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This study investigates the system-level performance of variable recruitment (VR) fluidic artificial muscle (FAM) actuator bundles using a model that incorporates FAM interaction effects. A VR bundle combines multiple FAMs to act as one actuator in which the FAMs are sequentially recruited to increase overall efficiency. In a VR bundle, inactive/low-pressure FAMs are compressed beyond their free strains, exerting resistive forces opposing that of active FAMs. A recent model that captures this behavior is used to simulate sinusoidal contraction of a VR bundle with a hanging mass load. The implications of inter-FAM effects on the force-strain space of a VR bundle are discussed and a method of recruitment state transition required to track a sinusoid is proposed. The dynamics of the electrohydraulic subsystems are presented and used to evaluate its system efficiency and bandwidth limits. Three different electrohydraulic configurations are considered: (1) continuous motor operation with constant pump displacement, (2) intermittent motor operation with constant pump displacement, and (3) continuous motor operation with variable pump displacement. Simulation results show the superior bandwidth capabilities of VR bundles by demonstrating its ability to track sinusoids with amplitudes up to 16% strain at frequencies greater than 0.5 Hz, compared to that of a single equivalent cross section area motor unit (SEMU). In addition to increased bandwidth limit, system efficiencies averaged over a range of amplitudes show up to 170% increase when comparing a VR bundle using variable pump displacement to a SEMU using constant pump displacement. [ABSTRACT FROM AUTHOR]

Lapatinib, an oral tyrosine kinase inhibitor used as a first-line treatment for HER2-positive breast cancer, has been reported to be associated with hepatotoxicity; however, the underlying mechanisms remain unclear. In this study, we report that lapatinib causes cytotoxicity in multiple types of hepatic cells, including primary human hepatocytes, HepaRG cells, and HepG2 cells. A 24-h treatment with lapatinib induced cell cycle disturbances, apoptosis, and DNA damage, and decreased the protein levels of topoisomerase in HepG2 cells. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in lapatinib-induced cytotoxicity using our previously established HepG2 cell lines, which express each of 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrate that lapatinib is metabolized by CYP1A1, 3A4, 3A5, and 3A7. Among these, lapatinib-induced cytotoxicity and DNA damage were attenuated in cells overexpressing CYP3A5 or 3A7. Additionally, we measured the production of three primary metabolites of lapatinib (O -dealkylated lapatinib, N -dealkylated lapatinib, and N -hydroxy lapatinib) in CYP1A1-, 3A4-, 3A5-, and 3A7-overexpressing HepG2 cells. We compared the cytotoxicity of lapatinib and its 3 metabolites in primary human hepatocytes, HepaRG cells, and HepG2 cells and demonstrated that N -dealkylated lapatinib is more toxic than the parent drug and the other metabolites. Taken together, our results indicate that lapatinib-induced cytotoxicity involves multiple mechanisms, such as apoptosis and DNA damage; that N -dealkylated lapatinib is a toxic metabolite contributing to the toxic effect of lapatinib; and that CYP3A5- and 3A7-mediated metabolism plays a role in attenuating the cytotoxicity of lapatinib. [ABSTRACT FROM AUTHOR]

In "Teaching History 157, Assessment Edition," a number of different teachers shared the ways in which their departments were approaching the assessment and reporting of students' progress in a "post-levels" world. This article adds to those examples, first by illustrating how teachers from different schools in the Bristol area are working together to examine, evaluate and build on others' ideas and then by presenting a further series of case studies of the particular strategies that individual departments have taken forward. In each case the teachers explain why those approaches have been valuable to them or particularly suitable, given the policies and constraints operating in their individual schools, and they acknowledge on-going areas for development.