Stroke is the third leading cause of death and the most common cause of disabilities worldwide. Apolipoprotein A5 gene (APO A5), which encodes a 369 amino acid protein called Apolipoprotein AV (apo AV), has several single nucleotide polymorphisms (SNPs) found to be associated with altered triglyceride (TG) levels. Atherosclerosis is a major cause of ischemic stroke and this pathology may be associated with variability of TG levels. The main objective of this study was to investigate the coding region (c.553G&gt / T) and promoter region (-1131T/C) polymorphisms of the APO A5 gene as a risk factor for ischemic stroke. The study group in Turkish population consisted of 198 unrelated ischemic stroke patients and 130 control subjects. There was no statistically significant difference between the groups with respect to age and gender. Total blood samples were obtained from G&uuml / lhane Military Medical Academy Hospital, Neurology Department, Ankara. In stroke patients, hypertension and diabetes were 2.5 times more common and high-density lipoprotein cholesterol (HDL-C) was significantly lower than controls. Logistic regression analysis showed that hypertension, diabetes and smoking were significant predictors of stroke. The frequency of risky alleles c.553T and -1131C were 0.003 and 0.098, respectively, in patients and were nearly the same with controls. The risk of hypertensive and diabetic individuals having ischemic stroke was higher in -1131C allele carriers (Odds ratio / OR= 3.4 and 6.4, respectively) than -1131TT individuals (OR= 2.3 and 1.9, respectively). Stroke patients with -1131C allele had significantly higher TG levels (1.70 mmol/L) and lower HDL-C levels (1.05 mmol/L) when compared to controls (1.35 mmol/L and 1.20 mmol/L, respectively) with the same genotype. Logistic regression analysis revealed elevated TG level to be associated with 2.2-fold and low levels of HDL-C to be associated with 1.8-fold increase in the risk of ischemic stroke versus control status. This is the first study investigating the relation between APO A5 c.553G&gt / T polymorphism and stroke risk. Additionally, in Turkish population -1131T/C polymorphism was analyzed for the first time in terms of its relation to ischemic stroke. The present study demonstrated that the frequency of risky alleles c.553T and-1131C were nearly the same in stroke patients and control subjects. Consequently, we decided that carrying minor alleles of c.553G&gt / T and-1131T/C polymorphisms do not constitute a risk for ischemic stroke.

Reintroduction of Anatolian mouflon population at Bozdag Protection &amp / Breeding Station to its former habitats(Emremsultan Wildlife Development Area in Ankara-Nallihan, and Karadag in Karaman) started in 2004. The magnitude of genetic change among Bozdag and reintroduced populations was evaluated by 11 microsatellite loci. Study populations revealed close results (&plusmn / st.dev.) &ndash / Bozdag population: nk = 2.9091 (&plusmn / 1.1362), AE = 2.0250 (&plusmn / 0.9537), Ho = 0.3830 (&plusmn / 0.2717), He = 0.3956 (&plusmn / 0.2746) / Nallihan population: nk = 2.9091 (&plusmn / 1.1362), AE = 2.0592 (&plusmn / 0.9451), Ho = 0.4086 (&plusmn / 0.2977), He = 0.4052 (&plusmn / 0.2767) / and Karadag population: nk = 2.5455 (&plusmn / 1.1282), AE = 1.8809 (&plusmn / 0.8758), Ho = 0.3388 (&plusmn / 0.2775), He = 0.3607 (&plusmn / 0.2716). Population differences for major genetic parameters were not significant (p &gt / 0.05) by comparisons with paired t-test. Also, temporal change in genetic diversity for Bozdag population was investigated by comparison with temporal data. Temporal changes in genetic parameters were found to be not significant and possible causes for differences were argued. Additionally, genetic diversity and PI computations for different traps were verified and compared to uncover any potential bias due to the catching method. Comparisons did not reveal significant differences illustrating the homogeneity among traps. On the other hand, simulations detected the higher sensitivity of allelic diversity (A) to founder events than P and heterozygosity (Ho &amp / He) levels which supports heterozygosity excess method for bottleneck analysis. With the same simulation analysis, observed genetic diversity within reintroduced samples were found to be in the ranges of expectation (99% CI) indicating that translocated individuals were chosen randomly. Bottleneck analysis based on heterozygosity excess method (one-tailed test for heterozygosity excess: pSMM = 0.28515, pTPM = 0.06445, pIAM = 0.02441) and allele frequency distributions method (normal L-shaped) could not detect a recent genetic bottleneck for Bozdag population. However, simulations determined that these two methods are prone to type II error. Bottleneck detection failure for the study population is probably due to type II error instead of other sources of error like violations of model assumptions.

Resistance to broad spectrum of chemotherapeutic agents in cancer cell lines and tumors has been called multiple drug resistance (MDR). In this study, the molecular mechanisms of resistance to two anticancer agents (paclitaxel and vincristine) in mammary carcinoma cell line MCF-7 were investigated. MCF-7 cells were selected in the presence of paclitaxel and vincristine by stepwise dose increments. The cell viability and growth profiles of resistant sublines were examined. As the resistance indices increased, the growth rates of sublines were found to decrease. Gene and protein expression levels of the basic drug resistance proteins P-gp and MRP1 were studied in sensitive and drug resistant MCF-7 cells. It was shown that P-gp overexpression is significantly contributing to the developed drug resistance phenotype. Mutation analysis of beta tubulin gene which encodes the target of paclitaxel and vincristine was performed. Single histidine to proline mutation was identified near GTP binding site of beta tubulin in vincristine resistant subline which was not reported before. Apoptosis related BCL-2 and BAX were examined at both gene and protein expression levels and they were not found to be significantly related to the developed resistance in the sublines. The reversal of drug resistance by various inhibitory agents of P-gp and MRP1 was investigated by using flow cytometry. Synthetic silicon compounds were found to be the most effective MDR reversal agents. The effects of various combinations of anticancer drugs and reversal agents on cell proliferation were examined by checkerboard microplate method. ALIS409-paclitaxel and paclitaxel-doxorubicin pairs seem to have highest antiproliferative effects on resistant sublines. The microarray expression profiling of sensitive and resistant MCF-7 cells was performed for a much detailed and comprehensive analysis of drug resistance. The results indicated that the upregulation of MDR1 gene is the dominating mechanism of paclitaxel and vincristine drug resistance. Additionally up regulation of the genes encoding the detoxifying enzymes (i.e. GSTP1) was observed. Significant down regulation of apoptotic genes (i.e. PDCD2/4/6/8) and alterations in expression levels of genes related to invasion and metastasis (MMPs, ADAMs, COL4A2, LAMA etc.) were detected. Upregulation of some oncogenes (i.e. ETS, RAS) and cell cycle regulatory genes (CDKN2A, CCNA2 etc.) was seen which may be in close relation to MDR in breast cancer. Further studies will demonstrate the relationship between the components contributing to drug resistance phenotype in breast cancer cells.

In this study influences of vertical ground motion on seismically isolated bridges were investigated for seven different earthquake data. One assessment of bearing effect involves the calculation of vertical earthquake load on the seismically isolated bridges. This paper investigates the influence of vertical earthquake excitation on the response of briefly steel girder composite bridges (SCB) with and without seismic isolation through specifically selected earthquakes. In detail, the bridge is composed of 30m long three spans, concrete double piers at each axis supported by mat foundations with pile systems. At both end of the spans there exists concrete abutments to support superstructure of the bridge. SCBs which were seismically isolated with nine commonly preferred different lead&amp / #8208 / rubber bearings (LRB) under each steel girder were analyzed. Then, the comparisons were made with a SCB without seismic isolation. Initially, a preliminary design was made and reasonable sections for the bridge have been obtained. As a result of this, the steel girder bridge sections were checked with AASHTO provisions and analytical model was updated accordingly. Earthquake records were thought as the main loading sources. Hence both cases were exposed to tri&amp / #8208 / axial earthquake loads in order to understand the effects under such circumstances. Seven near fault earthquake data were selected by considering possession of directivity. Several runs using the chosen earthquakes were performed in order to be able to derive satisfactory comparisons between different types of isolators. Analytical calculations were conducted using well known structural analysis software (SAS) SAP2000. Nonlinear time history analysis was performed using the analytical model of the bridge with and without seismic isolation. Response data collected from SAS was used to determine the vertical load on the piers and middle span midspan moment on the steel girders due to the vertical and horizontal component of excitation. Comparisons dealing with the effects of horizontal only and horizontal plus vertical earthquake loads were introduced.

Current seismic design approach of bridge structures can be categorized into two distinctive methods: (i) force based and (ii) performance based. AASHTO LRFD seismic design specification is a typical example of force based design approach especially used in Turkey. Three different importance categories are presented as &ldquo / Critical Bridges&rdquo / , &ldquo / Essential Bridges&rdquo / and &ldquo / Other Bridges&rdquo / in AASHTO LRFD. These classifications are mainly based on the serviceability requirement of bridges after a design earthquake. The bridge&rsquo / s overall performance during a given seismic event cannot be clearly described. Serviceability requirements specified for a given importance category are assumed to be assured by using different response modification factors. Although response modification factor is directly related with strength provided to resisting column, it might be correlated with selected performance levels including different engineering response measures. Within the scope of this study, 27216 single circular bridge column bent models designed according to AASHTO LRFD and having varying column aspect ratio, column diameter, axial load ratio, response modification factor and elastic design spectrum data are investigated through a series of analyses such as response spectrum analysis and push-over analysis. Three performance levels such as &ldquo / Fully Functional&rdquo / , &ldquo / Operational&rdquo / and &ldquo / Delayed Operational&rdquo / are defined in which their criteria are selected in terms of column drift measure corresponding to several damage states obtained from column tests. Using the results of analyses, performance categorization of single bridge column bents is conducted. Seismic responses of investigated cases are identified with several measures such as capacity over inelastic demand displacement and response modification factor.

Intestinal epithelial differentiation entails the formation of highly specialized cells with specific absorptive, secretory, digestive and immune functions. Cell-cell and cell-microenvironment interactions appear to be crucial in determining the outcome of the differentiation process. Using the Caco-2 cell line that can undergo spontaneous differentiation when grown past confluency, we observed a loss of VCAM1 (vascular cell adhesion molecule-1) expression while ICAM1 (intercellular cell adhesion molecule-1) expression was seen to be stable in the course of differentiation. Protein kinase C theta (PKC&theta / ) acted downstream of PKC to inactivate Inhibitor of kappa B (IB) and activate NF-&kappa / B in the undifferentiated cells and this axis was inhibited in the differentiated cells. The increase in ICAM1 expression in the differentiated cells was due to a transcriptional upregulation by C/EBP. The protein expressions of both ICAM-1 and VCAM-1, however, were found to decrease in the course of differentiation, with both proteins getting post-translationally degraded in the lysosome. Functionally, a decrease in adhesion to HUVEC cells was observed in the differentiated Caco-2 cells. Thus, the regulation of ICAM-1 and VCAM-1, although both NF-B target genes, appear to be different in the course of epithelial differentiation. microRNAs are known to regulate many cellular pathways. miR-146a, which is known to target NF-&kappa / B, was shown to be highly upregulated in differentiated Caco-2 cells. As a predicted target of miR-146a, mRNA and protein expression of MMP16 was inversely correlated with miR-146a during differentiation of Caco-2 cells. miR-146a could bind to the 3&rsquo / UTR of MMP16 and ectopic expression of miR-146a resulted in a decreased mRNA and protein expression of MMP16 in the undifferentiated Caco-2 and HT-29 cells. Functionally, decreased gelatinase activity determined by gelatin zymography and reduced invasion and migration through Transwells was observed. In the final part of the thesis, the inhibition of NF-&kappa / B via PPAR&gamma / in 15-Lipoxygenase-1 (15LOX1) expressing cells was investigated. The expression of 15LOX1, a member of the inflammatory arachidonate cascade, could lower phosphorylation of I&kappa / B&alpha / and NF-&kappa / B DNA binding activity which was reversed with a 15LOX1 inhibitor. This inhibition was mediated by phospho-PPAR&gamma / , which in turn was phosphorylated by ERK1/2.

Long span bridges are susceptible to wind. Hence it is important to study their wind-induced vibrations to avoid any probable structural failures. In this thesis, the results of an experimental and computational investigation of the aerodynamic characteristics of trapezoid bridge deck cross-sections with three different aspect ratios (10, 12 and 15) and four different side angles (75&ordm / , 60 &ordm / , 45 &ordm / and 30 &ordm / ) are analyzed and presented. The flow around rigid fixed bridge deck models is investigated to obtain the relevant aerodynamic coefficients and the vortex shedding frequency and Strouhal number. Two dimensional unsteady Reynolds Averaged Navier-Stokes equations are solved using commercial CFD software at different Reynolds numbers. The numerical results are compared with the experimental data obtained by testing the model bridge decks geometries in a low speed wind tunnel. The results of this study demonstrate that the models aerodynamic parameters except their lift coefficient are almost dependent on the aspect ratio. In addition, the influence of side angle on all aerodynamic parameters has to be taken in account.

GWAS mainly aim to identify variations associated with certain phenotypes or diseases. Recently the combined p-value approach is described as the next step after GWAS to map the significant SNPs to genes and pathways to evaluate SNP-gene-disease associations. Major bottleneck of standard GWAS approaches is the prioritization of statistically significant results. The connection between statistical analysis and biological relevance should be established to understand the underlying molecular mechanisms of diseases. There are few tools offered for SNP prioritization but these are mainly based on user-defined subjective parameters, which are hard to standardize. Our group has recently developed a novel AHP based SNP prioritization algorithm. Beside statistical association AHP based SNP prioritization algorithm scores SNPs according to their biological relevance in terms of genomic location, functional consequence, evolutionary conservation, and gene-disease association. This allows researchers to evaluate the significantly associated SNPs quickly and objectively. Here, we have investigated the performance of the AHP based prioritization as the next step in the utilization of the algorithm in comparison to the other available tools for SNP prioritization. The user-defined parameters for AHP based prioritization have been investigated and our suggestion on how to use these parameters are presented. Additionally, the GWAS results from the analysis of two different sets of Alzheimer Disease Genotyping data with the newly proposed AHP based prioritization and the integrated software, METU-SNP, it was implemented, is reported and our new findings on the association of SNPs and genes with AD based on this analysis is discussed.

Infrastructure systems are crucial facilities. They supply the necessary transportation, water and energy utilities for the public. However, while aging, these systems gradually deteriorate in time and approach the end of their lifespans. As a result, they require periodic maintenance and repair in order to function and be reliable throughout their lifetimes. Bridge infrastructure is an essential part of the transportation infrastructure. Bridge management systems (BMSs), used to monitor the condition and safety of the bridges in a bridge infrastructure, have evolved considerably in the past decades. The aim of BMSs is to use the resources in an optimal manner keeping the bridges out of risk of failure. The BMSs use the lifetime performance curves to predict the future condition of the bridge elements or bridges. The most widely implemented condition-based performance prediction and maintenance optimization model is the Markov Decision Process-based models (MDP). The importance of the Markov Decision Process-based model is that it defines the time-variant deterioration using the Markov Transition Probability Matrix and performs the lifetime cost optimization by finding the optimum maintenance policy. In this study, the Markov decision process-based model is examined and a computer program to find the optimal policy with discounted life-cycle cost is developed. The other performance prediction model investigated in this study is a probabilistic Bi-linear model which takes into account the uncertainties for the deterioration process and the application of maintenance actions by the use of random variables. As part of the study, in order to further analyze and develop the Bi-linear model, a Latin Hypercube Sampling-based (LHS) simulation program is also developed and integrated into the main computational algorithm which can produce condition, safety, and life-cycle cost profiles for bridge members with and without maintenance actions. Furthermore, a polynomial-based condition prediction is also examined as an alternative performance prediction model. This model is obtained from condition rating data by applying regression analysis. Regression-based performance curves are regenerated using the Latin Hypercube sampling method. Finally, the results from the Markov chain-based performance prediction are compared with Simulation-based Bi-linear prediction and the derivation of the transition probability matrix from simulated regression based condition profile is introduced as a newly developed approach. It has been observed that the results obtained from the Markov chain-based average condition rating profiles match well with those obtained from Simulation-based mean condition rating profiles. The result suggests that the Simulation-based condition prediction model may be considered as a potential model in future BMSs.

Epilepsy is neurological disorder affecting 0.5 to 1% of the population all around the world. It is characterized by the seizures, which are the sudden alterations of behavior due to a temporary change in electrical functioning of the brain. Idiopathic generalized epilepsy (IGE) accounts for one-fifth of all the other epilepsy types, and several gene mutations were identified as the causes of IGE. In general, voltage-gated and ligand-gated ion channel mutations are linked with seizure formation. Gamma amino butyric acid (GABA), the most important inhibitory neurotransmitter of the central nervous system, and its receptors are commonly mentioned in the pathophysiology of epilepsies. Decrease in the inhibitory effect of GABA in neurons causes epileptic discharges resulting in seizure development. The study population consisted of a total of 176 idiopathic generalized epilepsy (IGE) patients, 83 subjects having psychogenic non-epileptic seizures (PNES), 86 non-epileptic control subjects from Turkey. Total blood samples were obtained from G&uuml / lhane Military Medical Academy Hospital Neurology Department, Ankara. There was no statistically difference between the patient and control groups in terms of age. Genomic DNA isolations were performed and genotyping of G1465A and C59T polymorphisms of GABAB1 gene / rs1999501, rs967932, rs3780428 and rs944688 polymorphisms of GABAB2 gene were determined by PCR-RFLP technique. In this study, GABAB1 G1465A polymorphic allele was not observed in Turkish population. For GABAB1 C59T polymorphism, polymorphic allele frequencies were found as 0.097 in IGE patients / 0.072 in PNES subjects and 0.105 in non-epileptic control subjects. No significant difference is identified for C59T polymorphism in all three groups. Four SNPs of GABAB2 were studied / rs967932 was found to increase the risk of IGE 3.6-fold (P=0.031) compared to PNES subjects, polymorphic allele frequencies were found as 0.060 in IGE patients / 0.018 in PNES subjects and 0.035 in non-epileptic control subjects. For rs1999501 polymorphism, polymorphic allele frequencies were found as 0.077 in IGE patients / 0.048 in PNES subjects and 0.093 in non-epileptic control subjects. For rs3780428 polymorphism, polymorphic allele frequencies were found as 0.267 in IGE patients / 0.235 in PNES subjects and 0.256 in non-epileptic control subjects. For rs944688 polymorphism, polymorphic allele frequencies were found as 0.196 in IGE patients / 0.260 in PNES subjects and 0.227 in non-epileptic control subjects. No significant difference was identified for rs1999501, rs3780428 and rs944688 polymorphisms among IGE patients, PNES subjects and non-epileptic control groups. IGE risk was 6.54-fold higher for subjects having combined GA genotype for rs967932 and GG genotype for rs3780428 when compared with PNES subjects (P=0.042). The combination of CC genotype for rs1999501, GG genotype for rs967932 and TT genotype for rs944688 had around 9-fold protective effect against IGE when both compared with PNES subjects (P=0.038) and non-epileptic control subjects (P=0.041).