Accelerated Model Checking of Parametric Markov Chains

Parametric Markov chains occur quite naturally in various applications: they can be used for a conservative analysis of probabilistic systems (no matter how the parameter is chosen, the system works to specification); they can be used to find optimal settings for a parameter; they can be used to visualise the influence of system parameters; and they can be used to make it easy to adjust the analysis for the case that parameters change. Unfortunately, these advancements come at a cost: parametric model checking is---or rather was---often slow. To make the analysis of parametric Markov models scale, we need three ingredients: clever algorithms, the right data structure, and good engineering. Clever algorithms are often the main (or sole) selling point; and we face the trouble that this paper focuses on -- the latter ingredients to efficient model checking. Consequently, our easiest claim to fame is in the speed-up we have often realised when comparing to the state of the art

Bounded Model Checking for Probabilistic Programs

In this paper we investigate the applicability of standard model checking approaches to verifying properties in probabilistic programming. As the operational model for a standard probabilistic program is a potentially infinite parametric Markov decision process, no direct adaption of existing techniques is possible. Therefore, we propose an on-the-fly approach where the operational model is successively created and verified via a step-wise execution of the program. This approach enables to take key features of many probabilistic programs into account: nondeterminism and conditioning. We discuss the restrictions and demonstrate the scalability on several benchmarks

Spatial effects should be allowed for in primary care and other community-based cluster RCTS

<p>Abstract</p> <p>Background</p> <p>Typical advice on the design and analysis of cluster randomized trials (C-RCTs) focuses on allowance for the clustering at the level of the unit of allocation. However often C-RCTs are also organised spatially as may occur in the fields of Public Health and Primary Care where populations may even overlap.</p> <p>Methods</p> <p>We allowed for spatial effects on the error variance by a multiple membership model. These are a form of hierarchical model in which each lower level unit is a member of more than one higher level unit. Membership may be determined through adjacency or through Euclidean distance of centroids or in other ways such as the proportion of overlapping population. Such models may be estimated for Normal, binary and Poisson responses in Stata (v10 or above) as well as in WinBUGS or MLWin. We used this to analyse a dummy trial and two real, previously published cluster-allocated studies (one allocating general practices within one City and the other allocating general practices within one County) to investigate the extent to which ignoring spatial effects affected the estimate of treatment effect, using different methods for defining membership with Akaike's Information Criterion to determine the "best" model.</p> <p>Results</p> <p>The best fitting model included both a fixed North-South gradient and a random cluster effect for the dummy RCT. For one of the real RCTs the best fitting model included both a random practice effect plus a multiple membership spatial term, while for the other RCT the best fitting model ignored the clustering but included a fixed North-South gradient. Alternative models which fitted only slightly less well all included spatial effects in one form or another, with some variation in parameter estimates (greater when less well fitting models were included).</p> <p>Conclusions</p> <p>These particular results are only illustrative. However, we believe when designing C-RCTs in a primary care setting the possibility of spatial effects should be considered in relation to the intervention and response, as well as any explanatory effect of fixed covariates, together with any implications for sample size and methods for planned analyses.</p

Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrioanguillarum strain 775

Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site-directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently.

Interferon-inducible gene 202b controls CD8+ T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice

Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T-cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8+ Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8+ T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1–4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8+ T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8+ Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)β and interleukin-2 (IL-2), but not of interferon (IFN)-γ, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8+ T cells, IFNAR1, had no effect on the ability of CD8+ T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide-induced regulatory CD8+ Ti cells through effects on the expression of Foxp3 and the synthesis of TGFβ

Papillary thyroid cancer associated with syndrome of inappropriate antidiuresis: a case report

<p>Abstract</p> <p>Introduction</p> <p>The syndrome of inappropriate antidiuresis is the most common cause of euvolemic hypo-osmolality. This syndrome is associated with a wide variety of diseases. However, its most frequent causes are related to malignancies, especially lung cancer. In this case report, we describe an unknown association of the syndrome of inappropriate antidiuresis with papillary thyroid cancer.</p> <p>Case presentation</p> <p>We present the case of a 71-year-old Caucasian, German woman with marked hyponatremia and neurological symptoms. After a detailed clinical investigation, the common causes of syndrome of inappropriate antidiuresis and other malignancies were ruled out. A thyroid nodule was detected by ultrasound and magnetic resonance imaging. Although fine needle aspiration cytology showed negative results, our patient underwent surgery. Papillary thyroid cancer was later diagnosed. After total thyroidectomy, a complete remission of the clinical symptoms occurred and our patient subsequently had iodine-131 radioactive therapy. Hyponatremia was no longer observed during the follow-up investigations.</p> <p>Conclusion</p> <p>This is the first reported case of paraneoplastic syndrome of inappropriate antidiuresis caused by papillary thyroid carcinoma. Since its symptoms occurred before the development of local symptoms, total thyroidectomy may provide a timely and efficient treatment for the underlying malignancy.</p

Selective blockade of the discriminative stimulus effects of pentobarbital in pigeons

The ability of CNS stimulants to block the discriminative effects of pentobarbital was studied in pigeons trained to discriminate IM pentobarbital (5 mg/kg) from saline. Pentobarbital, when administered alone, consistently produced greater than 90% pentobarbital-appropriate responding. The concomitant administration of pentobarbital and increasing doses of bemegride or pentylenetetrazol resulted in a dose-related decrease in pentobarbital-appropriate responses. In contrast, picrotoxin, another CNS stimulant, had little or no effect on pentobarbital-appropriate responding produced by pentobarbital.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46426/1/213_2004_Article_BF00432447.pd

Controlling Population Evolution in the Laboratory to Evaluate Methods of Historical Inference

Natural populations of known detailed past demographic history are extremely valuable to evaluate methods of historical inference, yet are extremely rare. As an alternative approach, we have generated multiple replicate microsatellite data sets from laboratory-cultured populations of a gonochoric free-living nematode, Caenorhabditis remanei, that were constrained to pre-defined demographic histories featuring different levels of migration among populations or bottleneck events of different magnitudes. These data sets were then used to evaluate the performances of two recently developed population genetics methods, BayesAss+, that estimates recent migration rates among populations, and Bottleneck, that detects the occurrence of recent bottlenecks. Migration rates inferred by BayesAss+ were generally over-estimates, although these were often included within the confidence interval. Analyses of data sets simulated in-silico, using a model mimicking the laboratory experiments, produced less biased estimates of the migration rates, and showed increased efficiency of the program when the number of loci and sampled genotypes per population was higher. In the replicates for which the pre-bottleneck laboratory-cultured populations did not significantly depart from a mutation/drift equilibrium, an important assumption of the program Bottleneck, only a portion of the bottleneck events were detected. This result was confirmed by in-silico simulations mirroring the laboratory bottleneck experiments. More generally, our study demonstrates the feasibility, and highlights some of the limits, of the approach that consists in generating molecular genetic data sets by controlling the evolution of laboratory-reared nematode populations, for the purpose of validating methods inferring population history

Quantum Gravity in Everyday Life: General Relativity as an Effective Field Theory

This article is meant as a summary and introduction to the ideas of effective field theory as applied to gravitational systems. Contents: 1. Introduction 2. Effective Field Theories 3. Low-Energy Quantum Gravity 4. Explicit Quantum Calculations 5. ConclusionsComment: 56 pages, 2 figures, JHEP style, Invited review to appear in Living Reviews of Relativit