Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library

A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm . Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one scaffold that showed sub‐micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold‐hopping exercise led to the identification of a 1H‐pyrazolo[3,4‐b]pyridine scaffold, which retained potency. A number of examples were assessed in a T. b. brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one series were found to be either static or growth‐slowing and not cidal. Compounds with the 1H‐pyrazolo[3,4‐b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms.     

VEGFR-1 Overexpression Identifies a Small Subgroup of Aggressive Prostate Cancers in Patients Treated by Prostatectomy

The VEGFR-1 is suggested to promote tumor progression. In the current study we analyzed prevalence and prognostic impact of the VEGFR-1 by immunohistochemistry on a tissue microarray containing more than 3000 prostate cancer specimens. Results were compared to tumor phenotype, ETS-related gene (ERG) status, and biochemical recurrence. Membranous VEGFR-1 expression was detectable in 32.6% of 2669 interpretable cancers and considered strong in 1.7%, moderate in 6.7% and weak in 24.2% of cases. Strong VEGFR-1 expression was associated with TMPRSS2:ERG fusion status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (p < 0.0001 each). Elevated VEGFR-1 expression was linked to high Gleason grade and advanced pT stage in TMPRSS2:ERG negative cancers (p = 0.0008 and p = 0.001), while these associations were absent in TMPRSS2:ERG positive cancers. VEGFR-1 expression was also linked to phosphatase and tensin homolog (PTEN) deletions. A comparison with prostate specific antigen (PSA) recurrence revealed that the 1.7% of prostate cancers with the highest VEGFR-1 levels had a strikingly unfavorable prognosis. This could be seen in all cancers, in the subsets of TMPRSS2:ERG positive or negative, PTEN deleted or undeleted carcinomas (p < 0.0001 each). High level VEGFR-1 expression is infrequent in prostate cancer, but identifies a subgroup of aggressive cancers, which may be candidates for anti-VEGFR-1 targeted therapy.     

Transforming arbitrary tables into logical form with TARTAR

The tremendous success of the World Wide Web is countervailed by efforts needed to search and find relevant information. For tabular structures embedded in HTML documents, typical keyword or link-analysis based search fails. The Semantic Web relies on annotating resources such as documents by means of ontologies and aims to overcome the bottleneck of finding relevant information. Turning the current Web into a Semantic Web requires automatic approaches for annotation since manual approaches will not scale in general. Most efforts have been devoted to automatic generation of ontologies from text, but with quite limited success. However, tabular structures require additional efforts, mainly because understanding of table contents requires the comprehension of the logical structure of the table on the one hand, as well as its semantic interpretation on the other. The focus of this paper is on the automatic transformation and generation of semantic (F-Logic) frames from table-like structures. The presented work consists of a methodology, an accompanying implementation (called TARTAR) and a thorough evaluation. It is based on a grounded cognitive table model which is stepwise instantiated by the methodology. A typical application scenario is the automatic population of ontologies to enable query answering over arbitrary tables (e.g. HTML tables).     

A discontinuous phase field approach to variational growth-based topology optimization

Numerical instabilities cause the well-known problem of checkerboarding during topology optimization: elements that possess material are periodically neighbored to elements that are material-free. Furthermore, such numerical solutions depend on the finite element mesh and no reasonable processing techniques exist for manufacture. Thus, integral- or gradient-based regularization techniques are usually applied during topology optimization. In this paper, a novel approach to regularization is derived for a recently published variational approach to topology optimization that is based on material growth. The presented approach shares some similarities with the discontinuous Galerkin method and completely removes consideration of additional nodal quantities or complex integration schemes. The derivation and numerical treatment of the resulting phase field equation as well as exemplary numerical results are presented.     

Hypothesis generation in climate research with interactive visual data exploration

One of the most prominent topics in climate research is the investigation, detection, and allocation of climate change. In this paper, we aim at identifying regions in the atmosphere (e.g., certain height layers) which can act as sensitive and robust indicators for climate change. We demonstrate how interactive visual data exploration of large amounts of multi-variate and time-dependent climate data enables the steered generation of promising hypotheses for subsequent statistical evaluation. The use of new visualization and interaction technology--in the context of a coordinated multiple views framework--allows not only to identify these promising hypotheses, but also to efficiently narrow down parameters that are required in the process of computational data analysis. Two datasets, namely an ECHAM5 climate model run and the ERA-40 reanalysis incorporating observational data, are investigated. Higher-order information such as linear trends or signal-to-noise ratio is derived and interactively explored in order to detect and explore those regions which react most sensitively to climate change. As one conclusion from this study, we identify an excellent potential for usefully generalizing our approach to other, similar application cases, as well.     

High availability,elasticity, and strong consistency for massively parallel scans over relational data

An elastic and highly available data store is a key component of many cloud applications. Existing data stores with strong consistency guarantees are designed and optimized for small updates, key-value access, and (if supported) small range queries over a predefined key column. This raises performance and availability problems for applications which inherently require large updates, non-key access, and large range queries. This paper presents a solution to these problems: Crescando/RB; a distributed, scan-based, main memory, relational data store (single table) with robust performance and high availability. The system addresses a real, large-scale industry use case: the Amadeus travel management system. This paper focuses on the distribution layer of Crescando/RB, the problem and theory behind it, the rationale underlying key design decisions, and the novel multicast protocol and replication framework it is composed of. Highlighting the key features of the distribution layer, we present experimental results showing that even under permanent node failures and large-scale data repartitioning, Crescando/RB remains fully available and capable of sustaining a heavy query and update load.     

On the design of filters for fourier and oSVD-based deconvolution in bolus tracking perfusion MRI

Object  

Bolus tracking perfusion evaluation relies on the deconvolution of a tracers concentration time-courses in an arterial and a tissue voxel following the tracer kinetic model. The object of this work is to propose a method to design a data-driven Tikhonov regularization filter in the Fourier domain and to compare it to the singular value decomposition (SVD)–based approaches using the mathematical equivalence of Fourier and circular SVD (oSVD).     

Eine neue Methode zur Authentizitätsprüfung von Zitronenölen mit HPLC

For the control of the correctness of lemon oils essentially photometric methods are used. They are based on the absorbance of the coumarins and psoralens in the oils. For adulteration purposes substances with absorbance properties similar to those of the naturally occurring ones can be added, thus pretending a higher concentration and quality. -The presented HPLC method offers new possibilities for an easy, quick and precise characterization of lemon oils. Adulteration with ethylp-dimethylaminobenzoate and menthyl anthranilate can be proved without problems. The detection limit is so low that an adulteration of this kind is no longer attractive. When the usual photometric determination of the so-called CD value is applied for quality control, largely higher amounts must be added to give a delusive effect. In addition to this, the method allows statements on the provenance of the oil. In the case of concentrated oils the real degree of concentration can be checked.     

Regional differences in endothelial function in horse lungs: possible role in blood flow distribution?

We investigated regional differences of in vitro responses of pulmonary arteries (6-mm OD) from the dorsocaudal (top) and cranioventral (bottom) lung regions to endothelium-dependent vasodilators (methacholine, bradykinin, and calcium ionophore A-23187). Methacholine relaxed endothelium-intact top vessels; however, in bottom vessels, a small relaxation preceded a profound contraction. In top vessels, removal of endothelial cells converted relaxation to contraction, and in bottom vessels it abolished relaxation and enhanced contraction. Bradykinin and A-23187 were more potent and caused greater endothelium-mediated relaxation in top than in bottom arteries. The endothelium-independent vasodilator sodium nitroprusside caused similar relaxations in all rings. Nomega-nitro-L-arginine and NG-monomethyl-L-arginine and methylene blue abolished relaxation of top and bottom arteries to methacholine; meclofenamate had little effect. We conclude that regional differences in endothelium-mediated relaxation are caused by differences in the magnitude of the endothelial release of nitric oxide. Similar differences in endothelium-dependent flow-mediated vasodilation and endothelial nitric oxide release may result in preferential perfusion of caudodorsal lung regions.