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No pharmacy program, however well-resourced, has sufficient time or resources to teach students all current, practice-relevant knowledge. And while the volume of potential pharmacy education curriculum content increases exponentially each year, available time for direct instruction continues to decline. Given these constraints, pharmacy curricula must focus on promoting deep learning of the most critical, fundamental, broadly applicable, and lasting knowledge. Yet, in terms of didactic knowledge, pharmacy education currently has no agreed upon, evidence-based criteria for determining which foundational concepts are most important to teach nor any research-based assessment tools to demonstrate how well students have learned those core concepts.This lack of consensus regarding core conceptual knowledge makes disparities in learning outcomes both more likely to occur and less likely to be detected or addressed. Over the past 30 years, several scientific disciplines undergirding pharmacy have developed research-based lists of core concepts and related concept inventories, demonstrating their transformative educational potential. Core concepts are big, fundamental ideas that experts agree are critical for all students in their discipline to learn, remember, understand, and apply. Concept inventories are research-based, psychometrically validated, multiple-choice tests designed to uncover learners' prior knowledge and potential misconceptions and determine their depth of understanding of disciplinary core concepts.This commentary proposes adapting and applying this evidence-based core concepts approach to enhance pharmacy education's overall effectiveness and efficiency and outlines an ongoing, multinational research initiative to identify and define essential pharmacy concepts to be taught, learned, and assessed.

Objective Tegaserod is a 5-hydroxytryptamine type 4 (5-HT4) receptor agonist, formerly used in treating constipation predominant irritable bowel syndrome, which desensitizes 5-HT4 receptors in rat oesophagus and colon in vitro. Desensitization of 5-HT4 receptors is regulated by G-protein coupled receptor kinases. This study was designed to assess the effect of 5-HT4 receptor activation on the expression of GRK2 and GRK6 in the rat oesophagus and distal colon by acute administration of tegaserod. Results Rats were treated with a single dose of tegaserod (5 mg/kg) and tissue samples of the oesophagus and distal colon were prepared and level of GRK2 and GRK6 protein expression was determined using western blotting. The immunodensity of GRK2 and GRK6 was normalized against the loading control β-actin and compared with control animals. Acute administration of tegaserod for 1, 2, 3, 4, 6, and 8 h did not change significantly the immunodensity of GRK2 or GRK6 in the oesophagus or GRK2 in the distal colon when compared with control animals. This may indicate that the basal level of GRK2 and GRK6 expression is sufficient to regulate the desensitization of 5-HT4 receptors in acute drug treatment.

Problem solving is a fundamental skill that chemistry graduates should possess, yet many students have difficulties solving problems in chemistry. These difficulties may be either student- or instructor-driven. Instructor-related difficulties could stem from some teaching practices, such as expecting students to apply procedures without requiring them to show their reasoning or solely focusing on worked examples. Such practices could inhibit the development of problem-solving skills. To address these challenges, our group developed a metacognitive scaffold (Goldilocks Help) to support both students and instructors through structured problem solving. This scaffold breaks down the problem-solving process into phases and places emphasis on reasoning required throughout that process. This study explored how teaching associates (TAs) used the problem-solving scaffold and how this practice affected their teaching and perceptions of student learning. Seven TAs based at a large research-intensive Australian university were interviewed, and the data were analysed using the framework approach. Teaching with the problem-solving scaffold was found to be beneficial, albeit with initial student resistance. The scaffold provided a common thinking structure between the TAs and students, enabling TAs to easily identify mistakes and address specific areas of concern. However, TAs also experienced students’ attention shift from content to the scaffold. Initially, many students unproductively viewed the process as requiring two separate actions of solving the problem and being explicit about the problem-solving process they used, as opposed to an integrated activity. Through constant reinforcement and prompting by TAs during and prior to solving the problem, students continued to grasp how to effectively internalise the scaffold to assist their problem solving. Understanding how TAs use problem-solving scaffolds with students will add to the field of education research to inform innovations in supporting the development of students’ problem-solving skills.

In recent decades, a focus on the most critical and fundamental concepts has proven highly advantageous to students and educators in many science disciplines. Pharmacology, unlike microbiology, biochemistry, or physiology, lacks a consensus list of such core concepts.We sought to develop a research-based, globally relevant list of core concepts that all students completing a foundational pharmacology course should master. This two-part project consisted of exploratory and refinement phases. The exploratory phase involved empirical data mining of the introductory sections of five key textbooks, in parallel with an online survey of over 200 pharmacology educators from 17 countries across six continents. The refinement phase involved three Delphi rounds involving 24 experts from 15 countries across six continents.The exploratory phase resulted in a consolidated list of 74 candidate core concepts. In the refinement phase, the expert group produced a consensus list of 25 core concepts of pharmacology.This list will allow pharmacology educators everywhere to focus their efforts on the conceptual knowledge perceived to matter most by experts within the discipline. Next steps for this project include defining and unpacking each core concept and developing resources to help pharmacology educators globally teach and assess these concepts within their educational contexts.

Pharmacology education currently lacks a research‐based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC‐PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory—a valid and reliable tool to assess learner attainment of concepts. In the current study, CC‐PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug–response. First, a one‐sentence definition was developed for each core concept. Next, sub‐concepts were established for each core concept. These twenty core concepts, along with their respective definitions and sub‐concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning., The second stage of development of core concepts of pharmacology education; defining each concept, and unpacking the concept by articulation of sub‐concepts.

Whilst curriculum revision is commonplace, whole degree transformation is less so. In this paper we discuss the rationale, design and implementation of a unique pharmacy program by a research-intensive faculty. The new Monash pharmacy curriculum, which had its first intake in 2017, was built using a range of key innovations that aimed to produce graduates that demonstrate key conceptual understanding and all the skills required to deliver world-best patient outcomes. The key elements of the re-design are outlined and include the process and principles developed, as well as key features such as a student-centred individualised program of development arranged around specific, authentic tasks for each skill and earlier enhanced experiential placements where students become proficient in entrustable professional activities. It is hoped the dissemination of this process, as well as the lessons learnt in the process, will be useful to others looking to transform a health curriculum.

Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion‐based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology., Over 50 pharmacology educators from Australia and New Zealand worked together to identify the core concepts of pharmacology education. The figure shows the 19 concepts identified and the process taken to produce this list

The adenosine A2B receptor (A2BAR) is one of four adenosine receptor subtypes belonging to the Class A family of G protein-coupled receptors (GPCRs). Until recently, the A2BAR remained poorly characterised, in part due to its relatively low affinity for the endogenous agonist adenosine and therefore presumed minor physiological significance. However, the substantial increase in extracellular adenosine concentration, the sensitisation of the receptor and the upregulation of A2BAR expression under conditions of hypoxia and inflammation, suggest the A2BAR as an exciting therapeutic target in a variety of pathological disease states. Here we discuss the pharmacology of the A2BAR and outline its role in pathophysiology including ischaemia-reperfusion injury, fibrosis, inflammation and cancer.

Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal haemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+ influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signalling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted haemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.ONE-SENTENCE SUMMARYBiased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A1 adenosine receptor ligands.

In 2017, a revamped bachelor of pharmacy program was introduced at Monash University and incorporated a predominantly flipped classroom-based pedagogy. The attitudes and preferences of students towards this program had yet to be assessed using a reliable instrument. Since no instrument was readily available, the objective of this study was to identify, contextualize, and validate a suitable instrument.We conducted a literature search to identify and adapt a validated instrument. Cognitive interviews were conducted to examine students' understanding of scales and definitions of items. The instrument was then evaluated by education experts for further refinement. The reliability of the final instrument was assessed in a cohort of students, and unsuitable items were removed.Students had issues understanding the scales and specific terms used in the original instrument, potentially due to differences in terminologies used in the university's context and variance in English proficiency levels and exposure. In the preference domain, wording of the instrument to present exclusively traditional classroom or exclusively flipped classroom statements greatly influenced its reliability. This could be due to exposure of students to a predominantly flipped classroom environment since inception. The final instrument optimized in this study had α = 0.85, 0.86, and 0.9 for the pre-activities, in-class lectures, and in-class workshops attitude domains, respectively, and α = 0.73 for the preference domain.Our study highlights the necessity of contextualizing instruments to fit the local context in which they are administered and provides key recommendations when conducting such adaptations.

The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

Delivery of plasmids for gene expression in vivo is an inefficient process that requires improvement and optimization to unlock the clinical potential of DNA vaccines. With ease of manufacture and biocompatibility in mind, we explored condensation of DNA in aqueous solution with a self-crosslinking, endosome-escaping lipopeptide (LP), stearoyl-Cys-His-His-Lys-Lys-Lys-amide (stearoyl-CH2K3), to produce cationic LP/DNA complexes. To test whether poly(ethylene glycol) (PEG)-ylation of these cationic complexes to neutralize the surface charge would improve the distribution, gene expression, and immune responses poly(ethylene glycol), these LP/DNA complexes were combined with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000). Fluorescence imaging illustrated that the cationic complexes exhibited the highest degree of localization and lowest degree of dispersion throughout the injected muscle, suggesting impaired mobility of cationic particles upon administration. Nanoluciferase reporter assays over a 90-day period demonstrated that gene expression levels in muscle were highest for PEGylated particles, with over a 200-fold higher level of expression than the cationic particles observed at 30 days. Humoral and cell-mediated immune responses were evaluated in vivo after injection of an ovalbumin expression plasmid. PEGylation improved both immune responses to the DNA complexes in mice. Overall, this suggests that PEGylation of cationic lipopeptide complexes can significantly improve both the transgene expression and immunogenicity of intramuscular DNA vaccines., Graphical Abstract

The adenosine A1 receptor (A1AR) is a potential novel therapeutic target for myocardial ischemia-reperfusion injury. However, to date, clinical translation of prototypical A1AR agonists has been hindered due to dose limiting adverse effects. Recently, we demonstrated that the biased bitopic agonist 1, consisting of an adenosine pharmacophore linked to an allosteric moiety, could stimulate cardioprotective A1AR signaling in the absence of unwanted bradycardia. Therefore, this study aimed to investigate the structure–activity relationship of compound 1 biased agonism. A series of novel derivatives of 1 were synthesized and pharmacologically profiled. Modifications were made to the orthosteric adenosine pharmacophore, linker, and allosteric 2-amino-3-benzoylthiophene pharmacophore to probe the structure–activity relationships, particularly in terms of biased signaling, as well as A1AR activity and subtype selectivity. Collectively, our findings demonstrate that the allosteric moiety, particularly the 4-(trif...

Adenosine modulates many aspects of human physiology and pathophysiology through binding to the adenosine family of G protein-coupled receptors, which are comprised of four subtypes, the A1R, A2AR, A2BR and A3R. Modulation of adenosine receptor function by exogenous agonists, antagonists and allosteric modulators can be beneficial for a number of conditions including cardiovascular disease, Parkinson's disease, and cancer. Unfortunately, many preclinical drug candidates targeting adenosine receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning adenosine receptor ligands into the clinic, research efforts have focussed on exploiting the phenomenon of biased agonism. Biased agonism provides the opportunity to develop ligands that favour therapeutic signalling pathways, whilst avoiding signalling associated with on-target undesired effects. Recent studies have begun to define the structure-function relationships that underpin adenosine receptor biased agonism and establish how this phenomenon can be harnessed therapeutically. In this review we describe the recent advancements made towards achieving therapeutically relevant biased agonism at adenosine receptors.

In this study we determined the in vivo activity of model ovalbumin vaccines delivered by direct intramuscular delivery of plasmid DNA or oral delivery using a recombinant suicidal Listeria monocytogenes strain (rsΔ2). In a previous report we described how rsΔ2 is capable of delivering luciferase, as protein or DNA, in vitro, into non-dividing intestinal epithelial cells (Kuo et al., 2009). This is achieved by engineering a dual expression shuttle vector, pDuLX-Luc, that replicates in E. coli and rsΔ2 and drives gene expression from the Listeria promoter (Phly) as well as the eukaryotic cytomegalovirus promoter (CMV), thereby delivering both protein and plasmid DNA to the cell cytoplasm. For the current in vivo study rsΔ2 containing pDuLX-OVA was used to deliver both ovalbumin protein and the mammalian expression plasmid by the oral route. Controls were used to investigate the activity of this system versus positive and negative controls, as well as quantifying activity against direct intramuscular injection of expression plasmids. Oral administration of rsΔ2(pDuLX-OVA) produced significant titres of antibody and was effective at inducing targeted T-cell lysis (approximately 30% lysis relative to an experimental positive control, intravenous OVA-coated splenocytes+lipopolysaccharide). Intramuscular injection of plasmids pDuLX-OVA or p3L-OVA (which lacks the prokaryotic promoter) also produced significant CTL-mediated cell lysis. The delivery of the negative control rsΔ2 (pDuLX-Luc) confirmed that the observed activity was induced specifically by the ovalbumin vaccination. The data suggest that the oral activity of rsΔ2(pDuLX-OVA) is explained by delivery of OVA protein, expressed in rsΔ2 from the prokaryotic promoter present in pDuLX-OVA, but transfection of mammalian cells in vivo may also play a role. Antibody titres were also produced by oral delivery (in rsΔ2) of the p3L-OVA plasmid in which does not include a prokaryotic promoter.

The adenosine A2B receptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson). Capadenoson, currently classified as an adenosine A1 receptor (A1AR) partial agonist, has undergone two Phase IIa clinical trials, initially in patients with atrial fibrillation and subsequently in patients with stable angina. Capadenoson has also been shown to decrease cardiac remodeling in an animal model of advanced heart failure and a capadenoson derivative, neladenoson bialanate, recently entered clinical development for the treatment of chronic heart failure. The therapeutic effects of capadenoson are currently thought to be mediated through the A1AR. However, the ability of capadenoson to stimulate additional adenosine receptor subtypes, in particular the A2BAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant A2BAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the A2BAR. Relative to the non-selective adenosine receptor agonist NECA, capadenoson was a biased A2BAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous A2BAR expression. These findings suggest the reclassification of capadenoson as a dual A1AR/A2BAR agonist. Furthermore, a potential A2BAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the A2BAR can promote cardioprotection and modulate cardiac fibrosis in heart disease.

The A1 adenosine receptor (A1AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A1AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay. Insensitivity to antagonist addition in a real-time, label-free, xCELLigence assay was subsequently used to identify compounds that likely mediated their agonism through an irreversible interaction with the A1AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A1AR using membrane-based [3H]DPCPX and [35S]GTPγS binding experiments.

The adenosine A

We present research on the development of diode-pumped solid-state lasers suitable for quantum technologies applications at 698.45 nm and 780.24 nm targeting strontium (Sr) and rubidium (Rb) transitions.

The development of affinities between the production and consumption of people and place is crucial for tourism development. We trouble front and backstage distinctions to examine how destinations are framed and critically explore the power of the imaginary in shaping how individuals apprehend and in turn create social worlds. Combining critical discourse analysis with stakeholder interviews, we scrutinise an influential television travel documentary as an instrument of cultural pedagogy, which recycles, recreates and re-enacts the tourism imaginary. The paper's distinctive contribution is to show the multiple means through which travel journalism enrols tourists through imagined portrayals of people and place within globalised cultural texts by highlighting the multi-dimensional workings of power in and through a framing of Northern Norway.

The adenosine A1 G protein-coupled receptor (A1AR) is an important therapeutic target implicated in a wide range of cardiovascular and neuronal disorders. Although it is well established that the A1AR orthosteric site is located within the receptor's transmembrane (TM) bundle, prior studies have implicated extracellular loop 2 (ECL2) as having a significant role in contributing to orthosteric ligand affinity and signaling for various G protein-coupled receptors (GPCRs). We thus performed extensive alanine scanning mutagenesis of A1AR-ECL2 to explore the role of this domain on A1AR orthosteric ligand pharmacology. Using quantitative analytical approaches and molecular modeling, we identified ECL2 residues that interact either directly or indirectly with orthosteric agonists and antagonists. Discrete mutations proximal to a conserved ECL2-TM3 disulfide bond selectively affected orthosteric ligand affinity, whereas a cluster of five residues near the TM4-ECL2 juncture influenced orthosteric agonist efficacy. A combination of ligand docking, molecular dynamics simulations, and mutagenesis results suggested that the orthosteric agonist 5'-N-ethylcarboxamidoadenosine binds transiently to an extracellular vestibule formed by ECL2 and the top of TM5 and TM7, prior to entry into the canonical TM bundle orthosteric site. Collectively, this study highlights a key role for ECL2 in A1AR orthosteric ligand binding and receptor activation.

VCP746 is a novel A1 adenosine receptor (A1AR) biased agonist previously shown to be cytoprotective with no effect on heart rate. The aim of this study was to investigate the potential anti-hypertrophic effect of VCP746 in neonatal rat cardiac myocytes (NCM). NCM hypertrophy was stimulated with IL-1β (10 ng/mL), TNF-α (10 ng/mL) or Ang II (100 nM) and was assessed by 3H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by 3H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1AR agonist, N6-cyclopentyladenosine (CPA). Further investigation with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay showed that neither CPA nor VCP746 had any effect on cell viability, confirming that the reduction in 3H-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1β, TNF-α and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, β-MHC and α-SKA in NCM. Treatment with VCP746 at concentrations as low as 1 nM suppressed mRNA expression of ANP, β-MHC and α-SKA stimulated by IL-1β, TNF-α or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A1AR agonist, VCP746, is able to attenuate cardiac myocyte hypertrophy. As such, VCP746 is potentially useful as a pharmacological agent in attenuating cardiac remodelling, especially in the post-myocardial infarction setting, given its previously established cytoprotective properties. This article is protected by copyright. All rights reserved.

The mining industry is known for leaving dramatic landscapes in its wake, and among these are the workings hidden below the surface. As dangerous places, underground mines exerted important holds over community life and shaped the formation of mining identities. Despite this centrality to the mining life, historical archaeological research underground remains limited because the hazards have never dissipated. This article establishes prospective ground for the archaeology of underground mines, taking its lead from several pioneering studies in order to better assess the nature of recoverable archaeological information. In particular, it is argued that the material evidence from the workplace enables localized insights into scalar transformations occurring in the industry, the cultures of work practice, and the mechanisms by which miners coped with uncertain environments. This article also considers strategies by which future investigations might safely proceed.

Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A2B receptor (A2BAR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A2BAR signal transduction. The contribution of A2BAR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A2BAR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A2BAR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O2). The A2BAR inverse agonists, ZM241385 [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol] or PSB-603 (8-(4-(4-(4-chlorophenyl)piperazide-1-sulfonyl)phenyl)-1-propylxanthine), mediated a concentration-dependent decrease in baseline cAMP levels in both cellular systems. Proliferation of multiple prostate cancer cell lines was also attenuated in the presence of PSB-603. Importantly, both the decrease in baseline cAMP accumulation and the reduction of proliferation were not influenced by the addition of adenosine deaminase, demonstrating that these effects are not dependent on stimulation of A2BARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A2BARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A2BAR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A2BAR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

Objective. To examine the effects of student demographics, prior academic performance, course engagement, and time management on pharmacy students’ performance on course examinations and objective structured clinical examinations (OSCEs). Methods. Study participants were one cohort of pharmacy students enrolled in a five-year combined Bachelor and Master of Pharmacy degree program at one institution. Variables included student demographics, baseline factors (language assessment and situational judgement test scores), prior academic performance (high school admission rank), course engagement, and student time management of pre-class online activities. Data were collected from course, learning management system, and institutional databases. Data were analyzed for univariate, bivariate, and multivariate associations (four linear regression models) between explanatory factors and outcome variables. Results. Three years of data on 159 pharmacy students were obtained and entered in the dataset. Significant positive predictors of OSCE communication performance included domestic (ie, Australian) student designation, higher baseline written English proficiency, and pre-class online activity completion. Positive predictors of OSCE problem-solving included workshop attendance and low empathy as measured by a baseline situational judgment test (SJT). Positive predictors of performance on year 2 end-of-course examinations included the Australian Tertiary Academic Rank, completing pre-class online activities prior to lectures, and high integrity as measured by an SJT. Conclusion. Several explanatory factors predicted pharmacy students’ examination and OSCE performance in the regression models. Future research should continue to study additional contexts, explanatory factors, and outcome variables.

Clinical guidelines increasingly emphasise the importance of comprehensive and holistic care for older people. The objective of this education brief is to describe a workshop designed to improve first year pharmacy students' empathy and attitudes towards older people.A two-hour, interactive, university-based workshop was developed and evaluated. Small groups of first year pharmacy students (approximately five per group) worked with an older person to complete a number of scaffolded activities focused on the older person's life experiences with pharmacy and medication usage. The effectiveness of this intervention was measured using an eight-item, pre- and post-workshop survey adapted from published scales.Engaging older people as university-based instructors for first year pharmacy students was associated with significant improvements in three of the eight attitudinal items. Following the workshop, students were more likely to report that older people are: pleasant to be with (p 0.001), more likely to understand what it feels like to have problems with aging (p 0.005) and less likely to believe older people become less organised and more confused as they age (p 0.001).Engaging older people as university-based instructors for first year pharmacy students may be a useful strategy to develop empathy and positive attitudes towards older people. Further research is needed to determine if the attitudinal improvements are sustained over time.

Tegaserod is a 5-hydroxytryptamine type 4 (5-HTRats were treated with a single dose of tegaserod (5 mg/kg) and tissue samples of the oesophagus and distal colon were prepared and level of GRK2 and GRK6 protein expression was determined using western blotting. The immunodensity of GRK2 and GRK6 was normalized against the loading control β-actin and compared with control animals. Acute administration of tegaserod for 1, 2, 3, 4, 6, and 8 h did not change significantly the immunodensity of GRK2 or GRK6 in the oesophagus or GRK2 in the distal colon when compared with control animals. This may indicate that the basal level of GRK2 and GRK6 expression is sufficient to regulate the desensitization of 5-HT

Student engagement during classes includes behavioural, cognitive and emotional components, and is a pre-requisite for successful active learning environments. A novel approach to measuring student engagement was developed, involving triangulation of real-time student-self report, observation by trained observers and heart rate measurement. The self-report instrument was evaluated in four separate cohorts (n = 123) at Monash University and the University of North Carolina. The six item self-report demonstrated good reliability (Cronbach’s alpha values ranged from 0.7–0.81). The self-report showed predictive validity in that small group activities were rated as significantly more engaging than didactic lecturing. Additionally, there was significant inter-instructor variability and within-class variability, indicating good discrimination between classroom activities. This self-report may prove useful to academic teaching staff in evaluating and refining their active learning activities. Independent observation was not found to correlate with student self-report, due in part to students who were pretending to engage being rated as engaged by an observer. Strikingly, students reported that they were pretending to engage for 23% of class time, even for highly regarded instructors. Individual participants were rated as engaged for 42 of the 46 intervals for which they reported that they had “pretended to engage”, indicating that the two observers were unable to detect disengagement during periods in which students pretended to engage. Instructors should be aware that student cues such as eye contact and nodding may indicate pretending to engage. One particular self-report item; “I tried a new approach or way of thinking about the content”, correlated positively with heart rates, and a controlled study reproduced this finding during two activities that required students to try a new approach to understanding a concept. Agreement with this item also correlated with superior performance on two in-class written assessment tasks (n = 101, p

Adenosine receptors are a family of GPCRs containing four subtypes (A(1), A(2A), A(2B) and A(3) receptors), all of which bind the ubiquitous nucleoside adenosine. These receptors play an important role in physiology and pathophysiology and therefore represent attractive drug targets for a range of conditions. The theoretical framework surrounding drug action at adenosine receptors now extends beyond the notion of prototypical agonism and antagonism to encompass more complex pharmacological concepts. New paradigms include allostery, in which ligands bind a topographically distinct receptor site from that of the endogenous agonist, homomeric or heteromeric interactions across receptor oligomers and biased agonism, that is, ligand‐dependent differential intracellular signalling. This review provides a concise overview of allostery, oligomerization and biased agonism at adenosine receptors and outlines how these paradigms may enhance future drug discovery endeavours focussed on the development of novel therapeutic agents acting at adenosine receptors. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc