Activity profiles of elite wheelchair rugby players during competition

To quantify the activity profiles of elite wheelchair rugby and establish classification-specific arbitrary speed zones. Additionally, indicators of fatigue during full matches were explored. Methods: Seventy-five elite wheelchair rugby players from eleven national teams were monitored using a radio-frequency based, indoor tracking system across two international tournaments. Players who participated in complete quarters (n = 75) and full matches (n = 25) were included and grouped by their International Wheelchair Rugby Federation functional classification: group I (0-0.5), II (1.0-1.5), III (2.0-2.5) and IV (3.0-3.5). Results: During a typical quarter, significant increases in total distance (m), relative distance (m·minˉ¹), and mean speed (m·sˉ¹) were associated with an increase in classification group (P < 0.001), with the exception of group III and IV. However, group IV players achieved significantly higher peak speeds (3.82 ± 0.31 m·sˉ¹) than groups I (2.99 ± 0.28 m·sˉ¹), II (3.44 ± 0.26 m·sˉ¹) and III (3.67 ± 0.32 m·sˉ¹). Groups I and II differed significantly in match intensity during very low/low speed zones and the number of high-intensity activities in comparison with groups III and IV (P < 0.001). Full match analysis revealed that activity profiles did not differ significantly between quarters. Conclusions: Notable differences in the volume of activity were displayed across the functional classification groups. However, the specific on-court requirements of defensive (I and II) and offensive (III and IV) match roles appeared to influence the intensity of match activities and consequently training prescription should be structured accordingly

Strain-dependent host transcriptional responses to toxoplasma infection are largely conserved in mammalian and avian hosts

Toxoplasma gondii has a remarkable ability to infect an enormous variety of mammalian and avian species. Given this, it is surprising that three strains (Types I/II/III) account for the majority of isolates from Europe/North America. The selective pressures that have driven the emergence of these particular strains, however, remain enigmatic. We hypothesized that strain selection might be partially driven by adaptation of strains for mammalian versus avian hosts. To test this, we examine in vitro, strain-dependent host responses in fibroblasts of a representative avian host, the chicken (Gallus gallus). Using gene expression profiling of infected chicken embryonic fibroblasts and pathway analysis to assess host response, we show here that chicken cells respond with distinct transcriptional profiles upon infection with Type II versus III strains that are reminiscent of profiles observed in mammalian cells. To identify the parasite drivers of these differences, chicken fibroblasts were infected with individual F1 progeny of a Type II x III cross and host gene expression was assessed for each by microarray. QTL mapping of transcriptional differences suggested, and deletion strains confirmed, that, as in mammalian cells, the polymorphic rhoptry kinase ROP16 is the major driver of strain-specific responses. We originally hypothesized that comparing avian versus mammalian host response might reveal an inversion in parasite strain-dependent phenotypes; specifically, for polymorphic effectors like ROP16, we hypothesized that the allele with most activity in mammalian cells might be less active in avian cells. Instead, we found that activity of ROP16 alleles appears to be conserved across host species; moreover, additional parasite loci that were previously mapped for strain-specific effects on mammalian response showed similar strain-specific effects in chicken cells. These results indicate that if different hosts select for different parasite genotypes, the selection operates downstream of the signaling occurring during the beginning of the host's immune response. © 2011 Ong et al

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

Wall roughness induces asymptotic ultimate turbulence

Turbulence is omnipresent in Nature and technology, governing the transport of heat, mass, and momentum on multiple scales. For real-world applications of wall-bounded turbulence, the underlying surfaces are virtually always rough; yet characterizing and understanding the effects of wall roughness for turbulence remains a challenge, especially for rotating and thermally driven turbulence. By combining extensive experiments and numerical simulations, here, taking as example the paradigmatic Taylor-Couette system (the closed flow between two independently rotating coaxial cylinders), we show how wall roughness greatly enhances the overall transport properties and the corresponding scaling exponents. If only one of the walls is rough, we reveal that the bulk velocity is slaved to the rough side, due to the much stronger coupling to that wall by the detaching flow structures. If both walls are rough, the viscosity dependence is thoroughly eliminated in the boundary layers and we thus achieve asymptotic ultimate turbulence, i.e. the upper limit of transport, whose existence had been predicted by Robert Kraichnan in 1962 (Phys. Fluids {\bf 5}, 1374 (1962)) and in which the scalings laws can be extrapolated to arbitrarily large Reynolds numbers

Automated Detection of Malarial Retinopathy in Digital Fundus Images for Improved Diagnosis in Malawian Children with Clinically Defined Cerebral Malaria

Cerebral malaria (CM), a complication of malaria infection, is the cause of the majority of malaria-associated deaths in African children. The standard clinical case definition for CM misclassifies ~25% of patients, but when malarial retinopathy (MR) is added to the clinical case definition, the specificity improves from 61% to 95%. Ocular fundoscopy requires expensive equipment and technical expertise not often available in malaria endemic settings, so we developed an automated software system to analyze retinal color images for MR lesions: retinal whitening, vessel discoloration, and white-centered hemorrhages. The individual lesion detection algorithms were combined using a partial least square classifier to determine the presence or absence of MR. We used a retrospective retinal image dataset of 86 pediatric patients with clinically defined CM (70 with MR and 16 without) to evaluate the algorithm performance. Our goal was to reduce the false positive rate of CM diagnosis, and so the algorithms were tuned at high specificity. This yielded sensitivity/specificity of 95%/100% for the detection of MR overall, and 65%/94% for retinal whitening, 62%/100% for vessel discoloration, and 73%/96% for hemorrhages. This automated system for detecting MR using retinal color images has the potential to improve the accuracy of CM diagnosis

L1pred: A Sequence-Based Prediction Tool for Catalytic Residues in Enzymes with the L1-logreg Classifier

To understand enzyme functions, identifying the catalytic residues is a usual first step. Moreover, knowledge about catalytic residues is also useful for protein engineering and drug-design. However, to experimentally identify catalytic residues remains challenging for reasons of time and cost. Therefore, computational methods have been explored to predict catalytic residues. Here, we developed a new algorithm, L1pred, for catalytic residue prediction, by using the L1-logreg classifier to integrate eight sequence-based scoring functions. We tested L1pred and compared it against several existing sequence-based methods on carefully designed datasets Data604 and Data63. With ten-fold cross-validation, L1pred showed the area under precision-recall curve (AUPR) and the area under ROC curve (AUC) of 0.2198 and 0.9494 on the training dataset, Data604, respectively. In addition, on the independent test dataset, Data63, it showed the AUPR and AUC values of 0.2636 and 0.9375, respectively. Compared with other sequence-based methods, L1pred showed the best performance on both datasets. We also analyzed the importance of each attribute in the algorithm, and found that all the scores contributed more or less equally to the L1pred performance

Reduced Exercise Tolerance and Pulmonary Capillary Recruitment with Remote Secondhand Smoke Exposure

RATIONALE: Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest. METHODS: To determine whether pre-ban FAs increase their Dco and pulmonary blood flow (Qc) during exercise, we administered a symptom-limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake (VO2) achieved by FAs. After 30 min rest, we then measured Dco and Qc at 20, 40, 60, and 80 percent of maximum observed work. RESULTS: The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and VO2 compared to those with normal resting Dco (mean±SEM; 88.7±2.9 vs. 102.5±3.1%predicted VO2; p = 0.001). Exercise limitation was associated with the FAs' FEV(1) (r = 0.33; p = 0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean±SEM: 1.36±0.16 vs. 1.90±0.16 ml/min/mmHg per 20% increase in predicted watts; p = 0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in Qc was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in Qc during exercise (mean±SEM: 0.93±0.06 vs. 1.47±0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with ≥10 years of pre-ban experience (r = -0.32; p = 0.032). CONCLUSIONS: This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise

Dermatofibrosarcoma protuberans treated by micrographic surgery

Dermatofibrosarcoma protuberans is an uncommon cutaneous tumour which rarely metastasises. However, local recurrence following apparently adequate surgical excision is well recognised, presumably as a result of sub-clinical contiguous growth, for which micrographically controlled excision would be a logical treatment. A retrospective study of all patients treated by micrographic surgery, from April 1995–March 2000, at a tertiary skin oncology centre. Twenty-one patients (11 males), age 14 to 71 years with dermatofibrosarcoma protuberans on the trunk (10 patients), groin (four), head and neck (four), and limbs (three) were treated. In 15 patients one micrographic layer cleared the tumour, and four were cleared with two layers. For one patient the second stage was completed by conventional excision guided by positive margins. Another patient with a multiply recurrent perineal dermatofibrosarcoma protuberans, not cleared in one area after two layers, died from a pulmonary embolus before total clearance could be achieved. There was no correlation between tumour size and lateral excision margin. No recurrence was observed during the follow-up, from 21 to 80 months, median 47 months. The study provides further support for micrographic surgery as the treatment of choice for dermatofibrosarcoma protuberans

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown