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Prostaglandin E(2) Is Crucial In The Response Of Podocytes To Fluid Flow Shear Stress., Tarak Srivastava, Ellen T. McCarthy, Ram Sharma, Patricia A. Cudmore, Mukut Sharma, Mark L. Johnson, Lynda F. Bonewald 2010 Children's Mercy Hospital

Prostaglandin E(2) Is Crucial In The Response Of Podocytes To Fluid Flow Shear Stress., Tarak Srivastava, Ellen T. Mccarthy, Ram Sharma, Patricia A. Cudmore, Mukut Sharma, Mark L. Johnson, Lynda F. Bonewald

Manuscripts, Articles, Book Chapters and Other Papers

Podocytes play a key role in maintaining and modulating the filtration barrier of the glomerulus. Because of their location, podocytes are exposed to mechanical strain in the form of fluid flow shear stress (FFSS). Several human diseases are characterized by glomerular hyperfiltration, such as diabetes mellitus and hypertension. The response of podocytes to FFSS at physiological or pathological levels is not known. We exposed cultured podocytes to FFSS, and studied changes in actin cytoskeleton, prostaglandin E(2) (PGE(2)) production and expression of cyclooxygenase-1 and-2 (COX-1, COX-2). FFSS caused a reduction in transversal F-actin stress filaments and the appearance of ...


Role And Regulation Of Fat Specific Protein (Fsp27) In Lipolysis In 3t3-L1 Adipocytes: A Dissertation, Srijana Ranjit 2010 University of Massachusetts Medical School

Role And Regulation Of Fat Specific Protein (Fsp27) In Lipolysis In 3t3-L1 Adipocytes: A Dissertation, Srijana Ranjit

GSBS Dissertations and Theses

The alarming rate of increase in incidence and prevalence of the type 2 diabetes mellitus has prompted intense research on understanding the pathogenesis of the type 2 diabetes. It is observed that the development of type 2 diabetes is preceded by a state of insulin resistance and obesity. Previous studies have suggested that the obesity induced insulin resistance may be mediated by elevated levels of circulating free fatty acids (FFAs). The increase in circulating levels of FFAs may be contributed by the release of FFAs from stored triglycerides (TG) in adipocytes via lipolysis. It is hypothesized that the decrease in ...


A Tale Of Two Arfs: Tumor Suppressor And Anti-Viral Functions Of P14arf: A Dissertation, Michael W. Straza 2010 University of Massachusetts Medical School

A Tale Of Two Arfs: Tumor Suppressor And Anti-Viral Functions Of P14arf: A Dissertation, Michael W. Straza

GSBS Dissertations and Theses

Animals have evolved complicated and overlapping mechanisms to guard against the development of cancer and infection by pathogenic organisms. ARF, a potent tumor suppressor, positively regulates p53 by antagonizing p53’s negative regulator, MDM2, which in turn results in either apoptosis or cell cycle arrest. ARF also has p53-independent tumor suppressor activity. The CtBP transcriptional co-repressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is a target for negative regulation by ARF. ARF targets CtBP to the proteasome for degradation, which results in the up regulation of proapoptotic BH3-only proteins, and ...


Exploring Molecular Mechanisms Of Drug Resistance In Hiv-1 Protease Through Biochemical And Biophysical Studies: A Dissertation, Rajintha M. Bandaranayake 2010 University of Massachusetts Medical School

Exploring Molecular Mechanisms Of Drug Resistance In Hiv-1 Protease Through Biochemical And Biophysical Studies: A Dissertation, Rajintha M. Bandaranayake

GSBS Dissertations and Theses

The human immunodeficiency virus type-1 (HIV-1) is the leading cause of acquired immunodeficiency syndrome (AIDS) in the world. As there is no cure currently available to treat HIV-1 infections or AIDS, the major focus of drug development efforts has been to target viral replication in an effort to slow down the progression of the infection to AIDS. The aspartyl protease of HIV-1 is an important component in the viral replication cycle and thus, has been an important anti-HIV-1 drug target. Currently there are nine protease inhibitors (PIs) that are being used successfully as a part of highly active antiretroviral therapy ...


Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng 2010 University of Massachusetts Medical School

Novel Therapeutic Targets For Ph+ Chromosome Leukemia And Its Leukemia Stem Cells: A Dissertation, Cong Peng

GSBS Dissertations and Theses

The human Philadelphia chromosome (Ph) arises from a translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)]. The resulting chimeric BCR-ABLoncogene encodes a constitutively activated, oncogenic tyrosine kinase that induces chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, induces a complete hematologic and cytogenetic response in the majority of CML patients, but is unable to completely eradicate BCR-ABL–expressing leukemic cells, suggesting that leukemia stem cells are not eliminated. Over time, patients frequently become drug resistant and develop progressive disease despite continued treatment. Two major reasons cause ...


Role Of Internal Calcium Stores In Exocytosis And Neurotransmission: A Dissertation, Jason J. Lefkowitz 2010 University of Massachusetts Medical School

Role Of Internal Calcium Stores In Exocytosis And Neurotransmission: A Dissertation, Jason J. Lefkowitz

GSBS Dissertations and Theses

A central concept in the physiology of neurosecretion is that a rise in cytosolic [Ca2+] in the vicinity of plasmalemmal Ca2+ channels due to Ca2+ influx, elicits exocytosis. This dissertation examines the effect on both spontaneous and elicited exocytosis of a rise in focal cytosolic [Ca2+] in the vicinity of ryanodine receptors (RYRs) due to release from internal stores in the form of Ca2+ syntillas. Ca2+ syntillas are focal cytosolic transients mediated by RYRs, which we first found in hypothalamic magnocellular neuronal terminals. (Scintilla, Latin for spark, found in nerve terminals, normally synaptic structures ...


Age And Sex Differences In Duration Of Pre-Hospital Delay, Hospital Treatment Practices, And Short-Term Outcomes In Patients Hospitalized With An Acute Coronary Syndrome/Acute Myocardial Infarction: A Dissertation, Hoa L. Nguyen 2010 University of Massachusetts Medical School

Age And Sex Differences In Duration Of Pre-Hospital Delay, Hospital Treatment Practices, And Short-Term Outcomes In Patients Hospitalized With An Acute Coronary Syndrome/Acute Myocardial Infarction: A Dissertation, Hoa L. Nguyen

GSBS Dissertations and Theses

Background
The prompt seeking of medical care after the onset of symptoms suggestive of acute coronary syndromes (ACS)/acute myocardial infarction (AMI) is associated with the receipt of coronary reperfusion therapy, and effective cardiac medications in patients with an ACS/AMI and is crucial to reducing mortality and the risk of serious clinical complications in these patients. Despite declines in important hospital complications and short-term death rates in patients hospitalized with an ACS/AMI, several patient groups remain at increased risk for these adverse outcomes, including women and the elderly. However, recent trends in age and sex differences in extent ...


Glycosylation, Assembly And Trafficking Of Cardiac Potassium Channel Complexes: A Dissertation, Kshama D. Chandrasekhar 2010 University of Massachusetts Medical School

Glycosylation, Assembly And Trafficking Of Cardiac Potassium Channel Complexes: A Dissertation, Kshama D. Chandrasekhar

GSBS Dissertations and Theses

KCNE peptides are a class of type I transmembrane ß-subunits that assemble with and modulate the gating and ion conducting properties of a variety of voltage-gated K+ channels. Accordingly, mutations that affect the assembly and trafficking of K+ channel/KCNE complexes give rise to disease. The cellular mechanisms that oversee KCNE peptide assembly with voltage-gated K+ channels have yet to be elucidated. In Chapter II, we show that KCNE1 peptides are retained in the early stages of the secretory pathway until they co-assemble with KCNQ1 K+ channel subunits. Co-assembly with KCNQ1 channel subunits mediates efficient forward trafficking of KCNE1 peptides ...


Cip4 And Src In Promoting The Migration And Invasion Of Breast Cancers, Christina S. Pichot 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Cip4 And Src In Promoting The Migration And Invasion Of Breast Cancers, Christina S. Pichot

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Cellular invasion represents a critical early step in the metastatic cascade, and many proteins have been identified as part of an “invasive signature.” The non-receptor tyrosine kinase Src is commonly upregulated in breast cancers, often in conjunction with overexpression of EGFR. Signaling from this pathway stimulates cell proliferation, migration, and invasion and frequently involves proteins that regulate the cytoskeleton. My data demonstrates that inhibition of Src, using the small-molecule inhibitor dasatinib, impairs cellular migration and invasion. Furthermore, Src inhibition sensitizes the cells to the effects of the chemotherapeutic doxorubicin resulting in dramatic, synergistic inhibition of proliferation with combination treatments. The ...


Evidence And Impact Of Expectancies Associated With Psychotropic Medication Reductions In Persons With Mental Retardation, Christopher S. Baglio 2010 Olivet Nazarene University

Evidence And Impact Of Expectancies Associated With Psychotropic Medication Reductions In Persons With Mental Retardation, Christopher S. Baglio

Ed.D. Dissertations

This study was an attempt to understand the presence and impact of staff expectancies related to psychotropic medication reductions conducted with persons diagnosed with mental retardation. Within a state operated developmental center in the Midwest, results indicated that direct support staff overwhelmingly expected individuals to get worse following such a reduction. These expectancies significantly impacted data recording practice leading to discrepant elevations reported by staff expecting deterioration. Finally, while written communication about planned psychotropic medication reductions did not appear to elevate data recording as was hypothesized, reductions were associated with increases in both behaviors and psychiatric symptoms. This study has ...


Thioester Hydrolysis Reactivity Of Metal Complexes, James Justin Danford 2010 Utah State University

Thioester Hydrolysis Reactivity Of Metal Complexes, James Justin Danford

All Graduate Theses and Dissertations

Glyoxalase II is one of two metalloenzymes found in the glyoxalase pathway and is responsible for catalyzing the hydrolysis of a thioester substrate. Its bimetallic active site is found to contain a variety of metal combinations, including Fe(III)Zn(II). A recent report indicates that human glyoxalase II, while containing a Fe(II)Zn(II) center, is catalytically active as a mononuclear Zn(II) enzyme. Detailed mechanistic studies of glyoxalase II enzymes are limited due to uncertainty in the metal ion content of recombinantly prepared samples. The research presented in this thesis is focused on gaining mechanistic insight into ...


Characterization And Optimization Of Antigen-Specific T Cell Responses During Ex Vivo Expansion Of Melanoma Tumor-Infiltrating Lymphocytes, yufeng li 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Characterization And Optimization Of Antigen-Specific T Cell Responses During Ex Vivo Expansion Of Melanoma Tumor-Infiltrating Lymphocytes, Yufeng Li

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Treatment of metastatic melanoma with tumor reactive T cells (adoptive T cell therapy, ACT) is a promising approach associated with a high clinical response rate. However, further optimization of this treatment modality is required to increase the clinical response after this therapy. ACT in melanoma involves an initial phase (pre-REP) of tumor-infiltrating lymphocyte (TIL) expansion ex vivo from tumor isolates followed by a second phase, “rapid expansion protocol” (REP) generating the billions of cells used as the TIL infusion product. The main question addressed in this thesis was how the currently used REP affected the responsiveness of the CD8+ T ...


Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng 2010 University of Tennessee Health Science Center

Discovery Of Quinic Acid Derivatives As Oral Anti-Inflammatory Agents, Kui Zeng

Theses and Dissertations (ETD)

Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. Cat’s claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB). Herein, we described the synthesis and biological testing of novel QA derivatives. Inhibition of NF-κB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-κB response element. A549- NF-κB cells were stimulated with TNF-α (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP ...


Role Of The Monocyte/Macrophage Cell Lineage In Obesity-Related Insulin Resistance, Olga T. Hardy 2010 University of Massachusetts Medical School

Role Of The Monocyte/Macrophage Cell Lineage In Obesity-Related Insulin Resistance, Olga T. Hardy

GSBS Dissertations and Theses

Background

Obesity is an important risk factor for resistance to insulin-mediated glucose disposal, and is a precursor of type 2 diabetes and other disorders.

Objectives

To identify molecular pathways in adipose tissue and inflammatory cells that may result in obesity-associated insulin resistance, we exploited the fact that not all obese individuals are prone to insulin resistance. Thus the degree of obesity as a variable was removed by studying obese subjects of similar body mass index (BMI) who are insulin-sensitive (IS) versus insulin-resistant (IR).

Methods

Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental ...


Protein Evolution Via Amino Acid And Codon Elimination, Lise Goltermann, Marie Sofie Yoo Larsen, Ranat Banerjee, Andreas C. Joerger, Michael Ibba, Thomas Bentin 2010 University of Copenhagen

Protein Evolution Via Amino Acid And Codon Elimination, Lise Goltermann, Marie Sofie Yoo Larsen, Ranat Banerjee, Andreas C. Joerger, Michael Ibba, Thomas Bentin

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Background
Global residue-specific amino acid mutagenesis can provide important biological insight and generate proteins with altered properties, but at the risk of protein misfolding. Further, targeted libraries are usually restricted to a handful of amino acids because there is an exponential correlation between the number of residues randomized and the size of the resulting ensemble. Using GFP as the model protein, we present a strategy, termed protein evolution via amino acid and codon elimination, through which simplified, native-like polypeptides encoded by a reduced genetic code were obtained via screening of reduced-size ensembles.

Methodology/Principal Findings
The strategy involves combining a ...


Identification Of 2-Aminothiazole-4-Carboxylate Derivatives Active Against Mycobacterium Tuberculosis H37rv And The B-Ketoacyl-Acp Synthase Mtfabh, Philadelphia University 2010 Philadelphia University

Identification Of 2-Aminothiazole-4-Carboxylate Derivatives Active Against Mycobacterium Tuberculosis H37rv And The B-Ketoacyl-Acp Synthase Mtfabh, Philadelphia University

Philadelphia University, Jordan

No abstract provided.


The Role Of Rip2 Protein In The Nod Mediated Innate Immune Response: A Dissertation, Yibin Yang 2010 University of Massachusetts Medical School

The Role Of Rip2 Protein In The Nod Mediated Innate Immune Response: A Dissertation, Yibin Yang

GSBS Dissertations and Theses

The Rip2 kinase contains a caspase recruitment domain (CARD) and has been implicated in the activation of the transcriptional factor NF-кB downstream of Nod-like receptors. However, how Rip2 mediates innate immune responses is still largely unclear. We show that Rip2 and IKK-γ become stably polyubiquitinated upon treatment of cells with the Nod2 ligand, muramyl dipeptide. We demonstrate a requirement for the E2 conjugating enzyme Ubc13, the E3 ubiquitin ligase Traf6 and the ubiquitin activated kinase Tak1 in Nod2-mediated NF-кB activation. We also show that M. tuberculosisinfection stimulates Rip2 polyubiquitination. Collectively, this study revealed that the Nod2 pathway is ubiquitin ...


How The Sequence Of A Gene Can Tune Its Translation, Kurt Fredrick, Michael Ibba 2010 The Ohio State University

How The Sequence Of A Gene Can Tune Its Translation, Kurt Fredrick, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Sixty-one codons specify 20 amino acids, offering cells many options for encoding a polypeptide sequence. Two new studies (Cannarrozzi et al., 2010, Tuller et al., 2010) now foster the idea that patterns of codon usage can control ribosome speed, fine-tuning translation to increase the efficiency of protein synthesis.


Metal-Free Als Variants Of Dimeric Human Cu,Zn-Superoxide Dismutase Have Enhanced Populations Of Monomeric Species, Anna-Karin E. Svensson, Osman Bilsel, Can Kayatekin, Jessica A. Adefusika, Jill A. Zitzewitz, C. Robert Matthews 2010 University of Massachusetts Medical School

Metal-Free Als Variants Of Dimeric Human Cu,Zn-Superoxide Dismutase Have Enhanced Populations Of Monomeric Species, Anna-Karin E. Svensson, Osman Bilsel, Can Kayatekin, Jessica A. Adefusika, Jill A. Zitzewitz, C. Robert Matthews

Women’s Health Research Faculty Publications

Amino acid replacements at dozens of positions in the dimeric protein human, Cu,Zn superoxide dismutase (SOD1) can cause amyotrophic lateral sclerosis (ALS). Although it has long been hypothesized that these mutations might enhance the populations of marginally-stable aggregation-prone species responsible for cellular toxicity, there has been little quantitative evidence to support this notion. Perturbations of the folding free energy landscapes of metal-free versions of five ALS-inducing variants, A4V, L38V, G93A, L106V and S134N SOD1, were determined with a global analysis of kinetic and thermodynamic folding data for dimeric and stable monomeric versions of these variants. Utilizing this global analysis ...


Antibody Responses Elicited By Dna Prime-Protein Boost Hiv Vaccines: A Dissertation, Michael Vaine 2010 University of Massachusetts Medical School

Antibody Responses Elicited By Dna Prime-Protein Boost Hiv Vaccines: A Dissertation, Michael Vaine

GSBS Dissertations and Theses

The best known correlate of protection provided by vaccines is the presence of pathogen specific antibodies after immunization. However, against the Human Immunodeficiency Virus-1 (HIV-1) the mere presence of antibodies specific for the viral Envelope (Env) protein is not sufficient to provide protection. This necessitates in depth study of the humoral responses elicited during infection and by vaccination. While a significant amount of effort has been invested in studying the evolution of antibody responses to viral infection, only limited progress in understanding antibody responses elicited through vaccination has been made. In the studies described here, I attempt to rectify this ...


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