Researchers at Michigan State University have identified a test that can determine which children with malaria are likely to develop cerebral malaria, a much more life-threatening form of the disease. The screening tool could be a game-changer in resource

The latest research from a Kansas State University chemical engineer may help improve humidity and pressure sensors, particularly those used in outer space.

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The association of contemporary hosts and their parasites might reflect either cospeciation or more recent shifts among existing hosts. . . .

Patients with Plasmodium vivax malaria are treated with primaquine to prevent relapse infections. . . .

Measuring coverage of maternal, newborn and child health in low- and middle-income countries is critical to ensuring that health interventions are reaching the women and children who need them most, says a new Collection of articles published by PLOS this

Columbia Engineering researchers have developed a technique to isolate a single water molecule inside a buckyball and drive motion of the "big" nonpolar ball through the encapsulated "small" polar H2O molecule, a controlling transport mechanism in a nanoc

BMC Ecology, Vol. 13, No. 1. (08 April 2013), 15, doi:10.1186/1472-6785-13-15

BACKGROUND:Avian malaria (Plasmodium sp.) is globally widespread, but considerable variation exists in infection (presence/absence) patterns at small spatial scales. This variation can be driven by variation in ecology, demography, and phenotypic characters, in particular those that influence the host's resistance. Generation of reactive oxygen species (ROS) is one of the host's initial immune responses to combat parasitic invasion. However, long-term ROS exposure can harm the host and the redox response therefore needs to be adjusted according to infection stage and host phenotype. Here we use experimental and correlational approaches to assess the relative importance of host density, habitat composition, individual level variation and redox physiology for Plasmodium infection in a wild population of great tits, Parus major.RESULTS:We found that 36% of the great tit population was infected with Plasmodium (22% P. relictum and 15% P. circumflexum prevalence) and that patterns of infection were Plasmodium species-specific. First, the infection of P. circumflexum was significantly higher in areas with experimental increased host density, whereas variation in P. relictum infection was mainly attributed to age, sex and reproduction. Second, great tit antioxidant responses - total and oxidizied glutathione - showed age- , sex- and Plasmodium species-specific patterns between infected and uninfected individuals, but reactive oxygen metabolites (ROM) showed only a weak explanatory power for patterns of P. relictum infection. Instead ROM significantly increased with Plasmodium parasitaemia.CONCLUSIONS:These results identify some key factors that influence Plasmodium infection in wild birds, and provide a potential explanation for the underlying physiological basis of recently documented negative effects of chronic avian malaria on survival and reproductive success.
Caroline Isaksson, Irem Sepil, Vladimer Baramidze, Ben Sheldon

Background: An experimental hut station built at M'Be in 1998 was used for many years for the evaluation of insecticidal product for public health until the civil war broke out in 2002. Breeding sites of mosquitoes and selection pressure in the area were maintained by local farming practices and the West African Rice Development Association (WARDA, actually AfricaRice) in a large rice growing area. Ten years after the crisis, bioassays, molecular and biochemical analyses were conducted to update the resistance status and study the evolution of resistance mechanisms of Anopheles gambiae s.s population. Methods: Anopheles gambiae s.s larvae from M'Be were collected in breeding sites and reared until emergence. Resistance status of this population to conventional insecticides was assessed using WHO bioassay test kits for adult mosquitoes, with 10 insecticides belonging to pyrethroids, pseudo-pyrethroid, organochlorides, carbamates and organophosphate with and without the inhibitor piperonyl butoxyde (PBO). Molecular and biochemical assays were carried out to identify the L1014F kdr, L1014S kdr and ace-1R alleles in individual mosquitoes and to detect potential increase in mixed function oxidases (MFO) level, non-specific esterases (NSE) and glutathione S-transferases (GST) activities.Results and discussionAnopheles gambiae s.s from M'Be exerted high resistance levels to organochlorides, pyrethroids, and carbamates. Mortalities ranged from 3% to 21% for organochlorides, from 50% to 75% for pyrethroids, 34% for etofenprox, the pseudo-pyrethroid, and from 7% to 80% for carbamates. Tolerance to organophosphates was observed with mortalities ranging from 95% to 98%. Bioassays run with a pre-exposition of mosquitoes to PBO induced very high levels of mortalities compared to the bioassays without PBO, suggesting that the resistance to pyrethroid and carbamate relied largely on detoxifying enzymes' activities. The L1014F kdr allelic frequency was 0.33 in 2012 compared to 0.05 before the crisis in 2002. Neither the L1014S kdr nor ace-1R mutations were detected. An increased activity of NSE and level of MFO was found relative to the reference strain Kisumu. This was the first evidence of metabolic resistance based resistance in An. gambiae s.s from M'Be. Conclusion: The An. gambiae s.s population showed very high resistance to organochlorides, pyrethroids and carbamates. This resistance level relied largely on two major types of resistance: metabolic and target-site mutation. This multifactorial resistance offers a unique opportunity to evaluate the impact of both mechanisms and their interaction with the vector control tools currently used or in development.

Background: Tanzania achieved universal coverage with long-lasting insecticidal nets (LLINs) in October 2011, after three years of free mass net distribution campaigns and is now faced with the challenge of maintaining high coverage as nets wear out and the population grows. A process of exploring options for a continuous or "Keep-Up" distribution system was initiated in early 2011. This paper presents for the first time a comprehensive national process to review the major considerations, findings and recommendations for the implementation of a new strategy. Methods: Stakeholder meetings and site visits were conducted in five locations in Tanzania to garner stakeholder input on the proposed distribution systems. Coverage levels for LLINs and their decline over time were modelled using NetCALC software, taking realistic net decay rates, current demographic profiles and other relevant parameters into consideration. Costs of the different distribution systems were estimated using local data. Results: LLIN delivery was considered via mass campaigns, Antenatal Care-Expanded Programme on Immunization (ANC/EPI), community-based distribution, schools, the commercial sector and different combinations of the above. Most approaches appeared unlikely to maintain universal coverage when used alone. Mass campaigns, even when combined with a continuation of the Tanzania National Voucher Scheme (TNVS), would produce large temporal fluctuations in coverage levels; over 10 years this strategy would require 63.3 million LLINs and a total cost of $444 million USD. Community mechanisms, while able to deliver the required numbers of LLINs, would require a massive scale-up in monitoring, evaluation and supervision systems to ensure accurate application of identification criteria at the community level. School-based approaches combined with the existing TNVS would reach most Tanzanian households and deliver 65.4 million LLINs over 10 years at a total cost of $449 million USD and ensure continuous coverage. The cost of each strategy was largely driven by the number of LLINs delivered. Conclusions: The most cost-efficient strategy to maintain universal coverage is one that best optimizes the numbers of LLINs needed over time. A school-based approach using vouchers targeting all students in Standards 1, 3, 5, 7 and Forms 1 and 2 in combination with the TNVS appears to meet best the criteria of effectiveness, equity and efficiency.

Toxic waste sites with elevated levels of lead and chromium cause a high number of "healthy years of life lost" in individuals living near 373 sites located in India, Philippines and Indonesia, according to a study by a Mount Sinai researcher published on

Science, Vol. 340, No. 6130. (19 April 2013), pp. 284-286, doi:10.1126/science.1236958
Paul Sharp, Julian Rayner, Beatrice Hahn

Cell Microbiol (1 April 2013), pp. n/a-n/a, doi:10.1111/cmi.12151

The invasion of host erythrocytes by the parasite Plasmodium falciparum initiates the blood stage of infection responsible for the symptoms of malaria. Invasion involves extracellular protein interactions between host erythrocyte receptors and ligands on the merozoite, the invasive form of the parasite. Despite significant research effort, many merozoite surface ligands have no known erythrocyte binding partner, most likely due to the intractable biochemical nature of membrane-tethered receptor proteins and their interactions. The few receptor-ligand pairs that have been described have largely relied on sourcing erythrocytes from patients with rare blood groups, a serendipitous approach that is unsatisfactory for systematically identifying novel receptors. We have recently developed a scalable assay called AVEXIS (for AVidity-based EXtracellular Interaction Screen), designed to circumvent the technical difficulties associated with the identification of extracellular protein interactions, and applied it to identify erythrocyte receptors for orphan Plasmodium falciparum merozoite ligands. Using this approach, we have recently identified Basigin (CD147) and Semaphorin-7A (CD108) as receptors for RH5 and MTRAP, respectively. In this essay, we review techniques used to identify Plasmodium receptors and discuss how they could be applied in the future to identify novel receptors both for Plasmodium parasites but also other pathogens.
Josefin Bartholdson, Cécile Crosnier, Leyla Bustamante, Julian Rayner, Gavin Wright

Figs and fig trees are familiar to a wide cross-section of human society, both as a common food and for their spiritual importance. What is less well understood is the global nature of this association between figs and humans. This relationship is explore

J. Med. Chem., Vol. 51, No. 4. (31 January 2008), pp. 988-996, doi:10.1021/jm701141u

This paper describes the synthesis of a new class of peptidomimetic cysteine protease inhibitors based on a 1,4-benzodiazepine scaffold and on an electrophilic vinyl sulfone moiety. The former was introduced internally to a peptide sequence that mimics the fragment d-Ser-Gly; the latter was built on the P1-P1? site and reacts as a classical ?Michael acceptor?, leading to an alkylated enzyme by irreversible addition of the thiol group of the active site cysteine. The introduction of the vinyl sulfone moiety has been accomplished by olefin cross-metathesis, a powerful tool for the formation of carbon?carbon double bonds. New compounds 2?3 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.
Roberta Ettari, Emanuela Nizi, Maria Di Francesco, Marie-Adrienne Dude, Gabriele Pradel, Radim Vičík, Tanja Schirmeister, Nicola Micale, Silvana Grasso, Maria Zappalà

Nat Genet, Vol. advance online publication (28 April 2013), doi:10.1038/ng.2624
Olivo Miotto, Jacob Almagro-Garcia, Magnus Manske, Bronwyn MacInnis, Susana Campino, Kirk Rockett, Chanaki Amaratunga, Pharath Lim, Seila Suon, Sokunthea Sreng, Jennifer Anderson, Socheat Duong, Chea Nguon, Char Chuor, David Saunders, Youry Se, Chantap Lon, Mark Fukuda, Lucas Amenga-Etego, Abraham Hodgson, Victor Asoala, Mallika Imwong, Shannon Takala-Harrison, Francois Nosten, Xin-zhuan Su, Pascal Ringwald, Frederic Ariey, Christiane Dolecek, Tran Hien, Maciej Boni, Cao Thai, Alfred Amambua-Ngwa, David Conway, Abdoulaye Djimde, Ogobara Doumbo, Issaka Zongo, Jean-Bosco Ouedraogo, Daniel Alcock, Eleanor Drury, Sarah Auburn, Oliver Koch, Mandy Sanders, Christina Hubbart, Gareth Maslen, Valentin Ruano-Rubio, Dushyanth Jyothi, Alistair Miles, John O'Brien, Chris Gamble, Samuel Oyola, Julian Rayner, Chris Newbold, Matthew Berriman, Chris Spencer, Gilean McVean, Nicholas Day, Nicholas White, Delia Bethell, Arjen Dondorp, Christopher Plowe, Rick Fairhurst, Dominic Kwiatkowski

A novel drug developed by Gilead Sciences and tested in an animal model at the Texas Biomedical Research Institute in San Antonio suppresses hepatitis B virus infection by stimulating the immune system and inducing loss of infected cells.

PLoS Comput Biol, Vol. 9, No. 4. (18 April 2013), e1003018, doi:10.1371/journal.pcbi.1003018

Biomarker discovery aims to find small subsets of relevant variables in ‘omics data that correlate with the clinical syndromes of interest. Despite the fact that clinical phenotypes are usually characterized by a complex set of clinical parameters, current computational approaches assume univariate targets, e.g. diagnostic classes, against which associations are sought for. We propose an approach based on asymmetrical sparse canonical correlation analysis (SCCA) that finds multivariate correlations between the ‘omics measurements and the complex clinical phenotypes. We correlated plasma proteomics data to multivariate overlapping complex clinical phenotypes from tuberculosis and malaria datasets. We discovered relevant ‘omic biomarkers that have a high correlation to profiles of clinical measurements and are remarkably sparse, containing 1.5–3% of all ‘omic variables. We show that using clinical view projections we obtain remarkable improvements in diagnostic class prediction, up to 11% in tuberculosis and up to 5% in malaria. Our approach finds proteomic-biomarkers that correlate with complex combinations of clinical-biomarkers. Using the clinical-biomarkers improves the accuracy of diagnostic class prediction while not requiring the measurement plasma proteomic profiles of each subject. Our approach makes it feasible to use omics' data to build accurate diagnostic algorithms that can be deployed to community health centres lacking the expensive ‘omics measurement capabilities. Many infectious diseases such as tuberculosis and malaria are challenging both for scientists trying to understand the biochemical basis of the diseases and for medical doctors making diagnosis. The challenges arise both from the dependence of the diseases on sets of proteins and from the complexity of the symptoms. Biomarkers denote small sets of measurements that correlate with the phenotype of interest. They have potential use both in advancing the basic biomedical research of infectious diseases and in facilitating predictive diagnostic tools. We propose a new method for biomarker discovery that works by finding canonical correlations between two sets of data, the plasma proteomic profiles and clinical profiles of the subjects. We show that the method is able to find candidate proteomic biomarkers that correlate with combinations of clinical variables, called the clinical biomarkers. Using the clinical biomarkers improves the accuracy of diagnostic class prediction while not requiring the expensive plasma proteomic profiles to be measured for each subject.
Juho Rousu, Daniel Agranoff, Olugbemiro Sodeinde, John Shawe-Taylor, Delmiro Fernandez-Reyes

International Journal of Molecular Sciences, Vol. 14, No. 4. (08 April 2013), pp. 7583-7597, doi:10.3390/ijms14047583

Molecular biology is a rapidly evolving field that has led to the development of increasingly sophisticated technologies to improve our capacity to study cellular processes in much finer detail. Transcription is the first step in protein expression and the major point of regulation of the components that determine the characteristics, fate and functions of cells. The study of transcriptional regulation has been greatly facilitated by the development of reporter genes and transcription factor expression vectors, which have become versatile tools for manipulating promoters, as well as transcription factors in order to examine their function. The understanding of promoter complexity and transcription factor structure offers an insight into the mechanisms of transcriptional control and their impact on cell behaviour. This review focuses on some of the many applications of molecular cut-and-paste tools for the manipulation of promoters and transcription factors leading to the understanding of crucial aspects of transcriptional regulation.
Alena Pance

Nature, Vol. advance online publication (10 April 2013), doi:10.1038/nature12051

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.
CJ Paddon, PJ Westfall, DJ Pitera, K Benjamin, K Fisher, D McPhee, MD Leavell, A Tai, A Main, D Eng, DR Polichuk, KH Teoh, DW Reed, T Treynor, J Lenihan, M Fleck, S Bajad, G Dang, D Diola, G Dorin, KW Ellens, S Fickes, J Galazzo, SP Gaucher, T Geistlinger, R Henry, M Hepp, T Horning, T Iqbal, H Jiang, L Kizer, B Lieu, D Melis, N Moss, R Regentin, S Secrest, H Tsuruta, R Vazquez, LF Westblade, L Xu, M Yu, Y Zhang, L Zhao, J Lievense, PS Covello, JD Keasling, KK Reiling, NS Renninger, JD Newman