Discovery of Riociguat (BAY 63‐2521): A Potent,Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension

Direct stimulation of soluble guanylate cyclase (sGC) represents a promising therapeutic strategy for the treatment of a range of diseases, including the severely disabling pulmonary hypertension (PH). Optimization of the unfavorable DMPK profile of previous sGC stimulators provided riociguat, which is currently being investigated in phase III clinical trials for the oral treatment of PH.

     

Exogenous Integrin αIIbβ3 Inhibitors Revisited: Past,Present and Future Applications

The integrin αIIbβ3 is the most abundant integrin on platelets. Upon platelet activation, the integrin changes its conformation (inside-out signalling) and outside-in signalling takes place leading to platelet spreading, platelet aggregation and thrombus formation. Bloodsucking parasites such as mosquitoes, leeches and ticks express anticoagulant and antiplatelet proteins, which represent major sources of lead compounds for the development of useful therapeutic agents for the treatment of haemostatic disorders or cardiovascular diseases. In addition to hematophagous parasites, snakes also possess anticoagulant and antiplatelet proteins in their salivary glands. Two snake venom proteins have been developed into two antiplatelet drugs that are currently used in the clinic. The group of proteins discussed in this review are disintegrins, low molecular weight integrin-binding cysteine-rich proteins, found in snakes, ticks, leeches, worms and horseflies. Finally, we highlight various oral antagonists, which have been tested in clinical trials but were discontinued due to an increase in mortality. No new αIIbβ3 inhibitors are developed since the approval of current platelet antagonists, and structure-function analysis of exogenous disintegrins could help find platelet antagonists with fewer adverse side effects.     

Anisotropy Effects in the Shape-Memory Performance of Polymer Foams

Isotropic and anisotropic shape-memory polymer foams are prepared by supercritical carbon dioxide foaming from a multiblock copolymer (PDLCL) consisting of poly(ω-pentadecalactone) and poly(ε-caprolactone) segments. Analysis by micro-computed tomography reveals for the anisotropic PDLCL foam cells a high shape anisotropy ratio of R = 1.72 ± 0.62 with a corresponding Young's compression moduli ratio between longitudinal and transversal direction of 4.3. The experimental compression data in the linear elastic range can be well described by the anisotropic open foam model of Gibson and Ashby. A micro-morphological analysis for single pores using scanning electron microscopy images permits the correlation between the macroscopic stress-compression behavior and microscale structural changes.     

Water Incorporation in Tetragonal Zirconia

Samples of 3 mol% Y₂O₃-stabilized tetragonal ZrO₂ ceramics were annealed at 250°C in atmospheres of water vapor pressures of 1 bar and 26 mbar. As demonstrated by the water uptake and the lattice expansion, water molecules were incorporated into the ZrO₂ lattice during annealing, and the amount of the incorporated water is determined by the water vapor pressure. Owing to the filling of oxygen vacancies by the incorporated water molecules, part of the tetragonal ZrO₂ transformed to the monoclinic structure, and protonic defects were induced. The expected proton conduction was confirmed by the polarity of the water vapor concentration cells.     

Ultraviolet photodetectors and readout based on a-IGZO semiconductor technology

In this work, real-time ultraviolet photodetectors are realized through metal–semiconductor–metal (MSM) structures. Amorphous indium gallium zinc oxide (a-IGZO) is used as semiconductor material and gold as metal electrodes. The readout of an individual sensor is implemented by a transimpedance amplifier (TIA) consisting of an all-enhancement a-IGZO thin-film transistor (TFT) operational amplifier and a switched capacitor (SC) as feedback resistance. The photosensor and the transimpedance amplifier are both manufactured on glass substrates. The measured photosensor possesses a high responsivity R , a low response time t _{R E S} , and a good noise equivalent power value NEP .     

Enterprise JavaBeans

Large web-based information systems make high demands on scalability, maintainability, reliability and security. In order to ease the development of such systems appropriate software architectures are needed. These architectures have to take into account business aspects as well as requisite tools and products. Such an architecture is offered by Sun Microsystems in the form of the Enterprise JavaBeans specification. Based on our experience from different projects we undertake a close examination of this architecture.     

Stability-based validation of clustering solutions

Data clustering describes a set of frequently employed techniques in exploratory data analysis to extract "natural" group structure in data. Such groupings need to be validated to separate the signal in the data from spurious structure. In this context, finding an appropriate number of clusters is a particularly important model selection question. We introduce a measure of cluster stability to assess the validity of a cluster model. This stability measure quantifies the reproducibility of clustering solutions on a second sample, and it can be interpreted as a classification risk with regard to class labels produced by a clustering algorithm. The preferred number of clusters is determined by minimizing this classification risk as a function of the number of clusters. Convincing results are achieved on simulated as well as gene expression data sets. Comparisons to other methods demonstrate the competitive performance of our method and its suitability as a general validation tool for clustering solutions in real-world problems.     

High-performance implementation of in-network traffic pacing for small-buffer networks

Demands on data communication networks continue to drive the need for increasingly faster link speeds. Optical packet switching networks promise to provide data rates that are sufficiently high to satisfy the needs of the future Internet core network. However, a key technological problem with optical packet switching is the very small size of packet buffers that can be implemented in the optical domain. Existing protocols, for example the widely used Transmission Control Protocol (TCP), do not perform well in such small-buffer networks. To address this problem, we have proposed techniques for actively pacing traffic at edge networks to ensure that traffic bursts are reduced or eliminated and thus do not cause packet losses in routers with small buffers. We have also shown that this traffic pacing can improve the performance of conventional networks that use small buffers (e.g., to reduce the cost of buffer memory on routers). A key challenge in this context is to develop systems that can perform such packet pacing efficiently and at high data rates. In this paper, we present the design and prototype of a hardware implementation of our packet pacing technique. We discuss and evaluate design trade-offs and present performance results from an prototype implementation based on a NetFPGA fieldprogrammable gate array system. Our results show that traffic pacing can be implemented with few hardware resources and without reducing system throughput. Therefore, we believe that traffic pacing can be deployed widely to improve the operation of current and future networks.