A Novel Functional Interaction between Vav and PKCθ Is Required for TCR-Induced T Cell Activation

AbstractVav and PKCθ play an early and important role in the TCR/CD28-induced stimulation of MAP kinases and activation of the IL-2 gene. Vav is also essential for actin cytoskeleton reorganization and TCR capping. Here, we report that PKCθ function was selectively required in a Vav signaling pathway that mediates the TCR/CD28-induced activation of JNK and the IL-2 gene and the upregulation of CD69 expression. Vav also promoted PKCθ translocation from the cytosol to the membrane and cytoskeleton and induced its enzymatic activation in a CD3/CD28-initiated pathway that was dependent on Rac and on actin cytoskeleton reorganization. These findings reveal that the Vav/Rac pathway promotes the recruitment of PKCθ to the T cell synapse and its activation, essential processes for T cell activation and IL-2 production

A Learning Based Framework for Improving Querying on Web Interfaces of Curated Knowledge Bases

Knowledge Bases (KBs) are widely used as one of the fundamental components in Semantic Web applications as they provide facts and relationships that can be automatically understood by machines. Curated knowledge bases usually use Resource Description Framework (RDF) as the data representation model. To query the RDF-presented knowledge in curated KBs, Web interfaces are built via SPARQL Endpoints. Currently, querying SPARQL Endpoints has problems like network instability and latency, which affect the query efficiency. To address these issues, we propose a client-side caching framework, SPARQL Endpoint Caching Framework (SECF), aiming at accelerating the overall querying speed over SPARQL Endpoints. SECF identifies the potential issued queries by leveraging the querying patterns learned from clients’ historical queries and prefecthes/caches these queries. In particular, we develop a distance function based on graph edit distance to measure the similarity of SPARQL queries. We propose a feature modelling method to transform SPARQL queries to vector representation that are fed into machine-learning algorithms. A time-aware smoothing-based method, Modified Simple Exponential Smoothing (MSES), is developed for cache replacement. Extensive experiments performed on real-world queries showcase the effectiveness of our approach, which outperforms the state-of-the-art work in terms of the overall querying speed

Towards a framework for analysis of eye-tracking studies in the three dimensional environment: a study of visual search by experienced readers of endoluminal CT colonography.

Objective: Eye tracking in three dimensions is novel, but established descriptors derived from two-dimensional (2D) studies are not transferable. We aimed to develop metrics suitable for statistical comparison of eye-tracking data obtained from readers of three-dimensional (3D) “virtual” medical imaging, using CT colonography (CTC) as a typical example. Methods: Ten experienced radiologists were eye tracked while observing eight 3D endoluminal CTC videos. Sub-sequently, we developed metrics that described their visual search patterns based on concepts derived from 2D gaze studies. Statistical methods were developed to allow analysis of the metrics. Results: Eye tracking was possible for all readers. Visual dwell on the moving region of interest (ROI) was defined as pursuit of the moving object across multiple frames. Using this concept of pursuit, five categories of metrics were defined that allowed characterization of reader gaze behaviour. These were time to first pursuit, identi-fication and assessment time, pursuit duration, ROI size and pursuit frequency. Additional subcategories allowed us to further characterize visual search between readers in the test population. Conclusion: We propose metrics for the characterization of visual search of 3D moving medical images. These metrics can be used to compare readers’ visual search patterns and provide a reproducible framework for the analysis of gaze tracking in the 3D environment. Advances in knowledge: This article describes a novel set of metrics that can be used to describe gaze behaviour when eye tracking readers during interpretation of 3D medical images. These metrics build on those established for 2D eye tracking and are applicable to increasingly common 3D medical image displays

Fetal Testosterone Predicts Sexually Differentiated Childhood Behavior in Girls and in Boys

ABSTRACT—Mammals, including humans, show sex differences in juvenile play behavior. In rodents and nonhuman primates, these behavioral sex differences result, in part, from sex differences in androgens during early development. Girls exposed to high levels of androgen prenatally, because of the genetic disorder congenital adrenal hyperplasia, show increased male-typical play, suggesting similar hormonal influences on human development, at least in females. Here, we report that fetal testosterone measured from amniotic fluid relates positively to male-typical scores on a standardized questionnaire measure of sextypical play in both boys and girls. These results show, for the first time, a link between fetal testosterone and the development of sex-typical play in children from the general population, and are the first data linking high levels of prenatal testosterone to increased male-typical play behavior in boys. Sexual differentiation of the mammalian brain occurs under the control of gonadal hormones, particularly androgens, during early development (De Vries & Simerly, 2002; Ehrhardt &amp

“Dealing with the Hospital has Become too Difficult for Us to Do Alone” – Developing an Integrated Care Program for Children with Medical Complexity (CMC)

Introduction: Children with medical complexity (CMC) require highly specialised care, often from multiple providers and over many years. This paper describes the first 18 months of development of the Kids Guided Personalised Services (GPS) Integrated Care Program (the Program). This Program aims to improve health care experience; communication and to streamline provision of care. Discussion: Key enablers across the Program were put in place and 5 individual project streams were used to implement change. An extensive formative evaluation process was undertaken to truly understand all perspectives in developing the Program. Conclusion/Key Lessons: This Program supports families who are caring for CMC by developing shared care models that bring together local health services with the tertiary hospitals. The methodology used has resulted in comprehensive system change and transformation; reduced presentations to the Emergency Department (ED), avoidable admissions and travel time. A challenge remains in meaningfully engaging primary health care providers

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06–0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure

The use of the SF-36 questionnaire in adult survivors of childhood cancer: evaluation of data quality, score reliability, and scaling assumptions

BACKGROUND: The SF-36 has been used in a number of previous studies that have investigated the health status of childhood cancer survivors, but it never has been evaluated regarding data quality, scaling assumptions, and reliability in this population. As health status among childhood cancer survivors is being increasingly investigated, it is important that the measurement instruments are reliable, validated and appropriate for use in this population. The aim of this paper was to determine whether the SF-36 questionnaire is a valid and reliable instrument in assessing self-perceived health status of adult survivors of childhood cancer. METHODS: We examined the SF-36 to see how it performed with respect to (1) data completeness, (2) distribution of the scale scores, (3) item-internal consistency, (4) item-discriminant validity, (5) internal consistency, and (6) scaling assumptions. For this investigation we used SF-36 data from a population-based study of 10,189 adult survivors of childhood cancer. RESULTS: Overall, missing values ranged per item from 0.5 to 2.9 percent. Ceiling effects were found to be highest in the role limitation-physical (76.7%) and role limitation-emotional (76.5%) scales. All correlations between items and their hypothesised scales exceeded the suggested standard of 0.40 for satisfactory item-consistency. Across all scales, the Cronbach's alpha coefficient of reliability was found to be higher than the suggested value of 0.70. Consistent across all cancer groups, the physical health related scale scores correlated strongly with the Physical Component Summary (PCS) scale scores and weakly with the Mental Component Summary (MCS) scale scores. Also, the mental health and role limitation-emotional scales correlated strongly with the MCS scale score and weakly with the PCS scale score. Moderate to strong correlations with both summary scores were found for the general health perception, energy/vitality, and social functioning scales. CONCLUSION: The findings presented in this paper provide support for the validity and reliability of the SF-36 when used in long-term survivors of childhood cancer. These findings should encourage other researchers and health care practitioners to use the SF-36 when assessing health status in this population, although it should be recognised that ceiling effects can occur

Learning-based SPARQL query performance modeling and prediction

One of the challenges of managing an RDF database is predicting performance of SPARQL queries before they are executed. Performance characteristics, such as the execution time and memory usage, can help data consumers identify unexpected long-running queries before they start and estimate the system workload for query scheduling. Extensive works address such performance prediction problem in traditional SQL queries but they are not directly applicable to SPARQL queries. In this paper, we adopt machine learning techniques to predict the performance of SPARQL queries. Our work focuses on modeling features of a SPARQL query to a vector representation. Our feature modeling method does not depend on the knowledge of underlying systems and the structure of the underlying data, but only on the nature of SPARQL queries. Then we use these features to train prediction models. We propose a two-step prediction process and consider performances in both cold and warm stages. Evaluations are performed on real world SPRAQL queries, whose execution time ranges from milliseconds to hours. The results demonstrate that the proposed approach can effectively predict SPARQL query performance and outperforms state-of-the-art approaches

The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the Prostaglandin E2 human model of headache

Using a human Prostaglandin E2 (PGE2) model of headache, we examined whether a novel potent and selective EP4 receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE2. We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE2 induced headache and dilatation in normal subjects