Towards Runtime Verification of Programmable Switches

Is it possible to patch software bugs in P4 programs without human involvement? We show that this is partially possible in many cases due to advances in software testing and the structure of P4 programs. Our insight is that runtime verification can detect bugs, even those that are not detected at compile-time, with machine learning-guided fuzzing. This enables a more automated and real-time localization of bugs in P4 programs using software testing techniques like Tarantula. Once the bug in a P4 program is localized, the faulty code can be patched due to the programmable nature of P4. In addition, platform-dependent bugs can be detected. From P4_14 to P4_16 (latest version), our observation is that as the programmable blocks increase, the patchability of P4 programs increases accordingly. To this end, we design, develop, and evaluate P6 that (a) detects, (b) localizes, and (c) patches bugs in P4 programs with minimal human interaction. P6 tests P4 switch non-intrusively, i.e., requires no modification to the P4 program for detecting and localizing bugs. We used a P6 prototype to detect and patch seven existing bugs in eight publicly available P4 application programs deployed on two different switch platforms: behavioral model (bmv2) and Tofino. Our evaluation shows that P6 significantly outperforms bug detection baselines while generating fewer packets and patches bugs in P4 programs such as switch.p4 without triggering any regressions

Redox Enzymes of the Thioredoxin Family as Potential and Novel Markers in Pemphigus

Pemphigus vulgaris (PV) is a severe autoimmune blistering disease affecting both skin and mucous membranes. Its pathogenesis is related to IgG autoantibodies primarily targeting the cellular adhesion protein desmoglein (Dsg) 3, one of the major desmosome components. Impaired redox regulation is considered a major player in the pathogenesis of autoimmune diseases such as pemphigus by enhancing inflammation and breakdown of immunological tolerance by structural protein modifications. Despite many recent advances, local and systemic redox profiles that characterize the immune response in pemphigus are virtually unknown but potentially crucial in further advancing our understanding of redox-dependent modifications that eventually lead to clinical manifestation. Here, we have analyzed the individual expression pattern of four major redox enzymes that are members of the thioredoxin (Trx) fold superfamily (peroxiredoxins (Prxs) 1 and 4, glutaredoxin (Grx) 2, and Trx1) in serum and PBMCs as well as their distribution in the skin of pemphigus patients compared to healthy controls. We show that in groups of five pemphigus patients, Prx1 is upregulated in both serum and PBMCs, while its epithelial distribution remains within the spinous epithelial layer. Expression of Grx2 and Prx4 is both reduced in serum and PBMCs, while their distinct and similar expression in the skin changes from an even distribution throughout the basal layer (healthy) to ubiquitous nuclear localization in pemphigus patients. In PV patients, Trx1 is secreted into serum, and cellular distribution appears membrane-bound and cytosolic compared to healthy controls. We furthermore showed that a 3D ex vivo human skin model can indeed be used to reproduce similar changes in the protein levels and distribution of redox enzymes by application of cold atmospheric plasma. Deciphering the relationship between redox enzyme expression and autoimmunity in the context of pemphigus could be critical in elucidating key pathogenic mechanisms and developing novel interventions for clinical management

Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses

Background: Infections with human rhinoviruses (RVs) are responsible for millions of common cold episodes and the majority of asthma exacerbations, especially in childhood. No drugs specifically targeting RVs are available. Objective: We sought to identify specific anti-RV molecules based on DNAzyme technology as candidates to a clinical study. Methods: A total of 226 candidate DNAzymes were designed against 2 regions of RV RNA genome identified to be sufficiently highly conserved between virus strains (ie, the 5′-untranslated region and cis-acting replication element) by using 3 test strains: RVA1, RVA16, and RVA29. All DNAzymes were screened for their cleavage efficiency against in vitro–expressed viral RNA. Those showing any catalytic activity were subjected to bioinformatic analysis of their reverse complementarity to 322 published RV genomic sequences. Further molecular optimization was conducted for the most promising candidates. Cytotoxic and off-target effects were excluded in HEK293 cell–based systems. Antiviral efficiency was analyzed in infected human bronchial BEAS-2B cells and ex vivo–cultured human sinonasal tissue. Results: Screening phase–generated DNAzymes characterized by either good catalytic activity or by high RV strain coverage but no single molecule represented a satisfactory combination of those 2 features. Modifications in length of the binding domains of 2 lead candidates, Dua-01(-L12R9) and Dua-02(-L10R11), improved their cleavage efficiency to an excellent level, with no loss in eminent strain coverage (about 98%). Both DNAzymes showed highly favorable cytotoxic/off-target profiles. Subsequent testing of Dua-01-L12R9 in BEAS-2B cells and sinonasal tissue demonstrated its significant antiviral efficiency. Conclusions: Effective and specific management of RV infections with Dua-01-L12R9 might be useful in preventing asthma exacerbations, which should be verified by clinical trials. © 2018 American Academy of Allergy, Asthma & Immunolog

Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus

Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes