A Systems Biology Approach Reveals a Calcium-Dependent Mechanism for Basal Toxicity in Daphnia magna.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Environmental Science & Technology, copyright © American Chemical Society after peer review and technical editing by the publisher.The expanding diversity and ever increasing amounts of man-made chemicals discharged to the environment pose largely unknown hazards to ecosystem and human health. The concept of adverse outcome pathways (AOPs) emerged as a comprehensive framework for risk assessment. However, the limited mechanistic information available for most chemicals and a lack of biological pathway annotation in many species represent significant challenges to effective implementation of this approach. Here, a systems level, multistep modeling strategy demonstrates how to integrate information on chemical structure with mechanistic insight from genomic studies, and phenotypic effects to define a putative adverse outcome pathway. Results indicated that transcriptional changes indicative of intracellular calcium mobilization were significantly overrepresented in Daphnia magna (DM) exposed to sublethal doses of presumed narcotic chemicals with log Kow ≥ 1.8. Treatment of DM with a calcium ATPase pump inhibitor substantially recapitulated the common transcriptional changes. We hypothesize that calcium mobilization is a potential key molecular initiating event in DM basal (narcosis) toxicity. Heart beat rate analysis and metabolome analysis indicated sublethal effects consistent with perturbations of calcium preceding overt acute toxicity. Together, the results indicate that altered calcium homeostasis may be a key early event in basal toxicity or narcosis induced by lipophilic compounds

Leukotriene modifiers for asthma treatment

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB 4 , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT 1 and CysLT 2 , have been identified. The activation of the CysLT 1 receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB 4 might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT 1 receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT 1 receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT 1 receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT 1 receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.Cite this as: P. Montuschi and M. L. Peters-Golden, Clinical & Experimental Allergy , 2010 (40) 1732–1741.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79154/1/j.1365-2222.2010.03630.x.pd

Premature ovarian failure and ovarian autoimmunity

Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oophoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oophoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by th

Reliability of GENEActiv accelerometers to estimate sleep, physical activity, and sedentary time in children

Background Reliable estimates of habitual sleep, physical activity, and sedentary time are essential to investigate the associations between these behaviours and health outcomes. While the number of days needed and hours/day for estimates of physical activity and sedentary time are generally known, the criteria for sleep estimates are more uncertain. The objective of this study was to identify the number of nights needed to obtain reliable estimates of habitual sleep behaviour using the GENEActiv wrist worn accelerometer. The number of days to obtain reliable estimate of physical activity was also examined. Methods Data was used from a two-year longitudinal study. Children wore an accelerometer for up to 8 days 24 h/day across three timepoints. The sample included 2,745 children (51 % girls) between the ages of 7-12-years-old (mean = 9.8 years, SD = 1.1 year) with valid accelerometer data from any timepoint. Reliability estimates were calculated for sleep duration, sleep efficiency, sleep onset, wake time, time in bed, light physical activity, moderate physical activity, moderate-to-vigorous physical activity, vigorous physical activity, and sedentary time. Results Intraclass correlations and the Spearman Brown prophecy formula were used to determine the nights and days needed for reliable estimates. We found that between 3 and 5 nights were needed to achieve acceptable reliability (ICC = 0.7) in sleep outcomes, while physical activity and sedentary time outcomes required between 3 and 4 days. Conclusions To obtain reliable estimates, researchers should consider these minimum criteria when designing their studies and prepare strategies to ensure sufficient wear time compliance

Day-to-day and longer-term longitudinal associations between physical activity, sedentary behavior, and sleep in children

Study Objectives To determine the day-to-day and longer-term longitudinal associations between daytime physical activity and night-time sleep. Methods We used data from a 2-year longitudinal study which included three time points (i.e. baseline, year 1, and year 2). Participants were recruited from primary schools and included 1059 children (50% girls) with a mean age of 8.81-years-old (SD = 0.72) at baseline. Sleep variables included sleep duration, sleep efficiency, time in bed, sleep onset, and wake time. Physical activity variables included light, moderate, moderate-to-vigorous, and vigorous physical activity as well as sedentary time. We objectively assessed physical activity and sleep behaviors using the GENEActiv wrist-worn accelerometer over an 8-day period at each timepoint for a potential 21 190 observed days. Results We used fixed-effects multilevel models and parallel latent growth curve modeling to examine day-to-day and longer-term associations, respectively. Day-to-day, physical activity, and sleep variables were significantly, positively, and bidirectionally associated, except for sleep efficiency, which showed little association with physical activity. Longer-term, we found little association between physical activity and sleep variables. Conclusions Overall, our findings indicate that there is a day-to-day association between the amount of time spent being physically active and improved sleep. The lack of a longer-term association indicates that a focus on children’s daily behavior may be most appropriate to help children improve sleep and increase physical activity

Influences on user engagement in online professional learning : A narrative synthesis and meta-analysis

The internet has become the chosen medium for professional learning. Completing professional learning can improve work performance; however, many individuals who begin online courses do not complete them. It is not well understood which influences keep individuals engaged in online professional learning. We address these issues with a systematic review. Our review of 51 studies and 9,583 participants includes a narrative synthesis and a meta-analysis that examined influences on user engagement in online professional learning. We found that course design and employers’ provision of time to complete learning are key for engaging learners. Other important influences were learners’ reasons for learning (e.g., intrinsic value and perceived usefulness), access to learning support, and opportunities for interaction during the learning experience

Physical activity and sleep are inconsistently related in healthy children: a systematic review and meta-analysis

Physical activity is considered an effective method to improve sleep quality in adolescents and adults. However, there is mixed evidence among children. Our objectives were to investigate this association in children and to examine potential moderating variables. Eight databases were systematically searched, and we included all study designs with a sample of healthy children ages 3-13 years-old. We identified 47 studies for meta-analysis. Overall, we found little association between physical activity and sleep (r = 0.02, 95% confidence interval = −0.03 to 0.07). There was a high amount of heterogeneity in the overall model (I2 = 93%). However, none of the examined variables significantly moderated the overall effect, including age, gender, risk of bias, study quality, measurement methodology, study direction, and publication year. Exploratory analyses showed some weak, but statistically significant associations for vigorous physical activity with sleep (r = 0.09, 95% CI = 0.01 to 0.17, I2 = 66.3%), specifically sleep duration (r = 0.07, 95% CI = 0.00 to 0.14, I2 = 41.1%). High heterogeneity and the lack of experimental research suggest our findings should be interpreted with caution. The current evidence, however, shows little support for an association between physical activity and sleep i

The relationship between sleep and physical activity across the lifespan

Secondary observational data analysis investigating of the relationship between device-measured sleep and physical activity across the lifespan using a pooled analysis of individual participant data. By pooling individual participant data, we will be able to explore specific moderators of the sleep and physical activity relationship in a large and diverse cohort

Self-determination theory applied to physical education: a systematic review and meta-analysis

In this review we examine the evidence regarding self-determination theory within the school physical education context. We applied a multilevel structural equation modeling approach to meta-analyze data from a systematic review that identified 265 relevant studies. In line with theory, autonomous motivation was positively correlated with adaptive outcomes and negatively correlated with maladaptive outcomes. Introjected regulation was modestly correlated with both adaptive and maladaptive outcomes. External regulation and amotivation both showed negative relationships with adaptive outcomes, and positive relationship with maladaptive outcomes. Also supporting SDT, autonomy, competence, and relatedness satisfactions were strongly correlated with autonomous student motivation, and less strongly, but still positively, correlated with introjected regulation. Weak negative correlations were found between autonomy, competence, and relatedness and external regulation. Amotivation had moderate negative correlations with needs satisfaction. Findings further revealed that teachers more greatly impact classroom experiences of autonomy and competence, whereas relatedness in physical education is associated with both peer and teacher influences

A Systematic Review of Machine Learning for Assessment and Feedback of Treatment Fidelity

Many psychological treatments have been shown to be cost-effective and efficacious, as long as they are implemented faithfully. Assessing fidelity and providing feedback is expensive and time-consuming. Machine learning has been used to assess treatment fidelity, but the reliability and generalisability is unclear. We collated and critiqued all implementations of machine learning to assess the verbal behaviour of all helping professionals, with particular emphasis on treatment fidelity for therapists. We conducted searches using nine electronic databases for automated approaches of coding verbal behaviour in therapy and similar contexts. We completed screening, extraction, and quality assessment in duplicate. Fifty-two studies met our inclusion criteria (65.3% in psychotherapy). Automated coding methods performed better than chance, and some methods showed near human-level performance; performance tended to be better with larger data sets, a smaller number of codes, conceptually simple codes, and when predicting session-level ratings than utterance-level ones. Few studies adhered to best-practice machine learning guidelines. Machine learning demonstrated promising results, particularly where there are large, annotated datasets and a modest number of concrete features to code. These methods are novel, cost-effective, scalable ways of assessing fidelity and providing therapists with individualised, prompt, and objective feedback.</p