YAP/TAZ regulates the expression of proteoglycan 4 and tenascin C in superficial-zone chondrocytes

The roles of cell division control protein 42 homologue (CDC42) and actin polymerisation in regulating the phenotype of superficial-zone chondrocytes (SZCs) have been demonstrated in vitro; however, the signalling pathway(s) downstream have yet to be fully elucidated. The study hypothesis was that Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) act downstream to regulate proteoglycan 4 (PRG4) and tenascin C (TNC). Bovine SZCs grown in monolayer were treated with ML141 (CDC42 inhibitor) or the actin depolymerising agents, latrunculin B and cytochalasin D, to determine the effect on YAP/TAZ. Verteporfin (YAP/TAZ inhibitor) and YAP/TAZ siRNA-mediated knockdown were used to determine their role in regulating PRG4 and TNC. ML141 treatment reduced total YAP/TAZ protein, nuclear TAZ levels and the YAP/TAZ target gene, connective tissue growth factor (CTGF) mRNA levels. Latrunculin B decreased nuclear TAZ, while cytochalasin D treatment trended towards increased nuclear TAZ (p = 0.06), correlating with decreased and increased CTGF mRNA levels, respectively. Verteporfin treatment decreased PRG4 and TNC expression, with no effect on actin polymerisation. siRNA-mediated knockdown of YAP/TAZ revealed that PRG4 was regulated by YAP/TAZ while TNC was regulated by TAZ only. As cytochalasin D can activate myocardin-related transcription factor-A (MRTF-A), siRNA-mediated knockdown was performed to determine the role of MRTF-A in regulating YAP/TAZ. Although nuclear TAZ decreased, no significant changes in total protein levels were observed. Findings suggested that CDC42 and actin polymerisation regulated SZCs through multiple actin-regulated pathways. Understanding the regulation of these chondroprotective molecules may have important implications for prevention/treatment of osteoarthritis

Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis.

Background: We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres. Methods: Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks. Results: The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres. Conclusion: Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies

Two-Body Correlations in Nuclear Systems

Correlations in the nuclear wave-function beyond the mean-field or Hartree-Fock approximation are very important to describe basic properties of nuclear structure. Various approaches to account for such correlations are described and compared to each other. This includes the hole-line expansion, the coupled cluster or ``exponential S'' approach, the self-consistent evaluation of Greens functions, variational approaches using correlated basis functions and recent developments employing quantum Monte-Carlo techniques. Details of these correlations are explored and their sensitivity to the underlying nucleon-nucleon interaction. Special attention is paid to the attempts to investigate these correlations in exclusive nucleon knock-out experiments induced by electron scattering. Another important issue of nuclear structure physics is the role of relativistic effects as contained in phenomenological mean field models. The sensitivity of various nuclear structure observables on these relativistic features are investigated. The report includes the discussion of nuclear matter as well as finite nuclei.Comment: Review, 104 pages including figure

Assessing a risk tailored intervention to prevent disabling low back pain - protocol of a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Although most patients with low back pain (LBP) recover within a few weeks a significant proportion has recurrent episodes or will develop chronic low back pain. Several mainly psychosocial risk factors for developing chronic LBP have been identified. However, effects of preventive interventions aiming at behavioural risk factors and unfavourable cognitions have yielded inconsistent results. Risk tailored interventions may provide a cost efficient and effective means to take systematic account of the individual risk factors but evidence is lacking.</p> <p>Methods/Design</p> <p>This study will be a cluster-randomised controlled trial comparing screening and a subsequent risk tailored intervention for patients with low back pain to prevent chronic low back pain compared to treatment as usual in primary care. A total of 600 patients from 20 practices in each study arm will be recruited in Berlin and Goettingen. The intervention comprises the following elements: Patients will be assigned to one of four risk groups based on a screening questionnaire. Subsequently they receive an educational intervention including information and counselling tailored to the risk group. A telephone/email consulting service for back pain related problems are offered independent of risk group assignment. The primary outcomes will be functional capacity and sick leave.</p> <p>Discussion</p> <p>This trial will evaluate the effectiveness of screening for risk factors for chronic low back pain followed by a risk tailored intervention to prevent chronic low back pain. This trial will contribute new evidence regarding the flexible use of individual physical and psychosocial risk factors in general practice.</p> <p>Trial registration</p> <p>ISRCTN 68205910</p

Relevant prior knowledge moderates the effect of elaboration during small group discussion on academic achievement

This study set out to test whether relevant prior knowledge would moderate a positive effect on academic achievement of elaboration during small-group discussion. In a 2 × 2 experimental design, 66 undergraduate students observed a video showing a small-group problem-based discussion about thunder and lightning. In the video, a teacher asked questions to the observing participants. Participants either elaborated by responding to these questions, or did not elaborate, but completed a

An agenda-setting paper on data sharing platforms: euCanSHare workshop [version 1; peer review: awaiting peer review]

Various data sharing platforms are being developed to enhance the sharing of cohort data by addressing the fragmented state of data storage and access systems. However, policy challenges in several domains remain unresolved. The euCanSHare workshop was organized to identify and discuss these challenges and to set the future research agenda. Concerns over the multiplicity and long-term sustainability of platforms, lack of resources, access of commercial parties to medical data, credit and recognition mechanisms in academia and the organization of data access committees are outlined. Within these areas, solutions need to be devised to ensure an optimal functioning of platforms

Parallel mutual information estimation for inferring gene regulatory networks on GPUs

<p>Abstract</p> <p>Background</p> <p>Mutual information is a measure of similarity between two variables. It has been widely used in various application domains including computational biology, machine learning, statistics, image processing, and financial computing. Previously used simple histogram based mutual information estimators lack the precision in quality compared to kernel based methods. The recently introduced B-spline function based mutual information estimation method is competitive to the kernel based methods in terms of quality but at a lower computational complexity.</p> <p>Results</p> <p>We present a new approach to accelerate the B-spline function based mutual information estimation algorithm with commodity graphics hardware. To derive an efficient mapping onto this type of architecture, we have used the Compute Unified Device Architecture (CUDA) programming model to design and implement a new parallel algorithm. Our implementation, called CUDA-MI, can achieve speedups of up to 82 using double precision on a single GPU compared to a multi-threaded implementation on a quad-core CPU for large microarray datasets. We have used the results obtained by CUDA-MI to infer gene regulatory networks (GRNs) from microarray data. The comparisons to existing methods including ARACNE and TINGe show that CUDA-MI produces GRNs of higher quality in less time.</p> <p>Conclusions</p> <p>CUDA-MI is publicly available open-source software, written in CUDA and C++ programming languages. It obtains significant speedup over sequential multi-threaded implementation by fully exploiting the compute capability of commonly used CUDA-enabled low-cost GPUs.</p

Cognitive engagement in the problem-based learning classroom

The objective of the present study was to examine to what extent autonomy in problem-based learning (PBL) results in cognitive engagement with the topic at hand. To that end, a short self-report instrument was devised and validated. Moreover, it was examined how cognitive engagement develops as a function of the learning process and the extent to which cognitive engagement determines subsequent levels of cognitive engagement during a one-day PBL event. Data were analyzed by means of confirmatory factor analysis, repeated measures ANOVA, and path analysis. The results showed that the new measure of situational cognitive engagement is valid and reliable. Furthermore, the results revealed that students’ cognitive engagement significantly increased as a function of the learning event. Implications of these findings for PBL are discussed

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure