Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

A pilot Internet "Value of Health" Panel: recruitment, participation and compliance

Objectives To pilot using a panel of members of the public to provide preference data via the Internet Methods A stratified random sample of members of the general public was recruited and familiarised with the standard gamble procedure using an Internet based tool. Health states were perdiodically presented in "sets" corresponding to different conditions, during the study. The following were described: Recruitment (proportion of people approached who were trained); Participation (a) the proportion of people trained who provided any preferences and (b) the proportion of panel members who contributed to each "set" of values; and Compliance (the proportion, per participant, of preference tasks which were completed). The influence of covariates on these outcomes was investigated using univariate and multivariate analyses. Results A panel of 112 people was recruited. 23% of those approached (n = 5,320) responded to the invitation, and 24% of respondents (n = 1,215) were willing to participate (net = 5.5%). However, eventual recruitment rates, following training, were low (2.1% of those approached). Recruitment from areas of high socioeconomic deprivation and among ethnic minority communities was low. Eighteen sets of health state descriptions were considered over 14 months. 74% of panel members carried out at least one valuation task. People from areas of higher socioeconomic deprivation and unmarried people were less likely to participate. An average of 41% of panel members expressed preferences on each set of descriptions. Compliance ranged from 3% to 100%. Conclusion It is feasible to establish a panel of members of the general public to express preferences on a wide range of health state descriptions using the Internet, although differential recruitment and attrition are important challenges. Particular attention to recruitment and retention in areas of high socioeconomic deprivation and among ethnic minority communities is necessary. Nevertheless, the panel approach to preference measurement using the Internet offers the potential to provide specific utility data in a responsive manner for use in economic evaluations and to address some of the outstanding methodological uncertainties in this field

Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model

<p>Abstract</p> <p>Background</p> <p>Ethyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury.</p> <p>Objective</p> <p>To evaluate the effect of ethyl EP on improving the survival in mice with LPS-induced acute lung injury (ALI).</p> <p>Methods</p> <p>ALI was induced by administering lipopolysaccharide (LPS) intratracheally. The mice were treated intraperitoneally (i.p.) with 100, 50 and 10 mg/kg EP immediately before intratracheal instillation of LPS, and 100 mg/kg EP was administered 0, 12, 24 and 48 hours after induction of ALI. The mortality rate was recorded and analyzed by the Kaplan-Meier method. Serum tumor necrosis factor (TNF)-α, interleukin (IL) -6 and IL-1 β were measured in bronchial alveolar lavage fluid using an enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured by Western immunoblotting.</p> <p>Results</p> <p>Treatment with EP significantly inhibited the release of HMGB1, TNF-α, IL-6 and IL-1β into bronchoalveolar lavage (BAL) fluids of ALI mice, and reduced the permeability index of the injured lung. High EP doses reduced the mortality from ALI and the permeability index (100 mg/kg and 50 mg/kg EP versus control; P < 0.0001). Early administration of high-dose EP significantly increased survival rate (0, 12 and 24 h versus control; P < 0.0001, P < 0.0001 and P = 0.01 respectively by log-rank test). There was no survival advantage when EP was initiated at 48 h.</p> <p>Conclusion</p> <p>Ethyl pyruvate improves survival and reduces the lung permeability index in mice with LPS-induced ALI.</p

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

Narcissism in patients admitted to psychiatric acute wards: its relation to violence, suicidality and other psychopathology

<p>Abstract</p> <p>Background</p> <p>The objective was to examine various aspects of narcissism in patients admitted to acute psychiatric wards and to compare their level of narcissism to that of an age- and gender-matched sample from the general population (NORM).</p> <p>Methods</p> <p>This cross-sectional study interviewed 186 eligible acute psychiatric patients with the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning (GAF). The patients filled in the Narcissistic Personality Inventory-21 item version (NPI-21), The Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self-Esteem Scale. High and low narcissism was defined by the median of the total NPI-21 score. An age- and gender-matched control sample from the general population also scored the NPI-21 (NORM).</p> <p>Results</p> <p>Being male, involuntary admitted, having diagnosis of schizophrenia, higher self-esteem, and severe violence were significantly associated with high narcissism, and so were also low levels of suicidality, depression, anxiety and GAF scores. Severe violence and high self-esteem were significantly associated with high narcissism in multivariable analyses. The NPI-21 and its subscales showed test-retest correlations ≥0.83, while the BPRS and the HADS showed lower correlations, confirming the trait character of the NPI-21. Depression and suicidality were negatively associated with the NPI-21 total score and all its subscales, while positive association was observed with grandiosity. No significant differences were observed between patients and NORM on the NPI-21 total score or any of the NPI subscales.</p> <p>Conclusion</p> <p>Narcissism in the psychiatric patients was significantly associated with violence, suicidality and other symptoms relevant for management and treatment planning. Due to its trait character, use of the NPI-21 in acute psychiatric patients can give important clinical information. The similar level of narcissism found in patients and NORM is in need of further examination.</p

High performance computing for haplotyping: Models and platforms

\u3cp\u3eThe reconstruction of the haplotype pair for each chromosome is a hot topic in Bioinformatics and Genome Analysis. In Haplotype Assembly (HA), all heterozygous Single Nucleotide Polymorphisms (SNPs) have to be assigned to exactly one of the two chromosomes. In this work, we outline the state-of-the-art on HA approaches and present an in-depth analysis of the computational performance of GenHap, a recent method based on Genetic Algorithms. GenHap was designed to tackle the computational complexity of the HA problem by means of a divide-et-impera strategy that effectively leverages multi-core architectures. In order to evaluate GenHap’s performance, we generated different instances of synthetic (yet realistic) data exploiting empirical error models of four different sequencing platforms (namely, Illumina NovaSeq, Roche/454, PacBio RS II and Oxford Nanopore Technologies MinION). Our results show that the processing time generally decreases along with the read length, involving a lower number of sub-problems to be distributed on multiple cores.\u3c/p\u3

Hyperspectral image analysis techniques for the detection and classification of the early onset of plant disease and stress

This review explores how imaging techniques are being developed with a focus on deployment for crop monitoring methods. Imaging applications are discussed in relation to both field and glasshouse-based plants, and techniques are sectioned into ‘healthy and diseased plant classification’ with an emphasis on classification accuracy, early detection of stress, and disease severity. A central focus of the review is the use of hyperspectral imaging and how this is being utilised to find additional information about plant health, and the ability to predict onset of disease. A summary of techniques used to detect biotic and abiotic stress in plants is presented, including the level of accuracy associated with each method

Natural Single-Nucleosome Epi-Polymorphisms in Yeast

Epigenomes commonly refer to the sequence of presence/absence of specific epigenetic marks along eukaryotic chromatin. Complete histone-borne epigenomes have now been described at single-nucleosome resolution from various organisms, tissues, developmental stages, or diseases, yet their intra-species natural variation has never been investigated. We describe here that the epigenomic sequence of histone H3 acetylation at Lysine 14 (H3K14ac) differs greatly between two unrelated strains of the yeast Saccharomyces cerevisiae. Using single-nucleosome chromatin immunoprecipitation and mapping, we interrogated 58,694 nucleosomes and found that 5,442 of them differed in their level of H3K14 acetylation, at a false discovery rate (FDR) of 0.0001. These Single Nucleosome Epi-Polymorphisms (SNEPs) were enriched at regulatory sites and conserved non-coding DNA sequences. Surprisingly, higher acetylation in one strain did not imply higher expression of the relevant gene. However, SNEPs were enriched in genes of high transcriptional variability and one SNEP was associated with the strength of gene activation upon stimulation. Our observations suggest a high level of inter-individual epigenomic variation in natural populations, with essential questions on the origin of this diversity and its relevance to gene x environment interactions