Computational approaches for discovery of mutational signatures in cancer.

The accumulation of somatic mutations in a genome is the result of the activity of one or more mutagenic processes, each of which leaves its own imprint. The study of these DNA fingerprints, termed mutational signatures, holds important potential for furthering our understanding of the causes and evolution of cancer, and can provide insights of relevance for cancer prevention and treatment. In this review, we focus our attention on the mathematical models and computational techniques that have driven recent advances in the field

Corporate social responsibility:reviewed, rated, revised

Purpose: Critical literature review of CSR research in both general management and hospitality management literature. Discusses trends,commonalities, and inconsistencies to better understand the state of contemporary scholarship, and calls for a context-specific conceptual engagement with the phenomenon.Design/Methodology/Approach: Systematic literature review, noting and critiquing a general tendency towards measurement of financial and other internal benefit impacts.Findings: Hospitality management is well-positioned to evaluate the opportunities and challenges of CSR, yet research has uncritically adopted the instrumental emphasis on assessing processes, perceptions, and private profitability from the general management literature, without engaging on a contextually-specific and/or theoretical level.Research limitations: CSR research is abundant and therefore difficult to summarise in one article.The primarily Anglo-American and Asian contextual bias is reflected in this review.Practical implications: Consistently inconsistent results challenge the portability of financial impact studies.Studies are needed to re-evaluate the concept of CSR as it pertains to hospitality, and measure the effectiveness of CSR activities relative to context and resource availability.Social implications: Further research into the scope of CSR in hospitality management, with an emphasis on recuperating social value, would lead to widespread positive social implications.Originality/value: This critical review offers a new perspective on CSR in the hospitality literature and industry, calling for a reconsideration of the concept in context, and formulates a working definition

Galaxy Zoo: The large-scale spin statistics of spiral galaxies in the Sloan Digital Sky Survey

We re-examine the evidence for a violation of large-scale statistical isotropy in the distribution of projected spin vectors of spiral galaxies. We have a sample of $\sim 37,000$ spiral galaxies from the Sloan Digital Sky Survey, with their line of sight spin direction confidently classified by members of the public through the online project Galaxy Zoo. After establishing and correcting for a certain level of bias in our handedness results we find the winding sense of the galaxies to be consistent with statistical isotropy. In particular we find no significant dipole signal, and thus no evidence for overall preferred handedness of the Universe. We compare this result to those of other authors and conclude that these may also be affected and explained by a bias effect.Comment: Accepted for publication in MNRAS. 8 pages, 5 figure

Assessing the potential of RAD-sequencing to resolve phylogenetic relationships within species radiations: The fly genus Chiastocheta (Diptera: Anthomyiidae) as a case study

Determining phylogenetic relationships among recently diverged species has long been a challenge in evolutionary biology. Cytoplasmic DNA markers, which have been widely used, notably in the context of molecular barcoding, have not always proved successful in resolving such phylogenies. However, with the advent of next-generation-sequencing technologies and associated techniques of reduced genome representation, phylogenies of closely related species have been resolved at a much higher detail in the last couple of years. Here we examine the potential and limitations of one of such techniques—Restriction-site Associated DNA (RAD) sequencing, a method that produces thousands of (mostly) anonymous nuclear markers, in disentangling the phylogeny of the fly genus Chiastocheta (Diptera: Anthomyiidae). In Europe, this genus encompasses seven species of seed predators, which have been widely studied in the context of their ecological and evolutionary interactions with the plant Trollius europaeus (Ranunculaceae). So far, phylogenetic analyses using mitochondrial markers failed to resolve monophyly of most of the species from this recently diversified genus, suggesting that their taxonomy may need a revision. However, relying on a single, non-recombining marker and ignoring potential incongruences between mitochondrial and nuclear loci may provide an incomplete account of the lineage history. In this study, we applied both classical Sanger sequencing of three mtDNA regions and RAD-sequencing, for reconstructing the phylogeny of the genus. Contrasting with results based on mitochondrial markers, RAD-sequencing analyses retrieved the monophyly of all seven species, in agreement with the morphological species assignment. We found robust nuclear-based species assignment of individual samples, and low levels of estimated contemporary gene flow among them. However, despite recovering species’ monophyly, interspecific relationships varied depending on the set of RAD loci considered, producing contradictory topologies. Moreover, coalescence-based phylogenetic analyses revealed low supports for most of the interspecific relationships. Our results indicate that despite the higher performance of RAD-sequencing in terms of species trees resolution compared to cytoplasmic markers, reconstructing inter-specific relationships among recently-diverged lineages may lie beyond the possibilities offered by large sets of RAD-sequencing markers in cases of strong gene tree incongruence

Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure

Objectives: The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. Background: Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin–angiotensin system. Methods: In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. Results: At screening, the eGFR was 70 ± 20 ml/min/1.73 m2 and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (−1.61 ml/min/1.73 m2/year; [95% confidence interval: −1.77 to −1.44 ml/min/1.73 m2/year] vs. −2.04 ml/min/1.73 m2/year [95% CI: −2.21 to −1.88 ml/min/1.73 m2/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). Conclusions: Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR

Travelling for Umrah:destination attributes, destination image, and post-travel intentions

This paper examines the links between cosmopolitanism, self-identity, and a desire for social interaction perceived destination image and behavioural intentions. A model tested using a sample of 538 Iranian visitors to Mecca for the purpose of Umrah. The result from the structural model suggests that destination attributes influence perceived destination image. Further, such tourists are likely to revisit or recommend Islamic destinations if their experience matches their perceived image of the destination. This implies that, while the religious characteristics of the destination remain important, destination managers cannot disregard the tangential, non-religious attributes of a destination which are crucial in order to satisfy more conventional tourist desires. As such, this study suggests that those managing religious travel destinations should endeavour to foster a welcoming image, where experience, interaction and tolerance are at the forefront of the destination’s offering

The OMA orthology database in 2015: function predictions, better plant support, synteny view and other improvements

The Orthologous Matrix (OMA) project is a method and associated database inferring evolutionary relationships amongst currently 1706 complete proteomes (i.e. the protein sequence associated for every protein-coding gene in all genomes). In this update article, we present six major new developments in OMA: (i) a new web interface; (ii) Gene Ontology function predictions as part of the OMA pipeline; (iii) better support for plant genomes and in particular homeologs in the wheat genome; (iv) a new synteny viewer providing the genomic context of orthologs; (v) statically computed hierarchical orthologous groups subsets downloadable in OrthoXML format; and (vi) possibility to export parts of the all-against-all computations and to combine them with custom data for ‘client-side' orthology prediction. OMA can be accessed through the OMA Browser and various programmatic interfaces at http://omabrowser.or

Citrullination Was Introduced into Animals by Horizontal Gene Transfer from Cyanobacteria

Protein posttranslational modifications add great sophistication to biological systems. Citrullination, a key regulatory mechanism in human physiology and pathophysiology, is enigmatic from an evolutionary perspective. Although the citrullinating enzymes peptidylarginine deiminases (PADIs) are ubiquitous across vertebrates, they are absent from yeast, worms, and flies. Based on this distribution PADIs were proposed to have been horizontally transferred, but this has been contested. Here, we map the evolutionary trajectory of PADIs into the animal lineage. We present strong phylogenetic support for a clade encompassing animal and cyanobacterial PADIs that excludes fungal and other bacterial homologs. The animal and cyanobacterial PADI proteins share functionally relevant primary and tertiary synapomorphic sequences that are distinct from a second PADI type present in fungi and actinobacteria. Molecular clock calculations and sequence divergence analyses using the fossil record estimate the last common ancestor of the cyanobacterial and animal PADIs to be less than 1 billion years old. Additionally, under an assumption of vertical descent, PADI sequence change during this evolutionary time frame is anachronistically low, even when compared with products of likely endosymbiont gene transfer, mitochondrial proteins, and some of the most highly conserved sequences in life. The consilience of evidence indicates that PADIs were introduced from cyanobacteria into animals by horizontal gene transfer (HGT). The ancestral cyanobacterial PADI is enzymatically active and can citrullinate eukaryotic proteins, suggesting that the PADI HGT event introduced a new catalytic capability into the regulatory repertoire of animals. This study reveals the unusual evolution of a pleiotropic protein modification

Decadal changes in the mid-depth water mass dynamic of the Northeastern Atlantic margin (Bay of Biscay)

The lithium/magnesium (Li/Mg) molar ratios, radiocarbon measurements (?14C) and Nd-isotopic composition (eNd) of the aragonite skeleton of a branching cold-water coral (CWC) species Madrepora oculata collected alive in the Bay of Biscay at ~691 m water depth were investigated to reconstruct a robust record of the mid-depth water mass dynamics between 1950 and 1990 AD. Temperature estimates based on the skeletons Li/Mg molar ratios reveal small decadal changes of about 1 °C at thermocline depth synchronous to and of similar amplitude as surface temperature anomalies. ?14C measurements shows quasi-decadal oscillations of 15‰ around pre-bomb ?14C average value of -59±6‰ and post-bomb ?14C of -12±6‰, which most likely reflect decadal changes of water mass exchange across the thermocline. The coral eNd values remain in narrow ranges of -11.9 to -10.2, similar to the isotopic composition of East North Atlantic Central Water, but show highest values in the late 1950s, and early 1960s, 1970s, and 1980s. The punctuated changes of the coral Nd-isotopic composition may thus reflect periods of particular enhanced advection of temperate intermediate water (mid-depth Subpolar Gyre/Mediterranean Sea Water). Altogether, our robust multi-proxy record provides new evidence that Northern Hemisphere atmospheric variability (such as, North Atlantic Oscillation and East Atlantic pattern) drives changes not only in the thermocline but also in the mid-depth water-mass advection patterns in the Northeastern Atlantic margin. However, the interannual variability of our record remains to be tested