JMM Profile: Actinobacillus pleuropneumoniae: a major cause of lung disease in pigs but difficult to control and eradicate

The Gram-negative bacterium Actinobacillus pleuropneumoniae is the causative agent of pleuropneumonia in pigs, its only known natural host. Typical symptoms of peracute disease include fever, apathy and anorexia, and time from infection to death may only be 6 h. Severe lung lesions result from presence of one or two of the ApxI-III toxins. Control is through good husbandry practice, vaccines and antibiotic use. Culture and presence of the species-specific apxIV gene by PCR confirms diagnosis, and identification of serovar, of which 19 are known, informs on appropriate vaccine use and epidemiology

Characterisation of the Actinobacillus pleuropneumoniae SXT-related Integrative and Conjugative Element ICEApl2, and analysis of the encoded FloR protein: hydrophobic residues in transmembrane domains contribute dynamically to florfenicol and chloramphenicol efflux

Objectives To characterize ICEApl2, an SXT-related integrative and conjugative element (ICE) found in a clinical isolate of the porcine pathogen Actinobacillus pleuropneumoniae, and analyse the functional nature of the encoded FloR. Methods ICEApl2 was identified in the genome of A. pleuropneumoniae MIDG3553. Functional analysis was done using conjugal transfer experiments. MIDG3553 was tested for susceptibility to the antimicrobials for which resistance genes are present in ICEApl2. Lack of florfenicol/chloramphenicol resistance conferred by the encoded FloR protein was investigated by cloning and site-directed mutagenesis experiments in Escherichia coli. Results ICEApl2 is 92 660 bp and contains 89 genes. Comparative sequence analysis indicated that ICEApl2 is a member of the SXT/R391 ICE family. Conjugation experiments showed that, although ICEApl2 is capable of excision from the chromosome, it is not self-transmissible. ICEApl2 encodes the antimicrobial resistance genes floR, strAB, sul2 and dfrA1, and MIDG3553 is resistant to streptomycin, sulfisoxazole and trimethoprim, but not florfenicol or chloramphenicol. Cloning and site-directed mutagenesis of the floR gene revealed the importance of the nature of the hydrophobic amino acid residues at positions 160 and 228 in FloR for determining resistance to florfenicol and chloramphenicol. Conclusions Our results indicate that the nature of hydrophobic residues at positions 160 and 228 of FloR contribute dynamically to specific efflux of florfenicol and chloramphenicol, although some differences in resistance levels may depend on the bacterial host species. This is also, to our knowledge, the first description of an SXT/R391 ICE in A. pleuropneumoniae or any member of the Pasteurellaceae

An Empirical Study of Finding Approximate Equilibria in Bimatrix Games

While there have been a number of studies about the efficacy of methods to find exact Nash equilibria in bimatrix games, there has been little empirical work on finding approximate Nash equilibria. Here we provide such a study that compares a number of approximation methods and exact methods. In particular, we explore the trade-off between the quality of approximate equilibrium and the required running time to find one. We found that the existing library GAMUT, which has been the de facto standard that has been used to test exact methods, is insufficient as a test bed for approximation methods since many of its games have pure equilibria or other easy-to-find good approximate equilibria. We extend the breadth and depth of our study by including new interesting families of bimatrix games, and studying bimatrix games upto size $2000 \times 2000$. Finally, we provide new close-to-worst-case examples for the best-performing algorithms for finding approximate Nash equilibria

Phase diagram of the metal-insulator transition in 2D electronic systems

We investigated the interdependence of the effects of disorder and carrier correlations on the metal-insulator transition in two-dimensional electronic systems. We present a quantitative metal-insulator phase diagram. Depending on the carrier density we find two different types of metal-insulator transition - a continuous localization for rs=<8 and a discontinuous transition at higher rs. The critical level of disorder at the transition decreases with decreasing carrier density. At very low carrier densities we find that the system is always insulating. The value of the conductivity at the transition is consistent with recent experimental measurements. The self-consistent method which we have developed includes the effects of both disorder and correlations on the transition, using a density relaxation theory with the Coulomb correlations determined from numerical simulation data.Comment: 4 pages, RevTeX + epsf, 5 figures. New comments on conducting phase and on the conductivity. References updated and correcte

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

Abstract Background Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. Methods To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. Results The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. Conclusions This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1

An ambient agent architecture exploiting automated cognitive analysis

In this paper an agent-based ambient agent architecture is presented based on monitoring human's interaction with his or her environment and performing cognitive analysis of the causes of observed or predicted behaviour. Within this agent architecture, a cognitive model for the human is taken as a point of departure. From the cognitive model it is automatically derived how internal cognitive states affect human's performance aspects. Furthermore, for these cognitive states representation relations are derived from the cognitive model, expressed by temporal specifications involving events that will be monitored. The representation relations are verified on the monitoring information automatically, resulting in the identification of cognitive states, which affect the performance aspects. In such a way the ambient agent model is able to provide a more in depth cognitive analysis of causes of (un)satisfactory performance and based on this analysis to generate interventions in a knowledgeable manner. The application of the architecture proposed is demonstrated by two examples from the ambient-assisted living domain and the computer-assisted instruction domain. © 2011 The Author(s)