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Modified-Release Drugs, Chedva Farkas

The Science Journal of the Lander College of Arts and Sciences

The following is an excerpt from the introduction to this article: Ever since the discovery of bacteria and their role in the disease process in the mid-1800s, scientists have been heavily involved in the discovery and development of drug therapies and their mechanism of action in the human body. Shortly after the initial discovery came the era of drug discovery of the late 1800s-early 1900s, also known as the “drug revolution” (Dash and Cudworth 1998). Although the drug revolution led to the rapid discovery of many new drugs, pharmacological factors such as dosage forms, drug delivery systems, plasma drug levels, …

The Formin Fmnl3 Is A Cytoskeletal Regulator Of Angiogenesis, Clare Hetheridge, Alice N. Scott, Rajeeb K. Swain, John W. Copeland, Henry N. Higgs

Dartmouth Scholarship

The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human …

Sugar Consumption And Cognitive Aging In The Swedish Adoption/Twin Study Of Aging, Shyam Seetharaman

USF Tampa Graduate Theses and Dissertations

Abstract

Consumption of foods high in sugar content has been linked with the development of metabolic abnormalities such as cardiovascular disease and type II diabetes, major sources of global health concerns. Although the detrimental consequences of high intake of sugar on abnormal metabolic processes are established, it is not known how this association affects (or accelerates) cognitive aging.

The current project was based on data from the Swedish Adoption/Twin Study of Aging (SATSA) to test the hypothesis that high refined sugar intake contributes to accelerated trajectories of cognitive decline assessed longitudinally. Trajectories of cognitive change were assessed as a function …

Behavioral And Immunological Phenotypes Of Transgenic Mice Overexpressing Human Secreted Amyloid Precursor Protein Alpha: Implications For Autism, Antoinette R. Bailey

USF Tampa Graduate Theses and Dissertations

Autism is a heterogeneous neurodevelopmental disorder that is characterized by impaired social interaction and communication as well as restricted and repetitive behaviors and focused interests. In addition to the cardinal behavioral characteristics observed for diagnosis, autistic individuals exhibit a number of comorbid conditions as well as a variety of aberrant immunological features. Recent studies report that plasma from autistic children contained elevated levels of secreted amyloid precursor protein alpha (sAPP-á), the á-secretase cleavage product of the amyloid precursor protein (APP) which is ubiquitously expressed in the brain, spleen, thymus and other organs. Interestingly, the sAPP-á fragment functions as a neurotrophic …

Efficacy Of Increased Ube3a Protein Levels In The Brain In Rescuing The Phenotype Of An Angelman Syndrome Mouse, Jennifer L. Daily

USF Tampa Graduate Theses and Dissertations

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes an E6-AP ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve …

Cd2ap Regulates Sumoylation Of Cin85 In Podocytes, Irini Tossidou, Rainer Niedenthal, Malte Klaus, Beina Teng, Kirstin Worthmann, Benjamin King, Kevin Peterson

Dartmouth Scholarship

Podocytes are highly differentiated and polarized epithelial cells located on the visceral side of the glomerulus. They form an indispensable component of the glomerular filter, the slit diaphragm, formed by several transmembrane proteins and adaptor molecules. Disruption of the slit diaphragm can lead to massive proteinuria and nephrotic syndrome in mice and humans. CD2AP is an adaptor protein that is important for the maintenance of the slit diaphragm. Together with its paralogue, CIN85, CD2AP belongs to a family of adaptor proteins that are primarily described as being involved in endocytosis and downregulation of receptor tyrosine kinase activity. We have shown …

A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …

Mechanism Of Acetylcholinesterase's Neurotrophic Action On Drg Neurons Of Rat, Naga Venkata Pavan Kumar Kunala

Student Theses and Dissertations

The fundamental role of enzyme acetylcholinesterase (AChE) is to catalyze the neurotransmitter acetylcholine at cholinergic synapses. In addition to its catalytic activity, AChE appears to play a significant non-catalytic role of neurotropic activity on dorsal root ganglion (DRG) neurons of rat. However the mechanism responsible for AChE's neurotrophic activity is not fully understood. Earlier experiments in Dr. Srivatsan's laboratory demonstrated the binding of fluorophore conjugated AChE to cell surface of DRG neurons. These findings led to my hypothesis that AChE may bind to cell surface protein(s) in DRG neurons, and the resulting protein-protein interaction is responsible for activating downstream signaling …

Cns Recruitment Of Cd8+ T Lymphocytes Specific For A Peripheral Virus Infection Triggers Neuropathogenesis During Polymicrobial Challenge., Christine M Matullo, Kevin J O'Regan, Mark Curtis, Glenn F Rall

Department of Microbiology and Immunology Faculty Papers

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with …

Triterpenoid Modulation Of Il-17 And Nrf-2 Expression Ameliorates Neuroinflammation And Promotes Remyelination In Autoimmune Encephalomyelitis, Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio

Dartmouth Scholarship

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of …

Map Kinases Couple Hindbrain-Derived Catecholamine Signals To Hypothalamic Adrenocortical Control Mechanisms During Glycemia-Related Challenges, Khan, Kimberly Kaminski, Graciela Sanchez-Watts, Todd Ponzio, J. Kuzmiski, Jaideep Bains, Alan Watts

Departmental Papers (Biology)

No abstract provided.

Age Dependent Spatial Characteristics Of Epileptiform Activity In Malformed Cortex, L. Andrew Bell

Theses and Dissertations

Developmental cortical malformations are a major cause of intractable seizures. Determining the location and timing of susceptibility for epileptiform activity is critical to identifying what mechanisms contribute to epileptogenesis in any model. Using the freeze lesion rat model of polymicrogyria, we have identified, in lesioned cortex, these two aspects of epileptogenesis. Previous studies have demonstrated that epileptiform activity cannot be evoked prior to postnatal day (P) 12, but the malformed cortex is more susceptible to seizures as early as P10. An increase in excitatory afferents to the epileptogenic zone occurs before the onset of network epileptiform activity. Whether or not …

Mutant Tdp-43 In Motor Neurons Promotes The Onset And Progression Of Als In Rats, Cao Huang, Jianbin Tong, Fangfang Bi, Hongxia Zhou, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. …

De Novo Design Of Antiviral And Antibacterial Peptides With Varying Loop Structures, Guangshun Wang, Karen W. Buckheit, Biswajit Mishra, Tamara Lushnikova, Robert W. Buckheit Jr.

Journal Articles: Pathology and Microbiology

No abstract provided.

Wnt Signaling Exerts An Antiproliferative Effect On Adult Cardiac Progenitor Cells Through Igfbp3., Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F Bayomy, Gabriel C Fine, Karen Westerman, Travis L Biechele, Randall T Moon, Thomas Force, Ronglih Liao

Center for Translational Medicine Faculty Papers

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical …

Histone Deacetylase Inhibitor Valproic Acid Suppresses The Growth And Increases The Androgen Responsiveness Of Prostate Cancer Cells., Yu-Wei Chou, Nagendra K. Chaturvedi, Shougiang Ouyang, Fen-Fen Lin, Dharam Kaushik, Jue Wang, Isaac Kim, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

We identified the molecular target by histone deacetylase (HDAC) inhibitors for exploring their potential prostate cancer (PCa) therapy. Upon HDAC inhibitors-treatment, LNCaP cell growth was suppressed, correlating with increased cellular prostatic acid phosphatase (cPAcP) expression, an authentic protein tyrosine phosphatase. In those cells, ErbB-2 was dephosphorylated, histone H3/H4 acetylation and methylation increased and cyclin proteins decreased. In PAcP shRNA-transfected C-81 cells, valproic acid (VPA) efficacy of growth suppression was diminished. Further, VPA pre-treatment enhanced androgen responsiveness of C-81, C4-2 and MDA PCa2b-AI cells. Thus, cPAcP expression is involved in growth suppression by HDAC inhibitors in PCa cells, and VPA pre-treatments …

Identifying Modulators Of The Development Of Acute Functional Tolerance To Ethanol In Caenorhabditis Elegans., Ka-Po Leung

Theses and Dissertations

Alcohol abuse is a problem in our society. There are few treatments available, in part due to the unclear molecular mechanisms of ethanol’s effects. Human studies indicate that there is a genetic component influencing disease susceptibility, and that an individual’s initial response to alcohol can predict their development of addiction. We have taken a forward genetics approach to study one component of initial response, acute functional tolerance (AFT), in Caenorhabditis elegans. We identified bet11, a mutation that causes animals to be defective in the development of AFT. Genetic analysis suggested that the gene that bet11 disrupts participates in a synthetic …

Lessons From Chimpanzee-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Laboratory Experiments Collection

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98–99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus …

Specific Contributions Of Ventromedial, Anterior Cingulate, And Lateral Prefrontal Cortex For Attentional Selection And Stimulus Valuation., Daniel Kaping, Martin Vinck, R Matthew Hutchison, Stefan Everling, Thilo Womelsdorf

Brain and Mind Institute Researchers' Publications

Attentional control ensures that neuronal processes prioritize the most relevant stimulus in a given environment. Controlling which stimulus is attended thus originates from neurons encoding the relevance of stimuli, i.e. their expected value, in hand with neurons encoding contextual information about stimulus locations, features, and rules that guide the conditional allocation of attention. Here, we examined how these distinct processes are encoded and integrated in macaque prefrontal cortex (PFC) by mapping their functional topographies at the time of attentional stimulus selection. We find confined clusters of neurons in ventromedial PFC (vmPFC) that predominantly convey stimulus valuation information during attention shifts. …

Empathy-Based Conservation: An Interdisciplinary Approach To Conservation Policy And Decision-Making, Kaitlyn Delashmutt

Department of Environmental Studies: Undergraduate Student Theses

In the late 20^th century, neuroscientists in Italy discovered a neuron in the brain capable of mentally mimicking the emotions derived from the actions of others (Rizzolatti and Craighero, 2004). It is the process that makes your elbow ache when someone else knocks their elbow on the counter or the uncontrollable smile that creeps up when someone smiles at you. No questions asked, people intuitively sense what others are feeling. The old school of thought was that humans deduced through logic and reason the actions of others and interpreted the emotions through a rational process (Carew et al, 2008). …

Functional Genomics Reveals An Essential And Specific Role For Stat1 In Protection Of The Central Nervous System Following Herpes Simplex Virus Corneal Infection, Tracy J. Pasieka, Cristian Cilloniz, Victoria S. Carter, Pamela Rosato, Michael G. Katze, David A. Leib

Dartmouth Scholarship

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), …

Buffered Memory: A Hypothesis For The Maintenance Of Functional, Virus-Specific Cd8(+) T Cells During Cytomegalovirus Infection., Christopher M Snyder

Department of Microbiology and Immunology Faculty Papers

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and …

Novel Amino Acid Transporter-Targeted Radiotracers For Breast Cancer Imaging, Fanlin Kong

Dissertations and Theses (Open Access)

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. ¹⁸F-2-Fluoro-2-deoxy-glucose (¹⁸F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, ¹⁸F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, ¹⁸F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake …

Mechanisms Of Brain Edema Formation In Mouse Models Of Intracerebral Hemorrhage, Qingyi Ma

Loma Linda University Electronic Theses, Dissertations & Projects

Perihematomal edema causes major neurologic deterioration following intracerebral hemorrhage (ICH), mainly resulting from the disruption of the blood-brain barrier (BBB) by multiple mediators, including inflammatory mediators and thrombin. The objective of our study was to investigate the mechanisms by which inflammation and thrombin respectively lead to the formation of brain edema following ICH. Our long-term goal is to develop new therapeutic strategies against ICH-induced brain edema by targeting: (1) VAP-1 mediated inflammatory response and (2) PDGFR-α orchestrated BBB impairment. Vascular adhesion protein-1 (VAP-1) was previously shown to promote leukocyte adhesion and transmigration. Additionally, PDGFR-α was also found to play a …

Role Of Vima In Cell Surface Biogenesis In Porphyromonas Gingivalis, Devon Osbourne Jr.

Loma Linda University Electronic Theses, Dissertations & Projects

Porphyromonas gingivalis is an important etiological agent of periodontal disease - a disease that affects an estimated 49,000,000 people in the United States of America. Periodontal disease includes gingivitis – inflammation of the gums, and periodontitis – destruction of the teeth and their supporting tissues. Porphyromonas gingivalis is associated with the chronic form of periodontal disease in addition to several systemic diseases.

The vimA gene of P. gingivalis has been previously shown to play a significant role in the biogenesis of gingipains (trypsin-like cysteine proteases). The vimA has also been demonstrated to play a role in hemolysis, hemagglutination, autoaggregation, posttranslational …

Chronic Hypoxia Induces Epigenetic Modifications In The Fetal Rat Heart, Andrew James Grant Patterson

Loma Linda University Electronic Theses, Dissertations & Projects

Heart disease remains the leading cause of death worldwide. As a result of studies done by Barker and associates, our awareness of the significance of stress during gestation as a risk factor for heart diseases has expanded. We now know that events in utero can significantly alter gene expression patterns in heart tissue leading to increase susceptibility to ischemia reperfusion injury in adulthood. The focus of this project was to elucidate the role of chronic hypoxia in the programming of the cardio-protective gene, Protein Kinase C epsilon (PKCε) in fetal rat heart. We used an animal, organ base, and cell …

Mechanisms Of Erythropoietin-Induced Neuroprotection In: In-Vivo And In-Vitro Models Of Hypoxia Ischema, Rhonda Andrea Souvenir

Loma Linda University Electronic Theses, Dissertations & Projects

Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Approximately 60 % of preterm babies and 2% of full term infants suffer from asphyxia. Asphyxia related death accounts for approximately 23% of neonatal mortality annually. Many therapeutic interventions show promise in the laboratory but fail in clinics. A thorough understanding of mechanisms by which promising therapeutic intervention confers its neuroprotection is necessary to promote smoother transitions from bench to the bedside. Erythropoietin (EPO), a hematopoietic growth factor that increases oxygen availability during hypoxia/ischemia is associated with cell survival and neuroprotection in: in vivo and in …

Characterization Of The Mechanism Of Pparγ-Mediated Neointima Formation In Rodents, Ryoko Tsukahara

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) and its ether analog alkyl glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for …

Characterization Of The Key Mouse Cochlear Developmental Genes For Auditory Hair Cell Regeneration, Zhiyong Liu

Theses and Dissertations (ETD)

Mammalian inner ear cochlear auditory hair cells (HCs) and adjacent supporting cells (SCs) are believed to derive from the same progenitors during development. However, unlike SCs of nonmammalian vertebrates, mammalian cochlear SCs cannot be converted into functional hair cells (HCs) after damage, thus leading to permanent deafness. To entitle mammals with the ability to restore hearing capacity after HC damage, we first achieved proliferation of SCs by acute ablation of p27 or Sox2. Secondly, we overactivated Notch1 signaling in the mouse inner ear at different developmental stages, and found that the ability of Notch signaling in generating new HCs declines …

Autoimmune Consequences Of Histone Deimination During Neutrophil Activation, Nishant Dwivedi

Theses and Dissertations (ETD)

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or "trap" bacterial pathogens. Neutrophil …