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Search Results: 1 - 10 of 153744 matches for " Matthew B Avison "
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New approaches to combating antimicrobial drug resistance
Matthew B Avison
Genome Biology , 2006, DOI: 10.1186/gb-2005-6-13-243
Abstract: Bacterial resistance to antimicrobial drugs is currently receiving much publicity and political attention. The cost to health services around the world is counted in billions of dollars; an increase in morbidity and mortality are the costs to those infected. The problem is getting worse and treatment options for combating bacteria resistant to multiple drugs are narrowing. Unless something is done, we may well return to the horrors of the pre-antibiotic era. In a recent article, Cirz and colleagues [1] report the interesting finding that the rate of resistance to some drugs in Escherichia coli can be greatly reduced by interfering with a bacterial stress response. This article sets the work by Cirz et al. [1] in the general context of antimicrobial drug resistance and discusses whether this new finding could be helpful in the battle against the rise of drug-resistant bacteria.Resistance to antimicrobials occurs in four main ways (Figure 1). The first possible mechanism is the mutation of the drug's target; a classic example of this is the mutation of gyrA, encoding the essential DNA gyrase A subunit, the major target of quinolones such as ciprofloxacin in E. coli [2]. A second mechanism is a bypass of the drug's target by the acquisition of a similar but insensitive target protein. A good example here would be the acquisition of a plasmid-borne dihydrofolate reductase (DHFR) insensitive to trimethoprim; the acquired DHFR compensates for the inhibition of the host's DHFR in the presence of trimethoprim and is the predominant cause of resistance to this antimicrobial drug in E. coli [3]. A third mechanism is the enzymatic degradation or modification of the drug; a well-known example is the destruction of β-lactam antibiotics by plasmid-mediated TEM β-lactamase, which accounts for around 90% of all ampicillin resistance in E. coli [4]. And fourth, resistance can be caused by a nonspecific reduced permeability to antimicrobial drugs. This is typically caused by reduced
The complete genome, comparative and functional analysis of Stenotrophomonas maltophilia reveals an organism heavily shielded by drug resistance determinants
Lisa C Crossman, Virginia C Gould, J Maxwell Dow, Georgios S Vernikos, Aki Okazaki, Mohammed Sebaihia, David Saunders, Claire Arrowsmith, Tim Carver, Nicholas Peters, Ellen Adlem, Arnaud Kerhornou, Angela Lord, Lee Murphy, Katharine Seeger, Robert Squares, Simon Rutter, Michael A Quail, Mari-Adele Rajandream, David Harris, Carol Churcher, Stephen D Bentley, Julian Parkhill, Nicholas R Thomson, Matthew B Avison
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-4-r74
Abstract: The genome of the bacteremia-associated isolate S. maltophilia K279a is 4,851,126 bp and of high G+C content. The sequence reveals an organism with a remarkable capacity for drug and heavy metal resistance. In addition to a number of genes conferring resistance to antimicrobial drugs of different classes via alternative mechanisms, nine resistance-nodulation-division (RND)-type putative antimicrobial efflux systems are present. Functional genomic analysis confirms a role in drug resistance for several of the novel RND efflux pumps. S. maltophilia possesses potentially mobile regions of DNA and encodes a number of pili and fimbriae likely to be involved in adhesion and biofilm formation that may also contribute to increased antimicrobial drug resistance.The panoply of antimicrobial drug resistance genes and mobile genetic elements found suggests that the organism can act as a reservoir of antimicrobial drug resistance determinants in a clinical environment, which is an issue of considerable concern.The rise of antimicrobial drug resistance in bacteria is one of the biggest threats to healthcare provision in the developed world. Few new antimicrobial drugs are undergoing clinical trials, and almost none are effective against Gram-negative multi-drug resistant (MDR) pathogens [1]. A return to the pre-antibiotic era is a possibility, and for some infections is the current reality [2].Antimicrobial resistance in historically common pathogens is usually either acquired on a mobile genetic element or results from a mutation [3]. However, some opportunistic pathogens are intrinsically resistant to the actions of a number of antimicrobial classes. These tend to be of environmental origin, and their intrinsic drug resistance determinants either provide resistance to antibiotics produced by competitors, or represent broad-spectrum methods for removing toxic compounds or waste products that, by chance, protect against antimicrobials [3,4]. It is known that established opportuni
Isolation of Salmonella Mutants Resistant to the Inhibitory Effect of Salicylidene acylhydrazides on Flagella-Mediated Motility
Isabel Martinez-Argudo, Andreas K. J. Veenendaal, Xia Liu, A. Dorothea Roehrich, Maria C. Ronessen, Giulia Franzoni, Katerine N. van Rietschoten, Yusuke V. Morimoto, Yumiko Saijo-Hamano, Matthew B. Avison, David J. Studholme, Keiichi Namba, Tohru Minamino, Ariel J. Blocker
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052179
Abstract: Salicylidene acylhydrazides identified as inhibitors of virulence-mediating type III secretion systems (T3SSs) potentially target their inner membrane export apparatus. They also lead to inhibition of flagellar T3SS-mediated swimming motility in Salmonella enterica serovar. Typhimurium. We show that INP0404 and INP0405 act by reducing the number of flagella/cell. These molecules still inhibit motility of a Salmonella ΔfliH-fliI-fliJ/flhB(P28T) strain, which lacks three soluble components of the flagellar T3S apparatus, suggesting that they are not the target of this drug family. We implemented a genetic screen to search for the inhibitors' molecular target(s) using motility assays in the ΔfliH-fliI/flhB(P28T) background. Both mutants identified were more motile than the background strain in the absence of the drugs, although HM18 was considerably more so. HM18 was more motile than its parent strain in the presence of both drugs while DI15 was only insensitive to INP0405. HM18 was hypermotile due to hyperflagellation, whereas DI15 was not hyperflagellated. HM18 was also resistant to a growth defect induced by high concentrations of the drugs. Whole-genome resequencing of HM18 indicated two alterations within protein coding regions, including one within atpB, which encodes the inner membrane a-subunit of the FOF1-ATP synthase. Reverse genetics indicated that the alteration in atpB was responsible for all of HM18's phenotypes. Genome sequencing of DI15 uncovered a single A562P mutation within a gene encoding the flagellar inner membrane protein FlhA, the direct role of which in mediating drug insensitivity could not be confirmed. We discuss the implications of these findings in terms of T3SS export apparatus function and drug target identification.
Robust Data Driven Model Order Estimation for Independent Component Analysis of fMRI Data with Low Contrast to Noise
Waqas Majeed, Malcolm J. Avison
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094943
Abstract: Independent component analysis (ICA) has been successfully utilized for analysis of functional MRI (fMRI) data for task related as well as resting state studies. Although it holds the promise of becoming an unbiased data-driven analysis technique, a few choices have to be made prior to performing ICA, selection of a method for determining the number of independent components (nIC) being one of them. Choice of nIC has been shown to influence the ICA maps, and various approaches (mostly relying on information theoretic criteria) have been proposed and implemented in commonly used ICA analysis packages, such as MELODIC and GIFT. However, there has been no consensus on the optimal method for nIC selection, and many studies utilize arbitrarily chosen values for nIC. Accurate and reliable determination of true nIC is especially important in the setting where the signals of interest contribute only a small fraction of the total variance, i.e. very low contrast-to-noise ratio (CNR), and/or very focal response. In this study, we evaluate the performance of different model order selection criteria and demonstrate that the model order selected based upon bootstrap stability of principal components yields more reliable and accurate estimates of model order. We then demonstrate the utility of this fully data-driven approach to detect weak and focal stimulus-driven responses in real data. Finally, we compare the performance of different multi-run ICA approaches using pseudo-real data.
A graphical tool for demonstrating the techniques of radio interferometry
Adam Avison,Samuel J George
Physics , 2012, DOI: 10.1088/0143-0807/34/1/7
Abstract: We present a graphical interface designed to demonstrate the techniques of radio interferometry used by telescopes like ALMA, e-Merlin, the JVLA and SKA, in a manner accessible to the general public. Interferometry is an observational tech- nique used by astronomers to combine the signal from a few to tens to hundreds of individual small antennas to achieve high resolution images at radio and millimetre wavelengths. This graphical interface demonstrates how the number of antenna, their position relative to one another and the rotation of the Earth allow astronomers to create highly detailed images at long wavelengths.
Remodeling of inhibitory synaptic connections in developing ferret visual cortex
Matthew B Dalva
Neural Development , 2010, DOI: 10.1186/1749-8104-5-5
Abstract: Using scanning laser photostimulation in slices of developing ferret visual cortex, we assessed the overall patterns of developing inhibitory and excitatory synaptic connections converging onto individual neurons. Inhibitory synaptic inputs onto pyramidal neurons in cortical layers 2 and 3 were already present as early as postnatal day 20, well before eye opening, and originated from regions close to the recorded neurons. During the ensuing 2 weeks, the numbers of synaptic inputs increased, with the numbers of inhibitory (and excitatory) synaptic inputs peaking near the time of eye opening. The pattern of inhibitory inputs refined rapidly prior to the refinement of excitatory inputs. By uncaging the neurotransmtter GABA in brain slices from animals of different ages, we find that this rapid refinement correlated with a loss of excitatory activity by GABA.Inhibitory synapses, like excitatory synapses, undergo significant postnatal remodeling. The time course of the remodeling of inhibitory connections correlates with the emergence of orientation tuning in the visual cortex, implicating these rearrangements in the genesis of adult cortical response properties.Inhibitory circuitry in the cortex is generated through a diverse array of specific types of inhibitory neurons. Local inhibitory interactions target specific regions of neurons and act in particular layers of cortex [1]. Generation of these specific connections relies on molecular cues and neuronal activity [2,3]. Importantly, the emergence of the adult pattern of GABAergic connections has been shown to correlate with periods of cortical plasticity and the development of mature cortical response properties [4]. However, less is known about the development of the inhibitory inputs onto excitatory neurons within cortical layers.Pyramidal neurons form roughly 80% of neurons in layers 2/3 and 5 and send long axon collaterals horizontally to interconnect functionally similar domains. During development of layers 2 an
A linear program for testing local realism
Matthew B. Elliott
Physics , 2009,
Abstract: We present a linear program that is capable of determining whether a set of correlations can be captured by a local realistic model. If the correlations can be described by such a model, the linear program outputs a joint probability distribution that produces the given correlations. If the correlations cannot be described under the assumption of local realism, the program outputs a Bell inequality violated by the correlations.
Statistical Test for Dynamical Nonstationarity in Observed Time-Series Data
Matthew B. Kennel
Physics , 1995,
Abstract: Information in the time distribution of points in a state space reconstructed from observed data yields a test for ``nonstationarity''. Framed in terms of a statistical hypothesis test, this numerical algorithm can discern whether some underlying slow changes in parameters have taken place. The method examines a fundamental object in nonlinear dynamics, the geometry of orbits in state space, with corrections to overcome difficulties in real dynamical data which cause naive statistics to fail.
Renormalization Theory of Stochastic Growth
Matthew B. Hastings
Physics , 1996, DOI: 10.1103/PhysRevE.55.135
Abstract: An analytical renormalization group treatment is presented of a model which, for one value of parameters, is equivalent to diffusion limited aggregation. The fractal dimension of DLA is computed to be 2-1/2+1/5=1.7. Higher multifractal exponents are also calculated and found in agreement with numerical results. It may be possible to use this technique to describe the dielectric breakdown model as well, which is given by different parameter values.
Stabilizer states and local realism
Matthew B. Elliott
Physics , 2008,
Abstract: The central focus of this work is to make progress towards understanding entanglement as a resource for computation by examining the quantum correlations that can be extracted from stabilizer states. As such, we focus on the stabilizer formalism, local realism, and the convergence of the two.
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