Calendar

Dissertation Defense

Candidate: Christopher Lockhart
Title: All-Atom Explicit-Solvent Replica-Exchange Molecular Dynamics Simulations of the Alzheimer’s Disease Aβ Monomer

Abstract:

Using all-atom explicit-solvent replica-exchange molecular dynamics simulations, we have explored the changes in the conformational ensemble of the Aβ monomer in various environments. In the simplest case, the Aβ monomer in water forms mostly turn and random coil conformations. We show that the anti-aggregation agent ibuprofen, the zwitterionic DMPC lipid bilayer, and even the introduction of sequence truncation (to generate the Aβ29-40 monomer) are capable of dramatically altering Aβ conformations, resulting in stable helical structure present in the peptide’s C-terminal. For comparison, the FDDNP biomarker and other sequence truncations (e.g., Aβ23-40 and Aβ28-40 monomers) do not exhibit a strong influence on Aβ conformations. Thus, we conclude that there is an inherent helix propensity in the Aβ C-terminal that can be revealed by certain environments.

More specifically, our work has demonstrated that the small ligands ibuprofen and FDDNP bind to the Aβ monomer via the hydrophobic effect. Although ibuprofen promotes a change in Aβ helical content, its low binding affinity and stabilization of the Asp23-Lys28 salt-bridge may partially explain its modest efficiency as an anti-aggregation agent. At the same time, the biomarker FDDNP induces minor change in the Aβ conformational ensemble but binds with high affinity partially due to ligand clustering at hydrophobic binding sites. Although we argue that this benign effect on Aβ is advantageous for in vivo neuroimaging of Aβ fibrils, the high affinity binding of FDDNP to the Aβ monomer raises the question of selectivity of this biomarker.

Finally, we have investigated the interactions of the Aβ monomer with the zwitterionic DMPC bilayer. The bilayer causes a dramatic structural transition in Aβ, resulting in stable C-terminal helix and formation of the Asp23-Lys28 salt-bridge. The central hydrophobic cluster and C-terminal of Aβ not only govern binding to the bilayer but also penetrate into the bilayer hydrophobic core. As a result, Aβ reduces the density of lipids in its binding footprint and indents the bilayer. Addition of calcium to these simulations results in a more profound effect, where lipid disorder and bilayer thinning by Aβ are enhanced. These effects can be explained by a strengthening of Aβ-bilayer interactions by calcium via enhanced electrostatic interactions between charged amino acids and lipid polar headgroups. Binding of Aβ does not affect either water or calcium permeation into the bilayer. We propose that the limited scope of structural perturbations in the zwitterionic bilayer caused by the Aβ monomer represents the molecular basis of its low cytotoxicity.

Director or Committee Chair:

Dr. Dmitri Klimov

Committee:

Dr. Iosif Vaisman
Dr. Saleet Jafri
Dr. Estela Blaisten-Barojas

Notes: A copy of the dissertation is available in the Mercer Library, Prince William Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Gideon Bass
Title: Ensemble Supervised and Unsupervised Learning with Kepler Variable Stars

Abstract:

Variable star analysis and classification is an important task in the understanding of stellar features and processes. While historically classifications have been done manually by highly skilled experts, the recent and rapid expansion in the quantity and quality of data has demanded new techniques, most notably automatic classification through supervised machine learning. I present a study on variable stars in the Kepler field using these techniques, and the novel work of unsupervised learning. I use new methods of characterization and multiple independent classifiers to produce an ensemble classifier that equals or matches existing classification abilities. I also explore the possibilities of  unsupervised learning in discovering novel feature of these stars.

Dissertation Director:

Dr. Joe Weingartner

Committee:

Dr. Kirk Borne
Dr. Michael Summers
Dr. Ruixin Yang

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Massih Abawi
Title: Imbalance of Selected Hormones in Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)

Abstract:

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition affecting about 70% of obese individuals and is now considered a major cause of liver-related morbidity and mortality.  NAFLD encompasses a spectrum of hepatic pathologies with excessive accumulation of fat in the liver in patients consuming less than 20 grams of alcohol per day.  NAFLD related liver injury ranges from simple hepatic steatosis to more severe forms of the disease including NASH, which can progress to fibrosis, cirrhosis, and ultimately organ failure.  There is evidence that causally links NAFLD with imbalance of various hormones, especially these also involved in the development of insulin resistance and obesity.

The research presented herein involves quantitation of various soluble hormones in serum of morbidly obese bariatric patients with different confirmed stages of NAFLD. The first study explores the role of vitamin D deficiency in NAFLD/NASH patients. Serum samples of 210 morbidly obese bariatric patients were profiled for the following markers: 25(OH)D3; Vitamin D Binding protein (VDBP); Intact Parathyroid Hormone (1-84) and Cytokeratin 18 (M30) levels.  The second study herein profiles three small gastric peptides, acylated ghrelin (AG), non-acylated ghrelin (DAG), and Obestatin, and a number of proinflammatory cytokines in circulation of patients with obesity related NAFLD.  In both studies, correlation analysis was conducted to associate these biomarkers with clinical parameters routinely measured in NAFLD patients, including histological scores of inflammation and fibrosis of their liver biopsies, and predictive regression models were built. A third study reported herein investigates the interplay of circulatory melanogenesis-related hormones, α-Melanocyte Stimulating Hormone (α-MSH) and Melanin Concentrating Hormone (MCH), with NAFLD and obesity-induced low grade chronic.

Director or Committee Chair:

Dr. Ancha Baranova

Committee:

Dr. Kylene Kehn-Hall, Dr. Emanuel F. Petricoin III, Dr. Timothy Born

Notes: The thesis is on reserve in Gateway Library, Science and Technology Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Mohammed Sikder
Title: A Regional Crops Forecasting Model Integrating Satellite Remote Remote Sensing with the Localized EPIC Model

Abstract:

Airborne and satellite remote sensing data adds tremendous value in assessing crops phenology, green biomass, and yield forecasting. Also, satellite-based real/near-real time data is used for monitoring growth rates, water and nutrient status, and crop responses to biotic and abiotic stress conditions which could assist with efficient crop management decisions. The objectives of the study were to develop a regional crop yield and area estimation forecasting model for winter wheat in the Texas Panhandle integrating satellite remote sensing data with the localized EPIC crop forecasting model. The Normalized Difference Vegetation Index (NDVI) pixel-level precision data from the Landsat 7 (ETM+) sensor  spanning 5 years (2000, 2005, 2012, 2013, and 2014) during the period 2000-2014 for five counties of the Texas Panhandle region (~14,948 sq. km.) were used for this research and model development efforts. As part of the study, a sophisticated Java Application Programming Interface (API)-based set of toolkits called the Hi-Speed Interactive Landsat Image Processing (HILIP) was developed for processing a massive amount of satellite data as part of an Integrated EPIC model. The software is capable of doing complex image processing including supervised and Landsat-NDVI-based classification with almost 80-90% overall accuracy. This tool is also loaded with the capabilities for pixel-level geophysical positioning and area computation. In this study, an integrated Yearly Winter Wheat Yield prediction model has been developed. In this effort, USDA-NASS reports, adjusted with the EPIC simulated yearly winter wheat yield (bushels/acre) was integrated with the county total harvested winter wheat area (acres) calculated by the Landsat 7 (ETM+) using an NDVI-based model giving the total winter wheat yield in bushels for a specific county in a specified year. Additionally, a statistical winter wheat yield forecasting model was also developed. In this model the county-specific average yearly yield was calculated by taking past 15 years of yield data for that county, giving the yield in bushels/acre, and then multiplying by the Landsat 7 (ETM+) NDVI model-based total harvested winter wheat area for that county, resulting in the total winter wheat yield in bushels for that county for the specified year. The results suggest that the overall accuracy of the Integrated EPIC-NDVI model is within the 80-90% range and the accuracy of the NDVI-NASS statistics-based model is within 70-80%.

Director:

Dr. Ruixin Yang

Committee:

Dr. Daniel B. Carr, Dr. J Qu, Dr. Fernando Camelli

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Phillip Hess
Title: Understanding the Evolution and Propagation of Coronal Mass Ejections and Associated Plasma Sheaths in Interplanetary Space

Abstract:

A Coronal Mass Ejection (CME) is an eruption of magnetized plasma from the Corona of the Sun. Understanding the physical process of CMEs is a fundamental challenge in solar physics, and is also of increasing importance for our technological society. CMEs are known the main driver of space weather that has adverse effects on satellites, power grids, communication and navigation systems and astronauts. Understanding and predicting CMEs are still in the early stage. In this dissertation, much improved observational methods and advanced theoretical analysis are used to study CMEs.

Unlike many studies in the past that treat CMEs as a single object, this study divides a CME into two separate components: the ejecta from the corona and the sheath region that is the ambient plasma compressed by the shock/wave running ahead of the ejecta; both structures are geo-effective but evolve differently. Stereoscopic observations from multiple spacecraft, including STEREO and SOHO, are combined to provide a three-dimensional geometric reconstruction of the structures studied. True distances and true vector velocities of CMEs are accurately determined, free of projection effect, and with continuous tracking from the low corona to 1 AU.

To understand the kinematic evolution of CMEs, an advanced drag-based model (DBM) is proposed, with several key improvements to the original DMB model. First, the new model allows the drag parameter to vary with distance; the variation is constrained by the necessary conservation of physical parameters. Second, the deviation of CME-nose from the Sun-Earth-line is taken into account. Third, the geometric correction of the shape of the ejecta front is considered, based on the assumption that the true front is a flattened croissant-shaped flux rope front.

These improvements of the DBM model provide a framework for using measurement data to make accurate prediction of the arrival times of CME ejecta and sheaths. Using a set of seven events to test the model, it is found that the evolution of the ejecta front can be accurately predicted, with a slightly poorer performance on the sheath front. To improve the sheath prediction, the standoff-distance between the ejecta and the sheath front is used to model the evolution. The predicted arrivals of both the sheath and ejecta fronts at Earth are determined to within an average 3.5 hours and 1.5 hours of observed arrivals, respectively. These prediction errors show a significant improvement over predictions made by other researchers. The results of this dissertation study demonstrate that accurate space weather prediction is possible, and also reveals what observations are needed in the future for realistic operational space weather prediction.

Director or Committee Chair:

Dr. Jie Zhang

Committee:

Dr. Dusan Odstrcil
Dr. Arthur Poland
Dr. Robert Weigel
Dr. Chi Yang

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: David Hamilton
Title: Machine-Readable Knowledge Management of Neuron Properties

Abstract:

The advancement of neuroscience, perhaps one of the most information rich disciplines of all the life sciences, benefits greatly from neuroinformatic techniques to manage the vast amounts of data generated by the research community to promote novel insights and integrated understanding. Since Cajal, the neuron remains a fundamental unit of the nervous system, yet even with the explosion of information technology, we still have few comprehensive or systematic strategies for aggregating cell-level knowledge.

Widely spread naming inconsistencies in neuroscience pose a vexing obstacle to effective communication within and across areas of expertise. This problem is particularly acute when identifying neuron types and their properties. Hippocampome.org is a web-accessible neuroinformatics resource that organizes existing data about essential properties of all known neuron types in the rodent hippocampal formation. Hippocampome.org links evidence supporting the assignment of a property to a type with direct pointers to quotes and figures.

Mining this knowledge from peer-reviewed reports and Allen Brain Atlas (ABA) Mouse Brain (MB) in situ hybridization (ISH) data, reveals the troubling extent of terminological ambiguity and undefined terms. Examples span simple cases of using multiple synonyms and acronyms for the same molecular biomarkers (or other property) to more complex cases of neuronal naming. New publications often use different terms without mapping them to previous terms. As a result, neurons of the same type are assigned disparate names, while neurons of different types are bestowed the same name.

Furthermore, non-unique properties are frequently used as names, and several neuron types are not named at all. In order to alleviate this nomenclature confusion regarding hippocampal neuron types and properties, we introduce a new functionality of Hippocampome.org: a fully searchable, curated catalog of human and machine-readable definitions, each linked to the corresponding neuron and properties terms. Furthermore, we extend our robust approach to providing each neuron type with an informative name and unique identifier by mapping all encountered synonyms and homonyms.

In Hippocampome.org, given the biochemical profile is relatively sparse even for the best studied neuron types, we choose to extend these characterizations by leveraging the massive mouse brain gene expression analysis conducted by the Allen Institute. The Allen Brain Atlas (ABA) provides a wealth of data that when appropriately interpreted can be leveraged to substantially augment the biomarker knowledge in Hippocampome.org. In this study, we restrict the investigation to the principal cell layers of dentate gyrus (DG), CA3, CA2, and CA1, where the vast majority of the neurons are glutamatergic projecting neurons. Thus, ABA Mouse Brain (MB) in situ hybridization (ISH) data for those layers can justifiably be linked to the respective principal neuron types (i.e. Granule in DG and Pyramidal in CA3, CA2, and CA1). We filtered the whole-genome expression dataset to maximize consistency with current Hippocampome.org biomarker content. The resulting additional set of expressed/not-expressed genes expands the ~1K Hippocampome.org biomarker pieces of knowledge (PoK) by ~5K, yielding a considerably more complete genetic characterization of principal neuron types in the mouse hippocampus.

Committee Chair:

Dr. Giorgio A. Ascoli

Committee:

Dr. James L. Olds
Dr. J. Robert Cressman
Dr. Kenneth P. Smith

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Kelly Hamilton
Title: Basic Helix Loop Helix Enhancer 40 in Neuronal Excitability and Synaptic Plasticity

Abstract:

This dissertation describes the role of the Basic Helix Loop Helix Enhancer 40 (Bhlhe40) transcription factor in the adult murine brain at the molecular, cellular, network, and behavioral levels. Studies for this dissertation were performed on a congenic Bhlhe40 gene knock out mouse model (Bhlhe40 KO). The inspiration for this research project was based on prior findings in mice that were genetically null for the Bhlhe40 gene on a mixed genetic background (Jiang et al., 2008, J. Neurosci). Mixed background Bhlhe40 KO mice had enhanced seizure activity when injected intraperitoneally with the convulsant, Kainic Acid (KA). Changes in neuronal gene expression occur as a result of seizure activity, particularly in the hippocampus and in the gene encoding brain-derived neurotropohic factor (BDNF). In the hippocampus, BDNF levels are increased following seizure activity and are tho ught to lower the threshold for subsequent seizures, implicating BDNF in a positive feedback loop in epileptogenesis. Specifically, mixed background Bhlhe40 KO mice had elevated basal levels of BDNF-4 transcripts, which are normally expressed in an activity-dependent manner. The central hypothesis of this research was that congenic Bhlhe40 KO mice would have enhanced responses to KA-induced seizures due to excessive levels of basal BDNF. It was further thought that there would be coincident increases in neuronal activity in hippocampal slices and increased expression of genes modulating neuronal excitability.

The first objective of this research was to elucidate changes in gene expression occurring in the hippocampus of congenic Bhlhe40 KO mice. A whole genome expression array was utilized to capture an unbiased profile of hippocampal mRNA levels from Bhlhe40 KO mice compared to wild type (WT) mice. Gene expression array findings were independently validated by quantitative gene specific mRNA and protein assays. I found that mRNA and protein levels for Insulin Degrading Enzyme (IDE) were two-fold decreased in congenic Bhlhe40 KO hippocampi. Unlike in the mixed background Bhlhe40 KO mice, congenic Bhlhe40 KO hippocampi did not have elevated levels of BDNF mRNA or protein levels.

At the cellular level, I sought to determine the role of Bhlhe40 KO in neuronal excitability. To test this, Bhlhe40 KO hippocampal CA1 neurons, cells that express Bhlhe40 in WT mice, were measured for excitatory and inhibitory electrophysiological properties, and were determined to have enhanced excitation and reduced inhibition, indicating a hyperexcitable state. At the network level, I tested Bhlhe40 KO hippocampal slices for changes in synaptic plasticity and found a decrease in both Long Term Potentiation (LTP) and Long Term Depression (LTD), indicating an overall reduction in long term synaptic plasticity.

At the behavioral level, I tested seizure severity in Bhlhe40 KO mice by intrahippocampal KA-injection, but despite the increase in excitability on the cellular level I found no significant difference in seizure response between Bhlhe40 KO mice and WT controls. In addition, anxiety and learning and memory performance was determined in untreated congenic Bhlhe40 KO and WT mice. Despite the reduction in synaptic plasticity, no changes in spatial learning and memory were observed on the Morris Water Maze, however, there was an increase in anxiety behavior seen on the Open Field.

An interesting finding from this work was the effect of genetic background, namely in regards to seizure susceptibility and BDNF expression. Inter-strain differences can be explained at the genomic level by variation in promoter and other regulatory sequences in the genome. Importantly, I propose here that changes in IDE protein levels may be driving changes in basal excitability and reduced synaptic responses to stimulation, as well as the anxiety phenotype. Insulin levels were investigated and found to be non-significantly changed in Bhlhe40 KO hippocampus, however, IDE also degrades Insulin-like Growth Factor -1 & -2, and Amyloid beta. Further investigation into these other IDE substrates may elucidate the link between Bhlhe40-mediated IDE regulation, anxiety, neuronal excitability and synaptic plasticity.

Dissertation Director:

Dr. Robert H. Lipsky

Committee:

Dr. Mark P. Mattson
Dr. Ann Marini
Dr. Daniel N. Cox
Dr. Nadine Kabbani

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Thesis Defense

Candidate: Stephanie Barksdale
Title: Novel Antimicrobial Peptides in Alligator and Crocodile

Abstract:

Novel antibiotics are needed to fight the rising tide of drug resistance in pathogenic bacteria. One possible source is cationic antimicrobial peptides (AMPs), small proteins produced by the innate immune system. AMPs have a range of mechanisms including direct antibacterial action and immunomodulatory effects.

Crocodilians are part of an ancient clade, the Archosaurs, and are more closely related to birds and dinosaurs than other living reptiles. Very little is known about the innate immune systems of crocodilians, but research has found that the serum of these species have antimicrobial activity beyond that of human serum. This activity is thought to be partly due to AMPs, though only a handful of crocodilian AMPs have been described.

In this thesis, four novel AMPs from members of the order Crocodilia are investigated. A hepcidin from Crocodylus siamensis, an iron-regulating peptide with 4 intramolecular disulfide bonds, is found to have weak activity against Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus. Two fragments of an apolipoprotein found in the blood of Alligator mississippiensis were found to have strong activity against a range of Gram negative and Gram positive bacteria, including multi-drug resistant bacteria. These fragments were found to be alpha-helical and to depolarize the bacterial membrane. A cathelicidin from A. mississippiensis is strongly active against P. aeruginosa and multi-drug resistant Acinetobacter baumannii and forms pores in the bacterial membrane.

These analyses give us greater understanding of the crocodilian innate immune system. In addition, these AMPs could be used as a basis for new antimicrobials.

Thesis Director:

Dr. Monique van Hoek

Committee:

Dr. Serguei Popov
Dr. Barney Bishop

Notes: The thesis is on reserve in the Gateway Library, Science and Technology Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Lisa Frances LaCivita
Title: Amphibian Monitoring for Ecosystem Services, Citizen Engagement and Public Policy

Director or Committee Chair:

Dr. Thomas E. Lovejoy

Committee:

Dr. Lee Talbot
Dr. R. Christian Jones
Dr. K. Bruce Jones

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.

Dissertation Defense

Candidate: Manzhu Yu
Title: Spatiotemporal Methodologies and Analytics for Extreme Weather Study-Using Dust Storm Even as an Example

Abstract:

Dust storm represents a serious hazard to health, property, and the environment in arid and semi-arid areas. To mitigate the hazardous impact of dust storms, it is crucial to detect an upcoming dust event and predict its evolution to inform the early warning and decision-making process. In this dissertation, research is presented into spatiotemporal methods for addressing the problems and challenges, such as dust model uncertainty, challenges of automatically identifying dust features, tracking the evolution pattern of dust events, and challenges in spatiotemporal data modeling.
This dissertation makes innovative contribution for the following reasons: 1) integrating spatiotemporal thinking into the improvement of dust modeling, transforming the spatiotemporal variations of input from static to dynamic; 2) extending feature identification and tracking of dust features into a higher dimensionality, from 2D/2.5D to 3D/4D; 3) proposing a spatiotemporal data framework to better capture the evolution and transport paths of natural phenomena; and 4) integrating GIScience with geographic studies, computational science and geoscience together for a multidisciplinary study. The result of this dissertation can be helpful to provide insights on improving dust forecasting and interpreting simulation data for early warning of dust events, and ultimately provide information for real applications that sustain human lives and resources.

Director or Committee Chair:

Chaowei Yang

Committee:

George Taylor
Ruixin Yang
Dieter Pfoser
Songqing Chen

Notes: The thesis is on reserve in the Johnson Center Library, Fairfax Campus. All members of the George Mason University community are invited to attend.