Spatial Interpolants

We propose Splinter, a new technique for proving properties of heap-manipulating programs that marries (1) a new separation logic-based analysis for heap reasoning with (2) an interpolation-based technique for refining heap-shape invariants with data invariants. Splinter is property directed, precise, and produces counterexample traces when a property does not hold. Using the novel notion of spatial interpolants modulo theories, Splinter can infer complex invariants over general recursive predicates, e.g., of the form all elements in a linked list are even or a binary tree is sorted. Furthermore, we treat interpolation as a black box, which gives us the freedom to encode data manipulation in any suitable theory for a given program (e.g., bit vectors, arrays, or linear arithmetic), so that our technique immediately benefits from any future advances in SMT solving and interpolation.Comment: Short version published in ESOP 201

Beyond reachability: Shape abstraction in the presence of pointer arithmetic

Abstract. Previous shape analysis algorithms use a memory model where the heap is composed of discrete nodes that can be accessed only via access paths built from variables and field names, an assumption that is violated by pointer arithmetic. In this paper we show how this assumption can be removed, and pointer arithmetic embraced, by using an analysis based on separation logic. We describe an abstract domain whose elements are certain separation logic formulae, and an abstraction mechanism that automatically transits between a low-level RAM view of memory and a higher, fictional, view that abstracts from the representation of nodes and multiword linked-lists as certain configurations of the RAM. A widening operator is used to accelerate the analysis. We report experimental results obtained from running our analysis on a number of classic algorithms for dynamic memory management.

Verifying Programs with Dynamic 1-Selector-Linked Structures in Regular Model Checking

International audienceWe address the problem of automatic verification of programs with dynamic data structures. We consider the case of sequential, non-recursive programs manipulating 1-selector-linked structures such as traditional linked lists (possibly sharing their tails) and circular lists. We propose an automata-based approach for a symbolic verification of such programs using the regular model checking framework. Given a program, the configurations of the memory are systematically encoded as words over a suitable finite alphabet, potentially infinite sets of configurations are represented by finite-state automata, and statements of the program are automatically translated into finite-state transducers defining regular relations between configurations. Then, abstract regular model checking techniques are applied in order to automatically check safety properties concerning the shape of the computed configurations or relating the input and output configurations. For that, we introduce new techniques for the computation of abstractions of the set of reachable configurations, and to refine these abstractions if spurious counterexamples are detected. Finally, we present experimental results showing the applicability of the approach and its efficiency

Limiting phase trajectories and the origin of energy localization in nonlinear oscillatory chains

We demonstrate that the modulation instability of the zone boundary mode in a finite (periodic) Fermi-Pasta-Ulam chain is the necessary but not sufficient condition for the efficient energy transfer by localized excitations. This transfer results from the exclusion of complete energy exchange between spatially different parts of the chain, and the excitation level corresponding to that turns out to be twice more than threshold of zone boundary mode's instability. To obtain this result one needs in far going extension of the beating concept to a wide class of finite oscillatory chains. In turn, such an extension leads to description of energy exchange and transition to energy localization and transfer in terms of 'effective particles' and Limiting Phase Trajectories. The 'effective particles' appear naturally when the frequency spectrum crowding ensures the resonance interaction between zone boundary and two nearby nonlinear normal modes, but there are no additional resonances. We show that the Limiting Phase Trajectories corresponding to the most intensive energy exchange between 'effective particles' can be considered as an alternative to Nonlinear Normal Modes, which describe the stationary process

Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity

It is widely accepted that reactive oxygen species (ROS) promote tumorigenesis. However, the exact mechanisms are still unclear. As mice lacking the peroxidase peroxiredoxin1 (Prdx1) produce more cellular ROS and die prematurely of cancer, they offer an ideal model system to study ROS-induced tumorigenesis. Prdx1 ablation increased the susceptibility to Ras-induced breast cancer. We, therefore, investigated the role of Prdx1 in regulating oncogenic Ras effector pathways. We found Akt hyperactive in fibroblasts and mammary epithelial cells lacking Prdx1. Investigating the nature of such elevated Akt activation established a novel role for Prdx1 as a safeguard for the lipid phosphatase activity of PTEN, which is essential for its tumour suppressive function. We found binding of the peroxidase Prdx1 to PTEN essential for protecting PTEN from oxidation-induced inactivation. Along those lines, Prdx1 tumour suppression of Ras- or ErbB-2-induced transformation was mediated mainly via PTEN

Implications for oxidative stress and astrocytes following 26S proteasomal depletion in mouse forebrain neurones

Neurodegenerative diseases are characterized by progressive degeneration of selective neurones in the nervous system, but the underlying mechanisms involved in neuroprotection and neurodegeneration remain unclear. Dysfunction of the ubiquitin proteasome system is one of the proposed hypotheses for the cause and progression of neuronal loss. We have performed quantitative two-dimensional fluorescence difference in-gel electrophoresis combined with peptide mass fingerprinting to reveal proteome changes associated with neurodegeneration following 26S proteasomal depletion in mouse forebrain neurones. Differentially expressed proteins were validated by Western blotting, biochemical assays and immunohistochemistry. Of significance was increased expression of the antioxidant enzyme peroxiredoxin 6 (PRDX6) in astrocytes, associated with oxidative stress. Interestingly, PRDX6 is a bifunctional enzyme with antioxidant peroxidase and phospholipase A2 (PLA2) activities. The PLA2 activity of PRDX6 was also increased following 26S proteasomal depletion and may be involved in neuroprotective or neurodegenerative mechanisms. This is the first in vivo report of oxidative stress caused directly by neuronal proteasome dysfunction in the mammalian brain. The results contribute to understanding neuronal–glial interactions in disease pathogenesis, provide an in vivo link between prominent disease hypotheses and importantly, are of relevance to a heterogeneous spectrum of neurodegenerative diseases

A Correspondence between Two Approaches to Interprocedural Analysis in the Presence of Join

Many interprocedural static analyses perform a lossy join for reasons of termination or efficiency. We study the relationship between two predominant approaches to interprocedural analysis, the summary- based (or functional) approach and the call-strings (or k-CFA) approach, in the presence of a lossy join. Despite the use of radically different ways to distinguish procedure contexts by these two approaches, we prove that post-processing their results using a form of garbage collection ren- ders them equivalent. Our result extends the classic result by Sharir and Pnueli that showed the equivalence between these two approaches in the setting of distributive analysis, wherein the join is lossless. We also empirically compare these two approaches by applying them to a pointer analysis that performs a lossy join. Our experiments on ten Java programs of size 400K{900K bytecodes show that the summary-based approach outperforms an optimized implementation of the k-CFA approach: the k-CFA implementation does not scale beyond k=2, while the summary-based approach proves up to 46% more pointer analysis client queries than 2-CFA. The summary-based approach thus enables, via our equivalence result, to measure the precision of k-CFA with unbounded k, for the class of interprocedural analyses that perform a lossy join

α4β1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the α4-cytoplasmic domain

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which α4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the α4 tail that disrupts paxillin binding, α4(Y991A), reduced talin association to the α4β1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed α4β1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal α4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions

Cancer-selective, single agent chemoradiosensitising gold nanoparticles

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics