Targeting the Water Network in Cyclin G-Associated Kinase (GAK) with 4-Anilino-quin(az)oline Inhibitors

Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity for the target. Herein, we describe the design and testing of a targeted library of 4-anilinoquin(az)olines for use as inhibitors of cyclin G-associated kinase (GAK). GAK cellular target engagement assays, ATP binding-site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond.     

用碱回收炉增加电产量的可能性--用多种工艺参数比较背压汽轮机和冷凝汽轮机

人们对用黑液碱回收炉来增加发电量的重要性认识不断提高,这些变化的主要原因是电的价格.本文将介绍增加电产量的某些传统方法、一些新的思想和见解,特别是采用冷凝汽轮机.本研究的基本事例为一台传统的碱回收炉,能力为4000t(固形物)/24h,同时配备有背压汽轮机和冷凝汽轮机.将要介绍的这些方法为:增加黑液固形物含量、空气预热、吹灰系统、给水预热、蒸汽参数和电除尘后的热回收.     

Use of life cycle assessments to evaluate the environmental footprint of contaminated sediment remediation

Ecological and human risks often drive the selection of remedial alternatives for contaminated sediments. Traditional human and ecological risk assessment (HERA) includes assessing risk for benthic organisms and aquatic fauna associated with exposure to contaminated sediments before and after remediation as well as risk for human exposure but does not consider the environmental footprint associated with implementing remedial alternatives. Assessment of environmental effects over the whole life cycle (i.e., Life Cycle Assessment, LCA) could complement HERA and help in selecting the most appropriate sediment management alternative. Even though LCA has been developed and applied in multiple environmental management cases, applications to contaminated sediments and marine ecosystems are in general less frequent. This paper implements LCA methodology for the case of the polychlorinated dibenzo-p-dioxins and -furans (PCDD/F)-contaminated Grenland fjord in Norway. LCA was applied to investigate the environmental footprint of different active and passive thin-layer capping alternatives as compared to natural recovery. The results showed that capping was preferable to natural recovery when analysis is limited to effects related to the site contamination. Incorporation of impacts related to the use of resources and energy during the implementation of a thin layer cap increase the environmental footprint by over 1 order of magnitude, making capping inferior to the natural recovery alternative. Use of biomass-derived activated carbon, where carbon dioxide is sequestered during the production process, reduces the overall environmental impact to that of natural recovery. The results from this study show that LCA may be a valuable tool for assessing the environmental footprint of sediment remediation projects and for sustainable sediment management.     

Boron Fertilization Enhances the Induced Defense of Silver Birch

Boron (B) deficiency is a common micronutrient deficiency that has been reported to affect the phenolic metabolism of plants. Thus, it may play a role in defense against herbivorous animals. However, the role of B in a plant’s resistance to herbivores has not received any particular attention from researchers. In this study, we tested the effects of B nutrition 1) on the biochemical and mechanical defenses of birches and the growth of seedlings, and 2) the resistance of seedlings to larvae of the autumnal moth, Epirrita autumnata. Boron fertilization improved the resistance of birch, which was shown as reduced pupal weight of the herbivore. However, B fertilized trees suffered from heavier defoliation than unfertilized ones due to compensation feeding of larvae. The growth of the seedlings was diminished, and several biochemical changes occurred in leaves of herbivore seedlings, and B also played a role in these changes. Polyphenoloxidases (PPOs) and peroxidases (PODs) and their substrates, chlorogenic acids, were induced by herbivory in B fertilized seedlings but not in unfertilized seedlings. The lower pupal weights and increased consumption of the herbivores were probably linked to the plants’ phenoloxidase-mediated production of reactive quinones, which decrease the nutritive value. Herbivory upon new stems led to an increase in the number of resin glands that provide defense against mammalian herbivores. Herbivory also had a substantially negative effect on B concentration in leaves of B fertilized seedlings. We postulate that B nutrition of trees may play a significant role in the induced defense of birches.     

Novel detector implementations for 3G LTE downlink and uplink

We summarize our recent state-of-the-art programmable and reconfigurable detector and QR decomposition (QRD) implementations targeting 3G long term evolution (LTE) downlink and uplink requirements. The downlink transmission is based on the orthogonal frequency division multiplexing, whereas the uplink transmission uses a single-carrier frequency-division multiple access. The downlink implementations are based on the programmable transport triggered architecture (TTA) which provides a flexible and energy efficient architecture template. In TTA detector implementation, the LTE detection rate requirements up to 20 MHz bandwidth and 4 × 4 antenna system with 64-QAM, are achieved by using 1–6 programmable cores in parallel. Each core runs at 277 MHz clock frequency and consumes 55.5–64.0 mW depending on the detector configuration. The downlink detector is based on the selective spanning with fast enumeration algorithm. The uplink field-programmable gate array (FPGA) detector implementation is targeted for 4 × 4 antenna system and 64-QAM achieving a detection rate requirement for 20 MHz bandwidth. The used FPGA board for uplink implementation is Xilinx Virtex-6 and the implementation has been carried out using Xilinx Vivado high level synthesis tool. Two different detector architectures are implemented. The first one achieves the detection rate requirement with a single processing block running at 231 MHz and the latter one with four blocks in parallel, each running at 247 MHz. The implemented detector is based on the K-best algorithm. A multiple-input multiple-output receiver requires QRD to produce valid inputs for the detector. In addition to detector implementations, QRD is also implemented on both TTA and FPGA. Modified Gram–Schmidt algorithm is used in both QRD implementations.     

Bayesian Fusion for Indoor Positioning Using Bluetooth Fingerprints

This paper studies the use of received signal strength indicators (RSSI) applied to fingerprinting method in a Bluetooth network for indoor positioning. A Bayesian fusion (BF) method is proposed to combine the statistical information from the RSSI measurements and the prior information from a motion model. Indoor field tests are carried out to verify the effectiveness of the method. Test results show that the proposed BF algorithm achieves a horizontal positioning accuracy of about 4.7 m on the average, which is about 6 and 7 % improvement when compared with Bayesian static estimation and a point Kalman filter method, respectively.     

Investigation of the Pentathiepin Functionality as an Inhibitor of Feline Immunodeficiency Virus (FIV) via a Potential Zinc Ejection Mechanism,as a Model for HIV Infection

A small diverse library of pentathiepin derivatives were prepared to evaluate their efficacy against the nucleocapsid protein function of the feline immunodeficiency virus (FIV) as a model for HIV, using an in vitro cell culture approach. This study led to the development of nanomolar active compounds with low toxicity.     

Targeting an EGFR Water Network with 4-Anilinoquin(az)oline Inhibitors for Chordoma

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure–activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N-(3-ethynylphenyl)-6,7-dimethoxyquinolin-4-amine], 4 [N-(3-ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine], and 7 [4-((3-ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-carbonitrile]. We also identified 6,7-dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-amine (compound 18 ), which is the most potent inhibitor (IC₅₀=310 nm ) of the UCH-2 chordoma cell line to date.