16484 research outputs found
Sort by
Exploring the functionality of novel small molecule DAVEIs on HIV-1
No full textAlthough there have been many gains made in the fight against HIV it remains a global health crisis. Drug and vaccine development have focused on targeting the HIV envelope proteins (Env) for they are expressed across all strains of virus and thus can be broadly neutralizing. The Chaiken lab has recently developed a new type of Env targeting molecule called the dual acting virucidal entry inhibitor (DAVEI). The DAVEI molecule was originally a recombinant chimera comprised of the gp120 targeting protein cyanovirin-N (CVN) linked via a peptide linker to the gp41 targeting peptide sequence termed MPER. The exact mechanism of DAVEI lysis is currently unknown, however the prevailing theory suggests the dual binding of the CVN and MPER to gp120 and gp41 respectively leads to a tension that disrupts the stability of the membrane causing lysis. In order to determine the potential for a more translatable DAVEI, a new small molecule was synthetically engineered. This was done by first replacing the warhead CVN protein with the previously established gp120 binding cyclic peptide AAR029b (29b). Second, the MPER peptide was replaced with the MPER truncated peptide Trp3 and finally the linker was changed to a polyethylene glycol (PEG) polymer. This molecule was synthesized using solid phase peptide synthesis and characterized for lysis using a p24 sandwich ELISA, for antiviral activity using a luciferase based antiviral assay, and for gp120 binding activity via a 17b competition ELISA. Characterization of the small molecule DAVEI design showed first that it was able to induce viral lysis however with a weak potency. Second, it was shown that the small molecule DAVEI was able to demonstrate antiviral activity however with a weaker potency than the warhead group alone. Finally, it was shown that the small molecule DAVEI bound monomeric Yu2 gp120 with a lower affinity than the warhead group alone. The observed DAVEI lytic, antiviral, and gp120 binding characterization demonstrated that these mechanisms of action are translatable to smaller peptidic components. Although the small molecule DAVEI design lacked efficacy in the areas of examination, it has set the groundwork for future development of a more translatable designs.M.S., Biomedical Engineering -- Drexel University, 201
A New Approach to Detecting Frame Deletion in H.264 Encoded Digital Video
No full textDue to the increasing prevalence of falsified video content, it is important to be able to identify altered video recordings. For certain types of video, removing small portions of content can change the perception of the events that transpire without leaving visually detectable evidence. In particular, removing a set or sequence of frames from the beginning of a video can change the context of surrounding events, especially in newsworthy content. Digital forensic techniques have been developed to detect this type of video manipulation, but were originally proposed for use on MPEG-2 video. Advances in video encoding, particularly in MPEG-4 and H.264 have called the effectiveness of these techniques into question. In this thesis, we examine the performance of detectors built using the methodology from MPEG-2 when applied to H.264 video, and show that indeed new methods are needed to detect frame deletion in modern video. We propose a new method for extracting fingerprints left behind by frame deletion in H.264 as well as an expanded frame deletion detection framework for ensuring robustness across videos captured by different camera models as well as variation in scene content or motion. We evaluate the performance of our proposed techniques as well as examine current limitations.M.S., Computer Engineering -- Drexel University, 201
The Effects of Corporate Litigant Counterparties Sharing an Auditor
No full textI find economically significant effects to interfirm litigation disclosure and outcomes when both corporate counterparties share the same auditor. Shared auditors have concern to mitigate biased disclosure of an event occurring between their adversarial clients. I find defendant litigants sharing an auditor with their counterparty are more likely to recognize litigation threats in their financial disclosure and are less likely to disclose, expectedly biased, predictive loss estimates. In testing outcomes of litigation, I do not find evidence consistent with shared auditors acting as information intermediaries between counterparties during legal arbitration, which would result in shorter litigation duration or greater likelihood of negotiated settlement. However, I find support for their monitoring role, ex-post litigation, as a mutually shared and trusted agent. This is evidenced by an increased likelihood that settlement contracts include beneficial provisions that extend beyond loss payments (e.g. licensing agreements, partnerships, loans) which are aided by increased monitoring of contractual fulfillment and the application of consistent accounting treatment for contractual terms. Additional tests support these findings.Ph.D., Accounting -- Drexel University, 201
Investigating the Pathogenesis of Pre-clinical Diabetic Retinopathy: Transcription Factor Sp1 Glycosylation Upregulates VEGF-A
No full textDiabetes mellitus is a devastating metabolic disease. One of the earliest diabetic complications involves damage to the retina, known as diabetic retinopathy (DR). DR is indolent and progressively damages the tissue parenchyma and microvasculature, leading to blindness. Intermittent retinal exposure to hyperglycemia initiates a durable cascade of molecular consequences including upregulation of the pro-angiogenic factor vascular endothelial growth factor A (VEGF-A). This factor is central to DR pathogenesis, but initiation of VEGF-A upregulation is not well understood. In Müller glia and retinal pigment epithelium, transcription factor Sp1 and glucose-driven post-translational modification by O-GlcNAc were required for VEGF-A promoter stimulation and upregulation. The role for Sp1-specific O-GlcNAcylation was evaluated using a series of Sp1 point mutants. This analysis revealed that VEGF-A upregulation and secretion required modification of zinc finger Ser698 and 702. Glucose-driven upregulation of plasminogen activator inhibitor 1 (PAI-1) and transforming growth factor [beta]1 (TGF[beta]1) were also O-GlcNAc-dependent, but Sp1-independent. VEGF-A expression is negatively regulated through Sp1 sequestration by the anti-angiogenic tumor suppressor von Hippel Lindau (VHL) protein. The Sp1-VHL interaction was interrupted by hyperglycemia and restored by inhibition of PKC[zeta]. PKC[zeta] inhibition also abrogated glucose-driven VEGF-A and TGF[beta]1. As PKC[zeta] is an Sp1 kinase, the complex interplay between Sp1 modifications remains to be resolved. This investigation reveals a novel mechanism by which glucose drives pathological expression of VEGF-A. We report for the first time that Sp1-VHL complexes form in retinal cells and are dissociated by hyperglycemia. Inhibition of O-GlcNAc effectively prevented VEGF-A, PAI-1, and TGF[beta]1 upregulation, making it a compelling therapeutic target. Overall, these data contribute to our understanding of pre-clinical DR pathogenesis, as well as identify novel aspects of disease for future study.Ph.D., Molecular and Cell Biology and Genetics -- Drexel University, 201
Exploring Graduate Students' Perceptions of Using Social Media in Education Coursework
No full textThis study examined social media in graduate coursework and provides insight into how faculty and higher education administrators can strategically incorporate social media into graduate school coursework. Moreover, this study bridges an existing literature gap regarding graduate students' perceptions of social media use and its impact on their learning. Several research studies have linked the use of social media with improved academic performance; however, the role of social media as a pedagogical tool to support learning through academic engagement and collaboration in graduate education coursework needs further exploration. Millennials and post-millennials (ages 18-42) quickly embrace and adopt new technology, and most are either in graduate school or will be in the future. Higher education can use such tools, including social media, to connect more academically with their students, who are frequently on these platforms. Conducted over a one-month period, this cross-sectional study empirically examined the perceptions, attitudes, and experiences that graduate students hold about the pedagogical use of social media to support learning, academic engagement, and academic performance. An online quantitative survey collected data on 1,212 students enrolled in graduate courses in one university's School of Education. The survey results confirmed that social media was a useful pedagogical tool in graduate coursework to support academic performance and collaboration among students. While results partially supported that using social media in graduate coursework improved collaboration among students, it did not fully support improved collaboration between students and their professors. This study included a single discipline at a single institution; future research would benefit from a more robust study that included multiple disciplines or multiple institutions. Keywords: graduate education coursework; social media; pedagogical tool; academic performance; learningEd.D., Educational Leadership and Management -- Drexel University, 201
Knowledge Retention in Older Adults with Heart Failure and Impact on Readmission
No full textPeople are living longer due to the development of improved care modalities and older adults comprise the most rapidly growing percentage of the population (National Council on Aging, 2016). Congestive Heart Failure (CHF), a complication of Coronary Artery Disease (CAD), is a frequently diagnosed disease syndrome in this age group and is associated with increased hospital admissions because of its complexity (Ding, Yehle, Edward & Griggs, 2014). Decreased length of stay, additional comorbidities and perceptual/functional deficits also place elderly individuals at risk for acute care readmissions within 30 days or less (Whittaker, Sonia & Erich, 2015). The frequency of early readmissions is problematic from both a quality of care and cost perspective (Centers for Medicare and Medicaid Services, 2014). If patients are considered clinically stable at discharge it is important to investigate what issues contribute to these rates and are they addressed comprehensively. Transfer from the hospital setting to the home environment is a vulnerable transition period and can result in potential setbacks (Albert, Trochelman, Li & Lin, 2009; Moser, Doering & Chung, 2005). The Discharge Planning Process, a broad spectrum of education and identification of needed services, can be implemented at various times during a hospital stay based on the facility’s protocol (Hunter, Nelson & Birmingham, 2013). Patients and families need accurate information and time to absorb the material in order to manage possible setbacks using learned self-care skills (Paul, 2008; Rockwell & Riegel, 2001). The quality of educational content is critical to building confidence in self-care management (Rockwell & Riegel, 2001).D.N.P., Nursing Practice -- Drexel University, 201
PSD-95 deficiency disrupts PFC function and connectivity leading to sociability and cognitive deficits
No full textPostsynaptic density protein-95 (PSD-95) is a major regulator in the maturation of excitatory synapses by interacting and trafficking N-methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane of the dendritic spine. The medial prefrontal cortex (mPFC)--a brain region responsible for cognition and sociability--contains major reciprocal connections with the mediodorsal thalamus (MD), and this connectivity is severely disrupted in psychiatric disorders such as schizophrenia and autism. Coincidently, PSD-95 disruption has been implicated for both disorders, but how PSD-95 deficiency affects the mPFC during development and MD-mPFC connectivity remains unknown. Therefore, using PSD-95 deficient mouse models (PSD-95+/- & PSD-95-/-), we examined how PSD-95 deficiency affects NMDAR and AMPAR expression and function in the medial prefrontal cortex (mPFC) at postnatal days 21, 35, and 70 i.e., juvenile, adolescent, and adult periods, respectively. We found significant increases in total protein levels of NMDAR subunits GluN1, and GluN2B, accompanied with a significant decrease in AMPAR subunit GluA1 during adolescence. Whole-cell patch clamp recordings of NMDA- and AMPA-mediated currents revealed significant increases in NMDAR/AMPAR-mediated current amplitude during adolescence and adulthood. Behaviorally, we show PSD-95-/- mice exhibit a lack of social exploration and novelty, accompanied with learning and working memory deficits. Additionally, using optogenetics, we characterized cortico-cortical verses thalamo-cortical connections within the mPFC. Our results revealed a significant increase in NMDAR/AMPAR-mediated current amplitude ratio in cortico-cortical connections. In contrast, there is a significant reduction in NMDAR/AMPAR-mediated transmission in MD-mPFC connection in PSD-95+/- and PSD-95-/- mice. These data suggests input specific alterations within the mPFC in response to PSD-95 deficiency. These data indicate that PSD-95 deficiency disrupts mPFC synaptic function, connectivity and mPFC-associated behavior. This study describes the importance of PSD-95 during neurodevelopment in the mPFC and its potential roles in social and cognitive dysregulations.Ph.D., Neuroscience -- Drexel University, 201
Unexpected Gelators with Unforeseen Properties: A Spectroscopic Investigation of Alanine-Based Self-Assembling Hydrogels
No full textSelf-assembly of biomolecules is a prominent issue explored in biomedical, biophysical, and biomaterial research. Understanding how and why certain peptides/proteins prefer to self-assemble into larger networks can reveal the mechanism of amyloid formation and assist in bottom-up designs of supramolecular structures like gels and nanotubes. Hydrogels formed by polypeptides could be much-favored tools for drug delivery and other biotechnical applications due to their main ingredients being biodegradable. However, the gelation of peptides in aqueous solution is generally thought to require a minimal length of the peptide chain, as well as distinct sequences of hydrophilic and hydrophobic residues. This biodegradability and cheap manufacturing costs are increased for shorter peptides, but a high degree of hydrophobicity or aromaticity was deemed necessary. Contrary to expectation, it was discovered that cationic glycyl-alanyl-glycine (GAG) in ethanol/water mixtures forms a gel comprised of network spanning fibrils several 100 μm long. To explore how ethanol solvation and solvent-peptide interactions prepare the system for aggregation and fibrillization, we utilized amide I band profiles along with J-coupling constants and chemical shift from NMR measurements to observe conformational changes of the alanine residue caused by the addition of ethanol. We propose that GAG accumulates on the ethanol/water interface, which would increase the effective chemical potential of the peptide and thus would facilitate its self-assembly. We first focused our investigation of the gelation phase on 220 mM GAG in 55 mol% ethanol/45 mol% water. Rheology shows that under optimal conditions, the storage modulus is 106 Pa. UVCD, VCD and IR measurements, supported by DFT calculations, suggested that the underlying structure of the fibrils is dependent on the formation temperature of the fibrils and that it is not solely comprised of β-sheets. It was determined through annealing cycles that the fibrillar aggregates are not the thermodynamically preferred structure. Instead, amorphous aggregates were formed and stable. At short incubation times, the reformed gels are weakened suggesting the strength of the gel and melting temperature can be easily tuned. A phase diagram was constructed by systematically adjusted the amount of GAG dissolved into different ethanol/water mixtures. We observed that the gel phase is stabilized by increasing the ethanol fraction more so than by an increase of the peptide concentration. UVCD was utilized to determine the melting temperature of all formed gels to add a third dimension to the phase diagram.Ph.D., Chemistry -- Drexel University, 201
Reproductive History as a Surrogate for Lifetime Exposure to Unopposed Estrogen and Potential Mediation of its Association with Cardiovascular Disease by Inflammation
No full textEach year, cardiovascular disease (CVD) causes 1 in 3 deaths, killing approximately one woman every 80 seconds. While the burden of CVD can be explained by conventional risk factors (hypertension, smoking, overweight and obesity, diabetes, and elevated cholesterol), between 20 and 50 percent of CVD-related deaths occur among women without conventional risk factors or preexisting disease. Estrogen has been shown to be cardioprotective, however, the exact influence of timing and dosage of exposure over a woman's lifetime remains unclear. Reproductive history has gained prominence as a surrogate measure of estrogen exposure and a "sentinel of chronic disease" --- capturing rapid changes in cardiometabolic profiles. While studies have shown that independent of the natural aging process, reproductive history is associated with CVD risk, the mechanisms that mediate its effect on CVD risk are not fully understood. This dissertation examines how the use of reproductive history as a proxy for lifetime exposure to unopposed estrogen combined with inflammation in impacts the accuracy of CVD risk modelling. The first paper quantifies age at menarche, first pregnancy, and menopause into a measure of duration of unopposed estrogen exposure in women and utilizes this measure of estrogen exposure to assess the association between estrogen exposure and CVD risk. The second paper examines the role of inflammation as a mediator in the relationship between duration of estrogen exposure and CVD risk. The third paper tests the effectiveness of duration of estrogen exposure and inflammation in predicting CVD risk, compared to traditional CVD risk factors.Ph.D., Epidemiology -- Drexel University, 201
The Role of GSK3[beta] in the Parvalbumin-Pyramidal Prefrontal Cortex Microcircuit
No full textGlycogen synthase kinase 3[beta] (GSK3[beta]), an enzyme classically focused on in the context of metabolism, has gained interest regarding its involvement in psychiatric and neurodegenerative disorders largely due to the beneficial effects of lithium, a direct inhibitor of GSK3[beta], administration in both animal research and clinically. Recently GSK3 inhibitors were highlighted as promising rescuers of cognitive impairments for a gamut of CNS disorders. Complex cognitive behaviors regulated by the prefrontal cortex (PFC) depend on an optimal balance of excitation and inhibition (E/I), which is essential for driving computational activity of cortical circuits. Glutamatergic pyramidal neurons mediate the excitatory component, while GABAergic interneurons facilitate inhibition. Growing evidence supports that fast-spiking parvalbumin (PV) interneurons are critical regulators of the E/I balance, shaping and synchronizing excitatory activity that improves clarity through contrast. Furthermore, disruption of either NMDARs or PV-GABAergic neurotransmission is strongly implicated in disorders with cognitive impairments. Albeit, how excitatory receptors on PV interneurons are regulated and how this affects cognitive function remains unknown. Our previous findings support that GSK3[beta] is a promising therapeutic target, leading us to elucidate its role in PV interneurons. To address these questions, we have generated a novel triple-transgenic conditional mouse with GSK3[beta] genetically deleted from PV interneurons. PV-GSK3[beta]-/- resulted in increased excitability and sensitivity to synaptic inputs, as well as augmented excitatory synaptic strength in PV interneurons. PV-GSK3[beta]-/- also demonstrated augmented NMDA functionality in mPFC pyramidal neurons. More importantly, these synaptic changes are correlated with accelerated learning with no changes in locomotion and sociability. Our study, for the first time, examined how GSK3[beta] activity affects learning capability via regulation of PV interneurons. This study provides novel insight into how GSK3[beta] may contribute to the disorders afflicted by cognitive deficits.Ph.D., Neuroscience -- Drexel University, 201