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Identification Of The Conformational Transition Pathway In Pip2 Opening Kir Channels, Junwei Li, Shouqin Lü, Yuzhi Liu, Chunli Pang, Yafei Chen, Suhua Zhang, Hui Yu, Mian Long, Hailin Zhang, Diomedes E. Logothetis, Yong Zhan, Hailong An

Physiology and Biophysics Publications and Presentations

The gating of Kir channels depends critically on phosphatidylinositol 4,5-bisphosphate (PIP2), but the detailed mechanism by which PIP2regulates Kir channels remains obscure. Here, we performed a series of Targeted molecular dynamics simulations on the full-length Kir2.1 channel and, for the first time, were able to achieve the transition from the closed to the open state. Our data show that with the upward motion of the cytoplasmic domain (CTD) the structure of the C-Linker changes from a loop to a helix. The twisting of the C-linker triggers the rotation of the CTD, which induces a small downward movement of the CTD …

Starvation-Induced Collective Behavior In C. Elegans, Alex B. Artyukhin, Joshua J. Yim, Mi Cheong Cheong, Leon Avery

Physiology and Biophysics Publications and Presentations

We describe a new type of collective behavior in C. elegans nematodes, aggregation of starved L1 larvae. Shortly after hatching in the absence of food, L1 larvae arrest their development and disperse in search for food. In contrast, after two or more days without food, the worms change their behavior—they start to aggregate. The aggregation requires a small amount of ethanol or acetate in the environment. In the case of ethanol, it has to be metabolized, which requires functional alcohol dehydrogenase sodh-1. The resulting acetate is used in de novo fatty acid synthesis, and some of the newly made …

Addition Of Interleukin-21 For Expansion Of T-Cells For Adoptive Immunotherapy Of Murine Melanoma, Christine Kathryn Zoon, Wen Wan, Laura Graham, Harry D. Bear

Surgery Publications

We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitrofor adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and …

Women Of Faith In Science: The Double Glass Ceiling, K. Y. Michael

Journal of Mathematics and Science: Collaborative Explorations

The majority of female pre-service elementary school teachers pursuing licensure is choosing English as their cognate rather than mathematics or science. The reason females are not choosing science as their cognate may be due to the fact that science has long been considered a masculine pursuit. To complicate the issue, pre-service female teachers of deep religious faith are further challenged to navigate the dichotomy of science and religion. As a result, women, and especially women of deep religious faith, are at risk of not participating in science studies. The author suggests that there is room in the science classroom for …

Stemteach: Preparing The Next Generation Of Mathematics And Science Teachers, G. Bunn, D. Dailey, A. Cotabish

Journal of Mathematics and Science: Collaborative Explorations

With an increasing demand for individuals prepared in Science, Technology, Engineering, and Mathematics (STEM), one university responded to this call by changing its teacher preparation program. Better-prepared mathematics and science teachers have the opportunity to engage and excite students, thereby preparing and promoting more of them to enter the STEM professions. The described program is a replication of the national UTeach model that recruits content majors in mathematics and science to explore the teaching profession during a first-semester course that includes an early field experience in the elementary grades. This field experience is designed to be engaging for both the …

A Convergent Approach To The Continuous Synthesis Of Telmisartan Via A Suzuki Reaction Between Two Functionalized Benzimidazoles, Alex D. Martin

Theses and Dissertations

A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support.

The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially …

Elucidation Of A Novel Pathway In Staphylococcus Aureus: The Essential Site-Specific Processing Of Ribosomal Protein L27, Erin A. Wall

Theses and Dissertations

Ribosomal protein L27 is a component of the eubacterial large ribosomal subunit that has been shown to play a critical role in substrate stabilization during protein synthesis. This function is mediated by the L27 N-terminus, which protrudes into the peptidyl transferase center where it interacts with both A-site and P-site tRNAs as well as with 23S rRNA. We observed that L27 in S. aureus and other Firmicutes is encoded with a short N-terminal extension that is not present in most Gram-negative organisms, and is absent from mature ribosomes. The extension contains a conserved cleavage motif; nine N-terminal amino acids are …

Speaking For The Picture: Memory, Image, And Identity In The Works Of W.G. Sebald And Chris Marker, Connor Mccormick

Theses and Dissertations

The nineteenth and twentieth centuries saw the development of technologies for externalizing human memory beyond writing, painting, and sculpting. These modes of visual representation, namely photography and cinema carried with them a purported objective representation of reality, which has been used to create classifications, divide people groups, and construct grand historical narratives used to marginalize those that do not fit within the hegemonic center. Looking to the works of writer W.G. Sebald, and filmmaker Chris Marker, we see a complication of the divide between visual and verbal texts, as each artist deconstructs their own medium’s conventions. Using theories of ekphrasis …

Analytical Method Development For The Detection And Analysis Of Protein Carbonyls, Chelsea M. Coffey

Theses and Dissertations

Oxidative stress can result in changes to many biomolecules and also affect their activities. We are interested in protein carbonylation, a type of unnatural oxidation which has been associated with numerous degenerative disease states and is also a consequence of the natural aging process. Protein carbonyls are stable species, but countless analytical barriers exist in terms of their identification. Thus, the main goal of this work was to develop and optimize analytical methods that could be used to help us better understand which, where, and how proteins are being carbonylated.

Initial studies involved method validation for carbonylating, tagging, and enriching …

Oasis Link, Sarah Baugh

Theses and Dissertations

This document is written from the perspective of the Oasis Link community, a group of dissidents who have resettled in the Mojave Desert sometime in the near future. It is a speculative design document.

Surface is what is visible. It’s the crust of the earth and the face of a meteorite—the coat of a jackrabbit and the waxy skin of a Mojave Prickly Pear. Surface is superficial, but it also reflects and defines the underlying structure of something—it makes the hidden visible.

Coarse Woody Debris And The Carbon Balance Of A Moderately Disturbed Forest, Amy V. Schmid

Theses and Dissertations

Landscapes are comprised of multiple ecosystems shaped by disturbances varying in severity and source. Moderate disturbance from weather, pathogens, insects, and age-related senescence, in contrast to severe disturbances that fell trees, may increase standing woody debris and alter the contribution of coarse woody debris (CWD) to total ecosystem respiration (R_E). However, woody debris dynamics are rarely examined following moderate disturbances that substantially increase standing dead wood stocks. We used an experimental manipulation of moderate disturbance in an upper Great Lakes forest to: 1) examine decadal changes in CWD stocks through a moderate disturbance; 2) quantify in situ CWD …

High School Teacher And Administrator Perceptions Of Student Health Promotion: An Exploratory Study, Sarah B. Conklin

Theses and Dissertations

The current study explored the high school health promotion environment with regards to physical activity, nutrition, and sedentary behaviors from the perspective of high school health and physical education teachers and administrators. Specifically, potential strategies for a prevention program to promote student physical activity participation and healthy eating, and decrease student sedentary time were explored.

Individual semi-structured interviews were conducted with physical education teachers to explore potential strategies to promote student health behaviors. Next, interviews were conducted with high school administrators to determine the feasibility of recommended strategies. Teachers and administrators in the current study expressed a need for strategies …

Long-Term Effects Of Land Cover Change On Fish Assemblage Structure In The Piedmont And Coastal Plain Regions Of Virginia, Samuel F. Stickley

Theses and Dissertations

Changes in land cover and fish assemblage structure were assessed across two spatial and temporal scales in the Piedmont and Coastal Plain regions of the Chesapeake Bay watershed in Virginia. A long-term, local study (1953 to 2014) on the Tuckahoe Creek watershed used digitized aerial photography and satellite images (Landsat 5 TM and Landsat 8 OLI/TIRS) to quantify land cover change for five nested catchments in 1953, 1990, and 2014. Instream fish collections from 1958, 1990, and 2014 were utilized to assess a variety of fish assemblage metrics for each of the five catchments, and analyses were performed to assess …

Investigation Of Gain-Of-Function Induced By Mutant P53, Catherine Vaughan

Theses and Dissertations

p53 is mutated in 50% of all human cancers, and up to 70% of lung cancer. Mutant p53 is usually expressed at elevated levels in cancer cells and has been correlated with a poor prognosis. Cancer cells that express mutant p53 show an increase in oncogenic phenotypes including an increase in growth rate, resistance to chemotherapeutic drugs, and an increase in motility and tumorigenicity to name a few. We have identified several genes involved in cell growth and survival that are upregulated by expression of common p53 mutants: NFκB2, Axl, and epidermal growth factor receptor (EGFR). The aim of this …

Spiking Neural Networks: Neuron Models, Plasticity, And Graph Applications, Shaun Donachy

Theses and Dissertations

Networks of spiking neurons can be used not only for brain modeling but also to solve graph problems. With the use of a computationally efficient Izhikevich neuron model combined with plasticity rules, the networks possess self-organizing characteristics. Two different time-based synaptic plasticity rules are used to adjust weights among nodes in a graph resulting in solutions to graph prob- lems such as finding the shortest path and clustering.

The Effect Of Optogenetic Manipulation Of Ss Interneurons Within Malformed, Epileptogenic Cortex, Nicole Ekanem

Theses and Dissertations

A large percentage of individuals with intractable epilepsies have an accompanying cortical malformation, the underlying cellular mechanisms of which are poorly understood. It is known however that in an animal model for one such malformation, polymicrogyria, epileptogenesis occurs most easily from an adjacent area termed the paramicrogyral region (PMR). Previous studies implicate SS interneurons as a potential contributor to this pathology, which lead to our hypothesis: in PMR, SS interneurons exert a higher modulatory influence on excitatory pyramidal cells, as compared to the same by SS interneurons within homologous control cortex.

Using a freeze-lesion model for polymicrogyria in transgenic mice …

Characterization Of Mechanism Of Action Of Hydrogen Sulfide (H2s) In The Regulation Of Smooth Muscle Function, Ancy D. Nalli

Theses and Dissertations

Hydrogen sulfide (H₂S) is receiving increasing interest, as much as nitric oxide (NO) and carbon monoxide have received previously, to understand its physiological functions as it meets all the criteria to define as a third gasotransmitter. Endogenous synthesis from L-cysteine via cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) and the function of H₂S as an inhibitor of smooth muscle contraction in gastrointestinal tract are known. However, the loci of generation and action of H₂S, and the mechanism of inhibition of contraction are unknown. Hence, my aims in the present study are to: i) identify the expression …

Regulation Of Tie2 Extracellular Complex Formation In Angiogenesis, Annamarie Dalton

Theses and Dissertations

Pathological angiogenesis is an essential component of tumor growth, development, and metastasis for which few effective therapeutic options exist. Though many cancer therapies target the function of cell surface receptors, mechanisms regulating membrane receptor crosstalk remain unclear. Two important families of receptors in angiogenesis, the Ties and Integrins, respond to the extracellular environment via outside-in and, in the case of Integrins, also inside- out signaling. Recent reports showed that the endothelial specific tyrosine kinase receptor, Tie2, forms complexes with two of the endothelial Integrin heterodimers, α₅β₁ and α_Vβ₃, providing a convenient mechanism for …

Risperidone And Its Deconstructed Analogs: Functional Effects On The 5ht2ar, Sneha Shah

Theses and Dissertations

G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K⁺ channel (GIRK) inhibition and a downstream stimulation of Ca²⁺ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many …

Mitochondrial Biogenesis And Electrical Properties Of Hpsc-Derived Motor Neurons, Laura O'Brien

Theses and Dissertations

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great promise in the fields of drug development and regenerative medicine. If iPSCs reprogrammed from patient cells replicate what is seen in vivo they may be used as a model of disease. A process that is disrupted in many neurodegenerative diseases is mitochondrial biogenesis. One of these diseases is amyotrophic lateral sclerosis (ALS), which is characterized by loss of motor neurons in the brain and spinal cord. Differentiation of hPSCs into motor neurons offers a way to study a previous unavailable cell …

Development Of Non-Traditional Platinum Anticancer Agents: Trans-Platinum Planar Amine Compounds And Polynuclear Platinum Compounds, Daniel E. Lee

Theses and Dissertations

Development of Non-Traditional Platinum Anticancer Agents: trans-Platinum Planar Amine Compounds and Polynuclear Platinum Compounds

By Daniel E. Lee, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015

Major Director: Nicholas P Farrell, Ph.D., Professor, Department of Chemistry

Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied …

A Justification For The Trend Towards Indirect Pulp Therapy, Marissa Kuhnen

Theses and Dissertations

Purpose: The purpose of this retrospective chart review was to determine how primary molars needing vital pulp therapy have been treated in the past four years at Virginia Commonwealth University (VCU) and to determine which treatments: indirect pulp therapy (IPT), formocresol pulpotomy, and ferric sulfate pulpotomy have been successful. Methods: AxiUm records that contained the procedure codes D3120 (Pulp Cap – Indirect) or D3220 (Therapeutic Pulpotomy) were totaled by year. Visit records were queried again to identify treatment failures i.e. extractions or pulpectomy. Results: In 2010, 52% of vital pulp therapies were ferric sulfate pulpotomies and in …

Elucidating The Role Of Endogenous Electric Fields In Regulating The Astrocytic Response To Injury In The Mammalian Central Nervous System, Matthew L. Baer

Theses and Dissertations

Endogenous bioelectric fields guide morphogenesis during embryonic development and regeneration by directly regulating the cellular functions responsible for these phenomena. Although this role has been extensively explored in many peripheral tissues, the ability of electric fields to regulate wound repair and stimulate regeneration in the mammalian central nervous system (CNS) has not been convincingly established. This dissertation explores the role of electric fields in regulating the injury response and controlling the regenerative potential of the mammalian CNS. We place particular emphasis on their influence on astrocytes, as specific differences in their injury-induced behaviors have been associated with differences in the …

Identifying Problems During Transitions Of Care And Reasons For Emergency Department Utilization In Community-Dwelling Older Adults, Antoinette B. Coe

Theses and Dissertations

A mixed methods approach was used for this study. The setting was a low-income, subsidized housing apartment building for community-dwelling older and younger disabled adults identified as a health care hot spot due to high rates of ambulance use. The study purpose was to identify reasons for ED use and problems during transition from ED to home, predictors of zip code 23220 (health care hot spot) in emergent and non-emergent ED visits, and predictors of total ED costs in community-dwelling older adults living in a health care hot spot. Semi-structured interviews with residents who used the ED, an existing database …

Axon Initial Segment Stability In Multiple Sclerosis, Suneel K. Thummala

Theses and Dissertations

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS …

Mysteries Of The Trypanosomatid Maxicircles: Characterization Of The Maxicircle Genomes And The Evolution Of Rna Editing In The Order Kinetoplastida, Preethi Ranganathan Iyengar

Theses and Dissertations

The trypanosomatid protists belonging to Order Kinetoplastida are some of the most successful parasites ever known to mankind. Their extreme physiological diversity and adaptability to different environmental conditions and host systems make them some of the most widespread parasites, causing deadly diseases in humans and other vertebrates.

This project focuses on their unique mitochondrion, called the kinetoplast, and more specifically involves the characterization of a part of their mitochondrial DNA (also called kinetoplast DNA or kDNA), the maxicircles, which are functional homologs of eukaryotic mitochondrial DNA in the kinetoplastid protists. We have sequenced and characterized the maxicircle genomes of 20 …

Role Of Extracytoplasmic Rna Polymerase Sigma 70 Factor, Pg0214, In The Survival Of Porphyromonas Gingivalis And In Adaptation To Environmental Stress., David M. Smith

Theses and Dissertations

Porphyromonas gingivalis, a gram-negative anaerobic, pathogenic bacterium is a major etiological agent in the initiation and progression of periodontal disease. Due to the ever-changing environment of the oral cavity, inhabitants like Porphyromonas gingivalis must possess the ability to adapt to changes in environmental conditions like pH, temperature, oxygen tension, and metal concentration. P. gingivalis should therefore have an efficient regulatory system in order to adapt and survive in the oral cavity. This response adaptation occurs at the transcriptional level, which involves alternative sigma factors. Extracytoplasmic function sigma (ECF-s) factors are the largest group of alternative sigma factors that play …

The Effects Of Hydropeaking On Lotic Benthic Macroinvertebrate Assemblages, Andrew L. Garey

Theses and Dissertations

The term hydropeaking refers to anthropogenically induced, short-duration, high-magnitude discharge pulses that are generated in lotic systems for electricity production. The practice of hydropeaking produces the largest source of renewable energy worldwide, and its use is projected to increase through the year 2040. The primary objective of this work was to evaluate the effects of hydropeaking on benthic macroinvertebrate assemblages, which are important components of lotic ecosystems. Results of this work show that, across a wide range of impacted systems worldwide, the consistently observed patterns of elevated benthic macroinvertebrate drift in response to hydropeaking pulses are primarily related to the …

Sexual Behavior And Hiv Risk In Black College Women: The Influence Of Gender, Peer, And Relationship Beliefs, Melanie P. Moore

Theses and Dissertations

Black women in the United States disproportionately represent 64% of women with an HIV infection (CDC, 2013). Research is needed to better understand gender and culturally-specific factors that contribute to Black women’s HIV risk. The Theory of Gender and Power and the Theory of Planned behavior were used as theoretical frameworks in examining the effect of attitudinal beliefs (gender related beliefs), subjective norm beliefs (peer norms), and perceived behavioral control beliefs (relationship power) on sexual behavior in Black college women. Condom use and assertiveness in sexual communication were the dependent variables. Participants included 136 Black college women recruited through the …

Workplace Discrimination And Visual Impairment: An Analysis Of Eeoc Charges And Resolutions, Jane Mcneil

Theses and Dissertations

Workplace discrimination for individuals with visual impairments in the U.S. is an ongoing issue dating before the founding of the EEOC and the enactment of the ADA. Despite laws enacted to protect against unequal treatment in the workplace, the EEOC continues to receive submissions of formal discrimination charges from individuals with visual impairments.

The workplace is experiencing changes with increasing amounts of older adults, women, minorities, and the use of technology and the Internet. By examining characteristics of the discrimination charges and the resulting outcomes, the knowledge gained can describe the current situation and the historical progression of workplace discrimination …