Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons

<p>Abstract</p> <p>Members of the NR1I subfamily of nuclear receptors play a role in the transcriptional activation of genes involved in drug metabolism and transport. NR1I3, the constitutive androstane receptor (CAR), mediates the induction of several genes involved in drug response, including members of the <it>CYP3A</it>, <it>CYP2B </it>and <it>UGT1A </it>subfamilies. Large inter-individual variation in drug clearance has been reported for many drug metabolising enzyme genes. Sequence variation at the <it>CAR </it>locus could potentially contribute to variation in downstream targets, as well as to the substantial variation in expression level reported. We used a comparative genomics-based approach to select resequencing segments in 70 subjects from three populations. We identified 21 polymorphic sites, one of which results in an amino acid substitution. Our study reveals a common haplotype shared by all three populations which is remarkably similar to the ancestral sequence, confirming that CAR is under strong functional constraints. The level and pattern of sequence variation is approximately similar across populations, suggesting that interethnic differences in drug metabolism are not likely to be due to genetic variation at the <it>CAR </it>locus. We also identify several common non-coding variants that occur at highly conserved sites across four major branches of the mammalian phylogeny, suggesting that they may affect <it>CAR </it>expression and, ultimately, the activity of its downstream targets.</p

Prevention of diagonal tension failures in beams using a flexure—shear interaction approach

The development of a flexure–shear interaction design model for the prevention of the diagonal tension failure in beams is described in this paper. The model is based on the understanding that failure of structural concrete members occurs as a result of the development of critical tensile stresses in the compression region of the beam structure. In this model, confining the concrete compression region with closed stirrups prevented this type of failure. The enhancement of the concrete strength due to the confining influence of the stirrups was utilized to offset the reduction in the flexural capacity of beams due to the effects of shear. The results from tests on 24 specially designed beams were used in the development of the flexure–shear model. The programme of experimental work for the validation of the proposed model consisted of ten full-size rectangular beams, which were selected to cover the entire range of Kani's valley. The test results confirmed the applicability and the efficiency of the proposed design model. </jats:p

Shear and flexural strengths resulting from confinement of the compression regions in circular section structural concrete beams

This paper examines the effect of confinement of the compression regions on the behaviour of structural concrete beams with circular cross-sections. The programme of experimental work included eight 200 mm diameter beams traditionally designed to resist shear; however, the stimy, configurations inseveral of the beams were determined by the shape of the compressive force path. The results obtained from the test programme confirmed that the confined compression concrete regions in such beams are the main contributors to shear resistance and that the development of truss action is not necessarily required to transmit the applied loads to the support. It is concluded that the enhancement of the concrete strength in the compression regions due to the confining influence of the stirrups offsets the reduction in the flexural capacity of the beams due to the shear effects. The flexural capacity and ductility of the beams resulting from confinement were found to be higher than the corresponding values for traditionally detailed beams. A flexural-shear interaction model has been derived from a more general approach to determine the number of confinement stirrups required to prevent diagonal failures and also to evaluate the flexural strength of such beams. There was good agreement between the results obtained from the model and those obtained from the test programme. Eight structural concrete 200 mm diameter beams reinforced with semi-circular and/or circular shaped stirrups, were included in the investigation. The shape of the compressive force path was used to determine the stirrup configurations in several of the beams. The experimental results indicated that the ductility and strength of these beams were more than 50% and up to 32 % (depending on the level of confinement) greater than found in beams detailed according to current Code provisions. A flexure—shear interactive analytical model which recognizes the importance of the compression concrete in resisting lateral loads was found to closely predict the results obtained from the investigation. </jats:p

Prevention of diagonal tension failures in beams using a flexure - shear interaction approach

The development of a flexure–shear interaction design model for the prevention of the diagonal tension failure in beams is described in this paper. The model is based on the understanding that failure of structural concrete members occurs as a result of the development of critical tensile stresses in the compression region of the beam structure. In this model, confining the concrete compression region with closed stirrups prevented this type of failure. The enhancement of the concrete strength due to the confining influence of the stirrups was utilized to offset the reduction in the flexural capacity of beams due to the effects of shear. The results from tests on 24 specially designed beams were used in the development of the flexure–shear model. The programme of experimental work for the validation of the proposed model consisted of ten full-size rectangular beams, which were selected to cover the entire range of Kani's valley. The test results confirmed the applicability and the efficiency of the proposed design model

CYP3A Variation and the Evolution of Salt-Sensitivity Variants

Members of the cytochrome P450 3A subfamily catalyze the metabolism of endogenous substrates, environmental carcinogens, and clinically important exogenous compounds, such as prescription drugs and therapeutic agents. In particular, the CYP3A4 and CYP3A5 genes play an especially important role in pharmacogenetics, since they metabolize >50% of the drugs on the market. However, known genetic variants at these two loci are not sufficient to account for the observed phenotypic variability in drug response. We used a comparative genomics approach to identify conserved coding and noncoding regions at these genes and resequenced them in three ethnically diverse human populations. We show that remarkable interpopulation differences exist with regard to frequency spectrum and haplotype structure. The non-African samples are characterized by a marked excess of rare variants and the presence of a homogeneous group of long-range haplotypes at high frequency. The CYP3A5*1/*3 polymorphism, which is likely to influence salt and water retention and risk for salt-sensitive hypertension, was genotyped in >1,000 individuals from 52 worldwide population samples. The results reveal an unusual geographic pattern whereby the CYP3A5*3 frequency shows extreme variation across human populations and is significantly correlated with distance from the equator. Furthermore, we show that an unlinked variant, AGT M235T, previously implicated in hypertension and pre-eclampsia, exhibits a similar geographic distribution and is significantly correlated in frequency with CYP3A5*1/*3. Taken together, these results suggest that variants that influence salt homeostasis were the targets of a shared selective pressure that resulted from an environmental variable correlated with latitude