Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists

A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).     

Insulin signaling: inositol phosphates get into the Akt

An acute but transient response to insulin is essential for glucose homeostasis in mammals. Chakraborty et?al. (2010) uncover a new feedback mechanism regulating insulin signaling. They show that the inositol pyrophosphate IP7, which is produced in response to insulin, inhibits the Akt kinase, a primary effector of insulin signaling.     

The “balance” argument and the evolution of sex

The “balance” argument suggests that if sex were maladaptive at the individual level, it would be quickly lost from species with asexual/sexual alternation. Williams has suggested an “Aphid-Rotifer” model for such species. It has the following characteristics (a) parthenogenesis is favoured when the environment is stable (b) when the environment changes qualitatively, sex generates offspring with an increased fitness variance compared to parthenogenetic progeny (c) if selection is intense and sib competition occurs then sex is favoured. It is argued here that condition (b) is not essential to the model. An increased fitness variance may be generated by the recombination of unfavourable mutations when one or more of the following occur; (1) founder effects (2) inbreeding (3) haplo-diploidy (4) intra-male competition. Parthenogenesis sustains an advantage when selection is relaxed and the possession of mutations is not reflected in differences in fitness. Sex is favoured when selection is intense and fitness reflects the possession of unfavourable mutations.     

AKT/PKB signaling: navigating downstream

The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used to characterize its true cellular targets. In addition, we discuss those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration.     

Identification of novel small RNAs in tomato (<Emphasis Type="Italic">Solanum lycopersicum</Emphasis>)

To date, the majority of plant small RNAs (sRNA) have been identified in rice, poplar and Arabidopsis. To identify novel tomato sRNAs potentially involved in tomato specific processes such as fruit development and/or ripening, we cloned 4,018 sRNAs from tomato fruit tissue at the mature green stage. From this pool of sRNAs, we detected tomato homologues of nine known miRNAs, including miR482; a poplar miRNA not conserved in Arabidopsis or rice. We identified three novel putative miRNAs with flanking sequence that could be folded into a stem-loop precursor structure and which accumulated as 19-24nt RNA. One of these putative miRNAs (Put-miRNA3) exhibited significantly higher expression in fruit compared with leaf tissues, indicating a specific role in fruit development processes. We also identified nine sRNAs that accumulated as 19–24nt RNA species in tomato but genome sequence was not available for these loci. None of the nine sRNAs or three putative miRNAs possessed a homologue in Arabidopsis that had a precursor with a predicted stem-loop structure or that accumulated as a sRNA species, suggesting that the 12 sRNAs we have identified in tomato may have a species specific role in this model fruit species. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Evidence for assortative mating on digit ratio (2D:4D), a biomarker for prenatal androgen exposure

The second-to-fourth digit ratio (2D:4D) presents an anatomical sex difference in humans. On average, men tend to have lower 2D:4D compared with women. There is fairly strong evidence for a role of the 2D:4D ratio as a biomarker for the organizational (permanent) effects of prenatal testosterone on the brain and behaviour. Recently, an accumulating research programme has shown 2D:4D to be related to a multitude of sex-dependent, hormonally influenced biosocial traits and phenotypes which reach into the domains of ability, behaviour, fertility, health, personality and sexuality. This study investigated the degree of assortative mating (spousal similarity) in a sample of 239 native Austrian couples of parental or grandparental age, all of them having reproduced. Results included: (i) significant spousal correlations of +0.19 and +0.18 for right-hand and left-hand 2D:4D, respectively, and +0.24 for average 2D:4D; (ii) no assortative mating effect on the right-minus-left difference in 2D:4D; (iii) indications consistent with a possible generational decrease of spousal similarity in 2D:4D; (iv) a prevalence of couples with a lower right-hand 2D:4D observed in the husband compared with his wife; and (v) relations of spousal 2D:4D patterns to spousal age differences, such that matings of men with more male-typical trait expressions (namely, a generally low right-hand 2D:4D or showing a lower right-minus-left 2D:4D difference than their wives) implicated larger male-minus-female age differences, i.e. younger wives. It is argued that assortative mating on 2D:4D operates indirectly and may be mediated through the assortment on other, more perceptible, physical traits and psychological phenotypes that entertain associations with 2D:4D and are relevant for courtship and mate choice.     

The role of beetle marks and flower colour on visitation by monkey beetles (hopliini) in the greater cape floral region, South Africa

BACKGROUND AND AIMS: A deviation from the classical beetle pollination syndrome of dull-coloured flowers with an unpleasant scent is found in the Greater Cape Floral Region of South Africa. Here, monkey beetles (Scarabaeidae) visit brightly coloured, odourless flowers with conspicuous dark spots and centres (beetle marks). The role of flower colour and markings in attracting monkey beetles is still poorly understood. METHODS: Artificial model flowers with different marking patterns were used to test the effect of beetle marks on visitation by monkey beetles. To test whether monkey beetles are conditioned to the colour of the local matrix species, model flowers of different colours were placed in populations of three differently coloured species of Iridaceae. KEY RESULTS: Among all three matrix species the presence of dark markings of some kind (either centres or spots) increased visitation rates but the different matrix species differed in whether the effect was due to a dark centre or to dark spots. Monkey beetles were not conditioned for the colour of the matrix species: model colour was not significant in the Hesperantha vaginata and in the Romulea monadelpha matrices, whereas yellow model flowers were preferred over orange ones in the orange-flowered Sparaxis elegans matrix. CONCLUSIONS: This study is the first to demonstrate that beetle marks attract pollinating monkey beetles in the Greater Cape Floral Region. In contrast to plants with the classical beetle pollination syndrome that use floral scent as the most important attractant of pollinating beetles, plants with the monkey beetle pollination syndrome rely on visual signals, and, in some areas at least, monkey beetles favour flowers with dark beetle markings over unmarked flowers.     

Studies on acyclic pyrimidines as inhibitors of mycobacteria

In vitro anti-mycobacterial activities of several 5-substituted acyclic pyrimidine nucleosides containing 1-(2-hydroxyethoxy)methyl and 1-[(2-hydroxy-1-(hydroxymethyl) ethoxy)methyl] acyclic moieties are investigated against three mycobacteria viz. Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium avium, which cause serious infections and mortality in healthy people as well as patients with AIDS. 1-(2-Hydroxyethoxy)methyl-5-(1-azido-2-haloethyl or 1-azidovinyl) analogs (4-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-decynyluracil (37), and 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-dodecynyluracil (38) exhibited significant in vitro anti-tubercular activity against these mycobacteria.     

NEDD1: function in microtubule nucleation, spindle assembly and beyond

Nedd1 was originally identified as a developmentally regulated gene in the mouse central nervous system. NEDD1 has homologues across a range of species, being particularly conserved in a region of WD40 repeats contained in the amino-terminal half of the protein. Human NEDD1 was recently found to localise to the centrosome and mitotic spindle. It binds to the components of the gamma-tubulin ring complex and target this complex to the centrosome and spindle. Depletion of NEDD1 causes loss of the gamma-tubulin ring complex from the centrosome and results in the failure of microtubule nucleation and spindle assembly. In addition, phosphorylation of NEDD1 during mitosis is critical for targeting gamma-tubulin to the spindle, but not the centrosome. There is still much unknown about the function of this protein and how it may be involved in development and disease. This short review summarises some of the recent work on NEDD1 and discusses how this interesting protein may have additional yet unexplored functions.     

Spatial heterogeneity in the determinants of woody plant invasion of lowland heath

Questions: 1. What is the scale and extent of spatial variability in factors affecting Betula invasion of heaths? 2. How much effect does each factor have on within‐patch patterns of invasion? 3. How can this understanding aid in managing Betula invasions? Location: Lowland heath of southern England. Methods: Determinants of Betula (both B. pubescens and B. pendula) invasion: biomass density, necromass density, mean vegetation height, P‐availability, soil water content and total Betula seed bank density, were measured at two sites on a 5‐ha sampling grid. Spatial pattern was assessed using geostatistics. Contributions of each determinant to within‐site heterogeneity in predicted Betula seedling densities were estimated by varying variables over their full and interquartile ranges in a statistical model derived from experimental data. Results: Salient spatial trends were revealed: strong autocorrelation over distances of < 50 m for soil factors and more extensive autocorrelation (0 to > 150 m) in vegetation variables and Betula seed bank densities. The latter resulted in single across‐site gradients, the former small, distinct patches. All patterns were overlain with variance that was present at distances of < 17.6 m. Variables displaying spatial pattern also accounted for within‐site heterogeneity in predicted Betula seedling densities but their relative contribution to this varied between sites. Conclusions: Identifiable spatial autocorrelation in factors controlling patch‐scale invasion patterns allows managers to target invasion prone patches, potentially reducing management intensities. Furthermore, management effort may be optimised by spatially de‐coupling Betula seed from safe‐sites. This plan may adaptable to the management of other weeds and open‐land ecosystems.