Antioxidant responses of cortex neurons to iron loading

Brain cells have a highly active oxidative metabolism, yet they contain only low to moderate superoxide dismutase and catalase activities. Thus, their antioxidant defenses rely mainly on cellular reduced glutathione levels. In this work, in cortical neurons we characterized viability and changes in reduced and oxidized glutathione levels in response to a protocol of iron accumulation. We found that massive death occurred after 2 days in culture with 10 microM Fe. Surviving cells developed an adaptative response that included increased synthesis of GSH and the maintenance of a glutathione-based reduction potential. These results highlight the fundamental role of glutathione homeostasis in the antioxidant response and provide novel insights into the adaptative mechanisms of neurons subjected to progressive iron loads.     

Linking ecology,morphology, and metabolism: Niche differentiation in sympatric populations of closely related species of the genus Littorina (Neritrema)

Divergence of ecological niches in phylogenetically closely related species indicates the importance of ecology in speciation, especially for sympatric species are considered. Such ecological diversification provides an advantage of alleviating interspecies competition and promotes more efficient exploitation of environmental resources, thus being a basis for ecological speciation. We analyzed a group of closely related species from the subgenus Neritrema (genus Littorina, Caenogastropoda) from the gravel‐bouldery shores. In two distant sites at the Barents and Norwegian Sea, we examined the patterns of snail distribution during low tide (quantitative sampling stratified by intertidal level, presence of macrophytes, macrophyte species, and position on them), shell shape and its variability (geometric morphometrics), and metabolic characteristics (metabolomic profiling). The studied species diversified microbiotopes, which imply an important role of ecological specification in the recent evolution of this group. The only exception to this trend was the species pair L. arcana / L. saxatilis, which is specifically discussed. The ecological divergence was accompanied by differences in shell shape and metabolomic characteristics. Significant differences were found between L. obtusata versus L. fabalis and L. saxatilis / L. arcana versus L. compressa both in shell morphology and in metabolomes. L. saxatilis demonstrated a clear variability depending on intertidal level which corresponds to a shift in conditions within the occupied microhabitat. Interestingly, the differences between L. arcana (inhabiting the upper intertidal level) and L. compressa (inhabiting the lower one) were analogous to those between the upper and lower fractions of L. saxatilis. No significant level‐dependent changes were found between the upper and lower fractions of L. obtusata, most probably due to habitat amelioration by fucoid macroalgae. All these results are discussed in the contexts of the role of ecology in speciation, ecological niche dynamics and conservatism, and evolutionary history of the Neritrema species.     

Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.     

Synthesis of Modified Thiopurine Nucleosides for Structural Characterization of Human Thiopurine S-Methyltransferase

Abstract

Synthesis of a number of photoactive thiopurine-containing nucleosides was described. S-methylation of the synthesized compounds in the course of the reaction catalyzed by recombinant human thiopurine S-methyltransferase was studied by UV-spectroscopy.     

Polymorphisms in ten candidate genes are associated with conformational and locomotive traits in Spanish Purebred horses

The Spanish Purebred horses, also known as Andalusian horses, compete to the highest standards in international dressage events. Gait and conformation could be used as early selection criteria to detect young horses with promising dressage ability. Although the genetic background of equine size variation has been recently uncovered, the genetic basis of horse conformational and locomotive traits is not known, hampered by the complex genetic architecture underlying quantitative traits and the lack of phenotypic data. The aim of this study was to validate the loci associated with size in 144 Spanish Purebred horses, and to seek novel associations between loci previously associated with the development of osteochondrosis (OC) lesions and 20 conformational and locomotive traits. Ten loci were associated with different conformational and locomotive traits (LCORL/NCAPG, HMGA2, USP31, MECR, COL24A1, MGP, FAM184B, PTH1R, KLF3 and SGK1), and the LCORL/NCAPG association with size in the Spanish Purebred horse was validated. Except for HMGA2, all polymorphisms seem to influence both the prevalence of OC lesions and morphological characters, supporting the link between conformation and OC. Also, the implication of most genes in either immune and inflammatory responses and cellular growth, or ossification processes, reinforces the role that these mechanisms have in the aetiology of OC, as well as their reflection on the general conformation of the individual. These polymorphisms could be used in marker-assisted selection (MAS) programmes to improve desirable conformational traits, but taking into account their possible detrimental effect on OC prevalence.     

Mutational analysis of the stator subunit E of the yeast V-ATPase

Subunit E is a component of the peripheral stalk(s) that couples membrane and peripheral subunits of the V-ATPase complex. In order to elucidate the function of subunit E, site-directed mutations were performed at the amino terminus and carboxyl terminus. Except for S78A and D233A/T202A, which exhibited V(1)V(o) assembly defects, the function of subunit E was resistant to mutations. Most mutations complemented the growth phenotype of vma4Delta mutants, including T6A and D233A, which only had 25% of the wild-type ATPase activity. Residues Ser-78 and Thr-202 were essential for V(1)V(o) assembly and function. The mutation S78A destabilized subunit E and prevented assembly of V(1) subunits at the membranes. Mutant T202A membranes exhibited 2-fold increased V(max) and about 2-fold less of V(1)V(o) assembly; the mutation increased the specific activity of V(1)V(o) by enhancing the k(cat) of the enzyme 4-fold. Reduced levels of V(1)V(o) and V(o) complexes at T202A membranes suggest that the balance between V(1)V(o) and V(o) was not perturbed; instead, cells adjusted the amount of assembled V-ATPase complexes in order to compensate for the enhanced activity. These results indicated communication between subunit E and the catalytic sites at the A(3)B(3) hexamer and suggest potential regulatory roles for the carboxyl end of subunit E. At the carboxyl end, alanine substitution of Asp-233 significantly reduced ATP hydrolysis, although the truncation 229-233Delta and the point mutation K230A did not affect assembly and activity. The implication of these results for the topology and functions of subunit E within the V-ATPase complex are discussed.     

Eveningness is associated with higher risk-taking in dangerous driving situations

Inclination toward eveningness is often associated with risky behavior. But the existing studies are scarce, inconsistent and usually limited to self-reported measures. We sought to investigate in young adults whether morningness-eveningness is associated with risky behavior in dangerous driving situations, with self-reported drunk driving and with alcohol consumption. Results show that, indeed, inclination toward eveningness is associated with these risky behaviors. We also demonstrate a link between morningness-eveningness and sensation seeking. Therefore, young adults with a tendency toward eveningness might be more at risk to face negative consequences of alcohol abuse or to be involved in a road accident.     

No population genetic structure in a widespread aquatic songbird from the Neotropics

Neotropical lowland organisms often show marked population genetic structure, suggesting restricted migration among populations. However, most phylogeographic studies have focused on species inhabiting humid forest interior. Little attention has been devoted to the study of species with ecologies conducive to dispersal, such as those of more open and variable environments associated with watercourses. Using mtDNA sequences, we examined patterns of genetic variation in a widely distributed Neotropical songbird of aquatic environments, the Yellow-hooded Blackbird (Icteridae, Chrysomus icterocephalus). In contrast to many forest species, Yellow-hooded Blackbirds showed no detectable genetic structure across their range, which includes lowland populations on both sides of the Andes, much of northeastern South America, Amazonia, as well as a phenotypically distinct highland population in Colombia. A coalescent-based analysis of the species indicated that its effective population size has increased considerably, suggesting a range expansion. Our results support the hypothesis that species occurring in open habitats and tracking temporally dynamic environments should show increased dispersal propensities (hence gene flow) relative to species from closed and more stable environments. The phenotypic and behavioral variation among populations of our study species appears to have arisen recently and perhaps in the face of gene flow.