Constructive model-based analysis for safety assessment

The aerospace industry still uses fault trees to perform reliability analysis. This is because fault-tree modeling and analysis (FTA) seems easier to practical engineers when compared with Markov models, even though FTA provides a weaker form of analysis. In this paper, we propose an automatic strategy for generating Markov-based models and corresponding analysis formulations, according to ARP 4761, directly from Simulink diagrams annotated with failure information. The generated Markov-based models are expressed in the formal language PRISM, and the analysis is carried out by the PRISM model checker. The strategy is compositional and based on a comprehensive set of translation rules from Simulink to PRISM. We briefly address soundness and completeness of the rules and, to illustrate the application of the strategy, we apply it to a classical avionics case study: an actuator control system.     

The GPU on the simulation of cellular computing models

Membrane Computing is a discipline aiming to abstract formal computing models, called membrane systems or P systems, from the structure and functioning of the living cells as well as from the cooperation of cells in tissues, organs, and other higher order structures. This framework provides polynomial time solutions to NP-complete problems by trading space for time, and whose efficient simulation poses challenges in three different aspects: an intrinsic massively parallelism of P systems, an exponential computational workspace, and a non-intensive floating point nature. In this paper, we analyze the simulation of a family of recognizer P systems with active membranes that solves the Satisfiability problem in linear time on different instances of Graphics Processing Units (GPUs). For an efficient handling of the exponential workspace created by the P systems computation, we enable different data policies to increase memory bandwidth and exploit data locality through tiling and dynamic queues. Parallelism inherent to the target P system is also managed to demonstrate that GPUs offer a valid alternative for high-performance computing at a considerably lower cost. Furthermore, scalability is demonstrated on the way to the largest problem size we were able to run, and considering the new hardware generation from Nvidia, Fermi, for a total speed-up exceeding four orders of magnitude when running our simulations on the Tesla S2050 server.     

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.     

Neuroprotective Effects of Testosterone in the Hypothalamus of an Animal Model of Metabolic Syndrome

Metabolic syndrome (MetS) is known to be associated to inflammation and alteration in the hypothalamus, a brain region implicated in the control of several physiological functions, including energy homeostasis and reproduction. Previous studies demonstrated the beneficial effects of testosterone treatment (TTh) in counteracting some MetS symptoms in both animal models and clinical studies. This study investigated the effect of TTh (30 mg/kg/week for 12 weeks) on the hypothalamus in a high-fat diet (HFD)-induced animal model of MetS, utilizing quantitative RT-PCR and immunohistochemical analyses. The animal model recapitulates the human MetS features, including low testosterone/gonadotropin plasma levels. TTh significantly improved MetS-induced hypertension, visceral adipose tissue accumulation, and glucose homeostasis derangements. Within hypothalamus, TTh significantly counteracted HFD-induced inflammation, as detected in terms of expression of inflammatory markers and microglial activation. Moreover, TTh remarkably reverted the HFD-associated alterations in the expression of important regulators of energy status and reproduction, such as the melanocortin and the GnRH-controlling network. Our results suggest that TTh may exert neuroprotective effects on the HFD-related hypothalamic alterations, with positive outcomes on the circuits implicated in the control of energy metabolism and reproductive tasks, thus supporting a possible role of TTh in the clinical management of MetS.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.     

Tau Exon 10 Inclusion by PrPC through Downregulating GSK3β Activity

Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3β, whose activity is inhibited by the cellular prion protein (PrP^C), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrP^C and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrP^C and the implication of GSK3β in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrP^C ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrP^C expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrP^C levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3β activity downstream from PrP^C in this phenomenon. Our results indicate that PrP^C plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3β.     

Thermodynamic study of the phase equilibria in the Sn−Ti−Zn ternary system

The Sn−Ti−Zn ternary phase diagram has been constructed using the CALPHAD technique. The Ti−Zn binary system phase boundaries were determined using differential scanning calorimetry and the solid-liquid diffusion couples method. In addition, the formation energy of some stoichiometric compounds was obtained using first-principle band energy calculations. For the ternary system, some alloys were prepared by equilibration at 600 or 700 °C, and the compositions of the precipitates were analyzed using electron probe microanalysis. Thermodynamic assessment of the Ti−Zn and Sn−Ti−Zn systems was performed based on the experimental information and by adopting reported values of the thermodynamic properties of the Sn−Zn and Sn−Ti binary systems. Microstructural observation showed that Sn₃Ti₅Zn₁₂ exists in the ternary system. Seven types of invariant reaction on the Sn-rich liquidus surface of the ternary system are predicted by the phase diagram calculations. The ternary eutectic point falls at 0,0009 mass% Ti and 8.69 mass% Zn, at T=192.40°C, which is slightly lower than the calculated eutectic point of Sn−Zn binary alloy (T=192.41°C). Based on these results, a nonequilibrium solidification process using the Scheil model was simulated. This paper was presented at the International Symposium on User Aspects of Phase Diagrams, Materials Solutions Conference and Exposition, Columbus, Ohio, 18–20 October, 2004.