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Richard Myers

Publications and source records attributed to Richard Myers.

9 recordsLinked to original sources
PubMed2006

Genotyping Hepatitis B virus from whole- and sub-genomic fragments using position-specific scoring matrices in HBV STAR.

Hepatitis B virus (HBV) genomes have been classified into eight genotypes based on phylogenetic analysis of sequence variation. Identifying and tracking the movement of HBV genotypes is important in terms of both monitoring infection rates and predicting disease and treatment. An HBV genotyping tool has been developed that compares query sequences with position-specific scoring matrices representing the eight HBV genotypes. This tool (hbv star) is rapid, robust and accurate and assigns genotype based on a statistically defined scoring model. hbv star confidently assigned 90% of 590 full-length HBV genomes to an HBV genotype (Z score >2.0). Thirty-two of the residual 48 sequences were identified as non-human primate viruses and 16 sequences were identified as recombinant or putative recombinants. Receiver-Operated Characteristic (ROC) analysis was used to compare the accuracy of genotype prediction using basal core promoter sequences and surface and core genes with the accuracy achieved by using full-length sequences. A web interface to hbv star is available at http://www.vgb.ucl.ac.uk/starn.shtml.

Animals↗
PubMed2006

tRNAs promote nuclear import of HIV-1 intracellular reverse transcription complexes.

Infection of non-dividing cells is a biological property of HIV-1 crucial for virus transmission and AIDS pathogenesis. This property depends on nuclear import of the intracellular reverse transcription and pre-integration complexes (RTCs/PICs). To identify cellular factors involved in nuclear import of HIV-1 RTCs, cytosolic extracts were fractionated by chromatography and import activity examined by the nuclear import assay. A near-homogeneous fraction was obtained, which was active in inducing nuclear import of purified and labeled RTCs. The active fraction contained tRNAs, mostly with defective 3' CCA ends. Such tRNAs promoted HIV-1 RTC nuclear import when synthesized in vitro. Active tRNAs were incorporated into and recovered from virus particles. Mutational analyses indicated that the anticodon loop mediated binding to the viral complex whereas the T-arm may interact with cellular factors involved in nuclear import. These tRNA species efficiently accumulated into the nucleus on their own in a energy- and temperature-dependent way. An HIV-1 mutant containing MLV gag did not incorporate tRNA species capable of inducing HIV-1 RTC nuclear import and failed to infect cell cycle-arrested cells. Here we provide evidence that at least some tRNA species can be imported into the nucleus of human cells and promote HIV-1 nuclear import.

Active Transport, Cell Nucleus↗
PubMed2005

Variability and conservation in hepatitis B virus core protein.

BACKGROUND: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood. RESULTS: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells. CONCLUSION: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

Amino Acid Sequence↗
PubMed2005

A haplotype similarity based transmission/disequilibrium test under founder heterogeneity.

Taking advantage of increasingly available high-density single nucleotide polymorphisms (SNP) markers across the genome, various types of transmission/disequilibrium tests (TDT) using haplotype information have been developed. A practical challenge arising in such studies is the possibility that transmitted haplotypes have inherited disease-causing mutations from different ancestral chromosomes, or do not bear any disease-causing mutations (founder heterogeneity). To reduce the loss of signal strength due to founder heterogeneity, we propose an SP-TDT test that combines a sequential peeling procedure with the haplotype similarity based TDT method. The proposed SP-TDT method is applicable to any size of nuclear family with or without ambiguous phase information. Simulation studies suggest that the SP-TDT method has the correct type I error rate in stratified populations, and enhanced power compared with some existing haplotype similarity based TDT methods. Finally, we apply the proposed method to study the association of the leptin gene with obesity from the National Heart, Lung, and Blood Institute Family Heart Study.

Algorithms↗
PubMed2004

Development of a novel human immunodeficiency virus type 1 subtyping tool, Subtype Analyzer (STAR): analysis of subtype distribution in London.

We have developed a high throughput computational tool for assigning subtype to HIV-1, based solely on protease and reverse transcriptase (PR-RT) amino acid sequence, generated routinely for clinical assessment of genotypic drug resistance. Subtype-specific profiles were created by generation of position-specific scoring matrices (PSSMs) from multiple amino acids alignments of HIV-1 sequence data from GenBank, phylogenetically divided into subtypes A, AG, B, C, D, F/K, G, H, and J and the separate groups N and O. Query sequences of unknown subtype are aligned with these profiles and a score is derived by comparing each amino acid position in the unknown sequence to the normalized frequency distribution of amino acids at the corresponding positions in the subtype alignments. The highest score is used to assign subtype to the query sequence. Leave one out cross-validation analysis showed the Subtype Analyzer (STAR) was 99% accurate in subtype assignation. STAR can be updated with additional subtype-specific sequence data from sequence databases. STAR was used to classify HIV-1 PR-RT sequences from 843 HIV-1 clinical isolates submitted for drug resistance profiling in London. Within this dataset 26.9% of sequences were classified by STAR as non-B subtypes.

Algorithms↗
PubMed2004

Evidence and consequence of porcine endogenous retrovirus recombination.

The genetic nature and biological effects of recombination between porcine endogenous retroviruses (PERV) were studied. An infectious molecular clone was generated from a high-titer, human-tropic PERV isolate, PERV-A 14/220 (B. A. Oldmixon, et al. J. Virol. 76:3045-3048, 2002; T. A. Ericsson et al. Proc. Natl. Acad. Sci. USA 100:6759-6764, 2003). To analyze this sequence and 15 available full-length PERV nucleotide sequences, we developed a sequence comparison program, LOHA(TM) to calculate local sequence homology between two sequences. This analysis determined that PERV-A 14/220 arose by homologous recombination of a PERV-C genome replacing an 850-bp region around the pol-env junction with that of a PERV-A sequence. This 850-bp PERV-A sequence encompasses the env receptor binding domain, thereby conferring a wide host range including human cells. In addition, we determined that multiple regions derived from PERV-C are responsible for the increased infectious titer of PERV-A 14/220. Thus, a single recombination event may be a fast and effective way to generate high-titer, potentially harmful PERV. Further, local homology and phylogenetic analyses between 16 full-length sequences revealed evidence for other recombination events in the past that give rise to other PERV genomes that possess the PERV-A, but not the PERV-B, env gene. These results indicate that PERV-A env is more prone to recombination with heterogeneous backbone genomes than PERV-B env. Such recombination events that generate more active PERV-A appear to occur in pigs rather frequently, which increases the potential risk of zoonotic PERV transmission. In this context, pigs lacking non-human-tropic PERV-C would be more suitable as donor animals for clinical xenotransplantation.

Animals↗
PubMed2003

Combined analysis of genomewide scans for adult height: results from the NHLBI Family Blood Pressure Program.

A combined analysis of genome scans was performed for adult height in the NHLBI Family Blood Pressure Program. Height data were available on 6752 individuals. Linkage analysis was performed first separately for each of the eight ethnic groups in the four networks using the variance component method. To increase the power to detect the common genetic components affecting height for all the individuals, a linkage analysis was performed subsequently for the combined data set by pooling the average allele-sharing IBD () for all groups. By combining the data, we replicated evidence for a QTL influencing adult height on chromosome 7 (7q31) (LOD=2.46), which has been reported in two previous studies. Suggestive linkage (LOD>1) was found in another six regions in our combined analysis. Evidence for linkage for two of these regions (2p12, 20p11) has also been reported previously.

Adult↗
PubMed2002

An improved automated ECG algorithm for detecting acute and prior myocardial infarction.

Commercial electrocardiographic (ECG) algorithms for detection of prior myocardial infarction (MI) predominantly rely on QRS criteria and on established qualitative ST and T changes. The qualitative approach to ST-T changes in Cardiovise 2.5 is improved upon in version 3.0 with two distinct new approaches for quantifying ST and T changes to assist with the detection of prior MI. The first method uses the mean axes of vectorcardiographic T-loops taken from the inverse Dower transform of the 12-lead ECG to indicate ischemic regions of the left ventricular wall. The second method establishes regional scores for residual ST elevation supportive of ischemia or infarction. These 2 ST-T measures qualify borderline QRS infarct criteria, resulting in composite criteria having higher sensitivities and specificities than QRS criteria alone. Comparative results were created by studying an MI positive group of 360 patients with biochemical marker evidence for infarction and an MI negative group of 515 patients negative for risk factors, biochemical markers and/or coronary disease or wall motion abnormality. Three automated ECG methods that rely predominantly on QRS markers for infarction are compared to Cardiovise (CV) prior MI algorithm version 3.0: Cardiovise 3.0 also introduces criteria for detection of acute myocardial infarction (AMI). Two automated ECG methods are compared to Cardiovise for the detection and labeling of ST elevation (STE) AMI, and for detection of non-STE AMI.

Algorithms↗