Increased rates of apoptosis (programmed cell death) have been demonstrated in many hepatic diseases including chronic hepatitis C. IDN-6556 is a potent inhibitor of caspases, the proteases that execute apoptosis. In a prior phase 1 study, IDN-6556 lowered aminotransferase activity in a small number of patients with liver impairment. The purpose of this study was to further explore the effect of IDN-6556 in patients with liver disease in a multicenter, double-blind, placebo-controlled, dose-ranging study with a 14-day dosing period. A total of 105 patients were enrolled in the study; 79 received active drug; 80 patients had chronic hepatitis C and 25 had other liver diseases including nonalcoholic steatohepatitis (NASH), hepatitis B, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). IDN-6556 doses ranged from 5 mg to 400 mg daily, given from 1 to 3 times per day. In the HCV patients, all doses of IDN-6556 significantly lowered ALT and AST (P ‫؍‬ 0.0041 to P < 0.0001 for various dosing groups in Wilcoxon tests comparing IDN-6556 to placebo), with the exception of the lowest dose. Declines in aminotransferase activity were also seen in patients with NASH but effects were not apparent in the small number of other liver diseases. Adverse experiences were not different between IDN-6556 and placebo. There were no clinically meaningful changes in other laboratory parameters. In particular, mean HCV RNA levels did not show significant changes. Conclusion: Oral IDN-6556, given for 14 days, significantly lowered aminotransferase activity in HCV patients and appeared to be well tolerated. Longer studies to assess potential effects of IDN-6556 on liver inflammation and fibrosis are merited. (HEPATOLOGY 2007;46:324-329.) P rogrammed cell death or apoptosis is a tightly controlled process of cellular suicide that occurs during normal development, normal tissue turnover, and in numerous diseases. 1 Caspases are proteolytic enzymes that cleave a series of cellular substrates during the execution phase of apoptosis. Caspases are activated from their inactive zymogen forms (procaspases) when a cell is triggered to undergo apoptosis. IDN-6556 is a novel broad-

Integration of research experience into classroom is an important and vital experience for all undergraduates. These course‐based undergraduate research experiences (CUREs) have grown from independent instructor lead projects to large consortium driven experiences. The impact and importance of CUREs on students at all levels in biochemistry was the focus of a National Science Foundation funded think tank. The state of biochemistry CUREs and suggestions for moving biochemistry forward as well as a practical guide (supplementary material) are reported here. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):7–12, 2017.

Objectives. Despite the increasing utilization of point-of-care critical care ultrasonography (CCUS), standards establishing competency for its use are lacking. The purpose of this study was to evaluate the effectiveness of a 2-day CCUS course implementation on ultrasound-naïve critical care medicine (CCM) fellows. Methods. Prospective evaluation of the impact of a two-day CCUS course on eight CCM fellows' attitudes, proficiency, and use of CCUS. Ultrasound competency on multiple organ systems was assessed including abdominal, pulmonary, vascular, and cardiac systems. Subjects served as self-controls and were assessed just prior to, within 1 week after, and 3 months after the course. Results. There was a significant improvement in CCM fellows' written test scores, image acquisition ability, and pathologic image interpretation 1 week after the course and it was retained 3 months after the course. Fellows also had self-reported increased confidence and usage of CCUS applications after the course. Conclusions. Implementation of a 2-day critical care ultrasound course covering general CCUS and basic critical care echocardiography using a combination of didactics, live models, and ultrasound simulators is effective in improving critical care fellows' proficiency and confidence with ultrasound use in both the short- and long-term settings.

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off-target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure-based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds.

Historically, valuable insights have resulted from successful correlations between molecular structure and resulting macroscopic thermodynamic properties that are, by definition, structure independent. This communication provides data, obtained by infrared spectroscopy, on the degree of solvent-solvent hydrogen bonding in the hydration shells surrounding eight "hydrophobic" amino acids. These structural data are correlated with thermodynamic criteria for amino acid hydrophobicity.Hydrophobicity has traditionally been defined in classical thermodynamic terms that are based upon macroscopic properties of solutes and their solutions. These include (a) the free energy of transfer of compounds from a nonaqueous to an aqueous phasel-34a-h and for amino acids (b) estimates of the solventaccessible surface area that is lost as an amino acid is buried inside a fully folded protein1 234'-?•5•6 and (c) the effect of amino acid substitutions on protein stability.7The data presented below demonstrate systematic patterns in the vibrational transitions of water molecules that are associated with eight L-amino acids in aqueous solution. Shifts in vibrational frequencies and intensities of solvating water molecules are consistent with an increase in the degree of hydrogen-bonded structure8•9 that is generated as the hydrocarbon moieties of amino acid side chains increase in size. The measured vibrations result from a complex convolution of the numbers and the enthalpies of solvent-solvent intermolecular hydrogen bonds.8

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Percutaneous dilatational tracheostomy under real-time sonographic guidance using a long-axis approach may increase the rate of midline punctures and decrease the number of needle punctures when compared to the landmark technique. Sonographic guidance can also help guide accurate and efficient placement of a tracheostomy tube into the desired tracheal ring space.

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