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Biomedical subjects

J S Evans

Publications and source records attributed to J S Evans.

At least 19 recordsLinked to original sources
PubMed2001

Ab initio structure determination of BiPb2VO6 from powder diffraction data.

The crystal structure of BiPb2VO6 has been determined from powder diffraction data using a combination of direct methods and the novel approach of applying simulated annealing methods simultaneously to X-ray and neutron data; BiPb2VO6 is a polar, noncentrosymmetric, second harmonic generation active material and its crystal structure is one of the more complex to be solved ab initio from powder diffraction data.

Journal Article↗
PubMed2001

Cytoplasmic interactions between phospholamban residues 1-20 and the calcium-activated ATPase of the sarcoplasmic reticulum.

Phospholamban regulates the activity of the calcium-activated ATPase (CaATPase) of cardiac sarcoplasmic reticulum. Equilibrium fluorescence studies have shown that the N-terminal cytoplasmic region of phospholamban (residues 1-20, domain 1) causes a decrease in the intrinsic tryptophan fluorescence of the CaATPase. The interaction of phospholamban residues 1-20 with the CaATPase also results in spectral changes for the extrinsic chromophore FITC covalently attached to the cytoplasmic region of the calcium pump. The fluorescence changes for both reporter groups correlate with a dissociation constant of approximately 40 microM for the complex between phospholamban residues 1-20 and the CaATPase. Complex formation is notably weaker when phospholamban 1-20 is titrated into the CaATPase in the presence of calcium, with altered conformational effects resulting from binding. The interaction of domain 1 of phospholamban with the CaATPase is also reduced upon phosphorylation of phospholamban 1-20 at Ser-16. This region of phospholamban 1-20 is shown by isotope-edited NMR study to be involved in interaction with the CaATPase. Binding of the phosphorylated peptide is not abolished, however, indicating that phospholamban 1-20 remains associated with the CaATPase even after phosphorylation. The data provide direct evidence for the interaction between the cytoplasmic regions of phospholamban and the pump, and are discussed in the context of the mechanism for inhibition of cardiac CaATPase activity by phospholamban.

Animals↗
PubMed2001

Modeling AFM-induced PEVK extension and the reversible unfolding of Ig/FNIII domains in single and multiple titin molecules.

Molecular elasticity is associated with a select number of polypeptides and proteins, such as titin, Lustrin A, silk fibroin, and spider silk dragline protein. In the case of titin, the globular (Ig) and non-globular (PEVK) regions act as extensible springs under stretch; however, their unfolding behavior and force extension characteristics are different. Using our time-dependent macroscopic method for simulating AFM-induced titin Ig domain unfolding and refolding, we simulate the extension and relaxation of hypothetical titin chains containing Ig domains and a PEVK region. Two different models are explored: 1) a series-linked WLC expression that treats the PEVK region as a distinct entropic spring, and 2) a summation of N single WLC expressions that simulates the extension and release of a discrete number of parallel titin chains containing constant or variable amounts of PEVK. In addition to these simulations, we also modeled the extension of a hypothetical PEVK domain using a linear Hooke's spring model to account for "enthalpic" contributions to PEVK elasticity. We find that the modified WLC simulations feature chain length compensation, Ig domain unfolding/refolding, and force-extension behavior that more closely approximate AFM, laser tweezer, and immunolocalization experimental data. In addition, our simulations reveal the following: 1) PEVK extension overlaps with the onset of Ig domain unfolding, and 2) variations in PEVK content within a titin chain ensemble lead to elastic diversity within that ensemble.

Amino Acid Sequence↗
PubMed2001

Necessity, possibility and belief: a study of syllogistic reasoning.

The present study extended the investigation of the belief bias effect in syllogistic reasoning in two ways: (1) The effect was studied under instructions to decide whether conclusions were possible, as well as necessary, given the premises; and (2) the effect was studied for types of syllogism where people rarely endorse the conclusions as well as those (valid and fallacious) where endorsements are common. Three experiments are reported, which show first that there is a marked tendency to reject unbelievable conclusions relative to abstract or neutral controls on all kinds of syllogism and under both types of instruction. There was also significant evidence of positive belief bias (increased acceptance of believable conclusions) and of interactions between belief bias effects and logical form. The results are discussed with particular respect to accounts of belief bias offered by theorists in the mental-model tradition.

Cognition↗
PubMed2001

Limitations to empirical extrapolation studies: the case of BMD ratios.

Extrapolation relationships are of keen interest to chemical risk assessment in which they play a prominent role in translating experimentally derived (usually in animals) toxicity estimates into estimates more relevant to human populations. A standard approach for characterizing each extrapolation relies on ratios of pre-existing toxicity estimates. Applications of this "ratio approach" have overlooked several sources of error. This article examines the case of ratios of benchmark doses, trying to better understand their informativeness. The approach involves mathematically modeling the process by which the ratios are generated in practice. Both closed form and simulation-based models of this "data-generating process" (DGP) are developed, paying special attention to the influence of experimental design. The results show the potential for significant limits to informativeness, and revealing dependencies. Future applications of the ratio approach should take imprecision and bias into account. Bootstrap techniques are recommended for gauging imprecision, but more complicated techniques will be required for gauging bias (and capturing dependencies). Strategies for mitigating the errors are suggested.

Animals↗
PubMed2001

Reproductive and developmental risks from ethylene oxide: a probabilistic characterization of possible regulatory thresholds.

Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.

Animals↗
PubMed2001

Assessing the public health benefits of reduced ozone concentrations.

In this paper we examine scientific evidence and related uncertainties in two steps of benefit-cost analyses of ozone reduction: estimating the health improvements attributable to reductions in ozone and determining the appropriate monetary values of these improvements. Although substantial evidence exists on molecular and physiologic impacts, the evidence needed to establish concentration-response functions is somewhat limited. Furthermore, because exposure to ozone depends on factors such as air conditioning use, past epidemiologic studies may not be directly applicable in unstudied settings. To evaluate the evidence likely to contribute significantly to benefits, we focus on four health outcomes: premature mortality, chronic asthma, respiratory hospital admissions, and minor restricted activity days. We determine concentration-response functions for these health outcomes for a hypothetical case study in Houston, Texas, using probabilistic weighting reflecting our judgment of the strength of the evidence and the possibility of confounding. We make a similar presentation for valuation, where uncertainty is due primarily to the lack of willingness-to-pay data for the population affected by ozone. We estimate that the annual monetary value of health benefits from reducing ozone concentrations in Houston is approximately $10 per person per microgram per cubic meter (24-hr average) reduced (95% confidence interval, $0.70-$40). The central estimate exceeds past estimates by approximately a factor of five, driven by the inclusion of mortality. We discuss the implications of our findings for future analyses and determine areas of research that might help reduce the uncertainties in benefit estimation.

Activities of Daily Living↗
PubMed2000

Frequency versus probability formats in statistical word problems.

Three experiments examined people's ability to incorporate base rate information when judging posterior probabilities. Specifically, we tested the (Cosmides, L., & Tooby, J. (1996). Are humans good intuitive statisticians after all? Rethinking some conclusions from the literature on judgement under uncertainty. Cognition, 58, 1-73) conclusion that people's reasoning appears to follow Bayesian principles when they are presented with information in a frequency format, but not when information is presented as one case probabilities. First, we found that frequency formats were not generally associated with better performance than probability formats unless they were presented in a manner which facilitated construction of a set inclusion mental model. Second, we demonstrated that the use of frequency information may promote biases in the weighting of information. When participants are asked to express their judgements in frequency rather than probability format, they were more likely to produce the base rate as their answer, ignoring diagnostic evidence.

Adult↗
PubMed2000

Model peptide studies of sequence repeats derived from the intracrystalline biomineralization protein, SM50. II. Pro,Asn-rich tandem repeats.

In the biomineralization process, a number of Pro-rich proteins participate in the formation of three-dimensional supramolecular structures. One such protein superfamily, the Pro,Gly-rich sea urchin intracrystalline spicule matrix proteins, form protein-protein supramolecular assemblies that modify the microstructure of the inorganic mineral phase (calcite) within embryonic sea urchin spicules and adult sea urchin spines. These proteins represent a useful model for understanding Pro sequence usage and the resulting generation of extended or "open" structures for protein-protein and/or protein-crystal recognition. In the sea urchin spicule matrix protein, SM50 (Strongylocentrotus purpuratus), there exists an unusual 20-residue Pro,Asn-containing repeat, &bond;PNNPNNPNPNNPNNPNNPNPbond which links the upstream 15-residue C-terminal domain and the downstream 211-residue beta-spiral repeat domain. To define the structural preferences of this 20-residue repeat, we created a 20-residue N- and C-terminal "capped" peptidomimetic of this sequence. Using far-uv CD dichroism, CH(alpha) and alpha-(15)N conformational shifts, (3)J(NH-CHalpha) coupling constants, sequential d(NN(i, i + 1)) rotating frame nuclear Overhauser effect connectivities, d(alphaN(i, i + 1))/d(NN(i, i + 1)) intensity ratios, amide temperature shift coefficients, amide solvent exchange, and simulated annealing refinement protocols, we have determined that this 20-residue repeat motif adopts an extended "twist" structure consisting of turn- and coil-like regions. These findings are consistent with previous studies, which have shown that Pro-rich tandem repeats adopt extended, flexible structures in solution. We hypothesize that this 20-residue repeat may fulfill the role of a mineral-binding domain, a protein-protein docking domain, or as an internal "molecular spacer" for the SM50 protein during spicule biocomposite formation.

Amino Acid Motifs↗
PubMed2000

Assessing the impact of differential measurement error on estimates of fine particle mortality.

In air pollution epidemiology, error in measurements of correlated pollutants has been advanced as a reason to distrust regressions that find statistically significant weak associations. Much of the related debate in the literature and elsewhere has been qualitative. To promote quantitative evaluation of such errors, this paper develops an air pollution time-series model based on correlations among unit-normal variables. Assuming there are no other sources of bias present, the model shows the expected amount of relative bias in the regression coefficients of a bivariate regression of coarse and fine particulate matter measurements on daily mortality. The model only requires information on instrumental error and spatial variability, along with the observed regression coefficients and information on the true fine-course correlation. Analytical results show that if one pollutant is truly more harmful than the other, then it must be measured more precisely than the other in order not to bias the ratio of the fine and course regression coefficients. Utilizing published data, a case study of the Harvard Six-Cities study illustrates use of the model and emphasizes the need for data on spatial variability across the study area. Current epidemiology time-series regressions can use this model to address the general concern of correlated pollutants with differing measurement errors.

Air Pollutants↗
PubMed2000

Exposure efficiency: concept and application to perchloroethylene exposure from dry cleaners.

Standard approaches for computing population exposures due to specific sources of air pollutants are relatively complex. In many cases, more simple and approximate methods would be useful. This paper develops an approach, based on the concept of exposure efficiency, that may be used for estimating the impact of a source (or source class) on the integrated population exposure. The approach is illustrated by an example, which uses the concept of exposure efficiency to examine the impact of perchloroethylene emissions from dry cleaners in the United States. The paper explores the geographic variability of exposure efficiency by evaluating it for each of 100 randomly selected dry cleaners. For perchloroethylene, which has a long atmospheric residence time, the site-to-site variability in exposure efficiency is found to be relatively small. This suggests that simple exposure assessments, based on generic distributional characterizations of exposure efficiency, may be used in risk assessments without introducing appreciable uncertainty. For many compounds, like perchloroethylene, the uncertainty inherent in the estimation of cancer potency or source emissions would dominate these small errors.

Carcinogens↗
PubMed1999

Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well-characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Model peptide studies of sequence repeats derived from the intracrystalline biomineralization protein, SM50. I. GVGGR and GMGGQ repeats.

We report solution-state pulsed field gradient nmr studies of a native sequence-derived 23-residue peptidomimetic, N alpha-acetyl-QPGVGGRQPGMGGQPGVGGRQPG-C alpha-amid, that incorporates the prevalent GVGGR and GMGGQ repeats found in the sea urchin embryo intracrystalline spicule matrix protein, SM50 (Strongylocentrotus purpuratus). These repeats are sequence homologues of elastin protein repeats (VPGVG, VGGVG, and APGVGV) and spider dragline silk protein repeats (GPGG, GQGG, and QPGYG). Using rotating frame nuclear Overhauser effect (ROE) connectivities, CH alpha proton conformational shifts, 3JNH-CH alpha coupling constants, amide temperature shift coefficients, and pulsed field gradient ROE spectroscopy solvent exchange measurements, we find that the 23-mer peptidomimetic possesses a multiple beta-turn structure in aqueous solution, in equilibria with an extended or coil structure (60% beta-turn: 40% random coil). The GVGGR sequence adopts a double beta-turn conformation that is stabilized by two hydrogen bonds (R7-->V4, R20-->V17; G6-->G3, G19-->G16). The GMGGQ region adopts a single beta-turn conformation that is stabilized by a hydrogen bond involving residues Q14 and M11. Repeating beta-turn structures, or beta-spirals, may play an important role with regard to matrix assembly, protein stability, molecular elasticity, and/or protein-crystal recognition within the spicule mineralized matrix.

Amino Acid Sequence↗
PubMed1999

PFG-omega1-filtered TOCSY experiments for the determination of long-range heteronuclear and homonuclear coupling constants and estimation of J-coupling "crosstalk" artifacts in 2-D omega1-filtered "E. COSY-style" spectra.

We present novel one- and two-dimensional versions of the omega1-filtered TOCSY experiment. These experiments utilize pulsed-field gradient techniques and INEPT-reverse INEPT magnetization transfer to generate heteronuclear filtering by means of coherence pathway selection. The major advantages of this approach are twofold: first, each experiment requires a reasonable number of transmitter pulses, gradient pulses, and delays to implement. Second, the use of z-axis gradients at the beginning and termination of the pulse sequences prevents the recovery of dephased magnetization prior to FID detection. This technique was incorporated into 1-D and 2-D omega1-filtered JXH- and JHH-TOCSY-style experiments. As demonstrated on 15N-enriched peptide samples, the use of the pulsed-field-gradient coherence selection scheme effectively filters out unwanted magnetization components, thereby improving the overall sensitivity of the experiments. In addition to this suite of pulse sequences, we also present a method for correcting the reduction in J-coupling that results from crosspeak shifting in 2-D omega1-filtered E. COSY-style spectra. This correction is applicable to both Lorentzian and Gaussian 2-D crosspeak lineshapes.

Humans↗
PubMed1999

A kinetic molecular model of the reversible unfolding and refolding of titin under force extension.

Molecular elasticity is a physicomechanical property that is associated with a select number of polypeptides and proteins, such as the giant muscle protein, titin, and the extracellular matrix protein, tenascin. Both proteins have been the subject of atomic force microscopy (AFM), laser tweezer, and other in vitro methods for examining the effects of force extension on the globular (FNIII/Ig-like) domains that comprise each protein. In this report we present a time-dependent method for simulating AFM force extension and its effect on FNIII/Ig domain unfolding and refolding. This method treats the unfolding and refolding process as a standard three-state protein folding model (U right arrow over left arrow T right arrow over left arrow F, where U is the unfolded state, T is the transition or intermediate state, and F is the fully folded state), and integrates this approach within the wormlike chain (WLC) concept. We simulated the effect of AFM tip extension on a hypothetical titin molecule comprised of 30 globular domains (Ig or FNIII) and 25% Pro-Glu-Val-Lys (PEVK) content, and analyzed the unfolding and refolding processes as a function of AFM tip extension, extension rate, and variation in PEVK content. In general, we find that the use of a three-state protein-folding kinetic-based model and the implicit inclusion of PEVK domains can accurately reproduce the experimental force-extension curves observed for both titin and tenascin proteins. Furthermore, our simulation data indicate that PEVK domains exhibit extensibility behavior, assist in the unfolding and refolding of FNIII/Ig domains in the titin molecule, and act as a force "buffer" for the FNIII/Ig domains, particularly at low and moderate extension forces.

Amino Acid Sequence↗
PubMed1999

Estimating noncancer uncertainty factors: are ratios NOAELs informative?

The prominent role of animal bioassay evidence in environmental regulatory decisions compels a careful characterization of extrapolation uncertainties. In noncancer risk assessment, uncertainty factors are incorporated to account for each of several extrapolations required to convert a bioassay outcome into a putative subthreshold dose for humans. Measures of relative toxicity taken between different dosing regimens, different endpoints, or different species serve as a reference for establishing the uncertainty factors. Ratios of no observed adverse effect levels (NOAELs) have been used for this purpose; statistical summaries of such ratios across sets of chemicals are widely used to guide the setting of uncertainty factors. Given the poor statistical properties of NOAELs, the informativeness of these summary statistics is open to question. To evaluate this, we develop an approach to "calibrate" the ability of NOAEL ratios to reveal true properties of a specified distribution for relative toxicity. A priority of this analysis is to account for dependencies of NOAEL ratios on experimental design and other exogenous factors. Our analysis of NOAEL ratio summary statistics finds (1) that such dependencies are complex and produce pronounced systematic errors and (2) that sampling error associated with typical sample sizes (50 chemicals) is nonnegligible. These uncertainties strongly suggest that NOAEL ratio summary statistics cannot be taken at face value; conclusions based on such ratios reported in well over a dozen published papers should be reconsidered.

Algorithms↗
PubMed1999

Update on medications used to treat gastrointestinal disease in children.

Progress in the pharmacotherapy of pediatric gastrointestinal diseases continued during 1998 despite ongoing obstacles encountered by clinicians and researchers. The major change involved warnings that cisapride, a widely used prokinetic agent, could cause potentially fatal arrythmias in susceptible people. The risk for children is unclear and a consensus of prescribing guidelines is needed. Excellent pediatric-oriented reviews have been published that summarize our knowledge of proton pump inhibitors, probiotics, 5-hydroxtryptamine-3 (5-HT3) antagonists, and the treatment of gastrointestinal infections and chronic abdominal pain. Triple medication therapy for the eradication of Helicobacter pylori is now the standard of care, but the optimal combination and duration of therapy needs to be determined. Also described are interesting developments requiring further confirmation: the treatments of infectious diarrhea with zinc; achalasia and Hirschsprung's disease with botulinum toxin; weight loss with megestrol acetate; and sialorrhea with glycopyrollate.

Anti-Bacterial Agents↗