Artemisinins

Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced

Comparison of two gas chromatograph models and analysis of binary data

The overall objective of the gas chromatograph system studies is to generate fundamental design criteria and techniques to be used in the optimum design of the system. The particular tasks currently being undertaken are the comparison of two mathematical models of the chromatograph and the analysis of binary system data. The predictions of two mathematical models, an equilibrium absorption model and a non-equilibrium absorption model exhibit the same weaknesses in their inability to predict chromatogram spreading for certain systems. The analysis of binary data using the equilibrium absorption model confirms that, for the systems considered, superposition of predicted single component behaviors is a first order representation of actual binary data. Composition effects produce non-idealities which limit the rigorous validity of superposition

How successful are oral contraceptives?

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Hierarchical storage management system evaluation

The Numerical Aerodynamic Simulation (NAS) Program at NASA Ames Research Center has been developing a hierarchical storage management system, NAStore, for some 6 years. This evaluation compares functionality, performance, reliability, and other factors of NAStore and three commercial alternatives. FileServ is found to be slightly better overall than NAStore and DMF. UniTree is found to be severely lacking in comparison

Anonymization and Risk

Perfect anonymization of data sets that contain personal information has failed. But the process of protecting data subjects in shared information remains integral to privacy practice and policy. While the deidentification debate has been vigorous and productive, there is no clear direction for policy. As a result, the law has been slow to adapt a holistic approach to protecting data subjects when data sets are released to others. Currently, the law is focused on whether an individual can be identified within a given set. We argue that the best way to move data release policy past the alleged failures of anonymization is to focus on the process of minimizing risk of reidentification and sensitive attribute disclosure, not preventing harm. Process-based data release policy, which resembles the law of data security, will help us move past the limitations of focusing on whether data sets have been “anonymized.” It draws upon different tactics to protect the privacy of data subjects, including accurate deidentification rhetoric, contracts prohibiting reidentification and sensitive attribute disclosure, data enclaves, and query-based strategies to match required protections with the level of risk. By focusing on process, data release policy can better balance privacy and utility where nearly all data exchanges carry some risk

Leadership and approaches to the management of workplace bullying

Leadership behaviour has been identified as an important antecedent of workplace bullying, since managers may prevent, permit or engage in the mistreatment of others. However, the issue of how managers respond when bullying occurs has received limited attention. With this in mind, the aim of this study was to explore how managers behave when bullying occurs in their work group, and to elucidate the contextual issues that underlie this behaviour. This was achieved through analysis of in-depth interviews with individuals involved in cases of bullying. The findings revealed a typology of four types of management behaviour in cases of bullying, each underpinned by contextual factors at the individual, group and organizational level. The study shows that the role of leadership in workplace bullying is more complex than previously thought, and suggests several ways in which managers and organizations could deal with bullying behaviour

httk: R Package for High-Throughput Toxicokinetics

Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentrations resulting from chemical exposure, and a "reverse dosimetry" approach can be used to predict exposure doses sufficient to cause tissue concentrations that have been identified as bioactive by high-throughput screening. We have created four toxicokinetic models within the R software package httk. These models are designed to be parameterized using high-throughput in vitro data (plasma protein binding and hepatic clearance), as well as structure-derived physicochemical properties and species-specific physiological data. The package contains tools for Monte Carlo sampling and reverse dosimetry along with functions for the analysis of concentration vs. time simulations. The package can currently use human in vitro data to make predictions for 553 chemicals in humans, rats, mice, dogs, and rabbits, including 94 pharmaceuticals and 415 ToxCast chemicals. For 67 of these chemicals, the package includes rat-specific in vitro data. This package is structured to be augmented with additional chemical data as they become available. Package httk enables the inclusion of toxicokinetics in the statistical analysis of chemicals undergoing high-throughput screening

Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications