Large-scale preventive chemotherapy for the control of helminth infection in Western Pacific countries: six years later

In 2001, Urbani and Palmer published a review of the epidemiological situation of helminthiases in the countries of the Western Pacific Region of the World Health Organization indicating the control needs in the region. Six years after this inspiring article, large-scale preventive chemotherapy for the control of helminthiasis has scaled up dramatically in the region. This paper analyzes the most recent published and unpublished country information on large-scale preventive chemotherapy and summarizes the progress made since 2000. Almost 39 million treatments were provided in 2006 in the region for the control of helminthiasis: nearly 14 million for the control of lymphatic filariasis, more than 22 million for the control of soil-transmitted helminthiasis, and over 2 million for the control of schistosomiasis. In general, control of these helminthiases is progressing well in the Mekong countries and Pacific Islands. In China, despite harboring the majority of the helminth infections of the region, the control activities have not reached the level of coverage of countries with much more limited financial resources. The control of food-borne trematodes is still limited, but pilot activities have been initiated in China, Lao People's Democratic Republic, and Vietnam.     

Identification of a Potent Endothelium-Derived Angiogenic Factor

The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up₄U) from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up₄U was identified by MALDI-LIFT-fragment-mass-spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up₄U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up₄U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up₄U after stimulation with shear stress. Mean total plasma Up₄U concentrations of healthy subjects (N = 6) were sufficient to induce angiogenic and proliferative effects (1.34±0.26 nmol L^-1). In conclusion, Up₄U is a novel strong human endothelium-derived angiogenic factor.     

Phylogeny of Prokaryotes and Chloroplasts Revealed by a Simple Composition Approach on All Protein Sequences from Complete Genomes Without Sequence Alignment

The complete genomes of living organisms have provided much information on their phylogenetic relationships. Similarly, the complete genomes of chloroplasts have helped to resolve the evolution of this organelle in photosynthetic eukaryotes. In this paper we propose an alternative method of phylogenetic analysis using compositional statistics for all protein sequences from complete genomes. This new method is conceptually simpler than and computationally as fast as the one proposed by Qi et al. (2004b) and Chu et al. (2004). The same data sets used in Qi et al. (2004b) and Chu et al. (2004) are analyzed using the new method. Our distance-based phylogenic tree of the 109 prokaryotes and eukaryotes agrees with the biologists tree of life based on 16S rRNA comparison in a predominant majority of basic branching and most lower taxa. Our phylogenetic analysis also shows that the chloroplast genomes are separated to two major clades corresponding to chlorophytes s.l. and rhodophytes s.l. The interrelationships among the chloroplasts are largely in agreement with the current understanding on chloroplast evolution.Reviewing Editor: Dr. John Oakeshott     

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.     

The devil in the details of life-history evolution: Instability and reversal of genetic correlations during selection on<Emphasis Type="Italic">Drosophila</Emphasis> development

The evolutionary relationships between three major components of Darwinian fitness, development rate, growth rate and preadult survival, were estimated using a comparison of 55 distinct populations ofDrosophila melanogaster variously selected for age-specific fertility, environmental-stress tolerance and accelerated development. Development rate displayed a strong net negative evolutionary correlation with weight at eclosion across all selection treatments, consistent with the existence of a size-versus-time tradeoff between these characters. However, within the data set, the magnitude of the evolutionary correlation depended upon the particular selection treatments contrasted. A previously proposed tradeoff between preadult viability and growth rate was apparent only under weak selection for juvenile fitness components. Direct selection for rapid development led to sharp reductions in both growth rates and viability. These data add to the mounting results from experimental evolution that illustrate the sensitivity of evolutionary correlations to (i) genotype-by-environment (G X E) interaction, (ii) complex functional-trait interactions, and (iii) character definition. Instability, disappearance and reversal of patterns of genetic covariation often occur over short evolutionary time frames and as the direct product of selection, rather than some stochastic process. We suggest that the functional architecture of fitness is a rapidly evolving matrix with reticulate properties, a matrix that we understand only poorly.     

Association between variants of EXT2 and type 2 diabetes: a replication and meta-analysis

Recent publications have found an association between variants of exostosin 2 (EXT2) gene and the risk of type 2 diabetes in some population but not in others. In an attempt to address these inconsistencies, we investigated EXT2 variants in two independent cohorts, and conducted a literature-based meta-analysis. Through regression model, we assessed the relationship between the EXT2 single nucleotide polymorphisms (SNPs) (rs3740878, rs11037909 and rs1113132) and the risk of type 2 diabetes in Han Chinese population, including a total of 2,533 cases and 2,643 controls. We combined our data with that from previously published studies and performed a meta-analysis to evaluate the effect size of the gene. Consistent with some studies, we found marginal association for the rs3740878 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.09), rs11037909 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.08), and rs1113132 (OR = 1.08, 95 % CI = 1.00, 1.17, p = 0.06) in our 2 cohorts. Meta-analysis, comprising 9,224 type 2 diabetes and 10,484 controls, revealed that three SNPs (rs3740878, rs11037909 and rs1113132) in EXT2 were significantly associated with type 2 diabetes (ORs range from 1.06 to 1.07, p = 0.038, p = 0.008 and p = 0.005, respectively). Variation in the EXT2 locus appears to be associated with a small increase in the risk of type 2 diabetes. However, well-designed prospective studies with larger sample size and more ethnic groups are needed to further validate the results.     

Detection of Xeljanz Enantiomers in Diethyl Amine Active Pharmaceutical Ingredients and Tablets

A high‐performance liquid chromatography (HPLC) method was established to detect Xeljanz enantiomers in active pharmaceutical ingredients (APIs) and tablets. The separation was achieved on a Chiralpak IC column using a mobile phase of hexane‐ethanol‐diethylamine (65:35:0.1, v/v). The detection wavelength was 289 nm. The peak areas and the enantiomer concentrations in the range of 0.15–2.25 μg?mL^?1 were in high linearity, with correlation coefficients higher than 0.999. The recoveries were 86.44% at the concentrations of 7.5, 18.75, and 37.5 μg?mL^?1. The limit of detection (LOD) and limit of quantification (LOQ) were 0.042 and 0.14 μg?mL^?1, respectively. This HPLC method is suitable for detecting the enantiomers of Xeljanz in its APIs and tablets. Chirality 27:235–238, 2015. © 2014 Wiley Periodicals, Inc.     

Reduced levels of Cacna1c attenuate mesolimbic dopamine system function

Genetic variation in CACNA1C, which codes for the L‐type calcium channel (LTCC) Ca_v1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia. Dysregulation of the mesolimbic‐dopamine (ML‐DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk. Using constitutive and conditional knockout mice, and treatment with the LTCC antagonist nimodipine, we examined the role of Cacna1c in DA‐mediated behaviors elicited by psychomotor stimulants. Using fast‐scan cyclic voltammetry, DA release and reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter (DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of hyperlocomotion following acute administration of stimulants specific to DAT, and locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach the same level as wild‐type mice. The maintenance of sensitization to GBR12909 was attenuated by administration of nimodipine. Sensitization to GBR12909 was attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc. Our findings show that Cacna1c is crucial for normal behavioral responses to DA stimulants and that its activity in the VTA is required for behavioral sensitization. Cacna1c likely exerts these effects through modifications to presynaptic ML‐DA system function.     

Four putative entomopathogenic fungi of armoured scale insects on <Emphasis Type="Italic">Citrus</Emphasis> in Australia

This study led to the discovery of four putative entomopathogenic fungi of armoured scale insects on citrus trees in coastal New South Wales. Two of these species belong in Podonectria as P. coccicola (Ellis & Everh.) Petch (syn. Tetracrium coccicola (Höhn.) Ellis & Everh.) and P. novae-zelandiae Dingley. Members of this genus are grown in culture for the first time. Formerly placed in the Pleosporales, Tubeufiaceae, or more recently in the Tubeufiales, these species are herein placed in the new family Podonectriaceae fam. nov., Pleosporales. Another species is placed in the Hypocreales, Bionectriaceae as Clonostachys coccicola (J.A. Stev.) H.T. Dao comb. nov. (basionym Tubercularia coccicola J.A. Stev., syn. Nectria tuberculariae Petch). The fourth species is Myriangium citri Henn. (Myriangiales, Myriangiaceae). Each fungal species is characterized and the phylogenetic placement confirmed by molecular analyses of the ITS and 28 s rDNA regions. In addition, their biology is noted, including location of the fungi within tree canopies.