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Katherine Hu, 1, 2 Zhaowen Zhu, 1, 2 Meleah M Mathahs, 1, 2 Huy Tran, 1, 2 Jerry Bommer, 3, 4 Charles A Testa, 5 Warren N Schmidt 1, 2 1Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA; 2Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; 3Frontier Scientific, Logan, UT 84321, USA; 4Echelon Biosciences Inc, Salt Lake City, UT 84108, USA; 5Curza, Provo, UT and Cambridge, MA, USACorrespondence: Warren N SchmidtDepartment of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 4553 JCP, Iowa City, IA 52242, USATel +1 319 353-7048Fax +1 319 356-7918Email warren-schmidt@uiowa.eduBackground: Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure–activity relationships that may be useful for future drug design of HCV and related Flaviviruses.Methods: Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC 50 values in low micromolar ranges [CoPP (1.4 μM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 μM) = protoporphyrin].Results: Lineweaver–Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC 50 and IC 50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protop

?This is a book for everyone who wishes to contribute their unique gifts to the world.? ?Archbishop Desmond Tutu, Nobel Peace Laureate This brand new edition of a classic, international bestseller continues to bring keen insight to an important topic?workforce diversity. Written in a charming, engaging style, it is a contemporary corporate fable?a tale for our times. This special 20th anniversary edition includes many new tips, tools, and strategies for peacocks and penguins alike?as well as an entirely new bonus parable. Through the story of Perry the Peacock and his fine feathered friends, authors Gallagher and Schmidt bring to life the challenges of birds of different feathers who struggle to be successful in the conformity-minded Land of Penguins. Their travails illuminate the challenges of creating a pluralistic corporate culture in which the talent, energy, and commitment of all employees are fully engaged. People who have new ideas that differ from business as usual are often ignored or criticized for the very thing that makes them valuable: their originality and creativity. This unique book helps organizations break out of "penguin thinking? in order to tap into and leverage the creativity of diversity. Learn how to cultivate an organizational culture in which new ideas can flourish and innovation can take flight.

Zeid Kayali,1 Warren N Schmidt2,3 1Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, CA, USA; 2Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA; 3Roy G and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, USA Abstract: Chronic Hepatitis C virus (HCV) infection is the leading cause of advanced liver disease worldwide. The virus successfully evades host immune detection and for many years has hampered efforts to find a safe, uncomplicated, and reliable oral antiviral therapy. Initially, interferon and ribavirin therapy was the treatment standard of care, but it offered limited performance across the wide spectrum of HCV disease and was fraught with excessive and often limiting side effects. Sofosbuvir (SOF) is a potent first-in-class nucleoside inhibitor that has recently been approved for treatment of HCV. The drug has low toxicity, a high resistance barrier, and minimal drug interactions with other HCV direct-acting antiviral agents such as protease inhibitors or anti-NS5A agents. SOF is safe and can be used across different viral genotypes, disease stages, and special patient groups, such as those coinfected with human immunodeficiency virus. When used in combination with ribavirin or another direct-acting antiviral agent, SOF has revolutionized the HCV treatment spectrum and set the stage for nearly universal HCV antiviral therapy. More so than any other anti-HCV drug developed to date, SOF offers the widest applicability for all infected patients, and new regimens will be tailored to maximize performance. Keywords: Hepatitis C virus, sofosbuvir, polymerase inhibitors, interferon-free treatment