Pléistocène moyen et inférieur dans le Latium (Italie centrale)

Explorations and diggings of the Italian Institute of Human Palaeontology in Latium from 1950 to 2005, have brought out the following composite sequence: (1) for upper-middle Pleistocene of northern Latium: Travertine, gravels Acheulian-Mousterian transition, Riss. Homo (femur), Elephas antiquus, Hippopotamus, Bubalus murrensis, with upper Acheulian artefacts. (2) In middle Latium, middle Pleistocene: Volcanoclastic K-Ar 360 Ky. Below: Lower Acheulian complex and bone artefacts. Homo, Inuus, Elephas antiquus, Ursus deningeri, Dama clactoniana. Volcanic ash with Zelkowa, Buxus: caucasian flora. Hot pyroclastic flow about 15 m (50 feet) thick between 520 and 530 Ky. Limno-tuffite with Taxodiacea flora Lower-middle Pleistocene choppers artefacts below volcanic limit of 700 Ky. Southern Latium, lower Pleistocene: travertine reed Phragmites fragments. Ceprano hominid calvarium 800-900 Ky old. Gravel with chopper artefacts. Red sand with Unio shells. Lower palaeolithic gravelly sand, with very rough choppers artefacts, at Arce, Colle Marino, Colle Pece localities; at Castro dei Volsci chopper, assemblage is more evolved. Unconformity. Yellow sand layer with middle Villafranchian Anancus arvernensis and Mammuthus meridionalis fauna.     

Structural Basis for Resistance of the Genotype 2b Hepatitis C Virus NS5B Polymerase to Site A Non-Nucleoside Inhibitors

Hepatitis C virus (HCV) exists in six major genotypes. Compared with the 1b enzyme, genotype 2b HCV polymerase exhibits a more than 100-fold reduction in sensitivity to the indole-N-acetamide class of non-nucleoside inhibitors. These compounds have been shown to bind in a pocket occupied by helix A of the mobile Λ1 loop in the apoenzyme. The three-dimensional structure of the HCV polymerase from genotype 2b was determined to 1.9-Å resolution and compared with the genotype 1b enzyme. This structural analysis suggests that genotypic variants result in a different shape of the inhibitor binding site. Mutants of the inhibitor binding pocket were generated in a 1b enzyme and evaluated for their binding affinity and sensitivity to inhibition by indole-N-acetamides. Most of the point mutants showed little variation in activity and IC₅₀, with the exception of 15- and 7-fold increases in IC₅₀ for Leu392Ile and Val494Ala mutants (1b→2b), respectively. Furthermore, a 1b replicon with 20-fold resistance to this class of inhibitors was selected and shown to contain the Leu392Ile mutation. Chimeric enzymes, where the 2b fingertip Λ1 loop, pocket or both replaced the corresponding regions of the 1b enzyme, were also generated. The fingertip chimera retained 1b-like inhibitor binding affinity, whereas the other two chimeric constructs and the 2b enzyme displayed between 50- and 100-fold reduction in binding affinity. Together, these data suggest that differences in the amino acid composition and shape of the indole-N-acetamide binding pocket are responsible for the resistance of the 2b polymerase to this class of inhibitors.     

Differential roles of ATM- and Chk2-mediated phosphorylations of Hdmx in response to DNA damage

The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization in response to double strand breaks (DSBs) in DNA are regulated primarily by the ATM protein kinase. ATM mediates several posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB induction are mediated by phosphorylation of Hdmx on S403, S367, and S342, with S403 being targeted directly by ATM. Here we show that S367 phosphorylation is mediated by the Chk2 protein kinase, a downstream kinase of ATM. This phosphorylation, which is important for subsequent Hdmx ubiquitination and degradation, creates a binding site for 14-3-3 proteins which controls nuclear accumulation of Hdmx following DSBs. Phosphorylation of S342 also contributed to optimal 14-3-3 interaction and nuclear accumulation of Hdmx, but phosphorylation of S403 did not. Our data indicate that binding of a 14-3-3 dimer and subsequent nuclear accumulation are essential steps toward degradation of p53's inhibitor, Hdmx, in response to DNA damage. These results demonstrate a sophisticated control by ATM of a target protein, Hdmx, which itself is one of several ATM targets in the ATM-p53 axis of the DNA damage response.     

Bradykinin antagonists modified with dipeptide mimetic beta-turn inducers

Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers.     

Congruent embodied representations for visually presented actions and linguistic phrases describing actions

The thesis of embodied semantics holds that conceptual representations accessed during linguistic processing are, in part, equivalent to the sensory-motor representations required for the enactment of the concepts described . Here, using fMRI, we tested the hypothesis that areas in human premotor cortex that respond both to the execution and observation of actions-mirror neuron areas -are key neural structures in these processes. Participants observed actions and read phrases relating to foot, hand, or mouth actions. In the premotor cortex of the left hemisphere, a clear congruence was found between effector-specific activations of visually presented actions and of actions described by literal phrases. These results suggest a key role of mirror neuron areas in the re-enactment of sensory-motor representations during conceptual processing of actions invoked by linguistic stimuli.     

PCR-based methods to discriminateBacillus thuringiensis strains

Bacillus thuringiensis is a Gram positive bacterium that is used for the production of biopesticides. The toxic action of different strains and serovars ofB. thuringiensis can be extremely selective towards specific pests, or, in contrast, it can affect a wide variety of non-target organisms such as insects, vertebrates or humans. A reliable characterization of the cultivated strains is of primary importance for the biopesticide industry, in order to assess the contamination of the final product with strains with different pesticide actions or that might be dangerous for human health. The aim of this study was to develop useful methods for the typing of differentB. thuringiensis strains using two PCR-based methods, RAPD and Rep-PCR with BOXA1R and ERIC2 primers. The molecular fingerprints obtained using ERIC2-PCR showed a reliable ability to discriminateBacillus thuringiensis strains.