Synthesis of tetrazole analogues of phosphonohydroxamic acids: An attempt to improve the inhibitory activity against the DXR

This work is focused on the design of new antimicrobial drugs and on the development of lipophilic inhibitors of the DXR, the second enzyme of the MEP pathway for the biosynthesis of isoprene units in most bacteria, by replacing the phosphonate group of fosmidomycin derivatives by a tetrazoyl moiety capable of multiple hydrogen bonding. The N- and C-substituted tetrazole analogues of phosphonohydroxamate inhibitors were synthesized and tested on the DXR of Escherichia coli. This work points out the hypothesis that the phosphonate/phosphate recognition site might be too rigid to accommodate other functional groups.     

Pervasive selection or is it…? why are FST outliers sometimes so frequent?

It is now common for population geneticists to estimate F_ST for a large number of loci across the genome, before testing for selected loci as being outliers to the F_ST distribution. One surprising result of such F_ST scans is the often high proportion (>1% and sometimes >10%) of outliers detected, and this is often interpreted as evidence for pervasive local adaptation. In this issue of Molecular Ecolog, Fourcade et al. ( 2013 ) observe that a particularly high rate of F_ST outliers has often been found in river organisms, such as fishes or damselflies, despite there being no obvious reason why selection should affect a larger proportion of the genomes of these organisms. Using computer simulations, Fourcade et al. ( 2013 ) show that the strong correlation in co‐ancestry produced in long one‐dimensional landscapes (such as rivers, valleys, peninsulas, oceanic ridges or coastlines) greatly increases the neutral variance in F_ST, especially when the landscape is further reticulated into fractal networks. As a consequence, outlier tests have a high rate of false positives, unless this correlation can be taken into account. Fourcade et al.'s study highlights an extreme case of the general problem, first noticed by Robertson ( 1975a , b ) and Nei & Maruyama ( 1975 ), that correlated co‐ancestry inflates the neutral variance in F_ST when compared to its expectation under an island model of population structure. Similar warnings about the validity of outlier tests have appeared regularly since then but have not been widely cited in the recent genomics literature. We further emphasize that F_ST outliers can arise in many different ways and that outlier tests are not designed for situations where the genetic architecture of local adaptation involves many loci.     

The impact of strain diversity and mixed infections on the evolution of resistance to Bacillus thuringiensis

Pesticide mixtures can reduce the rate at which insects evolve pesticide resistance. However, with live biopesticides such as the naturally abundant pathogen Bacillus thuringiensis (Bt), a range of additional biological considerations might affect the evolution of resistance. These can include ecological interactions in mixed infections, the different rates of transmission post-application and the impact of the native biodiversity on the frequency of mixed infections. Using multi-generation selection experiments, we tested how applications of single and mixed strains of Bt from diverse sources (natural isolates and biopesticides) affected the evolution of resistance in the diamondback moth, Plutella xylostella, to a focal strain. There was no significant difference in the rate of evolution of resistance between single and mixed-strain applications although the latter did result in lower insect populations. The relative survivorship of Bt-resistant genotypes was higher in the mixed-strain treatment, in part owing to elevated mortality of susceptible larvae in mixtures. Resistance evolved more quickly with treatments that contained natural isolates, and biological differences in transmission rate may have contributed to this. Our data indicate that the use of mixtures can have unexpected consequences on the fitness of resistant and susceptible insects.     

N1,N3-disubstituted uracils as nonnucleoside inhibitors of HIV-1 reverse transcriptase

A series of phenyloxyethyl and cinnamyl derivatives of substituted uracils were synthesized and found to exhibit potent activity against HIV-RT and HIV replication in cell culture. In general, the cinnamyl derivatives proved superior to the phenyloxyethyl derivatives, however 1-[2-(4-methylphenoxy)ethyl]-3-(3,5-dimethylbenzyl)uracil (19) exhibited the highest activity (EC₅₀ = 0.27 μM) thus confirming that the 3-benzyluracil fragment in the NNRTI structure can be regarded as a functional analogue of the benzophenone pharmacophore typically found in NNRTIs.     

Ion channels of glutamate receptors: structural modeling

Ionotropic glutamate receptors belong to the superfamily of P-loop channels as well as K⁺, Na⁺, and Ca²⁺ channels. However, the structural similarity between ion channels of the glutamate receptors and K⁺ channels is a matter of discussion. The aim of this study was to analyze differences between the structures of K⁺ channels and glutamate receptor channels. For this purpose, homology models of NMDA and AMPA receptor channels (M2 and M3 segments) were built using X-ray structures of K⁺ channels as templates. The models were optimized and used to reproduce specific data on the structure of glutamate receptor channels. Particular attention was paid to the data of the binding of channel blockers and to the results of scanning mutagenesis. The modeling demonstrates that properties of glutamate receptor channel can be reproduced assuming only local structural deformations of the K⁺ channel templates. The most valuable differences were found in the selectivity-filter region, whereas helical parts of M2 and M3 segments could have similar spatial organization with homologous segments in K⁺ channels. It is concluded that the current experimental data on glutamate receptor channels does not reveal global structural differences with K⁺ channels.     

Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof

HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC₅₀ values within 5.5–12 μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure–activity relationship for the linker region.     

Composition,diversity and distribution of microbenthos across the intertidal zones of Ryazhkov Island (the White Sea)

The composition and distribution of the main unicellular eukaryotic groups (diatom algae, ciliates, dinoflagellates (DF), other phototrophic (PF) and heterotrophic flagellates (HF)) were investigated in sandy sediments at five stations allocated across the tidal sheltered beach of the White Sea. Overall, 75 diatoms, 98 ciliates, 16 DF, 3 PF and 34 HF species were identified; some are new records for the White Sea. Common species for each group are illustrated. Diatoms and ciliates showed high alpha-diversity (species richness per sample), whereas flagellates were characterized by high beta-diversity (species turnover across the intertidal flat). Each group demonstrated its own spatial pattern that was best matched with its own subset of abiotic variables, reflecting group-specific responses to environmental gradients. Species richness increased from the upper intertidal zone seaward for ciliates but decreased for HF, whereas autotrophs showed a relatively uniform pattern with a slight peak at the mid-intertidal zone. Across the littoral zone, all groups showed distinct compositional changes; however, the position of the boundary between “upper” and “lower” intertidal communities varied among groups. Most of the species found at Ryazhkov Island are known from many other regions worldwide, indicating a wide geographic distribution of microbial eukaryotic species.     

The control of branching morphogenesis

Many organs of higher organisms are heavily branched structures and arise by an apparently similar process of branching morphogenesis. Yet the regulatory components and local interactions that have been identified differ greatly in these organs. It is an open question whether the regulatory processes work according to a common principle and how far physical and geometrical constraints determine the branching process. Here, we review the known regulatory factors and physical constraints in lung, kidney, pancreas, prostate, mammary gland and salivary gland branching morphogenesis, and describe the models that have been formulated to analyse their impacts.     

Base-Calling Algorithm with Vocabulary (BCV) Method for Analyzing Population Sequencing Chromatograms

Sanger sequencing is a common method of reading DNA sequences. It is less expensive than high-throughput methods, and it is appropriate for numerous applications including molecular diagnostics. However, sequencing mixtures of similar DNA of pathogens with this method is challenging. This is important because most clinical samples contain such mixtures, rather than pure single strains. The traditional solution is to sequence selected clones of PCR products, a complicated, time-consuming, and expensive procedure. Here, we propose the base-calling with vocabulary (BCV) method that computationally deciphers Sanger chromatograms obtained from mixed DNA samples. The inputs to the BCV algorithm are a chromatogram and a dictionary of sequences that are similar to those we expect to obtain. We apply the base-calling function on a test dataset of chromatograms without ambiguous positions, as well as one with 3–14% sequence degeneracy. Furthermore, we use BCV to assemble a consensus sequence for an HIV genome fragment in a sample containing a mixture of viral DNA variants and to determine the positions of the indels. Finally, we detect drug-resistant Mycobacterium tuberculosis strains carrying frameshift mutations mixed with wild-type bacteria in the pncA gene, and roughly characterize bacterial communities in clinical samples by direct 16S rRNA sequencing.     

Conservation Efforts May Increase Malaria Burden in the Brazilian Amazon

Background

Large-scale forest conservation projects are underway in the Brazilian Amazon but little is known regarding their public health impact. Current literature emphasizes how land clearing increases malaria incidence, leading to the conclusion that forest conservation decreases malaria burden. Yet, there is also evidence that proximity to forest fringes increases malaria incidence, which implies the opposite relationship between forest conservation and malaria. We compare the effect of these environmental factors on malaria and explore its implications.

Methods and Findings

Using a large malaria dataset (∼1,300,000 positive malaria tests collected over ∼4.5 million km²), satellite imagery, permutation tests, and hierarchical Bayesian regressions, we show that greater forest cover (as a proxy for proximity to forest fringes) tends to be associated with higher malaria incidence, and that forest cover effect was 25 times greater than the land clearing effect, the often cited culprit of malaria in the region. These findings have important implications for land use/land cover (LULC) policies in the region. We find that cities close to protected areas (PA’s) tend to have higher malaria incidence than cities far from PA’s. Using future LULC scenarios, we show that avoiding 10% of deforestation through better governance might result in an average 2-fold increase in malaria incidence by 2050 in urban health posts.

Conclusions

Our results suggest that cost analysis of reduced carbon emissions from conservation efforts in the region should account for increased malaria morbidity, and that conservation initiatives should consider adopting malaria mitigation strategies. Coordinated actions from disparate science fields, government ministries, and global initiatives (e.g., Reduced Emissions from Deforestation and Degradation; Millenium Development Goals; Roll Back Malaria; and Global Fund to Fight AIDS, Tuberculosis and Malaria), will be required to decrease malaria toll in the region while preserving these important ecosystems.