P3 cap modified Phe*-Ala series BACE inhibitors

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).     

Chances and Limitations of Wild Bird Monitoring for the Avian Influenza Virus H5N1 — Detection of Pathogens Highly Mobile in Time and Space

Highly pathogenic influenza virus (HPAIV) H5N1 proved to be remarkably mobile in migratory bird populations where it has led to extensive outbreaks for which the true number of affected birds usually cannot be determined. For the evaluation of avian influenza monitoring and HPAIV early warning systems, we propose a time-series analysis that includes the estimation of confidence intervals for (i) the prevalence in outbreak situations or (ii) in the apparent absence of disease in time intervals for specified regional units. For the German outbreak regions in 2006 and 2007, the upper 95% confidence limit allowed the detection of prevalences below 1% only for certain time intervals. Although more than 25,000 birds were sampled in Germany per year, the upper 95% confidence limit did not fall below 5% in the outbreak regions for most of the time. The proposed analysis can be used to monitor water bodies and high risk areas, also as part of an early-warning system. Chances for an improved targeting of the monitoring system as part of a risk-based approach are discussed with the perspective of reducing sample sizes.     

A fair fight between molecular marker types in a seascape genetics setting

From its inception, population genetics has been nearly as concerned with the genetic data type—to which analyses are brought to bear—as it is with the analysis methods themselves. The field has traversed allozymes, microsatellites, segregating sites in multilocus alignments and, currently, single nucleotide polymorphisms (SNPs) generated by high‐throughput genomic sequencing methods, primarily whole genome sequencing and reduced representation library (RRL) sequencing. As each emerging data type has gained traction, it has been compared to existing methods, based on its relative ability to discern population structural complexity at increasing levels of resolution. However, this is usually done by comparing the gold standard in one data type to the gold standard in the new data type. These gold standards frequently differ in power and in sampling density, both across a genome and throughout a spatial range. In this issue of Molecular Ecology, D’Aloia et al. apply the high‐throughput approach as fully as possible to microsatellites, nuclear loci and SNPs genotyped through an RRL method; this is coupled with a spatially dense sampling scheme. Completing a battery of population genetics analyses across data types (including a series of down‐sampled data sets), the authors find that SNP data are slightly more sensitive to fine‐scale genetic structure, and the results are more resilient to down‐sampling than microsatellites and nonrepetitive nuclear loci. However, their results are far from an unqualified victory for RRL SNP data over all previous data types: the authors note that modest additions to the microsatellites and nuclear loci data sets may provide the necessary analytical power to delineate the fine‐scale genetic structuring identified by SNPs. As always, as the field begins to fully embrace the newest thing, good science reminds us that traditional data types are far from useless, especially when combined with a well‐designed sampling scheme.     

Identification and characterization of adenosine 5'-tetraphosphate in human myocardial tissue

Endocrine functions of the human heart have been studied extensively. Only recently, nucleotidergic mechanisms have been studied in detail. Therefore, an isolation strategy was developed to isolate novel nucleotide compounds from human myocardium. The human myocardial tissue was fractionated by several chromatographic studies. A substance purified to homogeneity was identified as adenosine 5'-tetraphosphate (Ap(4)) by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS), post-source decay MALDI MS, and enzymatic cleavage analysis. Furthermore, Ap(4) was also identified in ventricular specific granules. In the isolated perfused rat heart, Ap(4) elicited dose-dependent vasodilations. Vasodilator responses were abolished in the presence of the P(2Y1) receptor antagonist MRS 2179 (1 microm) or the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (50 microm). After removal of the endothelium by Triton X-100, Ap(4) induced dose-dependent vasoconstrictions. Inhibition of P(2X) receptors by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (30 microm) or desensitization of P(2X) receptors by alpha,beta-methylene ATP (alpha,beta-meATP, 1 microm) diminished these vasoconstrictor responses completely. In the present study Ap(4) has been isolated from human tissue. Ap(4) was shown to exist in human myocardial tissue and was identified in ventricular specific granules. In coronary vasculature the nucleotide exerted vasodilation via endothelial P(2Y1) receptors and vasoconstriction via P(2X) receptors on vascular smooth muscle cells. Ap(4) acts as an endogenous extracellular mediator and might contribute to the regulation of coronary perfusion.     

Identification and Characterization of Rvs162/Rvs167-3, a Novel N-BAR Heterodimer in the Human Fungal Pathogen Candida albicans

Membrane reshaping resides at the core of many important cellular processes, and among its mediators are the BAR (Bin, Amphiphysin, Rvs) domain-containing proteins. We have explored the diversity and function of the Rvs BAR proteins in Candida albicans and identified a novel family member, Rvs167-3 (orf19.1861). We show that Rvs167-3 specifically interacts with Rvs162 to form a stable BAR heterodimer able to bind liposomes in vitro. A second, distinct heterodimer is formed by the canonical BAR proteins Rvs161 and Rvs167. Purified Rvs161/Rvs167 complex also binds liposomes, indicating that C. albicans expresses two functional BAR heterodimers. We used live-cell imaging to localize green fluorescent protein (GFP)-tagged Rvs167-3 and Rvs167 and show that both proteins concentrate in small cortical spots. However, while Rvs167 strictly colocalizes with the endocytic marker protein Abp1, we do not observe any colocalization of Rvs167-3 with sites of endocytosis marked by Abp1. Furthermore, the rvs167-3Δ/Δ mutant is not defective in endocytosis and strains lacking Rvs167-3 or its partner Rvs162 do not display increased sensitivity to high salt concentrations or decreased cell wall integrity, phenotypes which have been observed for rvs167Δ/Δ and rvs161Δ/Δ strains and which are linked to endocytosis defects. Taken together, our results indicate different roles for the two BAR heterodimers in C. albicans: the canonical Rvs161/Rvs167 heterodimer functions in endocytosis, whereas the novel Rvs162/Rvs167-3 heterodimer seems not to be involved in this process. Nevertheless, despite their different roles, our phenotypic analysis revealed a genetic interaction between the two BAR heterodimers, suggesting that they may have related but distinct membrane-associated functions.     

Critical thermal maxima of juvenile alligator gar (Atractosteus spatula,Lacépède, 1803) from three Mississippi‐drainage populations acclimated to three temperatures

Local adaptation may cause thermal tolerance to vary between nearby but distinct populations of a species. During the summer of 2013, alligator gar Atractosteus spatula spawned from broodstock collected from three populations within the Mississippi River drainage separated by a 5° latitudinal gradient were acclimated to three temperatures (25, 30, and 35°C). Ten fish from each population were acclimated at each temperature. CT_Max was determined at each temperature for each population, using five fish for each population‐acclimation temperature pairing. CT_Max for each population‐acclimation temperature pairing was compared using two‐factor anova . CT_Max increased significantly with acclimation temperature (F_2,40 = 600.5, P < 0.001) but population had no significant effect (F_2,40 = 1.882, P = 0.166). Temperature tolerance appears to be consistent across populations of alligator gar, with no evidence of local adaptation.     

Will a warmer and wetter future cause extinction of native Hawaiian forest birds?

Isolation of the Hawaiian archipelago produced a highly endemic and unique avifauna. Avian malaria (Plasmodium relictum), an introduced mosquito‐borne pathogen, is a primary cause of extinctions and declines of these endemic honeycreepers. Our research assesses how global climate change will affect future malaria risk and native bird populations. We used an epidemiological model to evaluate future bird–mosquito–malaria dynamics in response to alternative climate projections from the Coupled Model Intercomparison Project. Climate changes during the second half of the century accelerate malaria transmission and cause a dramatic decline in bird abundance. Different temperature and precipitation patterns produce divergent trajectories where native birds persist with low malaria infection under a warmer and dryer projection (RCP4.5), but suffer high malaria infection and severe reductions under hot and dry (RCP8.5) or warm and wet (A1B) futures. We conclude that future global climate change will cause significant decreases in the abundance and diversity of remaining Hawaiian bird communities. Because these effects appear unlikely before mid‐century, natural resource managers have time to implement conservation strategies to protect this unique avifauna from further decimation. Similar climatic drivers for avian and human malaria suggest that mitigation strategies for Hawai'i have broad application to human health.     

Half a century of oligochaete research in Estonian running waters

About 51500 specimens from 1542 samples, collected over the years 1954–1975 and 1986–1999 in different running water bodies throughout Estonia, were identified. Tubificidae prevailed in the material, with Limnodrilus hoffmeisteri forming about 40%. This species was followed by the tubificids Tubifex tubifex, Potamothrix hammoniensis, Psammoryctides barbatus, L. udekemianus and Spirosperma ferox, the naidid Stylaria lacustris, and the lumbriculid Stylodrilus heringianus. Two main ecological assemblages were distinguished: the pelophilous assemblage, dominated by L. hoffmeisteri, and the psammophilous one, where usually P. barbatus was dominant. The relationships between different species and the chemical parameters of water were usually weak but in contrast, correlated well with sediment preferences. In organically enriched reaches, L. hoffmeisteri usually dominated. The fauna of the streams of the islands was poorer in species due to their small size rather than geographical isolation. Some recent antropochorous Ponto-Caspian invaders have only reached the lowermost reaches of the two largest rivers. Some brackish water species were found in the mouth of the Pärnu River. No essential differences were found between the comparable sets of oligochaete samples collected in 1954–1975 and 1987–1997 in the Estonian running waters.