Toward System Change to Tackle Antimicrobial Resistance: Improving the Voluntary Stewardship of Antimicrobials in US Agriculture

From Executive Summary:This report presents the details of a research study looking at the potential for improving voluntary stewardship of antimicrobials in US agriculture, in the interests of tackling antimicrobial resistance (AMR). Failure to address AMR could lead to significant impacts on both human and animal health. Voluntary stewardship is an approach that relies on the willingness of food-animal producers and supportive industries (e.g., veterinary services and pharmaceutical companies), as well as broader stakeholders (e.g., public health policymakers and consumer advocates), to ensure the judicious use of antimicrobials without the need for regulation, legislation, mandatory compliance or statutory enforcement

WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop

beta-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity2617993FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/50724-5; 2016/17469-0M.B.M. acknowledges support from the NIH (RO1-CA187799 and U24-DK116204-01). M.J.A. received financial support from NIH T32 Predoctoral Training Grants in Pharmacology (T32-GM007040-43 and T32-GM007040-42), an Initiative for Maximizing Student Diversity Grant (R25-GM055336-16), and the NIH National Cancer Institute (NCI) NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research (F31CA228289). M.P.W. received support from the Lymphoma Research Foundation (337444) and the NIH (T32-CA009156-35). Y.N. was supported by grants-in-aid from the Japan Society for the Promotion of Science (JSPS) (15KK0356 and 16K11493). T.T. was supported by the Howard Hughes Medical Institute Gilliam Fellowship for Advanced Study. M.V.G. was supported by Cancer Research UK (grants C7379/A15291 and C7379/A24639 to Mariann Bienz). The UNC Flow Cytometry Core Facility is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center, and research reported in this publication was supported by the Center for AIDS Research (award number 5P30AI050410), and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada, the Innovative Medicines Initiative (European Union [EU]/European Federation of Pharmaceutical Industries and Associations [EFPIA]) (ULTRA-DD grant no. 115766), Janssen, Merck & Company, Merck KGaA, Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, the São Paulo Research Foundation (FAPESP) (2013/50724-5), Takeda, and the Wellcome Trust (106169/ZZ14/Z). R.R.R. received financial support from FAPESP (2016/17469-0). We would also like to thank Claire Strain-Damerell and Pavel Savitsky for cloning various mutants of AAK1 and BMP2K proteins that were used in the crystallization trials. Additionally, we thank Dr. Sean Conner for providing the AAK1 plasmids, Dr. Stephane Angers for kindly providing the HEK293T DVL TKO cells, and Dr. Mariann Bienz for providing comments and feedback. We would like to thank members of the Major laboratory for their feedback and expertise regarding experimental design and project directio

UMW Theatre Remote Production of William Shakespeare\u27s Much Ado About Nothing

Beatrice and Benedick are meant for each other. Trouble is, they don’t see it that way. In one of Shakespeare’s wittiest and most romantic of comedies, mistaken identities, misdirected insults, devious fakery, and bumbling antics prove no match for the effervescent power of love. Will calculated swooning and conniving mischief succeed to find Beatrice and Benedick falling madly for each other, or will it all simply amount to Much Ado About Nothing? When campus closed on March 12 in order to transition to online learning in light of the rise of COVID-19, UMW Theatre was deep into preparation for the final offering of it’s 2019-20 season, Much Ado About Nothing by William Shakespeare. When there was a chance that we might return to in person classes on April 6, the faculty decided to put the production on hold and make arrangements for a delayed opening once classes resumed. When UMW announced that classes would remain online for the remainder of the academic year, the faculty and staff decided to present a performance of Much Ado About Nothing online. Gregg Stull, professor of theatre and chair of the department met with the Much Ado company on March 19 to share the plans. Rehearsals resumed on March 23. The cast presented a live stream performance on April 16 to a crowd of more than 1500 viewers watching from 37 states, Puerto Rico, the District of Columbia and five states. Within 24 hours of being posted as an on demand performance on YouTube, more than 2000 people have watched the UMW Theatre production of Much Ado. From the start of the production process until the performance, 107 UMW students contributed to bringing Much Ado About Nothing to life