A regional model of interprofessional education

This paper describes the innovative features of the first regional model of interprofessional education (IPE) in the US, developed by The Commonwealth Medical College, Scranton, PA, USA, as a new, independent, community-based medical school in northeastern Pennsylvania. Essential educational components include collaborative care seminars, interprofessional sessions, simulations, live web-based seminars and newly innovative virtual environment interactive exercises. All of these elements are being integrated into the curricula of 14 undergraduate and allied professional schools, and three graduate medical education programs located in the region. Activities incorporate simulation, standardized patients, student leadership, and faculty and student facilitation. As this new regional model of interprofessional education is fully implemented, its impact will be assessed using both quantitative and qualitative outcomes measurements. Appropriate ongoing modifications to the model will be made to ensure improvement and further applicability to collaborative learning

Scaling of the Nucleation Rate and a Monte Carlo Discrete Sum Approach to Water Cluster Free Energies of Formation

The intent of this work is to examine small cluster discrete size effects and their effect on the free energy of cluster formation. There is evidence that such terms can cancel in part the temperature dependence of the monomer flux factor of the classical nucleation rate and result in a scaled form for the nucleation rate. In this work, Monte Carlo configurational free energy differences between neighboring sized n molecule TIP4P water clusters are calculated and used in a Monte Carlo discrete summation (MCDS) technique to generate steady-state nucleation rates. The free energy differences, when plotted versus n-1/3, show evidence of a bulklike effective surface tension for n ≥ 10, and for the range of T examined the free energy differences appear to scale in temperature like (Tc/T - 1). This scaling can provide estimates of nucleation rates for arbitrary temperatures within the range of T simulated. Nucleation rates generated from the model TIP4P free energy differences are compared with the experimental water nucleation rate data of Wölk and Strey (J. Chem. Phys. 2001, 105, 11683) and with the data of Miller et al. (J. Chem. Phys. 1983, 78, 3204). The TIP4P MCDS results provide some evidence of the cancellation effect and generate the scaling of the nucleation rate data at higher temperatures. The magnitudes of the nucleation rates are, however, too large by a factor of 104. Other discrete sum models are also presented and give similar results

Intrinsic relative activities of κ opioid agonists in activating Gα proteins and internalizing receptor: Differences between human and mouse receptors

Several investigators recently identified biased κ opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [(35)S]GTPγS binding and KOP receptor internalization as measures of activation of G protein and β-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation (RAi-G) and receptor internalization (RAi-I) and the degree of functional selectivity between the two [Log RAi-G - logRAi-I, RAi-G/RAi-I and bias factor]. The parameter, RAi, represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1-17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12-epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed

Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in kappa opioid aversion.

Kappa opioid receptor (KOR) agonists produce analgesic and anti-pruritic effects, but their clinical application was limited by dysphoria and hallucinations. Nalfurafine, a clinically used KOR agonist, does not cause dysphoria or hallucinations at therapeutic doses in humans. We found that in CD-1 mice nalfurafine produced analgesic and anti-scratch effects dose-dependently, like the prototypic KOR agonist U50,488H. In contrast, unlike U50,488H, nalfurafine caused no aversion, anhedonia, or sedation or and a low level of motor incoordination at the effective analgesia and anti-scratch doses. Thus, we established a mouse model that recapitulated important aspects of the clinical observations. We then employed a phosphoproteomics approach to investigate mechanisms underlying differential KOR-mediated effects. A large-scale mass spectrometry (MS)-based analysis on brains revealed that nalfurafine perturbed phosphoproteomes differently from U50,488H in a brain-region specific manner after 30-min treatment. In particular, U50,488H and nalfurafine imparted phosphorylation changes to proteins found in different cellular components or signaling pathways in different brain regions. Notably, we observed that U50,488H, but not nalfurafine, activated the mammalian target of rapamycin (mTOR) pathway in the striatum and cortex. Inhibition of the mTOR pathway by rapamycin abolished U50,488H-induced aversion, without affecting analgesic, anti-scratch, and sedative effects and motor incoordination. The results indicate that the mTOR pathway is involved in KOR agonist-induced aversion. This is the first demonstration that phosphoproteomics can be applied to agonist-specific signaling of G protein-coupled receptors (GPCRs) in mouse brains to unravel pharmacologically important pathways. Furthermore, this is one of the first two reports that the mTOR pathway mediates aversion caused by KOR activation