Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyper-bilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT I Al activity and non-risk GS allele. Also, the UGT1A1 (TA)(n) promoter genotype is recognized as a clinically relevant phannacogenetic marker. The aim of this study was to access diagnostic value of UGTIAI (TA) n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)(n) genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess phannacogenetic potential ofUGT1A1 (TA)(n) variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerise chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)(n) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)(n) promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilimbin in pediatric GS patients at diagnosis wasUGT1A1 (TA)(n) promoter genotype-dependent. We found that the frequency of phannacogenetic relevant UGT1A1 (TA)(n) promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)(n) promoter genoty ping could be recommended for preemptive pharmacogendic testing in Serbia

Force-velocity relation and density profiles for biased diffusion in an adsorbed monolayer

In this paper, which completes our earlier short publication [Phys. Rev. Lett. 84, 511 (2000)], we study dynamics of a hard-core tracer particle (TP) performing a biased random walk in an adsorbed monolayer, composed of mobile hard-core particles undergoing continuous exchanges with a vapor phase. In terms of an approximate approach, based on the decoupling of the third-order correlation functions, we obtain the density profiles of the monolayer particles around the TP and derive the force-velocity relation, determining the TP terminal velocity, V_{tr}, as the function of the magnitude of external bias and other system's parameters. Asymptotic forms of the monolayer particles density profiles at large separations from the TP, and behavior of V_{tr} in the limit of small external bias are found explicitly.Comment: Latex, 31 pages, 3 figure

Dynamic correlations in an ordered c(2×\times2) lattice gas

We obtain the dynamic correlation function of two-dimensional lattice gas with nearest-neighbor repulsion in ordered c(2$\times$2) phase (antiferromagnetic ordering) under the condition of low concentration of structural defects. It is shown that displacements of defects of the ordered state are responsible for the particle number fluctuations in the probe area. The corresponding set of kinetic equations is derived and solved in linear approximation on the defect concentration. Three types of strongly correlated complex jumps are considered and their contribution to fluctuations is analysed. These are jumps of excess particles, vacancies and flip-flop jumps. The kinetic approach is more general than the one based on diffusion-like equations used in our previous papers. Thus, it becomes possible to adequately describe correlations of fluctuations at small times, where our previous theory fails to give correct results. Our new analytical results for fluctuations of particle number in the probe area agree well with those obtained by Monte Carlo simulations.Comment: 10 pages, 7 figure

Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

Nitrate transport capacity of the Arabidopsis thaliana NRT2 family members and their interactions with AtNAR2.1

Interactions between the Arabidopsis NitRate Transporter (AtNRT2.1) and Nitrate Assimilation Related protein (AtNAR2.1, also known as AtNRT3.1) have been well documented, and confirmed by the demonstration that AtNRT2.1 and AtNAR2.1 form a 150-kDa plasma membrane complex, thought to constitute the high-affinity nitrate transporter of Arabidopsis thaliana roots. Here, we have investigated interactions between the remaining AtNRT2 family members (AtNRT2.2 to AtNRT2.7) and AtNAR2.1, and their capacity for nitrate transport. Three different systems were used to examine possible interactions with AtNAR2.1: membrane yeast split-ubiquitin, bimolecular fluorescence complementation in A. thaliana protoplasts and nitrate uptake in Xenopus oocytes. All NRT2s, except for AtNRT2.7, restored growth and β-galactosidase activity in the yeast split-ubiquitin system, and split-YFP fluorescence in A. thaliana protoplasts only when co-expressed with AtNAR2.1. Thus, except for AtNRT2.7, all other NRT2 transporters interact strongly with AtNAR2.1. Co-injection into Xenopus oocytes of cRNA of all NRT2 genes together with cRNA of AtNAR2.1 resulted in statistically significant increases of ¹⁵NO₃⁻ uptake over and above that resulting from single cRNA injections.Zorica Kotur, Nenah Mackenzie, Sunita Ramesh, Stephen D. Tyerman, Brent N. Kaiser and Anthony D. M. Glas

Atherogenic dyslipidemia and oxidative stress: a new look

Although results from in vitro studies and clinical trials demonstrate strong associations between oxidative stress and cardiovascular risk, to date still no convincing data are available to suggest that treatment with antioxidants might reduce vascular events. Oxidative modifications of low-density lipoproteins (LDL) represent an early stage of atherosclerosis, and small, dense LDL are more susceptible to oxidation than larger, more buoyant particles. Oxidized LDL are independent predictors of subclinical and clinical atherosclerosis. Recent studies suggested that novel therapeutic strategies may take into account the removal of such particles from circulation. Future research is required to explore the potential synergistic impact of markers of oxidative stress and atherogenic dyslipidemia, particularly small dense LDL, on cardiovascular risk

HLA genotyping in pediatric celiac disease patients

© 2014 ABMSFBIH Celiac disease (CD) is a chronic inflammatory disease in the small intestine triggered by gluten uptake that occurs in genetically susceptible individuals. HLA-DQ2 protein encoded by HLA-DQA1*05 and DQB1*02 alleles is found in 90-95% of CD patients. All of the remaining patients carry HLA-DQ8 protein encoded by HLA-DQA1*03 and DQB1*03:02 alleles. Specific HLA-DQ genotypes define different risk for CD incidence. Presence of susceptible HLA-DQ genotypes does not predict certain disease development, but their absence makes CD very unlikely, close to 100%. Here we presented for the first time the distribution of HLA-DQ genotypes in the group of pediatric celiac patients from the University Children’s Hospital, Belgrade, Serbia and estimated risk for CD development that these genotypes confer. Seventy three celiac disease patients and 62 healthy individuals underwent genotyping for DQA1, DQB1 alleles and DRB1 allele. 94.5% of patients carried alleles that encode DQ2 protein variant and 2.7% carried alleles that encode DQ8 protein variant. Two patients carried single DQB1*02 allele. No patients were negative for all the alleles predisposing to CD. The highest HLA-DQ genotype risk for CD development was found in group of patients homozygous for DQ2.5 haplotype, followed by the group of heterozygous carriers of DQ2.5 haplotype in combination with DQB1*02 allele within the other haplotype. The lowest risk was observed in carriers of a single copy of DQB1*02 or DQA1*05 allele or other non-predisposing alleles. HLA genotyping, more informative than serological testing commonly used, proved to be a useful diagnostic tool for excluding CD development

UGT1A1

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyper-bilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT I Al activity and non-risk GS allele. Also, the UGT1A1 (TA)(n) promoter genotype is recognized as a clinically relevant phannacogenetic marker. The aim of this study was to access diagnostic value of UGTIAI (TA) n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)(n) genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess phannacogenetic potential ofUGT1A1 (TA)(n) variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerise chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)(n) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)(n) promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilimbin in pediatric GS patients at diagnosis wasUGT1A1 (TA)(n) promoter genotype-dependent. We found that the frequency of phannacogenetic relevant UGT1A1 (TA)(n) promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)(n) promoter genoty ping could be recommended for preemptive pharmacogendic testing in Serbia

UGT1A1 (TA)n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia