Life Sciences Commons^™

Role Of Tyk2 In Regulating Energy Expenditure And Preventing Obesity, Vidisha Raje

Theses and Dissertations

Obesity develops when energy intake exceeds energy expenditure. Defect in the function of brown fat and skeletal muscle, two of the major tissues that contribute towards energy expenditure, lead to the development of obesity and metabolic syndrome. Our previous findings suggest that Tyk2 deficient mice become obese and develop the metabolic syndrome. Tyk2, which is a tyrosine kinase of the JAK-STAT signaling family, is important for optimal brown development and function. Since brown fat and skeletal muscle, both are derived from the Myf5+ lineage of mesenchymal stem cells, we also characterized the role of Tyk2 in the development and function …

Physiological Mechanisms Of Shrub Encroachment: Linking Enhanced Hydraulic Capacity To Efficient Light Capture And Processing, Sheri Shiflett

Theses and Dissertations

Woody plant expansion has been documented for decades in many different ecosystems, often due to anthropogenic disturbances to the environment and yielding vast changes in ecosystem functioning. While causes and consequences of woody expansion have been well documented, few studies have investigated functional traits of woody species that promote rapid expansion in range. My objective was to determine if hydraulic efficiency confers enhanced photosynthetic efficiency so that functional traits representing light and water use may be possible mechanisms facilitating woody encroachment into grasslands and forest understories. I quantified leaf-level light environment, photosynthetic activity, and hydraulic characteristics of three sympatric broadleaf …

S3-S4 Linker Modulation Of Voltage Sensor Relaxation In Voltage Gated Potassium Channels, W. Everett Fox

Theses and Dissertations

It is commonly assumed that the voltage dependence for activation of voltage-gated channels is an intrinsic characteristic of the protein that remains unchanged during electrical activity. However, sporadic reports have suggested otherwise by showing that voltage dependence changes in a use-dependent manner resulting in a voltage dependence shift towards negative potentials (Bezanilla et al., 1982; Bruening-Wright and Larsson, 2007; Kuzmenkin et al., 2004; Labro et al., 2012; Larsson and Elinder, 2000; Olcese et al., 1997; Piper et al., 2003; Shirokov et al., 1992). Although the mechanism underlying the shift in voltage dependence remains unclear, this process seems to have two …

The Effects Of Gain Of Function Mutant P53 And P63 On Eps8 And Cxcl5 Expression In Head And Neck Squamous Cell Carcinoma, Rubana Masood

Theses and Dissertations

Head and neck squamous cell carcinoma (HNSCC) is one of the ten most common cancers worldwide, with a survival rate of less than 50%. A class of mutant p53, known as gain of function (GOF) mutant p53, has been found to be expressed in tumors in these patients. GOF mutant p53 not only loses the wild type tumor suppressor functions, but also gains aberrant functions that have been linked to tumorigenesis. In this current study, we utilized a model system consisting of cells derived from HNSCC tumors in order to investigate our hypothesis that GOF mutant p53 enhances, and p63 …

Identification Of Multiple Levels Of Trauma Induced Coagulopathy, Jason Newton

Theses and Dissertations

Trauma continues to be a major cause of death across the globe. While the exact causes of trauma differ greatly between the military and civilian lifestyles, the ability to stop bleeding after trauma is paramount for survival. Over the past decade coagulation research has transitioned from a classical understanding of plasma based protein coagulation to the current cell focused research. As part of this shift, platelets have become a central player in hemostasis. Unfortunately little is currently understood about how platelet function is affected by trauma. In an effort to better define platelet function during trauma and the resulting shock …

Impact Of Self-Fertilization On Fecundity, The Timing Of First Reproduction, And Population Genetic Structure: Is A Mate Worth The Wait?, Serena Caplins

Theses and Dissertations

Organisms capable of self-fertilization typically exhibit two evolutionary syndromes uniting high inbreeding depression with low levels of selfing, or low inbreeding depression and high levels of selfing. This study tests for inbreeding depression in an apparent self-compatible, hermaphroditic marine nemertean worm, Prosorhochmus americanus. Fecundity and timing to first reproduction were assessed in isolated and paired worms. Isolated worms produced significantly more offspring than paired worms and did not show inbreeding avoidance. The selfing rate of natural populations was evaluated using species-specific microsatellites and is consistent with preferential selfing (mean: 0.801), though some outcrossing appears to take place. Population genetic structure …

Genetic And Molecular Analysis Of The Maize R1 Locus, Jennifer Derkits

Theses and Dissertations

Canalization, the stability of phenotypes in the presence of a specific genotype and environment is important for trait selection and understanding gene expression pathways. The goal of this study was to investigate mechanisms involved in the loss of canalization at the maize r1 locus. A specific lightly colored R-sc derivative, R-sc:86-17(L), was mutagenized with ethyl methyl sulfonate (EMS), and the progeny screened for restoration of dark seed color and canalization. Putative revertants/mutants were mapped relative to the r1 locus, tested for complementation to each other to identify a minimum number of genes involved in canalization, tested for cis silencing of …

Structural Basis Of Dna Binding Complexes, Ninad Walavalkar

Theses and Dissertations

The nucleosome remodeling and deacetylase (NuRD) complex is an abundant deacetylase complex, which couples histone deacetylation and chromatin remodeling ATPase activities, and has a broad cellular and tissue distribution. Although the working model of how this complex forms and functions is not well known, we have demonstrated that the coiled-coil interaction between two proteins (MBD2 and p66α) is critical for DNA methylation dependent gene silencing in vivo. Chapter one: ‘Unique features of the anti-parallel, heterodimeric coiled-coil interaction between methyl-cytosine binding domain 2 (MBD2) homologues and p66α dictate high affinity binding’ describes this unique coiled coil interaction. Coiled-coils were studied using …

Intra-Mitochondrial Injury During Ischemia-Reperfusion, Hema Aluri

Theses and Dissertations

Cardiac injury is increased following ischemia-reperfusion. Mitochondria are the “effector organelles” that are damaged during ischemia (ISC) when there is no blood flow. Resumption of metabolism by damaged mitochondria during reperfusion (REP) results in increased cell injury. Current therapeutic interventions to pre-condition and post-condition the heart during ISC are ineffective during certain conditions like aging and diabetes due to defects in the signaling cascades. In contrast, mitochondrial-based strategies are effective in protecting the heart during ISC-REP. Hence direct therapeutic targeting of dysfunctional mitochondria will provide the potential to bypass the upstream signaling defects and intervene directly upon the effector organelle. …

Inhibition Of Retinoic Acid Receptors Results In Defasciculation Of The Trigeminal Nerve In Xenopus Laevis, Jeremy Thompson

Theses and Dissertations

The anatomy of the cranial peripheral nervous system has been studied for over a century, yet surprisingly little is known about how the nerves are guided to their targets. The study of the development of these nerves has important implications for our understanding of craniofacial anomalies and possible treatments for both injury and genetic disorders of nerve development such as Goldenhar-Gorlin syndrome. We have discovered that retinoic acid (RA) may play a role in the development of the trigeminal nerve. Inhibition of retinoic acid receptors (RAR) results in trigeminal nerves that become unbundled or defasciculated in the eye region. To …

Effects Of Ischemia And Reperfusion On The Local Regulation Of Oxygen Consumption, Tissue Oxygenation And Blood Supply In Rat Skeletal Muscle., Sami Dodhy

Theses and Dissertations

In resting muscle, blood flow is regulated to meet the demand for O2 by the tissue. A modified ischemia (I)/reperfusion(R) investigation was systematically run and PISFO2, PaO2, Q and VO2 were observed. Twenty-nine spinotrapezius muscles from male Sprague-Dawley rats (284±20 grams) were surgically exteriorized for intravital microscopy to test a model relating blood flow, O2 supply and O2 demand. The model can aid in the understanding of the regulation of tissue PO2. The interstitial PO2 (PISFO2) and perivascular PO2 (PaO2) measurements were made using phosphorescence quenching microscopy (PQM). O2 consumption (VO2) values were obtained with a quasi-continuous, flash-synchronized, pressurized airbag …

A Network View On Neurodegenerative Disorders, Sreedevi Chandrasekaran

Theses and Dissertations

Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the …

Phylometagenomics: A New Framework For Uncovering Microbial Community Diversity, Christopher J. Friedline

Theses and Dissertations

Microbial communities are recognized as major drivers of global biogeochemical processes. However, the genetic diversity and composition, as well as processes leading to the origin and diversification of these communities in space and time, are poorly understood. Character- ization of microbial communities using high-throughput sequencing of 16S tags shows that Operational Taxonomic Unit (OTU) abundances can be approximated by a gamma distribu- tion, which suggests structuring around small numbers of highly abundant OTUs and a large proportion of rare OTUs. The current methods used to characterize how communities are structured rely on multivariate statistics, which operate on pair-wise distance matrices. …

Differential Effects Of Growth Factors On Glycolysis In Ovarian Cancer Cells, Fang Yuan

Theses and Dissertations

Lysophosphatidic acid (LPA), a naturally-occurring, simple phospholipid, is present at elevated levels in the blood and ascites of ovarian cancer patients. LPA is a ligand of seven cell surface G protein-coupled receptors. It has been known as an oncogenic growth factor in ovarian cancer and other types of human malignancies. However, the precise biological functions of LPA in ovarian oncogenesis remain to be fully elucidated. Our laboratory is interested in studying the potential role of LPA, as a tumor microenvironment factor, in regulation of cancer cell metabolism. A fundamental change associated with most cancer is the switch of glucose metabolism …

Bioinformatics Approach To Probe Protein-Protein Interactions: Understanding The Role Of Interfacial Solvent In The Binding Sites Of Protein-Protein Complexes;Network Based Predictions And Analysis Of Human Proteins That Play Critical Roles In Hiv Pathogenesis., Mesay Habtemariam

Theses and Dissertations

The thesis work contains two projects under the same umbrella. The first project is to provide a detailed analysis on the behavior of interfacial water molecules at protein-protein complexes, in this case focusing on homodimeric complexes, and to investigate their effect with respect to different residue types. For that reason the homodimeric data-set, which includes high-resolution (≤ 2.30 Å) X-ray crystal structures of 252 (140 Biological & 112 Non-biological) protein complexes was chosen to explore fundamental differences between interfaces that Nature has “engineered” vs. compared to interfaces found under man-made conditions. The data set was comprised of 5391 water molecules …

Structural And Functional Characterization Of Sortase A, Vishaka Santosh

Theses and Dissertations

Sortases have been known to be essential in Gram-positive bacteria for attaching proteins onto the peptidoglycan layer of the bacterium. Sortase A has been found to be useful as a “molecular stapler”, although; in vivo, the enzyme is responsible for attaching proteins to the peptidoglycan layer of Gram-positive bacteria. It accomplishes both of these tasks by joining two proteins together via an LPXTG sorting sequence. The enzyme has been proven to be very useful in attaching any two proteins together without worrying about recombinant techniques to generate the fusion protein. The problem with this enzyme is that the catalytic diad, …

The Role Of Camk-Ii In Skeletal Muscle Function And Swimming Behavior In Zebrafish, Minh Nguyen

Theses and Dissertations

Previous research showed mutations in muscle sarcoplasmic reticulum-bound calcium handler proteins cause swimming defects in embryonic zebrafish. CaMK-II is a highly conserved Ca2+/calmodulin-dependent protein kinase expressed in all vertebrates has been defined to activate and inactivate multiple Ca2+ handler proteins involved in excitation- contraction coupling and relaxation of cardiac and skeletal muscle. In this study, evidence is provided through pharmacological and genetic intervention that CaMK-II inhibition and overexpression causes swimming defects, particularly response to stimuli and swimming ability, reinforced by immunolocalization of skeletal muscle. Transient CaMK-II inactivation does not have any long-term defects to swimming behavior. Overexpression of wild-type, constitutively …

The Effects Of Tarsh Overexpression On Lung Carcinomas, Young Kim

Theses and Dissertations

Lung cancer arises from epithelial cells that line the air passages of the lungs. It is the second most common malignancy in the United States; trends suggest that over 228,000 new patients will be diagnosed with lung cancer in 2013. Due to the fact that lung cancer is highly aggressive, it has proven difficult to control. The 5-year survival rate has been shown to be only 15.9%, despite the advances made in terms of diagnosis and treatment. Therefore, we are faced with the problem of finding more effective methods that allow for an earlier diagnosis and the improved treatment of …

Camk-Ii: An Integral Protein In Cell Migration, Jamie Josephine Avila Mcleod

Theses and Dissertations

Coordinated inductive and morphogenetic processes of gastrulation establish the zebrafish body plan. Gastrulation includes massive cell rearrangements to generate the three germ layers and shape the embryonic body. Three modes of cell migration must occur during vertebrate gastrulation and include: epiboly, internalization of the presumptive mesendoderm and convergent extension (C&E). C&E movements narrow the germ layers mediolaterally (convergence) and elongate them anteroposteriorly (extension) to define the embryonic axis. The molecular mechanisms regulating coordinated cell migrations remain poorly understand and studying these has become of great interest to researchers. Understanding cell migration during development is highly relevant to a number of …

The Inflammasome In Acute Myocarditis, Harsha Kannan

Theses and Dissertations

Acute myocarditis is an acute inflammatory syndrome characterized by myocardial damage and dysfunction often due to a viral infection followed by a variable development over time. There are currently no specific treatments and standard treatments for heart failure are generally applied. The inflammasome is a recently identified macromolecular structure that occupies a central role in the amplification of the inflammatory response and promotion of cell death during acute and chronic infections. We hypothesized the formation of the inflammasome in acute myocarditis. To investigate, samples of patients were collected from the Cardiomyopathy Registry in Trieste, with 12 cases of biopsy-proven myocarditis …

The Activation, Receptor Complexing And Endogenous Regulation Of The Type-I Interferon Response As It Pertains To Innate Immunity, James D. Marion Jr.

Theses and Dissertations

To defend against pathogen challenge, multi-cellular organisms mount an immune response that recognizes, sequesters and eradicates invading infectious agents. Critical to this safeguard is the receptor-mediated detection of pathogens. Pathogen recognition then initiates a variety of signaling cascades that lead to the modulation of genes orchestrating an immune response. Toll-like receptor 3 (TLR3), a transmembrane receptor found in endosomes, is vital to the innate immune response against viruses. Double-stranded RNA (dsRNA) stimulation of TLR3 initiates a signaling cascade that leads to the production of type-I interferons and proinflammatory cytokines necessary to trigger the protective defenses of the immune system. Critical …

Characterization Of The Neurotrophic Factor Brain-Derived Neurotrophic Factor (Bdnf) In Intestinal Smooth Muscle Cells, Mohammad Alqudah

Theses and Dissertations

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of secreted proteins, which include in addition to BDNF, nerve growth factor (NGF) and neurotrophin 3-6 (NT-3-6). BDNF mediates its functions by activating two cell surface receptors, pan-neurotrophin receptor (P75NTR) and tropomyosin-related kinase B (TrkB) and their downstream intracellular cascades. BDNF is best known for its role in neuronal survival, regulation of neuronal differentiation, migration and activity-dependent synaptic plasticity. However, BDNF is widely expressed in non-neuronal tissues as well. The localization and the function of BDNF in intestinal smooth muscle cells (SMCs) are not well defined. Thus, the main purpose of …

Sildenafil Attenuates Ethanol-Induced Cardiomyocyte Injury And Preserves Cardiac Function Through Protein Kinase G-Dependent Signaling, Gregory R. Sturz

Theses and Dissertations

Background: Ethanol is a cardiotoxic substance that damages the heart by increasing apoptosis, free radical formation and calcium overloading. Consequently, there is an increase in cell death leaving fewer functioning myocytes leading to heart failure. Sildenafil is a phosphodiesterase type-5 (PDE-5) inhibitor approved for treatment of erectile dysfunction. Studies from our lab have demonstrated that PDE-5 inhibition reduces myocardial infarct size and attenuates post-ischemic cardiac dysfunction in both ischemia-reperfusion and permanent coronary artery ligation models. Therefore, in the present study, we hypothesized that treatment with sildenafil will prevent cardiotoxicity associated with acute alcohol exposure by reducing myocyte apoptosis and preserving …

Regulation Of Gastrointestinal Smooth Muscle Function By Hydrogen Sulfide, Ancy Nalli

Theses and Dissertations

Inhibitory neurotransmitters, chiefly nitric oxide and vasoactive intestinal peptide, cause MLC20 dephosphorylation and muscle relaxation via inhibition of myosin light chain (MLC) kinase and activation of MLC phosphatase. Hydrogen sulfide (H2S) produced as a byproduct by luminal sulfate-reducing commensal bacteria or as an endogenous signaling molecule synthesized from L-cysteine via cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) regulates muscle contraction. However, the role of H2S in the regulation of MLC phosphatase activity and MLC20 phosphorylation is not known. The aim of the present study was to examine the expression of CSE and CBS in smooth muscle cells and to elucidate the molecular …

Studies On The Reaction Of High-Dose Hydroxocobalamin And Ascorbic Acid With Carbon Monoxide: Implications For Treatment Of Carbon Monoxide Poisoning, Joseph Roderique

Theses and Dissertations

Based upon experimental evidence from the 1970’s we proposed that a reduced form of hydroxocobalamin should be capable of producing carbon dioxide (CO2) from carbon monoxide (CO) in blood, and that this conversion should be detectable. Using resonance raman spectroscopy we demonstrated that a mixture of hydroxocobalamin and ascorbic acid could create the reduced form of hydroxocobalamin. We used a closed-loop circulation system with a hollow-fiber membrane oxygenator to produce carboxyhemoglobin. Using sensitive gas monitoring equipment to the gas-out port of the oxygenator we analyzed the CO and CO2 concentrations coming from the oxygenator. The mixture of hydroxocobalamin and ascorbic …

Global Taxonomic Diversity Of Living Reptiles, Daniel Pincheira-Donoso, Aaron M. Bauer, Shai Meiri, Peter Uetz

Study of Biological Complexity Publications

Reptiles are one of the most ecologically and evolutionarily remarkable groups of living organisms, having successfully colonized most of the planet, including the oceans and some of the harshest and more environmentally unstable ecosystems on earth. Here, based on a complete dataset of all the world’s diversity of living reptiles, we analyse lineage taxonomic richness both within and among clades, at different levels of the phylogenetic hierarchy. We also analyse the historical tendencies in the descriptions of new reptile species from Linnaeus to March 2012. Although (non-avian) reptiles are the second most species-rich group of amniotes after birds, most of …

Physical Activity And Sedentary Behavior Of Cancer Survivors And Non-Cancer Individuals: Results From A National Survey, Roy B. Kim, Allison Phillips, Kirsten Herrick, Marieka Helou, Carlin Rafie, Mitchell S. Anscher, Ross B. Mikkelsen, Yi Ning

Anatomy and Neurobiology Publications

Increasing physical activity and decreasing sedentary behavior are associated with a higher quality of life and lower mortality rates for cancer survivors, a growing population group. Studies detailing the behavior of cancer survivors are limited. Therefore, we investigated physical activity and sedentary behavior of cancer survivors using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2010. Participants were those who provided physical activity and sedentary behavior data. Those who were pregnant,old, or10,472 non-cancer participants. After adjustment for age, race, gender, education status, body mass index, and smoking status, cancer survivors (n = 10,472) reported significantly longer duration of …

Contributions Of Vldlr And Lrp8 In The Establishment Of Retinogeniculate Projections, Jianmin Su, Michael A. Klemm, Anne M. Josephson, Michael A. Fox

Anatomy and Neurobiology Publications

Background

Retinal ganglion cells (RGCs), the output neurons of the retina, project to over 20 distinct brain nuclei, including the lateral geniculate nucleus (LGN), a thalamic region comprised of three functionally distinct subnuclei: the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). We previously identified reelin, an extracellular glycoprotein, as a critical factor that directs class-specific targeting of these subnuclei. Reelin is known to bind to two receptors: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2). Here we examined the roles of these canonical reelin …

Biomedical Informatics For Computer-Aided Decision Support Systems: A Survey, Ashwin Belle, Mark A. Kon, Kayvan Najarian

Computer Science Publications

The volumes of current patient data as well as their complexity make clinical decision making more challenging than ever for physicians and other care givers. This situation calls for the use of biomedical informatics methods to process data and form recommendations and/or predictions to assist such decision makers. The design, implementation, and use of biomedical informatics systems in the form of computer-aided decision support have become essential and widely used over the last two decades. This paper provides a brief review of such systems, their application protocols and methodologies, and the future challenges and directions they suggest.

Whole Brain And Brain Regional Coexpression Network Interactions Associated With Predisposition To Alcohol Consumption, Lauren A. Vanderlinden, Laura M. Saba, Katerina Kechris, Michael F. Miles, Paula L. Hoffman, Boris Tabakoff

Study of Biological Complexity Publications

To identify brain transcriptional networks that may predispose an animal to consume alcohol, we used weighted gene coexpression network analysis (WGCNA). Candidate coexpression modules are those with an eigengene expression level that correlates significantly with the level of alcohol consumption across a panel of BXD recombinant inbred mouse strains, and that share a genomic region that regulates the module transcript expression levels (mQTL) with a genomic region that regulates alcohol consumption (bQTL). To address a controversy regarding utility of gene expression profiles from whole brain, vs specific brain regions, as indicators of the relationship of gene expression to phenotype, we …