Bechtel, Jason M.
Genomes encode many signals at multiple levels. They must therefore manifest
inhomogeneity in their nucleotide composition. Inhomogeneity is identifiable from the
where neighboring nucleotides influence the choice of base at a site, to the
commonly known as isochores, where a particular base composition can span
millions of nucleotides. This work explores the mostly overlooked phenomenon of
inhomogeneity (MRI). MRI is defined as an interdependence between
nucleotide choice and base composition over a distance of 301000
base pairs. Through the
investigation of thousands of human genes, the results presented herein establish the
existence of MRI throughout mammalian genomes, establish a link with strong local
secondary structures and characterize the properties...
This dissertation is focused on identification and characterization of novel genes in adipogenesis from different angles.
Wdnm1-like was identified as a novel 6.8 kDa adipokine secreted by adipocytes. Wdnm1-like is a differentiation-dependent gene in white and brown adipogenesis. TNFα treatment of 3T3-L1 adipocytes increases Wdnm1-like transcript level 2.4-fold and this can be attenuated by pretreatment with the p38 MAP kinase inhibitor SB203580. Ectopic overexpression of Wdnm1-like in HT1080 fibrosarcoma cells markedly increases active MMP-2 level.
TSC-36 was identified as a preadipocyte gene that is highly expressed in 3T3-L1 preadipocytes and downregulated to nearly undetectable levels in 3T3-L1 adipocytes. TSC-36 is therefore a...
Smigielski, Ken Alan
High efficiency particulate air (HEPA) filters by definition have an air particle removal efficiency of ≥ 99.97%. Installation of a HEPA filter, however, introduces variables that can compromise the filter’s efficiency. The main objective of this research project was to set up a “filter testing unit” to evaluate HEPA filter efficiency in relation to specific filter handling and installation variables. A closed system “HEPA filter testing unit” was assembled consisting of a fan, industrial damper, two ducts, and filter housing. The concentrations of a challenge aerosol up-stream and down-stream were used to calculate the filters capture efficiency. Eight filters were...
Bugno, Jacob R.
RadioChromic EBT film was used to create an in-vivo dosimetry system. General
properties of chromic film were investigated. Statistical analysis of previous diode doses
was used to create dose ranges encompassing 95% of clinical applications. Calibration
curves were generated for 6 MV, 10 MV, 18 MV, 6 MeV, 9 MeV, and 12 MeV energies
and fitted to polynomial equations of the third power. Calibration equations were used to
create clinical dose calculation forms. Statistical analysis was performed to measure dose
reproducibility and error. Skin doses and Dmax doses were measured and compared
against accepted values. Dmax measurements were shown to have an average percent error
of 4.47%. Skin...
Lee, Sang Jun
CEACAM1 mediates insulin clearance in the liver as a substrate of the insulin
receptor. Moreover, CEACAM1 appears to play a central role in regulating fat
metabolism and cell proliferation. The L-SACC1 mice with inactivation of CEACAM1 in
the liver developed hyperinsulinemia resulting from impaired insulin clearance and also
developed visceral adiposity with elevated plasma FFA and plasma and hepatic
Herein, we have shown that CEACAM1 is a substrate of the EGFR and reduces
EGFR-mediated cell growth in response to EGF, and that the CEACAM1 effect on EGFdependent
hepatocyte proliferation is mediated by its ability to bind to and sequester Shc,
thus uncoupling EGFR signaling from the Ras/Raf/MAP...
The classical mechanism of gene activation by androgen entails ligand-induced
dimerization of the androgen receptor (AR) for avid binding to repeat half-sites of a
target androgen response element (ARE). It is commonly assumed that the critical
hormone-independent transcriptional signaling by AR that supports the growth of many
prostate tumors also occurs through the ARE. However, our studies revealed that in the
prostate cancer cells in which proliferation was predominantly supported by AR but was
independent of hormone, the expression of 1291 genes was directly or indirectly
supported by AR, independent of hormone and significantly overlapping gene subsets
most consistently up-regulated in hormone refractory clinical tumors, when the cells...
Research has proven that Hyperthermia and Radiation work in synergy with one another
in killing cancer cells, with heat killing hypoxic cells and radiation killing oxygenated
The objective of this research project was twofold: a) to model the Best Medical, Inc.
seed Model 2301 125I seed and run in Monte Carlo N-Particle Transport Code version 5
(MCNP5). To compute the American Association of Physicists in Medicine (AAPM)
Task Group 43 (TG43) factors using this model. Then compare the results to Book values
as published by Sowards et al and the TG43 report. b) To model the new
thermobrachytherapy seed and run the TG-43 factors, comparing the results...
Bagalb, Hussein S.
The objective of this study is to determine the phenotype of lymphoma associated with temperature sensitive Moloney Murine Leukemia Virus (Mo-MuLV-ts1) retrovirus and the alteration in specific genes of mRNA expression in these lymphomas. MoMuLV-ts1 infection in BALB/c mice mimics HIV infection in humans. In previous work, we have demonstrated breast milk transmitted Mo-MuLV-ts1 infection and subsequent lymphoma development in offspring. In this experiment, a total of 146 pups from BALB/c mice were divided into 5 groups; one control and 4 experimental. Splenic tissues were used for immunohisto-chemistry, Inverse-PCR and quantitative real-time PCR (RT-PCR). Through studying viral integration sites, twenty-seven...
The Na/K-ATPase interacts with Src to form a functional receptor complex. Bind of ouabain to this receptor complex stimulates Src and subsequently activates multiple protein kinase cascades. To understand the molecular mechanism of Na/K-ATPase/Src interaction, we have further mapped the contacting sites between these two proteins. These studies have produced the following new findings. First, GST pulldown assays identified the N-termini of the a1 N-domain (ND1) and the Src kinase domain (KD1) as the contacting sites that are responsible for Src inhibition. Second, while ND1 works as the Na/K-ATPase and inhibits Src, the KD1 is capable of blocking Na/K-ATPase- or...
Glucocorticoids (GCs) are important regulators of carbohydrate and lipid metabolism, serving to antagonize the actions of insulin. As such, GC antagonists have held promise in the treatment of diabetes and metabolic syndrome. Yet, widespread and potent side effects have precluded such usage. To identify new and selective targets of GC action, we tested the roles of FKBP51 and FKBP52 in glucocorticoid receptor (GR)-controlled metabolism using FKBP - ablated mice. FKBP51 and FKBP52 serve as GR co-chaperones and we show that loss of FKBP51 increases GR transcriptional activity, while FKBP52 loss decreases it. Using high fat diet (HF) as a metabolic...
Maskiny, Charbel Farid
Innate inflammatory response is complex and involves biochemical processes leading to the activation of immune cells and subsequent production of a plethora of inflammatory mediators such as reactive oxygen species (ROS). To test the links between aerobic capacity, inflammation, ROS, and inflammatory diseases rat lines of Low Capacity Runners (LCR) and High Capacity Runners (HCR) were used. Substantial data suggests that these lines have separated for disease-related phenotypes such as blood pressure and insulin resistance. Because of the widespread association of inflammation with many diseases, we tested the hypothesis that LCR and HCR differ in their acute inflammatory response. The...
Nadkarni, Aditi A.
RAD51D performs functions in homologous recombination and telomere maintenance,
two genome stabilization mechanisms. A gene variant in the human RAD51D gene that
replaced glutamic acid (E) to glycine (G) at amino acid position 233 was identified as a
low penetrance allele in high-risk familial breast cancer cases not associated with either
BRCA1 or BRCA2 mutations. This dissertation describes the effects of this variant allele
on RAD51D protein interactions and function. Surprisingly, the Rad51d (E233G)
polymorphism increased cellular resistance to the DNA damaging agents, mitomycin C,
cisplatin, UV light and methyl methane sulfonate as well as to the microtubule inhibitor
taxol in mouse cells. Additionally, the Rad51d (E233G) variant...
Dutta, Ranendra Nath
RNA viruses have a high mutation rate due to the absence of post replicative error correction machinery. This, coupled with high yield and a short replication interval leads to the generation of extensive genetic diversity that promotes rapid adaptation to novel environments. The fitness of a population determines the frequency of neutral, deleterious and beneficial mutations that arise during replication, with the latter increasing in frequency as viral fitness increases. This work shows that there is a direct correlation between fitness and log CBS with population size ranging over five orders of magnitude, and this correlation explains limits to fitness...
Serrano Aybar, Pablo
The chemokine CCL20 is crucial for the development of the inflammatory response in the disease COPD. The alveolar epithelium is an important source of CCL20 after stimulation from particulate matter and bacteria. This process contributes to lymphocyte and dendritic cell activation, which is the link between innate and adaptive immunity, characteristic of chronic inflammation and chronic lung disease. Moraxella catarrhalis causes approximately 20% of COPD exacerbations; however, the cellular sources of the inflammatory mediators and the pathways by which it induces production of these mediators are as of yet unknown. This project examines the cytokine-inducing capacity of a wild-type Moraxella...
Smith, Sarah D.
RNA viruses, such as HIV, influenza, and hepatitis viruses, are major sources of
human infection and disease. Although vesicular stomatitis virus (VSV) is not a major
human pathogen, it serves as an excellent model for RNA virus evolution. In this work, I
used VSV to test two predictions of ecological theory that are relevant to speciation. The
first prediction is that viruses replicating in homogeneous environments will become
specialists as a result of fitness tradeoffs or costs due to differences in fitness landscapes,
while viruses that replicate in heterogeneous environments will become generalists.
Results show one example of fitness trade-off and two examples of costs associated with
Niranjan, Shalini S.
The gracile nucleus (GN) is a major brainstem processing center for somatosensory inputs. GN neurons often have functional receptive fields (RFs) on the toes, but there is little consensus on how these RFs are related to primary sensory inputs from toes. This project compared structural overlap in GN terminations of afferents from different toes, and numbers of toes in GN functional RFs. The results suggest that structural convergence of afferent terminations from at least 3-4 toes is common; in contrast, although some GN RFs reflected functional inputs from up to 4-5 toes, most RFs reflected inputs from 1-2 toes. These...
E12 is a member of the class I basic helix-loop-helix (bHLH) proteins, which contains a basic DNA binding domain and a helix-loop-helix (HLH) protein interaction domain. E12 is a multifunctional transcription factor that is involved in a large variety of developmental processes. It plays an important role in embryonic patterning, cell fate determination, cell differentiation and proliferation. In human prostate cancer cells, E12 interacts with Id1 (DNA binding inhibitor 1), a dominant negative member of the HLH family of transcriptional regulators. This complex may alter transcriptional activity, promote malignancy and facilitate transition to androgen independence. Using the bHLH domain of...
Presloid, John B.
Vesicular stomatitis virus (VSV) is an RNA virus commonly used for the study of RNA virus evolution. Like other RNA viruses, VSV has a high mutation rate, averaging one mutation per genome per round of replication. This high mutation rate leads to a genetically heterogeneous population; each produced virus will have at least one new mutation. This collection of mutants is termed a quasispecies. Bottlenecking of a population results in the fixation of random mutations, which are more likely to be deleterious than those that are fixed through selection. Previous studies have found bottlenecked virus strains with adaptability defects that...
Lupica, Samuel J.
Measurement of cortisol in fish fecal casts, in both aquaculture and natural settings, is a potentially valuable tool as it is both noninvasive and highly correlated to more commonly invasive methods, such as plasma monitoring. Performance of the cortisol ELISA developed in this study was validated by comparison to high performance liquid chromatography (HPLC), which has been used for measuring free glucocorticoids and glucocorticoid metabolites in feces of numerous mammalian species and has recently been incorporated into studies of fish physiology and behavior. Tests for parallelism and extraction efficiency showed that the ELISA and HPLC resulted in almost identical values....
Patients with chronic renal failure develop a “uremic” cardiomyopathy characterized by diastolic dysfunction, cardiac hypertrophy and systemic oxidant stress. Patients with chronic renal failure also are known to have increases in the circulating concentrations of the cardiotonic steroid marinobufagenin. On this background, we hypothesized that elevations in circulating marinobufagenin may be involved in the cardiomyopathy.
First, we observed that administration of marinobufagenin (10 μg/kg/day) for 4 weeks caused comparable increases in plasma MBG as partial nephrectomy at 4 weeks. Marinobufagenin infusion caused increases in conscious blood pressure, cardiac weight and the time constant for left ventricular relaxation similar to partial nephrectomy....