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Full-Text Articles in Molecular Biology

Role Of Heat Shock Transcription Factor 1 In Ovarian Cancer Epithelial-Mesenchymal Transition And Drug Sensitivity, Chase David Powell Nov 2017

Role Of Heat Shock Transcription Factor 1 In Ovarian Cancer Epithelial-Mesenchymal Transition And Drug Sensitivity, Chase David Powell

Graduate Theses and Dissertations

The heat shock response (HSR) is a robust cellular reaction to mitigate protein damage from heat and other challenges to the proteome. This protective molecular program in humans is controlled by heat shock transcription factor 1 (HSF1). Activation of HSF1 leads to the induction of an array of cytoprotective genes, many of which code for chaperones. These chaperones, known as heat shock proteins (HSPs), are responsible for maintaining the functional integrity of the proteome. HSPs achieve this by promoting proper folding and assembly of nascent proteins, refolding denatured proteins, and processing for degradation proteins and aggregates which cannot be returned ...


The Role Of Sgs1 And Exo1 In The Maintenance Of Genome Stability., Lillian Campos-Doerfler Nov 2017

The Role Of Sgs1 And Exo1 In The Maintenance Of Genome Stability., Lillian Campos-Doerfler

Graduate Theses and Dissertations

Genome instability is a hallmark of human cancers. Patients with Bloom’s syndrome, a rare chromosome breakage syndrome caused by inactivation of the RecQ helicase BLM, result in phenotypes associated with accelerated aging and develop cancer at a very young age. Patients with Bloom’s syndrome exhibit hyper-recombination, but the role of BLM and increased genomic instability is not fully characterized. Sgs1, the only member of the RecQ family of DNA helicases in Saccharomyces cerevisiae, is known to act both in early and late stages of homology-dependent repair of DNA damage. Exo1, a 5′–3′ exonuclease, first discovered to play ...


Mechanism Elucidation And Inhibitor Discovery Against Serine And Metallo-Beta-Lactamases Involved In Bacterial Antibiotic Resistance, Orville A. Pemberton Nov 2017

Mechanism Elucidation And Inhibitor Discovery Against Serine And Metallo-Beta-Lactamases Involved In Bacterial Antibiotic Resistance, Orville A. Pemberton

Graduate Theses and Dissertations

The emergence and proliferation of Gram-negative bacteria expressing β-lactamases is a significant threat to human health. β-Lactamases are enzymes that degrade the β-lactam antibiotics (e.g., penicillins, cephalosporins, monobactams, and carbapenems) that we use to treat a diverse range of bacterial infections. Specifically, β-lactamases catalyze a hydrolysis reaction where the β-lactam ring common to all β-lactam antibiotics and responsible for their antibacterial activity, is opened, leaving an inactive drug. There are two groups of β-lactamases: serine enzymes that use an active site serine residue for β-lactam hydrolysis and metalloenzymes that use either one or two zinc ions for catalysis. Serine ...


Cell Division Regulation In Staphylococcus Aureus, Catherine M. Spanoudis Oct 2017

Cell Division Regulation In Staphylococcus Aureus, Catherine M. Spanoudis

Graduate Theses and Dissertations

Cell division is a fundamental biological process that occurs in all kingdoms of life. Our understanding of cell division in bacteria stems from studies in the rod-shaped model organisms: Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. The molecular underpinnings of cell division regulation in non-rod-shaped bacteria remain to be studied in detail. Rod-shaped bacteria possess many positive and negative regulatory proteins that are essential to the proper placement of the division septa and ultimately the production of two identical daughter cells, many of which are absent in cocci. Given that essential cell division proteins are attractive antibacterial drug targets, it ...


Microfluidic Biopsy Trapping Device For The Real-Time Monitoring Of The Tumor Microenvironment, Angela Holton Oct 2017

Microfluidic Biopsy Trapping Device For The Real-Time Monitoring Of The Tumor Microenvironment, Angela Holton

Graduate Theses and Dissertations

The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent ...


Modeling Of Dynamic Allostery In Proteins Enabled By Machine Learning, Mohsen Botlani-Esfahani Jul 2017

Modeling Of Dynamic Allostery In Proteins Enabled By Machine Learning, Mohsen Botlani-Esfahani

Graduate Theses and Dissertations

Regulation of protein activity is essential for normal cell functionality. Many proteins are regulated allosterically, that is, with spatial gaps between stimulation and active sites. Biological stimuli that regulate proteins allosterically include, for example, ions and small molecules, post-translational modifications, and intensive state-variables like temperature and pH. These effectors can not only switch activities on-and-off, but also fine-tune activities. Understanding the underpinnings of allostery, that is, how signals are propagated between distant sites, and how transmitted signals manifest themselves into regulation of protein activity, has been one of the central foci of biology for over 50 years. Today, the importance ...


Discovering Antibacterial And Anti-Resistance Agents Targeting Multi-Drug Resistant Eskape Pathogens, Renee Fleeman Jul 2017

Discovering Antibacterial And Anti-Resistance Agents Targeting Multi-Drug Resistant Eskape Pathogens, Renee Fleeman

Graduate Theses and Dissertations

Antibiotic resistance has been a developing problem for mankind in recent decades and multi-drug resistant bacteria are now encountered that are resistant to all treatment options available. In 2014, the World Health Organization announced that this problem is driving us towards a “post-antibiotic era” that will change the face of modern medicine as we know it. If lack of novel antibiotic development and FDA approval continues, by the year 2050, 10 million people will die each year to an antimicrobial resistant bacterial infection. With lack of pharmaceutical industry involvement in developing novel antibiotics, the responsibility now lies within the academic ...


Functional Roles Of Matrix Metalloproteinases In Bone Metastatic Prostate Cancer, Jeremy S. Frieling May 2017

Functional Roles Of Matrix Metalloproteinases In Bone Metastatic Prostate Cancer, Jeremy S. Frieling

Graduate Theses and Dissertations

Skeletal metastasis is a lethal component of many advanced cancers including prostate, the second most common cancer among men. Patients whose prostate cancer is localized and detected early benefit from multiple treatment options ranging from active surveillance to radiation and surgery, resulting in a 5-year survival rate of nearly 100%. Unfortunately, the prognosis and survival for patients with advanced metastatic disease is much worse due to the highly aggressive nature of the disease and a paucity of treatment options. Understanding the mechanisms and interactions that occur between metastatic cancer cells and the bone will enable the future treatment landscape for ...


Therapeutic Modulation Of Cancer Metabolism With Dichloroacetate And Metformin, Nathan Patrick Ward Apr 2017

Therapeutic Modulation Of Cancer Metabolism With Dichloroacetate And Metformin, Nathan Patrick Ward

Graduate Theses and Dissertations

The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in the VM-M3 model of GBM. We demonstrated that metformin potentiated DCA-induced superoxide production and that this was required for enhanced cytotoxicity towards VM-M3 cells with the combination. Similarly, rotenone enhanced oxidative stress ...


Uncovering Transcriptional Activators And Targets Of Hsf-1 In Caenorhabditis Elegans, Jessica Brunquell Apr 2017

Uncovering Transcriptional Activators And Targets Of Hsf-1 In Caenorhabditis Elegans, Jessica Brunquell

Graduate Theses and Dissertations

In order to survive, cells must be able to cope with a variety of environmental stressors. The heat shock response (HSR) is a pro-survival mechanism employed by cells in response to protein denaturing stress, such as heat. Since its discovery in 1960, the heat shock response has been found to be regulated by the transcription factor heat shock factor 1 (HSF1). During periods of increased stress, HSF1 undergoes a multi-step process of activation that involves homotrimerization, DNA-binding, and post-translational regulatory modifications, all of which ultimately function to control the transcription of chaperone genes. These chaperone genes encode molecular chaperone proteins ...


Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers Mar 2017

Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers

Graduate Theses and Dissertations

The last century has seen a steady increase in the extension of the average lifespan. This has concomitantly produced higher incidences of age-related chronic degenerative diseases like Alzheimer’s and Parkinson’s diseases. Age is the single greatest risk factor for the development of not just these degenerative conditions but cancer as well. The aged niche undergoes a number of maladaptive changes that allow underlying conditions to present and progress. Exactly which changes, contribute to the progression of which disease is currently an area of intense study. However, these answers often present therapeutic targets for disease prevention. Age is characterized ...


Development Of Tools For Stable Transfection In The Human Filarial Parasite Brugia Malayi Via The Piggybac Transposon System, Johan Chabanon Mar 2017

Development Of Tools For Stable Transfection In The Human Filarial Parasite Brugia Malayi Via The Piggybac Transposon System, Johan Chabanon

Graduate Theses and Dissertations

Brugia malayi is one of three species of nematode known to cause lymphatic filariasis (LF) in humans. LF infects over 120 million people, causing debilitating disease. Various global programs have been launched in the past 20 years to eliminate LF. These programs have greatly scaled up the resources and efforts allocated to halting the transmission and reducing disease burden. Only a few drugs are used to treat LF, and resistance is thus a devastating possibility. Research aimed at identifying new drug targets could therefore prove essential in elimination of LF.

Genetic manipulation of B. malayi has been limited to transient ...


A Novel Abi-Domain Protein Controls Virulence Determinant Production In Staphylococcus Aureus, Stephanie Michelle Marroquin Mar 2017

A Novel Abi-Domain Protein Controls Virulence Determinant Production In Staphylococcus Aureus, Stephanie Michelle Marroquin

Graduate Theses and Dissertations

A major factor in the success of Staphylococcus aureus as a pathogen is its vast arsenal of virulence determinants and, more importantly, the tight and precisely- timed regulation of these factors. Here we investigate the product of the S. aureus gene, SAUSA300_1984, encoding a putative transmembrane protein. This as yet uncharacterized protein belongs to the Abi (abortive infection) family, which are commonly annotated as CAAX-proteases, and are significantly understudied in prokaryotes. In S. aureus the disruption of SAUSA300_1984 results in a drastic reduction of proteolytic and hemolytic activity, as well as diminished pigmentation. This phenotype appears to be mediated through ...


Changing The Pathobiological Paradigm In Myelodysplastic Syndromes: The Nlrp3 Inflammasome Drives The Mds Phenotype, Ashley Basiorka Jan 2017

Changing The Pathobiological Paradigm In Myelodysplastic Syndromes: The Nlrp3 Inflammasome Drives The Mds Phenotype, Ashley Basiorka

Graduate Theses and Dissertations

Note: Portions of this abstract have been previously published in the journal Blood, Basiorka et al. Blood. 2016 Oct 13, and has been reproduced in this manuscript with permission from the publisher.

Myelodysplastic syndromes (MDS) are genetically diverse hematopoietic stem cell malignancies that share a common phenotype of cytological dysplasia, ineffective hematopoiesis and aberrant myeloid lineage maturation. Apoptotic cell death potentiated by inflammatory cytokines has been considered a fundamental feature of MDS for over two decades. However, this non-inflammatory form of cell death cannot account for the inflammatory nature of these disorders. We report that a hallmark of lower-risk (LR ...


Insights Into Retinal Cell Fate Determination In Vertebrates Using Transcriptomic Profiling And Genome Editing, Rebecca Chowdhury Jan 2017

Insights Into Retinal Cell Fate Determination In Vertebrates Using Transcriptomic Profiling And Genome Editing, Rebecca Chowdhury

Graduate Theses and Dissertations

Deciphering the mechanisms of development of retinal neurons is not only of immense interest to developmental biologists, but is also vital for regenerative therapeutic applications. To attain this goal, it is critical to understand how specific intrinsic factors control cell fate decisions and neuronal maturation processes. In the retina, Atoh7 is a highly conserved transcription factor that is essential for retinal ganglion cell development in the developing mouse and zebrafish. Atoh7 labels a subset of cells in the developing retina that are progressing from a progenitor to a differentiated state. To capture cells during the window when the cell fate ...


A Structural Biology Approach To The Problem Of Antibiotic Resistance In Bacteria, Jared Armand Delmar Jan 2017

A Structural Biology Approach To The Problem Of Antibiotic Resistance In Bacteria, Jared Armand Delmar

Graduate Theses and Dissertations

X-ray crystallography remains the most robust method to determine protein structure at the atomic level. We demonstrate how these structural studies can directly contribute to unsolved problems in biology, with a focus on the growing problem of antibiotic resistance in bacterial infections. Multi-drug efflux transporters are common and powerful resistance mechanisms that are capable of extruding a number of structurally unrelated antimicrobials, including antibiotics and toxic heavy metal ions, from the bacterial cell. We begin by presenting the crystal structures of the individual pump components of the Escherichia coli Cus system, a paradigm for efflux machinery, and speculate on how ...


Evaluation Of Methods For Generating Senecavirus A Virus-Like Particles Utilizing The Baculovirus Expression Vector System, Jennifer Lynn English Jan 2017

Evaluation Of Methods For Generating Senecavirus A Virus-Like Particles Utilizing The Baculovirus Expression Vector System, Jennifer Lynn English

Graduate Theses and Dissertations

A recombinant subunit vaccine against Seneca Valley virus (SVV) would be valuable to the swine industry. Recent SVV outbreaks have raised concerns with national biosecurity. This is due to the potential of foreign vesicular animal diseases entering the United States undetected because of confounding clinical signs of SVV. Research with the baculovirus expression vector system (BEVS) has produced virus-like particles (VLP) that elicited neutralizing antibodies and protected against challenge for many Picornaviridae viruses. Building on this previous research, attempts of SVV VLP assembly for a vaccine candidate were performed using the BEVS.

All baculovirus constructs were designed to encode the ...


Functions And Mechanism Of Wrky Transcription Factors In Brassinosteroid-Regulated Plant Growth And Stress Response, Jiani Chen Jan 2017

Functions And Mechanism Of Wrky Transcription Factors In Brassinosteroid-Regulated Plant Growth And Stress Response, Jiani Chen

Graduate Theses and Dissertations

Brassinosteroids (BRs), a family of plant steroid hormones, play important role in plant growth and development. BR signal is perceived by receptors BRI1 and BAK1, which transduce the hormonal signal to downstream transcription factors BES1/BZR1 to regulate the expression of thousands of BR target genes. BRs also play a vital role in both abiotic and biotic stress responses. However, the molecular mechanisms by which BRs regulate stress responses have just begun to be revealed. Here, we characterized three group III transcription factors, WRKY46, WRKY 54 and WRKY70, which are involved in BR-regulated plant growth and drought stress by cooperating ...


Studies On The Molecular Underpinnings Of Sex Determination Mechanism Evolution And Molecular Sexing Tools In Turtles, Robert Alan Literman Jan 2017

Studies On The Molecular Underpinnings Of Sex Determination Mechanism Evolution And Molecular Sexing Tools In Turtles, Robert Alan Literman

Graduate Theses and Dissertations

Sex determination mechanisms (SDMs) direct the development of individuals towards a male or female fate, and in vertebrates they are typically controlled by an individual’s genotypic content (genotypic sex determination, GSD) or through an environmental cue experienced during development, mainly temperature (temperature-dependent sex determination, TSD). Among vertebrates, SDMs are surprisingly labile, transitioning between different forms of TSD and GSD in some lineages more than others. Turtles represent a model clade to study SDM evolution, as multiple independent transitions between TSD and GSD have occurred throughout their evolution and a growing number of genomic datasets have become available.

This dissertation ...


An Enzymology And Structural Biology Approach Towards Elucidation Of E. Coli Fatty Acid Biosynthesis And Its Application To The Production Of Bio-Renewables, Aaron Michael Marcella Jan 2017

An Enzymology And Structural Biology Approach Towards Elucidation Of E. Coli Fatty Acid Biosynthesis And Its Application To The Production Of Bio-Renewables, Aaron Michael Marcella

Graduate Theses and Dissertations

Prokaryotic fatty acid biosynthesis is an important process to study due to its necessity for cell survival and production of highly reduced carbon chains. A characterization of several proteins involved in E. coli fatty acid biosynthesis is presented. This work provides a method for generating large amounts of pure malonyl acyl-carrier-protein using both the wild type malonyl-CoA:holo-ACP transacylase (FabD) and a variant studied further in our lab. This preparation overcomes the phenomena of a 50:50 mixture of malonyl and acetyl-ACP in the reaction and is crucial for the efficacy of future assays involving malonyl-ACP. A new assay has ...


Rational Design And Validation Of Dna Fragments For Gene Assembly Based On Thermodynamics, Bhagyashree Shreekant Birla Jan 2017

Rational Design And Validation Of Dna Fragments For Gene Assembly Based On Thermodynamics, Bhagyashree Shreekant Birla

Graduate Theses and Dissertations

Synthetic biology is a research field that involves the design and synthesis of genes and genomes. It has a wide range of applications in building gene circuits, activating biochemical pathways and metabolic engineering. Over the last decade, there has been rapid progress in developing efficient DNA synthesis technologies that improve the overall quality of the constructed DNA. Currently, there are several different methods available for successful DNA assembly of long genes. However, these methods have certain drawbacks such as presence of restriction sites (scars) within the assembled sequences or multi-step reaction process to assemble a high-number of fragments. Thus, new ...


Investigations Into Nutritional Quality, Commercial Productivity, And Genetic Purity Of Maize Grain For Organic Production Systems, Ryan Huffman Jan 2017

Investigations Into Nutritional Quality, Commercial Productivity, And Genetic Purity Of Maize Grain For Organic Production Systems, Ryan Huffman

Graduate Theses and Dissertations

Consumer demand for organic maize grain has steadily increased in the past decade which has resulted in an increased interest for this market class by plant breeders and geneticist. Each chapter in this dissertation investigates areas of concern to the organic community and possible solutions for improvement. Chapter 2 seeks to understand which combinations of genetic mechanisms are capable of a further increase in the methionine concentration of maize grain over individual mechanisms. Based on the genetic mechanisms evaluated, it was concluded that crosses combining dzr1 and recurrent selection in hybrid combination can elevate methionine concentration and overall grain nutritional ...