Interoperable multimedia metadata through similarity-based semantic web service discovery

The increasing availability of multimedia (MM) resources, Web services as well as content, on the Web raises the need to automatically discover and process resources out of distributed repositories. However, the heterogeneity of applied metadata schemas and vocabularies – ranging from XML-based schemas such as MPEG-7 to formal knowledge representation approaches – raises interoperability problems. To enable MM metadata interoperability by means of automated similarity-computation, we propose a hybrid representation approach which combines symbolic MM metadata representations with a grounding in so-called Conceptual Spaces (CS). In that, we enable automatic computation of similarities across distinct metadata vocabularies and schemas in terms of spatial distances in shared CS. Moreover, such a vector-based approach is particularly well suited to represent MM metadata, given that a majority of MM parameters is provided in terms of quantified metrics. To prove the feasibility of our approach, we provide a prototypical implementation facilitating similarity-based discovery of publicly available MM services, aiming at federated MM content retrieval out of heterogeneous repositories

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

A semi-automated intestinal organoid screening method demonstrates epigenetic control of epithelial maturation

The intestinal epithelium maintains an important barrier throughout life. It consists of several epithelial cell lineages that are derived from LGR5+ intestinal stem cells. Although epigenetic regulation of embryonic stem cell differentiation is well established, its role in adult stem cell systems such as the intestinal epithelium is still undefined. Yet, targeting of epigenetic regulatory enzymes may be relevant for new therapeutics, for example in cancer treatment. Here, we combine a newly established organoid toolbox with an epigenetic probe library to identify epigenetic regulators of intestinal epithelial biology. We discover several probes that alter intestinal epithelial biology including those targeting HDACs, EP300/CREBBP, LSD1, and type I PRMTs. We conclude that epigenetic modifiers are primarily involved in mediating maturation of the epithelium rather than dictating specific cell lineage differentiation. Furthermore, we show that inhibiting type I PRMTs, which leads to epithelial maturation, blocks the growth of adenoma but not normal organoid cultures. Thus, epigenetic probes are a powerful tool in defining biological processes and demonstrate therapeutic potential

A semi-automated organoid screening method demonstrates epigenetic control of intestinal epithelial differentiation

Intestinal organoids are an excellent model to study epithelial biology. Yet, the selection of analytical tools to accurately quantify heterogeneous organoid cultures remains limited. Here, we developed a semi-automated organoid screening method, which we applied to a library of highly specific chemical probes to identify epigenetic regulators of intestinal epithelial biology. The role of epigenetic modifiers in adult stem cell systems, such as the intestinal epithelium, is still undefined. Based on this resource dataset, we identified several targets that affected epithelial cell differentiation, including HDACs, EP300/CREBBP, LSD1, and type I PRMTs, which were verified by complementary methods. For example, we show that inhibiting type I PRMTs, which leads enhanced epithelial differentiation, blocks the growth of adenoma but not normal organoid cultures. Thus, epigenetic probes are powerful tools to study intestinal epithelial biology and may have therapeutic potential

Pentafluorosulfanyl (SF(5)) as a superior (19)F magnetic resonance reporter group: signal detection and biological activity of teriflunomide derivatives

Fluorine ((19)F) magnetic resonance imaging (MRI) is severely limited by a low signal-to noise ratio (SNR), and tapping it for (19)F drug detection in vivo still poses a significant challenge. However, it bears the potential for label-free theranostic imaging. Recently, we detected the fluorinated dihydroorotate dehydrogenase (DHODH) inhibitor teriflunomide (TF) noninvasively in an animal model of multiple sclerosis (MS) using (19)F MR spectroscopy (MRS). In the present study, we probed distinct modifications to the CF(3) group of TF to improve its SNR. This revealed SF(5) as a superior alternative to the CF(3) group. The value of the SF(5) bioisostere as a (19)F MRI reporter group within a biological or pharmacological context is by far underexplored. Here, we compared the biological and pharmacological activities of different TF derivatives and their (19)F MR properties (chemical shift and relaxation times). The (19)F MR SNR efficiency of three MRI methods revealed that SF(5)-substituted TF has the highest (19)F MR SNR efficiency in combination with an ultrashort echo-time (UTE) MRI method. Chemical modifications did not reduce pharmacological or biological activity as shown in the in vitro dihydroorotate dehydrogenase enzyme and T cell proliferation assays. Instead, SF(5)-substituted TF showed an improved capacity to inhibit T cell proliferation, indicating better anti-inflammatory activity and its suitability as a viable bioisostere in this context. This study proposes SF(5) as a novel superior (19)F MR reporter group for the MS drug teriflunomide

The Shale Revolution: Global Gas and Oil Markets Under Transformation

Abstract The shale gas and oil revolution has unexpectedly and forcefully begun to change the energy landscape in the USA. It is expected to spread beyond the USA, with far reaching implications for the global energy map, but also for the macroeconomy and politics of many countries. The purpose of this paper is to bring a better understanding to what prompted the revolution, to assess the production methods and associated environmental concerns, to speculate what can reasonably be expected in coming decades, and to sketch the full impact of a ripening shale revolution on the emerging economic and political policy choices for energy exporting and importing countries. We find that a large scale expansion can be expected in US shale gas and oil activities in the coming two decades. Globally, the shale leaders are likely to be countries that are already significant gas and oil producers. Setting up a policy framework to allow and promote shale development in a safe manner is a necessity for the launch of shale exploitation. The most important implication of a successful shale revolution would arguably be a downward pressure on gas and coal prices in regional markets and on the global oil price