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GSBS Dissertations and Theses

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Characterization Of The Caspase-3 Cleavage Motif Of The Salmonella Typhimurium Effector Protein Sifa And Its Role In Pathogenesis, Samir Patel Nov 2018

Characterization Of The Caspase-3 Cleavage Motif Of The Salmonella Typhimurium Effector Protein Sifa And Its Role In Pathogenesis, Samir Patel

GSBS Dissertations and Theses

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative facultative anaerobe that induces severe inflammation resulting in gastroenteritis. In the case of S. Typhimurium infection, induction of an inflammatory response has been linked to its primary virulence mechanism, the type III secretion system (T3SS). The T3SS secretes protein effectors that exploit the host’s cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response.

One such effector, SifA, is a bi-functional T3SS effector protein that plays an important role in Salmonella virulence. The N-terminal domain of SifA binds SifA-Kinesin-Interacting-Protein (SKIP), and via an interaction ...


Predictors Of Patient Activation At Acs Hospital Discharge And Health Care Utilization In The Subsequent Year, Rebecca L. Kinney Aug 2018

Predictors Of Patient Activation At Acs Hospital Discharge And Health Care Utilization In The Subsequent Year, Rebecca L. Kinney

GSBS Dissertations and Theses

Background. AHA guidelines have been established to reduce Acute Coronary Syndrome (ACS)-related morbidity, mortality and recurrent events post-discharge. These recommendations emphasize the patient as an engaged member of the health care team in secondary prevention efforts. Patients with high levels of activation are more likely to perform activities that will promote their own health and are more likely to have their health care needs met. Despite evidence and strong expert consensus supporting patients as active collaborators in their own ACS care, the complexity and unexpected realities of self-managing one’s care at home are often underestimated. This study seeks ...


Engineered Exosomes For Delivery Of Therapeutic Sirnas To Neurons, Reka A. Haraszti May 2018

Engineered Exosomes For Delivery Of Therapeutic Sirnas To Neurons, Reka A. Haraszti

GSBS Dissertations and Theses

Extracellular vesicles (EVs), exosomes and microvesicles, transfer endogenous RNAs between neurons over short and long distances. We have explored EVs for siRNA delivery to brain. (1) We optimized siRNA chemical modifications and siRNA conjugation to lipids for EV-mediated delivery. (2) We developed a GMP-compatible, scalable method to manufacture active EVs in bulk. (3) We characterized lipid and protein content of EVs in detail. (4) We established how protein and lipid composition relates to siRNA delivering activity of EVs, and we reverse engineered natural exosomes (small EVs) into artificial exosomes based on these data.

We established that cholesterol-conjugated siRNAs passively associate ...


Identification Of Novel Genetic Variations For Amyotrophic Lateral Sclerosis (Als), Guang Xu Feb 2018

Identification Of Novel Genetic Variations For Amyotrophic Lateral Sclerosis (Als), Guang Xu

GSBS Dissertations and Theses

A list of genes have been identified to carry mutations causing familial ALS such as SOD1, TARDBP, C9orf72. But for sporadic ALS, which is 90% of all ALS cases, the underlying genetic variants are still largely unknown. There are multiple genome-wide association study (GWAS) for sporadic ALS, but usually a large number nominated SNP can hardly be replicated in larger cohort analysis. Also majority of GWAS SNP lie within noncoding region of genome, imposing a huge challenge to study their biological role in ALS pathology. With the rapid development of next-generation sequencing technology, we are able to sequence exome and ...


Identification Of Factors Involved In 18s Nonfunctional Ribosomal Rna Decay And A Method For Detecting 8-Oxoguanosine By Rna-Seq, Kelly A. Limoncelli Dec 2017

Identification Of Factors Involved In 18s Nonfunctional Ribosomal Rna Decay And A Method For Detecting 8-Oxoguanosine By Rna-Seq, Kelly A. Limoncelli

GSBS Dissertations and Theses

The translation of mRNA into functional proteins is essential for all life. In eukaryotes, aberrant RNAs containing sequence features that stall or severely slow down ribosomes are subject to translation-dependent quality control. Targets include mRNAs encoding a strong secondary structure (No-Go Decay; NGD) or stretches of positively-charged amino acids (Peptide-dependent Translation Arrest/Ribosome Quality Control; PDTA/RQC), mRNAs lacking an in-frame stop codon (Non-Stop Decay; NSD), or defective 18S rRNAs (18S Nonfunctional rRNA Decay; 18S NRD). Previous work from our lab showed that the S. cerevisiae NGD factors DOM34 and HBS1, and PDTA/RQC factor ASC1, all participate in the ...


Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho Dec 2017

Astrocytic Regulation Of Seizure-Like Behavior, Sukhee Cho

GSBS Dissertations and Theses

Astrocytes are emerging as important regulators of neural circuit function and behavior in the healthy and diseased nervous system. In a screen for astrocyte molecules that modulate neuronal hyperexcitability we identified multiple components of focal adhesion complexes (FAs) as potent suppressors of genetically- or pharmacologically-induced seizure-like activity. Depletion of astrocytic Tensin, b-integrin, Talin, Focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), which degrades extracellular matrix to activate b-integrin receptors, resulted in enhanced recovery from, or resistance to seizure activity. Reciprocally, promoting FA signaling by overexpression of Mmp1 in astrocytes led to enhanced-seizure severity. Blockade of FA signaling in astrocytes ...


Use Of Clinicaltrials.Gov Registry In Systematic Reviews And Meta-Analyses: A Master's Thesis, Richeek Pradhan Nov 2017

Use Of Clinicaltrials.Gov Registry In Systematic Reviews And Meta-Analyses: A Master's Thesis, Richeek Pradhan

GSBS Dissertations and Theses

Ensuring the objectivity of systematic reviews and meta-analyses (SRMA) begins with comprehensive searches into diverse resources mining primary studies. Guidelines for systematic reviews recommend authors to routinely search of trial registries to identify unpublished studies. In this dissertation, I investigated the utilization of ClinicalTrials.gov (CTG), the world’s largest clinical trial registry that contains data from clinical trials of products that are subject to United States Food and Drug Administration (FDA) regulation, as an information resource in SRMAs. First, I examined the use of various information resources including CTG in SRMAs published from 2005-2016, and identified the factors associated ...


Barriers To Healthcare Access And Patient Outcomes After A Hospitalization For An Acute Coronary Syndrome And Other Acute Conditions, Nathaniel A. K. Erskine Nov 2017

Barriers To Healthcare Access And Patient Outcomes After A Hospitalization For An Acute Coronary Syndrome And Other Acute Conditions, Nathaniel A. K. Erskine

GSBS Dissertations and Theses

Background: Guideline-concordant therapies for survivors of an acute coronary syndrome (ACS) hospitalization require healthcare access, something that millions of Americans lack.

Methods and Results: Using data from a prospective cohort study of over 2,000 survivors of a hospitalization for an ACS in central Massachusetts and Georgia from 2011 to 2013, the first two aims of this thesis sought to identify the post-discharge consequences for survival and health status of having: 1) financial barriers to healthcare, 2) no usual source of care, and 3) transportation barriers. We found that patients lacking a usual source of care and having a transportation ...


Investigating The Peptide-Mhc Specificity Of Alloreactive T Cells And Natural T Regulatory Cells Using A Self-Peptide Display Library, Brian R. Duke Nov 2017

Investigating The Peptide-Mhc Specificity Of Alloreactive T Cells And Natural T Regulatory Cells Using A Self-Peptide Display Library, Brian R. Duke

GSBS Dissertations and Theses

T cells use their highly variable T cell receptor (TCR) to engage major histocompatibility molecules (MHC) presenting peptides on the surface of antigen presenting cells during an immune response. The TCR repertoire of developing T cells is shaped by thymic selection, resulting in a self-tolerant and foreign peptide specific naïve T cell population. However, naive T cells are alloreactive and generate immune responses towards foreign MHC alleles in clinical settings involving transplantation. While T cell immune responses towards foreign pathogens are peptide specific, the overall specificity of allo-responses is still debated.

Under normal circumstances, immune system homeostasis and self-tolerance is ...


Characterization Of Adipose Tissue Inflammation In Alcoholic Liver Disease, Melissa A. Fulham Nov 2017

Characterization Of Adipose Tissue Inflammation In Alcoholic Liver Disease, Melissa A. Fulham

GSBS Dissertations and Theses

Adipose tissue inflammation has an impact on liver health and it has been demonstrated that chronic alcohol consumption leads to the expression of pro-inflammatory markers in the adipose tissue. A thorough characterization of alcohol-induced adipose inflammation is lacking, and is important to understand in order to identify immune-related mechanisms that drive this phenomenon. Current therapeutic regimens for alcoholic liver disease are ineffective. It is critical to understand how other organs influence liver injury in this disease when developing novel and effective therapies in the future.

Alcoholic liver disease exhibits a sexual dimorphism; women are more susceptible to liver injury than ...


Dosage Compensation Of Trisomy 21 And Its Implications For Hematopoietic Pathogenesis In Down Syndrome, Jen-Chieh Chiang Nov 2017

Dosage Compensation Of Trisomy 21 And Its Implications For Hematopoietic Pathogenesis In Down Syndrome, Jen-Chieh Chiang

GSBS Dissertations and Theses

Down Syndrome (DS), the most common aneuploidy seen in live-borns, is caused by trisomy for chromosome 21. DS imposes high risks for multiple health issues involving various systems of the body. The genetic complexity of trisomy 21 and natural variation between all individuals has impeded understanding of the specific cell pathologies and pathways involved. In addition, chromosomal disorders have been considered outside the hopeful progress in gene therapies for single-gene disorders. Here we test the feasibility of correcting imbalanced expression of genes across an extra chromosome by expression of a single gene, XIST, the key player in X chromosome inactivation ...


Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster Aug 2017

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster

GSBS Dissertations and Theses

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...


The Role Of Skeletal Survey In Identifying Non-Accidental Trauma In Pediatric Trauma Patients, Jonathan Green Jun 2017

The Role Of Skeletal Survey In Identifying Non-Accidental Trauma In Pediatric Trauma Patients, Jonathan Green

GSBS Dissertations and Theses

Background: Non-accidental Trauma (NAT) is a major cause of morbidity and mortality in children. Children less than 2 years old are at greater risk of NAT than older children. A skeletal survey is a series of X-rays of all the bones in the body, or at least the axial skeleton and the large cortical bones used to identify NAT in children. In this observational study, we examined the association between a child’s age, frequency of positive skeletal surveys, and the types of injuries discovered in pediatric patients undergoing a trauma work-up.

Methods: The study sample consisted of all pediatric ...


Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti May 2017

Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti

GSBS Dissertations and Theses

Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.

Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How ...


Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger May 2017

Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger

GSBS Dissertations and Theses

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI.

Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause ...


Characterization Of Severe Malaria In Liberian Children 5 Years Old And Younger, Patricia A. Mcquilkin May 2017

Characterization Of Severe Malaria In Liberian Children 5 Years Old And Younger, Patricia A. Mcquilkin

GSBS Dissertations and Theses

Malaria continues to be a challenging problem in the developing world, and the burden of this life threatening disease continues to be borne by young children living in Sub Saharan Africa. One of the biggest challenges to the prevention and control of this problem lies in accurately diagnosing malaria, and distinguishing it from the many other febrile illnesses which present in children in this age group.

Liberia is a West African country with a high burden of malaria. Very little is known about the presentation of severe malaria in children aged 5 years old and younger in Liberia. We undertook ...


Recent Trends In Sepsis Mortality, Associations Between Initial Source Of Sepsis And Hospital Mortality, And Predictors Of Sepsis Readmission In Sepsis Survivors, Christine Motzkus Apr 2017

Recent Trends In Sepsis Mortality, Associations Between Initial Source Of Sepsis And Hospital Mortality, And Predictors Of Sepsis Readmission In Sepsis Survivors, Christine Motzkus

GSBS Dissertations and Theses

Background: Sepsis, a leading cause of US deaths, is associated with high mortality, although advances in early recognition and treatment have increased survivorship. Many aspects of sepsis pathophysiology and epidemiology have not been fully elucidated; the heterogeneous nature of infections that lead to sepsis has made fully characterizing the underlying epidemiology challenging.

Methods: The University HealthSystem Consortium (UHC) from 2011-2014 and the Cerner HealthFacts® database from 2008-2014 were used. We examined associations between infection source and in-hospital mortality in the UHC dataset, stratified by age and presenting sepsis stage. We examined recent temporal trends in present-on-admission (POA) sepsis diagnoses and ...


Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles In Cardiac Progenitor Cells, Sara L. Lewandowski Dec 2016

Histone Deacetylase 3 Coordinates Heart Development Through Stage-Specific Roles In Cardiac Progenitor Cells, Sara L. Lewandowski

GSBS Dissertations and Theses

Disruptions in cardiac development cause congenital heart disease, the most prevalent and deadly congenital malformation. Genetic and environmental factors are thought to contribute to these defects, however molecular mechanisms remain largely undefined. Recent work highlighted potential roles of chromatin- modifying enzymes in congenital heart disease pathogenesis. Histone deacetylases, a class of chromatin-modifying enzymes, have developmental importance and recognized roles in the mature heart. This thesis aimed to characterize functions of Hdac3 in cardiac development. We found loss of Hdac3 in the primary heart field causes precocious progenitor cell differentiation, resulting in hypoplastic ventricular walls, ventricular septal defect, and mid- gestational ...


The Origin Of Human White, Brown, And Brite/Beige Adipocytes, So Yun Min Dec 2016

The Origin Of Human White, Brown, And Brite/Beige Adipocytes, So Yun Min

GSBS Dissertations and Theses

During embryonic development, adipocytes emerge from microvasculature. Lineage-­‐tracing studies in mice have shown that adipocyte progenitors reside in the adipose tissue capillaries. However, the direct evidence of an association between adipocyte progenitors and vasculature in humans is lacking. A specific class of adipocytes (brown and beige/brite) expresses the uncoupling protein 1 (UCP1), which consumes glucose and fatty acids to generate heat. The abundance of UCP1- containing adipocytes correlates with a lean metabolically healthy phenotype in human. However, a causal relationship between the presence of these cells and metabolic benefits in human is not clear.

In this thesis, I ...


A Translational Pathway For Recombinant Adeno-Associated Virus Human Gene Therapy: From Target Identification And Animal Modeling Of The Disease To Non-Human Primate And Human Studies, Alisha Gruntman Nov 2016

A Translational Pathway For Recombinant Adeno-Associated Virus Human Gene Therapy: From Target Identification And Animal Modeling Of The Disease To Non-Human Primate And Human Studies, Alisha Gruntman

GSBS Dissertations and Theses

Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will ...


Targeting Drug Resistance In Chronic Myeloid Leukemia: A Dissertation, Leyuan Ma Nov 2016

Targeting Drug Resistance In Chronic Myeloid Leukemia: A Dissertation, Leyuan Ma

GSBS Dissertations and Theses

Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.

First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.

Next, I performed single cell RNA-seq to compare ...


The Role Of Late Antigen In Cd4 Memory T Cell Formation During Influena [I.E. Influenza] Infection: A Dissertation, Bianca L. Bautista Oct 2016

The Role Of Late Antigen In Cd4 Memory T Cell Formation During Influena [I.E. Influenza] Infection: A Dissertation, Bianca L. Bautista

GSBS Dissertations and Theses

While memory CD4 T cells are critical for effective immunity to pathogens, the mechanisms underlying their generation are poorly defined. Although extensive work has been done to examine the role of antigen (Ag) in shaping memory formation, most studies focus on the requirements during the first few days of the response known as the priming phase. Little is known about whether or not Ag re-encounter by effector T cells (late Ag) alters CD4 memory T cell formation. Since influenza infection produces a large, heterogeneous, protective CD4 memory T cell population, I used this model to examine the role of late ...


Fc Receptor-Mediated Activities Of Env-Specific Monoclonal Antibodies Generated From Human Volunteers Receiving A Dna Prime-Protein Boost Hiv Vaccine: A Dissertation, Matthew R. Costa Oct 2016

Fc Receptor-Mediated Activities Of Env-Specific Monoclonal Antibodies Generated From Human Volunteers Receiving A Dna Prime-Protein Boost Hiv Vaccine: A Dissertation, Matthew R. Costa

GSBS Dissertations and Theses

Human immunodeficiency type 1 (HIV-1) is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years’ infection and as a result, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that a moderate protection is possible, which may correlate with antibody dependent cellular cytotoxicity (ADCC) activity. Previous studies in the Lu lab demonstrated that in an HIV-1 vaccine phase I trial, DP6-001, a polyvalent Env DNA prime-protein boost formulation, could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities along with multiple Fc ...


Evaluating Acceptability, Feasibility And Efficacy Of A Diabetes Care Support Program Facilitated By Cellular-Enabled Glucose Meters: A Dissertation, Daniel J. Amante Oct 2016

Evaluating Acceptability, Feasibility And Efficacy Of A Diabetes Care Support Program Facilitated By Cellular-Enabled Glucose Meters: A Dissertation, Daniel J. Amante

GSBS Dissertations and Theses

Background. Diabetes requires significant disease management, patient-provider communication, and interaction between patients, family members, caregivers, and care teams. Emerging patient-facing technologies, such as cellular-enabled glucose meters, can facilitate additional care support and improve diabetes self-management. This study evaluated patient acceptability, feasibility, and efficacy of a diabetes care support program facilitated by cellular-enabled glucose meters.

Methods. A two-phase study approach was taken. Get In Touch – Phase 1 (GIT-1) was a 1-month pilot involving patients with type 1 and type 2 diabetes. Get In Touch – Phase 2 (GIT-2) was a 12-month randomized controlled crossover trial involving patients with poorly-controlled type 2 diabetes ...


Histopathological Characterization Of The Dystrophic Phenotype And Development Of Therapeutic Candidates For A Gene Therapy Pre-Clinical Study In Dysferlin Deficient Mice, Leticia Fridman Sep 2016

Histopathological Characterization Of The Dystrophic Phenotype And Development Of Therapeutic Candidates For A Gene Therapy Pre-Clinical Study In Dysferlin Deficient Mice, Leticia Fridman

GSBS Dissertations and Theses

Dysferlin deficient muscular dystrophy is a devastating disease that leads to loss of mobility and quality of life in patients. Dysferlin is a 230 kD protein primarily expressed in skeletal muscle that functions in membrane resealing. Dysferlin loss of function leads to a decrease in the membrane resealing response after injury in skeletal muscle, which is thought to cause degeneration of the musculature over time. Dysferlin cDNA is 7.4 kb and exceeds AAV packaging capacity of ~ 5kb. This thesis focuses on the generation of mini dysferlin mutants that can be packaged in AAV for downstream testing of therapeutic efficacy ...


Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin Sep 2016

Viral Proteases As Drug Targets And The Mechanisms Of Drug Resistance: A Dissertation, Kuan-Hung Lin

GSBS Dissertations and Theses

Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.

First, I used X-ray crystallography ...


Investigation Of Rna Binding Protein Pumilio As A Genetic Modifier Of Mutant Chmp2b In Frontotemporal Dementia (Ftd): A Masters Thesis, Xing Du Aug 2016

Investigation Of Rna Binding Protein Pumilio As A Genetic Modifier Of Mutant Chmp2b In Frontotemporal Dementia (Ftd): A Masters Thesis, Xing Du

GSBS Dissertations and Theses

Frontotemporal dementia (FTD) is the second most common early-onset dementia. A rare mutation in CHMP2B gene was found to be associated with FTD linked to chromosome 3. Previous studies have shown that mutant CHMP2B could lead to impaired autophagy pathway and altered RNA metabolism. However, it is still unknown what genes mediate the crosstalk between different pathways affected by mutant CHMP2B. Genetic screens designed to identify genes interacting with mutant CHMP2B represents a key approach in solving the puzzle. Expression of mutant CHMP2B (CHMP2Bintron5) in Drosophila eyes leads to a neurodegenerative phenotype including melanin deposition and disrupted internal structure of ...


Tissue Compartmentalization And Tropism Of Hiv-1: A Dissertation, Robin L. Brese Aug 2016

Tissue Compartmentalization And Tropism Of Hiv-1: A Dissertation, Robin L. Brese

GSBS Dissertations and Theses

Despite the development of effective antiretroviral treatments, there is still no cure for HIV-1. Major barriers to HIV-1 eradication include the diversity of intrapatient viral quasispecies and the establishment of reservoirs in tissue sanctuary sites. A better understanding of these populations is required for targeted treatments. While previous studies have examined the relationship between brain and blood or immune tissues, few have looked at and compared the properties of viruses from other tissue compartments. In this study, 75 full length HIV-1 envelopes were isolated from the frontal lobe, occipital lobe, parietal lobe, colon, lung, and lymph node of an HIV-1 ...


Exploiting Dna Repair And Er Stress Response Pathways To Induce Apoptosis In Glioblastoma Multiforme: A Dissertation, Jessica L. Weatherbee Aug 2016

Exploiting Dna Repair And Er Stress Response Pathways To Induce Apoptosis In Glioblastoma Multiforme: A Dissertation, Jessica L. Weatherbee

GSBS Dissertations and Theses

Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we ...


Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace Jul 2016

Plague And The Defeat Of Mammalian Innate Immunity: Systematic Genetic Analysis Of Yersinia Pestis Virulence Factors: A Dissertation, Samantha G. Palace

GSBS Dissertations and Theses

Yersinia pestis, the causative agent of plague, specializes in causing dense bacteremia following intradermal deposition of a small number of bacteria by the bite of an infected flea. This robust invasiveness requires the ability to evade containment by the innate immune system. Of the various mechanisms employed by Y. pestis to subvert the innate immune response and to proliferate rapidly in mammalian tissue, only a few are well-characterized. Here, I present two complementary genetic analyses of Y. pestis adaptations to the mammalian environment. In the first, genome-wide fitness profiling for Y. pestis by Tn-seq demonstrates that the bacterium has adapted ...