The equine DNAH3 gene: SNP discovery and exclusion of an involvement in recurrent airway obstruction (RAO) in European Warmblood horses

Recurrent airway obstruction is one of the most common airway diseases affecting mature horses. Increased bronchoalveolar mucus, neutrophil accumulation in airways, and airway obstruction are the main features of this disease. Mucociliary clearance is a key component of pulmonary defense mechanisms. Cilia are the motile part of this system and a complex linear array of dynein motors is responsible for their motility by moving along the microtubules in the axonemes of cilia and flagella. We previously detected a QTL for RAO on ECA 13 in a half-sib family of European Warmblood horses. The gene encoding DNAH3 is located in the peak of the detected QTL and encodes a dynein subunit. Therefore, we analysed this gene as a positional and functional candidate gene for RAO. In a mutation analysis of all 62 exons we detected 53 new polymorphisms including 7 non-synonymous variants. We performed an association study using 38 polymorphisms in a cohort of 422 animals. However, after correction for multiple testing we did not detect a significant association of any of these polymorphisms with RAO (P>0.05). Therefore, it seems unlikely that variants at the DNAH3 gene are responsible for the RAO QTL in European Warmblood horses.

Discovery of a highly potent anti-inflammatory epoxyisoprostane-derived lactone.

Epoxyisoprostanes EI (1) and EC (2) are effective inhibitors of the secretion of proinflammatory cytokines IL-6 and IL-12. In detailed studies toward the investigation of the molecular mode of action of these structures, a highly potent lactone (3) derived from 1 was identified. The known isoprostanoids 1 and 2 are most likely precursors of 3, the product of facile intramolecular reaction between the epoxide with the carboxylic acid in 2.

History of the Jews in America : from the period of the discovery of the new world to the present time

by Peter Wiernik

Accelerated discovery of novel benzodiazepine ligands by experiment-guided virtual screening.

High throughput discovery of ligand scaffolds for target proteins can accelerate development of leads and drug candidates enormously. Here we describe an innovative workflow for the discovery of high affinity ligands for the benzodiazepine-binding site on the so far not crystallized mammalian GABAA receptors. The procedure includes chemical biology techniques that may be generally applied to other proteins. Prerequisites are a ligand that can be chemically modified with cysteine-reactive groups, knowledge of amino acid residues contributing to the drug-binding pocket, and crystal structures either of proteins homologous to the target protein or, better, of the target itself. Part of the protocol is virtual screening that without additional rounds of optimization in many cases results only in low affinity ligands, even when a target protein has been crystallized. Here we show how the integration of functional data into structure-based screening dramatically improves the performance of the virtual screening. Thus, lead compounds with 14 different scaffolds were identified on the basis of an updated structural model of the diazepam-bound state of the GABAA receptor. Some of these compounds show considerable preference for the α3β2γ2 GABAA receptor subtype.

Implications for the Discovery of Extraterrestrial Life: A Theological Approach

Recent remarks of Pope Francis spark anew an important discussion: are we alone in the Universe? The article follows traces of the idea of extraterrestrial life throughout philosophy, evaluates the current considerations about the probability of extraterrestrial life and discusses the potential implications for the discovery of such life from a theological point of view. This “thought experiment” covers basic insights on creation, revelation and redemption.

The mass-hierarchy and CP-violation discovery reach of the LBNO long-baseline neutrino experiment

The next generation neutrino observatory proposed by the LBNO collaboration will address fundamental questions in particle and astroparticle physics. The experiment consists of a far detector, in its first stage a 20 kt LAr double phase TPC and a magnetised iron calorimeter, situated at 2300 km from CERN and a near detector based on a highpressure argon gas TPC. The long baseline provides a unique opportunity to study neutrino flavour oscillations over their 1st and 2nd oscillation maxima exploring the L/E behaviour, and distinguishing effects arising from δCP and matter. In this paper we have reevaluated the physics potential of this setup for determining the mass hierarchy (MH) and discovering CP-violation (CPV), using a conventional neutrino beam from the CERN SPS with a power of 750 kW. We use conservative assumptions on the knowledge of oscillation parameter priors and systematic uncertainties. The impact of each systematic error and the precision of oscillation prior is shown. We demonstrate that the first stage of LBNO can determine unambiguously the MH to > 5δ C.L. over the whole phase space. We show that the statistical treatment of the experiment is of very high importance, resulting in the conclusion that LBNO has ~ 100% probability to determine the MH in at most 4-5 years of running. Since the knowledge of MH is indispensable to extract δCP from the data, the first LBNO phase can convincingly give evidence for CPV on the 3δ C.L. using today’s knowledge on oscillation parameters and realistic assumptions on the systematic uncertainties.

Content Discovery in Wireless Information-Centric Networks

Information-centric networking (ICN) enables communication in isolated islands, where fixed infrastructure is not available, but also supports seamless communication if the infrastructure is up and running again. In disaster scenarios, when a fixed infrastructure is broken, content discovery algorit hms are required to learn what content is locally available. For example, if preferred content is not available, users may also be satisfied with second best options. In this paper, we describe a new content discovery algorithm and compare it to existing Depth-first and Breadth-first traversal algorithms. Evaluations in mobile scenarios with up to 100 nodes show that it results in better performance, i.e., faster discovery time and smaller traffic overhead, than existing algorithms.