Contextualized B2B Registries

Abstract. Service discovery is a fundamental concept underpinning the move towards dynamic service-oriented business partnerships. The business process for integrating service discovery and underlying registry technologies into business relationships, procurement and project management functions has not been examined and hence existing Web Service registries lack capabilities required by business today. In this paper we present a novel contextualized B2B registry that supports dynamic registration and discovery of resources within management contexts to ensure that the search space is constrained to the scope of authorized and legitimate resources only. We describe how the registry has been deployed in three case studies from important economic sectors (aerospace, automotive, pharmaceutical) showing how contextualized discovery can support distributed product development processes

State Enterprise in International Mineral Markets

This study explores the implications for the international non-fuel mineral markets of the rapid growth of state enterprise in the mining and processing of minerals in the less developed countries (LDC). The first part defines state enterprise, and quantifies its prevalence and growth in LDC mineral industries. The particular characteristics of state enterprises are identified, and the implications of their behavior for international mineral markets are analyzed. In this regard, three hypotheses are formulated and assessed. 1) State enterprises are less flexible than private multinationals in adjusting capacity through the different phases of the business cycle. The increasing importance of state enterprises therefore results in greater price instability in international mineral markets. 2) State enterprises can disregard the political risk of explicit or covert nationalization. Ceteris paribus, the proliferation of state enterprise therefore results in more investment and capacity expansion in mineral rich LDCs that are considered especially "political risky" by the mining multinationals. Over time, this will lead to a closer geographical fit between geological potential and mineral extraction. 3) Takeovers by state enterprises of mineral activities in LDCs entails a substantial setting-up and learning cost. The widespread nationalizations of the 1960s and 1970s have typically been followed by extended periods of lesser efficiency, characterized by higher cost levels, and inability to operate the installations at full capacity or to establish new capacity. Output has been lower and prices higher during this learning period than they would have been under an uninterrupted private multinational regime. The second part of the study considers the support for the above hypotheses provided by three detailed case studies of nationalized mineral industries -- Indonesian tin, Venezuelan iron ore, and Zambian copper. These cases cover a range of experience in terms of minerals, continents, and levels of economic development in host countries. The third and final part of the study reviews the hypotheses in the light of the empirical work presented. Conclusions are formulated and generalizations derived from other countries and minerals

Test exploration and validation using transaction level models

The complexity of the test infrastructure and test strategies in systems-on-chip approaches the complexity of the functional design space. This paper presents test design space exploration and validation of test strategies and schedules using transaction level models (TLMs). Since many aspects of testing involve the transfer of a significant amount of test stimuli and responses, the communication-centric view of TLMs suits this purpose exceptionally wel

Revealing cytotoxic substructures in molecules using deep learning

In drug development, late stage toxicity issues of a compound are the main cause of failure in clinical trials. In silico methods are therefore of high importance to guide the early design process to reduce time, costs and animal testing. Technical advances and the ever growing amount of available toxicity data enabled machine learning, especially neural networks, to impact the field of predictive toxicology. In this study, cytotoxicity prediction, one of the earliest handles in drug discovery, is investigated using a deep learning approach trained on a highly consistent in-house data set of over 34,000 compounds with a share of less than 5% of cytotoxic molecules. The model reached a balanced accuracy of over 70%, similar to previously reported studies using Random Forest. Albeit yielding good results, neural networks are often described as a black box lacking deeper mechanistic understanding of the underlying model. To overcome this absence of interpretability, a Deep Taylor Decomposition method is investigated to identify substructures that may be responsible for the cytotoxic effects, the so-called toxicophores. Furthermore, this study introduces cytotoxicity maps which provide a visual structural interpretation of the relevance of these substructures. Using this approach could be helpful in drug development to predict the potential toxicity of a compound as well as to generate new insights into the toxic mechanism. Moreover, it could also help to de-risk and optimize compounds

Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin's lymphoma

Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted now a high-throughput pharmacological screening based on more than 28,000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote re-expression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of two of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the anti-leukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked re-expression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell Non-Hodgkin's lymphoma-tailored small compound inhibitors Ibrutinib and Idelalisib. In essence, we report here a conceptually novel, re-differentiation-based treatment strategy for cHL

High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs

Organotypic culture systems from disease-specific induced pluripotent stem cells (iPSCs) exhibit obvious advantages compared with immortalized cell lines and primary cell cultures, but implementation of iPSC-based high-throughput (HT) assays is still technically challenging. Here, we demonstrate the development and conduction of an organotypic HT Cl/I exchange assay using cystic fibrosis (CF) disease-specific iPSCs. The introduction of a halide-sensitive YFP variant enabled automated quantitative measurement of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function in iPSC-derived intestinal epithelia. CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of 42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format

Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis

BACKGROUND: The pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome-targeting treatment strategies for irritant contact dermatitis. METHODS: A high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck-like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)-1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome-mediated cytokines IL-1β and IL-18. RESULTS: Disulfiram induced a dose-dependent inhibition of ASC speck formation and IL-1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS-induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p < 0.001) and/or mometasone (p < 0.001). Also, corneocyte IL-18 levels were significantly reduced after application of disulfiram compared to vehicle (p < 0.001). CONCLUSION: We show that disulfiram is a dose-dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS-induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis