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Cancer-associated fibroblasts (CAFs) are one of the most significant components in the tumour microenvironment (TME), where they can perform several protumourigenic functions. Several studies have recently reported that CAFs are more heterogenous and plastic than was previously thought. As such, there has been a shift in the field to study CAF subpopulations and the emergent functions of these subsets in tumourigenesis. In this review, we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC). We also discuss therapeutic approaches to selectively target protumourigenic CAF functions, while avoiding normal fibroblasts, providing insight into the future of stromal targeting for the treatment of PDAC and other solid tumours.

Real-world studies show that the facial expressions produced during pain and orgasm—two different and intense affective experiences—are virtually indistinguishable. However, this finding is counterintuitive, because facial expressions are widely considered to be a powerful tool for social interaction. Consequently, debate continues as to whether the facial expressions of these extreme positive and negative affective states serve a communicative function. Here, we address this debate from a novel angle by modeling the mental representations of dynamic facial expressions of pain and orgasm in 40 observers in each of two cultures (Western, East Asian) using a data-driven method. Using a complementary approach of machine learning, an information-theoretic analysis, and a human perceptual discrimination task, we show that mental representations of pain and orgasm are physically and perceptually distinct in each culture. Cross-cultural comparisons also revealed that pain is represented by similar face movements across cultures, whereas orgasm showed distinct cultural accents. Together, our data show that mental representations of the facial expressions of pain and orgasm are distinct, which questions their nondiagnosticity and instead suggests they could be used for communicative purposes. Our results also highlight the potential role of cultural and perceptual factors in shaping the mental representation of these facial expressions. We discuss new research directions to further explore their relationship to the production of facial expressions. Significance Humans often use facial expressions to communicate social messages. However, observational studies report that people experiencing pain or orgasm produce facial expressions that are indistinguishable, which questions their role as an effective tool for communication. Here, we investigate this counterintuitive finding using a new data-driven approach to model the mental representations of facial expressions of pain and orgasm in individuals from two different cultures. Using complementary analyses, we show that representations of pain and orgasm are distinct in each culture. We also show that pain is represented with similar face movements across cultures, whereas orgasm shows differences. Our findings therefore inform understanding of the possible communicative role of facial expressions of pain and orgasm, and how culture could shape their representation.

Introduction: \ud Recent in-vitro studies have suggested that a critical checkpoint early in the inflammatory process involves the interaction between neutrophils and platelets. This confirms the importance of the innate immune system in the elaboration of the systemic inflammatory response. The aim of the present study was to examine whether a combination of the neutrophil and platelet counts were predictive of survival in patients with cancer.\ud Methods: \ud Patients with histologically proven colorectal cancer who underwent potentially curative resection at a single centre between March 1999 and May 2013 (n = 796) and patients with cancer from the Glasgow Inflammation Outcome Study, who had a blood sample taken between January 2000 and December 2007 (n = 9649) were included in the analysis.\ud Results: \ud In the colorectal cancer cohort, there were 173 cancer and 135 non-cancer deaths. In patients undergoing elective surgery, cancer-specific survival (CSS) at 5 years ranged from 97% in patients with TNM I disease and NPS = 0 to 57% in patients with TNM III disease and NPS = 2 (p = 0.019) and in patients undergoing elective surgery for node-negative colon cancer from 98% (TNM I, NPS = 0) to 65% (TNM II, NPS = 2) (p = 0.004). In those with a variety of common cancers there were 5218 cancer and 929 non-cancer deaths. On multivariate analysis, adjusting for age and sex and stratified by tumour site, incremental increase in the NPS was significantly associated with poorer CSS (p<0.001).\ud Conclusion: \ud The neutrophil-platelet score predicted survival in a variety of common cancers and highlights the importance of the innate immune system in patients with cancer.

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Background Epilepsy affects around 1% of people, but existing antiepileptic drugs (AEDs) only offer symptomatic relief and are ineffective in approximately 30% of patients. Hence, new AEDs are sorely needed. However, a major bottleneck is the low-throughput nature of early-stage AED screens in conventional rodent models. This process could potentially be expedited by using simpler invertebrate systems, such as the nematode Caenorhabditis elegans. New method Head-bobbing convulsions were previously reported to be inducible by pentylenetetrazol (PTZ) in C. elegans with loss-of-function mutations in unc-49, which encodes a GABAA receptor. Given that epilepsy-linked mutations in human GABAA receptors are well documented, this could represent a clinically-relevant system for early-stage AED screens. However, the original agar plate-based assay is unsuited to large-scale screening and has not been validated for identifying AEDs. Therefore, we established an alternative streamlined, higher-throughput approach whereby mutants were treated with PTZ and AEDs via liquid-based incubation. Results Convulsions induced within minutes of PTZ exposure in unc-49 mutants were strongly inhibited by the established AED ethosuximide. This protective activity was independent of ethosuximide’s suggested target, the T-type calcium channel, as a null mutation in the worm cca-1 ortholog did not affect ethosuximide’s anticonvulsant action. Comparison with existing method Our streamlined assay is AED-validated, feasible for higher throughput compound screens, and can facilitate insights into AED mechanisms of action. Conclusions Based on an epilepsy-associated genetic background, this C. elegans unc-49 model of seizure-like activity presents an ethical, higher throughput alternative to conventional rodent seizure models for initial AED screens. Highlights • Worms with mutant GABAA receptors exhibit convulsions upon exposure to pentylenetetrazol. • Convulsions are prevented by the approved anti-epileptic drug, ethosuximide. • C. elegans model is a higher throughput, ethical alternative to rodent seizure models.

Viruses have often evolved overlapping reading frames in order to maximise their coding capacity. Until recently, the segmented double-stranded (ds) RNA genome of viruses of the Orbivirus genus was thought to be monocistronic but the identification of the bluetongue virus (BTV) NS4 protein changed this assumption. A small open reading frame (ORF) in segment 10, overlapping the NS3 ORF in the +1 position that is maintained in more than 300 strains of the 26 different BTV serotypes and in more of 200 strains of the phylogenetically related African horse sickness (AHSV). In BTV, this ORF (named S10-ORF2 in this study) encodes a putative protein of 50-59 amino acid residues in length and appears to be under a strong positive selection. HA- or GFP-tagged versions of S10-ORF2 expressed from transfected plasmids localised within the nucleoli of transfected cells unless a putative nucleolar localisation signal was mutated S10-ORF2 inhibited gene expression, but not RNA translation, in transient transfection reporter assays. In both mammalian and insect cells, BTV S10-ORF2 deletion mutants (BTV8ΔS10-ORF2) displayed similar replication kinetics to wild type virus. In vivo, S10-ORF2 deletion mutants were pathogenic in mouse models of disease. Although further evidence is required for S10-ORF2 expression during infection, the data presented provide an initial characterisation of this open reading frame.

Abstract Statistical emulators are used to approximate the output of complex physical models when their computational burden limits any sensitivity and uncertainty analysis of model output to variation in the model inputs. In this paper, we introduce a flexible emulator which is able to handle multivariate model outputs and missing values. The emulator is based on a spatial model and the D-STEM software, which is extended to include emulator fitting using the EM algorithm. The missing values handling capabilities of the emulator are exploited to keep the number of model output realisations as low as possible when the computing burden of each realisation is high. As a case study, we emulate the output of the Atmospheric Dispersion Modelling System (ADMS) used by the Scottish Environment Protection Agency (SEPA) to model the air quality of the city of Aberdeen (UK). With the emulator, we study the city air quality under a discrete set of realisations and identify conditions under which, with a given probability, the 40 μ g m − 3 yearly average concentration limit for NO2 of EU legislation is not exceeded at the locations of the city monitoring stations. The effect of missing values on the emulator estimation and probability of exceedances are studied by means of simulations.

Background Schistosoma mansoni is a parasite of profound medical importance. Current control focusses on mass praziquantel (PZQ) treatment of populations in endemic areas, termed Preventative Chemotherapy (PC). Large-scale PC programmes exert prolonged selection pressures on parasites with the potential for, direct and/or indirect, emergence of drug resistance. Molecular methods can help monitor genetic changes of schistosome populations over time and in response to drug treatment, as well as estimate adult worm burdens through parentage analysis. Furthermore, methods such as in vitro drug sensitivity assays help phenotype in vivo parasite genotypic drug efficacy. Methods We conducted combined in vitro PZQ efficacy testing with population genetic analyses of S. mansoni collected from children from two schools in 2010, five years after the introduction of a National Control Programme. Children at one school had received four annual PZQ treatments and the other school had received two mass treatments in total. We compared genetic differentiation, indices of genetic diversity, and estimated adult worm burden from parasites collected in 2010 with samples collected in 2005 (before the control programme began) and in 2006 (six months after the first PZQ treatment). Using 2010 larval samples, we also compared the genetic similarity of those with high and low in vitro sensitivity to PZQ. Results We demonstrated that there were individual parasites with reduced PZQ susceptibility in the 2010 collections, as evidenced by our in vitro larval behavioural phenotypic assay. There was no evidence, however, that miracidia showing phenotypically reduced susceptibility clustered together genetically. Molecular analysis also demonstrated a significant reduction of adult worm load over time, despite little evidence of reduction in parasite infection intensity, as measured by egg output. Genetic diversity of infections did not reduce over time, despite changes in the genetic composition of the parasite populations. Conclusions Genotypic and phenotypic monitoring did not indicate a selective sweep, as may be expected if PZQ treatment was selecting a small number of related “resistant” parasites, but there was evidence of genetic changes at the population level over time. Genetic data were used to estimate adult worm burdens, which unlike parasite infection intensity, showed reductions over time, suggesting the relaxation of negative density-dependent constraints on parasite fecundity with PZQ treatment. We thereby demonstrated that density-dependence in schistosome populations may complicate evaluation and monitoring of control programmes. Electronic supplementary material The online version of this article (10.1186/s13071-017-2533-6) contains supplementary material, which is available to authorized users.

Measurements are presented of the branching fractions of the decays B-s(0) -> D-s(-/+) K--/+ and B-0 -> Ds-K+ relative to the decays B-s(0) -> D-s(-)pi(+) and B-0 -> D-s(-)pi(+), respectively. The data used correspond to an integrated luminosity of 3.0 fb(-1) of proton-proton collisions. The ratios of branching fractions areB(B-s(0) -> D-s(-/+) K--/+)/B(B-s(0) -> D-s(-)pi(+)) = 0.0752 +/- 0.0015 +/- 0.0019andB(B-0 -> Ds-K+)/B(B-0 -> D-pi(+)) = 0.0129 +/- 0.0005 +/- 0.0008,where the uncertainties are statistical and systematic, respectively.

Empirical models illustrating how mass publics organise their views on foreign policy issues abound. Models that posit militant internationalism and cooperative internationalism as the two factors structuring mass foreign policy attitudes and that typically rely on American survey data have given way to models positing a larger number of underlying factors supported by cross-national survey data. Still, there are few studies assessing the cross-national validity of multi-factor models. Further, middle power states that must navigate between international leadership and followership remain understudied. This article draws on new survey data from Canada and Australia—two archetypal middle power states—to replicate a recent and influential model of foreign policy attitudes comprised of four factors: cooperative internationalism, militant internationalism, isolationism, and support for global justice. Using an exploratory structural equation modelling (ESEM) framework, it finds that the four-factor structure of foreign policy attitudes observed in the United States, United Kingdom, France and Germany obtains among the Canadian and Australian publics, yet there are country-specific nuances that suggest differences in the ways Canadians and Australians perceive foreign policy options.