The pharmaceutical death-ride of dihydroartemisinin

In the 2010 second edition of WHO's guidelines for the treatment of malaria, the relatively new fixed dose combination dihydroartemisinin-piperaquine is included as one of the recommended artemisinin combination therapies. However, experimental testing demonstrates that, due to its intrinsic chemical instability, dihydroartemisinin is not suitable to be used in pharmaceutical formulations. In addition, data show that the currently available dihydroartemisinin preparations fail to meet the internationally accepted stability requirements. At a time when many efforts aim to ban counterfeit and substandard drugs from the malaria market, the obvious question rises how WHO and public-private partnerships, such as Medicine for Malaria venture (MMV), can support the production and marketing of anti-malarial drugs that do not even meet the International Pharmacopoeia requirements

Torpor on Demand: Heterothermy in the Non-Lemur Primate Galago moholi

Hibernation and daily torpor are energy- and water-saving adaptations employed to survive unfavourable periods mostly in temperate and arctic environments, but also in tropical and arid climates. Heterothermy has been found in a number of mammalian orders, but within the primates so far it seems to be restricted to one family of Malagasy lemurs. As currently there is no evidence of heterothermy of a primate outside of Madagascar, the aim of our study was to investigate whether small primates from mainland Africa are indeed always homeothermic despite pronounced seasonal changes in weather and food availability., which inhabits a highly seasonal habitat with a hot wet-season and a cold dry-season with lower food abundance, was investigated to determine whether it is capable of heterothermy. We measured skin temperature of free-ranging individuals throughout the cool dry season using temperature-sensitive collars as well as metabolic rate in captured individuals. Torpor was employed by 15% of 20 animals. Only one of these animals displayed heterothermy in response to natural availability of food and water, whereas the other animals became torpid without access to food and water. are physiologically capable of employing torpor. However they do not use it as a routine behaviour, but only under adverse conditions. This reluctance is presumably a result of conflicting selective pressures for energy savings versus other ecological and evolutionary forces, such as reproduction or territory defence. Our results support the view that heterothermy in primates evolved before the division of African and Malagasy Strepsirhini, with the possible implication that more primate species than previously thought might still have the potential to call upon this possibility, if the situation necessitates it

Impact of Age and Body Site on Adult Female Skin Surface pH

Background: pH is known as an important parameter in epidermal barrier function and homeostasis. Aim: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. Methods: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. Results: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. Conclusion: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. Copyright (C) 2012 S. Karger AG, Base

NMR Derived Model of GTPase Effector Domain (GED) Self Association: Relevance to Dynamin Assembly

Self-association of dynamin to form spiral structures around lipidic vesicles during endocytosis is largely mediated by its ‘coiled coil’ GTPase Effector Domain (GED), which, in vitro, self-associates into huge helical assemblies. Residue-level structural characterizations of these assemblies and understanding the process of association have remained a challenge. It is also impossible to get folded monomers in the solution phase. In this context, we have developed here a strategy to probe the self-association of GED by first dissociating the assembly using Dimethyl Sulfoxide (DMSO) and then systematically monitoring the refolding into helix and concomitant re-association using NMR spectroscopy, as DMSO concentration is progressively reduced. The short segment, Arg109 - Met116, acts as the nucleation site for helix formation and self-association. Hydrophobic and complementary charge interactions on the surfaces drive self-association, as the helices elongate in both the directions resulting in an antiparallel stack. A small N-terminal segment remains floppy in the assembly. Following these and other published results on inter-domain interactions, we have proposed a plausible mode of dynamin self assembly

Codon usage in vertebrates is associated with a low risk of acquiring nonsense mutations

<p>Abstract</p> <p>Background</p> <p>Codon usage in genomes is biased towards specific subsets of codons. Codon usage bias affects translational speed and accuracy, and it is associated with the tRNA levels and the GC content of the genome. Spontaneous mutations drive genomes to a low GC content. Active cellular processes are needed to maintain a high GC content, which influences the codon usage of a species. Loss-of-function mutations, such as nonsense mutations, are the molecular basis of many recessive alleles, which can greatly affect the genome of an organism and are the cause of many genetic diseases in humans.</p> <p>Methods</p> <p>We developed an event based model to calculate the risk of acquiring nonsense mutations in coding sequences. Complete coding sequences and genomes of 40 eukaryotes were analyzed for GC and CpG content, codon usage, and the associated risk of acquiring nonsense mutations. We included one species per genus for all eukaryotes with available reference sequence.</p> <p>Results</p> <p>We discovered that the codon usage bias detected in genomes of high GC content decreases the risk of acquiring nonsense mutations (Pearson's <it>r </it>= -0.95; <it>P </it>< 0.0001). In the genomes of all examined vertebrates, including humans, this risk was lower than expected (0.93 ± 0.02; mean ± SD) and lower than the risk in genomes of non-vertebrates (1.02 ± 0.13; <it>P </it>= 0.019).</p> <p>Conclusions</p> <p>While the maintenance of a high GC content is energetically costly, it is associated with a codon usage bias harboring a low risk of acquiring nonsense mutations. The reduced exposure to this risk may contribute to the fitness of vertebrates.</p

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Molecular control of sucrose utilization in Escherichia coli W, an efficient sucrose-utilizing strain

Sucrose is an industrially important carbon source for microbial fermentation. Sucrose utilization in Escherichia coli, however, is poorly understood, and most industrial strains cannot utilize sucrose. The roles of the chromosomally encoded sucrose catabolism (csc) genes in E. coli W were examined by knockout and overexpression experiments. At low sucrose concentrations, the csc genes are repressed and cells cannot grow. Removal of either the repressor protein (cscR) or the fructokinase (cscK) gene facilitated derepression. Furthermore, combinatorial knockout of cscR and cscK conferred an improved growth rate on low sucrose. The invertase (cscA) and sucrose transporter (cscB) genes are essential for sucrose catabolism in E. coli W, demonstrating that no other genes can provide sucrose transport or inversion activities. However, cscK is not essential for sucrose utilization. Fructose is excreted into the medium by the cscK-knockout strain in the presence of high sucrose, whereas at low sucrose (when carbon availability is limiting), fructose is utilized by the cell. Overexpression of cscA, cscAK, or cscAB could complement the W Delta cscRKAB knockout mutant or confer growth on a K-12 strain which could not naturally utilize sucrose. However, phenotypic stability and relatively good growth rates were observed in the K-12 strain only when overexpressing cscAB, and full growth rate complementation in W Delta cscRKA Balso required cscAB. Our understanding of sucrose utilization can be used to improve E. coli Wand engineer sucrose utilization in strains which do not naturally utilize sucrose, allowing substitution of sucrose for other, less desirable carbon sources in industrial fermentations

Technical aspects of CT imaging of the spine

This review article discusses technical aspects of computed tomography (CT) imaging of the spine. Patient positioning, and its influence on image quality and movement artefact, is discussed. Particular emphasis is placed on the choice of scan parameters and their relation to image quality and radiation burden to the patient. Strategies to reduce radiation burden and artefact from metal implants are outlined. Data acquisition, processing, image display and steps to reduce artefact are reviewed. CT imaging of the spine is put into context with other imaging modalities for specific clinical indications or problems. This review aims to review underlying principles for image acquisition and to provide a rough guide for clinical problems without being prescriptive. Individual practice will always vary and reflect differences in local experience, technical provisions and clinical requirements

Photolithographic Approaches for Fabricating Highly Ordered Nanopatterned Arrays

In this work, we report that large area metal nanowire and polymer nanotube arrays were successfully patterned by photolithographic approach using anodic aluminum oxide (AAO) templates. Nanowires were produced by electrochemical deposition, and nanotubes by solution-wetting. The highly ordered patterns of nanowire and nanotube arrays were observed using scanning electron microscopy (SEM) and found to stand free on the substrate. The method is expected to play an important role in the application of microdevices in the future

The assessment of the quality of reporting of meta-analyses in diagnostic research: a systematic review

<p>Abstract</p> <p>Background</p> <p>Over the last decade there have been a number of guidelines published, aimed at improving the quality of reporting in published studies and reviews. In systematic reviews this may be measured by their compliance with the PRISMA statement. This review aims to evaluate the quality of reporting in published meta-analyses of diagnostic tests, using the PRISMA statement and establish whether there has been a measurable improvement over time.</p> <p>Methods</p> <p>Eight databases were searched for reviews published prior to 31^stDecember 2008. Studies were selected if they evaluated a diagnostic test, measured performance, searched two or more databases, stated the search terms and inclusion criteria, and used a statistical method to summarise a test's performance. Data were extracted on the review characteristics and items of the PRISMA statement. To measure the change in the quality of reporting over time, PRISMA items for two periods of equal duration were compared.</p> <p>Results</p> <p>Compliance with the PRISMA statement was generally poor: none of the reviews completely adhered to all 27 checklist items. Of the 236 meta-analyses included following selection: only 2(1%) reported the study protocol; 59(25%) reported the searches used; 76(32%) reported the results of a risk of bias assessment; and 82(35%) reported the abstract as a structured summary. Only 11 studies were published before 2000. Thus, the impact of QUOROM on the quality of reporting was not evaluated. However, the periods 2001-2004 and 2005-2008 (covering 93% of studies) were compared using relative risks (RR). There was an increase in the proportion of reviews reporting on five PRISMA items: eligibility criteria (RR 1.13, 95% CI 1.00 - 1.27); risk of bias across studies (methods) (RR 1.81, 95% CI 1.34 - 2.44); study selection results (RR 1.48, 95% CI 1.05 - 2.09); results of individual studies (RR 1.37, 95% CI 1.09 - 1.72); risk of bias across studies (results) (RR 1.65, 95% CI 1.20 - 2.25).</p> <p>Conclusion</p> <p>Although there has been an improvement in the quality of meta-analyses in diagnostic research, there are still many deficiencies in the reporting which future reviewers need to address if readers are to trust the validity of the reported findings.</p