A formally verified compiler back-end

This article describes the development and formal verification (proof of semantic preservation) of a compiler back-end from Cminor (a simple imperative intermediate language) to PowerPC assembly code, using the Coq proof assistant both for programming the compiler and for proving its correctness. Such a verified compiler is useful in the context of formal methods applied to the certification of critical software: the verification of the compiler guarantees that the safety properties proved on the source code hold for the executable compiled code as well

Analysis of skeletal muscle function in the C57BL6/SV129 syncoilin knockout mouse

Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for syncoilin and the results of an investigation into the effect of a syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with syncoilin showed that ablation of syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in syncoilin-deficient muscle. This study establishes a second viable syncoilin knockout model and highlights the importance of further investigations to determine the role of syncoilin in skeletal muscle

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

The field of primary immunodeficiencies (PIDs) is one of several in the area of clinical immunology that has not been static, but rather has shown exponential growth due to enhanced physician, scientist and patient education and awareness, leading to identification of new diseases, new molecular diagnoses of existing clinical phenotypes, broadening of the spectrum of clinical and phenotypic presentations associated with a single or related gene defects, increased bioinformatics resources, and utilization of advanced diagnostic technology and methodology for disease diagnosis and management resulting in improved outcomes and survival. There are currently over 200 PIDs with at least 170 associated genetic defects identified, with several of these being reported in recent years. The enormous clinical and immunological heterogeneity in the PIDs makes diagnosis challenging, but there is no doubt that early and accurate diagnosis facilitates prompt intervention leading to decreased morbidity and mortality. Diagnosis of PIDs often requires correlation of data obtained from clinical and radiological findings with laboratory immunological analyses and genetic testing. The field of laboratory diagnostic immunology is also rapidly burgeoning, both in terms of novel technologies and applications, and knowledge of human immunology. Over the years, the classification of PIDs has been primarily based on the immunological defect(s) ("immunophenotype") with the relatively recent addition of genotype, though there are clinical classifications as well. There can be substantial overlap in terms of the broad immunophenotype and clinical features between PIDs, and therefore, it is relevant to refine, at a cellular and molecular level, unique immunological defects that allow for a specific and accurate diagnosis. The diagnostic testing armamentarium for PID includes flow cytometry - phenotyping and functional, cellular and molecular assays, protein analysis, and mutation identification by gene sequencing. The complexity and diversity of the laboratory diagnosis of PIDs necessitates many of the above-mentioned tests being performed in highly specialized reference laboratories. Despite these restrictions, there remains an urgent need for improved standardization and optimization of phenotypic and functional flow cytometry and protein-specific assays. A key component in the interpretation of immunological assays is the comparison of patient data to that obtained in a statistically-robust manner from age and gender-matched healthy donors. This review highlights a few of the laboratory assays available for the diagnostic work-up of broad categories of PIDs, based on immunophenotyping, followed by examples of disease-specific testing

Inhibition of Electrical Activity by Retroviral Infection with Kir2.1 Transgenes Disrupts Electrical Differentiation of Motoneurons

Network-driven spontaneous electrical activity in the chicken spinal cord regulates a variety of developmental processes including neuronal differentiation and formation of neuromuscular structures. In this study we have examined the effect of chronic inhibition of spinal cord activity on motoneuron survival and differentiation. Early spinal cord activity in chick embryos was blocked using an avian replication-competent retroviral vector RCASBP (B) carrying the inward rectifier potassium channel Kir2.1. Chicken embryos were infected with one of the following constructs: RCASBP(B), RCASBP(B)-Kir2.1, or RCASBP(B)-GFP. Infection of chicken embryos at E2 resulted in widespread expression of the viral protein marker p27 gag throughout the spinal cord. Electrophysiological recordings revealed the presence of functional Kir2.1 channels in RCASBP(B)-Kir2.1 but not in RCASBP(B)-infected embryos. Kir2.1 expression significantly reduced the generation of spontaneous motor movements in chicken embryos developing in ovo. Suppression of spontaneous electrical activity was not due to a reduction in the number of surviving motoneurons or the number of synapses in hindlimb muscle tissue. Disruption of the normal pattern of activity in chicken embryos resulted in a significant downregulation in the functional expression of large-conductance Ca2+-dependent K+ channels. Reduction of spinal cord activity also generates a significant acceleration in the inactivation rate of A-type K+ currents without any significant change in current density. Kir2.1 expression did not affect the expression of voltage-gated Na+ channels or cell capacitance. These experiments demonstrate that chronic inhibition of chicken spinal cord activity causes a significant change in the electrical properties of developing motoneurons

Fluid Intelligence and Psychosocial Outcome: From Logical Problem Solving to Social Adaptation

While fluid intelligence has proved to be central to executive functioning, logical reasoning and other frontal functions, the role of this ability in psychosocial adaptation has not been well characterized.Lower fluid intelligence scores were associated with physical violence, both in the role of victim and victimizer. Drug intake, especially cannabis, cocaine and inhalants and lower self-esteem were also associated with lower fluid intelligence. Finally, scores on the perceived mental health assessment were better when fluid intelligence scores were higher.Our results show evidence of a strong association between psychosocial adaptation and fluid intelligence, suggesting that the latter is not only central to executive functioning but also forms part of a more general capacity for adaptation to social contexts

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

Perceptual modification of the built environment to influence behaviour associated with physical activity: Quasi-experimental field studies of a stair banister illusion

Re-engineering the built environment to influence behaviours associated with physical activity potentially provides an opportunity to promote healthier lifestyles at a population level. Here we present evidence from two quasi-experimental field studies in which we tested a novel, yet deceptively simple, intervention designed to alter perception of, and walking behaviour associated with, stairs in an urban area. Objectives. To examine whether stair banister adjustment has an influence on perceptions of stair steepness or on walking behaviour when approaching the stairs. Methods. In Study 1, we asked participants (n=143) to visually estimate the steepness of a set of stairs viewed from the top, when the stair banister was adjusted so that it converged with or diverged from the stairs (±1.91º) or remained neutral (±0º). In Study 2, the walking behaviour of participants (n=36) was filmed as they approached the stairs to descend, unaware that the banister converged, diverged or was neutral. Results. In Study 1, participants estimated the stairs to be steeper if the banister diverged from rather than converged with the stairs. The effect was greater when participants were unaware of the adjustment. In Study 2, walking speed was significantly slower when the banister diverged from rather than converged with the stairs. Conclusions. These findings encourage us to speculate about the potential to economically re-engineer features of the built environment in order to provide opportunities for action (affordances) that invite physical activity behaviour or even promote safer navigation of the environment

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 ‘hotspot’ mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53–p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.JE Noll, J Jeffery, F Al-Ejeh, R Kumar, KK Khanna, DF Callen and PM Neilse

Age-dependent motor unit remodelling in human limb muscles.

Voluntary control of skeletal muscle enables humans to interact with and manipulate the environment. Lower muscle mass, weakness and poor coordination are common complaints in older age and reduce physical capabilities. Attention has focused on ways of maintaining muscle size and strength by exercise, diet or hormone replacement. Without appropriate neural innervation, however, muscle cannot function. Emerging evidence points to a neural basis of muscle loss. Motor unit number estimates indicate that by age around 71 years, healthy older people have around 40 % fewer motor units. The surviving low- and moderate-threshold motor units recruited for moderate intensity contractions are enlarged by around 50 % and show increased fibre density, presumably due to collateral reinnervation of denervated fibres. Motor unit potentials show increased complexity and the stability of neuromuscular junction transmissions is decreased. The available evidence is limited by a lack of longitudinal studies, relatively small sample sizes, a tendency to examine the small peripheral muscles and relatively few investigations into the consequences of motor unit remodelling for muscle size and control of movements in older age. Loss of motor neurons and remodelling of surviving motor units constitutes the major change in ageing muscles and probably contributes to muscle loss and functional impairments. The deterioration and remodelling of motor units likely imposes constraints on the way in which the central nervous system controls movements