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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 ...


Tumor-Stroma Interactions Differentially Alter Drug Sensitivity Based On The Origin Of Stromal Cells, Benjamin D. Landry Oct 2018

Tumor-Stroma Interactions Differentially Alter Drug Sensitivity Based On The Origin Of Stromal Cells, Benjamin D. Landry

GSBS Dissertations and Theses

Tumor heterogeneity observed between patients has made it challenging to develop universal or broadly effective cancer therapies. Therefore, an ever-growing movement within cancer research aims to tailor cancer therapies to individual patients or specific tumor subtypes. Tumor stratification is generally dictated by the genomic mutation status of the tumor cells themselves. Importantly, non-genetic influences – such as interactions between tumor cells and other components of the tumor microenvironment – have largely been ignored. Therefore, in an effort to increase treatment predictability and efficacy, we investigated how tumor-stroma interactions contribute to drug sensitivity and drug resistance.

I designed a high throughput co-culture screening ...


Fus And Excitotoxicity Cross Paths In Als: New Insights Into Cellular Stress And Disease, Maeve Tischbein Aug 2018

Fus And Excitotoxicity Cross Paths In Als: New Insights Into Cellular Stress And Disease, Maeve Tischbein

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disease characterized by motor neuron loss. Although pathological mutations exist in >15 genes, the mechanism(s) underlying ALS are unknown. FUS is one such gene and encodes the nuclear RNA-binding protein (RBP), fused in sarcoma (FUS), which actively shuttles between the nucleus and cytoplasm. Intriguingly, nearly half of the ALS mutations identified in FUS cause this protein to mislocalize, suggesting that FUS localization is relevant to disease.

Here, we found that excitotoxicity, a neuronal stress caused by aberrant glutamate signaling, induces the rapid redistribution of FUS and additional disease-linked RBPs ...


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 ...


Ventricular Arrhythmias Complicating Coronary Artery Disease: Recent Trends, Risk Associated With Serum Glucose Levels, And Psychological Impact, Hoang V. Tran Jun 2018

Ventricular Arrhythmias Complicating Coronary Artery Disease: Recent Trends, Risk Associated With Serum Glucose Levels, And Psychological Impact, Hoang V. Tran

GSBS Dissertations and Theses

Introduction: Ventricular arrhythmias (VAs) are common after an acute coronary syndrome (ACS) and are associated with worse clinical outcomes. However, little is known about recent trends in their occurrence, their association with serum glucose levels, and their psychological impact in ACS setting.

Methods: We examined 25-year (1986-2011) trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of VAs, and the association between serum glucose levels and VAs in patients with an acute myocardial infarction (AMI) in the Worcester Heart Attack Study. Lastly, we examined the relationship between in-hospital occurrence of VAs and 12-month progression of depression and anxiety ...


National Trends In Elective Ileal Pouch-Anal Anastomosis For Ulcerative Colitis, Chau Maggie Hoang Jun 2018

National Trends In Elective Ileal Pouch-Anal Anastomosis For Ulcerative Colitis, Chau Maggie Hoang

GSBS Dissertations and Theses

Background: Recent national trends and distribution of ileal pouch-anal anastomosis (IPAA) procedures for patients with ulcerative colitis (UC) are unknown. We examined the frequency of use of elective IPAA procedures among patients with UC and the distribution of IPAA procedures across more than 140 U.S. academic medical centers and their affiliates.

Methods: Data were obtained from the University HealthSystem Consortium for patients with a primary diagnosis of UC admitted electively between 2012 and 2015.

Results: The mean age of the study population (n=6,875) was 43 years and 57% were men. Among these, one-third (n=2,307) underwent ...


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 ...


Follow Your Heart: Evaluating Cardiac Function To Predict Outcomes Among Icu Patients With Traumatic Brain Injury, Patric Gibbons May 2018

Follow Your Heart: Evaluating Cardiac Function To Predict Outcomes Among Icu Patients With Traumatic Brain Injury, Patric Gibbons

GSBS Dissertations and Theses

Introduction: Traumatic Brain Injury (TBI) remains a significant public health burden in the United States. Persons afflicted with more severe TBIs are usually admitted to an ICU, where they are at risk for a number of complications throughout their hospitalization. Recent literature has attempted to describe such complications from a cardiovascular perspective as part of a “cardio-cerebral syndrome.” We described the frequency of cardiac complications in the ICU among patients with a TBI and compared patients with and without measured cardiac dysfunction. We investigated the potential impact of cardiac dysfunction on in-hospital mortality.

Methods: This was a retrospective review of ...


Evaluating Multi-Level Factors Influencing Adolescent Sugar Sweetened Beverage Consumption, Christina F. Griecci Mar 2018

Evaluating Multi-Level Factors Influencing Adolescent Sugar Sweetened Beverage Consumption, Christina F. Griecci

GSBS Dissertations and Theses

Background: Sugar sweetened beverages (SSBs) comprise the largest source of added sugars in US adolescents’ diets. SSB consumption is pervasive in US culture and is a critical risk factor for weight gain and obesity in adolescents. This thesis evaluates multi-level factors that influence adolescent SSB consumption.

Methods: The first two aims of this thesis utilized data from the cross sectional, internet based Family Life, Activity, Sun, Health and Eating (FLASHE) study to: 1) examine availability of SSBs in multiple settings (home, school, neighborhood) and adolescent SSB consumption, 2) examine the associations between perceptions of parenting practices and adolescent SSB consumption ...


Opioid Use And Safety In United States Nursing Homes, Jacob N. Hunnicutt Mar 2018

Opioid Use And Safety In United States Nursing Homes, Jacob N. Hunnicutt

GSBS Dissertations and Theses

Background: Opioids are often used in nursing homes to manage non-malignant pain, but little is known about their long-term use, initiation, and comparative safety.

Methods: We used the Minimum Data Set 3.0 from 2011-2013 merged to Medicare and facility characteristics data to study opioid use and safety among older, long-stay residents. The specific aims were to examine the 1) prevalence of long-term opioid use; 2) geographic variation in the initiation of commonly used opioids (oxycodone, hydrocodone, tramadol); and 3) comparative safety of commonly used opioids and fracture hospitalizations.

Results: One in seven long-stay residents were prescribed opioids long-term. There ...


A Suite Of Computational Tools To Interrogate Sequence Data With Local Haplotype Analysis Within Complex ​Plasmodium​ Infections And Other Microbial Mixtures, Nicholas J. Hathaway Mar 2018

A Suite Of Computational Tools To Interrogate Sequence Data With Local Haplotype Analysis Within Complex ​Plasmodium​ Infections And Other Microbial Mixtures, Nicholas J. Hathaway

GSBS Dissertations and Theses

The rapid development of DNA sequencing technologies has opened up new avenues of research, including the investigation of population structure within infectious diseases (both within patient and between populations). In order to take advantage of these advances in technologies and the generation of new types of data, novel bioinformatics tools are needed that won’t succumb to artifacts introduced by the data generation, and thus provide accurate and precise results. To achieve this goal I have create several tools.

First, SeekDeep, a pipeline for analyzing targeted amplicon sequencing datasets from various technologies, is able to achieve 1-base resolution even at ...


Clostridium Difficile Colonization And Infection In The Elderly And Associations With The Aging Intestinal Microbiome, John P. Haran Mar 2018

Clostridium Difficile Colonization And Infection In The Elderly And Associations With The Aging Intestinal Microbiome, John P. Haran

GSBS Dissertations and Theses

The widespread use of antibiotics has led to dramatic increases in the incidence and severity of Clostridium difficile infection (CDI). No group of patients suffers more from CDI than the elderly. Nursing homes (NH) represent the perfect storm of a vulnerable group of frail elders living in confined communities. Nursing home residents suffer from increased morbidity and mortality from CDI and corresponding high rates of C. difficile colonization. Upwards of 40 to 50% of CDI current cases originate from NHs and the prevalence of colonization rates remain high within these facilities, with as many as half of the residents being ...


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 ...


Investigating The Structural Basis For Human Disease: Apobec3a And Profilin, Tania V. Silvas Jan 2018

Investigating The Structural Basis For Human Disease: Apobec3a And Profilin, Tania V. Silvas

GSBS Dissertations and Theses

Analyzing protein tertiary structure is an effective method to understanding protein function. In my thesis study, I aimed to understand how surface features of protein can affect the stability and specificity of enzymes. I focus on 2 proteins that are involved in human disease, Profilin (PFN1) and APOBEC3A (A3A). When these proteins are functioning correctly, PFN1 modulates actin dynamics and A3A inhibits retroviral replication. However, mutations in PFN1 are associated with amyotrophic lateral sclerosis (ALS) while the over expression of A3A are associated with the development of cancer. Currently, the pathological mechanism of PFN1 in this fatal disease is unknown ...