PhAST : pharmacophore alignment search tool

We developed the Pharmacophore Alignment Search Tool (PhAST), a text-based technique for rapid hit and lead structure searching in large compound databases. For each molecule, a two-dimensional graph of potential pharmacophoric points (PPPs) is created, which has an identical topology as the original molecule with implicit hydrogen atoms. Each vertex is coloured by a symbol representing the corresponding PPP. The vertices of the graph are canonically labelled. The symbols associated with the vertices are combined to a so-called PhAST-Sequence beginning with the vertex with the lowest canonical label. Due to the canonical labelling the created PhAST-Sequence is characteristic for each molecule. For similarity assessment, PhAST-Sequences are compared using the sequence identity in their global pairwise alignment. The alignment score lies between 0 (no similarity) and 1 (identical PhAST-Sequences). In order to use global pairwise sequence alignment, a score matrix for pharmacophoric symbols was developed and gap penalties were optimized. PhAST performed comparably and sometimes superior to other similarity search tools (CATS2D, MOE pharmacophore quadruples) in retrospective virtual screenings using the COBRA collection of drugs and lead structures. Most importantly, the PhAST alignment technique allows for the computation of significance estimates that help prioritize a virtual hit list

Evidence for >5 Ma paleo-exposure of an Eocene–Miocene paleosol of the Bohnerz Formation, Switzerland

We obtained (U–Th)/He formation ages and cosmogenic ^3He concentrations for pisoliths from a paleosol of the Bohnerz Formation (Siderolithic) of Central Europe. The paleosol is exposed in the Almenbühl quarry near Lohn, Canton Schaffhausen, Switzerland. The paleosol consists of red clay of 3–4 m thickness developed on deeply weathered Jurassic limestone and overlain by Early Miocene conglomerates. The (U–Th)/He formation ages of the pisoliths are between 50 Ma and 8 Ma, with most ages being older than 17 Ma. There is a sharp decline in the frequency of ages at the time of burial of the paleosol at 17 Ma. These ages are inconsistent with the previous assumption that the Bohnerz Formation formed in a Cretaceous to Early Eocene laterite in a tropical climate. We propose that the Bohnerz Formation more closely resembles Terra Rossa soils, which do not require a tropical climate to form. The ^3He concentration in the pisoliths is roughly constant with depth throughout the paleosol at 300 Matoms/g. We interpret this as the result of soil convection during cosmic ray exposure. The minimum exposure duration at the surface of the paleosol is ∼5 Ma. A simple model of soil convection shows that the true exposure duration of the paleosol is approximately 10–20 Ma. These results indicate that the clay soils of the Bohnerz formation were continuously exposed at the surface for millions of years. Since the paleosol was covered by conglomerate since 17 Ma, the ^3He measured here was produced by cosmic ray exposure before burial. Cosmogenic ^3He concentrations measured in fine-grained soil iron-oxides (<1 μm) are similar to those measured in pisoliths. This might indicate that fine-grained iron-oxides are retentive to helium and might be used for studying the formation and cosmic ray exposure of modern soils and paleosols

Taking Lithography to the Third Dimension

Stereolithography is a new technology which allows the rapid building of plastic models directly from CAD data. The photopolymers needed for this process are developed at Ciba's research center in Marly by a project team from the Polymers Division and the corporate Materials Research. The stereolithography process is described as well as the requirements for the photosensitive monomer formulations. Two types of stereolithography resins have been developed so far: acrylate mixtures which polymerize by a radical mechanism and epoxy-based formulations which are cured cationically. The acrylate resins polymerize very rapidly and several formulations with different mechanical properties are available. Cationic resins are a development of the past two years. They are less photosensitive than the acrylates, but have other advantages, such as low viscosity, high green strength and very high dimensional accuracy. With these resins, parts can be built which can be used directly as patterns for the investment casting process

Evaluation of the LaserCyte: an in-house hematology analyzer for dogs and cats

In the present study, the LaserCyte instrument, a fully automated flow cytometer for use in veterinary practice, was evaluated for dogs and cats. Precision (coefficient of variation, CV) for red blood cell (RBC) parameters was ≤3.9%, for reticulocytes between 14.9 and 102%, for white blood cells (WBC) between 3 and 9.5%, for neutrophils between 3.9 and 6.5%, for lymphocytes between 7 and 17.9%, for monocytes between 4.9 and 13.1%, for eosinophils between 10.4 and 32.1%, for basophils between 7.8 and 32%, for platelets between 3.1 and 13.2%, and for platelet indices between 0 and 28.2%. The range of linearity extended the reference ranges. The agreement with reference methods (coefficient of correlation, r) were ≥0.96 (RBC), ≥0.94 (hematocrit), ≥0.96 (hemoglobin), ≥0.95 (mean corpuscular volume), ≥0.94 (WBC), ≥0.93 (neutrophils), ≥0.77 (lymphocytes), ≥0.77 (monocytes), ≥0.29 (eosinophils), ≥0.03 (basophils), ≥0.13 (reticulocytes), and ≥0.86 (platelets). The LaserCyte allowed the correct assessment of RBC and WBC parameters with respect to clinical relevance in the majority of samples. Lymphocytopenia was detected in only 51 out of 89 cases and monocytopenia in one out of 11 cases. The reticulocyte counts were correctly estimated in 85 out of 149 cases. It was concluded that the LaserCyte allowed reliable determination of the RBC parameters, WBCs, neutrophils in both species and platelets in dogs. Based on its capability to reliably determine feline platelets and of the parameters mentioned above, this instrument is considered a useful in-house analyzer for the veterinary practice. Qualitative microscopic assessment of blood smears is still necessary for detecting abnormal cell morphologies, certain cell precursors and blood parasite

Design of dual ligands using excessive pharmacophore query alignment : from 7th German Conference on Chemoinformatics: 25 CIC-Workshop Goslar, Germany, 6 - 8 November 2011

Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands

Exploring Causal Relationships Among Emotional and Topical Trajectories in Political Text Data

We explore relationships between dynamics of emotion (arousal and valence) and topical stability in political discourse in two diachronic corpora of Austrian German. In doing so, we assess interactions among emotional and topical dynamics related to political parties as well as interactions between two different domains of discourse: debates in the parliament and journalistic media. Methodologically, we employ unsupervised techniques, time-series clustering and Granger-causal modeling to detect potential interactions. We find that emotional and topical dynamics in the media are only rarely a reflex of dynamics in parliamentary discourse