Circulating levels of anti-angiogenic VEGF-A isoform (VEGF-Axxxb) in colorectal cancer patients predicts tumour VEGF-A ratios

Purpose: Bevacizumab as an adjunct to chemotherapy improves survival for some patients with metastatic colorectal cancer. Immunohistochemical staining of samples from the registration ECOG E3200 trial of bevacizumab with FOLFOX demonstrated that only patients with carcinomas expressing low levels of VEGF-A(165)b, an anti-angiogenic splice variant of the Vascular Endothelial Growth Factor family of proteins, benefited from bevacizumab treatment. To identify a more useful biomarker of response we tested the hypothesis that circulating VEGF-A(165)b levels correlate with immunohistochemical staining. Experimental Design: 17 patients with biopsy proven colorectal adenocarcinoma had pre-operative blood samples drawn. They underwent resection and had post-resection blood drawn. The plasma was analysed for levels of VEGF-A(xxx)b using enzyme-linked immunosorbent assay (ELISA) and the tumour blocks stained for VEGF-A(xxx)b and pan-VEGF-A. The normalised ratio of VEGF-A(xxx)b expression to that of panVEGF-A expression scored by IHC was calculated and correlated with plasma VEGF-A(165)b levels. Results: Plasma levels of VEGF-A(xxx)b significantly correlated with the VEGF-A(xxx)b:panVEGF-A ratio (r=0.594, P<0.02) in colorectal cancers. Median plasma VEGF-A(xxx)b levels were 151 pg/ml. The mean (1.5±0.17) and median, IQR (1.8, 1-2) IHC scores of the patients with greater than median plasma VEGF-A(xxx)b were significantly greater than those with less than median plasma VEGF-A(xxx)b levels (mean ± SEM=0.85±10.12, median, IQR=1, 0.54-1). Conclusion: These results suggest that plasma VEGF-A(xxx)b levels could be an effective biomarker of response to Bevacizumab. These results indicate that a prospective trial is warranted to explore the use of plasma VEGF-A(xxx)b levels to stratify patients for colorectal cancer treatment by bevacizumab

The Many Faces of Fear: Comparing the Pathways and Impacts of Nonconsumptive Predator Effects on Prey Populations

Background: Most ecological models assume that predator and prey populations interact solely through consumption: predators reduce prey densities by killing and consuming individual prey. However, predators can also reduce prey densities by forcing prey to adopt costly defensive strategies. Methodology/Principal Findings: We build on a simple Lotka-Volterra predator-prey model to provide a heuristic tool for distinguishing between the demographic effects of consumption (consumptive effects) and of anti-predator defenses (nonconsumptive effects), and for distinguishing among the multiple mechanisms by which anti-predator defenses might reduce prey population growth rates. We illustrate these alternative pathways for nonconsumptive effects with selected empirical examples, and use a meta-analysis of published literature to estimate the mean effect size of each pathway. Overall, predation risk tends to have a much larger impact on prey foraging behavior than measures of growth, survivorship, or fecundity. Conclusions/Significance: While our model provides a concise framework for understanding the many potential NCE pathways and their relationships to each other, our results confirm empirical research showing that prey are able to partially compensate for changes in energy income, mitigating the fitness effects of defensive changes in time budgets. Distinguishing the many facets of nonconsumptive effects raises some novel questions, and will help guide both empirica

Caenorhabditis elegans is a useful model for anthelmintic discovery

Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery

Modelling a response as a function of high frequency count data: the association between physical activity and fat mass

We present a new statistical modelling approach where the response is a function of high frequency count data. Our application is about investigating the relationship between the health outcome fat mass and physical activity (PA) measured by accelerometer. The accelerometer quantifies the intensity of physical activity as counts per epoch over a given period of time. We use data from the Avon longitudinal study of parents and children (ALSPAC) where accelerometer data is available as a time series of accelerometer counts per minute over seven days for a subset of children. In order to compare accelerometer profiles between individuals and to reduce the high dimension a functional summary of the profiles is used. We use the histogram as a functional summary due to its simplicity, suitability and ease of interpretation. Our model is an extension of generalised regression of scalars on functions or signal regression. It allows also multi-dimensional functional predictors and additive non-linear predictors for metric covariates. The additive multidimensional functional predictors allow investigating specific questions about whether the effect of PA varies over its intensity, by gender, by time of day or by day of the week. The key feature of the model is that it utilises the full profile of measured PA without requiring cut-points defining intensity levels for light, moderate and vigorous activity. We show that the (not necessarily causal) effect of PA is not linear and not constant over the activity intensity. Also, there is little evidence to suggest that the effect of PA intensity varies by gender or whether it happens on weekdays or on weekends

A dimensional summation account of polymorphous category learning

This is the author accepted manuscript. The final version is available from Springer via the DOI in this record.Data and code availaibility: The data and code for all analyses for all experiments are available at the OSF addresses given in each Results section. The stimuli are available at the same locations.Polymorphous concepts are hard to learn, and this is perhaps surprising because they, like many natural concepts, have an overall similarity structure. However, the dimensional summation hypothesis (Milton & Wills, 2004) predicts this difficulty. It also makes a number of other predictions about polymorphous concept formation, which are tested here. In Experiment 1 we confirm the theory’s prediction that polymorphous concept formation should be facilitated by deterministic pretraining on the constituent features of the stimulus. This facilitation is relative to an equivalent amount of training on the polymorphous concept itself. In Experiments 2–4, the dimensional summation account of this single feature pretraining effect is contrasted with some other accounts, including a more general strategic account (Experiment 2), seriality of training and stimulus decomposition accounts (Experiment 3), and the role of errors (Experiment 4). The dimensional summation hypothesis provides the best account of these data. In Experiment 5, a further prediction is confirmed — the single feature pretraining effect is eliminated by a concurrent counting task. The current experiments suggest the hypothesis that natural concepts might be acquired by the deliberate serial summation of evidence. This idea has testable implications for classroom learning.Biotechnology and Biological Sciences Research Council (BBSRC

Regional variability in peatland burning at mid- to high-latitudes during the Holocene

Acknowledgements This work developed from the PAGES (Past Global Changes) C-PEAT (Carbon in Peat on EArth through Time) working group. PAGES has been supported by the US National Science Foundation, Swiss National Science Foundation, Swiss Academy of Sciences and Chinese Academy of Sciences. We acknowledge the following financial support: UK Natural Environment Research Council Training Grants NE/L002574/1 (T.G.S.) and NE/S007458/1 (R.E.F.); Dutch Foundation for the Conservation of Irish Bogs, Quaternary Research Association and Leverhulme Trust RPG-2021-354 (G.T.S); the Academy of Finland (M.V); PAI/SIA 80002 and FONDECYT Iniciación 11220705 - ANID, Chile (C.A.M.); R20F0002 (PATSER) ANID Chile (R.D.M.); Swedish Strategic Research Area (SRA) MERGE (ModElling the Regional and Global Earth system) (M.J.G.); Polish National Science Centre Grant number NCN 2018/29/B/ST10/00120 (K.A.); Russian Science Foundation Grant No. 19-14-00102 (Y.A.M.); University of Latvia Grant No. AAp2016/B041/Zd2016/AZ03 and the Estonian Science Council grant PRG323 (TrackLag) (N.S. and A.M.); U.S. Geological Survey Land Change Science/Climate Research & Development Program (M.J., L.A., and D.W.); German Research Foundation (DFG), grant MA 8083/2-1 (P.M.) and grant BL 563/19-1 (K.H.K.); German Academic Exchange Service (DAAD), grant no. 57044554, Faculty of Geosciences, University of Münster, and Bavarian University Centre for Latin America (BAYLAT) (K.H.K). Records from the Global Charcoal Database supplemented this work and therefore we would like to thank the contributors and managers of this open-source resource. We also thank Annica Greisman, Jennifer Shiller, Fredrik Olsson and Simon van Bellen for contributing charcoal data to our analyses. Any use of trade, firm, or product name is for descriptive purposes only and does not imply endorsement by the U.S. Government.Peer reviewedPostprin

Rare germline variants are associated with rapid biochemical recurrence after radical prostate cancer treatment: a PPCG study

Background: Germline variants explain more than a third of prostate cancer (PrCa) risk, but very few associations have been identified between heritable factors and clinical progression.  Objective: To find rare germline variants that predict time to biochemical recurrence (BCR) after radical treatment in men with PrCa, and understand the genetic factors associated with such progression.  Design, Setting and Participants: Whole-genome sequencing data from blood DNA were analysed for 850 PrCa patients with radical treatment from the Pan Prostate Cancer Group (PPCG consortium) from UK, Canada, Germany, Australia and France. Findings were validated using 383 patients from The Cancer Genome Atlas (TCGA).  Outcome Measurements and Statistical analysis: 15,822 rare (MAF<1%) predicted-deleterious coding germline mutations were identified. Optimal multifactor and univariate Cox regression models were built to predict time to BCR after radical treatment, using germline variants grouped by functionally annotated gene-sets. Models were tested for robustness using bootstrap resampling.  Results: Optimal Cox regression multifactor models showed that rare predicted-deleterious germline variants in “Hallmark” gene-sets were consistently associated with altered time to BCR. Three gene-sets had a statistically significant association with risk-elevated outcome when modelling all samples: PI3K/AKT/mTOR, Inflammatory response and KRAS signalling (up). PI3K/AKT/mTOR and KRAS signalling (up) were also associated among patients with higher grade cancer, as were Pancreas-beta cells, TNFA signalling via NKFB and Hypoxia, the latter of which was validated in the independent TCGA dataset.  Conclusions: We demonstrate for the first time that rare deleterious coding germline variants robustly associate with time to BCR after radical treatment, including cohort-independent validation. Our findings suggest that germline testing at diagnosis could aid clinical decisions by stratifying patients for differential clinical management.  Patient summary: PrCa patients with particular genetic mutations have a higher chance of relapsing after initial radical treatment, potentially providing opportunities to identify which patients might need additional treatments earlier

National identity predicts public health support during a global pandemic (vol 13, 517, 2022) : National identity predicts public health support during a global pandemic (Nature Communications, (2022), 13, 1, (517), 10.1038/s41467-021-27668-9)

Publisher Copyright: © The Author(s) 2022.In this article the author name ‘Agustin Ibanez’ was incorrectly written as ‘Augustin Ibanez’. The original article has been corrected.Peer reviewe

National identity predicts public health support during a global pandemic.

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics