Efficacy switching SAR of mGluR5 allosteric modulators: highly potent positive and negative modulators from one chemotype

A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.     

Geography,Deer, and Host Biodiversity Shape the Pattern of Lyme Disease Emergence in the Thousand Islands Archipelago of Ontario,Canada

In the Thousand Islands region of eastern Ontario, Canada, Lyme disease is emerging as a serious health risk. The factors that influence Lyme disease risk, as measured by the number of blacklegged tick (Ixodes scapularis) vectors infected with Borrelia burgdorferi, are complex and vary across eastern North America. Despite study sites in the Thousand Islands being in close geographic proximity, host communities differed and both the abundance of ticks and the prevalence of B. burgdorferi infection in them varied among sites. Using this archipelago in a natural experiment, we examined the relative importance of various biotic and abiotic factors, including air temperature, vegetation, and host communities on Lyme disease risk in this zone of recent invasion. Deer abundance and temperature at ground level were positively associated with tick abundance, whereas the number of ticks in the environment, the prevalence of B. burgdorferi infection, and the number of infected nymphs all decreased with increasing distance from the United States, the presumed source of this new endemic population of ticks. Higher species richness was associated with a lower number of infected nymphs. However, the relative abundance of Peromyscus leucopus was an important factor in modulating the effects of species richness such that high biodiversity did not always reduce the number of nymphs or the prevalence of B. burgdorferi infection. Our study is one of the first to consider the interaction between the relative abundance of small mammal hosts and species richness in the analysis of the effects of biodiversity on disease risk, providing validation for theoretical models showing both dilution and amplification effects. Insights into the B. burgdorferi transmission cycle in this zone of recent invasion will also help in devising management strategies as this important vector-borne disease expands its range in North America.     

Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage–fusion–bridge for telomere stabilization

Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion syndrome, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion–duplication or duplication–triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in Caenorhabditis elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication.     

A “new” tree fern species from southeastern Brazil: <Emphasis Type="Italic">Cyathea myriotricha</Emphasis> (Cyatheaceae)

Morphological and plastid rbcL and trnG-R sequence data suggest that the fern currently recognized as Megalastrum lasiernos (Dryopteridaceae) is in fact a tree fern (Cyatheaceae) and a member of the Cyathea clade. Accordingly, a new combination is made: Cyathea myriotricha. Based on morphological and ecological similarities, this species appears most closely related to C. aterrima. Both species are described and illustrated herein.     

Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator

This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC₅₀ = 30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.     

Asplenium (sect. Hymenasplenium) basiscopicum, a new species from Bolivia

Asplenium basiscopicum is described, illustrated, and compared to the most similar species,A. purpurascens.     

Maternal investment and size-number trade-off in a bee, Megachile apicalis, in seasonal environments

Maternal investment in offspring size and number differed between spring- and summer-emerging individual females of Megachile apicalis, a solitary multivoltine bee. Data from experimentally initiated female populations indicated that spring-emerging females produced a relatively large number of progeny but allocated a small amount of food to each, resulting in small progeny. Adult females of larger body sizes provisioned food at a greater rate than did smaller females, and this body-size effect was significant in spring-emerging females. The large body size of these females allowed them to increase the number of progeny produced under the abundant floral resources that occurred during the spring. Conversely, summer-emerging females produced fewer progeny under the diminishing resources for brood production, but allocated each with more food, producing larger progeny, most of which emerged in the spring of the following year. Field data using trap-nests also indicated the same pattern of seasonal offspring size allocation found in the experimental populations. This maternal investment strategy entails a trade-off between the size and number of progeny, so that the daughters upon emergence can best perform in their brood production under the seasonally variable environments where they reproduce.     

6-(4-Benzylpiperazin-1-yl)benzodioxanes as selective ligands at cloned primate dopamine D(4) receptors.

A series of novel 6-(4-benzylpiperazin-1-yl)benzodioxanes were prepared and screened at selected dopamine receptor subtypes. 6-(4-[4-Chlorobenzyl]piperazin-1-yl)benzodioxane (2d) had high affinity and selectivity for the D₄ dopamine receptor subtype and was identified as a D₄ antagonist via its attenuation of dopamine-induced GTPγ³⁵S binding at the D₄ receptor.