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The Mevalonate Pathway: A Potential Therapeutic Target For Jak2-Driven Myeloproliferative Neoplasms, Lori Nicole Griner Jan 2013

The Mevalonate Pathway: A Potential Therapeutic Target For Jak2-Driven Myeloproliferative Neoplasms, Lori Nicole Griner

Graduate Theses and Dissertations

The Mevalonate Pathway: A Potential Therapeutic Target for JAK2-driven Myeloproliferative Neoplasms

Lori Nicole Griner

Abstract

Myeloproliferative neoplasms (MPNs) are diseases of hematopoietic stem cell origin and are characterized by uncontrolled growth of cells of the myeloid compartment. The Philadelphia chromosome negative classical MPNs, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are diseases of dysregulated JAK2 signaling. In fact, the majority of MPN patients have activating mutations in JAK2 (e.g JAK2-V617F), a tyrosine kinase that contributes to the growth and survival of myeloid cells. While MPNs were first described over sixty years ago, a significant need remains to develop therapeutic ...


Associations Between Vitamin D Status And Blood Lipid Parameters In Healthy, Older Adults, Felicia L. Steger Jan 2013

Associations Between Vitamin D Status And Blood Lipid Parameters In Healthy, Older Adults, Felicia L. Steger

Graduate Theses and Dissertations

Background. One explanation for the relationship between vitamin D and cardiovascular disease (CVD) mortality could be related to altered serum lipids. This study aimed to determine the association between 25OHD and serum lipid concentrations in healthy, older adults.

Methods. Serum lipid panels and 25OHD concentrations were obtained on 190 adults (median age 67 years) after a 12-hour overnight fast. 25OHD was measured by the DiaSorin Liason system. Subjects were stratified by 25OHD concentrations: <20.0 ng/mL, 20.0-29.9 ng/mL, 30.0-39.9 ng/mL and ≥40 ng/mL. One-way ANOVA was used to observe unadjusted differences and Student's t-tests were used to determine differences between groups. Multiple regression analyses were performed to determine the ability of 25OHD to predict serum lipid concentrations when accounting for BMI, sex, age, and statin use. Stepwise regression analyses were used to establish the best prediction model for each outcome.

Results. There was a significant relationship between 25OHD and BMI (p<0.001), glucose (p=0.042), TG (p=0.020), TC (p<0.001), LDL (p<0.001) and the TC:HDL ratio (p<0.001), but not for blood pressure, HDL, or TG:HDL ratio. When comparing subjects with 25OHD ≥40.0 ng/mL to those with <20 ng/mL, those in the highest group had a significantly lower BMI (26.1 0.7 and 29.9 0.8 kg/m2), TG (100.9 7.8 and 130.4 9.5 mg/dL), TC (182.7 5.2 and 217.4 6.3 mg/dL), LDL (100.3 4.5 and 131.2 5.4 mg/dL), and calcium (9.67 0.05 and 9.50 0.06 mg/dL) concentrations, and had significantly lower TC:HDL (3.09 0.15 and 4.15 0.08) and TG:HDL (1.79 0.22 and 2.56 0.27) ratios.

When adjusting for confounders, the relationship between 25OHD and TC (p<0.001) and LDL (p<0.001) remained significant, but that between TC:HDL and TG:HDL did not. When a stepwise regression analysis was performed to determine the best model for predicting serum lipid parameters, each 10 ng/mL increase in 25OHD predicted a statistically significant 6.72 mg/dL decline in TC (p<0.001) and 5.55 mg/dL decline in LDL (p<0.001).

Conclusions. 25OHD status is associated ...


Step-Specific Investigation Of Snare-Mediated Membrane Fusion, Sunae Kim Jan 2013

Step-Specific Investigation Of Snare-Mediated Membrane Fusion, Sunae Kim

Graduate Theses and Dissertations

Cholesterol is a major component of biological membranes and is known to affect vesicle fusion. However, the mechanism by which cholesterol modulates SNARE-dependent intracellular fusion is not well understood. First, using the fluorescence assay and employing dye-labeled SNAREs and the fluorescent lipids on yeast post golgi trafficking SNARE-mediated model membrane fusion, we dissected cholesterol effects on individual fusion steps including SNARE complex formation, hemifusion, pore formation, and pore dilation. At physiological high concentrations, cholesterol stimulated hemifusion as much as 30-fold, but its stimulatory effect diminished to 10- and 3-folds for subsequent pore formation and pore expansion at 40 mole%, respectively ...