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Homologous recombination requires nucleolytic degradation (resection) of DNA double-strand break ( DSB) ends. In Saccharomyces cerevisiae, the MRX complex and Sae2 are involved in the onset of DSB resection, whereas extensive resection requires Exo1 and the concerted action of Dna2 and Sgs1. Here, we show that the checkpoint protein Rad9 limits the action of Sgs1/Dna2 in DSB resection by inhibiting Sgs1 binding/persistence at the DSB ends. When inhibition by Rad9 is abolished by the Sgs1-ss mutant variant or by deletion of RAD9, the requirement for Sae2 and functional MRX in DSB resection is reduced. These results provide new insights into how early and long-range resection is coordinated. [ABSTRACT FROM AUTHOR]

Recognition of the identity of familiar faces in conditions with poor visibility or over large changes in head angle, lighting and partial occlusion is far more accurate than recognition of unfamiliar faces in similar conditions. Here we used a visual search paradigm to test if one class of social cues transmitted by faces-direction of another's attention as conveyed by gaze direction and head orientation-is perceived more rapidly in personally familiar faces than in unfamiliar faces. We found a strong effect of familiarity on the detection of these social cues, suggesting that the times to process these signals in familiar faces are markedly faster than the corresponding processing times for unfamiliar faces. In the light of these new data, hypotheses on the organization of the visual system for processing faces are formulated and discussed. [ABSTRACT FROM AUTHOR]

The Mec1 and Rad53 protein kinases are essential for budding yeast cell viability and are also required to activate the S-phase checkpoint, which supports DNA replication under stress conditions. Whether these two functions are related to each other remains to be determined, and the nature of the replication stress-dependent lethality of mec1 and rad53 mutants is still unclear. We show here that a decrease in cyclin-dependent kinase 1 (Cdk1) activity alleviates the lethal effects of mec1 and rad53 mutations both in the absence and in the presence of replication stress, indicating that the execution of a certain Cdk1-mediated event(s) is detrimental in the absence of Mec1 and Rad53. This lethality involves Cdk1 functions in both G1 and mitosis. In fact, delaying either the G1/S transition or spindle elongation in mec1 and rad53 mutants allows their survival both after exposure to hydroxyurea and under unperturbed conditions. Altogether, our studies indicate that inappropriate entry into S phase and segregation of incompletely replicated chromosomes contribute to cell death when the S-phase checkpoint is not functional. Moreover, these findings suggest that the essential function of Mec1 and Rad53 is not necessarily separated from the function of these kinases in supporting DNA synthesis under stress conditions. [ABSTRACT FROM AUTHOR]

We designed an fMRI experiment comparing perception of human faces and robotic faces producing emotional expressions. The purpose of our experiment was to investigate engagement of different parts of the social brain by viewing these animate and inanimate agents. Both human and robotic face expressions evoked activity in face-responsive regions in the fusiform gyrus and STS and in the putative human mirror neuron system. These results suggest that these areas mediate perception of agency, independently of whether the agents are living or not. By contrast, the human faces evoked stronger activity than did robotic faces in the medial pFC and the anterior temporal cortex—areas associated with the representation of others’ mental states (theory of mind), whereas robotic faces evoked stronger activity in areas associated with perception of objects and mechanical movements. Our data demonstrate that the representation of the distinction between animate and inanimate agents involves areas that participate in attribution of mental stance. [ABSTRACT FROM AUTHOR]

Abstract: We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na+,K+-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na+,K+-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na+,K+-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency. [Copyright &y& Elsevier]

We report the synthesis and biological properties of novel inhibitors of the Na +,K +-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5α,14α-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the ( E)-3-[( R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the Eisomers of the oxime are more potent than the Zform. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na +,K +-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5α,14α-androstane. [ABSTRACT FROM AUTHOR]

Digitalis compounds are used in the treatment of congestive heart failure as positive inotropic agents; their action is mainly due to the inhibition of Na + ,K + -ATPase. A well-known drawback is their arrhythmogenic potential. Attempts to find safer digitalis-like compounds by means of molecular simplifications of the typical 5 β ,14 β -steroidal skeleton, which appeared in the medicinal chemistry literature from 1990 until 2002, are briefly reviewed. Several novel achievements were obtained in order to better understand the requisites of the digitalis binding site on Na + , K + -ATPase. Only minor simplification, such as cleavage of the D ring of the digitalis skeleton, could preserve the desired inotropic activity, while highly simplified digitalis-like compounds failed to give sufficiently high inotropic potency, even in the presence of a powerful pharmacophore, such as the O -aminoalkyloxime group. [ABSTRACT FROM AUTHOR]