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

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 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

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)

Freezing of Enkephalinergic Functions by Multiple Noxious Foci: A Source of Pain Sensitization?

BACKGROUND:The functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments. METHODOLOGY/PRINCIPAL FINDINGS:Here we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously. CONCLUSION/SIGNIFICANCE:We have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The "freezing" of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis

Morphine Activates ?-Conotoxin-Sensitive Ca 2+

Morphine-induced release of adenosine from the spinal cord is believed to contribute to spinal antinociception. Although this release is Ca2+ dependent, little is known of the nature of this dependence. In this study, the effects of the dihydropyridine L-type Ca2+ channel agonist Bay K 8644 and the antagonist nifedipine, the N-type Ca2+ channel antagonist omega-conotoxin, and ruthenium red, a blocker of Ca2+ influx induced by capsaicin, on release of adenosine evoked by morphine were determined. The effect of partial depolarization with a minimally effective concentration of K+ on morphine-evoked release of adenosine also was examined. Morphine 10(-5)-10(-4) M produced a dose-dependent enhancement of adenosine release from dorsal spinal cord synaptosomes. Following the addition of 6 mM K+ (total K+ concentration of 10.7 mM), 10(-6) M morphine also enhanced release, and an additional component of action at 10(-8) M was revealed. Release was Ca(2+)-dependent as it was not observed in the absence of Ca2+ and presence of EGTA. Bay K 8644 (10 nM) and nifedipine (100 nM) had no effect on the release of adenosine evoked by morphine, but omega-conotoxin (100 nM) markedly reduced such release in both the absence and the presence of the additional 6 mM K+. Morphine-evoked adenosine release was not altered in the presence of a partially effective dose of capsaicin, nor by ruthenium red.(ABSTRACT TRUNCATED AT 250 WORDS