Targeting The Colchicine Binding Site On Tubulin To Overcome Multidrug Resistance And Anticancer Efficacy Of Selective Survivin Inhibitors,
2018
University of Tennessee Health Science Center
Targeting The Colchicine Binding Site On Tubulin To Overcome Multidrug Resistance And Anticancer Efficacy Of Selective Survivin Inhibitors, Kinsle E. Arnst
Theses and Dissertations (ETD)
Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug …
The Role Of Exosomal Transport Of Viral Agents In Persistent Hiv Pathogenesis,
2018
University of Tennessee Health Science Center
The Role Of Exosomal Transport Of Viral Agents In Persistent Hiv Pathogenesis, Benjamin J. Patters
Theses and Dissertations (ETD)
Human immunodeficiency virus (HIV) infection, despite great advances in antiretroviral therapy (ART), remains a lifelong affliction. Though current treatment regimens can effectively suppress viral load to undetectable levels and preserve healthy immune function, they cannot fully alleviate all symptoms caused by the presence of the virus, such as HIV-associated neurocognitive disorders (HAND). Exosomes are small vesicles that transport cellular proteins, RNA, and small molecules between cells as a mechanism of intercellular communication. Recent research has shown that HIV proteins and RNA can be packaged into exosomes and transported between cells, to pathogenic effect. This review summarizes the current knowledge on …
Sumo-Mediated Regulation Of Nlrp3 Modulates Inflammasome Activity.,
2018
The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research; Imperial College London
Sumo-Mediated Regulation Of Nlrp3 Modulates Inflammasome Activity., Rachael Barry, Sidonie Wicky John, Gianmaria Liccardi, Tencho Tenev, Isabel Jaco, Chih-Hong Chen, Justin Choi, Paulina Kasperkiewicz, Teresa Fernandes-Alnemri, Emad S Alnemri, Marcin Drag, Yuan Chen, Pascal Meier
Department of Biochemistry and Molecular Biology Faculty Papers
The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, …
Trna 3'-Amino-Tailing For Stable Amino Acid Attachment.,
2018
Thomas Jefferson University
Trna 3'-Amino-Tailing For Stable Amino Acid Attachment., Howard Gamper, Ya-Ming Hou
Department of Biochemistry and Molecular Biology Faculty Papers
Amino acids are attached to the tRNA 3'-end as a prerequisite for entering the ribosome for protein synthesis. Amino acid attachment also gives tRNA access to nonribosomal cellular activities. However, the normal attachment is via an ester linkage between the carboxylic group of the amino acid and the 3'-hydroxyl of the terminal A76 ribose in tRNA. The instability of this ester linkage has severely hampered studies of aminoacyl-tRNAs. Although the use of 3'-amino-3'-deoxy A76 in a 3'-amino-tailed tRNA provides stable aminoacyl attachment via an amide linkage, there are multiple tailing protocols and the efficiency of each relative to the others …
Dna Methylation-Based Age Prediction And Telomere Length In White Blood Cells And Cumulus Cells Of Infertile Women With Normal Or Poor Response To Ovarian Stimulation.,
2018
IVIRMA New Jersey; Thomas Jefferson University
Dna Methylation-Based Age Prediction And Telomere Length In White Blood Cells And Cumulus Cells Of Infertile Women With Normal Or Poor Response To Ovarian Stimulation., Scott J. Morin, Xin Tao, Diego Marin, Yiping Zhan, Jessica Landis, Jenna Bedard, Richard T. Scott, Emre Seli
Department of Biochemistry and Molecular Biology Faculty Papers
An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells …
Control Of Ccnd1 Ubiquitylation By The Catalytic Saga Subunit Usp22 Is Essential For Cell Cycle Progression Through G1 In Cancer Cells.,
2018
Thomas Jefferson University
Control Of Ccnd1 Ubiquitylation By The Catalytic Saga Subunit Usp22 Is Essential For Cell Cycle Progression Through G1 In Cancer Cells., Victoria J. Gennaro, Timothy J. Stanek, Amy R. Peck, Yunguang Sun, Feng Wang, Shuo Qie, Karen E. Knudsen, Hallgeir Rui, Tauseef Butt, J. Alan Diehl, Steven B. Mcmahon
Department of Biochemistry and Molecular Biology Faculty Papers
Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the …
Cysteine Residues Contribute To The Dimerization And Enzymatic Activity Of Human Nuclear Dutp Nucleotidohydrolase (Ndut).,
2018
Rowan University
Cysteine Residues Contribute To The Dimerization And Enzymatic Activity Of Human Nuclear Dutp Nucleotidohydrolase (Ndut)., Shawna M Rotoli, Julia L Jones, Salvatore J Caradonna
Rowan-Virtua School of Osteopathic Medicine Departmental Research
dUTPase is an enzyme found in all organisms that have thymine as a constituent of DNA. Through evolution, humans have two major isoforms of dUTPase: a mitochondrial (mDut) and a nuclear (nDut) isoform. The nuclear isoform of dUTPase is a 164-amino-acids-long protein containing three cysteine residues. nDut's starting methionine is post-translationally cleaved, leaving four unique amino acids on its amino-terminus including one cysteine residue (C3). These are not present in the mitochondrial isoform (mDut). Using mass spectrometry analyses of recombinant dUTPase constructs, we have discovered an intermolecular disulfide bridge between cysteine-3 of each nDut monomer. We have found that these …
Editorial: Ion Channel Trafficking And Cardiac Arrhythmias,
2018
University Medical Center Utrecht, Netherlands
Editorial: Ion Channel Trafficking And Cardiac Arrhythmias, Marcel A. G. Van Der Heyden, Brian P. Delisle, Hugues Abriel
Physiology Faculty Publications
No abstract provided.
Extracellular Interactions Between Fibulins And Transforming Growth Factor (Tgf)-Β In Physiological And Pathological Conditions.,
2018
Thomas Jefferson University
Extracellular Interactions Between Fibulins And Transforming Growth Factor (Tgf)-Β In Physiological And Pathological Conditions., Takeshi Tsuda
Department of Pediatrics Faculty Papers
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell⁻matrix interactions, including thrombospondins, SPARC (Secreted Protein …
Interfering With Dna Decondensation As A Strategy Against Mycobacteria,
2018
University of Amsterdam, Netherlands
Interfering With Dna Decondensation As A Strategy Against Mycobacteria, Enzo M. Scutigliani, Edwin R. Scholl, Anita E. Grootemaat, Sadhana Khanal, Jakub A. Kochan, Przemek M. Krawczyk, Eric A. Reits, Atefeh Garzan, Huy X. Ngo, Keith D. Green, Sylvie Garneau-Tsodikova, Jan M. Ruijter, Henk A. Van Veen, Nicole N. Van Der Wel
Pharmaceutical Sciences Faculty Publications
Tuberculosis is once again a major global threat, leading to more than 1 million deaths each year. Treatment options for tuberculosis patients are limited, expensive and characterized by severe side effects, especially in the case of multidrug-resistant forms. Uncovering novel vulnerabilities of the pathogen is crucial to generate new therapeutic strategies. Using high resolution microscopy techniques, we discovered one such vulnerability of Mycobacterium tuberculosis. We demonstrate that the DNA of M. tuberculosis can condense under stressful conditions such as starvation and antibiotic treatment. The DNA condensation is reversible and specific for viable bacteria. Based on these observations, we hypothesized …
Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches,
2018
Rowan University
Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin
Graduate School of Biomedical Sciences Theses and Dissertations
In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …
Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data.,
2018
University of Louisville
Bayesian Analytical Approaches For Metabolomics : A Novel Method For Molecular Structure-Informed Metabolite Interaction Modeling, A Novel Diagnostic Model For Differentiating Myocardial Infarction Type, And Approaches For Compound Identification Given Mass Spectrometry Data., Patrick J. Trainor
Electronic Theses and Dissertations
Metabolomics, the study of small molecules in biological systems, has enjoyed great success in enabling researchers to examine disease-associated metabolic dysregulation and has been utilized for the discovery biomarkers of disease and phenotypic states. In spite of recent technological advances in the analytical platforms utilized in metabolomics and the proliferation of tools for the analysis of metabolomics data, significant challenges in metabolomics data analyses remain. In this dissertation, we present three of these challenges and Bayesian methodological solutions for each. In the first part we develop a new methodology to serve a basis for making higher order inferences in metabolomics, …
Coupling Of Smoothened To Inhibitory G Proteins Reduces Voltage-Gated K,
2018
Thomas Jefferson University
Coupling Of Smoothened To Inhibitory G Proteins Reduces Voltage-Gated K, Lan Cheng, Moza Al-Owais, Manuel Covarrubias, Walter J. Koch, David R. Manning, Chris Peers, Natalia A Riobo-Del Galdo
Department of Biochemistry and Molecular Biology Faculty Papers
SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change …
Loss Of Marv1 Promotes Chop Signaling In Mouse Liver,
2018
Rowan University
Loss Of Marv1 Promotes Chop Signaling In Mouse Liver, Shad Anthony Mitchell
Graduate School of Biomedical Sciences Theses and Dissertations
Metabolic syndrome (MetS) is a term used to define a set of metabolic diseases: obesity, type 2 diabetes (T2D), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic hepatosteatosis (NASH). Those with MetS have a higher incidence of cardiovascular disease and stroke. Current drug treatments for MetS treat the individual pathologies associated with the diseases, rather than directly targeting MetS as a whole. We hypothesize that the inhibition of a ubiquitous lipid transporter known as ARV1 can improve pathologies associated with MetS. To test this hypothesis, we utilized liver tissue from mARV1 knockout mice fed a high-fat diet and examined …
Identifying Kif Subtype That Mediates Axonal Targeting Of Kv7 Channels,
2018
St. Charles Community College
Identifying Kif Subtype That Mediates Axonal Targeting Of Kv7 Channels, Allison Houghton, Jennifer Walters, Mary Hong, Dhruv Joshi, Hee Jung Chung
PRECS 2018
Early-onset Benign Familial Neonatal Epilepsy (BFNE) and Epileptic Encephalopathy (EE), are associated with mutations in neuronal KCNQ/Kv7 channel subunits Kv7.2 and Kv7.3. Kv7 channels are voltage-dependent potassium channels. Enriched at the axonal plasma membrane, they pump potassium ions out of the neurons and inhibit repetitive or burst firing of action potentials. A single neuronal Kv7 channel is a heterotetramer composed of two Kv7.2 and two Kv7.3 subunits. BFNE and EE mutations in Kv7.2 and Kv7.3 lead to decreased surface expression along the axon, which means less potassium ions are moved across the axonal membrane where action potentials are generated and …
Cloning Of An Overexpression Vector For The Rare And Uncharacterized Kras Mutant R164l,
2018
Philippine Science High School
Cloning Of An Overexpression Vector For The Rare And Uncharacterized Kras Mutant R164l, Julliane Jeanne Negre
The International Student Science Fair 2018
Mutations in the coding DNA of KRAS, which encodes for an active protein in the Ras signaling pathway regulating cell proliferation and growth, may be critical in the development of lung and colorectal cancer in humans. Clinical tests and therapies for cancer specifically target mutations, some of which may cause erroneous prognosis and prescription of cancer therapy posing more danger for patients with unique mutations. Therefore, characterization of non-hotspot mutations is becoming more important, where, KRAS R164L is an existing uncharacterized mutation identified through the Catalogue of Somatic Mutations in Cancer (COSMIC). The project aimed to clone a pTarget overexpression …
A Humanized Hypertrophic Cardiomyopathy Model To Elucidate Molecular Mechanism In Disease Pathology,
2018
NUS High School of Mathematics and Science
A Humanized Hypertrophic Cardiomyopathy Model To Elucidate Molecular Mechanism In Disease Pathology, Ragavi Vijayakumar, Maxine Hong
The International Student Science Fair 2018
Hypertrophic cardiomyopathy (HCM), that clinically manifests as an enlarged heart is a highly prevalent cardiac disorder with propensity towards arrhythmia-induced sudden cardiac death. The mechanism of HCM remains poorly defined, necessitating further understanding of the disease for improved therapeutic strategies. As it is challenging to obtain cardiac biopsies from human subjects, using induced pluripotent stem cells technology, we generated cardiomyocytes (CMs) in a dish from HCM patients. These HCM-CMs presented the clinical manifestation in that they were significantly larger in size in comparison to control (healthy)-CMs. Furthermore, gene expression profiling of cardiac ion channels revealed increased transcripts encoding for calcium …
Cloning Of An Overexpression Vector For The Rare And Uncharacterized Kras Mutant R164l,
2018
Philippine Science High School
Cloning Of An Overexpression Vector For The Rare And Uncharacterized Kras Mutant R164l, Julliane Jeanne Negre
The International Student Science Fair 2018
Mutations in the coding DNA of KRAS, which encodes for an active protein in the Ras signaling pathway regulating cell proliferation and growth, may be critical in the development of lung and colorectal cancer in humans. Clinical tests and therapies for cancer specifically target mutations, some of which may cause erroneous prognosis and prescription of cancer therapy posing more danger for patients with unique mutations. Therefore, characterization of non-hotspot mutations is becoming more important, where, KRAS R164L is an existing uncharacterized mutation identified through the Catalogue of Somatic Mutations in Cancer (COSMIC). The project aimed to clone a pTarget overexpression …
A Humanized Hypertrophic Cardiomyopathy Model To Elucidate Molecular Mechanism In Disease Pathology,
2018
NUS High School of Mathematics and Science
A Humanized Hypertrophic Cardiomyopathy Model To Elucidate Molecular Mechanism In Disease Pathology, Ragavi Vijayakumar, Maxine Hong
The International Student Science Fair 2018
Hypertrophic cardiomyopathy (HCM), that clinically manifests as an enlarged heart is a highly prevalent cardiac disorder with propensity towards arrhythmia-induced sudden cardiac death. The mechanism of HCM remains poorly defined, necessitating further understanding of the disease for improved therapeutic strategies. As it is challenging to obtain cardiac biopsies from human subjects, using induced pluripotent stem cells technology, we generated cardiomyocytes (CMs) in a dish from HCM patients. These HCM-CMs presented the clinical manifestation in that they were significantly larger in size in comparison to control (healthy)-CMs. Furthermore, gene expression profiling of cardiac ion channels revealed increased transcripts encoding for calcium …
Acetic Acid Induces Sch9p-Dependent Translocation Of Isc1p From The Endoplasmic Reticulum Into Mitochondria,
2018
Universidade do Minho (Portugal)
Acetic Acid Induces Sch9p-Dependent Translocation Of Isc1p From The Endoplasmic Reticulum Into Mitochondria, António Rego, Katrina F Cooper, Justin Snider, Yusuf A Hannun, Vítor Costa, Manuela Côrte-Real, Susana R Chaves
Rowan-Virtua School of Osteopathic Medicine Departmental Research
Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid-induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1∆ mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 …
