Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours

We show that activation of Wnt/{beta}-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of {beta}-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that {beta}-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking {beta}-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against {beta}-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/{beta}-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which {beta}-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours

Fast flowing populations are not well mixed

In evolutionary dynamics, well-mixed populations are almost always associated with all-to-all interactions; mathematical models are based on complete graphs. In most cases, these models do not predict fixation probabilities in groups of individuals mixed by flows. We propose an analytical description in the fast-flow limit. This approach is valid for processes with global and local selection, and accurately predicts the suppression of selection as competition becomes more local. It provides a modelling tool for biological or social systems with individuals in motion.Comment: 19 pages, 8 figure

Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study

<p>Abstract</p> <p>Background</p> <p>Antipsychotic treatment has been repeatedly found to be associated with an increased risk for venous thromboembolism in schizophrenia. The extent to which the propensity for venous thromboembolism is linked to antipsychotic medication alone or psychosis itself is unclear. The objective of this study was to determine whether markers of thrombogenesis are increased in psychotic patients who have not yet been treated with antipsychotic medication.</p> <p>Methods</p> <p>We investigated the plasma levels of markers indicating activation of coagulation (D-dimers and Factor VIII) and platelets (soluble P-selectin, sP-selectin) in an antipsychotic-naive group of fourteen men and eleven women with acute psychosis (age 29.1 ± 8.3 years, body mass index 23.6 ± 4.7), and twenty-five healthy volunteers were matched for age, gender and body mass index.</p> <p>Results</p> <p>D-dimers (median 0.38 versus 0.19 mg/l, mean 1.12 ± 2.38 versus 0.28 ± 0.3 mg/l; P = 0.003) and sP-selectin (median 204.1 versus 112.4 ng/ml, mean 209.9 ± 124 versus 124.1 ± 32; P = 0.0005) plasma levels were significantly increased in the group of patients with acute psychosis as compared with healthy volunteers. We found a trend (median 148% versus 110%, mean 160 ± 72.5 versus 123 ± 62.5; P = 0.062) of increased plasma levels of factor VIII in psychotic patients as compared with healthy volunteers.</p> <p>Conclusions</p> <p>The results suggest that at least a part of venous thromboembolic events in patients with acute psychosis may be induced by pathogenic mechanisms related to psychosis rather than by antipsychotic treatment. Finding an exact cause for venous thromboembolism in psychotic patients is necessary for its effective treatment and prevention.</p

Reward and punishment in climate change dilemmas

Mitigating climate change effects involves strategic decisions by individuals that may choose to limit their emissions at a cost. Everyone shares the ensuing benefits and thereby individuals can free ride on the effort of others, which may lead to the tragedy of the commons. For this reason, climate action can be conveniently formulated in terms of Public Goods Dilemmas often assuming that a minimum collective effort is required to ensure any benefit, and that decision-making may be contingent on the risk associated with future losses. Here we investigate the impact of reward and punishment in this type of collective endeavors - coined as collective-risk dilemmas - by means of a dynamic, evolutionary approach. We show that rewards (positive incentives) are essential to initiate cooperation, mostly when the perception of risk is low. On the other hand, we find that sanctions (negative incentives) are instrumental to maintain cooperation. Altogether, our results are gratifying, given the a-priori limitations of effectively implementing sanctions in international agreements. Finally, we show that whenever collective action is most challenging to succeed, the best results are obtained when both rewards and sanctions are synergistically combined into a single policy.This research was supported by Fundacao para a Ciencia e Tecnologia (FCT) through grants PTDC/EEISII/5081/2014 and PTDC/MAT/STA/3358/2014 and by multiannual funding of INESC-ID and CBMA (under the projects UID/CEC/50021/2019 and UID/BIA/04050/2013). F.P.S. acknowledges support from the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Dynamic and Multi-scale Systems Postdoctoral Fellowship Award. All authors declare no competing financial or non-financial interests in relation to the work described