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排序方式: 共有272条查询结果,搜索用时 125 毫秒
151.
152.
Pfefferkorn JA Litchfield J Hutchings R Cheng XM Larsen SD Auerbach B Bush MR Lee C Erasga N Bowles DM Boyles DC Lu G Sekerke C Askew V Hanselman JC Dillon L Lin Z Robertson A Olsen K Boustany C Atkinson K Goosen TC Sahasrabudhe V Chupka J Duignan DB Feng B Scialis R Kimoto E Bi YA Lai Y El-Kattan A Bakker-Arkema R Barclay P Kindt E Le V Mandema JW Milad M Tait BD Kennedy R Trivedi BK Kowala M 《Bioorganic & medicinal chemistry letters》2011,21(9):2725-2731
The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors. 相似文献
153.
Judith M. Sarneel Merel B. Soons Jeroen J.M. Geurts Boudewijn Beltman Jos T.A. Verhoeven 《植被学杂志》2011,22(3):551-563
Question: Dutch fen areas have become embedded in intensively used landscapes, resulting in biodiversity loss. Hence, plant species that colonize open water inducing the formation of species‐rich floating peat mats have disappeared. Despite many restoration efforts, they have not returned. Is natural succession towards floating mats impeded by site conditions, dispersal limitations or changed biotic interactions? Location: Six Dutch fen reserves: De Deelen, De Weerribben, De Wieden, Westbroek, Molenpolder and Terra Nova. Methods: In 62 fen ponds we determined plant species richness and expansion into open water. We related these to habitat quality (chemical composition of soil and surface water, pond morphology), dispersal potential (distance to remnant populations, likelihood of dispersal) and biotic interactions (presence of muskrats [Ondatra zibethicus L.] and the keystone species Stratiotes aloides). Results: Factor analysis showed that plants expanded further into open water and bank vegetation had higher species richness in areas with older ponds and lower muskrat densities. Locally, high turbidity hampered colonization. Whenever the water was clear, colonization was higher in shallow ponds, and in deep ponds only if Stratiotes was present. Species richness was negatively correlated to nutrient availability in soil and positively correlated to hydrological isolation (decreased sulphate concentrations). We also found that species richness was higher in sheltered banks. Conclusions: Multiple habitat characteristics (turbidity, water depth, nutrient and sulphate concentrations) and the influence of muskrats and Stratiotes all play a role in the lack of restoration success in Dutch fen ponds. Dispersal limitations seem to be overruled by habitat limitations, as colonization often fails even when sufficient propagule sources are present, or when connectivity is high. 相似文献
154.
A report on the 11th Cold Spring Harbor Laboratory/Wellcome Trust conference on Genome Informatics, Cold Spring Harbor Laboratories,
New York, USA, November 2-5, 2011. 相似文献
155.
Chung YD Sinzinger MD Bovee-Geurts P Krause M Dinkla S Joosten I Koopman WJ Adjobo-Hermans MJ Brock R 《Biophysical journal》2011,101(11):2807-2815
The determination of intracellular protein concentrations is a prerequisite for understanding protein interaction networks in systems biology. Today, protein quantification is based either on mass spectrometry, which requires large cell numbers and sophisticated measurement protocols, or on quantitative Western blotting, which requires the expression and purification of a recombinant protein as a reference. Here, we present a method that uses a transiently expressed fluorescent fusion protein of the protein-of-interest as an easily accessible reference in small volumes of crude cell lysates. The concentration of the fusion protein is determined by fluorescence correlation spectroscopy, and this concentration is used to calibrate the intensity of bands on a Western blot. We applied this method to address cellular protein homeostasis by determining the concentrations of the plasma membrane-located transmembrane scaffolding protein LAT and soluble signaling proteins in naïve T cells and transformed T-cell lymphoma (Jurkat) cells (with the latter having nine times the volume of the former). Strikingly, the protein numbers of soluble proteins scaled with the cell volume, whereas that of the transmembrane protein LAT scaled with the membrane surface. This leads to significantly different stoichiometries of signaling proteins in transformed and naïve cells in concentration ranges that may translate directly into differences in complex formation. 相似文献
156.
Debabrata Laha Philipp Johnen Cristina Azevedo Marek Dynowski Michael Wei? Samanta Capolicchio Haibin Mao Tim Iven Merel Steenbergen Marc Freyer Philipp Gaugler Marília K.F. de Campos Ning Zheng Ivo Feussner Henning J. Jessen Saskia C.M. Van Wees Adolfo Saiardi Gabriel Schaaf 《The Plant cell》2015,27(4):1082-1097
Diphosphorylated inositol polyphosphates, also referred to as inositol pyrophosphates, are important signaling molecules that regulate critical cellular activities in many eukaryotic organisms, such as membrane trafficking, telomere maintenance, ribosome biogenesis, and apoptosis. In mammals and fungi, two distinct classes of inositol phosphate kinases mediate biosynthesis of inositol pyrophosphates: Kcs1/IP6K- and Vip1/PPIP5K-like proteins. Here, we report that PPIP5K homologs are widely distributed in plants and that Arabidopsis thaliana VIH1 and VIH2 are functional PPIP5K enzymes. We show a specific induction of inositol pyrophosphate InsP8 by jasmonate and demonstrate that steady state and jasmonate-induced pools of InsP8 in Arabidopsis seedlings depend on VIH2. We identify a role of VIH2 in regulating jasmonate perception and plant defenses against herbivorous insects and necrotrophic fungi. In silico docking experiments and radioligand binding-based reconstitution assays show high-affinity binding of inositol pyrophosphates to the F-box protein COI1-JAZ jasmonate coreceptor complex and suggest that coincidence detection of jasmonate and InsP8 by COI1-JAZ is a critical component in jasmonate-regulated defenses. 相似文献
157.
Neuroprosthetic brain-computer interfaces are systems that decode neural activity into useful control signals for effectors, such as a cursor on a computer screen. It has long been recognized that both the user and decoding system can adapt to increase the accuracy of the end effector. Co-adaptation is the process whereby a user learns to control the system in conjunction with the decoder adapting to learn the user''s neural patterns. We provide a mathematical framework for co-adaptation and relate co-adaptation to the joint optimization of the user''s control scheme ("encoding model") and the decoding algorithm''s parameters. When the assumptions of that framework are respected, co-adaptation cannot yield better performance than that obtainable by an optimal initial choice of fixed decoder, coupled with optimal user learning. For a specific case, we provide numerical methods to obtain such an optimized decoder. We demonstrate our approach in a model brain-computer interface system using an online prosthesis simulator, a simple human-in-the-loop pyschophysics setup which provides a non-invasive simulation of the BCI setting. These experiments support two claims: that users can learn encoders matched to fixed, optimal decoders and that, once learned, our approach yields expected performance advantages. 相似文献
158.
Ralph R. E. G. Geuskens Jordi Borst Marit Lucas A. M. Merel Boers Olvert A. Berkhemer Yvo B. W. E. M. Roos Marianne A. A. van Walderveen Sjoerd F. M. Jenniskens Wim H. van Zwam Diederik W. J. Dippel Charles B. L. M. Majoie Henk A. Marquering MR CLEAN trial investigators 《PloS one》2015,10(11)
Background
CT perfusion (CTP) is used to estimate the extent of ischemic core and penumbra in patients with acute ischemic stroke. CTP reliability, however, is limited. This study aims to identify regions misclassified as ischemic core on CTP, using infarct on follow-up noncontrast CT. We aim to assess differences in volumetric and perfusion characteristics in these regions compared to areas that ended up as infarct on follow-up.Materials and Methods
This study included 35 patients with >100 mm brain coverage CTP. CTP processing was performed using Philips software (IntelliSpace 7.0). Final infarct was automatically segmented on follow-up noncontrast CT and used as reference. CTP and follow-up noncontrast CT image data were registered. This allowed classification of ischemic lesion agreement (core on CTP: rMTT≥145%, aCBV<2.0 ml/100g and infarct on follow-up noncontrast CT) and misclassified ischemic core (core on CTP, not identified on follow-up noncontrast CT) regions. False discovery ratio (FDR), defined as misclassified ischemic core volume divided by total CTP ischemic core volume, was calculated. Absolute and relative CTP parameters (CBV, CBF, and MTT) were calculated for both misclassified CTP ischemic core and ischemic lesion agreement regions and compared using paired rank-sum tests.Results
Median total CTP ischemic core volume was 49.7ml (IQR:29.9ml-132ml); median misclassified ischemic core volume was 30.4ml (IQR:20.9ml-77.0ml). Median FDR between patients was 62% (IQR:49%-80%). Median relative mean transit time was 243% (IQR:198%-289%) and 342% (IQR:249%-432%) for misclassified and ischemic lesion agreement regions, respectively. Median absolute cerebral blood volume was 1.59 (IQR:1.43–1.79) ml/100g (P<0.01) and 1.38 (IQR:1.15–1.49) ml/100g (P<0.01) for misclassified ischemic core and ischemic lesion agreement, respectively. All CTP parameter values differed significantly.Conclusion
For all patients a considerable region of the CTP ischemic core is misclassified. CTP parameters significantly differed between ischemic lesion agreement and misclassified CTP ischemic core, suggesting that CTP analysis may benefit from revisions. 相似文献159.
Sandro Boland Olivier Defert Jo Alen Arnaud Bourin Karolien Castermans Nele Kindt Nicki Boumans Laura Panitti Sarah Van de Velde Ingeborg Stalmans Dirk Leysen 《Bioorganic & medicinal chemistry letters》2013,23(23):6442-6446
Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymatic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compound 32 combined strong efficacy (ROCK2 IC50 = 2.5 nM) with rapid inactivation in plasma (t1/2 <5′). Compound 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects. 相似文献
160.