A Game-Theoretic Foundation for the Maximum Software Resilience against Dense Errors

Safety-critical systems need to maintain their functionality in the presence of multiple errors caused by component failures or disastrous environment events. We propose a game-theoretic foundation for synthesizing control strategies that maximize the resilience of a software system in defense against a realistic error model. The new control objective of such a game is called $k$ -resilience. In order to be $k$ -resilient, a system needs to rapidly recover from infinitely many waves of a small number of up to $k$ close errors provided that the blocks of up to $k$ errors are separated by short time intervals, which can be used by the system to recover. We first argue why we believe this to be the right level of abstraction for safety critical systems when local faults are few and far between. We then show how the analysis of $k$ -resilience problems can be formulated as a model-checking problem of a mild extension to the alternating-time $\mu$ -calculus (AMC). The witness for $k$ resilience, which can be provided by the model checker, can be used for providing control strategies that are optimal with respect to resilience. We show that the computational complexity of constructing such optimal control strategies is low and demonstrate the feasibility of our approach through an implementation and experimental results

Mining association rules for label ranking

Lecture Notes in Computer Science Volume 6635, 2011.Recently, a number of learning algorithms have been adapted for label ranking, including instance-based and tree-based methods. In this paper, we continue this line of work by proposing an adaptation of association rules for label ranking based on the APRIORI algorithm. Given that the original APRIORI algorithm does not aim to obtain predictive models, two changes were needed for this achievement. The adaptation essentially consists of using variations of the support and confidence measures based on ranking similarity functions that are suitable for label ranking. Additionally we propose a simple greedy method to select the parameters of the algorithm. We also adapt the method to make a prediction from the possibly con icting consequents of the rules that apply to an example. Despite having made our adaptation from a very simple variant of association rules for classification, partial results clearly show that the method is making valid predictions. Additionally, they show that it competes well with state-of-the-art label ranking algorithms.This work was partially supported by project Rank! (PTDC/EIA/81178/2006) from FCT and Palco AdI project Palco3.0 financed by QREN and Fundo Europeu de Desenvolvimento Regional (FEDER). We thank the anonymous referees for useful comments

Finite element-based micromechanical modeling of the influence of phase properties on the elastic response of cementitious mortars

This study reports the influence of inclusion stiffness and its distribution on the stress distributions in the microstructural phases of different cementitious mortars using microstructure-guided finite element simulations. Randomly generated periodic microstructures with single/multiple inclusion sizes and random spatial distribution, subjected to periodic boundary conditions and a strain-controlled virtual testing regime are chosen for final analysis. Numerical simulations reveal: (i) the differences in locations/magnitudes of stress concentrations as a function of inclusion stiffness and size distribution, and (ii) the sometimes detrimental influence of matrix and interface stiffening/strengthening on the overall composite response, leading to material design strategies when non-conventional inclusions are used in cementitious systems for special properties. The constitutive behavior in the linear elastic regime is extracted based on the predicted dominant principal stresses and strains in the representative area element. Thus, in addition to the microstructural phase stresses, this methodology also provides predictions of the composite elastic modulus, which are observed to be more reliable than those obtained from analytical prediction models

Increased expression of receptor phosphotyrosine phosphatase-β/ζ is associated with molecular, cellular, behavioral and cognitive schizophrenia phenotypes

Schizophrenia is a serious and chronic mental disorder, in which both genetic and environmental factors have a role in the development of the disease. Neuregulin-1 (NRG1) is one of the most established genetic risk factors for schizophrenia, and disruption of NRG1 signaling has been reported in this disorder. We reported previously that NRG1/ErbB4 signaling is inhibited by receptor phosphotyrosine phosphatase-β/ζ (RPTP β/ζ) and that the gene encoding RPTPβ/ζ (PTPRZ1) is genetically associated with schizophrenia. In this study, we examined the expression of RPTPβ/ζ in the brains of patients with schizophrenia and observed increased expression of this gene. We developed mice overexpressing RPTPβ/ζ (PTPRZ1-transgenic mice), which showed reduced NRG1 signaling, and molecular and cellular changes implicated in the pathogenesis of schizophrenia, including altered glutamatergic, GABAergic and dopaminergic activity, as well as delayed oligodendrocyte development. Behavioral analyses also demonstrated schizophrenia-like changes in the PTPRZ1-transgenic mice, including reduced sensory motor gating, hyperactivity and working memory deficits. Our results indicate that enhanced RPTPβ/ζ signaling can contribute to schizophrenia phenotypes, and support both construct and face validity for PTPRZ1-transgenic mice as a model for multiple schizophrenia phenotypes. Furthermore, our results implicate RPTPβ/ζ as a therapeutic target in schizophrenia

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods: SLC3A2 was assessed at the genomic level, using METABRIC data (n=1,980), and proteomic level, using immunohistochemistry on TMA sections constructed from a large well-characterised primary BC cohort (n=2,500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results: SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple negative (TN), HER2+, and ER+ high proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p<0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p<0.001)), but only in the ER+ high proliferation (p=0.01) and triple negative (p=0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter breast cancer specific survival (p<0.001). Conclusions: SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes

A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity

The coordinated regulation of mitochondrial and nuclear activities is essential for cellular respiration and its disruption leads to mitochondrial dysfunction, a hallmark of ageing. Mitochondria communicate with nuclei through retrograde signalling pathways that modulate nuclear gene expression to maintain mitochondrial homeostasis. The monooxygenase CLK-1 (human homologue COQ7) was previously reported to be mitochondrial, with a role in respiration and longevity. We have uncovered a distinct nuclear form of CLK-1 that independently regulates lifespan. Nuclear CLK-1 mediates a retrograde signalling pathway that is conserved from Caenorhabditis elegans to humans and is responsive to mitochondrial reactive oxygen species, thus acting as a barometer of oxidative metabolism. We show that, through modulation of gene expression, the pathway regulates both mitochondrial reactive oxygen species metabolism and the mitochondrial unfolded protein response. Our results demonstrate that a respiratory enzyme acts in the nucleus to control mitochondrial stress responses and longevity

Treatment with green tea extract attenuates secondary inflammatory response in an experimental model of spinal cord trauma

In this study, we evaluated the effect of green tea extract (that was administered 25 mg/kg intraperitoneal at 1 and 6 h after injury) in experimental animal model of spinal cord injury. The spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5–T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterised by oedema, neutrophilic infiltration and apoptosis. Also, immunohistochemical examination demonstrated a marked increase in immune reactivity for nitrotyrosine. All parameters of inflammation were attenuated by green tea extract. The degree of spinal cord inflammation, nitrotyrosine, poli (ADP-ribosio) synthetase (PARS) and neutrophilic infiltration was markedly reduced. Green tea extract significantly ameliorated the recovery of limb function. Values shown are mean ± SE mean of ten mice for each group. *p < 0.01 versus sham, °p < 0.01 versus spinal cord injury. Taken together, our results clearly demonstrate that green tea extract treatment ameliorates spinal cord injury oxidative stress

Complete Phenotypic Recovery of an Alzheimer's Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor

The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated β-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Aβ oligomerization and fibrillization, as well as the cytotoxic effect of Aβ oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Aβ while immuno-staining of the 3rd instar larval brains showed a significant reduction in Aβ accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Aβ. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease