Submitted to the faculty of Indiana University in partial fulfillment of the requirements for the degree Master of Science in the School of Informatics, December 2004 / The process of generating RNA message from a gene is termed "transcription," and is performed by aptly named "transcription factors." These transcription factors can function singly or in conjunction with other factors to regulate gene expression, and thereby control, at one level, the amount of protein product which a gene can produce. This transcriptional regulation can have profound biological effects. Identification of the DNA sequences bound by transcription factors (regulatory elements) is a challenge as these sequences can be very short and may be located large distances from the target gene. Also, many current approaches for discovering regulatory elements in genomic DNA are limited to those sequences previously identified as consensus sequences for transcription factors. We have developed a novel tool, ReguLocator, for the identification of putative regulatory element. It uses the Smith-Waterman algorithm to identify short, conserved DNA sequences (ranked by p-value) derived from 2 large DNA sequences of interest. No weighting is applied for spatial alignment. Although speed must be improved to make use of ReguLocator practical, initial comparisons to similar tools provide promising results, and may open the door to better regulatory element identification.

Thesis (Ph.D.). / Written for the Dept. of Anatomy and Cell biology. Title from title page of PDF (viewed 2008/05/09). Includes bibliographical references.

Parkinson’s disease (PD) is among the most devastating neurodegenerative disorders, and affects 1% of the global population above the age of 60. Several mechanisms have been proposed to explain the dopamine degeneration exhibited in PD: mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Inaccurate diagnosis is one of the greatest challenges to treatment of PD. Currently, there is no standard diagnostic test for PD. Neurotrophic factors (NTF) are secreted proteins that promote survival and maintenance of neurons during development. The loss of NTFs for specific neuronal populations could confer susceptibility to various neurodegenerative disorders. Cerebral dopamine neurotrophic factor (CDNF) is a novel NTF selective for dopamine neurons. CDNF has demonstrated profound neuroprotective and neurorestorative effects on dopamine neurons in well established animal models of PD. Presently, there are no studies examining endogenous levels of CDNF in PD models or clinical populations of PD, prompting the present study. Findings will bring insight into the neurobiological mechanisms underlying neurodegeneration in PD. This study has determined that CDNF protein and mRNA expression is not altered following 6-OHDA lesioning, suggesting a compensatory mechanism of CDNF in response to injury. We have also determined that CDNF mRNA expression declines with age, which could confer susceptibility to developing neurodegenerative diseases such as PD. In clinical populations of PD, platelets showed a significant increase in CDNF mRNA expression that was not seen in lymphocytes or whole blood. This suggests a role of CDNF in PD, specifically for platelets; however, it is important to delineate whether this increase is the result of treatment. Incidentally, we found that CDNF mRNA expression is significantly reduced following stroke. Together, these results stress the importance of CDNF in disorders stemming from ER stress. Future studies should examine the role of CDNF in preclinical models of stroke, as well as knockout models of PD. / Thesis / Master of Science (MSc)

No description available.

ABSTRACT In jet problems the conserved quantity plays a central role in the solution process. The conserved quantities for laminar jets have been established either from physical arguments or by integrating Prandtl's momentum boundary layer equation across the jet and using the boundary conditions and the continuity equation. This method of deriving conserved quantities is not entirely systematic and in problems such as the wall jet requires considerable mathematical and physical insight. A systematic way to derive the conserved quantities for jet °ows using conservation laws is presented in this dissertation. Two-dimensional, ra- dial and axisymmetric °ows are considered and conserved quantities for liquid, free and wall jets for each type of °ow are derived. The jet °ows are described by Prandtl's momentum boundary layer equation and the continuity equation. The stream function transforms Prandtl's momentum boundary layer equation and the continuity equation into a single third- order partial di®erential equation for the stream function. The multiplier approach is used to derive conserved vectors for the system as well as for the third-order partial di®erential equation for the stream function for each jet °ow. The liquid jet, the free jet and the wall jet satisfy the same partial di®erential equations but the boundary conditions for each jet are di®erent. The conserved vectors depend only on the partial di®erential equations. The derivation of the conserved quantity depends on the boundary conditions as well as on the di®erential equations. The boundary condi- tions therefore determine which conserved vector is associated with which jet. By integrating the corresponding conservation laws across the jet and imposing the boundary conditions, conserved quantities are derived. This approach gives a uni¯ed treatment to the derivation of conserved quantities for jet °ows and may lead to a new classi¯cation of jets through conserved vectors. The conservation laws for second order scalar partial di®erential equations and systems of partial di®erential equations which occur in °uid mechanics are constructed using di®erent approaches. The direct method, Noether's theorem, the characteristic method, the variational derivative method (mul- tiplier approach) for arbitrary functions as well as on the solution space, symmetry conditions on the conserved quantities, the direct construction formula approach, the partial Noether approach and the Noether approach for the equation and its adjoint are discussed and explained with the help of an illustrative example. The conservation laws for the non-linear di®usion equa- tion for the spreading of an axisymmetric thin liquid drop, the system of two partial di®erential equations governing °ow in the laminar two-dimensional jet and the system of two partial di®erential equations governing °ow in the laminar radial jet are discussed via these approaches. The group invariant solutions for the system of equations governing °ow in two-dimensional and radial free jets are derived. It is shown that the group invariant solution and similarity solution are the same. The similarity solution to Prandtl's boundary layer equations for two- dimensional and radial °ows with vanishing or constant mainstream velocity gives rise to a third-order ordinary di®erential equation which depends on a parameter. For speci¯c values of the parameter the symmetry solutions for the third-order ordinary di®erential equation are constructed. The invariant solutions of the third-order ordinary di®erential equation are also derived.

Comparative genomic studies have identified noncoding regions of the genome which are often more highly conserved between species than protein-coding sequences. One possible explanation for this conservation of non-coding sequences is some form of selective constraint since sequence conservation at great evolutionary depths is a preliminary indication of functional constraint. Here, I consider nearly 2500 putative regulatory elements, termed Conserved Noncoding Elements (CNEs), that are conserved across seven vertebrate species (human, macaque, mouse, chicken, frog, zebrafish and fugu). I distinguish between CNEs that show accelerated rates of evolution and those that have remained more constrained throughout evolution, and identify CNEs that show higher than expected substitution rates in the human lineage that may be potential candidates of adaptive evolution. However, it is not trivial to demonstrate the action of selection on such sequences. It is relatively easier in the case of protein-coding DNA, since selection would be predicted to result in different rates of substitution for synonymous and non-synonymous sites. Hence, I use the same seven species to define phylogenetically invariant positions in CNEs in contrast to those that have at least one substitution and analyse them independently to determine if there is a positive correlation between evolutionary conservation and the strength of purifying selection at individual sites. In the 1000 Genomes, but not the HapMap, data I find a significant excess of rare derived alleles in CNEs relative to coding sequences. This excess of rare alleles can be best explained if selection is relatively consistent across sites, with most mutations resulting in a similar reduction in fitness. Finally, I explore patterns of variation in the allele-frequencies within human populations, however do not detect any significant differences in the underlying distribution of negatively selected variants among human populations.

High levels of primary sequence conservation are observed in many noncoding regions of eukaryotic genomes. These conserved noncoding elements (CNEs) have shown to be robust indicators of functionally constrained elements. Nevertheless, the function of only a small fraction of such CNEs is known and their role in genome biology remains largely a mystery. Comparative genomics analysis in model organisms can shed light on CNE function and evolution of noncoding DNA in general. Recently, it has been reported that short CNEs in the Drosophila genome are typically very AT-rich but have unusually high levels of GC content in a much larger (~500 bp) window around them. To understand whether these "side effects" are dependent on their CNE definition or are a more general feature of the Drosophila genome, we analysed base composition of CNEs from two different CNE detection methods. We found side effects are real, but are restricted to a subset of CNEs in the genome. An alternative hypothesis to explain the existence of CNEs is the mutational cold spot hypothesis. Previous work using SNPs was shown evidence that CNEs are not mutational cold spots. Here, non-reference transposable elements (TEs) were used to test cold spot hypothesis. A significant reduction in levels of non-reference TEs was found in intronic and intergenic CNEs compared to the expected number of insertions. TEs in intergenic CNEs were also found at lower allele frequencies than TEs in intergenic spacers. Furthermore, we used simulation to explore the effects of insertion/deletion (indel) evolution on noncoding DNA sequences with and without constrained noncoding elements. We assessed several indel-capable simulators to test expected outcomes with no selectively constrained elements. Simulations with constrained elements show that sequences grow in length even when the deletion rate is exactly the same as the insertion rate. This result can be interpreted as being due to purifying selection on CNEs acting to remove an excess of deletion over insertions. Together, the results presented here provide insights into the evolution of noncoding DNA in one of the most important model organisms.

We show that the symplectic current obtained from the boundary term, which arises in the first variation of a local diffeomorphism invariant action, is covariantly conserved for any gravity theory described by that action.Therefore, a Poincar&eacute / invariant two-form can be constructed on the phase space, which is shown to be closed without reference to a specific theory.Finally, we show that one can obtain a charge expression for gravity theories in various dimensions, which plays the role of the Abbott-Deser-Tekin charge for spacetimes with nonconstant curvature backgrounds, by using the diffeomorphism invariance of the symplectic two-form. As an example, we calculate the conserved charges of some solutions of new massive gravity and compare the results with previous works.

We generalize the definition of conserved gravitational Killing charges of quadratic curvature gravity theories to arbitrary backgrounds that admit at least one global (time-like) Killing vector. This charge definition is background gauge invariant and reduces correctly to the already known limit given by [1] when the background is a space of constant curvature. As an application we use this definition to compute the charges of various black holes in New Massive Gravity / namely the BTZ black hole, the black hole given in [2] and the Lifshitz black hole. Finally we compare the charges of these black holes with the ones given in [3], which uses a different approach.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: p.146