Breadth First Search Vectorization on the Intel Xeon Phi

Breadth First Search (BFS) is a building block for graph algorithms and has recently been used for large scale analysis of information in a variety of applications including social networks, graph databases and web searching. Due to its importance, a number of different parallel programming models and architectures have been exploited to optimize the BFS. However, due to the irregular memory access patterns and the unstructured nature of the large graphs, its efficient parallelization is a challenge. The Xeon Phi is a massively parallel architecture available as an off-the-shelf accelerator, which includes a powerful 512 bit vector unit with optimized scatter and gather functions. Given its potential benefits, work related to graph traversing on this architecture is an active area of research. We present a set of experiments in which we explore architectural features of the Xeon Phi and how best to exploit them in a top-down BFS algorithm but the techniques can be applied to the current state-of-the-art hybrid, top-down plus bottom-up, algorithms. We focus on the exploitation of the vector unit by developing an improved highly vectorized OpenMP parallel algorithm, using vector intrinsics, and understanding the use of data alignment and prefetching. In addition, we investigate the impact of hyperthreading and thread affinity on performance, a topic that appears under researched in the literature. As a result, we achieve what we believe is the fastest published top-down BFS algorithm on the version of Xeon Phi used in our experiments. The vectorized BFS top-down source code presented in this paper can be available on request as free-to-use software

Contrasting effects of fluoroquinolone antibiotics on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, in human tendon-derived cells

Fluoroquinolone antibiotics may cause tendon pain and rupture. We reported previously that the fluoroquinolone ciprofloxacin potentiated interleukin (IL)-1ß-stimulated expression of matrix metalloproteinases (MMP)-3 and MMP-1 in human tendon-derived cells. We have now tested additional fluoroquinolones and investigated whether they have a similar effect on expression of MMP-13. Tendon cells were incubated for two periods of 48?h with or without fluoroquinolones and IL-1ß. Total ribonucleic acid (RNA) was assayed for MMP messenger RNA by relative quantitative reverse transcriptase polymerase chain reaction, with normalization for glyceraldehyde-3-phosphate dehydrogenase mRNA. Samples of supernatant medium were assayed for MMP output by activity assays. MMP-13 was expressed by tendon cells at lower levels than MMP-1, and was stimulated typically 10- to 100-fold by IL-1ß. Ciprofloxacin, norfloxacin and ofloxacin each reduced both basal and stimulated expression of MMP-13 mRNA. In contrast, ciprofloxacin and norfloxacin increased basal and IL-1ß-stimulated MMP-1 mRNA expression. Both the inhibition of MMP-13 and the potentiation of MMP-1 expression by fluoroquinolones were accompanied by corresponding changes in IL-1ß-stimulated MMP output. The non-fluorinated quinolone nalidixic acid had lesser or no effects. Fluoroquinolones show contrasting effects on the expression of the two collagenases MMP-1 and MMP-13, indicating specific effects on MMP gene regulation

Inhibition of interleukin-1β-stimulated collagenase and stromelysin expression in human tendon fibroblasts by epigallocatechin gallate ester

The medicinal benefits of green tea (Camellia sinensis) consumption have been attributed to bioavailable polyphenols, notably epigallocatechin gallate (EGCG). We have assessed the effects of EGCG and its non-esterified counterpart EGC on the expression of the collagenases, matrix metalloproteinases (MMP)-1 and -13, and the stromelysin, MMP-3, in human tendon-derived fibroblasts. Interleukin (IL)-1ß increased MMP-1, -3 and -13 mRNA and output at least 30-fold. EGCG reduced this stimulation, by 20–30% at 2.5 µM and more than 80% at 25 µM, and had a smaller effect on MMP-2 mRNA expression, which was not stimulated by IL-1ß. In all experiments EGCG was at least 10-fold more potent than EGC. EGCG reduced the stimulation of p54 JNK/SAPK phosphorylation by IL-1ß but did not affect p38 MAPK phosphorylation, the degradation of I?B or the activating phosphorylation of NF?B. We conclude that EGCG reduces the IL-1-stimulated expression of both collagenase and stromelysin mRNA species, an effect which may be mediated by inhibition of the JNK/SAPK pathway. Taken together with previous reports of EGCG effects on the expression and/or activity of gelatinases and aggrecanases, our results underline the importance of extracellular matrix breakdown as a potential target for the actions of green tea polyphenols

Reach modelling for drive-up self-service

People using a self-service terminal such as an automated teller machine (ATM) tend to adjust their physical position throughout a transaction. This is particularly apparent with terminals that are designed to be used from a vehicle (i.e. drive up automated teller machines or ATMs). Existing predictive tools tend to focus on static reach and provide limited predictions for how far people are willing to stretch to complete a task. Drive-up self-service products have 3 main challenges: the variability of vehicles, people and driver behaviour. Such conventional tools are therefore of limited use in understanding how much people are willing to move to use a self-service terminal. Work is described to build in-house predictive models based on 2 large empirical studies of reach in a drive up installation. These 2 studies assessed comfortable and extended reach from 10 vehicle categories. Extended reach was defined as stretching/leaning as far as participants would normally be willing to in order to complete a drive-up transaction. Findings from these studies indicated that participants are prepared to adopt more extreme postures at drive-up than in other situations with extended reach at drive-up being significantly different to what might be seen at a walk-up kiosk

The Regulation of Aggrecanase ADAMTS-4 Expression in Human Achilles Tendon and tendon-Derived Cells

Several members of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family have been identified as aggrecanases, whose substrates include versican, the principal large proteoglycan in the tendon extracellular matrix. We have characterized the expression of ADAMTS-4 in human Achilles tendon and tendon-derived cells. ADAMTS-4 mRNA levels were higher in ruptured tendon compared with normal tendon or chronic painful tendinopathy. In tissue extracts probed by Western blotting, mature ADAMTS-4 (68 kDa) was detected only in ruptured tendons, while processed ADAMTS-4 (53 kDa) was detected also in chronic painful tendinopathy and in normal tendon. In cultured Achilles tendon cells, transforming growth factor-ß (TGF-ß) stimulated ADAMTS-4 mRNA expression (typically 20-fold after 24 h), while interleukin-1 induced a smaller, shorter-term stimulation which synergised markedly with that induced by TGF-ß. Increased levels of immunoreactive proteins consistent with mature and processed forms of ADAMTS-4 were detected in TGF-ß-stimulated cells. ADAMTS-4 mRNA was expressed at higher levels by tendon cells in collagen gels than in monolayer cultures. In contrast, the expression of ADAMTS-1 and -5 mRNA was lower in collagen gels compared with monolayers, and these mRNA showed smaller or opposite responses to growth factors and cytokines compared with that of ADAMTS-4 mRNA. We conclude that both ADAMTS-4 mRNA and ADAMTS-4 protein processing may be differentially regulated in normal and damaged tendons and that both the matrix environment and growth factors such as TGF-ß are potentially important factors controlling ADAMTS aggrecanase activities in tendon pathology

In vivo biological response to extracorporeal shockwave therapy in human tendinopathy:Response of tendinopathy to shockwave therapy

Extracorporeal shock wave therapy (ESWT) is a non-invasive treatment for chronic tendinopathies, however little is known about the in-vivo biological mechanisms of ESWT. Using microdialysis, we examined the real-time biological response of healthy and pathological tendons to ESWT. A single session of ESWT was administered to the mid-portion of the Achilles tendon in thirteen healthy individuals (aged 25.7±7.0 years) and patellar or Achilles tendon of six patients with tendinopathies (aged 39.0±14.9 years). Dialysate samples from the surrounding peri-tendon were collected before and immediately after ESWT. Interleukins (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, vascular endothelial growth factor (VEGF) and interferon (IFN)-γ were quantified using a cytometric bead array while gelatinase activity (MMP-2 and -9) was examined using zymography. There were no statistical differences between the biological tissue response to ESWT in healthy and pathological tendons. IL-1β, IL-2, IL-6 and IL-8 were the cytokines predominantly detected in the tendon dialysate. IL-1β and IL-2 did not change significantly with ESWT. IL-6 and IL-8 concentrations were elevated immediately after ESWT and remained significantly elevated for four hours post-ESWT (p<0.001). Pro forms of MMP-2 and -9 activity also increased after ESWT (p<0.003), whereas there were no significant changes in active MMP forms. In addition, the biological response to ESWT treatment could be differentiated between possible responders and non-responders based on a minimum 5-fold increase in any inflammatory marker or MMP from pre- to post-ESWT. Our findings provide novel evidence of the biological mechanisms underpinning ESWT in humans in vivo. They suggest that the mechanical stimulus provided by ESWT might aid tendon remodelling in tendinopathy by promoting the inflammatory and catabolic processes that are associated with removing damaged matrix constituents. The non-response of some individuals may help to explain why ESWT does not improve symptoms in all patients and provides a potential focus for future research

Effect of fatigue loading on structure and functional behaviour of fascicles from energy-storing tendons

Tendons can broadly be categorized according to their function: those that act purely to position the limb and those that have an additional function as energy stores. Energy-storing tendons undergo many cycles of large deformations during locomotion, and so must be able to extend and recoil efficiently, rapidly and repeatedly. Our previous work has shown rotation in response to applied strain in fascicles from energy-storing tendons, indicating the presence of helical substructures which may provide greater elasticity and recovery. In the current study, we assessed how preconditioning and fatigue loading affect the ability of fascicles from the energy-storing equine superficial digital flexor tendon to extend and recoil. We hypothesized that preconditioned samples would exhibit changes in microstructural strain response, but would retain their ability to recover. We further hypothesized that fatigue loading would result in sample damage, causing further alterations in extension mechanisms and a significant reduction in sample recovery. The results broadly support these hypotheses: preconditioned samples showed some alterations in microstructural strain response, but were able to recover following the removal of load. However, fatigue loaded samples showed visual evidence of damage and exhibited further alterations in extension mechanisms, characterized by decreased rotation in response to applied strain. This was accompanied by increased hysteresis and decreased recovery. These results suggest that fatigue loading results in a compromised helix substructure, reducing the ability of energy-storing tendons to recoil. A decreased ability to recoil may lead to an impaired response to further loading, potentially increasing the likelihood of injury

‘Treading water but drowning slowly’: what are GPs’ experiences of living and working with mental illness and distress in England? A qualitative study

Objectives This paper provides an in-depth account of general practitioners’ (GPs) experiences of living and working with mental illness and distress, as part of a wider study reporting the barriers and facilitators to help-seeking for mental illness and burn-out, and sources of stress/distress for GP participants. Design Qualitative study using in-depth interviews with 47 GP participants. The interviews were audio recorded, transcribed, anonymised and imported into NVivo V.11 to facilitate data management. Data were analysed using a thematic analysis employing the constant comparative method. Setting England. Participants A purposive sample of GP participants who self-identified as: (1) currently living with mental distress, (2) returning to work following treatment, (3) off sick or retired early as a result of mental distress or (4) without experience of mental distress. Interviews were conducted face to face or over the telephone. Results The findings report GP participants’ in-depth experiences of distress and mental illness with many recollecting their distressing experiences and significant psychological and physical symptoms relating to chronic stress, anxiety, depression and/or burn-out, and a quarter articulating thoughts of suicide. Many talked about their shame, humiliation and embarrassment at their perceived inability to cope with the stresses of their job and/or their symptoms of mental illness. Conclusions These findings paint a concerning picture of the situation affecting primary care doctors, with participants’ accounts suggesting there is a considerable degree of mental ill health and reduced well-being among GPs. The solutions are complex and lie in prevention and provision. There needs to be greater recognition of the components and cumulative effect of occupational stressors for doctors, such as the increasing workload and the clinical and emotional demands of the job, as well as the need for a culture shift within medicine to more supportive and compassionate work environments

A clinical, biological, and biomaterials perspective into tendon injuries and regeneration

Tendon injury is common and debilitating, and it is associated with long-term pain and ineffective healing. It is estimated to afflict 25% of the adult population and is often a career-ending disease in athletes and racehorses. Tendon injury is associated with high morbidity, pain, and long-term suffering for the patient. Due to the low cellularity and vascularity of tendon tissue, once damage has occurred, the repair process is slow and inefficient, resulting in mechanically, structurally, and functionally inferior tissue. Current treatment options focus on pain management, often being palliative and temporary and ending in reduced function. Most treatments available do not address the underlying cause of the disease and, as such, are often ineffective with variable results. The need for an advanced therapeutic that addresses the underlying pathology is evident. Tissue engineering and regenerative medicine is an emerging field that is aimed at stimulating the body's own repair system to produce de novo tissue through the use of factors such as cells, proteins, and genes that are delivered by a biomaterial scaffold. Successful tissue engineering strategies for tendon regeneration should be built on a foundation of understanding of the molecular and cellular composition of healthy compared with damaged tendon, and the inherent differences seen in the tissue after disease. This article presents a comprehensive clinical, biological, and biomaterials insight into tendon tissue engineering and regeneration toward more advanced therapeutics