, 126-, and/or 141-to-R significantly attenuates VP35’s polymerase co-factor activity, but their mutation does not alter interactions with the viral polymerase or nucleoprotein. When looking into VP35’s non-covalent ubiquitin interaction, we found that VP35 specifically binds K63-linked ubiquitin chains via its C-terminus. The specific cleavage of unanchored ubiquitin chains, using the deubiquitinase isopeptidase T, impedes VP35’s non-covalent binding to ubiquitin and stunts EBOV’s polymerase activity. Finally, we also found that TRIM25, TRIM6’s relative, facilitates ubiquitin ligation onto VP35 and enhances VP35’s non-covalent interaction with ubiquitin. EBOV replication is attenuated 100-10,000 fold in cells lacking TRIM25. Overall, our data support that TRIM6- and TRIM25-mediated VP35 ubiquitination and VP35’s non-covalent interaction with unanchored ubiquitin is proviral
Molecular mechanisms of synaptic proteins
No full textSynaptic adhesion molecules (SAMs) are critical for regulating synapse development and synaptic plasticity. Many studies have linked their putative roles in neuropsychiatric and neurodevelopmental diseases, such as schizophrenia and autism spectrum disorder. Here, the structure-function relationships of a select group of synaptic organizers were explored for MDGA1 (MAM domain-containing glycosylphosphatidylinositol (GPI) anchor 1. In the following chapters, the SAMs neurexins (NRXNs), neuroligins (NLGNs), MDGAs, and immunoglobin superfamily 21 (IgSF21) are introduced. In our studies, we characterize how the structure-function relationships of SAMs and their interactions within the synaptic cleft could be regulated. We demonstrate the critical structural features of MDGA1 that impact the distribution of its three-dimensional conformations. We show that altering this distribution leads to unique functional consequences, including altered binding to NLGN2 ex vivo but not in vitro. We examine several missense mutations localized to strategic places within the MDGA1 protein structure that would be expected to destabilize the domain interfaces and possibly alter biological function. These results demonstrated that the entire 3D conformation of the MDGA1 ectodomain is critical for its function. The SAM, IgSF21, promotes the formation of inhibitory synapses and is known to bind specifically to NRXN2α (Tanabe et al., 2017). Delineating the IgSF21 3D structure and the IgSF21: NRXN2α interaction mechanism at a molecular level will further advance our understanding of the SAM interactome. We describe our valiant efforts to set up an over-expression system for IgSF21. Our work supports the idea that SAMs are not static adhesion molecules. The trans-synaptic bridges they form (via their interactions) are subject to different regulation mechanisms, some of which leverage key structural motifs
Parenting Beliefs During the Infant Year: Effects on Infant Growth
No full textRapid infant weight gain (RIWG) has been established as an infant predictor of adult diseases such as, coronary artery disease, hypertension, obesity, and diabetes type two. RIWG is well established in the literature with several key contributing factors, including infant feeding modality, ethnicity, maternal basal metabolic rate, socioeconomic status, timing of solid food introduction, and parenting response to infant temperament. The objective of this cross sectional retrospective quantitative study is to identify if parenting beliefs have an effect on infant growth. By better understanding the link between parenting and infant growth, this study will help to add evidence to the state of the science which seeks to establish a predictor set of variables surrounding RIWG. The specific aims of the study are to, (1) identify where along a spectrum of parenting beliefs a participant falls, (2) demonstrate infant growth patterns retrospectively across the first year of life, and (3) understand the impact that parenting beliefs have on infant growth after controlling for a set of predictor variables; maternal age, BMI, highest level of education, socio-economic status, ethnicity, perception of infant temperament, infant gender, breastfeeding status, and timing of solid food introduction. The sample for the study was that of English-peaking moms whose infant was between 12 and 24 months old. The infant must be a singleton, term infant with no medical diagnosis that would impact growth and development. Each mother completed a demographic and parenting survey, had their height and weight measured and then granted HIPPA access to their infant’s growth chart data for review. This sample contained 27 rapid gainers and 45 non-rapid gainers. A t-test looking at parenting style showed that when the infants were split into groups based on the presence of rapid growth or non-rapid growth, structure parenting score was significantly different between the two groups at the p=.02 level while attunement was not. When running a logistic regression with the two parenting variables, structure was again significant as a predictor of rapid weight gain while attunement was not. Using parenting style to better predict whether an infant is at increased risk for RIWG could help nurses tailor interventions to reduce this risk and perhaps effect change long term for both the infant and the mother
An Educational Intervention to Promote IEP Collaboration with Elementary Students
No full textAims: This study aimed to explore the occupational therapists' perceptions of collaborating with elementary students when developing Individualized Education Program (IEP) goals in the education plan. Methods: Sixteen occupational therapists (n = 16) participated in a mixed method pre- and post-experimental study using a one-module educational intervention based on adult learning theories. Results were analyzed descriptively and quantitatively using the Sign Test. Results: The educational intervention significantly changed the occupational therapists' perceptions (Mdn = 1.0) from not collaborating to collaborating with elementary students. However, the participants reported that the organization and team support, time, confidence, and student's functional ability negatively impact their practice to collaborating inclusively. The participants found that group learning activities, literature about collaboration, and paper resources were effective during the educational intervention. Discussion: Outcome measures revealed the educational intervention was effective to inform the occupational therapists about inclusive practices to include elementary students when developing IEP goals. The educational intervention contained evidence-based content and was designed based on blending adult learning principles to construct and apply new knowledge. The pilot study had limitations that can help refine future trainings to include other IEP team members. Conclusion: The educational intervention helped the occupational therapists reflect their perceptions to practice inclusively and equitably in giving elementary students a voice in choice of desired IEP goals. Through collaboration, occupational therapists can shape the elementary student's goals in accordance with the IEP plan. As a client-centered profession, occupational therapists must remain grounded and include elementary students as part of the IEP team
A Naturalistic Inquiry of Nigerian Immigrant Nursing Students’ Experiences in United States (U.S.) Baccalaureate Nursing Programs
No full textNigerian immigrant nursing students have been identified in the literature as having difficulty in making a transition to the teaching methods used in nursing programs in the U.S. Among the problems they experience are understanding the vocabulary and terminology of the Western culture. Previous research suggests Nigerian students remain silent in seeking help regarding the challenges of their learning in part due to the isolation they face from peers and faculty (Sanner, Wilson and Samson, 2002).
There is a paucity of research associated with Nigerian immigrant nursing students and how they acclimate to U.S. nursing programs. This study utilized Naturalistic Inquiry (Erlandson et al., 1993; Lincoln & Guba, 1985) to explore the perceptions and experiences of ten Nigerian immigrant nursing students. Study participants were Nigerian immigrant nursing students and the researcher recruited students enrolled in baccalaureate nursing programs in Texas. Interviews, face-to-face or by telephone, for the ten participants were conducted in a private, agreed upon place.
Data were collected until reaching saturation, indicating data redundancy, and with no new themes evolving. Analyzed data used procedures described by Lincoln and Guba (1985) and Erlandson et al. (1993) to seek emerging patterns. Guided by Lincoln and Guba (1985) procedures, the five emergent themes included Stepping into America, Navigating the Rough Waters, Unexpected Changes, Searching for Consistency, and Hopes of Finding Clarity. Lincoln and Guba’s (1985) criteria were used to evaluate trustworthiness of the data. Study findings revealed that Nigerian immigrant nursing students experience positive and negative encounters with faculty and classmates, challenges and obstacles related to the American English language, their Nigerian accent, family expectations, and work obligations. The study findings may aid U.S. nursing schools and faculty to incorporate strategies in the learning environment to assist Nigerian immigrants and other international nursing students, to better acclimate to Western programs to achieve success
Unmasking Impulsivity as a Glutamatergic Dysfunction Phenomenon: Presynaptic and Postsynaptic Considerations
No full textLoss of impulse control is a pervasive hallmark of many neuropsychiatric disorders, such as bipolar disorder, pathological gambling, schizophrenia, substance use disorders, obesity, etc. Characterized as action without thinking, impulsive behavior is recognized as a complex, behavioral endophenotype with multiple dimensions extending into motor activity, higher level cognition and executive functioning, reward/reinforcing attributes, and motivation. Motor impulsivity refers to the inability to withhold a response or delay gratification, and efforts to unmask its complex neurobiology constitutes ongoing areas of research. Indeed, impulsivity has been characterized as a phenomenon driven by the dopamine (DA) and serotonin (5-HT) systems, however the glutamate (Glu) system, localized throughout the central nervous system and responsible for most excitatory signaling, has largely been left untouched. This is striking because like impulsivity, Glu is heavily involved in many neuropsychiatric disorders, several of which overlap with impulsivity. Classically defined as a system that encodes learning and memory, the Glu system has extended roles in reward signaling and motivation. We conducted a series of preclinical studies that aimed to examine glutamatergic presynaptic and postsynaptic neural substrates in key brain regions underlying motor impulsivity. Impulsivity is thought to be a function of a cortical imbalance that results in excessive “go” signaling (i.e. loss of inhibitory control). We discovered that high trait impulsivity (relative to low trait impulsivity) is characterized by imbalances in N-methyl-D-aspartate receptor (NMDAR) expression and synaptic targeting and stabilization. To test the hypothesis that high motor impulsivity is driven by GluR dysfunction, we administered ketamine, a NMDAR channel blocker that induces synaptic plasticity (i.e. GluR strengthening) and the AMPAkine HJC0122, known for its neuroprotective and enhanced cognitive effects. We observed that ketamine and HJC0122, alone and in combination, reduced motor impulsivity, suggesting that indeed, impulsivity is driven partly by GluR dysfunction. We hypothesized that GluR dysfunction may extend to the nucleus accumbens, a limbic area that is largely known as one of the “reward centers” in the brain and involved in the some of the rewarding and motivational aspects of motor impulsivity. We identified the vesicular glutamate transporter 3 (VGLUT3) as a potential glutamatergic presynaptic target. VGLUT3 co-packages Glu and 5-HT into synaptic vesicle for release at the synapse and is localized to the NAc and other brain regions, such as the dorsal raphe nucleus (DRN). We observed that a loss of VGLUT3 tone attenuates impulsive responding in high trait impulsivity rats. Taken together, we implicate the Glu system, from a presynaptic and postsynaptic perspective, as a modulator of high motor impulsivity. These studies and others will inform future clinical decisions on managing neuropsychiatric disorders characterized by loss of impulse control
Commercial Sexual Exploitation of Children and School Nursing: A Non-Experimental Quantitative Study
No full textUnderlying the healthy learning environments of our nation’s schools are students who are unwillingly entangled in the darkness of a form of human trafficking known as commercial sexual exploitation of children (CSEC). There is substantial and compelling evidence that CSEC is a serious problem in the United States with immediate and long-term adverse consequences for children and adolescents. These victims are attending school and school nurses are uniquely positioned in a frontline role to identify and intervene with victims of CSEC. Therefore, the overall objective of this study was to investigate the awareness, attitudes, and perceptions that Kansas school nurses have regarding CSEC. To attain the objective, a non-experimental quantitative study was conducted using the SNAPS survey. Quantitative data was analyzed and the theoretical framework, School Nurses ‘Seeing’ Youth Vulnerability to Trafficking, was applied. The study revealed that Kansas school nurses significantly lack awareness of CSEC and have negative attitudes regarding CSEC. Surprisingly, Kansas school nurses have positive role perceptions regarding CSEC and their student populations