Benchmarking the effects of operating system interference on extreme-scale parallel machines

We investigate operating system noise, which we identify as one of the main reasons for a lack of synchronicity in parallel applications. Using a microbenchmark, we measure the noise on several contemporary platforms and find that, even with a general-purpose operating system, noise can be limited if certain precautions are taken. We then inject artificially generated noise into a massively parallel system and measure its influence on the performance of collective operations. Our experiments indicate that on extreme-scale platforms, the performance is correlated with the largest interruption to the application, even if the probability of such an interruption on a single process is extremely small. We demonstrate that synchronizing the noise can significantly reduce its negative influence.

Fungal hydroxylation of (−)-santonin and its analogues

Santonin (1) was incubated with separate growing cultures of Aspergillus niger ATCC 9142, Mucor plumbeus ATCC 4740, Whetzelinia sclerotiorum ATCC 18687, Cunninghamella echinulata var. elegans ATCC 8688a and Phanerochaete chrysosporium ATCC 24725. Three novel metabolites were isolated: 11β,13-dihydroxysantonin (3), 6,7-dehydosantonin (5) and 3,6-dihydroxy-9-keto-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (7). 11β-Hydroxysantonin (2), 14-hydroxysantonin (4) and 3,6,9-trihydroxy-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (6) were also isolated. Hydroxylation at C-9 followed by a retro-aldol reaction was postulated to have produced 6 and 7. Through the synthesis and fermentation of the santonin analogues: tetrahydrosantonin (8) and α-desmotroposantonin (12), several new compounds were obtained; the most significant being 9-keto-desmotroposantonin (14), which was indicative of C-9 monohydroxylation.     

Are age-related impairments in change-in-support balance reactions dependent on the method of balance perturbation?

Rapid “change-in-support” (stepping or grasping) balance-recovery reactions play a critical role in preventing falls. Studies investigating age-related impairments in these reactions using differing perturbation methods have shown contradictory results. The discrepancies could be due to the different mechanical and sensory stimuli provided by the different perturbation methods, but could also be due to other confounding factors (e.g. differences in perturbation predictability). This study compared two commonly used perturbation methods: weight-drop cable-pulls (CPs) and motor-driven surface-translations (STs). For each perturbation method, effects of aging on the change-in-support reactions were established by comparing 10 young (22–28 years) and 30 older (64–79 years) adults, using large unpredictable multi-directional perturbations similar to those used in previous studies showing age-related differences. Age-related differences in the pattern and spatio-temporal features of the limb movements were examined for stepping and grasping reactions evoked by antero-posterior perturbation of stance, as well as stepping reactions evoked by lateral perturbations delivered while subjects walked “in-place”. Although age-group effects were almost always more pronounced for ST perturbations, the direction of the effect was always the same for both perturbation methods; hence, the perturbation-dependent differences in mechanical and sensory stimuli did not seem to be a critical factor. Perturbation waveform appeared to be a more important factor. For the perturbation methods used here, the ST perturbations were more destabilising than the CP perturbations (leading to a more rapid rise in perturbatory ankle-torque and greater centre-of-mass motion prior to the onset of the postural reaction), and were consequently more effective in revealing age-related deficiencies.     

Borderline pulmonary arterial pressure in systemic sclerosis patients: a post-hoc analysis of the DETECT study

Introduction

Patients with mean pulmonary artery pressures (mPAP) of 21 to 24 mm Hg have a so-called borderline elevation of mPAP (BoPAP)—a condition thought to represent early-stage pulmonary arterial vasculopathy. Based on the DETECT study, this post-hoc analysis examined patient characteristics of systemic sclerosis (SSc) patients with normal mPAP, BoPAP and elevated mPAP, fulfilling pulmonary arterial hypertension (PAH) criteria.

Methods

Adult patients with a duration of SSc more than 3 years, a diffusing capacity of the lung for carbon monoxide less than 60% predicted, and no previous diagnosis of any form of pulmonary hypertension (PH) underwent screening tests followed by right heart catheterization. Subjects were divided into three groups: normal mPAP, BoPAP, and PAH. Exploratory comparative and binary logistic regression analyses were performed for the BoPAP versus normal mPAP and PAH versus BoPAP groups.

Results

Of 244 patients evaluated, 148 (60%) had normal mPAP, 36 (15%) had BoPAP, and 60 (25%) had definite PAH. Univariable logistic regression (ULR) showed the mean tricuspid regurgitation velocity in patients with BoPAP to be intermediate between normal mPAP and PAH. In the ULR analyses BoPAP versus normal mPAP and PAH versus BoPAP, the statistically significant predictors were, amongst others: demographic, clinical, pulmonary function, echocardiographic and hemodynamic variables.

Conclusions

In this exploratory post-hoc analysis of the DETECT study population patients with BoPAP could be distinguished from patients with normal mPAP and PAH, and it appears that BoPAP may be an intermediate stage on the continuum between normal PA pressures and PAH.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0493-1) contains supplementary material, which is available to authorized users.     

Thermal Nociceptive Threshold Testing Detects Altered Sensory Processing in Broiler Chickens with Spontaneous Lameness

Lameness is common in commercially reared broiler chickens but relationships between lameness and pain (and thus bird welfare) have proved complex, partly because lameness is often partially confounded with factors such as bodyweight, sex and pathology. Thermal nociceptive threshold (TNT) testing explores the neural processing of noxious stimuli, and so can contribute to our understanding of pain. Using an acute model of experimentally induced articular pain, we recently demonstrated that TNT was reduced in lame broiler chickens, and was subsequently attenuated by administration of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). This study extended these findings to a large sample of commercial broilers. It examined factors affecting thermal threshold (Part 1) and the effect of an NSAID drug (meloxicam, 5 mg/kg) and of an opioid (butorphanol; 4 mg/kg) (Part 2). Spontaneously lame and matched non-lame birds (n = 167) from commercial farms were exposed to ramped thermal stimulations via a probe attached to the lateral aspect of the tarsometatarsus. Baseline skin temperature and temperature at which a behavioural avoidance response occurred (threshold) were recorded. In Part 1 bird characteristics influencing threshold were modelled; In Part 2 the effect of subcutaneous administration of meloxicam or butorphanol was investigated. Unexpectedly, after accounting for other influences, lameness increased threshold significantly (Part 1). In Part 2, meloxicam affected threshold differentially: it increased further in lame birds and decreased in non-lame birds. No effect of butorphanol was detected. Baseline skin temperature was also consistently a significant predictor of threshold. Overall, lameness significantly influenced threshold after other bird characteristics were taken into account. This, and a differential effect of meloxicam on lame birds, suggests that nociceptive processing may be altered in lame birds, though mechanisms for this require further investigation.     

Behavioural Repertoire of Working Donkeys and Consistency of Behaviour over Time,as a Preliminary Step towards Identifying Pain-Related Behaviours

Background

The donkey has a reputation for stoicism and its behavioural repertoire in clinical contexts is under-reported. Lack of understanding of the norms of donkey behaviour and how it may vary over time can compromise use of behavioural measures as indicators of pain or emotional state. The objective of this study was to find out whether the behaviour of working donkeys was influenced by gender, the time of day or differed between days with a view to assessing how robust these measures are for inclusion in a working donkey ethogram.

Methodology/Principal Findings

Frequency and consistency of postural and event behaviours were measured in 21 adult working donkeys (12 females; 9 males). Instantaneous (scan) and focal sampling were used to measure maintenance, lying, ingestive and investigative behaviours at hourly intervals for ten sessions on each of two consecutive days. High head carriage and biting were seen more frequently in male donkeys than females (P<0.001). Level head carriage, licking/chewing and head-shaking were observed more frequently in female donkeys (P<0.001). Tail position, ear orientation, foot stamping, rolling/lying and head-shaking behaviours were affected by time of day (P<0.001). However, only two variations in ear orientation were found to be significantly different over the two days of observations (P<0.001). Tail swishing, head shaking, foot stamping, and ears held sideways and downwards were significantly correlated (P<0.001) and are assumed to be behaviours to discourage flies.

Conclusions/Significance

All donkeys expressed an extensive behavioural repertoire, although some differences in behaviour were evident between genders. While most behaviours were consistent over time, some behaviours were influenced by time of day. Few behaviours differed between the two test days. The findings can be used to inform the development of a robust, evidence-based ethogram for working donkeys.     

Mechanical action of the blood onto atheromatous plaques: influence of the stenosis shape and morphology

The vulnerability of atheromatous plaques in the carotid artery may be related to several factors, the most important being the degree of severity of the endoluminal stenosis and the thickness of the fibrous cap. It has recently been shown that the plaque length can also affect the mechanical response significantly. However, in their study on the effect of the plaque length, the authors did not consider the variations of the plaque morphology and the shape irregularities that may exist independently of the plaque length. These aspects are developed in this paper. The mechanical interactions between the blood flow and an atheromatous plaque are studied through a numerical model considering fluid–structure interaction. The simulation is achieved using the arbitrary Lagrangian–Eulerian scheme in the COMSOL TM commercial finite element package. The stenosis severity and the plaque length are, respectively, set to 45% and 15 mm. Different shapes of the stenosis are modelled, considering irregularities made of several bumps over the plaque. The resulting flow patterns, wall shear stresses, plaque deformations and stresses in the fibrous cap reveal that the effects of the blood flow are amplified if the slope upstream stenosis is steep or if the plaque morphology is irregular with bumps. More specifically, the maximum stress in the fibrous cap is 50% larger for a steep slope than for a gentle slope. These results offer new perspectives for considering the shape of plaques in the evaluation of the vulnerability.     

Development of neutralizing scFv-Fc against botulinum neurotoxin A light chain from a macaque immune library

Botulinum toxins (BoNTs) are among the most toxic substances on earth, with serotype A toxin being the most toxic substance known. They are responsible for human botulism, a disease characterized by flaccid muscle paralysis that occurs naturally through food poisoning or the colonization of the gastrointestinal tract by BoNT-producing clostridia. BoNT has been classified as a category A agent by the Centers for Disease Control, and it is one of six agents with the highest potential risk of use as bioweapons. Human or human-like neutralizing antibodies are thus required for the development of anti-botulinum toxin drugs to deal with this possibility. In this study, Macaca fascicularis was hyperimmunized with a recombinant light chain of BoNT/A. An immune phage display library was constructed and, after multistep panning, several scFv with nanomolar affinities that inhibited the endopeptidase activity of BoNT/A1 in vitro as scFv-Fc, with a molar ratio (ab binding site:toxin) of up to 1:1, were isolated. The neutralization of BoNT/A-induced paralysis by the SEM120-IID5, SEM120-IIIC1 and SEM120-IIIC4 antibodies was demonstrated in mouse phrenic nerve-hemidiaphragm preparations with the holotoxin. The neutralization observed is the strongest ever measured in the phrenic nerve-hemidiaphragm assay for BoNT/A1 for a monoclonal antibody. Several scFv-Fc inhibiting the endopeptidase activity of botulinum neurotoxin A were isolated. For SEM120-IID5, SEM120-IIIC1, and SEM120-IIIC4, inhibitory effects in vitro and protection against the toxin ex vivo were observed. The human-like nature of these antibodies makes them promising lead candidates for further development of immunotherapeutics for this disease.