Parameterized Model-Checking for Timed-Systems with Conjunctive Guards (Extended Version)

In this work we extend the Emerson and Kahlon's cutoff theorems for process skeletons with conjunctive guards to Parameterized Networks of Timed Automata, i.e. systems obtained by an \emph{apriori} unknown number of Timed Automata instantiated from a finite set $U_1, \dots, U_n$ of Timed Automata templates. In this way we aim at giving a tool to universally verify software systems where an unknown number of software components (i.e. processes) interact with continuous time temporal constraints. It is often the case, indeed, that distributed algorithms show an heterogeneous nature, combining dynamic aspects with real-time aspects. In the paper we will also show how to model check a protocol that uses special variables storing identifiers of the participating processes (i.e. PIDs) in Timed Automata with conjunctive guards. This is non-trivial, since solutions to the parameterized verification problem often relies on the processes to be symmetric, i.e. indistinguishable. On the other side, many popular distributed algorithms make use of PIDs and thus cannot directly apply those solutions

Regular symmetry patterns

Symmetry reduction is a well-known approach for alleviating the state explosion problem in model checking. Automatically identifying symmetries in concurrent systems, however, is computationally expensive. We propose a symbolic framework for capturing symmetry patterns in parameterised systems (i.e. an infinite family of finite-state systems): two regular word transducers to represent, respectively, parameterised systems and symmetry patterns. The framework subsumes various types of "symmetry relations" ranging from weaker notions (e.g. simulation preorders) to the strongest notion (i.e. isomorphisms). Our framework enjoys two algorithmic properties: (1) symmetry verification: given a transducer, we can automatically check whether it is a symmetry pattern of a given system, and (2) symmetry synthesis: we can automatically generate a symmetry pattern for a given system in the form of a transducer. Furthermore, our symbolic language allows additional constraints that the symmetry patterns need to satisfy to be easily incorporated in the verification/synthesis. We show how these properties can help identify symmetry patterns in examples like dining philosopher protocols, self-stabilising protocols, and prioritised resource-allocator protocol. In some cases (e.g. Gries's coffee can problem), our technique automatically synthesises a safety-preserving finite approximant, which can then be verified for safety solely using a finite-state model checker.UPMAR

Titanium, Sinusitis, and the Yellow Nail Syndrome

Yellow nail syndrome is characterized by nail changes, respiratory disorders, and lymphedema. In a yellow nail patient with a skeletal titanium implant and with gold in her teeth, we found high levels of titanium in nail clippings. This study aims to examine the possible role of titanium in the genesis of the yellow nail syndrome. Nail clippings from patients with one or more features of the yellow nail syndrome were analyzed by energy dispersive X-ray fluorescence. Titanium was regularly found in finger nails in patients but not in control subjects. Visible nail changes were present in only half of the patients. Sinusitis with postnasal drip and cough was the most common complaint. The dominant source of titanium ions was titanium implants in the teeth or elsewhere. The titanium ions were released through the galvanic action of dental gold or amalgam or through the oxidative action of fluorides. In other patients the titanium was derived from titanium dioxide in drugs and confectionary. Stopping galvanic release of titanium ions or canceling exposure to titanium dioxide led to recovery. In one patient with a titanium implant, the symptoms recurred after renewed exposure to titanium. Yellow nail syndrome is caused by titaniu

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Double Digest RADseq: An Inexpensive Method for De Novo SNP Discovery and Genotyping in Model and Non-Model Species

The ability to efficiently and accurately determine genotypes is a keystone technology in modern genetics, crucial to studies ranging from clinical diagnostics, to genotype-phenotype association, to reconstruction of ancestry and the detection of selection. To date, high capacity, low cost genotyping has been largely achieved via “SNP chip” microarray-based platforms which require substantial prior knowledge of both genome sequence and variability, and once designed are suitable only for those targeted variable nucleotide sites. This method introduces substantial ascertainment bias and inherently precludes detection of rare or population-specific variants, a major source of information for both population history and genotype-phenotype association. Recent developments in reduced-representation genome sequencing experiments on massively parallel sequencers (commonly referred to as RAD-tag or RADseq) have brought direct sequencing to the problem of population genotyping, but increased cost and procedural and analytical complexity have limited their widespread adoption. Here, we describe a complete laboratory protocol, including a custom combinatorial indexing method, and accompanying software tools to facilitate genotyping across large numbers (hundreds or more) of individuals for a range of markers (hundreds to hundreds of thousands). Our method requires no prior genomic knowledge and achieves per-site and per-individual costs below that of current SNP chip technology, while requiring similar hands-on time investment, comparable amounts of input DNA, and downstream analysis times on the order of hours. Finally, we provide empirical results from the application of this method to both genotyping in a laboratory cross and in wild populations. Because of its flexibility, this modified RADseq approach promises to be applicable to a diversity of biological questions in a wide range of organisms

Tight Cutoffs for Guarded Protocols with Fairness

Guarded protocols were introduced in a seminal paper by Emerson and Kahlon (2000), and describe systems of processes whose transitions are enabled or disabled depending on the existence of other processes in certain local states. We study parameterized model checking and synthesis of guarded protocols, both aiming at formal correctness arguments for systems with any number of processes. Cutoff results reduce reasoning about systems with an arbitrary number of processes to systems of a determined, fixed size. Our work stems from the observation that existing cutoff results for guarded protocols i) are restricted to closed systems, and ii) are of limited use for liveness properties because reductions do not preserve fairness. We close these gaps and obtain new cutoff results for open systems with liveness properties under fairness assumptions. Furthermore, we obtain cutoffs for the detection of global and local deadlocks, which are of paramount importance in synthesis. Finally, we prove tightness or asymptotic tightness for the new cutoffs.Comment: Accepted for publication at VMCAI 2016. Extended version, revised after conference review

Minimal stress shielding with a Mallory-Head titanium femoral stem with proximal porous coating in total hip arthroplasty

<p>Abstract</p> <p>Background</p> <p>As longevity of cementless femoral components enters the third decade, concerns arise with long-term effects of fixation mode on femoral bone morphology. We examined the long-term consequences on femoral remodeling following total hip arthroplasty with a porous plasma-sprayed tapered titanium stem.</p> <p>Methods</p> <p>Clinical data and radiographs were reviewed from a single center for 97 randomly selected cases implanted with the Mallory-Head Porous femoral component during primary total hip arthroplasty. Measurements were taken from preoperative and long-term follow-up radiographs averaging 14 years postoperative. Average changes in the proximal, middle and diaphyseal zones were determined.</p> <p>Results</p> <p>On anteroposterior radiographs, the proximal cortical thickness was unchanged medially and the lateral zone increased 1.3%. Middle cortical thickness increased 4.3% medially and 1.2% laterally. Distal cortical thickness increased 9.6% medially and 1.9% laterally. Using the anteroposterior radiographs, canal fill at 100 mm did not correlate with bony changes at any level (Spearman's rank correlation coefficient of -0.18, 0.05, and 0.00; p value = 0.09, 0.67, 0.97). On lateral radiographs, the proximal cortical thickness increased 1.5% medially and 0.98% laterally. Middle cortical thickness increased 2.4% medially and 1.3% laterally. Distal cortical thickness increased 3.5% medially and 2.1% laterally. From lateral radiographs, canal fill at 100 mm correlated with bony hypertrophy at the proximal, mid-level, and distal femur (Spearman's rank correlation coefficient of 0.85, 0.33, and 0.28, respectively; p value = 0.001, 0.016, and 0.01, respectively).</p> <p>Conclusion</p> <p>Stress shielding is minimized with the Mallory-Head titanium tapered femoral stem with circumferential proximal plasma-sprayed coating in well-fixed and well-functioning total hip arthroplasty. Additionally, the majority of femora demonstrated increased cortical thickness in all zones around the stem prosthesis. Level of Evidence: Therapeutic Level III.</p

Automata for true concurrency properties

We present an automata-theoretic framework for the model checking of true concurrency properties. These are specified in a fixpoint logic, corresponding to history-preserving bisimilarity, capable of describing events in computations and their dependencies. The models of the logic are event structures or any formalism which can be given a causal semantics, like Petri nets. Given a formula and an event structure satisfying suitable regularity conditions we show how to construct a parity tree automaton whose language is non-empty if and only if the event structure satisfies the formula. The automaton, due to the nature of event structure models, is usually infinite. We discuss how it can be quotiented to an equivalent finite automaton, where emptiness can be checked effectively. In order to show the applicability of the approach, we discuss how it instantiates to finite safe Petri nets. As a proof of concept we provide a model checking tool implementing the technique

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Adherence with tobramycin inhaled solution and health care utilization

<p>Abstract</p> <p>Background</p> <p>Adherence with tobramycin inhalation solution (TIS) during routine cystic fibrosis (CF) care may differ from recommended guidelines and affect health care utilization.</p> <p>Methods</p> <p>We analyzed 2001-2006 healthcare claims data from 45 large employers. Study subjects had diagnoses of CF and at least 1 prescription for TIS. We measured adherence as the number of TIS therapy cycles completed during the year and categorized overall adherence as: low ≤ 2 cycles, medium >2 to <4 cycles, and high ≥ 4 cycles per year. Interquartile ranges (IQR) were created for health care utilization and logistic regression analysis of hospitalization risk was conducted by TIS adherence categories.</p> <p>Results</p> <p>Among 804 individuals identified with CF and a prescription for TIS, only 7% (n = 54) received ≥ 4 cycles of TIS per year. High adherence with TIS was associated with a decreased risk of hospitalization when compared to individuals receiving ≤ 2 cycles (adjusted odds ratio 0.40; 95% confidence interval 0.19-0.84). High adherence with TIS was also associated with lower outpatient service costs (IQR: $2,159-$8444 vs. $2,410-$14,423) and higher outpatient prescription drug costs (IQR: $35,125-$60,969 vs. $10,353-$46,768).</p> <p>Conclusions</p> <p>Use of TIS did not reflect recommended guidelines and may impact other health care utilization.</p