Goal-oriented test data generation for pointer programs

Goal-oriented test data generation; Constraint Logic Programming; Static Single Assignment formInternational audienceAutomatic test data generation leads to the identification of input values on which a selected path or a selected branch is executed within a program (path-oriented vs goal-oriented methods). In both cases, several approaches based on constraint solving exist, but in the presence of pointer variables only path-oriented methods have been proposed. Pointers are responsible for the existence of conditional aliasing problems that usually provoke the failure of the goal-oriented test data generation process. In this paper, we propose an overall constraint-based method that exploits the results of an intraprocedural points-to analysis and provides two specific constraint combinators for automatically generating goal-oriented test data. This approach correctly handles multi-levels stack-directed pointers that are mainly used in C programs. The method has been fully implemented in the test data generation tool INKA and first experiences in applying it to a variety of existing programs are presented

Visualizing Pyrazinamide Action by Live Single-Cell Imaging of Phagosome Acidification and Mycobacterium tuberculosis pH Homeostasis.

Mycobacterium tuberculosis segregates within multiple subcellular niches with different biochemical and biophysical properties that, upon treatment, may impact antibiotic distribution, accumulation, and efficacy. However, it remains unclear whether fluctuating intracellular microenvironments alter mycobacterial homeostasis and contribute to antibiotic enrichment and efficacy. Here, we describe a live dual-imaging approach to monitor host subcellular acidification and M. tuberculosis intrabacterial pH. By combining this approach with pharmacological and genetic perturbations, we show that M. tuberculosis can maintain its intracellular pH independently of the surrounding pH in human macrophages. Importantly, unlike bedaquiline (BDQ), isoniazid (INH), or rifampicin (RIF), the drug pyrazinamide (PZA) displays antibacterial efficacy by disrupting M. tuberculosis intrabacterial pH homeostasis in cellulo. By using M. tuberculosis mutants, we confirmed that intracellular acidification is a prerequisite for PZA efficacy in cellulo. We anticipate this imaging approach will be useful to identify host cellular environments that affect antibiotic efficacy against intracellular pathogens. IMPORTANCE We still do not completely understand why tuberculosis (TB) treatment requires the combination of several antibiotics for up to 6 months. M. tuberculosis is a facultative intracellular pathogen, and it is still unknown whether heterogenous and dynamic intracellular populations of bacteria in different cellular environments affect antibiotic efficacy. By developing a dual live imaging approach to monitor mycobacterial pH homeostasis, host cell environment, and antibiotic action, we show here that intracellular localization of M. tuberculosis affects the efficacy of one first-line anti-TB drug. Our observations can be applicable to the treatment of other intracellular pathogens and help to inform the development of more effective combined therapies for tuberculosis that target heterogenous bacterial populations within the host

High-throughput functional metagenomics for the discovery of glycan metabolizing pathways

Glycans are widely distributed in nature. Produced by almost all organisms, they are involved in numerous cellular processes, such as energy supply and storage, cell structuration, protein maturation and signalling, and cell recognition. Glycans are thus key elements mediating the interactions between mammals, plants, bacteria, fungi and even viruses. They also represent a reliable source of carbon for microbes, which have developed complex strategies to face their structural diversity and to harvest them. However between 70 and 99% of these microorganisms are still uncultured, while they represent a goldmine for the discovery of new enzymes. In order to boost their identification and characterization, a functional metagenomic approach was developed, based on the design of various high-throughput, robust and sensitive screening strategies. The functional potential of Gbp of metagenomic DNA from various origins was explored, revealing dozens of novel enzyme families and functions. Integration of biochemical, structural, meta-omic and omic data allowed us to decipher, from the molecular to the ecosystemic scale, novel mechanisms of plant, microbial and mammal glycan metabolization. These new metabolic pathways involve batteries of glycoside-hydrolases, glycoside-phosphorylases and sugar transporters. These fascinating proteins appear as new targets to control host-microbe interactions. They also constitute very efficient biotechnological tools for biorefineries and synthetic biology

Iso-singlet Down Quark Mixing And CP Violation Experiments

We confront the new physics models with extra iso-singlet down quarks in the new CP violation experimental era with $\sin{(2\beta)}$ and $\epsilon'/\epsilon$ measurements, $K^+ \to \pi^+ \nu \bar{\nu}$ events, and $x_s$ limits. The closeness of the new experimental results to the standard model theory requires us to include full SM amplitudes in the analysis. In models allowing mixing to a new isosinglet down quark, as in E$_6$, flavor changing neutral currents are induced that allow a $Z^0$ mediated contribution to $B-\bar B$ mixing and which bring in new phases. In $(\rho,\eta)$, $(x_s,\sin{(\gamma)})$, and $(x_s, \sin{(2\phi_s)})$ plots we still find much larger regions in the four down quark model than in the SM, reaching down to $\eta \approx 0$, $0 \leq \sin{(\gamma)} \leq 1$, $-.75 \leq \sin{(2\alpha)} \leq 0.15$, and $\sin{(2\phi_s)}$ down to zero, all at 1$\sigma$. We elucidate the nature of the cancellation in an order $\lambda^5$ four down quark mixing matrix element which satisfies the experiments and reduces the number of independent angles and phases. We also evaluate tests of unitarity for the $3\times3$ CKM submatrix.Comment: 14 pages, 16 figures, REVTeX

Automating structural testing of C programs: Experience with PathCrawler

Structural testing is widely used in industrial verific

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Pinch Technique: Theory and Applications

We review the theoretical foundations and most important physical applications of the Pinch Technique (PT). This method allows the construction of off-shell Green's functions in non-Abelian gauge theories that are independent of the gauge-fixing parameter and satisfy ghost-free Ward identities. We first present the diagrammatic formulation of the technique in QCD, deriving at one loop the gauge independent gluon self-energy, quark-gluon vertex, and three-gluon vertex, together with their Abelian Ward identities. The generalization to theories with spontaneous symmetry breaking is carried out in detail, and the connection with the optical theorem and the dispersion relations are explained within the electroweak sector of the Standard Model. The equivalence between the PT and the Feynman gauge of the Background Field Method (BFM) is elaborated, and the crucial differences between the two methods are critically scrutinized. The Batalin-Vilkovisky quantization method and the general formalism of algebraic renormalization are introduced, and the all-order generalization of the PT is thoroughly examined. The extension of the PT to the non-perturbative domain of the QCD Schwinger-Dyson equations is presented systematically, and the main advantages of the resulting self-consistent truncation scheme are discussed. A plethora of physical applications relying on the PT are reviewed, such as the definition of gauge-independent off-shell form-factors, the construction of non-Abelian effective charges, the gauge-invariant treatment of resonant transition amplitudes and unstable particles, and the dynamical generation of an effective gluon mass.Comment: 245 pages, 92 figure

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery