Plasticity of the Berry Ripening Program in a White Grape Variety

Grapevine (Vitis vinifera L) is considered one of the most environmentally sensitive crops and is characterized by broad phenotypic plasticity, offering important advantages such as the large range of different wines that can be produced from the same cultivar, and the adaptation of existing cultivars to diverse growing regions. The uniqueness of berry quality traits reflects complex interactions between the grapevine plant and the combination of natural factors and human cultural practices, defined as terroir, which leads to the expression of wine typicity. Despite the scientific and commercial importance of genotype interactions with growing conditions, few studies have characterized the genes and metabolites directly involved in this phenomenon. Here we used two large-scale analytical approaches to explore the metabolomic and transcriptomic basis of the broad phenotypic plasticity of Garganega, a white berry variety grown at four sites characterized by different pedoclimatic conditions (altitudes, soil texture and composition). These conditions determine berry ripening dynamics in terms of sugar accumulation and the abundance of phenolic compounds. Multivariate analysis unraveled a highly plastic metabolomic response to different environments, especially the accumulation of hydroxycinnamic and hydroxybenzoic acids and flavonols. Principal component analysis revealed that the four sites strongly affected the berry transcriptome allowing the identification of environmentally-modulated genes and the plasticity of commonly-modulated transcripts at different sites. Many genes that control transcription, translation, transport and carbohydrate metabolism showed different expression depending on the environmental conditions, indicating a key role in the observed transcriptomic plasticity of Garganega berries. Interestingly, genes representing the phenylpropanoid/flavonoid pathway showed plastic responses to the environment mirroring the accumulation of the corresponding metabolites. The comparison of Garganega and Corvina berries showed that the metabolism of phenolic compounds is more plastic in ripening Garganega berries under different pedoclimatic conditions

Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial

BACKGROUND: The number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP. METHODS/DESIGN: A multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway. DISCUSSION: The study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment. TRIAL REGISTRATION: ISRCTN17545443 . Registered on 12 September 2016

Ethnic and mouse strain differences in central corneal thickness and association with pigmentation phenotype

The cornea is a transparent structure that permits the refraction of light into the eye. Evidence from a range of studies indicates that central corneal thickness (CCT) is strongly genetically determined. Support for a genetic component comes from data showing significant variation in CCT between different human ethnic groups. Interestingly, these studies also appear to show that skin pigmentation may influence CCT. To validate these observations, we undertook the first analysis of CCT in an oculocutaneous albinism (OCA) and Ugandan cohort, populations with distinct skin pigmentation phenotypes. There was a significant difference in the mean CCT of the OCA, Ugandan and Australian-Caucasian cohorts (Ugandan: 517.3±37 µm; Caucasian: 539.7±32.8 µm, OCA: 563.3±37.2 µm; p<0.001). A meta-analysis of 53 studies investigating the CCT of different ethnic groups was then performed and demonstrated that darker skin pigmentation is associated with a thinner CCT (p<0.001). To further verify these observations, we measured CCT in 13 different inbred mouse strains and found a significant difference between the albino and pigmented strains (p = 0.008). Specific mutations within the melanin synthesis pathway were then investigated in mice for an association with CCT. Significant differences between mutant and wild type strains were seen with the nonagouti (p<0.001), myosin VA (p<0.001), tyrosinase (p = 0.025) and tyrosinase related protein (p = 0.001) genes. These findings provide support for our hypothesis that pigmentation is associated with CCT and identifies pigment-related genes as candidates for developmental determination of a non-pigmented structure.David P. Dimasi, Alex W. Hewitt, Kenneth Kagame, Sam Ruvama, Ludovica Tindyebwa, Bastien Llamas, Kirsty A. Kirk, Paul Mitchell, Kathryn P. Burdon and Jamie E. Crai

Patch management applied to naval systems

Évoluant dans des environnements contraints et rassemblant dans des espaces réduits des sous-systèmes fortement critiques et hétérogènes, les navires d'aujourd'hui font partie des objets les plus complexes qui soient. À l'heure où croît à leur bord le nombre de systèmes informatiques contrôlant parfois des actionneurs d'importance cruciale, leur maintien en condition de sécurité est une problématique majeure. Les travaux présentés dans cette thèse définissent un processus de gestion des vulnérabilités et des contremesures associées adapté au contexte des systèmes industriels complexes. Ce processus s'appuie sur une méthode et un formalisme de modélisation de ces systèmes permettant d'abstraire leur comportement, discret ou continu, et leurs évolutions éventuelles – apparition d'une vulnérabilité, déploiement d'une contremesure ou survenue d'une attaque – que nous avons définis dans le cadre de ces travaux. Il repose également sur une méthode de calcul des impacts associés aux vulnérabilités, attaques et contremesures aboutissant à leur expression sous la forme d'une métrique adaptée pour la prise de décision. Ce calcul étant permis par la modélisation du système mais aussi par celle des vulnérabilités, attaques et contremesures, nous introduisons par ailleurs une méthode et un formalisme adapté – les mutations d'automates et de réseaux d'automates – permettant leur abstraction. Ces propositions théoriques et méthodologiques sont enfin confrontées à une expérimentation sur un cas fictif représentatif d'un système de propulsion et de gouverne d'un bâtiment de type ferry ou paquebot, permettant de discuter de leur pertinence et de leurs limites ainsi que d'esquisser les perspectives de recherche naissant de nos travaux.Operating in constrained environments and composed of heterogeneous subsystems, today's ships are among the most complex objects that exist. Due to the increasing number of cyber assets among their components, patch and vulnerability management applied to naval systems is an essential process. The work detailed in this PhD thesis aims to define such a process tailored to complex cyber-physical systems. This process relies on a modelling method and formalism allowing to depict CPS behaviour and cyber events – a vulnerability discovery, a cyber attack occurrence or a patch deployment. It also relies on an impact assessment method, allowing to compute the effects of cyber events on CPS ability to fulfill their missions. These impacts are expressed through a specially designed metric aiming to help in decision-making. The process, methods, formalisms and metrics we propose in this work are then evaluated through an experimentation based on a fictitious case-study

Maîtrise des correctifs de sécurité pour les systèmes navals

Operating in constrained environments and composed of heterogeneous subsystems, today's ships are among the most complex objects that exist. Due to the increasing number of cyber assets among their components, patch and vulnerability management applied to naval systems is an essential process. The work detailed in this PhD thesis aims to define such a process tailored to complex cyber-physical systems. This process relies on a modelling method and formalism allowing to depict CPS behaviour and cyber events – a vulnerability discovery, a cyber attack occurrence or a patch deployment. It also relies on an impact assessment method, allowing to compute the effects of cyber events on CPS ability to fulfill their missions.These impacts are expressed through a specially designed metric aiming to help in decision-making. The process, methods, formalisms and metrics we propose in this work are then evaluated through an experimentation based on a fictitious case-study.Évoluant dans des environnements contraints et rassemblant dans des espaces réduits des sous-systèmes fortement critiques et hétérogènes, les navires d'aujourd'hui font partie des objets les plus complexes qui soient. À l'heure où croît à leur bord le nombre de systèmes informatiques contrôlant parfois des actionneurs d'importance cruciale, leur maintien en condition de sécurité est une problématique majeure. Les travaux présentés dans cette thèse définissent un processus de gestion des vulnérabilités et des contremesures associées adapté au contexte des systèmes industriels complexes. Ce processus s'appuie sur une méthode et un formalisme de modélisation de ces systèmes permettant d'abstraire leur comportement, discret ou continu, et leurs évolutions éventuelles – apparition d'une vulnérabilité, déploiement d'une contremesure ou survenue d'une attaque – que nous avons définis dans le cadre de ces travaux. Il repose également sur une méthode de calcul des impacts associés aux vulnérabilités, attaques et contremesures aboutissant à leur expression sous la forme d'une métrique adaptée pour la prise de décision. Ce calcul étant permis par la modélisation du système mais aussi par celle des vulnérabilités, attaques et contremesures, nous introduisons par ailleurs une méthode et un formalisme adapté – les mutations d'automates et de réseaux d'automates – permettant leur abstraction. Ces propositions théoriques et méthodologiques sont enfin confrontées à une expérimentation sur un cas fictif représentatif d'un système de propulsion et de gouverne d'un bâtiment de type ferry ou paquebot, permettant de discuter de leur pertinence et de leurs limites ainsi que d'esquisser les perspectives de recherche naissant de nos travaux

Maîtrise des Correctifs de Sécurité pour les Systèmes Navals

National audienceUn navire est un système complexe, opéré dans le but d'accomplir un ensemble de missions. Les composants d'un tel système peuvent être affectés de vulnérabilités dont l'exploitation peut avoir des conséquences sur les missions en cours. Il est donc nécessaire d'appliquer des correctifs réduisant le risque lié à ces vulnérabilités. Mais il est important de s'assurer que ces correctifs n'ont pas eux-mêmes d'impact négatif sur les missions du navire. Nous proposons, dans cet article, l'architecture d'un processus de gestion des correctifs appliqué au contexte des systèmes navals. Nous extrayons de ce processus les problématiques principales qu'il pose : la modélisation d'un système complexe, et le calcul des impacts liés aux correctifs et vulnérabilités. Nous évoquons ensuite l'intérêt de la fédération de modèles pour représenter le système naval, puis nous proposons une mesure de l'impact des correctifs et vulnérabilités sur la sûreté de fonctionnement du système, basée sur l'utilisation d'automates temporisés

Safety, Security and Performance Assessment of Security Countermeasures with SysML-Sec

International audienceDeploying security countermeasures on Cyber-Physical Systems (CPS) can induce side-effects that can exceed their benefits. When CPS are safety-critical systems, performing efficiency and impact assessments of security countermeasures early in the design flow is essential. The paper introduces the W-Sec method, based on SysML-Sec. The W-Sec method consists in two interwoven formal modeling and verification cycles aiming at providing countermeasures with objective and quantitative efficiency and impact assessments in terms of safety, security and performance. The paper evaluates the W-Sec method with an autonomous rover swarm case-study, and finally discusses the method's strengths and weaknesses highlighted by the case-study results

A Methodology to Assess Vulnerabilities and Countermeasures Impact on the Missions of a Naval System

International audienceThe paper proposes a methodology to assess the impacts of vulnerabilities, attacks and countermeasures on a vessel's missions, and a metric designed to express and compare these impacts. A behavioral modeling approach for depicting naval systems and missions is presented. Then the paper introduces a model-checking based impact assessment method. The cyber events are integrated in the behavioral model through model mutation. Then, for each mission, their impact is computed by performing a series of model checks. The paper also discusses the algorithmic complexity of the impact assessment method

Safety, Security and Performance Assessment of Security Countermeasures with SysML-Sec

International audienceDeploying security countermeasures on Cyber-Physical Systems (CPS) can induce side-effects that can exceed their benefits. When CPS are safety-critical systems, performing efficiency and impact assessments of security countermeasures early in the design flow is essential. The paper introduces the W-Sec method, based on SysML-Sec. The W-Sec method consists in two interwoven formal modeling and verification cycles aiming at providing countermeasures with objective and quantitative efficiency and impact assessments in terms of safety, security and performance. The paper evaluates the W-Sec method with an autonomous rover swarm case-study, and finally discusses the method's strengths and weaknesses highlighted by the case-study results

W-Sec: a Model-Based Formal Method for Assessing the Impacts of Security Countermeasures

International audienceThe chapter provides a detailed description of W-Sec, a formal model-based countermeasures' impact assessment method. It also introduces a new formal definition of the two SysML profiles used in SysML-Sec and W-Sec, enabling (i) for the future automation of several W-Sec stages and (ii) for the definition of consistency rules ensuring the consistency of the models written in these two distinct modeling languages. In addition, the chapter evaluates W-Sec with a new industry 4.0 case-study and discusses the strengths and the current limitations of the approach in this new application field