Fragment-Based QSAR and Molecular Modeling Studies on a Series of Discodermolide Analogs as Microtubule-Stabilizing Anticancer Agents

Inhibition of microtubule function is an attractive rational approach to anticancer therapy. Although taxanes are the most prominent among the microtubule-stabilizers, their clinical toxicity, poor pharmacokinetic properties, and resistance have stimulated the search for new antitumor agents having the same mechanism of action. Discodermolide is an example of nontaxane natural product that has the same mechanism of action, demonstrating superior antitumor efficacy and therapeutic index. The extraordinary chemical and biological properties have qualified discodermolide as a lead structure for the design of novel anticancer agents with optimized therapeutic properties. In the present work, we have employed a specialized fragment-based method to develop robust quantitative structure - activity relationship models for a series of synthetic discodermolide analogs. The generated molecular recognition patterns were combined with three-dimensional molecular modeling studies as a fundamental step on the path to understanding the molecular basis of drug-receptor interactions within this important series of potent antitumoral agents.

Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT(1A) receptor ligands

5-HT(1A) receptor antagonists have been employed to treat depression, but the lack of structural information on this receptor hampers the design of specific and selective ligands. In this study, we have performed CoMFA studies on a training set of arylpiperazines (high affinity 5-HT(1A) receptor ligands) and to produce an effective alignment of the data set, a pharmacophore model was produced using Galahad. A statistically significant model was obtained, indicating a good internal consistency and predictive ability for untested compounds. The information gathered from our receptor-independent pharmacophore hypothesis is in good agreement with results from independent studies using different approaches. Therefore, this work provides important insights on the chemical and structural basis involved in the molecular recognition of these compounds. (C) 2010 Elsevier Masson SAS. All rights reserved.

New insights on surface-enhanced Raman scattering based on controlled aggregation and spectroscopic studies, DFT calculations and symmetry analysis for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine adsorbed onto citrate-stabilized gold nanoparticles

Asystematic study on the surface-enhanced Raman scattering (SERS) for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine (bptz) adsorbed onto citrate-modified gold nanoparticles (cit-AuNps) was carried out based on electronic and vibrational spectroscopy and density functional methods. The citrate/bptz exchange was carefully controlled by the stepwise addition of bptz to the cit-AuNps, inducing flocculation and leading to the rise of a characteristic plasmon coupling band in the visible region. Such stepwise procedure led to a uniform decrease of the citrate SERS signals and to the rise of characteristic peaks of bptz, consistent with surface binding via the N heterocyclic atoms. In contrast, single addition of a large amount of bptz promoted complete aggregation of the nanoparticles, leading to a strong enhancement of the SERS signals. In this case, from the distinct Raman profiles involved, the formation of a new SERS environment became apparent, conjugating the influence of the local hot spots and charge-transfer (CT) effects. The most strongly enhanced vibrations belong to a(1) and b(2) representations, and were interpreted in terms of the electromagnetic and the CT mechanisms: the latter involving significant contribution of vibronic coupling in the system. Copyright (C) 2010 John Wiley & Sons, Ltd.

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents

In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400 nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones. (C) 2010 Elsevier Ltd. All rights reserved.

Exploring the influence of context in a community-based facilitation intervention focusing on neonatal health and survival in Vietnam : a qualitative study

Background In the Neonatal health – Knowledge into Practice (NeoKIP) trial in Vietnam, local stakeholder groups, supported by trained laywomen acting as facilitators, promoted knowledge translation (KT) resulting in decreased neonatal mortality. In general, as well as in the community-based NeoKIP trial, there is a need to further understand how context influences KT interventions in low- and middle-income countries (LMICs). Thus, the objective of this study was to explore the influence of context on the facilitation process in the NeoKIP intervention. Methods A secondary content analysis was performed on 16 Focus Group Discussions with facilitators and participants of the stakeholder groups, applying an inductive approach to the content on context through naïve understanding and structured analysis. Results The three main-categories of context found to influence the facilitation process in the NeoKIP intervention were: (1) Support and collaboration of local authorities and other communal stakeholders; (2) Incentives to, and motivation of, participants; and (3) Low health care coverage and utilization. In particular, the role of local authorities in a KT intervention was recognized as important. Also, while project participants expected financial incentives, non-financial benefits such as individual learning were considered to balance the lack of reimbursement in the NeoKIP intervention. Further, project participants recognized the need to acknowledge the needs of disadvantaged groups. Conclusions This study provides insight for further understanding of the influence of contextual aspects to improve effects of a KT intervention in Vietnam. We suggest that future KT interventions should apply strategies to improve local authorities’ engagement, to identify and communicate non-financial incentives, and to make disadvantaged groups a priority. Further studies to evaluate the contextual aspects in KT interventions in LMICs are also needed.

Chalk and cheese: Grounded theory case studies of the introduction and usage of activity-based information in two British banks

During the conduct of a research project into influences on the use of management accounting information, the use of activity-based techniques and information in two British banks was studied by the application of grounded theory principles. Juxtaposition of these two case studies reveals insights about the managers' significantly different experiences of ongoing applications, and the different outcomes of implementation that may arise, despite commonality in the organization and industry environment. This paper presents these two case studies, highlights the similarities and differences between them, and draws some conclusions about the causes of the differences. Factors that can be managed to achieve a greater use of these particular management accounting techniques, and the information they generate, are revealed. In particular, the findings suggest that the introduction of transfer charging between the bank's internal units highlights the need for activity-based techniques, and that education, communication and implementor support are vital, both for implementation success and for the widespread continuing use of the resultant applications. Further, between the two cases the greatest consensus was found in a common concern about the amount of detail in the databank and reports.

The role and theoretical evolution of knowledge translation and exchange in public health

Background There is an increased emphasis in public health research on effective models and strategies to support knowledge translation (KT), the exchange, synthesis and ethically sound application of research findings within a complex set of interactions among researchers and knowledge users. In other words, KT can be seen as an acceleration of the knowledge cycle—an acceleration of the natural transformation of knowledge into use (Canadian Institutes of Health Services Research. Knowledge Translation Strategy, 2004). The most recent conceptualizations consider the complexities of public health decision-making. The role of practitioners and communities is increasingly considered.

Methods We identify, describe and discuss the theoretical underpinnings of KT and recommend a way forward to build the evidence for more effective practice.

Results Theoretical perspectives increasingly influence research on KT in public health. A range of innovative work is being conducted to explore methods for KT using practical tools, often with the support of government.

Conclusions KT describes a crucial and to date under-developed element of the research process. There is an important gap in theoretically informed empirical studies of effectiveness of proposed approaches in public health, health promotion and preventive medicine, and thus much of the debate remains abstract. There is clearly an urgent policy need to establish the effectiveness of KT models in a range of contexts. This must include both the consideration of development and the utilization of knowledge.

Case studies for contract-based systems

Of the ways in which agent behaviour can be regulated in a multiagent system, electronic contracting – based on explicit representation of different parties' responsibilities, and the agreement of all parties to them – has significant potential for modern industrial applications. Based on this assumption, the CONTRACT project aims to develop and apply electronic contracting and contract-based monitoring and verification techniques in real world applications. This paper presents results from the initial phase of the project, which focused on requirements solicitation and analysis. Specifically, we survey four use cases from diverse industrial applications, examine how they can benefit from an agent-based electronic contracting infrastructure and outline the technical requirements that would be placed on such an infrastructure. We present the designed CONTRACT architecture and describe how it may fulfil these requirements. In addition to motivating our work on the contract-based infrastructure, the paper aims to provide a much needed community resource in terms of use case themselves and to provide a clear commercial context for the development of work on contract-based system.

fMRI studies in neuro-fuzzy and behavioral finance : a case based approach

Financial decision making mechanisms have not been identified. Using event-related fMRI without MR compatible switch which can be performed by all MRI system which has only Echo Planar Imaging (EPI) feature, we examined financial decision-making task with three risk levels in two participants. We saw activation regions differences between risk-seeking and risk-aversion selection in addition to larger activated regions in selection funding in comparison with no selection. Thus, consideration of anticipatory neural mechanisms may add predictive power for economic decision- making.

Study protocol for the translating research in elder care (TREC): Building context through case studies in long-term care project (project two)

Background: The organizational context in which healthcare is delivered is thought to play an important role in mediating the use of knowledge in practice. Additionally, a number of potentially modifiable contextual factors have been shown to make an organizational context more amenable to change. However, understanding of how these factors operate to influence organizational context and knowledge use remains limited. In particular, research to understand knowledge translation in the long-term care setting is scarce. Further research is therefore required to provide robust explanations of the characteristics of organizational context in relation to knowledge use.
Aim: To develop a robust explanation of the way organizational context mediates the use of knowledge in practice in long-term care facilities.
Design: This is longitudinal, in-depth qualitative case study research using exploratory and interpretive methods to explore the role of organizational context in influencing knowledge translation. The study will be conducted in two phases. In phase one, comprehensive case studies will be conducted in three facilities. Following data analysis and proposition development, phase two will continue with focused case studies to elaborate emerging themes and theory. Study sites will be purposively selected. In both phases, data will be collected using a variety of approaches, including non-participant observation, key informant interviews, family perspectives, focus groups, and documentary evidence (including, but not limited to, policies, notices, and photographs of physical resources). Data analysis will comprise an iterative process of identifying convergent evidence within each case study and then examining and comparing the evidence across multiple case studies to draw conclusions from the study as a whole. Additionally, findings that emerge through this project will be compared and considered alongside those that are emerging from project one. In this way, pattern matching based on explanation building will be used to frame the analysis and develop an explanation of organizational context and knowledge use over time. An improved understanding of the contextual factors that mediate knowledge use will inform future development and testing of interventions to enhance knowledge use, with the ultimate aim of improving the outcomes for residents in long-term care settings.

Stoichiometric changes in lithium conducting materials based on Li1+xAlxTi2−x(PO4)3: impedance, X-ray and NMR studies

The lithium fast-ion conductor, Li_1+xAl_xTi_2−x(PO₄)₃ (LATP) has been modified via changes in stoichiometry during the processing steps. The resultant changes have been followed using ²⁷Al MAS NMR, X-ray powder diffraction and impedance spectroscopy. The most important changes were those of the form Li_1.3+4yAl_0.3Ti_1.7−y(PO₄)₃. It was possible to remove the AlPO₄ phase (both tridymite and berlinite polymorphs), as monitored by X-ray diffractograms and ²⁷Al NMR spectra. Consequently, these changes appear to result in increased grain boundary conductivity of the LATP material.

NMR and Raman studies of a novel fast-ion-conducting polymer-in-salt electrolyte based on LiCF3SO3 and PAN

We report spectroscopic results from investigations of a novel solid polymeric fast-ion-conductor based on poly(acrylonitrile), (PAN, of repeat unit [CH₂CH(CN)]_n), and the salt LiCF₃SO3 . From NMR studies of the temperature and concentration dependencies of ⁷Li- and ^lH-NMR linewidths, we conclude that significant ionic motion occurs at temperatures close to the glass transition temperature of these polymer-in-salt electrolytes, in accordance with a recent report on the ionic conductivity. In the dilute salt-in-polymer regime, however, ionic motion appears mainly to be confined to local salt-rich domains, as determined from the dramatic composition dependence of the ionic conductivity. FT-Raman spectroscopy is used to directly probe the local chemical anionic environment, as well as the Li⁺–PAN interaction. The characteristic δ_s(CF₃) mode of the CF₃SO₃⁻ anion at _~750–780 cm^−l shows that the ionic substructure is highly complex. Notably, no spectroscopic evidence of free anions is found even at relatively salt-depleted compositions (e.g. N:Li_~60–10:1). A strong Li⁺–PAN interaction is manifested as a pronounced shift of the characteristic polymer C=N stretching mode, found at _~2244 cm^−l in pure PAN, to _~2275 cm^−l for Li⁺-coordinated C=N moieties. Our proton-NMR data suggest that upon complexation of PAN with LiCF3 SO₃, the glass transition occurs at progressively lower temperatures.