Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury?

BackgroundBlood–nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway.MethodsUsing a classical neuropathic pain model, the infraorbital nerve chronic constriction injury (IoN-CCI), we investigated the role of the Wnt/β-catenin pathway in chronic constriction injury-mediated blood–nerve barrier disruption and in its interactions with the toll-like receptor 4 and Sonic Hedgehog pathways. In the IoN-CCI model versus control, mRNA expression levels and/or immunochemical detection of major Wnt/Sonic Hedgehog pathway (Frizzled-7, vascular endothelial-cadherin, Patched-1 and Gli-1) and/or tight junction proteins (Claudin-1, Claudin-5, and Occludin) readouts were assessed. Vascular permeability was assessed by sodium fluorescein extravasation.ResultsIoN-CCI induced early alterations in the vascular endothelial-cadherin/β-catenin/Frizzled-7 complex, shown to participate in local blood–nerve barrier disruption via a β-catenin-dependent tight junction protein downregulation. Wnt pathway also mediated a crosstalk between toll-like receptor 4 and Sonic Hedgehog signaling within endoneurial endothelial cells. Nevertheless, preemptive inhibition of Wnt/β-catenin signaling before IoN-CCI could not prevent the downregulation of key Sonic Hedgehog pathway readouts or the disruption of the infraorbital blood–nerve barrier, suggesting that Sonic Hedgehog pathway inhibition observed following IoN-CCI is an independent event responsible for blood–nerve barrier disruption.ConclusionA crosstalk between Wnt/β-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood–nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development

Automatic Quantification of Cache Side-Channels

The latency gap between caches and main memory has been successfully exploited for recovering sensitive input to programs, such as cryptographic keys from implementation of AES and RSA. So far, there are no practical general-purpose countermeasures against this threat. In this paper we propose a novel method for automatically deriving upper bounds on the amount of information about the input that an adversary can extract from a program by observing the CPU\u27s cache behavior. At the heart of our approach is a novel technique for efficient counting of concretizations of abstract cache states that enables us to connect state-of-the-art techniques for static cache analysis and quantitative information-flow. We implement our counting procedure on top of the AbsInt TimingExplorer, one of the most advanced engines for static cache analysis. We use our tool to perform a case study where we derive upper bounds on the cache leakage of a 128-bit AES executable on an ARM processor with a realistic cache configuration. We also analyze this implementation with a commonly suggested (but until now heuristic) countermeasure applied, obtaining a formal account of the corresponding increase in security

A Static Analyzer for Large Safety-Critical Software

We show that abstract interpretation-based static program analysis can be made efficient and precise enough to formally verify a class of properties for a family of large programs with few or no false alarms. This is achieved by refinement of a general purpose static analyzer and later adaptation to particular programs of the family by the end-user through parametrization. This is applied to the proof of soundness of data manipulation operations at the machine level for periodic synchronous safety critical embedded software. The main novelties are the design principle of static analyzers by refinement and adaptation through parametrization, the symbolic manipulation of expressions to improve the precision of abstract transfer functions, the octagon, ellipsoid, and decision tree abstract domains, all with sound handling of rounding errors in floating point computations, widening strategies (with thresholds, delayed) and the automatic determination of the parameters (parametrized packing)

A Framework for Combining Algebraic and Logical Abstract Interpretations

We introduce a reduced product combining algebraic and logical abstractions to design program correctness verifiers and static analyzers by abstract interpretation. The key new idea is to show that the Nelson-Oppen procedure for combining theories in SMT-solvers computes a reduced product in an observational semantics, so that algebraic and logical abstract interpretations can naturally be combined in a classical way using a reduced product on this observational semantics. The main practical benefit is that reductions can be performed within the logical abstract domains, within the algebraic abstract domains, and also between the logical and the algebraic abstract domains, including the case of abstractions evolving during the analysis

A Scalable Segmented Decision Tree Abstract Domain

International audienceThe key to precision and scalability in all formal methods for static program analysis and verification is the handling of disjunctions arising in relational analyses, the flow-sensitive traversal of conditionals and loops, the context-sensitive inter-procedural calls, the interleaving of concurrent threads, etc. Explicit case enumeration immediately yields to combinatorial explosion. The art of scalable static analysis is therefore to abstract disjunctions to minimize cost while preserving weak forms of disjunctions for expressivity. Building upon packed binary decision trees to handle disjunction in tests, loops and procedure/function calls and array segmentation to handle disjunctions in array content analysis, we have introduced segmented decision trees to allow for more expressivity while mastering costs via widenings

Preliminary Hazard Analysis Generation Integrated with Operational Architecture - Application to Automobile

Abstract. We are witnessing evolution of standards (as the functional safety one) and increas-ing of complexity. This implies to perform safety studies efficiently and earlier in the context of Model-Based System Engineering. So, in this article, we will propose an evolution of the Pre-liminary Hazard Analysis (PHA) method in order to comply with the overall safety require-ments in the automotive domain. To demonstrate its usefulness, we apply this method to an industrial case which concerns the hazard analysis of unintended acceleration of a vehicle

Secrecy capacity of a class of orthogonal relay eavesdropper channels

The secrecy capacity of relay channels with orthogonal components is studied in the presence of an additional passive eavesdropper node. The relay and destination receive signals from the source on two orthogonal channels such that the destination also receives transmissions from the relay on its channel. The eavesdropper can overhear either one or both of the orthogonal channels. Inner and outer bounds on the secrecy capacity are developed for both the discrete memoryless and the Gaussian channel models. For the discrete memoryless case, the secrecy capacity is shown to be achieved by a partial decode-and-forward (PDF) scheme when the eavesdropper can overhear only one of the two orthogonal channels. Two new outer bounds are presented for the Gaussian model using recent capacity results for a Gaussian multi-antenna point-to-point channel with a multi-antenna eavesdropper. The outer bounds are shown to be tight for two sub-classes of channels. The first sub-class is one in which the source and relay are clustered and the and the eavesdropper receives signals only on the channel from the source and the relay to the destination, for which the PDF strategy is optimal. The second is a sub-class in which the source does not transmit to the relay, for which a noise-forwarding strategy is optimal.Comment: Submitted to Eurasip Journal on Wireless Communications and Networking special issue on Wireless physical layer security, Dec. 2008, Revised Jun. 200

Certified compilation for cryptography: Extended x86 instructions and constant-time verification

We present a new tool for the generation and verification of high-assurance high-speed machine-level cryptography implementations: a certified C compiler supporting instruction extensions to the x86. We demonstrate the practical applicability of our tool by incorporating it into supercop: a toolkit for measuring the performance of cryptographic software, which includes over 2000 different implementations. We show i. that the coverage of x86 implementations in supercop increases significantly due to the added support of instruction extensions via intrinsics and ii. that the obtained verifiably correct implementations are much closer in performance to unverified ones. We extend our compiler with a specialized type system that acts at pre-assembly level; this is the first constant-time verifier that can deal with extended instruction sets. We confirm that, by using instruction extensions, the performance penalty for verifiably constant-time code can be greatly reduced.This work is financed by National Funds through the FCT - Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) within the project PTDC/CCI-INF/31698/2017, and by the Norte Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and also by national funds through the FCT, within project NORTE-01-0145-FEDER-028550 (REASSURE)