A MicroRNA Signature of Response to Erlotinib is Descriptive of TGFβ Behaviour in NSCLC

Our previous work identified a 13-gene miRNA signature predictive of response to the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in Non-Small Cell Lung Cancer cell lines. Bioinformatic analysis of the signature showed a functional convergence on TGFβ canonical signalling. We hypothesized that TGFβ signalling controls expression of the miRNA genes comprising an erlotinib response signature in NSCLC. Western analysis revealed that TGFβ signalling via Smad2/3/4 occurred differently between erlotinib-resistant A549 and erlotinib- sensitive PC9 cells. We showed that TGFβ induced an interaction between Smad4 and putative Smad Binding Elements in PC9. However, qRT-PCR analysis showed that endogenous miR-140/141/200c expression changes resulted from time in treatments, not the treatments themselves. Moreover, flow cytometry indicated that cells exited the cell cycle in the same manner. Taken together these data indicated that the miRNA comprising the signature are likely regulated by the cell cycle rather than by TGFβ. Importantly, this work revealed that TGFβ did not induce EMT in PC9 cells, but rather TGFβ-inhibition induced an EMT-intermediate. These data also show that growth/proliferation signals by constitutively-activated EGFR may rely on TGFβ and a possible relationship between TGFβ and EGFR signalling may prevent EMT progression in this context rather than promote it

Inter-rater reliability of cyclic and non-cyclic task assessment using the hand activity level in appliance manufacturing

This study evaluated the inter-rater reliability of the American Conference of Governmental Industrial Hygienists (ACGIH) hand activity level (HAL), an observational ergonomic assessment method used to estimate physical exposure to repetitive exertions during task performance. Video recordings of 858 cyclic and non-cyclic appliance manufacturing tasks were assessed by sixteen pairs of raters using the HAL visual-analog scale. A weighted Pearson Product Moment-Correlation Coefficient was used to evaluate the agreement between the HAL scores recorded by each rater pair, and the mean weighted correlation coefficients for cyclic and non-cyclic tasks were calculated. Results indicated that the HAL is a reliable exposure assessment method for cyclic (r-barw = 0.69) and non-cyclic work tasks (r-barw = 0.68). When the two reliability scores were compared using a two-sample Student’s t-test, no significant difference in reliability (p = 0.63) between these work task categories was found. This study demonstrated that the HAL may be a useful measure of exposure to repetitive exertions during cyclic and non-cyclic tasks. Relevance to industry: Exposure to hazardous levels of repetitive action during non-cyclic task completion has traditionally been difficult to assess using simple observational techniques. The present study suggests that ergonomists could use the HAL to reliably and easily evaluate exposures associated with some non-cyclic work tasks

Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism

Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism

Bicycle-Safe Grate Inlets Study Volume 1 - Hydraulic and Safety Characteristics of Selected Grate Inlets on Continuous Grades

PO-5-3-0166Eleven drain inlet grates were tested to evaluate their safety characteristics for bicycle as well as pedestrian traffic. Four of the grates that rated highest were selected for hydraulic testing. Three other grates with designs and bar spacings similar to grates proven safe were also selected for hydraulic testing. Test results show that two of the grate designs (a cast and a steel fabricated grate) are nearly as hydraulically efficient as the parallel bar grate and considerably more efficient than the other grate designs tested. One other design (a steel fabricated grate) shows high hydraulic efficiencies at longitudinal slopes up to 6 percent. These three grate designs are recommended for additional testing. A grate's ability to handle debris without clogging was shown to be most dependent on the spacing of its longitudinal bars

A framework for characterising and evaluating the effectiveness of environmental modelling

Environmental modelling is transitioning from the traditional paradigm that focuses on the model and its quantitative performance to a more holistic paradigm that recognises successful model-based outcomes are closely tied to undertaking modelling as a social process, not just as a technical procedure. This paper redefines evaluation as a multi-dimensional and multi-perspective concept, and proposes a more complete framework for identifying and measuring the effectiveness of modelling that serves the new paradigm. Under this framework, evaluation considers a broader set of success criteria, and emphasises the importance of contextual factors in determining the relevance and outcome of the criteria. These evaluation criteria are grouped into eight categories: project efficiency, model accessibility, credibility, saliency, legitimacy, satisfaction, application, and impact. Evaluation should be part of an iterative and adaptive process that attempts to improve model-based outcomes and foster pathways to better futures

Effective modeling for integrated water resource management: a guide to contextual practices by phases and steps and future opportunities

The effectiveness of Integrated Water Resource Management (IWRM) modeling hinges on the quality of practices employed through the process, starting from early problem definition all the way through to using the model in a way that serves its intended purpose. The adoption and implementation of effective modeling practices need to be guided by a practical understanding of the variety of decisions that modelers make, and the information considered in making these choices. There is still limited documented knowledge on the modeling workflow, and the role of contextual factors in determining this workflow and which practices to employ. This paper attempts to contribute to this knowledge gap by providing systematic guidance of the modeling practices through the phases (Planning, Development, Application, and Perpetuation) and steps that comprise the modeling process, positing questions that should be addressed. Practice-focused guidance helps explain the detailed process of conducting IWRM modeling, including the role of contextual factors in shaping practices. We draw on findings from literature and the authors’ collective experience to articulate what and how contextual factors play out in employing those practices. In order to accelerate our learning about how to improve IWRM modeling, the paper concludes with five key areas for future practice-related research: knowledge sharing, overcoming data limitations, informed stakeholder involvement, social equity and uncertainty management. © 2019 Elsevier Lt

Social science in a water observing system

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95008/1/wrcr12336.pd