An intrinsic curvature towards the minor groove in the cAMP-responsive element DNA found by combined NMR and molecular modelling studies.
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The cAMP-responsive element (CRE, 5'-TGACGTCA-3') is essential to the transcriptional function of numerous gene promoters in eukaryotic cells. We carried out NMR restrained molecular mechanics studies using two different force fields (Flex and "AMBER94") on a hexadecanucleotide d(GAGATGACGTCATCTC) containing CRE. Results indicated that free CRE is a B-DNA that is intrinsically curved towards the minor groove. To our knowledge, NMR restraints have not previously been useful in accounting for a global DNA curvature. In order to validate the bend in CRE, we applied a new strategy in which DNA structures displaying different curvatures were generated and then compared with NMR data. Conformations of CRE curved towards the minor groove provided the best agreement with NMR data. Our results contrast with previous results obtained from NMR restrained modelling and gel methods; these suggested conformations that were straight or curved towards the major groove, respectively. The curve in free CRE is spread along the DNA helix: several kinks are repeated in phase within the helical turn, although they are centred mainly on CpG in between the TGA half-sites, thus slightly increasing their spacing within the major groove. Comparison with the crystal structure of CRE complexed to general control protein 4 showed that the curve orientation is reversed from the minor to the major groove upon protein binding, due to a helix distortion concentrated mainly on CpG. (+info)
An apparent excess of sex- and reproduction-related genes on the human X chromosome.
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We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose-dependent processes, the number of such genes necessary to be regulated in a dose-dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian-marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage. (+info)
A quantitative method for the detection of edges in noisy time-series.
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A modification of the edge detector of Chung & Kennedy is proposed in which the output provides confidence limits for the presence or absence of sharp edges (steps) in the input waveform. Their switching method with forward and backward averaging windows is retained, but the output approximates an ideal output function equal to the difference in these averages divided by the standard deviation of the noise. Steps are associated with peak output above a pre-set threshold. Formulae for the efficiency and reliability of this ideal detector are derived for input waveforms with Gaussian white noise and sharp edges, and serve as benchmarks for the switching edge detector. Efficiency is kept high if the threshold is a fixed fraction of the step size of interest relative to noise, and reliability is improved by increasing the window width W to reduce false output. For different steps sizes D, the window width for fixed efficiency and reliability scales as 1/D2. Versions with weighted averaging (flat, ramp, triangular) or median averaging but the same window width perform similarly. Binned above-threshold output is used to predict the locations and signs of detected steps, and simulations show that efficiency and reliability are close to ideal. Location times are accurate to order square root of W. Short pulses generate reduced output if the number of data points in the pulse is less than W. They are optimally detected by choosing W as above and collecting data at a rate such that the pulse contains approximately W data points. A Fortran program is supplied. (+info)
Bayesian mapping of multiple quantitative trait loci from incomplete outbred offspring data.
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A general fine-scale Bayesian quantitative trait locus (QTL) mapping method for outcrossing species is presented. It is suitable for an analysis of complete and incomplete data from experimental designs of F2 families or backcrosses. The amount of genotyping of parents and grandparents is optional, as well as the assumption that the QTL alleles in the crossed lines are fixed. Grandparental origin indicators are used, but without forgetting the original genotype or allelic origin information. The method treats the number of QTL in the analyzed chromosome as a random variable and allows some QTL effects from other chromosomes to be taken into account in a composite interval mapping manner. A block-update of ordered genotypes (haplotypes) of the whole family is sampled once in each marker locus during every round of the Markov Chain Monte Carlo algorithm used in the numerical estimation. As a byproduct, the method gives the posterior distributions for linkage phases in the family and therefore it can also be used as a haplotyping algorithm. The Bayesian method is tested and compared with two frequentist methods using simulated data sets, considering two different parental crosses and three different levels of available parental information. The method is implemented as a software package and is freely available under the name Multimapper/outbred at URL http://www.rni.helsinki.fi/mjs/. (+info)
Computer analysis of qualitative data: the use of ethnograph.
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Ethnograph, a code and retrieve software program for computer analysis of qualitative data, was utilized to assist in analyzing the content of in-depth interviews and focus group data. This program requires basic computer hardware and is fairly easy to use. The main advantage of the program is easy access to data dealing with a particular issue and easy retrieval of text for analysis and illustration. However, to get the maximum benefit from this program, documents need to be structured In the format suitable for the software. Among the difficulties encountered were the absence of on-line documents dummy coding, lack of options in printing facility and the tendency for the program to hang whenever there was a printing error. (+info)
A reassessment of the cost-effectiveness of water and sanitation interventions in programmes for controlling childhood diarrhoea.
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Cost-effectiveness analysis indicates that some water supply and sanitation (WSS) interventions are highly cost-effective for the control of diarrhoea among under-5-year-olds, on a par with oral rehydration therapy. These are relatively inexpensive "software-related" interventions such as hygiene education, social marketing of good hygiene practices, regulation of drinking-water, and monitoring of water quality. Such interventions are needed to ensure that the potentially positive health impacts of WSS infrastructure are fully realized in practice. The perception that WSS programmes are not a cost-effective use of health sector resources has arisen from three factors: an assumption that all WSS interventions involve construction of physical infrastructure, a misperception of the health sector's role in WSS programmes, and a misunderstanding of the scope of cost-effectiveness analysis. WSS infrastructure ("hardware") is generally built and operated by public works agencies and financed by construction grants, operational subsidies, user fees and property taxes. Health sector agencies should provide "software" such as project design, hygiene education, and water quality regulation. Cost-effectiveness analysis should measure the incremental health impacts attributable to health sector investments, using the actual call on health sector resources as the measure of cost. The cost-effectiveness of a set of hardware and software combinations is estimated, using US$ per case averted, US$ per death averted, and US$ per disability-adjusted life year (DALY) saved. (+info)
Comparison of cephalometric analysis using a non-radiographic sonic digitizer (DigiGraph Workstation) with conventional radiography.
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Cephalometric analysis conventionally requires radiographic exposure which may not be compatible with the growing concern over radiation hazards. Recently, the Dolphin Workstation Imaging System introduced to the dental profession a non-radiographic system, called the DigiGraph Workstation which may be an alternative to cephalometric radiography. The aims of this study were to compare the validity and reproducibility of cephalometric measurements obtained from the DigiGraph Workstation with conventional cephalometric radiographs. The sample consisted of 30 human dry skulls. Two replicated sets of lateral cephalograms were obtained with steel ball markers placed at the majority of the cephalometric landmarks. Duplicate tracings prepared from each radiograph were digitized to obtain cephalometric measurements using the computer software, Dentofacial Planner. For the DigiGraph Workstation, double sonic digitizations were repeated twice for each skull, on two occasions. Fifteen angular and one linear measurements were obtained from both methods and these findings compared using ANOVA, paired t-tests and F-tests. All, except one, cephalometric measurement showed significant differences between the two methods (P < 0.0001). The DigiGraph Workstation consistently produced higher values in 11 measurements (mean differences +0.5 to +15.7 degrees or mm) and lower values in four measurements (mean differences -0.2 to -3.5 degrees). The standard deviations of the differences between readings of both methods were large (0.4-5.8 degrees or mm). The reproducibility of the DigiGraph Workstation measurements was lower than that of the radiographic measurements. The method error of the DigiGraph Workstation ranged from 7 to 70 per cent, while that of radiographic tracings was less than 2 per cent. It was concluded that measurements obtained with the DigiGraph Workstation should be interpreted with caution. (+info)
Power and sample size calculations in case-control studies of gene-environment interactions: comments on different approaches.
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Power and sample size considerations are critical for the design of epidemiologic studies of gene-environment interactions. Hwang et al. (Am J Epidemiol 1994;140:1029-37) and Foppa and Spiegelman (Am J Epidemiol 1997;146:596-604) have presented power and sample size calculations for case-control studies of gene-environment interactions. Comparisons of calculations using these approaches and an approach for general multivariate regression models for the odds ratio previously published by Lubin and Gail (Am J Epidemiol 1990; 131:552-66) have revealed substantial differences under some scenarios. These differences are the result of a highly restrictive characterization of the null hypothesis in Hwang et al. and Foppa and Spiegelman, which results in an underestimation of sample size and overestimation of power for the test of a gene-environment interaction. A computer program to perform sample size and power calculations to detect additive or multiplicative models of gene-environment interactions using the Lubin and Gail approach will be available free of charge in the near future from the National Cancer Institute. (+info)