A Plant-Derived Morphinan as a Novel Lead Compound Active against Malaria Liver Stages

BACKGROUND: The global spread of multidrug–resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. METHODS AND FINDINGS: Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC(50)] 3.1 μM, therapeutic index [TI] 14) and P. falciparum (IC(50) 4.2 μM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC(50) 3.3 μM, TI 46, and IC(50) 42.4 μM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. CONCLUSIONS: A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs

The effectiveness of mathematics teaching: a cross-national investigation in primary schools in England and China

This study focuses on the effectiveness of mathematics teaching to children aged 9-10 years, applies a mixture of six methods to classroom-level data collected in England and China, correlates observable teacher behaviours with pupil mathematics performance and collects multiple perceptions that indirectly connect with the differences of teaching and learning cross-nationally. It has been found in the study that 9-to 10-year-olds (n = 343) from China outscored their English peers (n = 236) at the same age by over 20 per cent in each of two mathematics tests derived from TIMSS 2003. Structured analysis of lesson videos has revealed that Chinese mathematics teachers scored much higher than their English colleagues on an internationally validated observation instrument which focused on the quality of six dimensions of teacher behaviours. Furthermore, the quantity of teacher behaviours was also measured and the subsequent correlational analysis on pooled data indicated a positive effect of whole-class interactive teaching (r = 0.97, p < 0.01) and pupil time on task (r = 0.95, p < 0.01) and a negative impact of whole-class lecture (r = -0.91, p < 0.01), individual/group work (r=-0.81, p < 0.05) and classroom management (r = -0.77, p < 0.05) on pupils’ mathematics performance cross-nationally. Qualitative findings are connected with quantitative results to explain how teachers think, how this relates to the way they teach and how the differences of teaching result in the performance gap cross-nationally. The study replicated previous TER findings from the West across two geographically and culturally different countries, suggested possible directions for future enquiries, and recommended potential ways for practice and policy innovations