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The purpose of this article is to collect and structure the various characteristics, technologies and enabling factors available in the current body of knowledge that are associated with smart manufacturing. Eventually, it is expected that this selection of characteristics, technologies and enabling factors will help compare and distinguish other initiatives such as Industry 4.0, cyber-physical production systems, smart factory, intelligent manufacturing and advanced manufacturing, which are frequently used synonymously with smart manufacturing. The result of this article is a comprehensive list of such characteristics, technologies and enabling factors that are regularly associated with smart manufacturing. This article also considers principles of ''semantic similarity'' to establish the basis for a future smart manufacturing ontology, since it was found that many of the listed items show varying overlaps; therefore, certain characteristics and technologies are merged and/or clustered. This results in a set of five defining characteristics, 11 technologies and three enabling factors that are considered relevant for the smart manufacturing scope. This article then evaluates the derived structure by matching the characteristics and technology clusters of smart manufacturing with the design principles of Industry 4.0 and cyber-physical systems. The authors aim to provide a solid basis to start a broad and interdisciplinary discussion within the research and industrial community about the defining characteristics, technologies and enabling factors of smart manufacturing.

Abstract.A vision for the Operator 4.0 is presented in this paper in the context of human cyber-physical systems and adaptive automation towards humanautomation symbiosis work systems for a socially sustainable manufacturing workforce. Discussions include base concepts and enabling technologies for the development of human-automation symbiosis work systems in Industry 4.0.

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ABSTRACT:(R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine (PF02341066) was identified as an orally available, ATP-competitive small molecule inhibitor of cMet receptor tyrosine kinase. The objectives of the present studies were to characterize 1) the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF02341066 to cMet phosphorylation in tumor (biomarker) and 2) the relationship of cMet phosphorylation to antitumor efficacy (pharmacological response). Athymic mice implanted with GTL16 gastric carcinoma or U87MG glioblastoma xenografts were treated with PF02341066 once daily at doses selected to encompass ED 50 values. Plasma concentrations of PF02341066 were best described by a one-compartment pharmacokinetic model. A time-delay (hysteresis) was observed between the plasma concentrations of PF02341066 and the cMet phosphorylation response. A link model was therefore used to account for this hysteresis. The model fitted the time courses of cMet phosphorylation well, suggesting that the main reason for the hysteresis is a rate-limiting distribution from plasma into tumor. The EC 50 and EC 90 values were estimated to be 19 and 167 ng/ml, respectively. For tumor growth inhibition, the exponential tumor growth model fitted the time courses of individual tumor growth inhibition well. The EC 50 for the GTL16 tumor growth inhibition was estimated to be 213 ng/ml. Thus, the EC 90 for the inhibition of cMet phosphorylation corresponded to the EC 50 for the tumor growth inhibition, suggesting that near-complete inhibition of cMet phosphorylation (>90%) is required to significantly inhibit tumor growth (>50%). The present results will be helpful in determining the appropriate dosing regimen and in guiding dose escalation to rapidly achieve efficacious systemic exposure in the clinic.Pharmacokinetic-pharmacodynamic (PKPD) modeling is increasingly being applied in drug discovery and development. Specific applications include 1) the selection of drug candidates with most favorable PKPD properties and 2) the prediction of exposure response in patients with the aim of optimizing the design of early clinical trials. The increased understanding of drug action derived from PKPD-based drug development leads to more information, especially with regard to the identification of drug dosage regimen that results in optimal therapeutic outcome (Derendorf et al., 2000;Lesko et al., 2000;Chien et al., 2005). The use of PKPD modeling in this context relies on prediction of the time course of drug effects in patients, using information from preclinical investigation. Preclinical studies are useful alternatives to investigate PKPD relationships to get insight into the in vivo mechanism of drug action. The integration of PKPD modeling and simulation in drug development has provided opportunities to accelerate the evaluation of new chemical entities in the clinic. Thus, the PKPD investigation could contribute to shortening the overall period of drug development.

An analysis of the conjugative transfer of pRetCFN42d, the symbiotic plasmid (pSym) of Rhizobium etli, has revealed a novel gene, rctA, as an essential element of a regulatory system for silencing the conjugative transfer of R. etli pSym by repressing the transcription of conjugal transfer genes in standard laboratory media. The rctA gene product lacks sequence conservation with other proteins of known function but may belong to the winged-helix DNA-binding subfamily of transcriptional regulators. Similar to that of many transcriptional repressors, rctA transcription seems to be positively autoregulated. rctA expression is greatly reduced upon overexpression of another gene, rctB, previously identified as a putative activator of R. etli pSym conjugal transfer. Thus, rctB seems to counteract the repressive action of rctA. rctA homologs are present in at least three other bacterial genomes within the order Rhizobiales, where they are invariably located adjacent to and divergently transcribed from putative virB-like operons. We show that similar to that of R. etli pSym, conjugative transfer of the 1.35-Mb symbiotic megaplasmid A of Sinorhizobium meliloti is also subjected to the inhibitory action of rctA. Our data provide strong evidence that the R. etli and S. meliloti pSym plasmids are indeed self-conjugative plasmids and that this property would only be expressed under optimal, as yet unknown conditions that entail inactivation of the rctA function. The rctA gene seems to represent novel but probably widespread regulatory systems controlling the transfer of conjugative elements within the order Rhizobiales.

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