Antimalarial 4(1H)-pyridones bind to the Qisite of cytochromebc1

Cytochrome bc1 is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles

The personal and contextual contributors to school belongingness among primary school students

School belongingness has gained currency among educators and school health professionals as an important determinant of adolescent health. The current cross-sectional study presents the 15 most significant personal and contextual factors that collectively explain 66.4% (two-thirds) of the variability in 12-year old students' perceptions of belongingness in primary school. The study is part of a larger longitudinal study investigating the factors associated with student adjustment in the transition from primary to secondary school. The study found that girls and students with disabilities had higher school belongingness scores than boys, and their typically developing counterparts respectively; and explained 2.5% of the variability in school belongingness. The majority (47.1% out of 66.4%) of the variability in school belongingness was explained by student personal factors, such as social acceptance, physical appearance competence, coping skills, and social affiliation motivation; followed by parental expectations (3% out of 66.4%), and school-based factors (13.9% out of 66.4%) such as, classroom involvement, task-goal structure, autonomy provision, cultural pluralism, and absence of bullying. Each of the identified contributors of primary school belongingness can be shaped through interventions, system changes, or policy reforms

Enhanced biological carbon consumption in a high CO2 ocean

The oceans have absorbed nearly half of the fossil-fuel carbon dioxide (CO2) emitted into the atmosphere since pre-industrial times1, causing a measurable reduction in seawater pH and carbonate saturation2. If CO2 emissions continue to rise at current rates, upper-ocean pH will decrease to levels lower than have existed for tens of millions of years and, critically, at a rate of change 100 times greater than at any time over this period3. Recent studies have shown effects of ocean acidification on a variety of marine life forms, in particular calcifying organisms4, 5, 6. Consequences at the community to ecosystem level, in contrast, are largely unknown. Here we show that dissolved inorganic carbon consumption of a natural plankton community maintained in mesocosm enclosures at initial CO2 partial pressures of 350, 700 and 1,050 μatm increases with rising CO2. The community consumed up to 39% more dissolved inorganic carbon at increased CO2 partial pressures compared to present levels, whereas nutrient uptake remained the same. The stoichiometry of carbon to nitrogen drawdown increased from 6.0 at low CO2 to 8.0 at high CO2, thus exceeding the Redfield carbon:nitrogen ratio of 6.6 in today’s ocean7. This excess carbon consumption was associated with higher loss of organic carbon from the upper layer of the stratified mesocosms. If applicable to the natural environment, the observed responses have implications for a variety of marine biological and biogeochemical processes, and underscore the importance of biologically driven feedbacks in the ocean to global change

Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial

<p>Abstract</p> <p>Background</p> <p>Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on <it>Plasmodium </it>infections in preschool children.</p> <p>Methods</p> <p>A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on <it>Plasmodium </it>infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months.</p> <p>Results</p> <p>320 children (out of 1228, 26.1%) complied with all the follow-up assessments. <it>Plasmodium </it>prevalence and mean <it>Plasmodium </it>parasite density was significantly higher in the treatment group (44.9% and 2319 ± SE 511) compared to the placebo group (33.3% and 1471 ± 341) at baseline. The odds of having <it>Plasmodium </it>infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean <it>Plasmodium </it>density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in <it>Plasmodium </it>density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant.</p> <p>Conclusions</p> <p>Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of <it>Plasmodium </it>infection in preschool children which coincided with a reduction in both the prevalence and intensity of <it>A. lumbricoides </it>infections.</p> <p>Trial Registration</p> <p>Current controlled trials ISRCTN44215995</p

Insights into the Ecology and Evolutionary Success of Crocodilians Revealed through Bite-Force and Tooth-Pressure Experimentation

BackgroundCrocodilians have dominated predatory niches at the water-land interface for over 85 million years. Like their ancestors, living species show substantial variation in their jaw proportions, dental form and body size. These differences are often assumed to reflect anatomical specialization related to feeding and niche occupation, but quantified data are scant. How these factors relate to biomechanical performance during feeding and their relevance to crocodilian evolutionary success are not known.Methodology/Principal FindingsWe measured adult bite forces and tooth pressures in all 23 extant crocodilian species and analyzed the results in ecological and phylogenetic contexts. We demonstrate that these reptiles generate the highest bite forces and tooth pressures known for any living animals. Bite forces strongly correlate with body size, and size changes are a major mechanism of feeding evolution in this group. Jaw shape demonstrates surprisingly little correlation to bite force and pressures. Bite forces can now be predicted in fossil crocodilians using the regression equations generated in this research.Conclusions/SignificanceCritical to crocodilian long-term success was the evolution of a high bite-force generating musculo-skeletal architecture. Once achieved, the relative force capacities of this system went essentially unmodified throughout subsequent diversification. Rampant changes in body size and concurrent changes in bite force served as a mechanism to allow access to differing prey types and sizes. Further access to the diversity of near-shore prey was gained primarily through changes in tooth pressure via the evolution of dental form and distributions of the teeth within the jaws. Rostral proportions changed substantially throughout crocodilian evolution, but not in correspondence with bite forces. The biomechanical and ecological ramifications of such changes need further examination

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being