Life Sciences Commons^™

Serpin-Derived Novel Peptide For The Treatment Against Hiv-Induced Inflammation In The Central Nervous System, Yemmy Soler

FIU Electronic Theses and Dissertations

In the brain, HIV predominantly infects microglia/macrophages and astrocytes to a lesser extent. These cells form virus reservoirs with low levels of infection that are very hard to eradicate. Even though the use of cART increases survival rate in HIV patients, the virus persists as a chronic condition. cART is not able to effectively cross the BBB, control HIV replication, or attenuate inflammation in brain reservoirs. Therefore, the virus still causes neuronal dysfunction, pain-related pathology, and ultimately HAND. In this study, we decided to test the hypothesis that a serpin-derived small peptide, SP16, can serve as an anti-viral, anti-inflammatory, pro-survival, …

Understanding Exosomal Extracellular Vesicles And Morphine In The Neuropathology Of Human Immunodeficiency Virus And Differential Zika Virus Strain-Associated Pathology, Allen Caobi

FIU Electronic Theses and Dissertations

Exosomal Extracellular Vesicles (xEVs), integral to intercellular communication and regulation of immune responses, have functional effects based on their contents, which they transport to neighboring cells. However, in the context of infection, EV cargo can be modulated, by either infected or uninfected cells. We hypothesize that CNS-associated neuropathology, is partially, due to the cargo transported by the exosomes. We theorize that the cargo released from infected cell-derived xEVs may either facilitate or inhibit viral neuropathogenicity. Here we investigated xEVs in the case of two neurotropic viruses, Zika virus (ZIKV) and Human Immunodeficiency Virus (HIV). The hallmark characteristic of ZIKV-infection is …

Type I Topoisomerases As Potential Targets For Therapeutics, Ahmed Seddek

FIU Electronic Theses and Dissertations

DNA topoisomerases are universal enzymes that control the topological features of DNA in all forms of life. This study aims to find potential inhibitors of some of the DNA topoisomerases in bacteria and humans that can be developed into potential therapeutics.

The first aim of this study is to find potential inhibitors of bacterial topoisomerase I that can be developed into antibiotics. There is an urgent need to develop novel antibiotics to overcome the world-wide health crisis of antimicrobial resistance. Virtual screening and biochemical assays were combined to screen thousands of compounds for potential inhibitors of bacterial topoisomerase I. NSC76027 …

Food Insecurity Is Associated With Nonalcoholic Fatty Liver Disease, Cognitive Impairment, And Immune Activation In People Living With Hiv, Javier A. Tamargo

FIU Electronic Theses and Dissertations

Food insecurity (FI) is a socioeconomic condition characterized by inadequate access to enough food and nutrition to sustain health and wellbeing. Food insecurity is a risk factor for chronic and age-related conditions, raising concerns for the aging population of people living with HIV (PLWH), in whom food insecurity is disproportionately prevalent. PLWH are at increased risk of nutrition-related complications and chronic co-morbidities, thus food insecurity may exacerbate adverse health outcomes in this population. This study investigated whether food insecurity was associated with nonalcoholic fatty liver disease (NAFLD), cognitive impairment, and immune activation among socioeconomically disadvantaged adults living with and without …

Carbapenem-Resistant Enterobacteriaceae (Cre): Epidemiology, Duration Of Carriage, And Progression To Infection In A Large Healthcare System In Miami, Fl, Adriana Jimenez

FIU Electronic Theses and Dissertations

Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant organisms (MDRO) considered by the CDC as an urgent public health threat that is spreading globally. Little is known about the epidemiology of CRE in Miami, FL. The purpose of this dissertation was to 1) Evaluate trends in the epidemiology of CRE among patients admitted to the acute care facilities of the largest healthcare system in Miami, FL between 2012 and 2016, 2) Identify factors associated with progressing to infection among patients colonized with carbapenemase-producing Enterobacteriaceae (CPE), and 3) Determine the duration of CPE carriage and factors associated with long-term carriage in our cohort.

A …

Scalable Profiling And Visualization For Characterizing Microbiomes, Camilo Valdes

FIU Electronic Theses and Dissertations

Metagenomics is the study of the combined genetic material found in microbiome samples, and it serves as an instrument for studying microbial communities, their biodiversities, and the relationships to their host environments. Creating, interpreting, and understanding microbial community profiles produced from microbiome samples is a challenging task as it requires large computational resources along with innovative techniques to process and analyze datasets that can contain terabytes of information.

The community profiles are critical because they provide information about what microorganisms are present in the sample, and in what proportions. This is particularly important as many human diseases and environmental disasters …

The Role Of Inositol Polyphosphate-4-Phosphatase Type Ii B (Inpp4b) In Obese Models And Endocrine Cancers, Manqi Zhang

FIU Electronic Theses and Dissertations

INPP4B is a dual-specificity phosphatase and a tumor suppressor in prostate and breast cancers. Progression of the prostate and breast cancers depends on the androgen receptor (AR) or estrogen receptor alpha (ERα) signaling, respectively. In this work we demonstrated that INPP4B reprograms ERα transcriptional activity in breast cancer. INPP4B maintains expression and protein levels of progesterone receptor (PR), an ERα direct target gene required for mammary gland development. Consistently we demonstrated that Inpp4b knockout severely impairs lateral branching in the mammary gland of maturing virgin females. In advanced prostate cancer, activation and transcriptional reprogramming of AR frequently coincides with the …

Topoisomerase And Tyrosyl-Dna-Phosphodiesterase Ratio As An Indicator For The Response Of Glioblastoma Cancer To Topoisomerase Targeting Anticancer Drugs, Wenjie Wang

FIU Electronic Theses and Dissertations

Glioblastoma (GBM) patients have an estimated survival of ~15 months, with the standard of care (surgery, radiation, and chemotherapy) that has only modestly enhanced patient survival. Identifying biomarkers representing vulnerabilities in GBM biology may allow for the selection of effective and safe chemotherapy options. Irinotecan (IRT), a genotoxic compound currently in clinical trials for GBM, targets topoisomerase I (TOP1) by forming an irreversible ternary DNA-TOP1 cleavage complex (TOP1cc) and leads to apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that rescues TOP1cc and reduces the effectiveness of IRT. In the current study, we evaluate the value of the …

Molecular Mechanism(S) Of Zika Virus Infection And Associated Neuropathogenesis, Chet Raj Ojha

FIU Electronic Theses and Dissertations

Zika virus (ZIKV), a mosquito-borne flavivirus, is known to induce various neurodevelopmental disorders including microcephaly and growth retardation in newborns from infected mothers. However, the exact mechanism of ZIKV-associated neurodevelopmental disorders is still unknown. The study was aimed at identifying the molecular mechanism(s) of ZIKV infection using in-vitro and in vivo methods. Using three isolated strains of ZIKV (MR766, R103451, and PRVABC59), we show that the Asian strains of ZIKV are more infective and toxic to glial cells and neurons compared to the African strain. Infection by PRVABC59 induces markedly higher release of inflammatory molecules; IP10, RANTES, IL-6, and IFN-β. …

The Immunosuppressive Role Of Edn3/Ednrb Signaling In The Melanoma Microenvironment, Juliano Tiburcio De Freitas

FIU Electronic Theses and Dissertations

Endothelins are cytokines ubiquitously expressed in the microenvironment of several tumors. In melanoma is not clear whether stromal cells respond to the endothelin present in the microenvironment. To address this question, I generated tumors derived from different murine melanoma cell lines (B16F10, YUMM1.7, YUMMER1.7) in a transgenic mouse that overexpresses endothelin 3 (Edn3) by keratinocytes in the skin (K5-Edn3). Tumors from all the cell lines grew larger and were more aggressive when Edn3 was overexpressed in the skin. In tumors derived from YUMM1.7-GFP cells, very few tumorigenic cells expressed the Edn3 receptor, Endothelin receptor b (Ednrb) suggesting an …

Hiv Tat And Morphine-Induced Neurodegeneration In A Beclin 1 Hemizygous Mouse Model, Jessica A. Lapierre

FIU Electronic Theses and Dissertations

Early in infection, HIV crosses the blood-brain barrier and induces neuropathology. Viral presence in the CNS coupled with secretion of neurotoxic proteins causes neuroinflammation, glial dysfunction, excitotoxicity, and neuronal death. Despite advances in combined antiretroviral therapy, HIV-infected patients present with a spectrum of cognitive and psychomotor deficits collectively referred to as HIV-associated neurological disorders (HAND). A subset of HAND patients abuses drugs such as opiates like heroin and morphine show an exacerbation and rapid progression of HIV neuropathology; however, the mechanisms of this synergy are not well understood. Autophagy is a lysosomal degradative process which eliminates and recycles cytosolic components …

Epigenetic Mechanisms Regulating The Functional Effects Of Chronic Alcohol Exposure Of Human Monocyte-Derived Dendritic Cells, Tiyash Parira

FIU Electronic Theses and Dissertations

The effects of alcohol abuse are multi-dimensional since alcohol is widely known to affect both the innate and adaptive immune systems. Recently, epigenetics has come into focus and has been implicated in many diseases as well as substance abuse disorders. Therefore, research efforts of understanding the epigenetic mechanisms underlying substance abuse effects including alcohol abuse have become more predominant.

In our laboratory, we have studied different epigenetic changes induced by alcohol exposure including regulation of histone deacetylases (HDACs), histone quantity, and histone modifications such as acetylation and deacetylation. We have observed differential effects of acute and chronic alcohol exposure in …

Mycobacterium Tuberculosis Inhibitors: Action And Resistance, Pamela K. Garcia-Moreno

FIU Electronic Theses and Dissertations

Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, has been a global health problem for years. The emergence of drug resistance in this organism generates the necessity of exploring novel targets and developing new drugs. Topoisomerases are enzymes found in all kingdoms of life responsible for overcoming the topological barriers encountered during essential cellular processes. The genomes of mycobacteria encode only one type IA topoisomerase (MtopI), which has been validated as a novel TB drug target. The goal of this study is to obtain new information on the mechanism and resistance of endogenous and synthetic inhibitors of MtopI.

Rv1495 is …

The Role Of Id3 And Pcb153 In The Hyperproliferation And Dysregulation Of Lung Endothelial Cells, Mayur Arvind Doke

FIU Electronic Theses and Dissertations

Uncontrolled growth of vascular stem cells as a result of endothelial-mesenchymal transition is considered to cause hyper-proliferative vascular remodeling in severe pulmonary arterial hypertension (PAH) patients. Hyperplastic intimal growth is one of the causes of closure of the lumen of pulmonary arterioles. This abnormal vessel remodeling leads to the progressive increase in pressure of the pulmonary arterioles causing severe PAH; and debilitating harm to patients resulting in mortality from right heart failure. Environmental factors, including polychlorinated biphenyls (PCBs), are considered to be involved in hyper-proliferative vascular remodeling because genetic makeup can only explain about 10% of severe PAH cases. PCB …

Id3, Estrogenic Chemicals, And The Pathogenesis Of Tumor-Like Proliferative Vascular Lesions, Vincent E. Avecilla

FIU Electronic Theses and Dissertations

Tumor-like proliferative vascular lesions manifest in several diseases such as peripheral arterial disease (PAD) and atherosclerosis (AS) after arterial injury. The cause of the vascular cell dysfunction in PAD patients is not known. Our recent novel discovery shows that inhibitor of differentiation 3 (ID3) is highly expressed in intimal lesions of clinical vascular disease samples. The central hypothesis of our study is: estrogenic chemical induced dysregulation of ID3 target genes is involved in the development of vascular disease. NHANES data analysis demonstrated higher geometric levels of all 6 PCB congeners in both PAD diagnosed participants and participants at risk of …

The Effect Of Vitamin D3 Supplementation On Kidney Function And Cardiovascular Disease Markers Among Hispanics And African Americans With Type 2 Diabetes, Gustavo G. Zarini

FIU Electronic Theses and Dissertations

Serum vitamin D deficiency/insufficiency, Chronic Kidney Disease (CKD) and elevated blood pressure are important health concerns especially among minorities with type 2 diabetes. The effect of vitamin D₃ supplementation (cholecalciferol) at 6,000 IU/day (d) vs. 4,000 IU/d on kidney function and cardiovascular disease markers among Hispanics and African Americans with type 2 diabetes and hypovitaminosis D (/ml) was evaluated. Subjects (n=63) were recruited from two clinics in Miami-Dade County, FL. Fasting venous blood and fresh, single-voided first morning urine samples were collected from each participant by a certified phlebotomist and analyzed by Solstas Lab Partners, Davie, FL. Linear mixed …

Identification And Phenotypic Plasticity Of Metastatic Cells In A Mouse Model Of Melanoma, Xiaoshuang Li

FIU Electronic Theses and Dissertations

Melanoma is the deadliest form of skin cancer due to its high propensity to metastasize and resistance to current therapies. We have created a spontaneous mouse model of metastatic melanoma (Dct-Grm1/K5-Edn3) where metastasis to the lungs is 80% penetrant. The primary tumors of these mice present cellular heterogeneity with cells at varying levels of differentiation. The main goal of this study was to determine the metastatic potential of the primary tumor resident Tyrosinase positive cells and evaluate the dynamic phenotypic changes as those cells move from the primary tumors to the sites of metastasis. To accomplish this aim …

Medicinal Plants Of Trinidad And Tobago: Selection Of Antidiabetic Remedies, Angelle L. Bullard-Roberts

FIU Electronic Theses and Dissertations

Diabetes mellitus (DM) is a group of non-infectious diseases that cause hyperglycemia. DM symptoms were first clinically described by ancient Greek physicians whose prescriptions included plant-based remedies. Today, DM affects >400 million people globally and prevalence rates are rapidly increasing in developing countries where basic healthcare relies on local knowledge of botanical remedies. Many developing countries are home to diverse peoples and plants—providing fodder for varied plant-selection strategies and unique botanical pharmacopoeias.

I addressed the plant-selection strategies used in a multi-ethnic, developing country, Trinidad and Tobago (T&T), to ascertain their role in shaping the local antidiabetic pharmacopoeia and to assess …

Understanding Ten-Eleven Translocation-2 In Hematological And Nervous Systems, Feng Pan

FIU Electronic Theses and Dissertations

I proposed the study of two distinct aspects of Ten-Eleven Translocation 2 (TET2) protein for understanding specific functions in different body systems.

In Part I, I characterized the molecular mechanisms of Tet2 in the hematological system. As the second member of Ten-Eleven Translocation protein family, TET2 is frequently mutated in leukemic patients. Previous studies have shown that the TET2 mutations frequently occur in 20% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% T-cell lymphoma leukemia and 2% B-cell lymphoma leukemia. Genetic mouse models also display distinct phenotypes of various types of hematological malignancies. I performed 5-hydroxymethylcytosine (5hmC) chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA …

Pseudomonas Aeruginosa Ampr Transcriptional Regulatory Network, Deepak Balasubramanian

FIU Electronic Theses and Dissertations

In Enterobacteriaceae, the transcriptional regulator AmpR, a member of the LysR family, regulates the expression of a chromosomal β-lactamase AmpC. The regulatory repertoire of AmpR is broader in Pseudomonas aeruginosa, an opportunistic pathogen responsible for numerous acute and chronic infections including cystic fibrosis. Previous studies showed that in addition to regulating ampC, P. aeruginosa AmpR regulates the sigma factor AlgT/U and production of some quorum sensing (QS)-regulated virulence factors. In order to better understand the ampR regulon, the transcriptional profiles generated using DNA microarrays and RNA-Seq of the prototypic P. aeruginosa PAO1 strain with its isogenic ampR deletion …