VESPA: Very large-scale Evolutionary and Selective Pressure Analyses

Background: Large-scale molecular evolutionary analyses of protein coding sequences requires a number of preparatory inter-related steps from finding gene families, to generating alignments and phylogenetic trees and assessing selective pressure variation. Each phase of these analyses can represent significant challenges, particularly when working with entire proteomes (all protein coding sequences in a genome) from a large number of species. Methods: We present VESPA, software capable of automating a selective pressure analysis using codeML in addition to the preparatory analyses and summary statistics. VESPA is written in python and Perl and is designed to run within a UNIX environment. Results: We have benchmarked VESPA and our results show that the method is consistent, performs well on both large scale and smaller scale datasets, and produces results in line with previously published datasets. Discussion: Large-scale gene family identification, sequence alignment, and phylogeny reconstruction are all important aspects of large-scale molecular evolutionary analyses. VESPA provides flexible software for simplifying these processes along with downstream selective pressure variation analyses. The software automatically interprets results from codeML and produces simplified summary files to assist the user in better understanding the results

A New Differential Positioning Method using Modulation Correlation of Signals of Opportunity

Global Navigation Satellite Systems (GNSS) have become the positioning systems of choice for many applications. However, GNSS signals are susceptible to obstruction, interference and jamming. Therefore, to maximize robustness and integrity, it is necessary to employ a dissimilar positioning technology that can operate independently and back-up GNSS. One such technology exploits 'signals of opportunity' - signals that are designed for purposes other than navigation.This paper presents a system that uses amplitude modulation (AM) radio broadcasts in the medium frequency (MF) band. At these frequencies, the predominant ground-wave propagation mode offers better coverage in remote areas and over sea than is achievable with higher frequency signals.The system is differential and operates by correlating modulation information between the reference and user receivers. A system of this form mitigates the deterioration in and around buildings encountered in prior systems and can provide absolute position using fewer signals than a system using only carrier phase.The system presented in this paper uses generalized cross correlation to obtain time difference of arrival measurements that are subsequently used for position determination. Preliminary results indicate the system provides a robust position solution. Moreover, the system offers the potential to be combined with carrier phase measurements to achieve enhanced performance, while the modulation correlation technique is readily extendable to other types of signal

A Differential Positioning System Using Modulation Correlation of Signals of Opportunity

Global Navigation Satellite Systems (GNSS) have become the positioning systems of choice for many applications. However, GNSS signals are susceptible to obstruction, interference and jamming. Therefore, to maximize robustness and integrity, it is necessary to employ a dissimilar positioning technology that can operate independently and back-up GNSS. One such technology exploits ‘signals of opportunity’ – signals that are designed for purposes other than navigation. This paper presents a system that uses amplitude modulation (AM) radio broadcasts in the medium frequency (MF) band. At these frequencies, the predominant ground-wave propagation mode offers better coverage in remote areas and over sea than is achievable with higher frequency signals. The system is differential and operates by correlating modulation information between the reference and user receivers. A system of this form mitigates the deterioration in and around buildings encountered in prior systems and can provide absolute position using fewer signals than a system using only carrier phase. The system presented in this paper uses generalized cross correlation to obtain time difference of arrival measurements that are subsequently used for position determination. Preliminary results indicate the system provides a robust position solution. Moreover, the system offers the potential to be combined with carrier phase measurements to achieve enhanced performance, while the modulation correlation technique is readily extendable to other types of signal

Adaptive Evolution as a Predictor of Species-Specific Innate Immune Response

It has been proposed that positive selection may be associated with protein functional change. For example, human and macaque have different outcomes to HIV infection and it has been shown that residues under positive selection in the macaque TRIM5α receptor locate to the region known to influence species-specific response to HIV. In general, however, the relationship between sequence and function has proven difficult to fully elucidate, and it is the role of large-scale studies to help bridge this gap in our understanding by revealing major patterns in the data that correlate genotype with function or phenotype. In this study, we investigate the level of species-specific positive selection in innate immune genes from human and mouse. In total, we analyzed 456 innate immune genes using codon-based models of evolution, comparing human, mouse, and 19 other vertebrate species to identify putative species-specific positive selection. Then we used population genomic data from the recently completed Neanderthal genome project, the 1000 human genomes project, and the 17 laboratory mouse genomes project to determine whether the residues that were putatively positively selected are fixed or variable in these populations. We find evidence of species-specific positive selection on both the human and the mouse branches and we show that the classes of genes under positive selection cluster by function and by interaction. Data from this study provide us with targets to test the relationship between positive selection and protein function and ultimately to test the relationship between positive selection and discordant phenotypes

A New Differential Positioning Technique Applicable to Generic FDMA Signals of Opportunity

A differential positioning technique is proposed that is capable of exploiting the many radio frequency (RF) signals that are transmitted using frequency division multiple access (FDMA). The technique is designed to operate on ‘signals of opportunity’ (signals that are designed for purposes other than navigation), and requires no knowledge of the modulation format or signal content. Example FDMA signals of opportunity include amplitude modulated (AM) broadcast signals, frequency modulated (FM) broadcast signals, and television signals. In principle, the system can operate simultaneously on these different types of signals, maximizing performance by exploiting heterogeneous signal qualities and using whatever signals are available at a particular location. As a result, the technology has the potential to provide positioning in Global Navigation Satellite System (GNSS) deprived environments, such as in urban canyons, and deep indoors. The proposed positioning technique operates by bringing portions of a signal received at reference and user locations together and adaptively correlation testing them. The correlation-testing is used to jointly estimate the differential time offset (DTO) and the differential frequency offset (DFO). In order to improve accuracy the DTO measurements are Doppler-smoothed using the DFO measurements. The DTO measurements are used to calculate ranging measurements that are used to obtain a position. The concept is experimentally validated on AM broadcast signals in the medium frequency (MF) and low frequency (LF) bands. Preliminary results indicate that the system provides a position solution in difficult environments, such as indoors. It is expected that expanding the system to incorporate more signals will result in significant performance gains

Secure referee selection for fair and responsive peer-to-peer gaming

Peer-to-Peer (P2P) architectures for Massively Multiplayer Online Games (MMOG) provide better scalability than Client/Server (C/S); however, they increase the possibility of cheating. Recently proposed P2P protocols use trusted referees that simulate/validate the game to provide security equivalent to C/S. When selecting referees from untrusted peers, selecting non-colluding referees becomes critical. Further, referees should be selected such that the range and length of delays to players is minimised (maximising game fairness and responsiveness). In this paper we formally define the referee selection problem and propose two secure referee selection algorithms, SRS-1 and SRS-2, to solve it. Both algorithms ensure the probability of corrupt referees controlling a zone/region is below a predefined limit, while attempting to maximise responsiveness and fairness. The trade-off between responsiveness and fairness is adjustable for both algorithms. Simulations of three different scenarios show the effectiveness of our algorithms

Erratum to: Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response

“Upon publication of the original article [1], it was noticed that there was an error in the author name. The author’s name should be "Micheál Mac Aogáin" instead of Micheál MacAogain.

Does clinical management improve outcomes following self-Harm? Results from the multicentre study of self-harm in England

Background Evidence to guide clinical management of self-harm is sparse, trials have recruited selected samples, and psychological treatments that are suggested in guidelines may not be available in routine practice. Aims To examine how the management that patients receive in hospital relates to subsequent outcome. Methods We identified episodes of self-harm presenting to three UK centres (Derby, Manchester, Oxford) over a 10 year period (2000 to 2009). We used established data collection systems to investigate the relationship between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for specialist mental health follow up) and repetition of self-harm within 12 months, adjusted for differences in baseline demographic and clinical characteristics. Results 35,938 individuals presented with self-harm during the study period. In two of the three centres, receiving a psychosocial assessment was associated with a 40% lower risk of repetition, Hazard Ratios (95% CIs): Centre A 0.99 (0.90–1.09); Centre B 0.59 (0.48–0.74); Centre C 0.59 (0.52–0.68). There was little indication that the apparent protective effects were mediated through referral and follow up arrangements. The association between psychosocial assessment and a reduced risk of repetition appeared to be least evident in those from the most deprived areas. Conclusion These findings add to the growing body of evidence that thorough assessment is central to the management of self-harm, but further work is needed to elucidate the possible mechanisms and explore the effects in different clinical subgroups

Identification and proteomic profiling of exosomes in human cerebrospinal fluid

<p>Abstract</p> <p>Background</p> <p>Exosomes are released from multiple cell types, contain protein and RNA species, and have been exploited as a novel reservoir for disease biomarker discovery. They can transfer information between cells and may cause pathology, for example, a role for exosomes has been proposed in the pathophysiology of Alzheimer's disease. Although studied in several biofluids, exosomes have not been extensively studied in the cerebrospinal fluid (CSF) from humans. The objective of this study was to determine: 1) whether human CSF contains exosomes and 2) the variability in exosomal protein content across individuals.</p> <p>Methods</p> <p>CSF was collected from 5 study participants undergoing thoraco-abdominal aortic aneurysm repair (around 200 - 500 ml per participant) and low-density membrane vesicles were concentrated by ultracentrifugation. The presence of exosomes was determined by western blot for marker proteins, isopycnic centrifugation on a sucrose step gradient and transmission electron microscopy with immuno-labelling. Whole protein profiling was performed using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR).</p> <p>Results</p> <p>Flotillin 1 and tumor susceptibility gene 101 (TSG101), two exosomal marker proteins, were identified in the ultracentrifugation pellet using western blot. These markers localized to a density consistent with exosomes following isopycnic centrifugation. Transmission electron microscopy visualized structures consistent with exosomes in size and appearance that labelled positive for flotillin 1. Therefore, the pellet that resulted from ultracentrifugation of human CSF contained exosomes. FT-ICR profiling of this pellet was performed and 84-161 ions were detected per study participant. Around one third of these ions were only present in a single study participant and one third were detected in all five. With regard to ion quantity, the median coefficient of variation was 81% for ions detected in two or more samples.</p> <p>Conclusions</p> <p>Exosomes were identified in human CSF and their proteome is a potential new reservoir for biomarker discovery in neurological disorders such as Alzheimer's disease. However, techniques used to concentrate exosomes from CSF need refinement to reduce variability. In this study we used relatively large starting volumes of human CSF, future studies will focus on exosome isolation from smaller 'real life' clinical samples; a key challenge in the development of exosomes as translational tools.</p