Loss of the DNA methyltransferase MET1 Induces H3K9 hypermethylation at PcG target genes and redistribution of H3K27 trimethylation to transposons in Arabidopsis thaliana.

Dimethylation of histone H3 lysine 9 (H3K9m2) and trimethylation of histone H3 lysine 27 (H3K27m3) are two hallmarks of transcriptional repression in many organisms. In Arabidopsis thaliana, H3K27m3 is targeted by Polycomb Group (PcG) proteins and is associated with silent protein-coding genes, while H3K9m2 is correlated with DNA methylation and is associated with transposons and repetitive sequences. Recently, ectopic genic DNA methylation in the CHG context (where H is any base except G) has been observed in globally DNA hypomethylated mutants such as met1, but neither the nature of the hypermethylated loci nor the biological significance of this epigenetic phenomenon have been investigated. Here, we generated high-resolution, genome-wide maps of both H3K9m2 and H3K27m3 in wild-type and met1 plants, which we integrated with transcriptional data, to explore the relationships between these two marks. We found that ectopic H3K9m2 observed in met1 can be due to defects in IBM1-mediated H3K9m2 demethylation at some sites, but most importantly targets H3K27m3-marked genes, suggesting an interplay between these two silencing marks. Furthermore, H3K9m2/DNA-hypermethylation at these PcG targets in met1 is coupled with a decrease in H3K27m3 marks, whereas CG/H3K9m2 hypomethylated transposons become ectopically H3K27m3 hypermethylated. Our results bear interesting similarities with cancer cells, which show global losses of DNA methylation but ectopic hypermethylation of genes previously marked by H3K27m3

Beyond Formal Methods for Critical Interactive Systems: Dealing with Faults at Runtime

International audienceFormal methods provide support for validation and verification of interactive systems by means of complete and unambiguous description of the envisioned system. They can also be used (for instance in the requirements/needs identification phase) to define precisely what the system should do and how it should meet user needs. If the entire development process in supported by formal methods (for instance as required by DO 178C [7] and its supplement 333 [8]) then classical formal method engineers would argue that the resulting software is defect free. However, events that are beyond the envelope of the specification may occur and trigger unexpected behaviors from the formally specified system resulting in failures. Sources of such failures can be permanent or transient hardware failures, due to (when such systems are deployed in the high atmosphere e.g. aircrafts or spacecrafts) natural faults triggered by alpha-particles from radioactive contaminants in the chips or neutron from cosmic radiation. This position paper proposes a complementary view to formal approaches first by presenting an overview of causes of unexpected events on the system side as well as on the human side and then by discussing approaches that could provide support for taking into account system faults and human errors at design time

Hierarchical action and inhibition of plant Dicer-like proteins in antiviral defense

[EN] The mechanisms underlying induction and suppression of RNA silencing in the ongoing plant-virus arms race are poorly understood. We show here that virus-derived small RNAs produced by Arabidopsis Dicer-like 4 (DCL4) program an effector complex conferring antiviral immunity. Inhibition of DCL4 by a viral-encoded suppressor revealed the subordinate antiviral activity of DCL2. Accordingly, inactivating both DCL2 and DCL4 was necessary and sufficient to restore systemic infection of a suppressor-deficient virus. The effects of DCL2 were overcome by increasing viral dosage in inoculated leaves, but this could not surmount additional, non - cell autonomous effects of DCL4 specifically preventing viral unloading from the vasculature. These findings define a molecular framework for studying antiviral silencing and defense in plants.We thank members of the Voinnet laboratory for discussions and Z. Xie for dcl seeds. Funded by CNRS grant to A.D.; NSF grant MCB-0209836, NIH grant AI43288, and U.S. Department of Agriculture grant NRI 2005-35319-15280 to J.C.; and Pao Schloarship (Zhejiang University, China) to J.B. This work is dedicated to the memory of M. and G. Voinnet.Deleris, A.; Gallego Bartolomé, J.; Bao, J.; Kasschau, KD.; Carrinton, JC.; Voinnet, O. (2006). Hierarchical action and inhibition of plant Dicer-like proteins in antiviral defense. Science. 313(5783):68-71. https://doi.org/10.1126/science.11282146871313578

Beyond Formal Methods for Critical Interactive Systems: Dealing with Faults at Runtime

Formal methods provide support for validation and verification of interactive systems by means of complete and unambiguous description of the envisioned system. They can also be used (for instance in the requirements/needs identification phase) to define precisely what the system should do and how it should meet user needs. If the entire development process in supported by formal methods (for instance as required by DO 178C [7] and its supplement 333 [8]) then classical formal method engineers would argue that the resulting software is defect free. However, events that are beyond the envelope of the specification may occur and trigger unexpected behaviors from the formally specified system resulting in failures. Sources of such failures can be permanent or transient hardware failures, due to (when such systems are deployed in the high atmosphere e.g. aircrafts or spacecrafts) natural faults triggered by alpha-particles from radioactive contaminants in the chips or neutron from cosmic radiation. This position paper proposes a complementary view to formal approaches first by presenting an overview of causes of unexpected events on the system side as well as on the human side and then by discussing approaches that could provide support for taking into account system faults and human errors at design time

The Human Behaviour-Change Project: Harnessing the power of Artificial Intelligence and Machine Learning for evidence synthesis and interpretation

Background Behaviour change is key to addressing both the challenges facing human health and wellbeing and to promoting the uptake of research findings in health policy and practice. We need to make better use of the vast amount of accumulating evidence from behaviour change intervention (BCI) evaluations and promote the uptake of that evidence into a wide range of contexts. The scale and complexity of the task of synthesising and interpreting this evidence, and increasing evidence timeliness and accessibility, will require increased computer support. The Human Behaviour-Change Project (HBCP) will use Artificial Intelligence and Machine Learning to (i) develop and evaluate a ‘Knowledge System’ that automatically extracts, synthesises and interprets findings from BCI evaluation reports to generate new insights about behaviour change and improve prediction of intervention effectiveness and (ii) allow users, such as practitioners, policy makers and researchers, to easily and efficiently query the system to get answers to variants of the question ‘What works, compared with what, how well, with what exposure, with what behaviours (for how long), for whom, in what settings and why?’. Methods The HBCP will: a) develop an ontology of BCI evaluations and their reports linking effect sizes for given target behaviours with intervention content and delivery and mechanisms of action, as moderated by exposure, populations and settings; b) develop and train an automated feature extraction system to annotate BCI evaluation reports using this ontology; c) develop and train machine learning and reasoning algorithms to use the annotated BCI evaluation reports to predict effect sizes for particular combinations of behaviours, interventions, populations and settings; d) build user and machine interfaces for interrogating and updating the knowledge base; and e) evaluate all the above in terms of performance and utility. Discussion The HBCP aims to revolutionise our ability to synthesise, interpret and deliver evidence on behaviour change interventions that is up-to-date and tailored to user need and context. This will enhance the usefulness, and support the implementation of, that evidence.The project is funded by a Wellcome Trust collaborative award [The Human Behaviour-Change Project: Building the science of behaviour change for complex intervention development’, 201,524/Z/16/Z]. During the preparation of the manuscript RW’s salary was funded by Cancer Research UK

Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

The atypical MAP kinases ERK3 and ERK4 are activated by phosphorylation of a serine residue lying within the activation loop signature sequence S-E-G. However, the regulation of ERK3 and ERK4 phosphorylation and activity is poorly understood. Here we report that the inducible nuclear dual-specificity MAP kinase phosphatase (MKP) DUSP2, a known regulator of the ERK and p38 MAPKs, is unique amongst the MKP family in being able to bind to both ERK3 and ERK4. This interaction is mediated by a conserved common docking (CD) domain within the carboxyl-terminal domains of ERK3 and ERK4 and the conserved kinase interaction motif (KIM) located within the non-catalytic amino terminus of DUSP2. This interaction is direct and results in the dephosphorylation of ERK3 and ERK4 and the stabilization of DUSP2. In the case of ERK4 its ability to stabilize DUSP2 requires its kinase activity. Finally, we demonstrate that expression of DUSP2 inhibits ERK3 and ERK4-mediated activation of its downstream substrate MK5. We conclude that the activity of DUSP2 is not restricted to the classical MAPK pathways and that DUSP2 can also regulate the atypical ERK3/4-MK5 signalling pathway in mammalian cells

Unsupervised information extraction from behaviour change literature

This paper describes our approach to construct a scalable system for unsupervised information extraction from the behaviour change intervention literature. Due to the many different types of attribute to be extracted, we adopt a passage retrieval based framework that provides the most likely value for an attribute. Our proposed method is capable of addressing variable length passage sizes and different validation criteria for the extracted values corresponding to each attribute to be found. We evaluate our approach by constructing a manually annotated ground-truth from a set of 50 research papers with reported studies on smoking cessation.Wellcome Trus

Temporal dominance of sensations of peanuts and peanut products in relation to Hutchings and Lillford’s “breakdown path"

Hutchings and Lillford’s (Journal of Texture Studies, 19, 103-115, 1988) proposed a “breakdown path” whereby particle size reduction occurs through mastication in conjunction with the secretion of saliva to form a swallowable bolus. The swallowing trajectory of whole peanuts, peanut meal and peanut paste were studied with the temporal dominance of sensations technique. The sensations for whole peanuts progressed from hard, to crunchy, to chewy, to soft and ended compacted on teeth. Predictably peanut meal missed out the first two sensations, progressing from chewy, to soft and ending compacted on teeth. However peanut paste, which starts as a soft suspension with relatively little structure appears to thicken and stick to the palate during oral processing. We propose that the “hard to swallow” sensation elicited by peanut paste may be due to water absorption from the saliva as they mix in the mouth