Towards a Rule-based Manufacturing Integration Assistant

Recent developments and steadily declining prices in ICT enable an economic application of advanced digital tools in wide areas of manufacturing. Solutions based on concepts and technologies of the “Internet of Things” or “cyber physical systems” can be used to implement monitoring as well as self-organization of production, maintenance or logistics processes. However, integration of new digital tools in existing heterogeneous manufacturing IT systems and integration of machines and devices into manufacturing environments is an expensive and tedious task. Therefore, integration issues on IT and manufacturing level significantly prevent agile manufacturing. Especially small and medium-sized enterprises do not have the expertise or the investment possibilities to realize such an integration. To tackle this issue, we present the approach of the Manufacturing Integration Assistant - MIALinx. The objective is to develop and implement a lightweight and easy-to-use integration solution for small and medium-sized enterprises based on recent web automation technologies. MIALinx aims to simplify the integration using simple programmable, flexible and reusable “IF-THEN” rules that connect occurring situations in manufacturing, such as a machine break down, with corresponding actions, e.g., an automatic maintenance order generation. For this purpose, MIALinx connects sensors and actuators based on defined rules whereas the rule set is defined in a domain-specific, easy-to-use manner to enable rule modeling by domain experts. Through the definition of rule sets, the workers’ knowledge can be also externalized. Using manufacturing-approved cloud computing technologies, we enable robustness, security, and a low-effort, low-cost integration of MIALinx into existing manufacturing environments to provide advanced digital tools also for small and medium-sized enterprises

Lifespan extension and the doctrine of double effect

Recent developments in biogerontology—the study of the biology of ageing—suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan—a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the ‘double effect argument’, has gone unnoticed. This article exposes and critically evaluates this ‘double effect argument’. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the ‘double effect argument’ is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning

Systematic Comparison of Three Methods for Fragmentation of Long-Range PCR Products for Next Generation Sequencing

Next Generation Sequencing (NGS) technologies are gaining importance in the routine clinical diagnostic setting. It is thus desirable to simplify the workflow for high-throughput diagnostics. Fragmentation of DNA is a crucial step for preparation of template libraries and various methods are currently known. Here we evaluated the performance of nebulization, sonication and random enzymatic digestion of long-range PCR products on the results of NGS. All three methods produced high-quality sequencing libraries for the 454 platform. However, if long-range PCR products of different length were pooled equimolarly, sequence coverage drastically dropped for fragments below 3,000 bp. All three methods performed equally well with regard to overall sequence quality (PHRED) and read length. Enzymatic fragmentation showed highest consistency between three library preparations but performed slightly worse than sonication and nebulization with regard to insertions/deletions in the raw sequence reads. After filtering for homopolymer errors, enzymatic fragmentation performed best if compared to the results of classic Sanger sequencing. As the overall performance of all three methods was equal with only minor differences, a fragmentation method can be chosen solely according to lab facilities, feasibility and experimental design

Engineered hybrid spider silk particles as delivery system for peptide vaccines

The generation of strong T-cell immunity is one of the main challenges for the development of successful vaccines against cancer and major infectious diseases. Here we have engineered spider silk particles as delivery system for a peptide-based vaccination that leads to effective priming of cytotoxic T-cells. The recombinant spider silk protein eADF4(C16) was fused to the antigenic peptide from ovalbumin, either without linker or with a cathepsin cleavable peptide linker. Particles prepared from the hybrid proteins were taken up by dendritic cells, which are essential for T-cell priming, and successfully activated cytotoxic T-cells, without signs of immunotoxicity or unspecific immunostimulatory activity. Upon subcutaneous injection in mice, the particles were taken up by dendritic cells and accumulated in the lymph nodes, where immune responses are generated. Particles from hybrid proteins containing a cathepsin-cleavable linker induced a strong antigen-specific proliferation of cytotoxic T-cells in vivo, even in the absence of a vaccine adjuvant. We thus demonstrate the efficacy of a new vaccine strategy using a protein-based all-in-one vaccination system, where spider silk particles serve as carriers with an incorporated peptide antigen. Our study further suggests that engineered spider silk-based vaccines are extremely stable, easy to manufacture, and readily customizable

Are Better Workers Also Better Humans? On Pharmacological Cognitive Enhancement in the Workplace and Conflicting Societal Domains

The article investigates the sociocultural implications of the changing modern workplace and of pharmacological cognitive enhancement (PCE) as a potential adaptive tool from the viewpoint of social niche construction. We will attempt to elucidate some of the sociocultural and technological trends that drive and influence the characteristics of this specific niche, and especially to identify the kind of capabilities and adaptations that are being promoted, and to ascertain the capabilities and potentialities that might become diminished as a result. In this context, we will examine what PCE is, and how and why it might be desirable as a tool for adaptation within the workplace. As human beings are, or at least should be allowed to be, more than merely productive, able-bodied and able-minded workers, we will further examine how adaptation to the workplace niche could result in problems in other domains of modern societal life that require the same or other cognitive capabilities. In this context we will also focus on the concept of responsibility and how it pertains to PCE and the modern workplace niche. This will shed some light on the kind of trends related to workplace niche construction, PCE and capability promotion that we can expect in the future, and on the contexts in which this might be either beneficial or detrimental to the individual as a well-rounded human being, and to other members of society

The Role of Monocytes in Angiogenesis and Atherosclerosis

New vessel formation inside the arterial wall and atherosclerotic plaques plays a critical role in pathogenesis of heart attacks and strokes. The 2 known mechanisms resulting in the formation of new vessels within the plaque are local ischemia and inflammation. Blood monocytes play an important role in both processes. First, they express receptors for vascular endothelial growth factor and some of them may serve as circulating ancestors of endothelial cells. Second, monocytes are associated with inflammation by synthesis of inflammatory molecules following their activation (e.g., after stimulation of Toll-like receptors). Neovascularization is a reparative response to ischemia, and includes 3 processes: angiogenesis, arteriogenesis, and vasculogenesis. Angiogenesis, the formation of new capillary vessels is known to occur in response to a hypoxic environment. The interaction between leukocytes and vascular wall via overexpression of various molecules facilitates the migration of inflammatory cells into the plaque microenvironment. Monocytes are intimately involved in tissue damage and repair and an imbalance of these processes may have detrimental consequences for plaque development and stability. Importantly, monocytes are comprised of distinct subsets with different cell surface markers and functional characteristics and this heterogeneity may be relevant to angiogenic processes in atherosclerosis. The aim of this review article is to present an overview of the available evidence supporting a role for monocytes in angiogenesis and atherosclerosis

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer

Objective: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2). Design: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-Analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-Analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as â € positive' and â € less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin. Results: We initially identified 18 independent variants at 16 loci that were classified as â € positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as â € less-credible positive' SNPs; 72.2% of the â € positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to â € less-credible' positive (reducing the â € positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-Analyses found no evidence to support their associations with CRC risk. Conclusion: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.</p

A Mouse Model of Post-Arthroplasty Staphylococcus aureus Joint Infection to Evaluate In Vivo the Efficacy of Antimicrobial Implant Coatings

Post-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs.To evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5x10(3) and 5x10(4) CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5x10(2) CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin-impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation.Taken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections

Impairment of circulating endothelial progenitors in Down syndrome

<p>Abstract</p> <p>Background</p> <p>Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome.</p> <p>Methods</p> <p>Circulating endothelial progenitors of Down syndrome affected individuals were isolated, <it>in vitro </it>cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of <it>CXCL12 </it>gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis.</p> <p>Results</p> <p>We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells.</p> <p>Conclusions</p> <p>Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.</p