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Biomedical subjects

I Holmes

Publications and source records attributed to I Holmes.

At least 19 recordsLinked to original sources
PubMed2006

No evidence of Mycobacterium avium subsp. paratuberculosis in in vitro produced cryopreserved embryos derived from subclinically infected cows.

The aim of the project was to ascertain if Mycobacterium avium subsp. paratuberculosis (Map) could be cultured from frozen-thawed in vitro produced (IVP) embryos derived from cows with subclinical Johne's disease (JD). Straws of 109 IVP embryos were obtained from 267 cumulus-oocyte-complexes (COCs) collected from 12 clinically normal cows in which antibodies against Map were detected in blood by an enzyme-linked immunosorbent assay (ELISA). These embryos were processed, washed using the standard protocol as described by the International Embryo Transfer Society (IETS) and frozen in a commercial IVP embryo laboratory. Of the 12 donor cows, 11 had histopathological or bacteriological evidence of infection at post-mortem inspection. The frozen embryos were thawed and the contents of the straws were cultured using the radiometric mycobacterial culture method. No Map was detected in any of the 109 embryos or freezing media. This suggests that the use of in vitro produced and cryopreserved embryos derived from cows with subclinical JD poses very low, if any, risk of spreading infection to susceptible animals.

Animals↗
PubMed2005

A grid-enabled lightweight computational steering client: a .NET PDA implementation.

The grid has been developed to support large-scale computer simulations in a diverse range of scientific and engineering fields. Consequently, the increasing availability of powerful distributed computing resources is changing how scientists undertake large-scale modelling/simulation. Instead of being limited to local computing resources, scientists are now able to make use of supercomputing facilities around the world. These grid resources comprise specialized distributed three-dimensional visualization environments through to massive computational systems. The scientist usually accesses these resources from reasonably high-end desktop computers. Even though most modern desktop computers are provided with reasonably powerful three-dimensional graphical hardware, not all scientific applications require high-end three-dimensional visualization because the data of interest is essentially numerical or two-dimensional graphical data. For these applications, a much simpler two-dimensional graphical displays can be used. Since large jobs can take many hours to complete the scientist needs access to a technology that will allow them to still monitor and control their job while away from their desks. This paper describes an effective method of monitoring and controlling a set of chained computer simulations by means of a lightweight steering client based on a small personal digital assistant (PDA). The concept of using a PDA to steer a series of computational jobs across a supercomputing resource may seem strange at first but when scientists realize they can use these devices to connect to their computation wherever there is a wireless network (or cellular phone network) the concept becomes very compelling. Apart from providing a much needed easy-to-use interface, the PDA-based steering client has the benefit of freeing the scientist from the desktop. It is during this monitoring stage that the hand-held PDA client is of particular value as it gives the application scientist greater freedom to leave his or her desk but still communicate with their simulation, with the proviso that they remain within the range of a wireless network.

Computer Graphics↗
PubMed2003

A "Long Indel" model for evolutionary sequence alignment.

We present a new probabilistic model of sequence evolution, allowing indels of arbitrary length, and give sequence alignment algorithms for our model. Previously implemented evolutionary models have allowed (at most) single-residue indels or have introduced artifacts such as the existence of indivisible "fragments." We compare our algorithm to these previous methods by applying it to the structural homology dataset HOMSTRAD, evaluating the accuracy of (1) alignments and (2) evolutionary time estimates. With our method, it is possible (for the first time) to integrate probabilistic sequence alignment, with reliability indicators and arbitrary gap penalties, in the same framework as phylogenetic reconstruction. Our alignment algorithm requires that we evaluate the likelihood of any specific path of mutation events in a continuous-time Markov model, with the event times integrated out. To this effect, we introduce a "trajectory likelihood" algorithm (Appendix A). We anticipate that this algorithm will be useful in more general contexts, such as Markov Chain Monte Carlo simulations.

Algorithms↗
PubMed2003

Using guide trees to construct multiple-sequence evolutionary HMMs.

MOTIVATION: Score-based progressive alignment algorithms do dynamic programming on successive branches of a guide tree. The analogous probabilistic construct is an Evolutionary HMM. This is a multiple-sequence hidden Markov model (HMM) made by combining transducers (conditionally normalised Pair HMMs) on the branches of a phylogenetic tree. METHODS: We present general algorithms for constructing an Evolutionary HMM from any Pair HMM and for doing dynamic programming to any Multiple-sequence HMM. RESULTS: Our prototype implementation, Handel, is based on the Thorne-Kishino-Felsenstein evolutionary model and is benchmarked using structural reference alignments.

Algorithms↗
PubMed2002

An expectation maximization algorithm for training hidden substitution models.

We derive an expectation maximization algorithm for maximum-likelihood training of substitution rate matrices from multiple sequence alignments. The algorithm can be used to train hidden substitution models, where the structural context of a residue is treated as a hidden variable that can evolve over time. We used the algorithm to train hidden substitution matrices on protein alignments in the Pfam database. Measuring the accuracy of multiple alignment algorithms with reference to BAliBASE (a database of structural reference alignments) our substitution matrices consistently outperform the PAM series, with the improvement steadily increasing as up to four hidden site classes are added. We discuss several applications of this algorithm in bioinformatics.

Algorithms↗
PubMed2002

Pairwise RNA structure comparison with stochastic context-free grammars.

Pairwise stochastic context-free grammars ("Pair SCFGs") are powerful tools for finding conserved RNA structures, but unconstrained alignment to Pair SCFGs is prohibitively expensive. We develop versions of the Pair SCFG dynamic programming algorithms that can be conditioned on precomputed structures, significantly reducing the time complexity of alignment. We have implemented these algorithms for general Pair SCFGs in software that is freely available under the GNU Public License.

Algorithms↗
PubMed2001

Are changes in left ventricular volume as measured with the biplane Simpson's method predominantly related to changes in its area or long axis in the prognostic evaluation of remodelling following a myocardial infarction?

AIMS: Two-dimensional (2D) echocardiography has been widely applied to measure left ventricular volumes with the biplane Simpson's method in the assessment of left ventricular remodelling following an acute myocardial infarction. This volume formula is based upon tracings of endocardium and measurement of long axis on left ventricular images. In the present follow-up study of post-myocardial infarction patients we evaluated the prognostic impact of changes in left ventricular areas and geometry versus long axis to determine if only long-axis measurements may be used for prognostic purposes. METHODS AND RESULTS: Two-dimensional echocardiographic video recordings of the apical four-chamber and long-axis views were obtained in 756 patients 2--7 days and 3 months following an acute myocardial infarction. All videotapes were sent to a core laboratory and left ventricular volumes were measured with the biplane Simpson's method in end-diastole and end-systole. During the first 3 months 44 patients had suffered one of the following end-points and were excluded: cardiac death, recurrent myocardial infarction, heart failure or chronic arrhythmia. Over a period of 3--24 months 58 such end-points occurred. With the Cox proportional hazards model the increase in left ventricular systolic volume was the strongest predictor for such events (Chi-square 18.5, P<0.0001), followed by an increase in end-systolic area (Chi-square 17.0, P<0.0001) and end-systolic spherity index (Chi-square 8.74,P =0.003). The increase in end-systolic long axis had only a borderline predictive value (Chi-square 4.3, P=0.04). The change in long-axis shortening from end-diastole to end-systole had no significant predictive value at all. CONCLUSION: In the studied population changes in left ventricular area and geometry, but not in the long axis, were mainly related to cardiac morbidity. The proper assessment of changes in left ventricular dimensions should therefore be based upon tracings of the area and not on long axis measurements only.

Aged↗
PubMed2001

Evolutionary HMMs: a Bayesian approach to multiple alignment.

MOTIVATION: We review proposed syntheses of probabilistic sequence alignment, profiling and phylogeny. We develop a multiple alignment algorithm for Bayesian inference in the links model proposed by Thorne et al. (1991, J. Mol. Evol., 33, 114-124). The algorithm, described in detail in Section 3, samples from and/or maximizes the posterior distribution over multiple alignments for any number of DNA or protein sequences, conditioned on a phylogenetic tree. The individual sampling and maximization steps of the algorithm require no more computational resources than pairwise alignment. METHODS: We present a software implementation (Handel) of our algorithm and report test results on (i) simulated data sets and (ii) the structurally informed protein alignments of BAliBASE (Thompson et al., 1999, Nucleic Acids Res., 27, 2682-2690). RESULTS: We find that the mean sum-of-pairs score (a measure of residue-pair correspondence) for the BAliBASE alignments is only 13% lower for Handelthan for CLUSTALW(Thompson et al., 1994, Nucleic Acids Res., 22, 4673-4680), despite the relative simplicity of the links model (CLUSTALW uses affine gap scores and increased penalties for indels in hydrophobic regions). With reference to these benchmarks, we discuss potential improvements to the links model and implications for Bayesian multiple alignment and phylogenetic profiling. AVAILABILITY: The source code to Handelis freely distributed on the Internet at http://www.biowiki.org/Handel under the terms of the GNU Public License (GPL, 2000, http://www.fsf.org./copyleft/gpl.html).

Algorithms↗
PubMed2000

Rotavirus VP7 epitope mapping using fragments of VP7 displayed on phages.

cDNA copies of the complete porcine rotavirus CRW-8 VP7 gene were randomly digested to fragments of about 30-60 or 30-500 base pairs by DNase1 in the presence of Mn(2+). The fragments were cloned and expressed in a filamentous phage fd-tet-derived vector to create specific-gene-related peptide libraries. Polyclonal antibodies were then used to pan the SGRP libraries for antibody-binding phages. Analysis of the phage isolates revealed that the majority (86%) of them only had a single insert. However, phages displaying composite inserts containing the VP7 antigenic regions A, B, and C, originally defined by neutralising monoclonal antibody escape mutants, were also isolated. Inserts containing A or C region peptide were found to contain extra sequences from the C region, while the B region epitope was linear and had additional sequence from either upstream or downstream. In addition a dominant and possibly non-neutralising VP7 epitope was identified around amino acids 263-270. One of the recreated antigenic epitopes has also been fused to the outer membrane protein A (OmpA) of Escherichia coli and shown to maintain its antigenicity. The results in this study may have significant implication for recreation of conformational epitopes and vaccine development.

Amino Acid Sequence↗
PubMed2000

Finding regulatory elements using joint likelihoods for sequence and expression profile data.

A recent, popular method of finding promoter sequences is to look for conserved motifs upstream of genes clustered on the basis of expression data. This method presupposes that the clustering is correct. Theoretically, one should be better able to find promoter sequences and create more relevant gene clusters by taking a unified approach to these two problems. We present a likelihood function for a "sequence-expression" model giving a joint likelihood for a promoter sequence and its corresponding expression levels. An algorithm to estimate sequence-expression model parameters using Gibbs sampling and Expectation/Maximization is described. A program, called kimono, that implements this algorithm has been developed: the source code is freely available on the Internet.

Algorithms↗
PubMed1999

Bacterial expression of the major antigenic regions of porcine rotavirus VP7 induces a neutralizing immune response in mice.

The outer capsid protein of rotavirus, VP7, is a major neutralization antigen. A chimeric protein comprising Escherichia coli (E. coli) outer membrane protein A (OmpA) and part of porcine rotavirus VP7 containing all three antigenic regions (217 amino acids) was expressed in Salmonella and E. coli as an outer-membrane associated protein. Mice immunized intraperitoneally or orally, respectively, with live E. coli or Salmonella cells expressing this chimeric protein produced antibodies against native VP7 as determined by enzyme-linked immunosorbent assays and neutralization tests. This indicates that the VP7 fragment from a porcine rotavirus which is antigenically similar to human rotavirus serotype 3, when expressed in bacteria as a chimeric protein, can form a structure resembling its native form at least in some of the major neutralization domains. These results indicate that the use of a live bacterial vector expressing rotavirus VP7 may represent a strategy for the development of vaccines against rotavirus-induced diarrhoea in infants.

Animals↗
PubMed1998

Dynamic programming alignment accuracy.

Algorithms for generating alignments of biological sequences have inherent statistical limitations when it comes to the accuracy of the alignments they produce. Using simulations, we measure the accuracy of the standard global dynamic programming method and show that it can be reasonably well modelled by an "edge wander" approximation to the distribution of the optimal scoring path around the correct path in the vicinity of a gap. We also give a table from which accuracy values can be predicted for commonly used scoring schemes and sequence divergences (the PAM and BLOSUM series). Finally we describe how to calculate the expected accuracy of a given alignment, and show how this can be used to construct an optimal accuracy alignment algorithm which generates significantly more accurate alignments than standard dynamic programming methods in simulated experiments.

Algorithms↗
PubMed1988

Interaction between furosemide and the converting enzyme inhibitor benazepril in healthy volunteers.

Single oral doses of 10 mg converting enzyme inhibitor benazepril (CGS 14824A) and 40 mg furosemide were administered to 12 healthy male volunteers either separately or concomitantly. The pharmacokinetic parameters of benazepril were not influenced by coadministration of furosemide. Urinary excretion of total furosemide was significantly reduced by 10 to 20% in the presence of benazepril. This effect was considered clinically insignificant. Erect blood pressure decreased and pulse rate increased only during concomitant treatment.

Adult↗
PubMed1988

Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man.

1. The efficacy and tolerability of CV-3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2. The compound, in doses from 750 to 2,000 micrograms kg-1, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 +/- 162% of the basal TAC at the end and 266 +/- 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3. CV-3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4. Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can safely be administered to man and should be useful in elucidating the role of PAF in disease.

Adult↗
PubMed1985

[Biochemical study of rotavirus strains isolated in New Caledonia between 1980 and 1983. Electrophoretypes].

Between 1980 and 1983, 150 Rotavirus strains have been identified by ELISA test. RNA was extracted from 90 strains. We used a very simple and rapid extraction technique. Polyacrylamide gel electrophoresis permits the separation of double stranded RNA segments. The system of classification we retained, allows to recognize 8 classes of electrophoretypes. This study confirms the great variability of human rotaviruses.

Electrophoresis, Polyacrylamide Gel↗