Mutations in Transmembrane Domains 1, 4 and 9 of the Plasmodium falciparum Chloroquine Resistance Transporter Alter Susceptibility to Chloroquine, Quinine and Quinidine

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) can result in verapamil-reversible CQ resistance and altered susceptibility to other antimalarials. PfCRT contains 10 membrane-spanning domains and is found in the digestive vacuole (DV) membrane of intraerythrocytic parasites. The mechanism by which PfCRT mediates CQ resistance is unclear although it is associated with decreased accumulation of drug within the DV. On the permissive background of the P. falciparum 106/1(K76) parasite line, we used single-step drug selection to generate isogenic clones containing unique pfcrt point mutations that resulted in amino acid changes in PfCRT transmembrane domains 1 (C72R, K76N, K76I and K76T) and 9 (Q352K, Q352R). The resulting changes of charge and hydropathy affected quantitative CQ susceptibility and accumulation as well as the stereospecific responses to quinine and quinidine. These results, together with a previously described S163R mutation in transmembrane domain 4, indicate that transmembrane segments 1, 4 and 9 of PfCRT provide important structural components of a substrate recognition and translocation domain. Charge-affecting mutations within these segments may affect the ability of PfCRT to bind different quinoline drugs and determine their net accumulation in the DV. © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Lt

Simultaneous Relevant Feature Identification and Classification in High-Dimensional Spaces

Molecular profiling technologies monitor thousands of transcripts, proteins, metabolites or other species concurrently in biological samples of interest. Given two-class, high-dimensional profiling data, nominal Liknon [4] is a specific implementation of a methodology for performing simultaneous relevant feature identification and classification. It exploits the well-known property that minimising an l_1 norm (via linear programming) yields a sparse hyperplane [15, 26, 2, 8, 17]. This work (i) examines computational, software and practical issues required to realise nominal Liknon, (ii) summarises results from its application to five real world data sets, (iii) outlines heuristic solutions to problems posed by domain experts when interpreting the results and (iv) defines some future directions of the research

Causality as validity: some implications for the social sciences

Causality, Validity, Temporal asymmetry, Simultaneous relations, Non-directional causality, Causal models, Social sciences,