535 research outputs found

    Calculating τ-confluence compositionally

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    τ-confluence is a reduction technique used in enumerative model-checking of labeled transition systems to avoid the state explosion problem. In this paper, we propose a new on-the-fly algorithm to calculate partial τ-confluence, and propose new techniques to do so on large systems in a compositional manner. Using information inherent in the way a large system is composed of smaller systems, we show how we can deduce partial τ-confluence in a computationally cheap manner. Finally, these techniques are applied to a number of case studies, including the rel/REL atomic multicast protocol.peer-reviewe

    Confluence Reduction for Probabilistic Systems (extended version)

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    This paper presents a novel technique for state space reduction of probabilistic specifications, based on a newly developed notion of confluence for probabilistic automata. We prove that this reduction preserves branching probabilistic bisimulation and can be applied on-the-fly. To support the technique, we introduce a method for detecting confluent transitions in the context of a probabilistic process algebra with data, facilitated by an earlier defined linear format. A case study demonstrates that significant reductions can be obtained

    Geochemical constraints on the Hadean environment from mineral fingerprints of prokaryotes

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    The environmental conditions on the Earth before 4 billion years ago are highly uncertain, largely because of the lack of a substantial rock record from this period. During this time interval, known as the Hadean, the young planet transformed from an uninhabited world to the one capable of supporting, and inhabited by the first living cells. These cells formed in a fluid environment they could not at first control, with homeostatic mechanisms developing only later. It is therefore possible that present-day organisms retain some record of the primordial fluid in which the first cells formed. Here we present new data on the elemental compositions and mineral fingerprints of both Bacteria and Archaea, using these data to constrain the environment in which life formed. The cradle solution that produced this elemental signature was saturated in barite, sphene, chalcedony, apatite, and clay minerals. The presence of these minerals, as well as other chemical features, suggests that the cradle environment of life may have been a weathering fluid interacting with dry-land silicate rocks. The specific mineral assemblage provides evidence for a moderate Hadean climate with dry and wet seasons and a lower atmospheric abundance of CO2 than is present today.Fil: Novoselov, Alexey A.. Universidad de Concepción; ChileFil: Silva, Dailto. Universidade Estadual de Campinas; BrasilFil: Schneider, Jerusa. Universidade Estadual de Campinas; BrasilFil: Abrevaya, Ximena Celeste. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Chaffin, Michael S.. State University Of Colorado Boulder; Estados UnidosFil: Serrano, Paloma. Alfred Wegener Institute Helmholtz Centre For Polar And Marine Research,; AlemaniaFil: Navarro, Margareth Sugano. Universidade Estadual de Campinas; BrasilFil: Conti, Maria Josiane. André Tosello Institute; BrasilFil: Souza Filho, Carlos Roberto de. Universidade Estadual de Campinas; Brasi

    On-the-fly confluence detection for statistical model checking (extended version)

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    Statistical model checking is an analysis method that circumvents the state space explosion problem in model-based verification by combining probabilistic simulation with statistical methods that provide clear error bounds. As a simulation-based technique, it can only provide sound results if the underlying model is a stochastic process. In verification, however, models are usually variations of nondeterministic transition systems. The notion of confluence allows the reduction of such transition systems in classical model checking by removing spurious nondeterministic choices. In this paper, we show that confluence can be adapted to detect and discard such choices on-the-fly during simulation, thus extending the applicability of statistical model checking to a subclass of Markov decision processes. In contrast to previous approaches that use partial order reduction, the confluence-based technique can handle additional kinds of nondeterminism. In particular, it is not restricted to interleavings. We evaluate our approach, which is implemented as part of the modes simulator for the Modest modelling language, on a set of examples that highlight its strengths and limitations and show the improvements compared to the partial order-based method

    Gamma-ray spectrometry in the field: Radioactive heat production in the Central Slovakian Volcanic Zone

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    We report 62 sets of measurements from central-southern Slovakia, obtained using a modern portable gamma-ray spectrometer, which reveal the radioactive heat production in intrusive and extrusive igneous rocks of the Late Cenozoic Central Slovakian Volcanic Zone. Sites in granodiorite of the Štiavnica pluton are thus shown to have heat production in the range ~ 2.2–4.9 μW m− 3, this variability being primarily a reflection of variations in content of the trace element uranium. Sites in dioritic parts of this pluton have a lower, but overlapping, range of values, ~ 2.1–4.4 μW m− 3. Sites that have been interpreted in adjoining minor dioritic intrusions of similar age have heat production in the range ~ 1.4–3.3 μW m− 3. The main Štiavnica pluton has zoned composition, with potassium and uranium content and radioactive heat production typically increasing inward from its margins, reflecting variations observed in other granodioritic plutons elsewhere. It is indeed possible that the adjoining dioritic rocks, hitherto assigned to other minor intrusions of similar age, located around the periphery of the Štiavnica pluton, in reality provide further evidence for zonation of the same pluton. The vicinity of this pluton is associated with surface heat flow ~ 40 mW m− 2 above the regional background. On the basis of our heat production measurements, we thus infer that the pluton has a substantial vertical extent, our preferred estimate for the scale depth for its downward decrease in radioactive heat production being ~ 8 km. Nonetheless, this pluton lacks any significant negative Bouguer gravity anomaly. We attribute this to the effect of the surrounding volcanic caldera, filled with relatively low-density lavas, ‘masking’ the pluton's own gravity anomaly. We envisage that emplacement occurred when the pluton was much hotter, and thus of lower density, than at present, its continued uplift, evident from the local geomorphology, being the isostatic consequence of localized erosion. The heat production in this intrusion evidently plays a significant role, hitherto unrecognized, in the regional geothermics

    Computer-aided verification : how to trust a machine with your life

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    Mathematical predictive analysis of the behaviour of circuits and computer pro- grams is a core problem in computer science. Research in formal verification and semantics of programming languages has been an active field for a number of decades, but it was only through techniques developed over these past twenty years that they have been scaled up to work on non-trivial case-studies. This report gives an overview of a number of computer- aided formal verification areas I have been working on over these past couple of years in such a way to be accessible to computer scientists in other disciplines. Brief mention is made of problems in these areas I am actively working on. It does not purport to be an overview of the whole field of computer-aided formal verification or a detailed technical account of my research.peer-reviewe

    Bisimulator 2.0: An On-the-Fly Equivalence Checker based on Boolean Equation Systems

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    International audienceEquivalence checking is a classical verification method determining if a finite-state concurrent system (protocol) satisfies its desired external behaviour (service) by comparing their underlying labeled transition systems (LTSs) modulo an appropriate equivalence relation. Local (or on-the-fly) equivalence checking explores the synchronous product of the LTSs incrementally, allowing an efficient detection of errors in complex systems. In this paper, we consider the technique based on translating the equivalence checking problem in terms of the local resolution of a boolean equation system (BES). We propose two enhancements of this technique in the case of equivalent LTSs: a new, faster BES encoding of weak equivalence relations, and a new local BES resolution algorithm with a good average complexity. These enhancements were incorporated into the BISIMULATOR 2.0 equivalence checker of the CADP toolbox, and led to significant performance improvements

    Understanding and Exploiting MYCN Addiction in High-Risk Neuroblastoma Using the Example of CDK13

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    Neuroblastoma (NB) is an extracranial childhood cancer and accounts for 15 % of all childhood cancer-related deaths. It is a remarkably heterogeneous disease and cases range from spontaneous regression to aggressive high risk disease. Amplification of the oncogene MYCN occurs in 20-30 % of cases and is an indicator of poor prognosis. As a transcription factor, MYCN drives several cellular programs favoring malignant behavior, for example proliferation, angiogenesis and metastasis. In order to gain a better understanding of direct and secondary transcriptional targets of MYCN, gene expression was analyzed in a time course experiment using cell cycle-synchronized cells with regulatable MYCN level. This approach revealed the continued upregulation of a number of cell cycle driver genes as well as genes involved in protein and DNA biosynthesis in MYCN high cells. Differences in the expression of other cell cycle and DNA replication genes occurred only in specific phases of the cell cycle. On the other hand, genes involved in alternative splicing and cell adhesion were constantly downregulated. The expression of snoRNAs strongly increased in the MYCN low condition towards the end of the observation period. An analysis of miRNA expression revealed that many differentially regulated miRNAs targeted genes involved in ribosome biogenesis, cancer processes and signaling pathways. Taken together, this data set indicates that MYCN directly regulates the expression of genes and miRNAs which contribute to accelerated proliferation, metabolism and metastatic growth in NB cells. As a consequence of the induced phenotype, a larger number of secondary targets are deregulated. As MYCN heavily contributes to tumor malignancy, MYCN-amplified NB cells become addicted to high amounts of the protein. However, MYCN itself is notoriously difficult to target, therefore two siRNA screens were performed to detect synthetic lethal relationships with high MYCN levels. The second part of this thesis deals with the transcriptional kinase CDK13, which was identified as a potential candidate for novel targeted therapies. CDK13 and its highly homologous family member CDK12 were knocked down by several technical approaches. In a cellular MYCN overexpression model, CDK13 repression induced strong cell death only in MYCN high cells. CDK12 repression also elicited a small amount of cell death comparing MYCN high with low cells. Inducible CDK13 knockdown in a MYCN-amplified cell line caused modest reductions in cellular viability and colony formation capacity. CDK13, but not CDK12, knockout induced by the clustered regularly interspaced short palindromic repeats (CRISPR) technique reduced viability and caused a small increase in cells arrested in G1. However, analysis of CDK13 mRNA level revealed significant residual expression, suggesting that the majority of the polyclonal culture might be heterozygous for the induced mutation. A novel small compound inhibitor against CDK12 and CDK13 (BAY-587) was tested in a panel of eight NB cell lines and the effects were compared to that of a commercially available inhibitor, THZ531. BAY-587 was active at lower concentrations than THZ531. Both compounds strongly reduced viability, colony formation capacity and disrupted cell cycle distributions. BAY-587 treatment reduced the level of CDK12 protein and further induced apoptosis. Gene expression analysis revealed that CDK12/13 inhibition by BAY-587 caused downregulation of genes involved in alternative splicing and DNA damage repair, while transcription regulation genes were upregulated. In summary, CDK13 emerged as a promising new therapeutic candidate for the treatment of high risk NB patients
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