Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-Arnt-Sim (PAS)-containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Our previous three-dimensional homology model of the mouse AhR (mAhR) PAS B ligand binding domain allowed identification of the binding site and its experimental validation. We have extended this analysis by conducting comparative structural modeling studies of the ligand binding domains of six additional highaffinity mammalian AhRs. These results, coupled with site-directed mutagenesis and AhR functional analysis, have allowed detection of the "TCDD binding-fingerprint" of conserved residues within the ligand binding cavity necessary for high-affinity TCDD binding and TCDD-dependent AhR transformation DNA binding. The essential role of selected residues was further evaluated using molecular docking simulations of TCDD with both wild-type and mutant mAhRs. Taken together, our results dramatically improve our understanding of the molecular determinants of TCDD binding and provide a basis for future studies directed toward rationalizing the observed species differences in AhR sensitivity to TCDD and understanding the mechanistic basis for the dramatic diversity in AhR ligand structure. © 2009 American Chemical Society

A Linked Data Approach to Sharing Workflows and Workflow Results

A bioinformatics analysis pipeline is often highly elaborate, due to the inherent complexity of biological systems and the variety and size of datasets. A digital equivalent of the ‘Materials and Methods’ section in wet laboratory publications would be highly beneficial to bioinformatics, for evaluating evidence and examining data across related experiments, while introducing the potential to find associated resources and integrate them as data and services. We present initial steps towards preserving bioinformatics ‘materials and methods’ by exploiting the workflow paradigm for capturing the design of a data analysis pipeline, and RDF to link the workflow, its component services, run-time provenance, and a personalized biological interpretation of the results. An example shows the reproduction of the unique graph of an analysis procedure, its results, provenance, and personal interpretation of a text mining experiment. It links data from Taverna, myExperiment.org, BioCatalogue.org, and ConceptWiki.org. The approach is relatively ‘light-weight’ and unobtrusive to bioinformatics users

Not even the past: The joint influence of former leader and new leader during leader successions in the midst of organizational change

Leader succession often occurs during organizational change processes, but the implications of leader succession, in terms of reactions to the change, rarely have been investigated. Employee attitudes and behaviors during organizational change may be influenced jointly by a former leader who recently has transitioned out of the team and the new leader who recently has transitioned into it. We predict an interaction between former and new leaders’ transformational leadership on employees’ behavioral resistance to and support for change. Based on contrast effect theory, a highly transformational former leader constrains the potential effectiveness of the new leader, but a former leader low in transformational leadership enhances this potential effectiveness. We also propose conditional indirect effects transmitted through commitment to the changing organization. Our research was conducted in a large Chinese hospitality organization that was implementing radical organizational change, during which virtually all aspects of processes and products are changed. We collected a 2-wave multisource data from employees who had recently experienced a leader succession and their newly assigned leaders. Based on a final sample of 203 employees from 22 teams, we find empirical support for the proposed interaction effects. The conditional indirect effects were also consistent with our expectations, but the effect on behavioral resistance to change was stronger than the effect on behavioral support for change.postprin

The core Planar Cell Polarity gene, Vangl2, maintains apical-basal organisation of the corneal epithelium

This work was performed under Biotechnology and Biological Sciences Research Council (BBSRC) research grant BB/J015237/1 to JMC. DAP was funded by an Anatomical Society PhD Studentship whose support is gratefully acknowledged. ASF was funded by a BBSRC DTG PhD Studentship. We thank staff at the Medical Research Facility and Aberdeen Microscopy Services for technical assistance.Peer reviewedPostprin

Evaluating the Impact of an Interprofessional Practice Experience Involving Pharmacy and Dental Students on Medication Histories within an Urban Academic Dental Admissions Clinic

Primary Objective: To compare interprofessional (IP) care versus standard care on medication history clarifications in dental patients. Secondary Objectives: To assess the clinical significance of these clarifications with regards to the potential impact on dental treatment plans. To describe the interventions provided by IP care to clarify discrepancies and/or resolve medication-related problems

Does moxibustion work? An overview of systematic reviews

Abstract Background Several systematic reviews (SRs) have assessed the effectiveness of moxibustion for a range of conditions, often with contradictory conclusions. Our aim was to provide a critical evaluation and summary of these data. Methods Electronic searches were conducted to locate all SRs of moxibustion for any condition. Data were extracted by two authors according to predefined criteria. Results Ten SRs met our inclusion criteria, which related to the following conditions: cancer, ulcerative colitis, stroke rehabilitation, constipation, hypertension, pain conditions and breech presentation. Their conclusions were contradictory in several instances. Relatively clear evidence emerged to suggest that moxibustion is effective for breech presentation. Conclusions Based on evidence from the currently available SRs, the effectiveness of moxibustion has been demonstrated for several conditions; however, due to the poor quality of the primary studies, there remains considerable uncertainty.</p

Live-cell imaging to detect phosphatidylserine externalization in brain endothelial cells exposed to ionizing radiation: Implications for the treatment of brain arteriovenous malformations

© 2016 AANS. Objective Stereotactic radiosurgery (SRS) is an established intervention for brain arteriovenous malformations (AVMs). The processes of AVM vessel occlusion after SRS are poorly understood. To improve SRS efficacy, it is important to understand the cellular response of blood vessels to radiation. The molecular changes on the surface of AVM endothelial cells after irradiation may also be used for vascular targeting. This study investigates radiation-induced externalization of phosphatidylserine (PS) on endothelial cells using live-cell imaging. methods An immortalized cell line generated from mouse brain endothelium, bEnd.3 cells, was cultured and irradiated at different radiation doses using a linear accelerator. PS externalization in the cells was subsequently visualized using polarity-sensitive indicator of viability and apoptosis (pSIVA)-IANBD, a polarity-sensitive probe. Live-cell imaging was used to monitor PS externalization in real time. The effects of radiation on the cell cycle of bEnd.3 cells were also examined by flow cytometry. results Ionizing radiation effects are dose dependent. Reduction in the cell proliferation rate was observed after exposure to 5 Gy radiation, whereas higher radiation doses (15 Gy and 25 Gy) totally inhibited proliferation. In comparison with cells treated with sham radiation, the irradiated cells showed distinct pseudopodial elongation with little or no spreading of the cell body. The percentages of pSIVA-positive cells were significantly higher (p = 0.04) 24 hours after treatment in the cultures that received 25-and 15-Gy doses of radiation. This effect was sustained until the end of the experiment (3 days). Radiation at 5 Gy did not induce significant PS externalization compared with the sham-radiation controls at any time points (p > 0.15). Flow cytometric analysis data indicate that irradiation induced growth arrest of bEnd.3 cells, with cells accumulating in the G2 phase of the cell cycle. coNclusioNs Ionizing radiation causes remarkable cellular changes in endothelial cells. Significant PS externalization is induced by radiation at doses of 15 Gy or higher, concomitant with a block in the cell cycle. Radiation-induced markers/targets may have high discriminating power to be harnessed in vascular targeting for AVM treatment

Analysis of airborne particulate matter (pm₂.₅) over Hong Kong using remote sensing and GIS

2011-2012 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Diversifying search in bee algorithms for numerical optimisation

© Springer Nature Switzerland AG 2018. Swarm intelligence offers useful instruments for developing collective behaviours to solve complex, ill-structured and large-scale problems. Efficiency in collective behaviours depends on how to harmonise the individual contributions so that a complementary collective effort can be achieved to offer a useful solution. The harmonisation helps blend diversification and intensification suitably towards efficient collective behaviours. In this study, two renown honeybees-inspired algorithms were analysed with respect to the balance of diversification and intensification and a hybrid algorithm is proposed to improve the efficiency accordingly. The proposed hybrid algorithm was tested with solving well-known highly dimensional numerical optimisation (benchmark) problems. Consequently, the proposed hybrid algorithm has demonstrated outperforming the two original bee algorithms in solving hard numerical optimisation benchmarks

Murine model for Fusarium oxysporum invasive fusariosis reveals organ-specific structures for dissemination and long-term persistence

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