Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice.

Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (MAT1A) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of MAT1A in individuals who received chemotherapy. Overexpression of MAT1A in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting MAT1A upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy

DNA barcoding the native flowering plants and conifers of Wales

We present the first national DNA barcode resource that covers the native flowering plants and conifers for the nation of Wales (1143 species). Using the plant DNA barcode markers rbcL and matK, we have assembled 97.7% coverage for rbcL, 90.2% for matK, and a dual-locus barcode for 89.7% of the native Welsh flora. We have sampled multiple individuals for each species, resulting in 3304 rbcL and 2419 matK sequences. The majority of our samples (85%) are from DNA extracted from herbarium specimens. Recoverability of DNA barcodes is lower using herbarium specimens, compared to freshly collected material, mostly due to lower amplification success, but this is balanced by the increased efficiency of sampling species that have already been collected, identified, and verified by taxonomic experts. The effectiveness of the DNA barcodes for identification (level of discrimination) is assessed using four approaches: the presence of a barcode gap (using pairwise and multiple alignments), formation of monophyletic groups using Neighbour-Joining trees, and sequence similarity in BLASTn searches. These approaches yield similar results, providing relative discrimination levels of 69.4 to 74.9% of all species and 98.6 to 99.8% of genera using both markers. Species discrimination can be further improved using spatially explicit sampling. Mean species discrimination using barcode gap analysis (with a multiple alignment) is 81.6% within 10×10 km squares and 93.3% for 2×2 km squares. Our database of DNA barcodes for Welsh native flowering plants and conifers represents the most complete coverage of any national flora, and offers a valuable platform for a wide range of applications that require accurate species identification

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research. FASEB J 2018 Mar; 32(3):1537-1549

Dragon-kings: mechanisms, statistical methods and empirical evidence

This introductory article presents the special Discussion and Debate volume "From black swans to dragon-kings, is there life beyond power laws?" published in Eur. Phys. J. Special Topics in May 2012. We summarize and put in perspective the contributions into three main themes: (i) mechanisms for dragon-kings, (ii) detection of dragon-kings and statistical tests and (iii) empirical evidence in a large variety of natural and social systems. Overall, we are pleased to witness significant advances both in the introduction and clarification of underlying mechanisms and in the development of novel efficient tests that demonstrate clear evidence for the presence of dragon-kings in many systems. However, this positive view should be balanced by the fact that this remains a very delicate and difficult field, if only due to the scarcity of data as well as the extraordinary important implications with respect to hazard assessment, risk control and predictability.Comment: 20 page

Linking Grass Pollen Biodiversity and Human Health: an Environmental Genomic Approach

In Europe and the UK, grass pollen is the single most important outdoor aeroallergen; 27% of the population are sensitised to grass pollen. Grass pollen allergy has been linked to increased risk of allergic asthma exacerbations, which can lead to hospitalisation and fatalities. Sensitivity towards grass pollen varies between species, of which there are over 150 in the UK. However, due to few unique morphological features, grass pollen from different species cannot be discriminated using traditional observational methods. Currently, there is no way of detecting, modelling or forecasting the aerial-dispersion of pollen from the biodiversity of UK grasses. Consequently, grasses are coalesced into a single group in the UK forecast. PollerGEN is an interdisciplinary NERC project with the aim of revolutionising the way that pollen dispersion is measured and forecast, with concomitant synergies for understanding the ecology of aerial dispersed pollen. In collaboration with the UK Met Office, a key goal is to build a more accurate forecast of individual grass pollen species. Using environmental genomics, we will identify which species of grass pollen are present during the summer months across 16 specific collection sites in the UK, and measure the abundance of the different allergenic species of grass. The information will be used to model the spatial and temporal deposition of different species of grass pollen and identify linkages to human health. The project therefore aims to provide a paradigm shift in our understanding of the ecology of windborne pollen in time and space and inform the public about the timing and environmental factors that put them at risk of exposure to pollen they are allergic to; a key strategy in the prevention of allergy and asthma attacks

Short Term Synaptic Depression Imposes a Frequency Dependent Filter on Synaptic Information Transfer

Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse

Beliefs and perceptions about the causes of breast cancer: a case-control study

Background: Attributions of causality are common for many diseases, including breast cancer. The risk of developing breast cancer can be reduced by modifications to lifestyle and behaviours to minimise exposure to specific risk factors, such as obesity. However, these modifications will only occur if women believe that certain behaviours/lifestyle factors have an impact on the development of breast cancer. Method: The Breast Cancer, Environment and Employment Study is a case-control study of breast cancer conducted in Western Australia between 2009 and 2011. As part of the study 1109 women with breast cancer and 1633 women without the disease completed a Risk Perception questionnaire in which they were asked in an open-ended question for specific cause/s to the development of breast cancer in themselves or in others. The study identified specific causal beliefs, and assessed differences in the beliefs between women with and without breast cancer. Results: The most common attributions in women without breast cancer were to familial or inherited factors (77.6%), followed by lifestyle factors, such as poor diet and smoking (47.1%), and environmental factors, such as food additives (45.4%). The most common attributions in women with breast cancer were to mental or emotional factors (46.3%), especially stress, followed by lifestyle factors (38.6%) and physiological factors (37.5%), particularly relating to hormonal history.Conclusions: While the majority of participants in this study provided one or more causal attributions for breast cancer, many of the reported risk factors do not correspond to those generally accepted by the scientific community. These misperceptions could be having a significant impact on the success of prevention and early detection programs that seek to minimise the pain and suffering caused by this disease. In particular, women who have no family history of the disease may not work to minimise their exposure to the modifiable risk factors

Evaluation in artificial intelligence: From task-oriented to ability-oriented measurement

The final publication is available at Springer via http://dx.doi.org/ 10.1007/s10462-016-9505-7.The evaluation of artificial intelligence systems and components is crucial for the progress of the discipline. In this paper we describe and critically assess the different ways AI systems are evaluated, and the role of components and techniques in these systems. We first focus on the traditional task-oriented evaluation approach. We identify three kinds of evaluation: human discrimination, problem benchmarks and peer confrontation. We describe some of the limitations of the many evaluation schemes and competitions in these three categories, and follow the progression of some of these tests. We then focus on a less customary (and challenging) ability-oriented evaluation approach, where a system is characterised by its (cognitive) abilities, rather than by the tasks it is designed to solve. We discuss several possibilities: the adaptation of cognitive tests used for humans and animals, the development of tests derived from algorithmic information theory or more integrated approaches under the perspective of universal psychometrics. We analyse some evaluation tests from AI that are better positioned for an ability-oriented evaluation and discuss how their problems and limitations can possibly be addressed with some of the tools and ideas that appear within the paper. Finally, we enumerate a series of lessons learnt and generic guidelines to be used when an AI evaluation scheme is under consideration.I thank the organisers of the AEPIA Summer School On Artificial Intelligence, held in September 2014, for giving me the opportunity to give a lecture on 'AI Evaluation'. This paper was born out of and evolved through that lecture. The information about many benchmarks and competitions discussed in this paper have been contrasted with information from and discussions with many people: M. Bedia, A. Cangelosi, C. Dimitrakakis, I. GarcIa-Varea, Katja Hofmann, W. Langdon, E. Messina, S. Mueller, M. Siebers and C. Soares. Figure 4 is courtesy of F. Martinez-Plumed. Finally, I thank the anonymous reviewers, whose comments have helped to significantly improve the balance and coverage of the paper. This work has been partially supported by the EU (FEDER) and the Spanish MINECO under Grants TIN 2013-45732-C4-1-P, TIN 2015-69175-C4-1-R and by Generalitat Valenciana PROMETEOII2015/013.José Hernández-Orallo (2016). Evaluation in artificial intelligence: From task-oriented to ability-oriented measurement. 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