Formal Modelling, Testing and Verification of HSA Memory Models using Event-B

The HSA Foundation has produced the HSA Platform System Architecture Specification that goes a long way towards addressing the need for a clear and consistent method for specifying weakly consistent memory. HSA is specified in a natural language which makes it open to multiple ambiguous interpretations and could render bugs in implementations of it in hardware and software. In this paper we present a formal model of HSA which can be used in the development and verification of both concurrent software applications as well as in the development and verification of the HSA-compliant platform itself. We use the Event-B language to build a provably correct hierarchy of models from the most abstract to a detailed refinement of HSA close to implementation level. Our memory models are general in that they represent an arbitrary number of masters, programs and instruction interleavings. We reason about such general models using refinements. Using Rodin tool we are able to model and verify an entire hierarchy of models using proofs to establish that each refinement is correct. We define an automated validation method that allows us to test baseline compliance of the model against a suite of published HSA litmus tests. Once we complete model validation we develop a coverage driven method to extract a richer set of tests from the Event-B model and a user specified coverage model. These tests are used for extensive regression testing of hardware and software systems. Our method of refinement based formal modelling, baseline compliance testing of the model and coverage driven test extraction using the single language of Event-B is a new way to address a key challenge facing the design and verification of multi-core systems.Comment: 9 pages, 10 figure

Anomalous metamagnetism in the low carrier density Kondo lattice YbRh3Si7

We report complex metamagnetic transitions in single crystals of the new low carrier Kondo antiferromagnet YbRh3Si7. Electrical transport, magnetization, and specific heat measurements reveal antiferromagnetic order at T_N = 7.5 K. Neutron diffraction measurements show that the magnetic ground state of YbRh3Si7 is a collinear antiferromagnet where the moments are aligned in the ab plane. With such an ordered state, no metamagnetic transitions are expected when a magnetic field is applied along the c axis. It is therefore surprising that high field magnetization, torque, and resistivity measurements with H||c reveal two metamagnetic transitions at mu_0H_1 = 6.7 T and mu_0H_2 = 21 T. When the field is tilted away from the c axis, towards the ab plane, both metamagnetic transitions are shifted to higher fields. The first metamagnetic transition leads to an abrupt increase in the electrical resistivity, while the second transition is accompanied by a dramatic reduction in the electrical resistivity. Thus, the magnetic and electronic degrees of freedom in YbRh3Si7 are strongly coupled. We discuss the origin of the anomalous metamagnetism and conclude that it is related to competition between crystal electric field anisotropy and anisotropic exchange interactions.Comment: 23 pages and 4 figures in the main text. 7 pages and 5 figures in the supplementary materia

A low exhaled nitric oxide level excludes a short-term benefit from inhaled corticosteroids in suspected asthma: A randomized placebo-controlled trial

Background and objective: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker that reflects IL-4/IL-13 production and therefore represents T2 allergic inflammation. FeNO has previously been used to guide inhaled corticosteroid (ICS) treatment in asthma. The purpose of this study was to determine if a low FeNO (≤27 ppb) could be used to reliably identify patients with symptoms suggestive of asthma who would not benefit from initiating treatment with an ICS. Methods: A total of 180 steroid-naïve adults with healthcare professional suspected asthma and an FeNO of ≤27 ppb were randomized to receive either 400 mcg of budesonide or placebo daily for 3 months. The primary outcome was the difference in the Asthma Control Questionnaire 7 (ACQ7) between treatment groups and the study was powered to determine equivalence. Secondary outcomes were the difference in FEV , Medical Research Council and Leicester Cough Questionnaire scores. Results: One hundred and thirty-four patients (68 budesonide and 66 placebo) completed the study and were included in the analysis. The between-group mean difference in ACQ7 from baseline to the end of the study was −0.25 and the 95% CI around this difference was −0.004 to 0.495 confirming equivalence (p < 0.05). Differences in forced expiratory volume over 1 s and other secondary outcomes were also small and clinically unimportant. Conclusion: The results of this study suggest that steroid-naïve patients with symptoms suggestive of asthma and an FeNO ≤ 27 ppb are unlikely to benefit from initiating treatment with an ICS over 3 months. However, further research is recommended to confirm these findings before withholding ICS treatment.

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy

Successful immunization against a parasitic nematode by vaccination with recombinant proteins

AbstractInfection of humans and livestock with parasitic nematodes can have devastating effects on health and production, affecting food security in both developed and developing regions. Despite decades of research, the development of recombinant sub-unit vaccines against these pathogens has been largely unsuccessful. We have developed a strategy to identify protective antigens from Teladorsagia circumcincta, the major pathogen causing parasitic gastroenteritis in small ruminants in temperate regions, by studying IgA responses directed at proteins specific to post-infective larvae. Antigens were also selected on the basis of their potential immunomodulatory role at the host/parasite interface. Recombinant versions of eight molecules identified by immunoproteomics, homology with vaccine candidates in other nematodes and/or with potential immunoregulatory activities, were therefore administered to sheep in a single vaccine formulation. The vaccine was administered three times with Quil A adjuvant and the animals subsequently subjected to a repeated challenge infection designed to mimic field conditions. Levels of protection in the vaccinates were compared to those obtained in sheep administered with Quil A alone. The trial was performed on two occasions. In both trials, vaccinates had significantly lower mean fecal worm egg counts (FWECs) over the sampling period, with a mean reduction in egg output of 70% (Trial 1) and 58% (Trial 2). During the period of peak worm egg shedding, vaccinates shed 92% and 73% fewer eggs than did controls in Trials 1 and 2, respectively. At post mortem, vaccinates had 75% (Trial 1) and 56% (Trial 2) lower adult nematode burdens than the controls. These levels of protection are the highest observed in any system using a nematode recombinant sub-unit vaccine in the definitive ruminant host and indicate that control of parasitic helminths via vaccination with recombinant subunit vaccine cocktails is indeed an alternative option in the face of multi-drug resistance

Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy

Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified