Analyzing kinetic signaling data for G-protein-coupled receptors

In classical pharmacology, bioassay data are fit to general equations (e.g. the dose response equation) to determine empirical drug parameters (e.g. EC50 and Emax), which are then used to calculate chemical parameters such as affinity and efficacy. Here we used a similar approach for kinetic, time course signaling data, to allow empirical and chemical definition of signaling by G-protein-coupled receptors in kinetic terms. Experimental data are analyzed using general time course equations (model-free approach) and mechanistic model equations (mechanistic approach) in the commonly-used curve-fitting program, GraphPad Prism. A literature survey indicated signaling time course data usually conform to one of four curve shapes: the straight line, association exponential curve, rise-and-fall to zero curve, and rise-and-fall to steady-state curve. In the model-free approach, the initial rate of signaling is quantified and this is done by curve-fitting to the whole time course, avoiding the need to select the linear part of the curve. It is shown that the four shapes are consistent with a mechanistic model of signaling, based on enzyme kinetics, with the shape defined by the regulation of signaling mechanisms (e.g. receptor desensitization, signal degradation). Signaling efficacy is the initial rate of signaling by agonist-occupied receptor (kτ), simply the rate of signal generation before it becomes affected by regulation mechanisms, measurable using the model-free analysis. Regulation of signaling parameters such as the receptor desensitization rate constant can be estimated if the mechanism is known. This study extends the empirical and mechanistic approach used in classical pharmacology to kinetic signaling data, facilitating optimization of new therapeutics in kinetic terms

Increase Employee Engagement by Using the Finding Joy at Work Framework to Identify and Remedy Items that Remove Joy from our Work Life

Improving engagement scores within MaineHealth Corporate has been a focus for a number of years. The most recent data has shown a marked improvement from 2014 to 2017, moving us to the 49th percentile, but the MaineHealth goal is to bring us to the 75th percentile so there is still work to be done. The Institute for Healthcare Improvement offers training in “Finding and Creating Joy at Work”, a framework for identifying “pebbles in your shoes” that detract from your joy at work, finding and addressing the underlying root causes. We would like to use that framework to find and alleviate things that remove joy in our daily work lives in our department, therefore improving engagement and happiness at work

PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity

Transient receptor potential canonical 6 (TRPC6) is a cation selective, DAG-regulated, Ca2+-permeable channel activated by the agonists of Gq-protein-coupled heptahelical receptors. Dysfunctions of TRPC6 are implicated in the pathogenesis of various cardiovascular and kidney conditions such as vasospasm and glomerulosclerosis. When stimulated by agonists of the histamine H1 receptor (H1R), TRPC6 activity decays to the baseline despite the continuous presence of the agonist. In this study, we examined whether H1R desensitization contributes to regulating the decay rate of TRPC6 activity upon receptor stimulation. We employed the HEK expression system and a biosensor allowing us to simultaneously detect the changes in intracellular diacylglycerol (DAG) and Ca2+ concentrations. We found that the histamine-induced DAG response was biphasic, in which a transient peak was followed by maintained elevated plateau, suggesting that desensitization of H1R takes place in the presence of histamine. The application of PKC inhibitor Gö6983 slowed the decay rate of intracellular DAG concentration. Activation of the mouse H1R mutant lacking a putative PKC phosphorylation site, Ser399, responsible for the receptor desensitization, resulted in a prolonged intracellular DAG increase and greater Mn2+ influx through the TRPC6 channel. Thus, our data support the hypothesis that PKC-dependent H1R phosphorylation leads to a reduced production of intracellular DAG that contributes to TRPC6 activity regulation

The Grizzly, February 13, 2003

Iraqi Speaker Describes his Country as a Prison of Suffering • Ursinus Student Heroes 30 Years Ago • To Fight or not to Fight: You May not Have the Option • Opinions: Skiing Fun Close to Home; Lonely this Valentine\u27s Day? • Female Pride, Guerrilla Warfare • First of Pew Fellows Speaks • Francis Moore Lappe to Visit Ursinus on February 19th • Ursinus Swimmers Look Towards Champions Meet • Men\u27s Basketball Dominate Centennial Conference • Track Handling Business Indoors • Women\u27s Basketball Can\u27t Find the Right Touchhttps://digitalcommons.ursinus.edu/grizzlynews/1529/thumbnail.jp

The Grizzly, March 6, 2003

Preparing for the Future Today: Job and Internship Fair 2003 • The Art of Kissing • Trading the Beach for Hard Work • Celebrating Women\u27s History Month with Ursinus Legends • Showcasing Women\u27s Pride in Berman • Bloody Poetry Director Speaks Out • Women\u27s History Month Events • Centennial Conference Champions! • UC Swimmers Make a Splash • Ykoruk Named Women\u27s Head Soccer Coachhttps://digitalcommons.ursinus.edu/grizzlynews/1531/thumbnail.jp

The Grizzly, February 6, 2003

Fallen Heroes: Space Shuttle Columbia Disaster • Best Buddies Goes Under da Sea • A New Semester Means New Members for Ursinus Greeks • The World Beyond Ursinus: Study Abroad Experience • Plans in Progress: Contemporary Design Class Visits NYC • The Hunt for J.D. Salinger: Ursinus\u27 Most Mysterious Alumnus • Spring Break from Winter Fashions • Beat of a Different Drummer • D.C. Demonstration: First Hand Account • Fallen Angels: East Asian Film Introduction • Pledging in the Past • Bridget Hussey Scores 1,000 • Strong Season for Men\u27s Basketball • Women\u27s Basketball Having Ups and Downs • Nolan Named Honorable Mentionhttps://digitalcommons.ursinus.edu/grizzlynews/1528/thumbnail.jp

Cost-effectiveness of adrenaline for out-of-hospital cardiac arrest

Abstract: Background: The ‘Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration In Cardiac Arrest’ (PARAMEDIC2) trial showed that adrenaline improves overall survival, but not neurological outcomes. We sought to determine the within-trial and lifetime health and social care costs and benefits associated with adrenaline, including secondary benefits from organ donation. Methods: We estimated the costs, benefits (quality-adjusted life years (QALYs)) and incremental cost-effectiveness ratios (ICERs) associated with adrenaline during the 6-month trial follow-up. Model-based analyses explored how results altered when the time horizon was extended beyond 6 months and the scope extended to include recipients of donated organs. Results: The within-trial (6 months) and lifetime horizon economic evaluations focussed on the trial population produced ICERs of £1,693,003 (€1,946,953) and £81,070 (€93,231) per QALY gained in 2017 prices, respectively, reflecting significantly higher mean costs and only marginally higher mean QALYs in the adrenaline group. The probability that adrenaline is cost-effective was less than 1% across a range of cost-effectiveness thresholds. Combined direct economic effects over the lifetimes of survivors and indirect economic effects in organ recipients produced an ICER of £16,086 (€18,499) per QALY gained for adrenaline with the probability that adrenaline is cost-effective increasing to 90% at a £30,000 (€34,500) per QALY cost-effectiveness threshold. Conclusions: Adrenaline was not cost-effective when only directly related costs and consequences are considered. However, incorporating the indirect economic effects associated with transplanted organs substantially alters cost-effectiveness, suggesting decision-makers should consider the complexity of direct and indirect economic impacts of adrenaline

The Grizzly, October 3, 2002

Students Show Parents Their Second Home: Family Day 2002 • Students Voice Opinions in Campus Terrorism Talk • Memory of Fountain Trickles Away • Davis Professor to Deliver Lectures for Students and Faculty • New Technical Director Brings Different View Behind the Scenes • Read All About it: Newspapers in the Bookstore • Opinions: Eminem: Good or Bad • Four Doors: A Memorial • Fun Historic Event: The Heritage Festival Held on the Wentz Farmstead • Women\u27s Rugby Score First try in Ursinus History • Dougherty Sprints to Second Place • Renovate Your Room by Swappin\u27 Suites • Comparative Pricing: Comfort Foodhttps://digitalcommons.ursinus.edu/grizzlynews/1521/thumbnail.jp

The Grizzly, October 10, 2002

The 2002 Homecoming Nominees • Former White House Aide Speaks at Ursinus • New Student Art in the Library • Students Riots at the University of Oregon • First Play of the Semester to Cure the Blues • New Meal Plan Hard to Swallow • Major Workshops for Sophomore Department Events Oct. 14-25 • Everyone\u27s Talking About the Music Man • Opinions: Family Day 2002 a Success; Ursinus and Marriage; Party Scene: UC vs. PSU Surprisingly Similar • Donald Meyer Art Exhibit in Berman Museum • Student Profile: Dana Mazzenga • Ursinus College Choir • CAB: Exciting Events for Campus • Women\u27s Rugby Continuing to Improve • Intramural Sports Start up Again • McCarney Named C.C. Player of the Week • Dougherty Races Back on Top • Comparing Prices: Halloween Costumes • Cancer Causing Foods: What to Avoid When You\u27re Eating • 3 Years at Ursinushttps://digitalcommons.ursinus.edu/grizzlynews/1522/thumbnail.jp

The Grizzly, September 26, 2002

Students Take on Wismer: Committee to Address Dining Issues • Pennsylvania Liquor Control Board: Coming to a Party Near You? • Slow Internet Fast Becoming a Problem • I Just Called to Say : UC Phone-a-thon • UCNet Available through Career Services • From Italy with Love: The Life of Students Abroad • Opinions: Taking the Plunge to Clean up the Environment; Sorority Life or Sorority Joke?; Are Rules Really Rules? • Berman Collects: Museum\u27s Permanent Collection Holds Wide Variety of Objects • Bears Football Falls to F&M • Field Hockey Dominates the Field • Women\u27s Soccer Drop Decisions to Widener, Gettysburg • UC Men\u27s Soccer Win Over DeSales, 2-1 • Dougherty Notches Third Victory of Season • Preview of Family Day 2002https://digitalcommons.ursinus.edu/grizzlynews/1520/thumbnail.jp