Introduction | Approaching Potent Substances in Medicine and Ritual across Asia

Introduction to themed research articles on Approaching Potent Substances in Medicine and Ritual across Asia

A novel approach in glioblastoma multiforme drug discovery: Perturbation studies in vitro

Despite impressive advances in drug discovery methods, predicting cellular response to anticancer drugs remains challenging. In glioblastoma multiforme, this fact is even marked as many promising drugs were followed by disappointment. As a result, the aim of this study is to clarify the effects of inhibition of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in glioblastoma multiforme, while exploring how the focus on potency might ignore the potential impact of variation in other pharmacological parameters. The evaluation of the induced drug perturbation in glioblastoma cancer cells and a multiparametric characterization dose-response of two PDK1 inhibitors were performed. Singular analysis of potency would lead to the conclusion that FC100 compound would be the most promising to treat glioblastoma multiforme. However, exploring other pharmacological parameters shows the opposite giving more information about the cell response. The study shows that potency should not be the critical factor in developing new drugs as our most potent compound lacks growth inhibition effect. So, the evaluation of promising drugs during the drug discovery phase needs to be re-evaluated and multiparametric dose-response analysis might be a useful approach to compare drugs and potentially better characterization of both drug and disease profiles

Work of a Nation: Christian Funerary Ecumenism and Institutional Disruption in Swaziland

This article traces how contemporary funerary practices—foodways, prayer and burial cooperative participation—configure a Christian public culture in Swaziland that draws from ordinary citizens’ religious, ritual and political work and membership in diverse Christian churches. This kind of grassroots ecumenism importantly challenges the potency of orthodox institutional ecumenical projects of religious elites in the Kingdom. These projects include attempts to legislate Christianity as an official religion and the building of a national interdenominational church, both of which have failed to materialize. Exploring this emergent tension between religious institutions’ ideological goals versus communities’ practical engagement on pressing social problems invites a rethinking of how citizens produce public cultures. Research is based on intermittent fieldwork at funerals, burial cooperatives, family ceremonies, and churches, interviews with local church leaders and theologians, and document research in Swaziland from 2008 to 2015

Development and characterization of a potent free fatty acid receptor 1 (FFA1) fluorescent tracer

The free fatty acid receptor 1 (FFA1/GPR40) is a potential target for treatment of type 2 diabetes. Although several potent agonists have been described, there remains a strong need for suitable tracers to interrogate ligand binding to this receptor. We address this by exploring fluorophore-tethering to known potent FFA1 agonists. This led to the development of 4, a high affinity FFA1 tracer with favorable and polarity-dependent fluorescent properties. A close to ideal overlap between the emission spectrum of the NanoLuciferase receptor tag and the excitation spectrum of 4 enabled the establishment of a homogenous BRET-based binding assay suitable for both detailed kinetic studies and high throughput competition binding studies. Using 4 as a tracer demonstrated that the compound acts fully competitively with selected synthetic agonists but not with lauric acid and allowed for the characterization of binding affinities of a diverse selection of known FFA1 agonists, indicating that 4 will be a valuable tool for future studies at FFA1

Normal and Abnormal Personality Traits are Associated with Marital Satisfaction for both Men and Women: An Actor–Partner Interdependence Model Analysis

Research has demonstrated associations between relationship satisfaction and personality traits. Using the Actor–Partner Interdependence Model, we explored associations between self-reported relationship satisfaction in couples (n = 118) and various measures of normal and abnormal personality, including higher-order dimensions of PE/Extraversion, NE/Neuroticism, Constraint (CON), and their lower-order facets. We also examined gender differences and moderators of associations. Consistent with the Vulnerability Stress Adaptation Model, self- and partner-reported NE and PE were related to satisfaction, and their lower-order traits demonstrated differential associations with satisfaction. Further, abnormal personality traits specific to the interpersonal domain and personality disorder symptoms demonstrated effects. Relationship length emerged as a significant moderator, with associations weakening as relationship duration increased

Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs

Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors.

The homotrimeric HIV-1 envelope glycoprotein (Env) undergoes receptor-triggered structural changes that mediate viral entry through membrane fusion. This process is inhibited by chemokine receptor antagonists (CoRAs) that block Env-receptor interactions and by fusion inhibitors (FIs) that disrupt Env conformational transitions. Synergy between CoRAs and FIs has been attributed to a CoRA-dependent decrease in the rate of viral membrane fusion that extends the lifetime of the intermediate state targeted by FIs. Here, we demonstrated that the magnitude of CoRA/FI synergy unexpectedly depends on FI-binding affinity and the stoichiometry of chemokine receptor binding to trimeric Env. For C-peptide FIs (clinically represented by enfuvirtide), synergy waned as binding strength decreased until inhibitor combinations behaved additively. Curiously, this affinity dependence on synergy was absent for 5-Helix-type FIs. We linked this complex behavior to the CoRA dependence of Env deactivation following FI binding. For both FI classes, reducing chemokine receptor levels on target cells or eliminating competent chemokine receptor-binding sites on Env trimers resulted in a loss of synergistic activity. These data imply that the stoichiometry required for CoRA/FI synergy exceeds that required for HIV-1 entry. Our analysis suggests two distinct roles for chemokine receptor binding, one to trigger formation of the FI-sensitive intermediate state and another to facilitate subsequent conformational transitions. Together, our results could explain the wide variety of previously reported activities for CoRA/FI combinations. These findings also have implications for the combined use of CoRAs and FIs in antiviral therapies and point to a multifaceted role for chemokine receptor binding in promoting HIV-1 entry

Clarke and Kubrick’s 2001: a queer odyssey

This article is a queer reading of 2001: A Space Odyssey. It begins by situating the film in the context of the careers of Arthur C. Clarke and Stanley Kubrick. Clarke is shown to have been a homosexual or bisexual who explored same-sex desires in a number of his later fictions, whilst Kubrick is discussed as having a fascination with problematising normative masculinity and asserting, by contrast, the superior potency of his artistic vision. The alien monolith is interpreted as a visualisation of the masculine closet. Bowman’s encounter with the monolith in the extra-terrestrial hotel room is presented as a homosexual encounter that leads to the revelation of the sublimity of infantile polymorphous perversion. Finally, the film’s queer liberatory potential is understood to lie in its refusal to provide a didactic framework for a future form of normative sexuality

Theorising interprofessional pedagogic evaluation: framework for evaluating the impact of interprofessional CPD on practice change

This paper outlines the development of a conceptual framework to guide the evaluation of the impact of the pedagogy employed in continuing professional development for professionals in education, health and social care. The work is developed as part of the Centre for Excellence in Teaching and Learning: Interprofessional Learning across the Public Sector (CETL: IPPS) at the University of Southampton. The paper briefly outlines the field for pedagogic research and comments on the underpinning theories that have so far been used to guide research into interprofessional learning (IPL). It maps out the development of interprofessional CPD in its specific context as part of the CETL: IPPS with its links to a local authority undergoing service reorganisation and the role of the continuing professional development (CPD) in effecting change. It then brings together a theoretical framework with the potential toexplore, explain and evaluate the essential features of the model of pedagogy used in interprofessional CPD, in which professionals from education have for the first time been included alongside those from health and social care. The framework draws upon elements of situated learning theory, Activity Theory and Dreier’s work (2002, 1999) on trajectories of participation, particularly Personal Action Potency. By combining the resulting analytic framework with an adapted version of an established evaluation model, a theoretically-driven, practicable evaluation matrix is developed. The matrix has potential use in evaluating the impact of pedagogic input on practice change. The paper models a process for developing a conceptual framework to steer pedagogic evaluation. Such a process and the resulting matrix may be of use to other researchers who are similarly developing pedagogic evaluation