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Search Results: 1 - 10 of 293146 matches for " Matthew T. G. Holden "
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The Impact of Recombination on dN/dS within Recently Emerged Bacterial Clones
Santiago Castillo-Ramírez,Simon R. Harris,Matthew T. G. Holden,Miao He,Julian Parkhill,Stephen D. Bentley,Edward J. Feil
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002129
Abstract: The development of next-generation sequencing platforms is set to reveal an unprecedented level of detail on short-term molecular evolutionary processes in bacteria. Here we re-analyse genome-wide single nucleotide polymorphism (SNP) datasets for recently emerged clones of methicillin resistant Staphylococcus aureus (MRSA) and Clostridium difficile. We note a highly significant enrichment of synonymous SNPs in those genes which have been affected by recombination, i.e. those genes on mobile elements designated “non-core” (in the case of S. aureus), or those core genes which have been affected by homologous replacements (S. aureus and C. difficile). This observation suggests that the previously documented decrease in dN/dS over time in bacteria applies not only to genomes of differing levels of divergence overall, but also to horizontally acquired genes of differing levels of divergence within a single genome. We also consider the role of increased drift acting on recently emerged, highly specialised clones, and the impact of recombination on selection at linked sites. This work has implications for a wide range of genomic analyses.
Routine Use of Microbial Whole Genome Sequencing in Diagnostic and Public Health Microbiology
Claudio U. K?ser ,Matthew J. Ellington,Edward J. P. Cartwright,Stephen H. Gillespie,Nicholas M. Brown,Mark Farrington,Matthew T. G. Holden,Gordon Dougan,Stephen D. Bentley,Julian Parkhill,Sharon J. Peacock
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002824
Abstract:
Superantigenic Activity of emm3 Streptococcus pyogenes Is Abrogated by a Conserved, Naturally Occurring smeZ Mutation
Claire E. Turner, Mary Sommerlad, Karen McGregor, Frances J. Davies, Bruno Pichon, Deborah L. W. Chong, Leili Farzaneh, Matthew T. G. Holden, Brian G. Spratt, Androulla Efstratiou, Shiranee Sriskandan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046376
Abstract: Streptococcus pyogenes M/emm3 strains have been epidemiologically linked with enhanced infection severity and risk of streptococcal toxic shock syndrome (STSS), a syndrome triggered by superantigenic stimulation of T cells. Comparison of S. pyogenes strains causing STSS demonstrated that emm3 strains were surprisingly less mitogenic than other emm-types (emm1, emm12, emm18, emm28, emm87, emm89) both in vitro and in vivo, indicating poor superantigenic activity. We identified a 13 bp deletion in the superantigen smeZ gene of all emm3 strains tested. The deletion led to a premature stop codon in smeZ, and was not present in other major emm-types tested. Expression of a functional non-M3-smeZ gene successfully enhanced mitogenic activity in emm3 S. pyogenes and also restored mitogenic activity to emm1 and emm89 S. pyogenes strains where the smeZ gene had been disrupted. In contrast, the M3-smeZ gene with the 13 bp deletion could not enhance or restore mitogenicity in any of these S. pyogenes strains, confirming that M3-smeZ is non-functional regardless of strain background. The mutation in M3-smeZ reduced the potential for M3 S. pyogenes to induce cytokines in human tonsil, but not during invasive infection of superantigen-sensitive mice. Notwithstanding epidemiological associations with STSS and disease severity, emm3 strains have inherently poor superantigenicity that is explained by a conserved mutation in smeZ.
Genome-Wide Analysis Reveals Loci Encoding Anti-Macrophage Factors in the Human Pathogen Burkholderia pseudomallei K96243
Andrea J. Dowling,Paul A. Wilkinson,Matthew T. G. Holden,Michael A. Quail,Stephen D. Bentley,Julia Reger,Nicholas R. Waterfield,Richard W. Titball,Richard H. ffrench-Constant
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015693
Abstract: Burkholderia pseudomallei is an important human pathogen whose infection biology is still poorly understood. The bacterium is endemic to tropical regions, including South East Asia and Northern Australia, where it causes melioidosis, a serious disease associated with both high mortality and antibiotic resistance. B. pseudomallei is a Gram-negative facultative intracellular pathogen that is able to replicate in macrophages. However despite the critical nature of its interaction with macrophages, few anti-macrophage factors have been characterized to date. Here we perform a genome-wide gain of function screen of B. pseudomallei strain K96243 to identify loci encoding factors with anti-macrophage activity. We identify a total of 113 such loci scattered across both chromosomes, with positive gene clusters encoding transporters and secretion systems, enzymes/toxins, secondary metabolite, biofilm, adhesion and signal response related factors. Further phenotypic analysis of four of these regions shows that the encoded factors cause striking cellular phenotypes relevant to infection biology, including apoptosis, formation of actin ‘tails’ and multi-nucleation within treated macrophages. The detailed analysis of the remaining host of loci will facilitate genetic dissection of the interaction of this important pathogen with host macrophages and thus further elucidate this critical part of its infection cycle.
A Single Multilocus Sequence Typing (MLST) Scheme for Seven Pathogenic Leptospira Species
Siriphan Boonsilp equal contributor,Janjira Thaipadungpanit equal contributor ,Premjit Amornchai,Vanaporn Wuthiekanun,Mark S. Bailey,Matthew T. G. Holden,Cuicai Zhang,Xiugao Jiang,Nobuo Koizumi,Kyle Taylor,Renee Galloway,Alex R. Hoffmaster,Scott Craig,Lee D. Smythe,Rudy A. Hartskeerl,Nicholas P. Day,Narisara Chantratita,Edward J. Feil,David M. Aanensen,Brian G. Spratt,Sharon J. Peacock
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0001954
Abstract: Background The available Leptospira multilocus sequence typing (MLST) scheme supported by a MLST website is limited to L. interrogans and L. kirschneri. Our aim was to broaden the utility of this scheme to incorporate a total of seven pathogenic species. Methodology and Findings We modified the existing scheme by replacing one of the seven MLST loci (fadD was changed to caiB), as the former gene did not appear to be present in some pathogenic species. Comparison of the original and modified schemes using data for L. interrogans and L. kirschneri demonstrated that the discriminatory power of the two schemes was not significantly different. The modified scheme was used to further characterize 325 isolates (L. alexanderi [n = 5], L. borgpetersenii [n = 34], L. interrogans [n = 222], L. kirschneri [n = 29], L. noguchii [n = 9], L. santarosai [n = 10], and L. weilii [n = 16]). Phylogenetic analysis using concatenated sequences of the 7 loci demonstrated that each species corresponded to a discrete clade, and that no strains were misclassified at the species level. Comparison between genotype and serovar was possible for 254 isolates. Of the 31 sequence types (STs) represented by at least two isolates, 18 STs included isolates assigned to two or three different serovars. Conversely, 14 serovars were identified that contained between 2 to 10 different STs. New observations were made on the global phylogeography of Leptospira spp., and the utility of MLST in making associations between human disease and specific maintenance hosts was demonstrated. Conclusion The new MLST scheme, supported by an updated MLST website, allows the characterization and species assignment of isolates of the seven major pathogenic species associated with leptospirosis.
The Complete Genome Sequence and Comparative Genome Analysis of the High Pathogenicity Yersinia enterocolitica Strain 8081
Nicholas R Thomson ,Sarah Howard,Brendan W Wren,Matthew T. G Holden,Lisa Crossman,Gregory L Challis,Carol Churcher,Karen Mungall,Karen Brooks,Tracey Chillingworth,Theresa Feltwell,Zahra Abdellah,Heidi Hauser,Kay Jagels,Mark Maddison,Sharon Moule,Mandy Sanders,Sally Whitehead,Michael A Quail,Gordon Dougan,Julian Parkhill,Michael B Prentice
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020206
Abstract: The human enteropathogen, Yersinia enterocolitica, is a significant link in the range of Yersinia pathologies extending from mild gastroenteritis to bubonic plague. Comparison at the genomic level is a key step in our understanding of the genetic basis for this pathogenicity spectrum. Here we report the genome of Y. enterocolitica strain 8081 (serotype 0:8; biotype 1B) and extensive microarray data relating to the genetic diversity of the Y. enterocolitica species. Our analysis reveals that the genome of Y. enterocolitica strain 8081 is a patchwork of horizontally acquired genetic loci, including a plasticity zone of 199 kb containing an extraordinarily high density of virulence genes. Microarray analysis has provided insights into species-specific Y. enterocolitica gene functions and the intraspecies differences between the high, low, and nonpathogenic Y. enterocolitica biotypes. Through comparative genome sequence analysis we provide new information on the evolution of the Yersinia. We identify numerous loci that represent ancestral clusters of genes potentially important in enteric survival and pathogenesis, which have been lost or are in the process of being lost, in the other sequenced Yersinia lineages. Our analysis also highlights large metabolic operons in Y. enterocolitica that are absent in the related enteropathogen, Yersinia pseudotuberculosis, indicating major differences in niche and nutrients used within the mammalian gut. These include clusters directing, the production of hydrogenases, tetrathionate respiration, cobalamin synthesis, and propanediol utilisation. Along with ancestral gene clusters, the genome of Y. enterocolitica has revealed species-specific and enteropathogen-specific loci. This has provided important insights into the pathology of this bacterium and, more broadly, into the evolution of the genus. Moreover, wider investigations looking at the patterns of gene loss and gain in the Yersinia have highlighted common themes in the genome evolution of other human enteropathogens.
Genomic Evidence for the Evolution of Streptococcus equi: Host Restriction, Increased Virulence, and Genetic Exchange with Human Pathogens
Matthew T. G. Holden equal contributor,Zoe Heather equal contributor,Romain Paillot,Karen F. Steward,Katy Webb,Fern Ainslie,Thibaud Jourdan,Nathalie C. Bason,Nancy E. Holroyd,Karen Mungall,Michael A. Quail,Mandy Sanders,Mark Simmonds,David Willey,Karen Brooks,David M. Aanensen,Brian G. Spratt,Keith A. Jolley,Martin C. J. Maiden,Michael Kehoe,Neil Chanter,Stephen D. Bentley,Carl Robinson,Duncan J. Maskell,Julian Parkhill,Andrew S. Waller
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000346
Abstract: The continued evolution of bacterial pathogens has major implications for both human and animal disease, but the exchange of genetic material between host-restricted pathogens is rarely considered. Streptococcus equi subspecies equi (S. equi) is a host-restricted pathogen of horses that has evolved from the zoonotic pathogen Streptococcus equi subspecies zooepidemicus (S. zooepidemicus). These pathogens share approximately 80% genome sequence identity with the important human pathogen Streptococcus pyogenes. We sequenced and compared the genomes of S. equi 4047 and S. zooepidemicus H70 and screened S. equi and S. zooepidemicus strains from around the world to uncover evidence of the genetic events that have shaped the evolution of the S. equi genome and led to its emergence as a host-restricted pathogen. Our analysis provides evidence of functional loss due to mutation and deletion, coupled with pathogenic specialization through the acquisition of bacteriophage encoding a phospholipase A2 toxin, and four superantigens, and an integrative conjugative element carrying a novel iron acquisition system with similarity to the high pathogenicity island of Yersinia pestis. We also highlight that S. equi, S. zooepidemicus, and S. pyogenes share a common phage pool that enhances cross-species pathogen evolution. We conclude that the complex interplay of functional loss, pathogenic specialization, and genetic exchange between S. equi, S. zooepidemicus, and S. pyogenes continues to influence the evolution of these important streptococci.
Rapid Evolution of Virulence and Drug Resistance in the Emerging Zoonotic Pathogen Streptococcus suis
Matthew T. G. Holden, Heidi Hauser, Mandy Sanders, Thi Hoa Ngo, Inna Cherevach, Ann Cronin, Ian Goodhead, Karen Mungall, Michael A. Quail, Claire Price, Ester Rabbinowitsch, Sarah Sharp, Nicholas J. Croucher, Tran Bich Chieu, Nguyen Thi Hoang Mai, To Song Diep, Nguyen Tran Chinh, Michael Kehoe, James A. Leigh, Philip N. Ward, Christopher G. Dowson, Adrian M. Whatmore, Neil Chanter, Pernille Iversen, Marcelo Gottschalk, Josh D. Slater, Hilde E. Smith, Brian G. Spratt, Jianguo Xu, Changyun Ye, Stephen Bentley, Barclay G. Barrell, Constance Schultsz, Duncan J. Maskell, Julian Parkhill
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006072
Abstract: Background Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood. Methodology/Principal Findings The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, ~40% of the ~2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three ~90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors. Conclusions/Significance The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance.
Statistics for fixed points of the self-power map
Matthew Friedrichsen,Joshua Holden
Mathematics , 2014,
Abstract: The map x -> x^x modulo p is related to a variation of the digital signature scheme in a similar way to the discrete exponentiation map, but it has received much less study. We explore the number of fixed points of this map by a statistical analysis of experimental data. In particular, the number of fixed points can in many cases be modeled by a binomial distribution. We discuss the many cases where this has been successful, and also the cases where a good model may not yet have been found.
Gene expression changes linked to antimicrobial resistance, oxidative stress, iron depletion and retained motility are observed when Burkholderia cenocepacia grows in cystic fibrosis sputum
Pavel Drevinek, Matthew TG Holden, Zhaoping Ge, Andrew M Jones, Ian Ketchell, Ryan T Gill, Eshwar Mahenthiralingam
BMC Infectious Diseases , 2008, DOI: 10.1186/1471-2334-8-121
Abstract: A novel microarray was designed to the genome of Burkholderia cenocepacia J2315 and transcriptomics used to identify genes that were differentially regulated when the pathogen was grown in a CF sputum-based infection model. Sputum samples from CF individuals infected with the same B. cenocepacia strain as genome isolate were used, hence, other than a dilution into a minimal growth medium (used as the control condition), no further treatment of the sputum was carried out.A total of 723 coding sequences were significantly altered, with 287 upregulated and 436 downregulated; the microarray-observed expression was validated by quantitative PCR on five selected genes. B. cenocepacia genes with putative functions in antimicrobial resistance, iron uptake, protection against reactive oxygen and nitrogen species, secretion and motility were among the most altered in sputum. Novel upregulated genes included: a transmembrane ferric reductase (BCAL0270) implicated in iron metabolism, a novel protease (BCAL0849) that may play a role in host tissue destruction, an organic hydroperoxide resistance gene (BCAM2753), an oxidoreductase (BCAL1107) and a nitrite/sulfite reductase (BCAM1676) that may play roles in resistance to the host defenses. The assumptions of growth under iron-depletion and oxidative stress formulated from the microarray data were tested and confirmed by independent growth of B. cenocepacia under each respective environmental condition.Overall, our first full transcriptomic analysis of B. cenocepacia demonstrated the pathogen alters expression of over 10% of the 7176 genes within its genome when it grows in CF sputum. Novel genetic pathways involved in responses to antimicrobial resistance, oxidative stress, and iron metabolism were revealed by the microarray analysis. Virulence factors such as the cable pilus and Cenocepacia Pathogenicity Island were unaltered in expression. However, B. cenocepacia sustained or increased expression of motility-associated genes in
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