Structural disjoining potential for grain boundary premelting and grain coalescence from molecular-dynamics simulations

We describe a molecular dynamics framework for the direct calculation of the short-ranged structural forces underlying grain-boundary premelting and grain-coalescence in solidification. The method is applied in a comparative study of (i) a Sigma 9 120 degress twist and (ii) a Sigma 9 {411} symmetric tilt boundary in a classical embedded-atom model of elemental Ni. Although both boundaries feature highly disordered structures near the melting point, the nature of the temperature dependence of the width of the disordered regions in these boundaries is qualitatively different. The former boundary displays behavior consistent with a logarithmically diverging premelted layer thickness as the melting temperature is approached from below, while the latter displays behavior featuring a finite grain-boundary width at the melting point. It is demonstrated that both types of behavior can be quantitatively described within a sharp-interface thermodynamic formalism involving a width-dependent interfacial free energy, referred to as the disjoining potential. The disjoining potential for boundary (i) is calculated to display a monotonic exponential dependence on width, while that of boundary (ii) features a weak attractive minimum. The results of this work are discussed in relation to recent simulation and theoretical studies of the thermodynamic forces underlying grain-boundary premelting.Comment: 24 pages, 8 figures, 1 tabl

Satisfiability Modulo Transcendental Functions via Incremental Linearization

In this paper we present an abstraction-refinement approach to Satisfiability Modulo the theory of transcendental functions, such as exponentiation and trigonometric functions. The transcendental functions are represented as uninterpreted in the abstract space, which is described in terms of the combined theory of linear arithmetic on the rationals with uninterpreted functions, and are incrementally axiomatized by means of upper- and lower-bounding piecewise-linear functions. Suitable numerical techniques are used to ensure that the abstractions of the transcendental functions are sound even in presence of irrationals. Our experimental evaluation on benchmarks from verification and mathematics demonstrates the potential of our approach, showing that it compares favorably with delta-satisfiability /interval propagation and methods based on theorem proving

Proving Tight Bounds on Univariate Expressions with Elementary Functions in Coq

International audienceThe verification of floating-point mathematical libraries requires computing numerical bounds on approximation errors. Due to the tightness of these bounds and the peculiar structure of approximation errors, such a verification is out of the reach of generic tools such as computer algebra systems. In fact, the inherent difficulty of computing such bounds often mandates a formal proof of them. In this paper, we present a tactic for the Coq proof assistant that is designed to automatically and formally prove bounds on univariate expressions. It is based on a formalization of floating-point and interval arithmetic, associated with an on-the-fly computation of Taylor expansions. All the computations are performed inside Coq's logic, in a reflexive setting. This paper also compares our tactic with various existing tools on a large set of examples

Role of the Two Component Signal Transduction System CpxAR in Conferring Cefepime and Chloramphenicol Resistance in Klebsiella pneumoniae NTUH-K2044

Background: Klebsiella pneumoniae is a Gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the c-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum b-lactamase producing strains. Twocomponent systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress. Principal Findings: In the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (DcpxAR) deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of DcpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The DcpxAR was more susceptible to b-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxR KP to promoter region of ompC KP in a concentration dependent manner

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and to the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospo-proteomics profiles confirm the cell-specific feedback effects and synergy of MEK and IGFR targeted treatements. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies, and our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma

The relationship between cadence, pedalling technique and gross efficiency in cycling

Technique and energy saving are two variables often considered as important for performance in cycling and related to each other. Theoretically, excellent pedalling technique should give high gross efficiency (GE). The purpose of the present study was to examine the relationship between pedalling technique and GE. 10 well-trained cyclists were measured for GE, force effectiveness (FE) and dead centre size (DC) at a work rate corresponding to ~75% of VO2max during level and inclined cycling, seat adjusted forward and backward, at three different cadences around their own freely chosen cadence (FCC) on an ergometer. Within subjects, FE, DC and GE decreased as cadence increased (p < 0.001). A strong relationship between FE and GE was found, which was to great extent explained by FCC. The relationship between cadence and both FE and GE, within and between subjects, was very similar, irrespective of FCC. There was no difference between level and inclined cycling position. The seat adjustments did not affect FE, DC and GE or the relationship between them. Energy expenditure is strongly coupled to cadence, but force effectiveness, as a measure for pedalling technique, is not likely the cause of this relationship. FE, DC and GE are not affected by body orientation or seat adjustments, indicating that these parameters and the relationship between them are robust to coordinative challenges within a range of cadence, body orientation and seat position that is used in regular cycling

The Mw = 6.3, November 21, 2004, Les Saintes earthquake (Guadeloupe): Tectonic setting, slip model and static stress changes,

International audienceOn November 21, 2004, a magnitude 6.3 earthquake occurred offshore, 10 km south of Les Saintes archipelago in Guadeloupe (French West Indies). There were more than 30000 aftershocks recorded in the following two years, most of them at shallow depth near the islands of the archipelago. The main shock and its main aftershock of February 14, 2005 (Mw = 5.8) ruptured a NE-dipping normal fault (Roseau fault), mapped and identified as active from high-resolution bathymetric data a few years before. This fault belongs to an arc-parallel en echelon fault system that follows the inner edge of the northern part of the Lesser Antilles arc, accommodating the sinistral component of oblique convergence between the North American and Caribbean plates. The distribution of aftershocks and damage (destruction and landslides) are consistent with the main fault plane location and attitude. The slip model of the main shock, obtained by inverting jointly global broadband and local strong motion records, is characterized by two main slip zones located 5 to 10 km to the SE and NW of the hypocenter. The main shock is shown to have increased the Coulomb stress at the tips of the ruptured plane by more than 4 bars where most of the aftershocks occurred, implying that failures on fault system were mainly promoted by static stress changes. The earthquake also had an effect on volcanic activity since the Boiling Lake in Dominica drained twice, probably as a result of the extensional strain induced by the earthquake and its main aftershock

Global Analysis of Extracytoplasmic Stress Signaling in Escherichia coli

The Bae, Cpx, Psp, Rcs, and σE pathways constitute the Escherichia coli signaling systems that detect and respond to alterations of the bacterial envelope. Contributions of these systems to stress response have previously been examined individually; however, the possible interconnections between these pathways are unknown. Here we investigate the dynamics between the five stress response pathways by determining the specificities of each system with respect to signal-inducing conditions, and monitoring global transcriptional changes in response to transient overexpression of each of the effectors. Our studies show that different extracytoplasmic stress conditions elicit a combined response of these pathways. Involvement of the five pathways in the various tested stress conditions is explained by our unexpected finding that transcriptional responses induced by the individual systems show little overlap. The extracytoplasmic stress signaling pathways in E. coli thus regulate mainly complementary functions whose discrete contributions are integrated to mount the full adaptive response