Genetic variants in the cytochrome P450 2D6 gene in the Sri Lankan population

INTRODUCTION:

Cytochrome P450 2D6 (CYP2D6) enzymes are involved in the metabolism of a large number of commonly prescribed drugs such as antidepressants and cardiovascular drugs. The CYP2D6 *3, *4 and *14 variants associated with the loss of enzyme function; CYP2D6 *10 and *17 variants with reduced enzyme function; and CYP2D6 *2 variant with no effect on enzyme function. Establishing the frequency of these variant alleles in Sri Lankan population would be useful for optimizing pharmacotherapy with CYP2D6-substrate drugs.

OBJECTIVE:

The objective of this study was to determine the prevalence of CYP2D6 *2, *3, *4, *10, *14 and *17 variants in the main ethnic groups in the Sri Lankan population.

MATERIALS AND METHODS:

A total of 90 deoxyribonucleic acid (DNA) samples (30 each from Sinhalese, Tamils and Moors) were selected from a DNA resource at the Human Genetic Unit, Faculty of Medicine, University of Colombo. This collection had been made for population genetic studies from a random population based volunteers. Genotyping was performed using published polymerase chain reaction/restriction fragment length polymorphism methods.

RESULTS:

The prevalence of the CYP2D6 variants in Sinhalese, Sri Lankan Tamils and Moors respectively were CYP2D6 *2: 37%, 41.6% and 37.9%; CYP2D6 *3: 60.3%, 45% and 30%; CYP2D6 *4: 21.6%, 6.6% and 8.3%; CYP2D6 *10: 40%, 35% and 44%. CYP2D6 *14 and *17 variants were not identified.

CONCLUSION:

CYP2D6*3, *4 and *10 variants, which are associated with reduced or loss of CYP2D6 enzyme function were found in our population in significant frequencies. CYP2D6*4, which is reported to be a Caucasian variant was also found in all three ethnic groups.     

基于综合气象干旱指数的石羊河流域近50年气象干旱特征分析

借助数理统计理论和GIS空间分析技术,利用综合气象干旱指数(composite index,CI),根据石羊河流域5个气象站1961-2010年实测气象资料,对石羊河流域近50a的干旱在时空上的变化特征进行分析.首先计算了各站历年逐日的CI指数,统计近50 a各站点出现的干旱过程、各时段的干旱事件,在此基础上分析了石羊河流域干旱发生的频率、覆盖范围和强度和不同等级干旱发生的多年平均日数.分析结果表明:(1)石羊河流域四季干旱发生频率均呈现北高南低的空间分布规律;在四季中,夏季干旱发生频率最高,冬季频率最低;极小值都在乌鞘岭,极大值略有不同:春、夏、冬季干旱发生频率极大值在民勤,秋季极大值在武威.(2)石羊河流域有大范围干旱发生的年份夏季和秋季较多分别有22 a、11a,冬季最少只有4a.(3)石羊河流域不同等级干旱日数总体上呈现夏季多冬季少、北部多南部少的规律,和降水量的空间分布有较好的负相关性.(4)干旱发生成因除了主要受东亚季风和西南季风的影响外,还应考虑到径流的影响.研究结果与实际情况相符,可为相关部门根据本地区干旱特征制定相应抗旱对策提供理论依据.     

The Theory and Applications of Measuring Broad-Range and Chromosome-Wide Recombination Rate from Allele Frequency Decay around a Selected Locus

Recombination is the exchange of genetic material between homologous chromosomes via physical crossovers. High-throughput sequencing approaches detect crossovers genome wide to produce recombination rate maps but are difficult to scale as they require large numbers of recombinants individually sequenced. We present a simple and scalable pooled-sequencing approach to experimentally infer near chromosome-wide recombination rates by taking advantage of non-Mendelian allele frequency generated from a fitness differential at a locus under selection. As more crossovers decouple the selected locus from distal loci, the distorted allele frequency attenuates distally toward Mendelian and can be used to estimate the genetic distance. Here, we use marker selection to generate distorted allele frequency and theoretically derive the mathematical relationships between allele frequency attenuation, genetic distance, and recombination rate in marker-selected pools. We implemented nonlinear curve-fitting methods that robustly estimate the allele frequency decay from batch sequencing of pooled individuals and derive chromosome-wide genetic distance and recombination rates. Empirically, we show that marker-selected pools closely recapitulate genetic distances inferred from scoring recombinants. Using this method, we generated novel recombination rate maps of three wild-derived strains of Drosophila melanogaster, which strongly correlate with previous measurements. Moreover, we show that this approach can be extended to estimate chromosome-wide crossover interference with reciprocal marker selection and discuss how it can be applied in the absence of visible markers. Altogether, we find that our method is a simple and cost-effective approach to generate chromosome-wide recombination rate maps requiring only one or two libraries.     

Involvement of midkine expression in the inhibitory effects of low-frequency magnetic fields on cancer cells

Effects of magnetic fields (MFs) on cancer cells may depend on cell type and exposure conditions. Gene expression levels are different among cancer cells. However, the effect of MFs on cancer cells with different gene expressions is still unclear. In this study, the cancer cell lines BGC-823, MKN-45, MKN-28, A549, SPC-A1, and LOVO were exposed to a low-frequency MF. Specific parameters of MFs were determined. Furthermore, the potential of the MF to influence cancer cell growth with midkine (MK) expression was evaluated. Cell proliferation and cell cycle were detected using the CCK-8 assay and flow cytometry. Cell ultrastructure was observed by transmission electron microscopy. BGC-823 cells with over-expression of MK (BGC-MK cells) and stanniocalcin-1 were generated by plasmid construction and transfection. Results showed that exposure to a 0.4-T, 7.5 Hz MF inhibited the proliferation of BGC-823, MKN-28, A549, and LOVO cells, but not MKN-45 and SPC-A1 cells. Moreover, the inhibitory effect of the MF on BGC-MK cells was lower (12.3%) than that of BGC-823 cells (20.3%). Analysis of the cell cycle showed that exposure to the MF led to a significant increase in the S phase in BGC-823 cells, but not in BGC-MK cells. In addition, organelle morphology was modified in BGC-823 cells exposed to the MF. These results suggest that exposure to a 0.4-T, 7.5 Hz MF could inhibit tumor cell proliferation and disturb the cell cycle. The alteration of MK expression in cancer cells may be related to the inhibitory effect of the MF on these cells.     

Ciliary beat co-ordination by calcium

Motile cilia in the airway epithelium are the engine for mucociliary clearance, the mechanism responsible for cleaning the airways from inhaled particles. Human airway epithelial cilia appear to have a slow constitutive rate of beating, driven by inherent and spontaneous dynein ATPase activity. Additionally, cilia can increase their beating frequency by activation of several different control mechanisms. One of these controllers is calcium. Its intracellular concentration is regulated by purinergic and acetylcholine receptors. Besides the rate regulatory effect of calcium on ciliary beat, calcium is also involved in synchronizing the beat among cilia of one single cell as well as between cilia on different cells. This article gives an overview of the complex effects of calcium on the beating of motile cilia in the airways.     

Mechanisms of mammalian ciliary motility: Insights from primary ciliary dyskinesia genetics

Motile cilia and flagella are organelles that, historically, have been poorly understood and inadequately investigated. However, cilia play critical roles in fluid clearance in the respiratory system and the brain, and flagella are required for sperm motility. Genetic studies involving human patients and mouse models of primary ciliary dyskinesia over the last decade have uncovered a number of important ciliary proteins and have begun to elucidate the mechanisms underlying ciliary motility. When combined with genetic, biochemical, and cell biological studies in Chlamydomonas reinhardtii, these mammalian genetic analyses begin to reveal the mechanisms by which ciliary motility is regulated.     

Thermal responses of juvenile squaretail mullet (Liza vaigiensis) and juvenile crescent terapon (Terapon jarbua) acclimated at near-lethal temperatures, and the implications for climate change

The negative effects of climate alteration on coral reef fishes receive ever increasing attention; however, implications of rising sea temperatures on fishes inhabiting marine nursery environments are poorly understood. We used critical thermal methodology to quantify critical thermal maxima (CTmaxima) of juvenile squaretail mullet (Liza vaigiensis) and juvenile crescent terapon (Terapon jarbua) captured from shallow seagrass nursery areas around Hoga Island, southeast Sulawesi, Indonesia. We tested the hypothesis that these distantly related fishes, when acclimated to cycling temperatures, would display higher CTmaxima than groups acclimated at constant temperatures. Groups of mullet acclimated to a constant temperature of 37 °C and temperature cycles of 35 to 39 °C or 37 to 41 °C displayed statistically similar mean CTmaxima of 44.7, 44.4 and 44.8 °C, respectively. Likewise, terapon acclimated at temperature cycles of 37 to 40 °C did not display a higher CTmaxima than fish acclimated at a constant temperature of 37 °C, with both acclimation groups' mean CTmaxima equal to 43.8 °C. Acclimation to higher cycling temperatures did not result in significant upper temperature tolerance acquisition for either species; however, mullet values were significantly higher than those seen in terapon (P < 0.0001). These data suggest that mullet and terapon will not suffer direct thermal effects should shallow nursery temperature increases be marginally higher than 1-2 °C above ~ 27 °C, and they provide evidence that the upper thermal tolerance of fishes inhabiting shallow seagrass and mangrove areas can approach the biokinetic limits for vertebrate life. Tropical marine fishes inhabiting fringing nursery environments may have the upper thermal tolerance necessary to endure substantial increases in sea temperatures.     

Respiratory pattern transitions in three species of Glossina (Diptera, Glossinidae)

Glossina exhibit cyclic (^CYCGE) or continuous gas exchange (^CONGE) patterns at rest. However, the factors influencing the transition from one pattern to another are not well understood for these or other insect species. This study examines which factors could aid in predicting the presence or absence of ^CYCGE in adults of three Glossina species: G. palpalis, G. brevipalpis and G. austeni. We report the results of temperature effects on VCO₂, pattern type and the proportion of a population showing ^CYCGE, and the prediction of ^CYCGE versus ^CONGE in Glossina. First, we investigated the influence of temperature on VCO₂ and found significant elevation in resting metabolic rate (RMR) with higher temperature in all three species (P < 0.001). Temperature-induced increases in VCO₂ were modulated by increased burst volume and by cycle frequency, except in G. brevipalpis which only appeared to modulate burst volume. These results are largely in keeping with VCO₂ modulation reported for other Glossina species previously. Second, elevating temperature resulted in significantly reduced numbers of individuals showing ^CYCGE (P < 0.001 for all three species) contrary to previous reports for other Glossing species. Finally, we examined a range of variables as potential predictors of presence or absence of ^CYCGE in these three species. Using an information theoretic approach (Akaike weights) to select the best explanatory combination of variables which predicts likelihood of ^CYCGE, we found that results varied among species. When species were pooled, the simplest, best-fit model (ΔAIC < 2 from the best model, 44.4% probability of being the best model) for predicting pattern type variation was RMR. Overall these results suggest that RMR is a key variable driving pattern type and that elevated temperature reduces the number of individuals showing cyclic patterns through elevation of RMR in these species. This study supports the idea that an interaction between cellular metabolic demand, morphological features of the gas exchange system (e.g. tracheal and spiracular conductances), and CO₂ buffer capacity likely determine gas exchange pattern variation over short time-scales.     

From physics to biology by extending criticality and symmetry breakings

Symmetries play a major role in physics, in particular since the work by E. Noether and H. Weyl in the first half of last century. Herein, we briefly review their role by recalling how symmetry changes allow to conceptually move from classical to relativistic and quantum physics. We then introduce our ongoing theoretical analysis in biology and show that symmetries play a radically different role in this discipline, when compared to those in current physics. By this comparison, we stress that symmetries must be understood in relation to conservation and stability properties, as represented in the theories. We posit that the dynamics of biological organisms, in their various levels of organization, are not “just” processes, but permanent (extended, in our terminology) critical transitions and, thus, symmetry changes. Within the limits of a relative structural stability (or interval of viability), variability is at the core of these transitions.     

Physicochemical characterization and functional site analysis of lactoferrin gene of Vechur cow

The Bos indicus Vechur breed cow milk is known for its medicinal value and the breed is listed under the category of critically maintained breeds by the Food and Agriculture Organization. The lactoferrin protein in milk is known for its nutritional value. Gene polymorphisms have been reported for Bovine lactoferrin. Mutations in the evolutionarily conserved sites tend to impair protein function and are related with the physicochemical difference between the known variants with 11 SNPs within the wild type. Structural differences are located due to these SNPs that may lead to functional variations. The structural variation is seen primarily in the first 48 residues at 5' end in all the samples modelled. Out of 11 SNPs 5 amino acid variations fall under alpha helix and beta sheet region, this might be of functional significance. This result may provide evidence that the SNPs detected in lactoferrin gene might have potential effects on milk composition. Our result demonstrates one major domain that could be a common binding pocket to all the samples, and important as an active site common to all the breeds that could be utilized for effective drug designing. Moreover, at some SNP positions in Vechur breed, antimicrobial peptides were located indicating importance of those residues for enhanced antimicrobial activity in lactoferrin of Vechur breed. Second binding pocket found in N- lobe region with the three required residues aspartic acid, histidine and tyrosine for iron binding, was considered as major binding site.