Intergeneric hybridization between Psathyrostachys and Hordeum

A total of 38 intergeneric combinations with Hordeum and Psathyrostachys was attempted. Generally the seed set was high, and 23 new intergeneric hybrid combinations were synthesized by the aid of embryo culture technique. All combinations showed complete sterility. The meiotic pairing behaviour in 8 combinations is reported. On the basis of these data it is clear that the N genome in Psathyrostachys is distinct and shows no genomic relationship, neither with the "X" and I nor with the H genomes in Hordeum.     

Gestational and Early Infancy Exposure to Margarine Fortified with Vitamin D through a National Danish Programme and the Risk of Type 1 Diabetes: The D-Tect Study

The objective of the study was to assess whether gestational and early infancy exposure to low dose vitamin D from a mandatory margarine fortification programme in Denmark influenced the risk of developing type 1 diabetes (T1D) before age of 15 years. The study population included all individuals born in Denmark from 1983 to 1988 and consisted of 331,623 individuals. The 1^st of June 1985, which was the date of issue of the new ministerial order cancelling mandatory fortification of margarine with vitamin D in Denmark, served as a reference point separating the studied population into various exposure groups. We further modelled birth cohort effects in children developing T1D as a linear spline, and compared the slopes between the birth cohorts with various prenatal and infancy exposures to vitamin D fortification. In total, 886 (0.26%) individuals developed T1D before the age of 15 years. The beta coefficients (95% CI), or slopes, for linear birth cohort effect in log Hazard Ratio (HR) per one month of birth in individuals born during the periods of gestational exposure, wash-out, and non-exposure were: 0.010 (-0.002/0.021), -0.010 (-0.035/0.018), and 0.008 (- 0.017/0.032), respectively. The beta coefficients (95% CI) for individuals born during the periods of first postnatal year exposure, wash-out, and non-exposure were: 0.007 (-0.016/0.030), 0.006 (-0.004/0.016), and 0.007 (-0.002/0.016), respectively. In conclusion, we found no evidence to support that exposure to low dose vitamin D from the Danish mandatory margarine fortification regimen during gestational and first postnatal year of life changed the risk of developing T1D before the age of 15 years.     

Invertebrate Metacommunity Structure and Dynamics in an Andean Glacial Stream Network Facing Climate Change

Under the ongoing climate change, understanding the mechanisms structuring the spatial distribution of aquatic species in glacial stream networks is of critical importance to predict the response of aquatic biodiversity in the face of glacier melting. In this study, we propose to use metacommunity theory as a conceptual framework to better understand how river network structure influences the spatial organization of aquatic communities in glacierized catchments. At 51 stream sites in an Andean glacierized catchment (Ecuador), we sampled benthic macroinvertebrates, measured physico-chemical and food resource conditions, and calculated geographical, altitudinal and glaciality distances among all sites. Using partial redundancy analysis, we partitioned community variation to evaluate the relative strength of environmental conditions (e.g., glaciality, food resource) vs. spatial processes (e.g., overland, watercourse, and downstream directional dispersal) in organizing the aquatic metacommunity. Results revealed that both environmental and spatial variables significantly explained community variation among sites. Among all environmental variables, the glacial influence component best explained community variation. Overland spatial variables based on geographical and altitudinal distances significantly affected community variation. Watercourse spatial variables based on glaciality distances had a unique significant effect on community variation. Within alpine catchment, glacial meltwater affects macroinvertebrate metacommunity structure in many ways. Indeed, the harsh environmental conditions characterizing glacial influence not only constitute the primary environmental filter but also, limit water-borne macroinvertebrate dispersal. Therefore, glacier runoff acts as an aquatic dispersal barrier, isolating species in headwater streams, and preventing non-adapted species to colonize throughout the entire stream network. Under a scenario of glacier runoff decrease, we expect a reduction in both environmental filtering and dispersal limitation, inducing a taxonomic homogenization of the aquatic fauna in glacierized catchments as well as the extinction of specialized species in headwater groundwater and glacier-fed streams, and consequently an irreversible reduction in regional diversity.     

Speciation and demographic history of Atlantic eels (Anguilla anguilla and A. rostrata) revealed by mitogenome sequencing

Processes leading to speciation in oceanic environments without obvious physical barriers remain poorly known. European and American eel (Anguilla anguilla and A. rostrata) spawn in partial sympatry in the Sargasso Sea. Larvae are advected by the Gulf Stream and other currents towards the European/North African and North American coasts, respectively. We analyzed 104 mitogenomes from the two species along with mitogenomes of other Anguilla and outgroup species. We estimated divergence time between the two species to identify major events involved in speciation. We also considered two previously stated hypotheses: one where the ancestral species was present in only one continent but was advected across the Atlantic by ocean current changes and another where population declines during Pleistocene glaciations led to increasing vicariance, facilitating speciation. Divergence time was estimated to ∼3.38 Mya, coinciding with the closure of the Panama Gateway that led to reinforcement of the Gulf Stream. This could have advected larvae towards European/North African coasts, in which case American eel would be expected to be the ancestral species. This scenario could, however, not be unequivocally confirmed by analyses of dN/dS, nucleotide diversity and effective population size estimates. Extended bayesian skyline plots showed fluctuations of effective population sizes and declines during glaciations, and thus also lending support to the importance of vicariance during speciation. There was evidence for positive selection at the ATP6 and possibly ND5 genes, indicating a role in speciation. The findings suggest an important role of ocean current changes in speciation of marine organisms.     

Design and synthesis of aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors with enhanced brain permeability

The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..     

Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors

8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S₁ to the S₃ pocket.