Acetylcholinesterase (AChE) inhibition is one of the most currently available therapies for the management of Alzheimer’s disease (AD) symptoms. In this context, NMR spectroscopy binding studies were accomplished to explain the inhibition of AChE activity by Salvia sclareoides extracts. HPLC-MS analyses of the acetone, butanol and water extracts eluted with methanol and acidified water showed that rosmarinic acid is present in all the studied samples and is a major constituent of butanol and water extracts. Moreover, luteolin 4′-O-glucoside, luteolin 3′,7-di-O-glucoside and luteolin 7-O-(6′′-O-acetylglucoside) were identified by MS2 and MS3 data acquired during the LC-MSn runs. Quantification of rosmarinic acid by HPLC with diode-array detection (DAD) showed that the butanol extract is the richest one in this component (134 μg mg−1 extract). Saturation transfer difference (STD) NMR spectroscopy binding experiments of S. sclareoides crude extracts in the presence of AChE in buffer solution determined rosmarinic acid as the only explicit binder for AChE. Furthermore, the binding epitope and the AChE-bound conformation of rosmarinic acid were further elucidated by STD and transferred NOE effect (trNOESY) experiments. As a control, NMR spectroscopy binding experiments were also carried out with pure rosmarinic acid, thus confirming the specific interaction and inhibition of this compound against AChE. The binding site of AChE for rosmarinic acid was also investigated by STD-based competition binding experiments using Donepezil, a drug currently used to treat AD, as a reference. These competition experiments demonstrated that rosmarinic acid does not compete with Donepezil for the same binding site. A 3D model of the molecular complex has been proposed. Therefore, the combination of the NMR spectroscopy based data with molecular modelling has permitted us to detect a new binding site in AChE, which could be used for future drug development.

The continuing size reduction of electronic devices imposes design challenges to optimize the performances of modern electronic systems, such as: wireless services, telecom and mobile computing. Fortunately, those design challenges can be overcome thanks to the development of Electronic Design Automation (EDA) tools. In the analog, mixed signal and radio-frequency (AMS/RF) domains, circuit optimization tools have demonstrated their usefulness in addressing design problems taking into account downscaling technological aspects. Recent advances in EDA have shown that the simulation-based sizing technique is a very interesting solution to the ‘complex’ modelling task in the circuit design optimization problem. In this paper we propose a multi-objective simulation-based optimization tool. A CMOS LC-VCO circuit is presented to show the viability of this tool. The tool is used to generate the Pareto front linking two conflicting objectives, namely the VCO Phase Noise and Power Consumption. The accuracy of the results is checked against HSPICE/RF simulations.

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Prion protein (PrPC) biosynthesis involves a multi-step process that includes translation and post-translational modifications. While PrP has been widely investigated, for the homolog Doppel (Dpl), limited knowledge is available. In this study, we focused on a vital step of eukaryotic protein biosynthesis: targeting by the signal recognition particle (SRP). Taking the ovine Dpl (OvDpl(1-30)) peptide as a template, we studied its behavior in two different hydrophobic environments using CD and NMR spectroscopy. In both trifluoroethanol (TFE) and dihexanoyl-sn-glycero-3-phosphatidylcholine (DHPC), the OvDpl(1-30) peptide revealed to fold in an alpha-helical conformation with a well-defined central region extending from residue Cys8 until Ser22. The NMR structure was subsequently included in a computational docking complex with the conserved M-domain of SRP54 protein (SRP54M), and further compared with the N-terminal structures of mouse Dpl and bovine PrPC proteins. This allowed the determination of (i) common predicted N-terminal/SRP54M polar contacts (Asp331, Gln335, Glu365 and Lys432) and (ii) different N–C orientations between prion and Dpl peptides at the SRP54M hydrophobic groove, that are in agreement with each peptide electrostatic potential. Together, these findings provide new insights into the biosynthesis of prion-like proteins. Besides they also show the role of protein conformational switches in signalization toward the endoplasmic membrane, a key event of major significance in the cell cycle. They are thus of general applicability to the study of the biological function of prion-like as well as other proteins.

The paper analyses numerical solutions for the process leading to debonding failure of fiber reinforced polymers (FRP)-to-concrete interfaces in shear tests with the FRP plate subjected to a tensile load at one end. Any realistic local nonlinear bond-slip law can be used in the numerical analysis proposed in the present study. However, only a Popovics’ type expression is employed in the numerical process due to its use in different studies found in the literature. Effective bond length (Leff) is discussed and an expression depending on the Popovics’ constant (nP) is proposed to calculate it. Assuming a fracture in pure Mode II, the debonding process is analyzed in detail and distributions of bond stresses and strains in the FRP plate along the interface are presented. The load-displacement behaviour is also presented and the influence of the local bond-slip law on the debonding process is discussed.

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This paper is discussing the intuitive interaction with robotic systems and the conceptualisation connected with known organisational problems. In particular, the focus will be on the manufacturing industry with respect to its social dimension. One of the aims is to identify relevant research questions about the possibility of development of safer robot systems in closer human-machine intuitive interaction systems at the manufacturing shop-floor level. We try to contribute to minimize the cognitive and perceptual workload for robot operators in complex working systems. In particular that will be highly relevant when more different robots with different roles and produced by different companies or designers are to be used in the manufacturing industry to a larger extent. The social sciences approach to such technology assessment is of high relevance to understand the dimensions of the intuitive interaction concept.

Titanosauriforms represent a diverse and globally distributed clade of neosauropod dinosaurs, but their inter-relationships remain poorly understood. Here we redescribe Lusotitan atalaiensis from the Late Jurassic Lourinhã Formation of Portugal, a taxon previously referred to Brachiosaurus. The lectotype includes cervical, dorsal, and caudal vertebrae, and elements from the forelimb, hindlimb, and pelvic girdle. Lusotitan is a valid taxon and can be diagnosed by six autapomorphies, including the presence of elongate postzygapophyses that project well beyond the posterior margin of the neural arch in anterior-to-middle caudal vertebrae. A new phylogenetic analysis, focused on elucidating the evolutionary relationships of basal titanosauriforms, is presented, comprising 63 taxa scored for 279 characters. Many of these characters are heavily revised or novel to our study, and a number of ingroup taxa have never previously been incorporated into a phylogenetic analysis. We treated quantitative characters as discrete and continuous data in two parallel analyses, and explored the effect of implied weighting. Although we recovered monophyletic brachiosaurid and somphospondylan sister clades within Titanosauriformes, their compositions were affected by alternative treatments of quantitative data and, especially, by the weighting of such data. This suggests that the treatment of quantitative data is important and the wrong decisions might lead to incorrect tree topologies. In particular, the diversity of Titanosauria was greatly increased by the use of implied weights. Our results support the generic separation of the contemporaneous taxa Brachiosaurus, Giraffatitan, and Lusotitan, with the latter recovered as either a brachiosaurid or the sister taxon to Titanosauriformes. Although Janenschia was recovered as a basal macronarian, outside Titanosauria, the sympatric Australodocus provides body fossil evidence for the pre-Cretaceous origin of titanosaurs. We recovered evidence for a sauropod with close affinities to the Chinese taxon Mamenchisaurus in the Late Jurassic Tendaguru beds of Africa, and present new information demonstrating the wider distribution of caudal pneumaticity within Titanosauria. The earliest known titanosauriform body fossils are from the late Oxfordian (Late Jurassic), although trackway evidence indicates a Middle Jurassic origin. Diversity increased throughout the Late Jurassic, and titanosauriforms did not undergo a severe extinction across the Jurassic/Cretaceous boundary, in contrast to diplodocids and non-neosauropods. Titanosauriform diversity increased in the Barremian and Aptian–Albian as a result of radiations of derived somphospondylans and lithostrotians, respectively, but there was a severe drop (up to 40%) in species numbers at, or near, the Albian/Cenomanian boundary, representing a faunal turnover whereby basal titanosauriforms were replaced by derived titanosaurs, although this transition occurred in a spatiotemporally staggered fashion.

This research has been motivated by a real-life problem of a waste cooking oil collection system characterized by the existence of multiple depots with an outsourced vehicle fleet, where the collection routes have to be plan. The routing problem addressed allows open routes between depots, i.e., all routes start at one depot but can end at the same or at a different one, depending on what minimizes the objective function considered. Such problem is referred as a Multi-Depot Vehicle Routing Problem with Mixed Closed and Open Inter-Depot Routes and is, in this paper, modeled through a Mixed Integer Linear Programming (MILP) formulation where capacity and duration constraints are taken into account. The model developed is applied to the real case study providing, as final results, the vehicle routes planning where a decrease of 13% on mileage and 11% on fleet hiring cost are achieved, when comparing with the current company solution.