Using global analysis, partial specifications, and an extensible assertion language for program validation and debugging

We discuss a framework for the application of abstract interpretation as an aid during program development, rather than in the more traditional application of program optimization. Program validation and detection of errors is first performed statically by comparing (partial) specifications written in terms of assertions against information obtained from (global) static analysis of the program. The results of this process are expressed in the user assertion language. Assertions (or parts of assertions) which cannot be checked statically are translated into run-time tests. The framework allows the use of assertions to be optional. It also allows using very general properties in assertions, beyond the predefined set understandable by the static analyzer and including properties defined by user programs. We also report briefly on an implementation of the framework. The resulting tool generates and checks assertions for Prolog, CLP(R), and CHIP/CLP(fd) programs, and integrates compile-time and run-time checking in a uniform way. The tool allows using properties such as types, modes, non-failure, determinacy, and computational cost, and can treat modules separately, performing incremental analysis

The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Contribution to the understanding of tribological properties of graphite intercalation compounds with metal chloride

Intrinsic tribological properties of lamellar compounds are usually attributed to the presence of van der Waals gaps in their structure through which interlayer interactions are weak. The controlled variation of the distances and interactions between graphene layers by intercalation of electrophilic species in graphite is used in order to explore more deeply the friction reduction properties of low-dimensional compounds. Three graphite intercalation compounds with antimony pentachloride, iron trichloride and aluminium trichloride are studied. Their tribological properties are correlated to their structural parameters, and the interlayer interactions are deduced from ab initio bands structure calculations

Special electronic structures and quantum conduction of B/P co-doping carbon nanotubes under electric field using the first principle

Boron (B)/phosphorus (P) doped single wall carbon nanotubes (B-PSWNTs) are studied by using the First- Principle method based on density function theory (DFT). Mayer bond order, band structure, electrons density and density of states are calculated. It concludes that the B-PSWNTs have special band structure which is quite different from BN nanotubes, and that metallic carbon nanotubes will be converted to semiconductor due to boron/phosphorus co-doping which breaks the symmetrical structure. The bonding forms in B-PSWNTs are investigated in detail. Besides, Mulliken charge population and the quantum conductance are also calculated to study the quantum transport characteristics of B-PSWNT hetero-junction. It is found that the position of p-n junction in this hetero-junction will be changed as the applied electric field increase and it performs the characteristics of diode.Comment: 11 pages, 6 fiugres, 2 table

A rapid mechanism to remobilize and homogenize highly crystalline magma bodies

International audienceThe largest products of magmatic activity on Earth, the great bodies of granite and their corresponding large eruptions, have a dual nature: homogeneity at the large scale and spatial and temporal heterogeneity at the small scale1-4. This duality calls for amechanism that selectively removes the large-scale heterogeneities associated with the incremental assembly4 of these magmatic systems and yet occurs rapidly despite crystal-rich, viscous conditions seemingly resistant to mixing2,5. Here we show that a simple dynamic template can unify a wide range of apparently contradictory observations from both large plutonic bodies and volcanic systems by a mechanism of rapid remobilization (unzipping) of highly viscous crystalrich mushes. We demonstrate that this remobilization can lead to rapid overturn and produce the observed juxtaposition ofmagmatic materials with very disparate ages and complex chemical zoning. What distinguishes our model is the recognition that the process has two stages. Initially, a stiff mushy magma is reheated from below, producing a reduction in crystallinity that leads to the growth of a subjacent buoyant mobile layer. When the thickening mobile layer becomes sufficiently buoyant, it penetrates the overlying viscous mushy magma. This second stage rapidly exports homogenized material from the lower mobile layer to the top of the system, and leads to partial overturn within the viscous mush itself as an additional mechanism of mixing. Model outputs illustrate that unzipping can rapidly produce large amounts of mobile magma available for eruption. The agreement between calculated and observed unzipping rates for historical eruptions at Pinatubo and at Montserrat demonstrates the general applicability of the model. This mechanism furthers our understanding of both the formation of periodically homogenized plutons (crust building) and of ignimbrites by large eruptions

Cryptococcal Cell Morphology Affects Host Cell Interactions and Pathogenicity

Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 µm. Cell enlargement was observed in vivo, producing cells up to 100 µm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aΔ pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection

Cryptococcal Neuroradiological Lesions Correlate with Severity during Cryptococcal Meningoencephalitis in HIV-Positive Patients in the HAART Era

Cryptococcal meningoencephalitis has an overall global mortality rate of 20% in AIDS patients despite antifungals. There is a need for additional means of precise assessment of disease severity. We thus studied the radiological brain images available from 62 HIV-positive patients with cryptococcocal meningoencephalitis to analyse the brain lesions associated with cryptococcosis in relationship with disease severity, and the respective diagnostic contribution of magnetic resonance (MR) versus computed tomography (CT)

Finite Element Modeling of Ultrasonic Waves in Viscoelastic Media

Linear viscoelasticity theory offers a minimal framework within which to construct a consistent, linear and causal model of mechanical wave dispersion. The term dispersion is used here to imply temporal wave spreading and amplitude reduction due to absorptive material properties rather than due to geometrical wave spreading. Numerical modeling of wave propagation in absorptive media has been the subject of recent research in such areas as material property measurement [1] [2], seismology [3] [4] [5] and medical ultrasound [6] [7]. Previously, wave attenuation has been included in transient finite element formulations via a constant damping matrix [8] or functionally in terms of a power law relation [9]. The formulation presented here is based on representing the viscoelastic shear and bulk moduli of the medium as either a discrete or continuous spectrum of decaying exponentials [10]. As a first test of the correctness of the viscoelastic finite element formulation, the finite element results for a simple hypothetical medium are compared with an equivalent Laplace-Hankel transform domain solution.</p

At Least Ten Genes Define the Imprinted Dlk1-Dio3 Cluster on Mouse Chromosome 12qF1

Background: Genomic imprinting is an exception to Mendelian genetics in that imprinted genes are expressed monoallelically, dependent on parental origin. In mammals, imprinted genes are critical in numerous developmental and physiological processes. Aberrant imprinted gene expression is implicated in several diseases including Prader-Willi/ Angelman syndromes and cancer. Methodology/Principal Findings: To identify novel imprinted genes, transcription profiling was performed on two uniparentally derived cell lines, androgenetic and parthenogenetic primary mouse embryonic fibroblasts. A maternally expressed transcript termed Imprinted RNA near Meg3/Gtl2 (Irm) was identified and its expression studied by Northern blotting and whole mounts in situ hybridization. The imprinted region that contains Irm has a parent of origin effect in three mammalian species, including the sheep callipyge locus. In mice and humans, both maternal and paternal uniparental disomies (UPD) cause embryonic growth and musculoskeletal abnormalities, indicating that both alleles likely express essential genes. To catalog all imprinted genes in this chromosomal region, twenty-five mouse mRNAs in a 1.96Mb span were investigated for allele specific expression. Conclusions/Significance: Ten imprinted genes were elucidated. The imprinting of three paternally expressed protein coding genes (Dlk1, Peg11, and Dio3) was confirmed. Seven noncoding RNAs (Meg3/Gtl2, Anti-Peg11, Meg8, Irm/‘‘Rian’’