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Search Results: 1 - 10 of 234353 matches for " Simon R. Harris "
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A High-Resolution View of Genome-Wide Pneumococcal Transformation
Nicholas J. Croucher ,Simon R. Harris,Lars Barquist,Julian Parkhill,Stephen D. Bentley
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002745
Abstract: Transformation is an important mechanism of microbial evolution through which bacteria have been observed to rapidly adapt in response to clinical interventions; examples include facilitating vaccine evasion and the development of penicillin resistance in the major respiratory pathogen Streptococcus pneumoniae. To characterise the process in detail, the genomes of 124 S. pneumoniae isolates produced through in vitro transformation were sequenced and recombination events detected. Those recombinations importing the selected marker were independent of unselected events elsewhere in the genome, the positions of which were not significantly affected by local sequence similarity between donor and recipient or mismatch repair processes. However, both types of recombinations were sometimes mosaic, with multiple non-contiguous segments originating from the same molecule of donor DNA. The lengths of the unselected events were exponentially distributed with a mean of 2.3 kb, implying that recombinations are stochastically resolved with a fixed per base probability of 4.4×10?4 bp?1. This distribution of recombination sizes, coupled with an observed under representation of large insertions within transferred sequence, suggests transformation has the potential to reduce the size of bacterial genomes, and is unlikely to act as an efficient mechanism for the uptake of accessory genomic loci.
Mutations in Non-Acid Patch Residues Disrupt H2A.Z’s Association with Chromatin through Multiple Mechanisms
Thomas J. Wood, Angela Thistlethwaite, Michael R. Harris, Simon C. Lovell, Catherine B. Millar
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076394
Abstract: The incorporation of histone variants into nucleosomes is a critical mechanism for regulating essential DNA-templated processes and for establishing distinct chromatin architectures with specialised functions. H2A.Z is an evolutionarily conserved H2A variant that has diverse roles in transcriptional regulation, heterochromatin boundary definition, chromosome stability and DNA repair. The H2A.Z C-terminus diverges in sequence from canonical H2A and imparts unique functions to H2A.Z in the yeast S. cerevisiae. Although mediated in part through the acid patch-containing M6 region, many molecular determinants of this divergent structure-function relationship remain unclear. Here, by using an unbiased random mutagenesis screen of H2A.Z alleles, we identify point mutations in the C-terminus outside of the M6 region that disrupt the normal function of H2A.Z in response to cytotoxic stress. These functional defects correlate with reduced chromatin association, which we attribute to reduced physical stability within chromatin, but also to altered interactions with the SWR and INO80 chromatin remodeling complexes. Together with experimental data, computational modelling of these residue changes in the context of protein structure suggests the importance of C-terminal domain integrity and configuration for maintaining the level of H2A.Z in nucleosomes.
Horizontally Acquired Glycosyltransferase Operons Drive Salmonellae Lipopolysaccharide Diversity
Mark R. Davies,Sarah E. Broadbent,Simon R. Harris,Nicholas R. Thomson,Marjan W. van der Woude
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003568
Abstract: The immunodominant lipopolysaccharide is a key antigenic factor for Gram-negative pathogens such as salmonellae where it plays key roles in host adaptation, virulence, immune evasion, and persistence. Variation in the lipopolysaccharide is also the major differentiating factor that is used to classify Salmonella into over 2600 serovars as part of the Kaufmann-White scheme. While lipopolysaccharide diversity is generally associated with sequence variation in the lipopolysaccharide biosynthesis operon, extraneous genetic factors such as those encoded by the glucosyltransferase (gtr) operons provide further structural heterogeneity by adding additional sugars onto the O-antigen component of the lipopolysaccharide. Here we identify and examine the O-antigen modifying glucosyltransferase genes from the genomes of Salmonella enterica and Salmonella bongori serovars. We show that Salmonella generally carries between 1 and 4 gtr operons that we have classified into 10 families on the basis of gtrC sequence with apparent O-antigen modification detected for five of these families. The gtr operons localize to bacteriophage-associated genomic regions and exhibit a dynamic evolutionary history driven by recombination and gene shuffling events leading to new gene combinations. Furthermore, evidence of Dam- and OxyR-dependent phase variation of gtr gene expression was identified within eight gtr families. Thus, as O-antigen modification generates significant intra- and inter-strain phenotypic diversity, gtr-mediated modification is fundamental in assessing Salmonella strain variability. This will inform appropriate vaccine and diagnostic approaches, in addition to contributing to our understanding of host-pathogen interactions.
Branching Brownian motion: Almost sure growth along scaled paths
Simon Harris,Matthew Roberts
Mathematics , 2009,
Abstract: We give a proof of a result on the growth of the number of particles along chosen paths in a branching Brownian motion. The work follows the approach of classical large deviations results, in which paths in $C[0,1]$ are rescaled onto $C[0,T]$ for large $T$. The methods used are probabilistic and take advantage of modern spine techniques.
Branching Brownian motion: Almost sure growth along unscaled paths
Simon Harris,Matthew Roberts
Mathematics , 2008,
Abstract: We give new results on the growth of the number of particles in a dyadic branching Brownian motion which follow within a fixed distance of a path $f:[0,\infty)\to \mathbb{R}$. We show that it is possible to count the number of particles without rescaling the paths. Our results reveal that the number of particles along certain paths can oscillate dramatically. The methods used are entirely probabilistic, taking advantage of the spine technique developed by, amongst others, Lyons et al, Kyprianou, and Hardy & Harris.
Measure changes with extinction
Simon Harris,Matthew Roberts
Mathematics , 2008,
Abstract: We consider a change of measure by a martingale $Z_t$ and clarify that in general $1/Z_t$ is only a supermartingale under the changed measure. We then give a necessary and sufficient condition for the event that the limit of the martingale is zero to coincide with the event that the martingale hits zero in finite time (up to a set of zero probability).
Heterogeneity in the Frequency and Characteristics of Homologous Recombination in Pneumococcal Evolution
Rafal Mostowy equal contributor,Nicholas J. Croucher equal contributor,William P. Hanage,Simon R. Harris,Stephen Bentley,Christophe Fraser
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004300
Abstract: The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro-recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes.
Angiogenesis - still a worthwhile target for breast cancer therapy?
Simon Lord, Adrian L Harris
Breast Cancer Research , 2010, DOI: 10.1186/bcr2748
Abstract: Several mechanisms for intrinsic and acquired tumour resistance to anti-angiogenic therapy have now been proposed. It is now clear that revascularisation can occur after the inhibition of VEGF signalling due to the upregulation of alternative angiogenic signalling path-ways. This was first revealed in a mouse model of pancreatic neuroendocrine cancer treated with the anti-VEGF receptor (VEGFR) monoclonal antibody DC101; in this model an initial response was followed by tumour regrowth and revascularisation. This was associated with higher levels of mRNAs for the pro-angiogenic factors fibroblast growth factor 1 and 2, Ephrin A1 and A2 (Efna1 and Efna2) and Angiopoietin 1 (Angpt1) [1]. Further in vivo studies have suggested the importance of the promotion of a multitude of pro-angiogenic factors in response to anti-angiogenic therapy, including inter-leukin-8, VEGF, platelet derived growth factor (PDGF)A and placental growth factor [2-4].Another angiogenic pathway, Delta-like ligand-4 (DLL4)-Notch signalling, is induced by VEGF and acts as a counterbalance to VEGF upregulation by inhibiting angiogenesis. Inhibition of DLL4-Notch signalling leads to an increase in blood vessel density, intratumoural hypoxia and the induction of pro-angiogenic factors. Preclinical studies have suggested that tumours that are resistant to anti-VEGF therapy are susceptible to blockade of DLL4-Notch signalling due to the promotion of non-productive angiogenesis [5,6].Pericytes, the periendothelial support cells of the microvascular structure, also seem to play an important role in treatment resistance. It has been observed that even after tumour devascularisation in response to VEGF inhibition, vessels remain that are heavily covered with pericytes. Furthermore, those vessels that do not have this 'pericyte scaold' are more susceptible to VEGF inhibition. Lastly, pericytes have the ability to release pro-angiogenic factors in response to PDGF. Hence, one strategy to overcome this 'pericyt
Branching Random Walk in an inhomogeneous breeding potential
Sergey Bocharov,Simon C. Harris
Mathematics , 2013,
Abstract: We consider a continuous-time branching random walk in the inhomogeneous breeding potential $\beta|.|^p$, where $\beta > 0$, $p \geq 0$. We prove that the population almost surely explodes in finite time if $p > 1$ and doesn't explode if $p \leq 1$. In the non-explosive cases, we determine the asymptotic behaviour of the rightmost particle.
Branching Brownian Motion with catalytic branching at the origin
Sergey Bocharov,Simon C. Harris
Mathematics , 2013,
Abstract: We consider a branching Brownian motion in which binary fission takes place only when particles are at the origin at a rate \beta > 0 on the local time scale. We obtain results regarding the asymptotic behaviour of the number of particles above \lambda t at time t, for \lambda > 0. As a corollary, we establish the almost sure asymptotic speed of the rightmost particle. We also prove a Strong Law of Large Numbers for this catalytic branching Brownian motion.
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