Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.     

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Building kernels from binary strings for image matching.

In the statistical learning framework, the use of appropriate kernels may be the key for substantial improvement in solving a given problem. In essence, a kernel is a similarity measure between input points satisfying some mathematical requirements and possibly capturing the domain knowledge. In this paper, we focus on kernels for images: we represent the image information content with binary strings and discuss various bitwise manipulations obtained using logical operators and convolution with nonbinary stencils. In the theoretical contribution of our work, we show that histogram intersection is a Mercer's kernel and we determine the modifications under which a similarity measure based on the notion of Hausdorff distance is also a Mercer's kernel. In both cases, we determine explicitly the mapping from input to feature space. The presented experimental results support the relevance of our analysis for developing effective trainable systems.     

Petri net based process scheduling: A model of the control system of flexible manufacturing systems

In this paper, we propose a class of algorithms for the sub-optimal solution of a particular class of problems of process scheduling, particularly focusing on a case study in the area of flexible manufacturing systems (FMSs). The general class of problems we face in our approach is characterized as follows: there is a set of concurrent processes, each formed by a number of temporally related tasks (segments). Tasks are executable by alternate resource sets, different both in performance and costs. Processes and tasks are characterized by release times, due dates, and deadlines. Time constraints are also present in the availability of each resource in resource sets. It has been proven that such a problem does not admit an algorithm for an optimal solution in polynomial time. Our proposed algorithm finds a sub-optimal schedule according to a set of optimization criteria, based on task and process times (earliness, tardiness), and/or time independent costs of resources. Our approach to process scheduling is based on Timed Coloured Petri Nets. We describe the structure of the coordination and scheduling algorithms, concentrating on (i) the general-purpose component, and (ii) the application-dependent component. In particular, the paper focuses on the following issues: (i) theautomatic synthesis of Petri net models of the coordination subsystem, starting from the problem knowledge base; (ii) the dynamic behavior of the coordination subsystem, whose kernel is a High Level Petri net executor, a coordination process based on an original, general purpose algorithm; (iii) the structure of the real-time scheduling subsystem, based on particular heuristic sub-optimal multi-criteria algorithms. Furthermore, the paper defines the interaction mechanisms between the coordination and scheduling subsystems. Our approach clearly distinguishes the mechanism of the net execution from the decision support system. Two conceptually distinct levels, which correspond to two different, interacting implementation modules in the prototype CASE tool, have been defined: theexecutor and thescheduler levels. One of the outstanding differences between these levels is that the executor is conceived as a fast, efficient coordination process, without special-purpose problem-solving capabilities in case of conflicts. The scheduler, on the other hand, is the adaptive, distributed component, whose behavior may heavily depend on the problem class. If the scheduler fails, the executor is, in any case, able to proceed with a general-purpose conflict resolution strategy. Experimental results on the real-time performance of the kernel of the implemented system are finally shown in the paper. The approach described in this paper is at the basis of a joint project with industrial partners for the development of a CASE tool for the simulation of blast furnaces.     

Cerebral dominance and asynchrony between bimanual two-dimensional movements.

The asynchrony of bimanual movements was investigated. Right- and left-handers traced simple geometrical patterns (ellipses) continuously with both hands. All combinations of the direction of rotation in each hand were executed at different rhythms. Geometrically, performances were largely independent of manual dominance. However, by comparing the passage times at homologous positions, the authors found that the dominant hand led the nondominant one by about 25 msec. The asynchrony was affected by neither movement type nor rhythm. The variability of the asynchrony varied along the trajectory, with well-defined maxima and minima. The variability profiles for movements that engaged homologous muscles differed markedly from those that engaged nonhomologous muscles. The authors discuss the hypotheses that bimanual periodic movements are timed by a lateralized functional module and that asynchrony is due to the necessity of transmitting time-keeping information to the other hemisphere. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of Particle Size on Monometallic and Bimetallic (Au,Pd)/C on the Liquid Phase Oxidation of Glycerol

The influence of metal particle size of monometallic and bimetallic supported catalysts (Au, Pd, Au–Pd)/C was studied using as a model reaction the liquid phase oxidation of glycerol. By tuning the metal particle size from 2 to 16 nm a progressive decrease of activity and simultaneously an increase in the selectivity to sodium glycerate was observed. Moreover, the influence of the temperature was studied and it was found that by increasing the temperature, only with a large particle size the formed glycerate was retained and not over-oxidized to tartronate.