Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks

Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells

Internet gaming disorder as a formative construct : implications for conceptualization and measurement

Background. Some people have serious problems controlling their internet and video game use. The DSM-5 now includes a proposal for ‘Internet Gaming Disorder’ as a condition in need of further study. Various studies aim to validate the proposed diagnostic criteria for Internet Gaming Disorder and multiple new scales have been introduced that cover the suggested criteria. Approach. Using a structured approach, we demonstrate that Internet Gaming Disorder might be better interpreted as a formative construct, as opposed to the current practice of conceptualizing it as a reflective construct. Incorrectly approaching a formative construct as a reflective one causes serious problems in scale development including (a) incorrect reliance on item-to-total scale correlation to exclude items and incorrectly relying on indices of inter-item reliability that do not fit the measurement model (e.g., Cronbach’s α) (b) incorrect interpretation of composite or mean scores that assume all items are equal in contributing value to a sum score, and (c) biased estimation of model parameters in statistical models. Implications. We show that these issues are impacting current validation efforts through two recent examples. A reinterpretation of Internet Gaming Disorder as a formative construct has broad consequences for current validation efforts and provides opportunities to reanalyze existing data. We discuss three broad implications for current research: (1) Composite latent constructs should be defined and used in models, (2) Item exclusion and selection should not rely on item-to-total scale correlations, and (3) Existing definitions of Internet Gaming Disorder should be enriched further

Psychometric properties of the Dutch version of the Evidence-Based Practice Attitude Scale (EBPAS).

BackgroundThe Evidence-Based Practice Attitude Scale (EBPAS) was developed in the United States to assess attitudes of mental health and welfare professionals toward evidence-based interventions. Although the EBPAS has been translated in different languages and is being used in several countries, all research on the psychometric properties of the EBPAS within youth care has been carried out in the United States. The purpose of this study was to investigate the psychometric properties of the Dutch version of the EBPAS.MethodsAfter translation into Dutch, the Dutch version of the EBPAS was examined in a diverse sample of 270 youth care professionals working in five institutions in the Netherlands. We examined the factor structure with both exploratory and confirmatory factor analyses and the internal consistency reliability. We also conducted multiple linear regression analyses to examine the association of EBPAS scores with professionals' characteristics. It was hypothesized that responses to the EBPAS items could be explained by one general factor plus four specific factors, good to excellent internal consistency reliability would be found, and EBPAS scores would vary by age, sex, and educational level.ResultsThe exploratory factor analysis suggested a four-factor solution according to the hypothesized dimensions: Requirements, Appeal, Openness, and Divergence. Cronbach's alphas ranged from 0.67 to 0.89, and the overall scale alpha was 0.72. The confirmatory factor analyses confirmed the factor structure and suggested that the lower order EBPAS factors are indicators of a higher order construct. However, Divergence was not significantly correlated with any of the subscales or the total score. The confirmatory bifactor analysis endorsed that variance was explained both by a general attitude towards evidence-based interventions and by four specific factors. The regression analyses showed an association between EBPAS scores and youth care professionals' age, sex, and educational level.ConclusionsThe present study provides strong support for a structure with a general factor plus four specific factors and internal consistency reliability of the Dutch version of the EBPAS in a diverse sample of youth care professionals. Hence, the factor structure and reliability of the original version of the EBPAS seem generalizable to the Dutch version of the EBPAS

Lines-of-inquiry and sources of evidence in work-based research

There is synergy between the investigative practices of police detectives and social scientists, including work-based researchers. They both develop lines-of-inquiry and draw on multiple sources of evidence in order to make inferences about people, trends and phenomena. However, the principles associated with lines-of-inquiry and sources of evidence have not so far been examined in relation to work-based research methods, which are often unexplored or ill-defined in the published literature. We explore this gap by examining the various direct and indirect lines-of-inquiry and the main sources of primary and secondary evidence used in work-based research, which is especially relevant because some work-based researchers are also police detectives. Clearer understanding of these intersections will be useful in emerging professional contexts where the work-based researcher, the detective, and the social scientist cohere in the one person and their research project. The case we examined was a Professional Studies programme at a university in Australia, which has many police detectives doing work-based research, and from their experience we conclude there is synergy between work-based research and lines of enquiry. Specifically, in the context of research methods, we identify seven sources of evidence: 1) creative, unstructured, and semi-structured interviews; 2) structured interviews; 3) consensus group methods; 4) surveys; 5) documentation and archives; 6) direct observations and participant observations; and 7) physical or cultural artefacts, and show their methodological features related to data and method type, reliability, validity, and types of analysis, along with their respective advantages and disadvantages. This study thereby unpacks and isolates those characteristics of work-based research which are relevant to a growing body of literature related to the messy, co-produced and wicked problems of private companies, government agencies, and non-government organisations and the research methods used to investigate them

Initial evidence for the criterion-related and structural validity of the long versions of the direct and meta-perspectives of the Coach-Athlete Relationship Questionnaire

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Taylor & Francis.The aim of the present study was to develop and initially validate a longer version of the direct (Jowett & Ntoumanis, 2004) and meta-perspectives (Jowett, 2009a, 2009b) of the Coach-Athlete Relationship Questionnaire (CART-Q). In Study 1, instruments (e.g. questionnaires, scales, and inventories) that have been used to assess relationship quality in the broader psychological literature were examined and items potentially relevant to the coach-athlete relationship were identified. The content validity of the identified items was then assessed using expert panels. A final questionnaire was subsequently prepared and administered to 693 participants (310 coaches and 383 athletes). Confirmatory factor analysis was employed to assess the multidimensional nature of the questionnaire based on the 3Cs (i.e. closeness, commitment, and complementarity) model of the coach-athlete relationship. The findings indicated that the direct and meta-perspective items of the long versions of the CART-Q approached an adequate data fit. Moreover, evidence for the internal consistency and criterion validity of the new instruments was also obtained. In Study 2, the newly developed measure was administered to an independent sample of 251 individuals (145 athletes and 106 coaches). Further statistical support was gained for the factorial validity and reliability of the longer version of the CART-Q

Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials : a consensus study

Background: Current methodological guidelines provide advice about the assessment of sub-group analysis within RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of criteria that will facilitate the grading of evidence for moderators, in systematic reviews. Method: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique, and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising authors who have published methodological papers in this area, and researchers who have been active in the study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers’ Handbook, and the process was repeated. Results: The recommendations are that meta-analysts report both confirmatory and exploratory findings for subgroups analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based apriori statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study: Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions must be presented. Conclusions: There is consensus from a group of 21 international experts that methodological criteria to assess moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research. These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies

The measurement of guanxi: Introducing the GRX scale

This is the post-print version of the final paper published in Industrial Marketing Management. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2010 Elsevier B.V.This study posits and examines a measurement scale for measuring guanxi based on three Chinese relational constructs – ganqing, renqing and xinren. Focusing on Anglo-Chinese buyer–seller relationships, the research reports the findings from six qualitative in-depth interviews and survey data obtained from over 200 Taiwanese trading companies. Based on exploratory and confirmatory factor analyses the findings from the final second-order confirmatory factor analysis of the guanxi model identified 11 items for measuring ganqing, renqing, xinren and guanxi respectively. The results offer a useful starting point in order for business practitioners to assess their guanxi and at the same time provide academics with a scale for operationalizing the measurement of guanxi

Bias and Equivalence in Cross-Cultural Research

Bias and equivalence are key concepts in the methodology of cross-cultural studies. Bias is a generic term for any challenge of the comparability of cross-cultural data; bias leads to invalid conclusions. The demonstration of equivalence (lack of bias) is a prerequisite for any cross-cultural comparison. we first describe considerations that are relevant when choosing instruments in a cross-cultural study, notably the question of whether an existing or new instrument is to be preferred.We then describe the definition, manifestation, and sources of three types of bias (construct, method, and item bias), and three levels of equivalence (construct, measurement unit, and full score equivalence). We provide strategies to minimize bias and achieve equivalence that apply either to the design, implementation, or statistical analysis phase of a study. The need to integrate these strategies in cross-cultural studies is emphasized so as to increase the validity of conclusions regarding cross-cultural similarities and differences and rule out alternative explanations of cross-cultural differences

Measuring the competence-quality of vocational teachers: An advocatory approach

Using a sample of 110 persons, this study examined the ”advocatory approach” for predicting the quality of (VET) teacher’s competency profiles. The participants (teachers, experts, non-teachers) observed a concrete teaching behavior using a film vignette, and judged it by means of different quality criteria. The hypothesis that differences in the groups, who evaluate, elicit differing sensitivity about the quality of specified teaching competencies (and not teaching performance) was mostly confirmed. We suggest that teachers can individually compare their values with expert values and non-teacher values, and thus use the discrepancies in quality sensitivity for the purposes of self-guided in-service training. (DIPF/Orig.

Untenable nonstationarity: An assessment of the fitness for purpose of trend tests in hydrology

The detection and attribution of long-term patterns in hydrological time series have been important research topics for decades. A significant portion of the literature regards such patterns as ‘deterministic components’ or ‘trends’ even though the complexity of hydrological systems does not allow easy deterministic explanations and attributions. Consequently, trend estimation techniques have been developed to make and justify statements about tendencies in the historical data, which are often used to predict future events. Testing trend hypothesis on observed time series is widespread in the hydro-meteorological literature mainly due to the interest in detecting consequences of human activities on the hydrological cycle. This analysis usually relies on the application of some null hypothesis significance tests (NHSTs) for slowly-varying and/or abrupt changes, such as Mann-Kendall, Pettitt, or similar, to summary statistics of hydrological time series (e.g., annual averages, maxima, minima, etc.). However, the reliability of this application has seldom been explored in detail. This paper discusses misuse, misinterpretation, and logical flaws of NHST for trends in the analysis of hydrological data from three different points of view: historic-logical, semantic-epistemological, and practical. Based on a review of NHST rationale, and basic statistical definitions of stationarity, nonstationarity, and ergodicity, we show that even if the empirical estimation of trends in hydrological time series is always feasible from a numerical point of view, it is uninformative and does not allow the inference of nonstationarity without assuming a priori additional information on the underlying stochastic process, according to deductive reasoning. This prevents the use of trend NHST outcomes to support nonstationary frequency analysis and modeling. We also show that the correlation structures characterizing hydrological time series might easily be underestimated, further compromising the attempt to draw conclusions about trends spanning the period of records. Moreover, even though adjusting procedures accounting for correlation have been developed, some of them are insufficient or are applied only to some tests, while some others are theoretically flawed but still widely applied. In particular, using 250 unimpacted stream flow time series across the conterminous United States (CONUS), we show that the test results can dramatically change if the sequences of annual values are reproduced starting from daily stream flow records, whose larger sizes enable a more reliable assessment of the correlation structures