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Lipid and protein contributions to viral proliferation as studied using MD simulations and advanced MD techniques
No full textHIV infection is a continuing public health crisis with more than 36 million people living with HIV/AIDS and about 1.8 million people newly infected in 2017. Continuous research efforts have given rise to effective treatments to maintain undetectable viral loads for the duration of treatment, but a cure for AIDS has not been determined. The current thesis examines two independent functional processes within the HIV lifecycle using novel computational approaches to further elucidate the mechanisms of viral replication. Membrane fusion is the first step in viral infection, allowing transport of viral contents to the cytoplasm. Due to its necessity within the viral lifecycle and applicability to other biological processes, the fusion process harbors significant information which may help fight various human ailments. Membrane fusion is not understood in molecular detail, but it is thought to proceed through the stalk-pore mechanism with an intermediate hemifusion diaphragm (HD) structure. The HD is a rearrangement of two independent lipid bilayers into a new structure consisting of a three independent bilayers: the two merging bilayers and the HD bilayer consisting of the distal monolayers of the merging bilayers. The rearrangement introduces a line defect surrounding the HD bilayer where the three monolayers involved in the fusion process intersect called the three-junction. Biological bilayers include many types of lipids and proteins with unique functions. In this thesis, we focus on the functionality of negatively curved lipids and the availability of transmembrane lipid transport mechanisms known as flip-flop to stabilize the three-junction region and, by extension, stabilize the HD intermediate structure. The lipid effects on three-junction stability were studied through the use of a highly coarse-grained lipid model, the Cooke Model, which represents lipids as three sequential beads, one head bead followed by two body beads. Negative intrinsic curvature may be incorporated by reducing the size of the head bead and maintaining the size of the body beads thus producing a conical shape. In the first set of studies, the three-junction line defect was removed from the HD interface in order to better understand the effects of this defect on the larger system. Mixed-membrane bilayers were placed on a honey-comb lattice in a environment to allow bilayers to relax but maintain tension and structure of the three-junction. The study was performed with varying degrees of negatively curved lipids at increasing compositions to sweep the available membrane curvature landscape. The results showed that a specific range of membrane curvature was required to stabilize the three-junction without destabilizing the membrane. Without adequate negative membrane curvature, the three-junction ruptured to produce a free-edge and opposing flat bilayer. Both the free-edge and three-junction structures harbor a line tension and the stable structure occurs due to a competition between the free energy of these two systems at a certain membrane curvature. The negatively curved lipids sorted according to the curvature of the three-junction region with depletion occurring when a positively curved free-edge exists and enrichment in the region when the negatively-curved intact three-junction exists. An equation was derived from simple thermodynamic arguments that accurately described the relationship between membrane curvature and three-junction stability reinforcing the dependence. The results of the three-junction study steered further studies into the stability of the three-junction surrounding the HD bilayer. {\it In-situ} HD bilayers of 20 nm in radius surrounded by a tensionless bilayer were simulated using the Cooke Model and varying compositions and degrees of negatively curved lipids. The stability of the HD was found to directly correlate to the composition of negatively curved lipids in the system and the stability of the three-junction. The two independent forms of the three-junction structure, intact and ruptured free-edge, were visualized in the HD systems with similar reliance on membrane curvature as found in the three-junction studies. The HD systems relax to three distinct end results. HD's with the least negative membrane curvature underwent a fission event and ended in two defect free bilayers with no indication of the previous HD or three-junction. These systems included ruptured three-junctions with interchanged free-edge and flat bilayer states with almost no intact three-junction as indicated by visual inspection and the depletion of negatively curved lipids in the region. HD's with moderate negative curvature dissipated the entire HD bilayer but formed a fusion pore connecting the two opposing chambers of the merging bilayers. The rate of dissipation when a fusion pore formed was much slower than when a double bilayer was formed and dissipation occurred through an intact three-junction surrounding the HD bilayer as indicated by significant sorting towards the region during dissipation. HD's with high-moderate membrane curvature relaxed to a stable, long-lived HD structure. When accounting for the intermediate state of the three-junction during dissipation, the HD end-states represent two distinct systems: non-fusogenic systems ending in the double bilayer and proceeding through the free-edge three-junction state and fusogenic systems ending in the fusion pore or stable HD and proceeding through the intact three-junction state. When lipid movement is studied in these two structures, evidence of two competing dissipation mechanisms arose during HD relaxation. In order for the HD to decrease in area, lipids must move from the distal monolayers to the proximal monolayers, a process typically reserved for transmembrane flip-flop movement. The mechanism for the fusogenic, intact three-junction systems proceeds through the flip-flop mechanism as discovered through rates dependent on membrane curvature similar to the flip-flop rates of Cookie lipids and inspection of the structure. For non-fusogenic systems, the dissipation was mostly independent of the composition of negatively curved lipids similar to the lateral diffusive movement of Cooke lipids. The free-edge system produces a flat bilayer connecting the distal and proximal monolayers from the opposing bilayers and thus allows for HD relaxation through a diffusion-based mechanism. Addressing a second important aspect of the viral lifecycle, the thesis continues to study the effect of large scale conformational changes on the binding of a ligand fragment to HIV-1 protease (PR). HIV-1 protease (PR) is a functional protein within the HIV virus. When HIV buds from an infected cell, it does so in the immature state. This state holds the integral proteins as one connected poly-protein. PR is the enzyme which cleaves the poly-protein into smaller functional proteins. Due to it's necessity for viral maturation, PR is a commonly targeted protein for drug development and has been extensively studied using experimental approaches and MD simulations. The current work uses an all-atom, explicit-water MD simulations using the PDB entry 1F7A, a closed-form PR bound with a ligand representative of the GAG poly-protein cleavage site to study the conformational changes present during ligand unbinding. The system was studied through long MD simulations in an NPT ensemble which revealed the closed and bound form of protease is long-lived. Ligand unbinding was studied using Temperature Accelerated MD (TAMD) simulations, a technique which increases the likelihood of rare events through a high-temperature biasing of a slow, auxiliary collective variable (CV) that is adiabatically separated from the atomic system. The slow moving variables in the PR binding process were determined to be (1) flap opening and (2) ligand diffusion and binding. Two unique CV sets are studied to determine the most energetically costly step of flap opening, flap unbinding or conformational opening of the flaps. TAMD simulations revealed (1) the most energetically costly mechanism of flap opening is the unbinding of the flap tips, (2) flaps must open for ligand unbinding to occur, (3) the system does not show preference towards wide flap opening, (4) the system does not show a preference towards threaded or lateral ligand movement, and (5) the system does not show preference towards asymmetric or symmetric flap opening. A hydrophobic pocket distal to the binding pocket is discovered which appears to have significant effects on the preparation of the protein for ligand binding. The distal pocket is found to be related to the engagement of a previously-noted elbow region and remains open in unbound proteins but appears closed in proteins prepared for ligand binding. String method in collective variables (SMCV) was used to study the free energy barriers associated with the conformational change to the wide open flap state and preparing the pocket for ligand entry. SMCV is an advanced MD technique that uses multiple replica simulations to minimize the free energy pathway of an event and uncover the most probable mechanistic pathway. In this case, PR binding mechanism is characterized using trajectories from representative TAMD simulations through two protein movements believed to be crucial for accessibility of the native ligand to the binding site: wide flap opening and distal pocket closing. A correlation is uncovered between releasing contact between the crucial ILE-50 residues at the flap turn and the distal pocket closing. The distal hydrophobic pocket appears to stabilize the wide open conformation by recovering the energy necessary to disengage the flap tips. A crucial residue in the distal pocket, PHE99, is mutated to TYR, a similar but hydrophobic residue. When TAMD is performed on the mutant, the elbow region is resistant to engage and distal pockets remain open. The ligand appears to be unhappy in the binding pocket, quickly exiting. Despite the qualitative change in behavior, when SMCV is performed on the mutant, the resulting free energy profile is very similar to WT. These findings indicate that the energetic costs associated with opening the flaps is much larger than that harbored by the hydrophobic interactions in the distal pockets or the ILE-50 residues.Ph.D., Chemical Engineering -- Drexel University, 201
Geometric and Combinatorial Methods for Digital Elevation Models
No full textDigital Elevation Models (DEMs) are the de facto 3D models used to represent geo-spatial structures in many natural systems and are used in process-based modeling. From a computational perspective, DEMs are discrete, 2D manifold-grids in 3D space from which flow properties can be computed. An important family of problems involves identifying iso-flow surfaces from DEMs at discrete locations. In practical terms, such iso-flow surfaces correspond to sub-regions of the 3D-manifold whose aggregate flow passesthrough a single grid cell. Algorithmic solutions to these types of problems have numerous applications in Geographic Information Systems and Environmental Science research, allowing the efficient mapping of watershed boundaries. Existing algorithms for identifying iso-surfaces run in quadratic complexity as a function of the number of cells on their boundary. Our investigation shows that linear time algorithms to identify iso-surfaces are possible due to the combinatorial geometric properties of DEMs. Finally, a general method to return univariate statistical values for an iso-flow surfaces is developed. These algorithms rely on a number of new data structures, the Modified Nested Sets, Log Reduced Nested Sets, and a Modified Interval Search Tree. In empirical tests we show significant ( 500 faster) for a number of these iso-surface problems.Ph.D., Computer Science -- Drexel University, 201
When Failures are Left Unspoken: a Case Study of How Engineering Design Failure was Situated in an Elementary Science Classroom
No full textThis qualitative research examines design failure within a 5th grade science classroom that embedded engineering design activities. In adhering with a situative learning perspective, the goal of this research was to understand how design failure was portrayed to students through the written and enacted curriculum and in turn, how students described these experiences within a particular context or situation. Data collection included 90 hours of classroom observations, 18 student interviews, one teacher interview, curricular materials, and student artifacts associated with a seven-week science unit on the topic of forces and motion. Data analyses included summative content analysis as well as open-coding procedures designed to identify patterns. Analyses of the research revealed several important findings related to the notion of design failure. First, the written curriculum limited the ways that design failure was portrayed to the students. A primary reason for this was that the curricular materials restricted the emphasis in which engineering design, or even engineering, was presented to the students. Next, the enacted curriculum left the topic of failure unspoken or hidden within the classroom context. The teacher presented the students with implicit notions of failure, such as encouraging them to "try again" despite "challenges" and "difficulties." However, both science investigations and engineering design activities were discussed using these terms, which provided the students with conflicting messages about design failure. Furthermore, the classroom constraints (i.e., time) also provided students with contradictory messages about failure within the context of the classroom. While students received productive messages of persistence and understood the need to "try again," they did not associate these messages with concepts related to design failure. Students descriptions of failure also did not align with conceptualizations of design failure. This could have been due to the fact that they had a limited understanding of the goals of the engineering design challenges or that their definitions of failure were situational in nature.Ed.D., Educational Leadership and Management -- Drexel University, 201
Cooperative Education and Its Impact on the Student Learning Outcomes of Business Undergraduate Students: A Case Study
No full textDuring a college undergraduate's scholastic experience, it should be recognized that learning occurs in many ways, in different places and times, and through a variety of interactions. Deep and enhanced learning transpires when individuals are provided with a complex set of activities to grasp emerging concepts. The study of experiential learning, and cooperative education (co-op) in particular, is significant because it can inform how experiential teaching and learning can help students meet the contemporary challenges of the workplace. The educational experience of each student naturally extends beyond the classroom, and, while ultimately the entire learning experience is unique to each student, an institution that introduces experiential elements, such as a cooperative education, in the curriculum design believes in the academic importance of these elements. Such institutions consider to varying levels of strategies for integration within the total academic experience, rather a niche for these institutions. Within the framework of this study, through an investigation of established student and employer co-op surveys for business majors having participated in three cooperative education experiences, the research provides insights into their perceptions of co-op in the academic experience. This research investigates the extent to which work attributes developed during three co-op terms influenced the learning outcomes of business administration students at Drexel University. The researcher investigated whether students increased in their work attributes while in the co-op program and then mapped the work attributes to the student learning outcomes prescribed by a college of business. Through interviews, the researcher further examined whether feedback collected after the students' co-op experiences was being used to shape the curriculum and guide student development. The findings reveal limitations and opportunities in the survey instrument that may lead to refined survey design and learning outcomes assessment strategies, as well as the increased use of survey data to inform curriculum content and design.Ed.D., Educational Leadership and Management -- Drexel University, 201
Utilizing a convolutional neural network to predict HIV-1 Tat biological functions and the impact of Tat genetic variation on neurocognitive impairment
No full textHuman immunodeficiency virus type 1 (HIV-1) infections have been associated with neurocognitive impairment. However, this cognitive decline occurs at a rate that is specific to individual patients. Evidence suggests that the protein sequence of HIV-1 Tat may have an impact on this rate. The mutations within Tat can affect the biological function of this viral protein. This study proposes to utilize deep learning techniques to perform inference on amino acid changes and their effects on Tat functions. To predict biological functions consistent with annotations of the Gene Ontology (GO) Consortium, a convolutional neural network (CNN) was developed and trained on more than 500,000 GO-annotated sequences from the Uniprot Knowledgebase. Analysis was performed on various lengths of Tat protein sequences, considering the prevalence of naturally truncated Tat protein sequences in HIV-1-infected patients from the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) cohort. Results of processing truncated Tat subtype B sequences with lengths between 20 and 60 amino acids revealed a decreased sequence similarity with proteins found in the nucleus and an increased sequence similarity with proteins associated with pathogenesis, extracellular regions, and cellular toxicity. With the focus of examining which regions of Tat are responsible for its known biological functions, a windowing strategy was implemented. Using 30-mer windows, there was an increase in sequence v similarity to proteins associated with ribosomal function and translation for the Tat polypeptide region between residues 40 and 80. The CNN achieved an area under the receiver operating curve (AUC) of 0.985 for GO predictions and 0.541 for neurocognitive impairment. The evaluation metric of AUC has been used in several peer-reviewed papers, but it is not an ideal evaluation method. Although some neurocognitive impairment (NCI) prediction AUC scores are fairly high, there is little to no correlation between the predicted and calculated, actual score using Pearson correlation.M.S., Biomedical Science -- Drexel University, 201
Guideline to Reduce Door-to-ECG Time Within the Emergency Department
No full textBackground: The American College of Cardiology and the American Heart Association recommend an electrocardiogram be obtained and interpreted within 10-minutes of arrival to improve patient outcomes. Research findings suggest that only 7.4% of patients that presented to the emergency department had an electrocardiogram performed in the first 10-minutes of arrival as recommended by the American College of Cardiology. Purpose: The purpose of this project was to implement and evaluate a quality improvement initiative subsequently improving the door-to-electrocardiogram time. Methods: The foundation of the Doctoral of Nursing Project was based using the Johns Hopkins Nursing Evidence-Based Practice Model. The evidence was used to inform guideline construction. The guideline was implemented into practice using the Plan-Do-Study-Act model. The PICOT question for the project was: In patients who presented to the emergency department with a complaint of chest pain, how did implement a guideline effect obtaining an electrocardiogram within 10-minutes? Evaluation: Statistical analysis was performed using SPSS version 25 software. Data were cleaned and checked prior to analysis. The mean differences between pre-and-post implementation groups in regards to door-to-ECG times were compared using t-test analysis. The significance level was 0.05. The t-test determined the means of the pre-post implementation data sets differed significantly. A statistician was consulted for additional guidance, as one was available for consultation. Results: Before implementation, the mean door-to-ECG time was 28.8-minutes. Post-implementation, the mean door-to-ECG time was 16.6-minutes. A t-test to compare the means of the door-to-ECG times from September 2018 and May 2019 using a level of significance of 0.05 identified a statistical difference between the pre–and post-implementation groups. The t-test demonstrated there was a correlation to the intervention and the door-to-ECG time.D.N.P., Nursing Practice -- Drexel University, 201
The Effect of Simulation on the development of Clinical Judgment in Second-Degree Nursing Students
No full textNurses are challenged to use critical thinking skills and make sound clinical judgment in achieving optimal patient outcomes and improving patient safety (Alfaro-LeFevre, 2017). Clinical judgment is the ability to interpret patient data, and develop appropriate and timely interventions (Bussard, 2018). The effect of simulation on the development of clinical judgment has been investigated extensively in traditional nursing students. The rapid development of second-degree nursing students to address the nursing shortage (Sedgwick, Kellet, & Kalischuck, 2014), requires further investigation of the effect of simulation on the development of clinical judgment in second-degree nursing students. Opportunities for simulation experiences promote the development of clinical judgment in second-degree nursing students (Mariani, Cantrell, Meakin, & Jenkinson, 2015). This study encompassed a regularly scheduled simulation experience for students enrolled in a gerontology course in a second-degree nursing program. The study used a cross sectional design and encompasses an educational preparation video and demographic survey prior to the simulation. The Lasater Clinical Judgment Rubric (Lasater, 2007) was used post debriefing and reflection to assess the effect of the simulation on the development of clinical judgment. Statistical analysis using SPSS software was used for data analysis, results, and understanding the implications for translating the evidence into practice.D.N.P., Nursing Practice -- Drexel University, 201
Wireless Network-on-Chip for Multi-Die Systems
No full textHigh performance computing and the need for processing power have cultivated increasing number of on-chip processing elements (PEs), therefore increasing the total overall area. The increase in distance has a negative effect in packet latency, congestion, and total throughput of the system. Network-on-Chip (NoC) is the de facto communication infrastructure for these large scale processors. Wireless NoCs, through the inclusion of on-chip antennas, are introduced to improve the performance of long-distance communication within a package. On-chip wireless interconnects offer improved network performance due to improved long distance communication, additional bandwidth, and broadcasting capabilities of antennas. This dissertation challenges the on-chip antenna design conventions, and pushes toward a Through-Silicon Via (TSV)-based antenna design called "TSV_A" that establishes multi-band wireless communication for computing packages. Finite element method simulations, printed circuit board prototyping, and system-level network simulations show that TSV_A is the perfect candidate for improved signal performance and flexibility in design and implementation. Comparisons to traditional wire-based NoCs, technology scaling to demonstrate the substantial area improvements, and analysis of wireless multi-bands are performed. In addition, this dissertation introduces a scalable interconnect infrastructure for multi-die system with multiple 3D chiplets connected through an active interposer and compatible with TSV_A.Ph.D., Electrical Engineering -- Drexel University, 201
Exploring the Principal-Assistant Principal Relationship to Discover Principal Practices Influencing the Assistant Principal's Instructional Leadership: A Case Study
No full textInstructional leadership must be consistent and pervasive in order for principals to lead schools and meet the ever-evolving needs of students. Over the years, the role of the building principal has evolved from building manager to instructional leader. While this evolution has engrossed much scholarly attention, minimal research has been conducted regarding the role of an assistant principal. The roles and responsibilities of assistant principals vary greatly depending on the principal, who determines the responsibilities he or she is willing to share or delegate to their assistant. To assist with providing consistent and pervasive instructional leadership, the role of the assistant principal must be called upon to develop instructional leadership. This qualitative study explored the unique experiences of two assistant principals practicing instructional leadership in a Pennsylvania high school. The intrinsic case study approach was selected in order to develop an in-depth description and analysis of how the assistant principals experience the dynamics of their relationship with their principal and the principal practices leading to the development of the assistant principals as instructional leaders. The researcher explored the central research question: How does the working relationship between a high school principal and assistant principals influence the assistant principals' instructional leadership? Additionally, the following sub-questions were explored: 1. How do high school administrators in a Pennsylvania district describe the essential skills and responsibilities of an instructional leader? 2. How do high school administrators in a Pennsylvania district describe the roles and responsibilities of assistant principals? 3. How do high school administrators in a Pennsylvania district describe principal practices that support assistant principals' instructional leadership? This qualitative case study extends current research and provides a greater understanding of how a high school principal in south, central Pennsylvania fosters the instructional leadership of his assistant principals. Data collection included semi-structured interviews and a review of documents, totaling 11 datasets. Data analysis yielded five major themes including: (a) Instructional Leaders Know and Show the Way, (b) Assistant Principals Serve as Liaisons, (c) Communication is Critical to Instructional Leadership, (d) Assembling a Strong Principal-Assistant Principal Team, and (e) Principals Facilitate the Leadership Development of Assistant Principals. Five primary results derived from the findings: (a) instructional leaders create and communicate a shared vision, provide teachers with individualized professional learning, and are committed to personal growth; (b) assistant principals and principals fulfill similar instructional leadership responsibilities; however, the role of the assistant principal is reactive in nature and the assistant principal serves as a liaison between the principal and all stakeholder groups; (c) principals and assistant principals must engage in open and honest communication in all directions in order to fulfill their leadership roles and increase their leadership growth, specifically with regard to instructional leadership; (d) when hiring an assistant principal, principals need to find a candidate that possesses a similar philosophy, but different strengths in order to assemble a strong, compatible team; and (e) principals must facilitate the leadership development of their assistant principals by getting to know their interests and strengths, empowering and supporting them, and providing meaningful leadership opportunities. The following recommended principal practices emerged during the research study. To assist with establishing the roles and responsibilities of assistant principals as instructional leaders, principals should: (a) foster professional learning networks to stay abreast of current best practices in education; (b) look for assistant principal candidates with similar philosophical beliefs, but varied strengths and differing skill sets; (c) create and communicate the specific roles and responsibilities of assistant principals; (d) assume the role of mentor and create opportunities to provide guidance to assistant principals while partaking in leadership tasks together; (e) spend time with their assistant principal every day; (f) schedule time each day to dialogue with their assistant principals--discussions should include brainstorming, planning, reflection, and feedback; (g) provide opportunities to assistant principals who align with the assistant principal's interests and strengths; (h) provide assistant principals with opportunities to communicate with all stakeholders; (i) delegate authentic, meaningful instructional leadership tasks to assistant principals; (j) model and hold high expectations for the assistant principal's instructional leadership; (k) identify teacher leaders and provide them with exposure to administrative activities and responsibilities; and (l) keep administrative teams intact as long as possible. The results could assist with redefining and restructuring the roles and responsibilities of assistant principals to include instructional leadership to improve student and school performance.Ed.D., Educational Leadership and Management -- Drexel University, 201
Female Sportscasters and the Issue of Gender Equality in Sports Television
No full textWomen who aspire to enter the field of TV sports casting confront many barriers arising out of the structure of legacy media corporations and their hiring and retention practices. Once they gain entry to positions in sports journalism, women often find that they are not treated seriously and this situation can affect their on-air assignments and advancements. this study addressed these issues as seen through the eyes of incumbent female sportscasters. Sports Journalism has been a difficult area for women to enter and be taken seriously.M.S., Television Management -- Drexel University, 201