Translating between Alloy specifications and UML class diagrams annotated with OCL

Model-driven engineering (MDE) is a software engineering approach based on model transformations at different abstraction levels. It prescribes the development of software by successively transforming the models from abstract (specifications) to more concrete ones (code). Alloy is an increasingly popular lightweight formal specification language that supports automatic verification. Unfortunately, its widespread industrial adoption is hampered by the lack of an ecosystem of MDE tools, namely code generators. This paper presents a model transformation from Alloy to UML class diagrams annotated with OCL (UML+OCL) and shows how an existing transformation from UML+OCL to Alloy can be improved to handle dynamic issues. The proposed bidirectional transformation enables a smooth integration of Alloy in the current MDE contexts, by allowing UML+OCL specifications to be transformed to Alloy for validation and verification, to correct and possibly refine them inside Alloy, and to translate them back to UML+OCL for sharing with stakeholders or to reuse current model-driven architecture tools to refine them toward code.This work was funded by European Regional Development Fund (ERDF) through the COMPETE Programme (operational program for competitiveness) and by national funds through the FCT (Fundaaco para a Ciencia e a Tecnologia-portuguese Foundation for Science and Technology) within project FCOMP-01-0124-FEDER-020532. Part of the work was done while the first author was visiting the Software Design Group at CSAIL, MIT, USA, funded by FCT sabbatical grant SFRH/BSAB/1187/2011. The second author was also partially supported by QREN (the portuguese National Strategy Reference Chart) project 1621, while visiting the High-Assurance Software Laboratory at Universidade do Minho, Portugal. Finally, we would also like to thank all anonymous reviewers for the valuable comments and suggestions

A de novo 2.9 Mb interstitial deletion at 13q12.11 in a child with developmental delay accompanied by mild dysmorphic characteristics

Background: Proximal deletions in the 13q12.11 region are very rare. Much larger deletions including this region have been described and are associated with complex phenotypes of mental retardation, developmental delay and various others anomalies. Results: We report on a 3-year-old girl with a rare 2.9 Mb interstitial deletion at 13q12.11 due to a de novo unbalanced t(13;14) translocation. She had mild mental retardation and relatively mild dysmorphic features such as microcephaly, flat nasal bridge, moderate micrognathia and clinodactyly of 5th finger. Molecular karyotyping revealed a deletion on the long arm of chromosome 13 as involving sub-bands 13q12.11, a deletion of about 2.9 Mb. Discussion: The clinical application of array-CGH has made it possible to detect submicroscopical genomic rearrangements that are associated with varying phenotypes.The description of more patients with deletions of the 13q12.11 region will allow a more precise genotype-phenotype correlation

The diverse nature of island isolation and its effect on land bridge insular faunas

Aim: Isolation is a key factor in island biology. It is usually defined as the distance to the geographically nearest mainland, but many other definitions exist. We explored how testing different isolation indices affects the inference of impacts of isolation on faunal characteristics. We focused on land bridge islands and compared the relationships of many spatial and temporal (i.e., through time) isolation indices with community‐, population‐ and individual‐level characteristics (species richness, population density and body size, respectively). Location: Aegean Sea islands, Greece. Time period: Current. Taxon: Many animal taxa. Methods: We estimated 21 isolation indices for 205 islands and recorded species richness data for 15 taxa (invertebrates and vertebrates). We obtained body size data for seven lizard species and population density data for three. We explored how well indices predict each characteristic, in each taxon, by conducting a series of ordinary least squares regressions (controlling for island area when needed) and a meta‐analysis. Results: Isolation was significantly (and negatively) associated with species richness in 10 of 15 taxa. It was significantly (and positively) associated with body size in only one of seven species and was not associated with population density. The effect of isolation on species richness was much weaker than that of island area, regardless of the index tested. Spatial indices generally out‐performed temporal indices, and indices directly related to the mainland out‐performed those related mainly to neighbouring islands. No index was universally superior to others, including the distance to the geographically nearest mainland. Main conclusions: The choice of index can alter our perception of the impacts of isolation on biological patterns. The nearly automatic, ubiquitous use of distance to the geographically nearest mainland misrepresents the complexity of the effects of isolation. We recommend the simultaneous testing of several indices that represent different aspects of isolation, in order to produce more constructive and thorough investigations and avoid imprecise inference

The European Union, borders and conflict transformation: the case of Cyprus

Much of the existing literature on the European Union (EU), conflict transformation and border dynamics has been premised on the assumption that the nature of the border determines EU intervention and the consequences that flow from this in terms of EU impact. The article aims to transcend this literature through assessing how domestic interpretations influence EU border transformation in conflict situations, taking Cyprus as a case study. Moreover, the objective is to fuse the literature on EU bordering impact and perceptions of the EU’s normative projection in conflict resolution. Pursuing this line of inquiry is an attempt to depart from the notion of borders being constructed solely by unidirectional EU logics of engagement or bordering practices to a conceptualization of the border as co-constituted space, where the interpretations of the EU’s normative projections by conflict parties, and the strategies that they pursue, can determine the relative openness of the EU border

Clinical Profile of Cardiac Involvement in Danon Disease: A Multicenter European Registry

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P<0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients. Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations

Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases

In this paper the Working Group on Myocardial and Pericardial Disease proposes a revised definition of dilated cardiomyopathy (DCM) in an attempt to bridge the gap between our recent understanding of the disease spectrum and its clinical presentation in relatives, which is key for early diagnosis and the institution of potential preventative measures. We also provide practical hints to identify subsets of the DCM syndrome where aetiology directed management has great clinical relevance

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients

Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol: Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology

he 1996 American Heart Association consensus panel recommendations stated that pre-participation cardiovascular screening for young competitive athletes is justifiable and compelling on ethical, legal, and medical grounds. The present article represents the consensus statement of the Study Group on Sports Cardiology of the Working Group on Cardiac Rehabilitation and Exercise Physiology and the Working Group on Myocardial and Pericardial diseases of the European Society of Cardiology, which comprises cardiovascular specialists and other physicians from different European countries with extensive clinical experience with young competitive athletes, as well as with pathological substrates of sudden death. The document takes note of the 25-year Italian experience on systematic pre-participation screening of competitive athletes and focuses on relevant issues, mostly regarding the relative risk, causes, and prevalence of sudden death in athletes; the efficacy, feasibility, and cost-effectiveness of population-based pre-participation cardiovascular screening; the key role of 12-lead ECG for identification of cardiovascular diseases such as cardiomyopathies and channelopathies at risk of sudden death during sports; and the potential of preventing fatal events. The main purpose of the consensus document is to reinforce the principle of the need for pre-participation medical clearance of all young athletes involved in organized sports programmes, on the basis of (i) the proven efficacy of systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy-the leading cause of sports-related sudden death-and to prevent athletic field fatalities; (ii) the potential screening ability in detecting other lethal cardiovascular diseases presenting with ECG abnormalities. The consensus document recommends the implementation of a common European screening protocol essentially based on 12-lead ECG

HNRNPK is retained in the cytoplasm by Keratin 19 to stabilize target mRNAs

Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on posttranscriptional gene regulation remain uncharacterized. Here we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We mapped cytoplasmic HNRNPK target mRNAs using PAR-CLIP where transcriptome data to show that, in the cytoplasm, HNRNPK stabilizes target mRNAs bound to the 3’ untranslated region at the expected C-rich sequence elements. Furthermore, these mRNAs are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown or K19 knockout. This study identifies how a cytoskeletal protein can directly regulate gene expression by controlling subcellular localization of RNA binding proteins to support pathways involved in cancer progression