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PubMed1996

An efficient method for sampling the essential subspace of proteins.

A method is presented for a more efficient sampling of the configurational space of proteins as compared to conventional sampling techniques such as molecular dynamics. The method is based on the large conformational changes in proteins revealed by the "essential dynamics" analysis. A form of constrained dynamics is performed, forcing the system to move along some of the essential coordinates. This results in a broader sampling of the essential subspace than in a comparable conventional molecular dynamics simulation without constraints. The new sampling method (essential dynamics sampling) was applied to the histidine-containing phosphocarrier protein HPr. The results indicate that the essential dynamics sampling method produces physically allowed structures, as estimated by the evaluation of many geometrical properties. In addition, a study of the motions in the essential subspace reveals a diffusion-like behavior.

Bacterial Proteins↗
PubMed1998

Computational analysis of the thermal stability in thioredoxins: a molecular dynamics approach.

The knowledge of the relationship between the three-dimensional structure of a protein and its biological and stability is one of the most challenging problem in protein chemistry, since offers the possibility of changing both the specific action of a protein and its stability. In this work, we have approached the problem with studies on a protein family, the thioredoxins, using homology procedures, molecular dynamics simulations in vacuo at 300 K and 500 K and in water solution at 300 K, to determine the relationship between the three-dimensional structure of these proteins and their thermal stability. A comparative analysis, using computational approach, was performed between two thioredoxins with different resistance to temperature. Results obtained using the molecular dynamics techniques and minimization procedures give explanations of the experimental data, underlining that these techniques are able to correlate the increase in protein stabilization with the conformational and structural changes caused by single amino acid replacement. In addition, we report the factors that can be used as a guide in protein engineering and in site-directed mutagenesis to increase or decrease thermal stabilization for this protein family.

Amino Acid Sequence↗
PubMed1997

Robustness of bioequivalence procedures under Box-Cox alternatives.

This study investigates the robustness of Schuirmann's two one-sided tests procedure under a set of Box-Cox alternatives. A simulation is conducted to study the level of significance and the power of the procedure. Empirical results show that Schuirmann's procedure is robust under Box-Cox alternatives when the mean of the underlying distribution of the reference formulation is known, which suggests that the assumptions of normality or lognormality are sufficient but may not be necessary. It appears that Schuirmann's procedure cannot maintain the proper level of significance when the mean of the reference formulation is unknown, even under the normality or lognormality assumptions.

Chemistry, Pharmaceutical↗
PubMed1997

Variation of the peak concentration following single and repeated drug administrations in investigations of bioavailability and bioequivalence.

Contrasts were evaluated for the maximum blood or plasma concentration (C(max)) of drugs measured after repeated and single oral administrations. Variances of C(max) were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (CV) of C(max) was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k(a)). In turn, the CV of C(max) was substantially lower following repeated than after single drug administration when the variability of k(a) dominated that of k. The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k). The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C(max) following repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates.

Biological Availability↗
PubMed2005

Blood flow quantification in adults by phase-contrast MRI combined with SENSE--a validation study.

PURPOSE: To evaluate the feasibility of rapid free-breathing phase-contrast MRI (PC-MRI) at different in-plane resolutions combined with sensitivity encoding (SENSE) for flow quantification in the great arteries in healthy adult volunteers. METHODS: In 13 volunteers (mean age 33.0 +/- 7.4 years), blood flow rates in the pulmonary artery (Qp), ascending aorta (Qs), and flow ratio Qp/Qs were determined by PC-MRI with SENSE reduction-factor 2 and 3 (SF-2, SF-3). Additionally, we used PC-MRI with higher spatial in-plane resolution (1.6 x 2.1 mm vs. 2.3 x 3.1 mm) with/without SF-3. Standard (= reference) PC-MRI, which used two excitations (NEX=2), was compared with PC-MRI sequences with NEX=1. RESULTS: Reduction of signal averages and application of SENSE accelerated flow measurements by a factor of 3.8 (5.5) using PC-MRI with SF-2 (SF-3): Scan time was 36 sec (SF-2) and 25 sec (SF-3) at average heart rate of 69/min. The mean Qp/Qs by reference PC-MRI was 1.03 +/- 0.07 (range, 0.89-1.16), and 1.0 +/- 0.11 (range, 0.86-1.24) by PC-MRI + SF-3, respectively. For blood flow rate through the pulmonary artery and aorta, and for Qp/Qs ratio, we found differences of -3% to +4%. The lower limits of agreement (mean - 2 SD) ranged between -14% and -21%, and upper limits (mean + 2 SD) between +9% and +30%, demonstrating clinically acceptable agreement with standard PC-MRI (Bland-Altman analysis). PC-MRI at higher in-plane resolution both with/without SENSE yielded slightly smaller aortic and pulmonary flows (mean differences 5% to 7%, p < 0.05). CONCLUSIONS. In adults, PC-MRI may be safely combined with SENSE to reduce scan time for a quantitative flow measurement in the great arteries to "30 seconds. High in-plane resolution was not advantageous.

Adult↗
PubMed1981

The implementation of a generalised Batho inhomogeneity correction for radiotherapy planning with direct use of CT numbers.

A method for performing inhomogeneity corrections using a generalised Batho equation is described. The corrections are performed using the quantitative anatomical data produced by a CT scanner. The generalised Batho equation has been implemented on an EMIPLAN 7000 interactive treatment planning system. Details are given of the acquisition of the required data from the CT scan and from the existing stored beam data of the therapy machines.

Computers↗
PubMed2006

An inverse method to design RF coil arrays optimized for SENSE imaging.

A new method to design MRI RF coils that are optimized for SENSE (sensitivity encoding) imaging is introduced. In this approach, the inverse problem was solved where the surface current density distribution on a coil former was calculated to maximize the SNR(sense) within a volume of interest (VOI). For that purpose, an analytic relationship was formulated between the SNR(sense) and surface current density on the coil former. The SNR at pixel rho in a SENSE-MR image, SNR(sense,rho), is inversely proportional to the g-factor: therefore, the g-factor was formulated in terms of the B1 distribution of the coils. Then, by specifying the geometry of the desired coil former and using a finite element mesh (FEM), the surface current distribution was calculated to maximize the SNR(sense), by minimizing (1/SNR(sense)) in the VOI using a least squares procedure. A simple two-coil array was designed and built to test the method and phantom images were collected. The results show that the new coil design method yielded better uniformity and SNR in SENSE images compared to those of standard coils.

Algorithms↗
PubMedDate not supplied

Chronic ethanol consumption modulates myocardial ischaemia-reperfusion injury in murine AIDS.

AIMS: The severity of cardiovascular complications in acquired immune deficiency syndrome (AIDS) patients may be associated with acute ischaemia-reperfusion injury. Epidemiological studies suggest that moderate ethanol consumption has myocardial protective effects. However, it is unknown if chronic ethanol consumption benefits acute myocardial ischaemia-reperfusion injury in AIDS. The aim of this study was to determine if chronic ethanol consumption modulates myocardial ischaemia-reperfusion injury in murine AIDS. METHODS: Four groups were studied: control, murine AIDS, ethanol, and ethanol plus murine AIDS. All mice were subjected to 30 min of left anterior descending branch (LAD) occlusion and 120 min of reperfusion. RESULTS: We found that the survival from an acute myocardial infarction was reduced in advanced-stage murine AIDS mice. Although early-stage murine AIDS hearts did survive in acute myocardial infarction, the infarct size was significantly larger. Chronic ethanol consumption significantly decreased infarct size compared to the control group. Chronic ethanol consumption also improved the survival of murine AIDS mice from an acute myocardial infarction. However, chronic ethanol consumption did not significantly reduce infarct size in murine AIDS. CONCLUSIONS: Our results indicate that multiple deleterious effects may enhance acute ischaemia-reperfusion injury in murine AIDS. The beneficial effects of chronic ethanol consumption in myocardial ischaemia-reperfusion injury may be due to modulation of neutrophil adhesion molecule expression and cytokine secretion.

Alcohol Drinking↗
PubMedDate not supplied

MR volumetry during acute alcohol withdrawal and abstinence: a descriptive study.

AIMS: The brain volume of chronic drinkers is known to partially recover with abstinence from alcohol. To investigate the relative contribution of grey and white brain matter to this process, magnetic resonance imaging and brain tissue segmentation was used to study brain tissue in acute alcohol withdrawal and abstinence in seven alcohol-dependent men. METHODS: The patients were studied on three occasions; within 48 h after the last drink and approximately one month and two and a half months later. Total brain tissue class volumes [grey matter (GM) and white matter (WM) and cerebrospinal fluid (CSF)] were measured. Eleven healthy volunteers were scanned twice to serve as a control group. The alcohol-dependent patients were investigated with regard to drinking variables, neuropsychological performance and blood biochemistry. RESULTS: In the alcohol-dependent patients, intracranial volume and total GM volume did not change between scan occasions, except in a single patient who demonstrated a GM increase of 4.8% (4.2% relative volume) between scans 2 and 3. For all patients, the increase in total WM volume ranged between 1.9 and 22.4% (absolute volumes) and 2.1 and 21.2% (relative volumes). Between scans 2 and 3, the increase in total WM volume ranged between 0.3 and 13.2% (absolute volumes), and between 1.5 and 14.0% (relative volumes). One patient resumed drinking and was investigated a second time during acute withdrawal. In this patient, the measured decrease of 8.1 and 8.5% of absolute and relative WM volumes corresponded to the size of the volume increase between scans 1 and 2. CSF, GM and WM volumes in the healthy subjects were constant over time. CONCLUSIONS: The results demonstrate that changes in brain volume during short-term abstinence in chronic alcohol-dependent patients are confined to the WM. The time limit of WM volume restitution is variable and continues longer than 3 weeks after withdrawal.

Adult↗
PubMed2000

Inferring qualitative relations in genetic networks and metabolic pathways.

MOTIVATION: Inferring genetic network architecture from time series data of gene expression patterns is an important topic in bioinformatics. Although inference algorithms based on the Boolean network were proposed, the Boolean network was not sufficient as a model of a genetic network. RESULTS: First, a Boolean network model with noise is proposed, together with an inference algorithm for it. Next, a qualitative network model is proposed, in which regulation rules are represented as qualitative rules and embedded in the network structure. Algorithms are also presented for inferring qualitative relations from time series data. Then, an algorithm for inferring S-systems (synergistic and saturable systems) from time series data is presented, where S-systems are based on a particular kind of nonlinear differential equation and have been applied to the analysis of various biological systems. Theoretical results are shown for Boolean networks with noises and simple qualitative networks. Computational results are shown for Boolean networks with noises and S-systems, where real data are not used because the proposed models are still conceptual and the quantity and quality of currently available data are not enough for the application of the proposed methods.

Algorithms↗
PubMed1991

GELYMAC: a Macintosh application for calculating DNA fragment size from gel electrophoresis migration data.

A program called GELYMAC takes data on the distances migrated by DNA fragments in a one-dimensional electrophoretic gel and, using a cubic-spline best-fit of marker fragment distance migrated versus molecular size, calculates the molecular sizes of the fragments. Written in the Rascal (Real-time Pascal) programming language, the program runs on the Macintosh family of microcomputers. Rapid entry of marker and experimental fragment migration data is afforded using a scroll bar system adjacent to a graphic representation of a gel. Output includes tabular listing of the data, graphic cartoons of the gel, and the fragment locations and molecular sizes for individual gel lanes, and the calibration curve used in data computations.

Calibration↗
PubMed1997

A test of neutrality based on interlocus associations.

The evolutionary processes governing variability within genomic regions of low recombination have been the focus of many studies. Here, I investigate the statistical properties of a measure of interlocus genetic associations under the assumption that mutations are selectively neutral and sites are completely linked. This measure, denoted ZnS, is based on the squared correlation of allelic identity at pairs of polymorphic sites. Upper bounds for ZnS are determined by simulations. Various deviations from the neutral model, including several different forms of natural selection, will inflate the value of ZnS relative to its neutral theory expectations. Larger than expected values of ZnS are observed in genetic samples from the yellow-ac-scute and Adh regions of Drosophila melanogaster.

Alcohol Dehydrogenase↗
PubMed2005

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site.

Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand-solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand-DNA binding.

Anti-Bacterial Agents↗
PubMed2003

Compromised pontocerebellar and cerebellothalamocortical systems: speculations on their contributions to cognitive and motor impairment in nonamnesic alcoholism.

BACKGROUND: Corticopontocerebellar and cerebellothalamocortical circuits underlie a wide range of neuropsychological processes compromised by alcoholism. The analyses herein tested whether abnormalities of volumes of brain structures forming nodes of these separate feed-forward and feedback systems are selectively related to each other and whether any of these noncortical regions can account for cognitive and motor deficits occurring as sequelae of chronic alcoholism. METHODS: Regional brain measures originated from our prior neuroimaging studies, showing in alcoholics significant volume deficits in the principal structures of interest: cerebellar hemispheres, vermis, pons, and thalamus as well as prefrontal, frontal, and parietal cortex. Neuropsychological functions targeted for analysis-problem solving, visuospatial ability, and static postural stability-showed 0.6 to 1.6 SD deficits in these alcoholic men. RESULTS: In alcoholics, the patterns of correlations were consistent with dissociation of thalamic and pontine circuitry. Pontine and thalamic volumes were not correlated with each other. Pontine volumes correlated with white matter volumes of anterior superior vermis and gray and white matter volumes of the cerebellar hemispheres but not with cortical regional volumes. Thalamic volumes correlated with gray matter volumes of the cerebellar hemispheres, parietal cortex, and inferior posterior vermian lobule, which itself correlated with parietal, prefrontal, and frontal cortical volumes. Controls did not show these correlational patterns. Brain structure-function relationships in alcoholics examined with multiple regression identified anterior vermian but not prefrontal or parietal volume as a unique predictor of balance scores; vermian and thalamic but not prefrontal cortical volumes as predictors of card sorting scores; and cerebellar hemispheric white matter but not parietal cortical volume as a predictor of visuospatial ability. CONCLUSIONS: Each major node of frontocerebellar circuitry shows volume deficits in alcoholics but can be independently compromised. Disruption of these circuits may underlie alcoholism-related neuropsychological deficits, either by abnormalities present in individual nodes or by disconnection via interruption of selective circuitry.

Adult↗
PubMed2006

Temporal lobe anatomy and psychiatric symptoms in velocardiofacial syndrome (22q11.2 deletion syndrome).

OBJECTIVE: To investigate the association between mesial temporal lobe morphology, ratios of prefrontal cortex to amygdala and hippocampus volumes, and psychiatric symptomatology in children and adolescents with velocardiofacial syndrome (VCFS). METHOD: Scores on behavioral rating scales and volumetric measures of the amygdala, hippocampus, and prefrontal cortex based on high-resolution magnetic resonance imaging were compared among 47 children with VCFS, 15 of their siblings, and 18 community controls. RESULTS: After covarying for whole brain volume, children with VCFS exhibited 11% greater volume of the left amygdala (p =.002) and 8% greater volume of the right amygdala (p =.01). Children with VCFS exhibited smaller volumes of the hippocampus, but not disproportionately to reductions in whole brain volume. Children with VCFS exhibited smaller volumetric ratios of prefrontal and orbitofrontal cortex to amygdala, but not prefrontal cortex to hippocampus. For children with VCFS, but not for the comparison sample, larger volumes of the amygdala and smaller ratios of prefrontal cortex to amygdala were associated with higher scores on the Internalizing, Externalizing, Anxiety, and Aggression scales of the Child Behavior Checklist and on the parent version of the Young Mania Rating Scale. CONCLUSIONS: These findings suggest that the prefrontal cortex-amygdala circuit that underlies emotional processing is disrupted in children with VCFS and may be an important neurobiological substrate of psychiatric disorder in these children.

Adolescent↗
PubMed2005

Scientific Grid computing.

We introduce a definition of Grid computing which is adhered to throughout this Theme Issue. We compare the evolution of the World Wide Web with current aspirations for Grid computing and indicate areas that need further research and development before a generally usable Grid infrastructure becomes available. We discuss work that has been done in order to make scientific Grid computing a viable proposition, including the building of Grids, middleware developments, computational steering and visualization. We review science that has been enabled by contemporary computational Grids, and associated progress made through the widening availability of high performance computing.

Computer Simulation↗
PubMed2003

Estimating the repeat structure and length of DNA sequences using L-tuples.

In shotgun sequencing projects, the genome or BAC length is not always known. We approach estimating genome length by first estimating the repeat structure of the genome or BAC, sometimes of interest in its own right, on the basis of a set of random reads from a genome project. Moreover, we can find the consensus for repeat families before assembly. Our methods are based on the l-tuple content of the reads.

Algorithms↗
PubMed1995

Experimental design and error detection for polyploid radiation hybrid mapping.

In this paper we consider issues of experimental design and error detection and correction for polyploid radiation hybrid mapping. Using analytic methods and computer simulation, we first consider the combinations of fragment retention rate, ploidy, and marker spacing that provide the best chance to order markers. We find that in general, combinations of ploidy and chromosome-specific retention rates that lead to a per-hybrid retention rate of approximately 50% result in the greatest power to order markers. We also find that analyzing polyploid radiation hybrids as if they were haploid does not compromise the ability to order markers but does result in less accurate intermarker distance estimates. Second, we examine the effect of typing errors on two-locus information, ability to order multiple loci, and estimation of intermarker distances and total map length. Even low levels of error result in large losses of information about breakage probabilities, markedly reduce ability to order loci, and inflate estimates of intermarker distances and total map length. We compare the ordering accuracy that results from duplicate typing of hybrids to that of single typing twice as many hybrids and find that duplicate typing results in a higher probability of identifying the true order as one of the best orders, but that single typing of twice as many hybrids results in stronger support for the true order. For low error rates, framework maps constructed from the larger single-typed panels are only slightly less likely to be correct and include substantially more markers than the smaller double-typed panels. Third, we develop a method to calculate the distribution of the number of obligate chromosome breaks for a polyploid radiation hybrid under a given locus order and discuss how this method may be used to identify hybrids with suspiciously large numbers of chromosome breaks.

Animals↗