Synthesis, Evaluation And Structural Studies Of Antiproliferative Tubulin-Targeting Azetidin-2-Ones,
2011
Technological University Dublin
Synthesis, Evaluation And Structural Studies Of Antiproliferative Tubulin-Targeting Azetidin-2-Ones, Niamh O'Boyle, Lisa M. Greene, Orla Bergin, Jean-Baptiste Fichet, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan
Articles
A series of azetidin-2-ones substituted at positions 2, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerization that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the …
Lead Identification Of Β-Lactam And Related Imine Inhibitors Of The Molecular Caperone Heat Shock Protein 90,
2011
Technological University Dublin
Lead Identification Of Β-Lactam And Related Imine Inhibitors Of The Molecular Caperone Heat Shock Protein 90, Niamh O'Boyle, Andrew Js Knox, Trevor P. Price, D. Clive Williams, Daniela M. Zisterer, David G. Lloyd, Mary J. Meegan
Articles
Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the identification of inhibitors based on β-lactam and imine templates. β-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC50 values of 5.6 μM, 14.5 μM and 22.1 μM respectively. The binding affinity displayed …
Synthesis, Biochemical And Molecular Modelling Studies Of Antiproliferative Azetidinones Causing Microtubule Disruption And Mitotic Catastrophe,
2011
Technological University Dublin
Synthesis, Biochemical And Molecular Modelling Studies Of Antiproliferative Azetidinones Causing Microtubule Disruption And Mitotic Catastrophe, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Niall O. Keely, Andrew Js Knox, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan
Articles
The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC50 value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for …
Disorder Predictors Also Predict Backbone Dynamics For A Family Of Disordered Proteins,
2011
University of South Florida
Disorder Predictors Also Predict Backbone Dynamics For A Family Of Disordered Proteins, Gary W. Daughdrill, Wade M. Borcherds, Hongwei Wu
Molecular Biosciences Faculty Publications
Several algorithms have been developed that use amino acid sequences to predict whether or not a protein or a region of a protein is disordered. These algorithms make accurate predictions for disordered regions that are 30 amino acids or longer, but it is unclear whether the predictions can be directly related to the backbone dynamics of individual amino acid residues. The nuclear Overhauser effect between the amide nitrogen and hydrogen (NHNOE) provides an unambiguous measure of backbone dynamics at single residue resolution and is an excellent tool for characterizing the dynamic behavior of disordered proteins. In this report, we show …
The Proteomic Response Of Sea Squirts (Genus Ciona Congeners) To Heat Stress: Evidence For Differential Thermal Sensitivities,
2011
California Polytechnic State University, San Luis Obispo
The Proteomic Response Of Sea Squirts (Genus Ciona Congeners) To Heat Stress: Evidence For Differential Thermal Sensitivities, Loredana Serafini
Master's Theses
The sea squirts Ciona intestinalis and C. savignyi have disparate distribution patterns, which may result from differences in their thermal tolerance limits. Because C. intestinalis, an almost cosmopolitan species, has a more widespread distribution, it is thought that it is better adapted to endure a wide range of temperatures. In order to compare the heat stress response between these two congeners, we studied global changes in protein expression, using a proteomics approach. To characterize the response to extreme heat stress, animals of both species were exposed to temperatures of 22°C, 25°C, and 28°C for 6 h, and then were …
The Sumo-Targeted Ubiquitin Ligase Subunit Slx5 Functional Interacts With The Sumo E3 Ligase Siz1,
2011
College of William & Mary - Arts & Sciences
The Sumo-Targeted Ubiquitin Ligase Subunit Slx5 Functional Interacts With The Sumo E3 Ligase Siz1, Jason William Westerbeck
Dissertations, Theses, and Masters Projects
No abstract provided.
Development Of Biomarkers For Endocrine Disrupting Compounds In The Fathead Minnow, Pimephales Promelas,
2011
Bridgewater State University
Development Of Biomarkers For Endocrine Disrupting Compounds In The Fathead Minnow, Pimephales Promelas, Tara Frare
Undergraduate Review
Organic waste compounds (OWC’s) are an environmental concern that can have adverse effects on humans, animals, and the environment. Ethinyl estradiol (EE2) is one common OWC and is an active ingredient in oral birth control pills. The presence of EE2 in aquatic environments and drinking water can be linked to decreased fertility and altered physiology in fish. I am developing Q-PCR biomarkers to detect changes in fish at low concentrations before adverse effects occur at higher concentrations. RNA was extracted from twenty fathead minnows that had not been exposed to OWC’s and will be used to synthesize cDNA. Thus far …
Computational Network Analysis Of The Anatomical And Genetic Organizations In The Mouse Brain,
2011
Old Dominion University
Computational Network Analysis Of The Anatomical And Genetic Organizations In The Mouse Brain, Shuiwang Ji
Computer Science Faculty Publications
Motivation: The mammalian central nervous system (CNS) generates high-level behavior and cognitive functions. Elucidating the anatomical and genetic organizations in the CNS is a key step toward understanding the functional brain circuitry. The CNS contains an enormous number of cell types, each with unique gene expression patterns. Therefore, it is of central importance to capture the spatial expression patterns in the brain. Currently, genome-wide atlas of spatial expression patterns in the mouse brain has been made available, and the data are in the form of aligned 3D data arrays. The sheer volume and complexity of these data pose significant challenges …
Advanced Statistical Methods For Biochemical And Forensic Applications Of Raman Spectroscopy,
2011
University at Albany, State University of New York
Advanced Statistical Methods For Biochemical And Forensic Applications Of Raman Spectroscopy, Vitali Sikirzhytski
Legacy Theses & Dissertations (2009 - 2024)
This work is dedicated to the development and application of advanced statistical methods for biochemical and forensic applications of Raman spectroscopy. We developed a new concept of multidimensional Raman signatures for forensic identification of body fluid traces, which was successfully applied to the study of dried blood, semen, saliva, sweat and vaginal fluid stains. Several alternative advanced chemometric techniques were also successfully tested for the problems of pure body fluids discrimination and mixture analysis. Studies of body fluid mixtures with low blood and semen concentrations indicated that the detection limit of a minor contributor was as low as a few …
Design And Application Of Composite Rna Aptamers,
2011
University at Albany, State University of New York
Design And Application Of Composite Rna Aptamers, Shengchun Wang
Legacy Theses & Dissertations (2009 - 2024)
aptamers are being developed as an essential tool in many fields of biological research. Their utility is not limited to being protein inhibitors; a lot of novel functions can be realized. However, in vivo application of RNA aptamers still faces many challenges. The aim of this dissertation is to design and apply composite aptamers in multiple expression and delivery systems to address some critical issues, such as correct folding, high level production, degradation by nucleases, excessive consumption of cellular resource and potential toxic effect.
Single Cell Analysis For The Characterization Of Cell Populations Using A Live Cell Array,
2011
University at Albany, State University of New York
Single Cell Analysis For The Characterization Of Cell Populations Using A Live Cell Array, Maureen Ann Walling
Legacy Theses & Dissertations (2009 - 2024)
In the past decade, the shift from whole cell population analyses towards single cell measurement methods and techniques is based on experimental results that reveal significant levels of non-genetic heterogeneity in clonal cell populations. This heterogeneity manifests in multiple aspects of cell activity and is, in part, a result of stochastic noise in processes leading to gene expression, namely transcription and translation. The growing understanding of this occurrence has led to the development of methods to monitor and analyze heterogeneity for a more thorough description of cell populations and overall activity.
Biophysical Investigations Of The Molecular Basis Of Cataract Associated With The R76s Mutation In Human Gammad-Crystallin,
2011
University at Albany, State University of New York
Biophysical Investigations Of The Molecular Basis Of Cataract Associated With The R76s Mutation In Human Gammad-Crystallin, Vurghun Ahmadov
Legacy Theses & Dissertations (2009 - 2024)
Cataract disease results when the eye lens becomes opaque and scatters a significant part of the incoming light into the eye. The lens contains very high concentrations of the lens proteins, called crystallins, which are present at concentrations comparable to those found in protein crystals (about 400-600 mg/mL). Chemical modifications of the crystallins, such as oxidation and deamidation, or genetic mutations are known to result in increased light-scattering in vitro, and are implicated in cataract formation in vivo. Here we present the in vitro work on a mutant protein of human gammaD crystallin (HGD), namely R76S (i.e. Arg 76 to …
Homologous And Heterologous Crystallin Protein Interactions As The Molecular Basis Of Inherited Cataract,
2011
University at Albany, State University of New York
Homologous And Heterologous Crystallin Protein Interactions As The Molecular Basis Of Inherited Cataract, Priya Ranjan Banerjee
Legacy Theses & Dissertations (2009 - 2024)
Age-related cataract is the most common cause of blindness worldwide. Nearly fifty percent of Americans above the age of 75 are diagnosed with this disease (http://www.nei.nih.gov/eyedata/pbd_tables.asp), and surgical intervention is the sole method of treatment at present (http://www.nei.nih.gov/healthyvision/objective/cataracts.asp). In the developing world, even this treatment is not readily available. These are compelling reasons to search for better treatments to delay, prevent or arrest cataract formation. Recent evidence suggests that age-related cataracts also have a genetic component. Therefore, determining the mechanisms underlying genetic cataracts with a known association to a protein-mutation is one important strategy towards understanding the molecular basis for …
Regulation Of The Aryl Hydrocarbon Receptor And The Signal Transducer And Activator Of Transcription 1 By Long-Term Estrogen Exposure In Breast Carcinoma Cells,
2011
University at Albany, State University of New York
Regulation Of The Aryl Hydrocarbon Receptor And The Signal Transducer And Activator Of Transcription 1 By Long-Term Estrogen Exposure In Breast Carcinoma Cells, Neal Englert
Legacy Theses & Dissertations (2009 - 2024)
The risk of developing breast cancer is known to be associated with a woman's lifetime exposure to estrogens, both endogenous and exogenous. Increased exposure to estrogens stimulates cellular proliferation, which is a widely accepted theory of estrogen receptor positive mammary carcinogenesis. The molecular mechanisms of gene expression regulation in response to long-term estrogen exposure (LTEE) of MCF-7 breast cancer cells were addressed in this study, with a focus on the aryl hydrocarbon receptor (AHR) and signal transducer and activator of transcription 1 (STAT1).
Distinct Functions Of The Fshr Ck2 Consensus Sequence And Ck2 Kinase Activity In Fsh Action,
2011
University at Albany, State University of New York
Distinct Functions Of The Fshr Ck2 Consensus Sequence And Ck2 Kinase Activity In Fsh Action, Kerri S. Kluetzman
Legacy Theses & Dissertations (2009 - 2024)
Human reproduction in the female is a complex process requiring coordinated control of gonadotropic hormone signaling in a temporal, spatial and contextually defined manner. Paracrine and autocrine signaling between granulosa cells and oocytes of the developing ovarian follicle result in production of steroids, inhibin and growth factors that dictate maturation, ovulation or atresia. Follicular stimulating hormone (FSH) stimulation of the FSH receptor (FSHR), a G-protein coupled receptor (GPCR) is a key regulator of these processes. Recent developments in GPCR molecular and structural biology have helped define activation and signaling mechanisms that will aid in further defining the etiology of infertility …
Structure And Function Of Coding And Non-Coding Rna Domains,
2011
University at Albany, State University of New York
Structure And Function Of Coding And Non-Coding Rna Domains, Fei Liu
Legacy Theses & Dissertations (2009 - 2024)
As a versatile molecule, RNA exhibits an astonishing variety of functional activities, which is typically attributed to its particular structure-forming capacity. There are an increasing number of established roles and systems where RNA structures, in particular, RNA pseudoknots, affect specific biological processes based on their structural features. The structure-function-relationships of RNA in three systems has been invesgated: the telomerase RNA pseudoknot domain from S. cerevisiae, a poteintial unusual H-type pseudoknot forming region near the 3'-splice-site in the influenza virus NS1 mRNA, and the 5'-untranslated-region of the CC16 mRNA where mutations in the wildtype sequence have been related to asthma. UV-monitored …
In-Cell And In Vitro Studies Of Disease Related Protein-Protein Interactions Using Nmr-Spectroscopy,
2011
University at Albany, State University of New York
In-Cell And In Vitro Studies Of Disease Related Protein-Protein Interactions Using Nmr-Spectroscopy, Andres Yudiel Maldonado
Legacy Theses & Dissertations (2009 - 2024)
The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule that plays a central role in the etiology of diabetes, inflammation, and neurodegeneration. The cytoplasmic domain of RAGE, ctRAGE, is critical for RAGE-dependent signal transduction. As the most membrane proximal event, mDia1 binds to ctRAGE and is essential for RAGE ligand-stimulated phosphorylation of AKT and cell proliferation/migration. We show that ctRAGE contains an unusual alpha-turn that mediates the mDia1-ctRAGE interaction and is required for RAGE dependent signaling. The results establish a novel mechanism through which an extracellular signal initiated by RAGE ligands regulates RAGE signaling in …
The Role Of Trm9 In Stress Responses,
2011
University at Albany, State University of New York
The Role Of Trm9 In Stress Responses, Ashish Ravindra Patil
Legacy Theses & Dissertations (2009 - 2024)
Cells need to respond appropriately to environmental changes in order to maintain homeostasis. The cellular response to an environmental stress is regulated at transcriptional, translational and post translational levels. The tRNA, which acts as an adaptor molecule between the mRNA and the protein, plays an important role in the translational regulation of cellular responses to stress and is one of the most heavily modified biomolecules. In Saccharomyces cerevisiae , the wobble uracil of the tRNA(3'-UCU-5') Arg, tRNA(3'-UUC-5') Glu and certain other specific tRNAs are modified to 5-methoxycarbonylmethyluridine (mcm5U) and 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) residues by the tRNA methyltransferase 9 (Trm9). Modifications at …
Structural Interactions And Dynamics Of Disease Related Proteins By Using Nmr Spectroscopy,
2011
University at Albany, State University of New York
Structural Interactions And Dynamics Of Disease Related Proteins By Using Nmr Spectroscopy, Shadakshara Swamy Puttamadappa
Legacy Theses & Dissertations (2009 - 2024)
Nuclear Magnetic Resonance (NMR) is a powerful spectroscopic technique to study the structure, molecular interactions, and dynamics of proteins. Modern NMR instrumentation, advancements in experimental techniques and revolutionary developments in recombinant DNA technology have made NMR a versatile and very convenient tool for biomolecule characterization.
Conformation And Ion Transport Of Neuronal Uncoupling Proteins: Ucp2, Ucp4, And Ucp5,
2011
Wilfrid Laurier University
Conformation And Ion Transport Of Neuronal Uncoupling Proteins: Ucp2, Ucp4, And Ucp5, Tuan Hoang
Theses and Dissertations (Comprehensive)
Located in the inner mitochondrial membrane of brown adipose tissue, uncoupling protein -1 (UCP1) dissipates the proton electrochemical gradient, causing reduction in the rate of ATP synthesis, and generates heat by non-shivering thermogenesis. Three other UCP homologs (UCP2, UCP4 and UCP5), expressed in neurons, are suggested to have potential roles in the function and protection of the central nervous system (CNS). Up to date, structural information for UCPs still remains limited. Extensive biochemical studies on UCP2 have provided adequate evidence for its participation in proton and anion transport. So far, no functional studies in proteoliposome systems have been performed on …
