Formal methods integration for the specification of dependable distributed systems

This paper describes a real-world case study in the specification and analysis of dependable distributed systems. The case study is an automated transport system with safety requirements. In order to manage the complexity of the problem of specifying the dynamic behavior of the whole system, a compositional approach is used, based on the integration of the trace logic of the Communicating Sequential Processes (CSP) theory, and stochastic Petri nets (SPNs). It is argued that the integration of different formal methods is a useful approach in the definition of practical engineering methodologies for the specification, design and analysis of complex dependable distributed systems.     

Scale-effects on mean and standard deviation of the mechanical properties of condensed matter: an energy-based unified approach

The size effects on the mean values of the mechanical properties of condensed matter and on the related variances are analysed by means of a unified approach based on the multiscale character of energy dissipation. In particular, the scaling law for fragmentation energy density is obtained taking into account the self-similarity of fragments. It is based on a generalization of the three classical comminution laws that has been performed to evaluate the energy dissipation, computing volume and surface area of the particles for one- two- and three-dimensional fragmented objects. The result is general and can be applied to different fractal energy dissipation mechanisms, e.g., plasticity. Based on this approach, the scaling laws for mean and standard deviation values of the main mechanical properties of materials can be derived, like Young's and shear elastic moduli, ultimate normal and shear stresses and strains, fracture energy and toughness.     

Scaling of energy dissipation in crushing and fragmentation: a fractal and statistical analysis based on particle size distribution

An extensive experimental investigation on concrete specimens under crushing and fragmentation over a large scale range (1:10) – exploring even very small specimen dimensions (1 cm) – was carried out to evaluate the influence of fragment size distribution on energy density dissipation and related size effect. To obtain a statistically significant fragment production as well as the total energy dissipated in a given specimen, the experimental procedure was unusually carried out up to a strain of approximately –95%, practically corresponding to the initial fragment compaction between the loading platens. The experimental fragment analysis suggests a fractal law for the distribution in particle size; this simply means that fragments derived from a given specimen appear geometrically self-similar at each observation scale. In addition, clear size effects on dissipated energy density are experimentally observed. Fractal concepts permit to quantify the correlation between fragment size distribution and size effect on dissipated energy density, the latter being governed by the total surface area of produced fragments. The experimental results agree with the proposed multi-scale interpretation satisfactorily.     

Reliable regulation in centralized control systems

This paper addresses the design of a reliable control system for a linear, asymptotically stable plant. Specifically, the considered problem consists in finding a regulator which guarantees asymptotic stability, signal tracking and disturbance rejection when all the instrumentation is operational, and ensures that these properties are preserved, to the maximum possible extent, when an arbitrary number of sensors and/or actuators faults occur, that is, some of the feedback loops open. With reference to a centralized control structure and exogenous signals with multiple poles on the imaginary axis, the paper supplies a necessary and sufficient condition for the problem to admit a solution, and a possible least order regulator.     

Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN.     

Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers

The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m². In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19–3.23)), DM (OR = 2.59, 95% CI 1.63–4.13), body mass index (BMI) ≥ 27 kg/m² (OR = 2.17, 95% CI 1.33–3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49–4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa.     

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).     

Formulations for an inventory routing problem

In this paper, we present and compare formulations for the inventory routing problem (IRP) where the demand of customers has to be served, over a discrete time horizon, by capacitated vehicles starting and ending their routes at a depot. The objective of the IRP is the minimization of the sum of inventory and transportation costs. The formulations include known and new mathematical programming formulations. Valid inequalities are also presented. The formulations are tested on a large set of benchmark instances. One of the most significant conclusions is that the formulations that use vehicle‐indexed variables are superior to the more compact, aggregate formulations.