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排序方式: 共有5212条查询结果,搜索用时 15 毫秒
1.
Viktoria M. S. Kjær Loukas Ieremias Dr. Viktorija Daugvilaite Dr. Michael Lückmann Prof. Thomas M. Frimurer Prof. Trond Ulven Prof. Mette M. Rosenkilde Dr. Jon Våbenø 《ChemMedChem》2021,16(17):2623-2627
The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch. 相似文献
2.
Dr. Yahu A. Liu Dr. Qihui Jin Qiang Ding Dr. Xueshi Hao Tingting Mo Shanshan Yan Dr. Yefen Zou Dr. Zhihong Huang Xiaoyue Zhang Wenqi Gao Dr. Tom Y.-H. Wu Chun Li Dr. Badry Bursalaya Dr. Michael Di Donato Dr. You-Qing Zhang Lisa Deaton Dr. Weijun Shen Dr. Brandon Taylor Anwesh Kamireddy Dr. George Harb Dr. Jing Li Dr. Yong Jia Dr. Andrew M. Schumacher Dr. Bryan Laffitte Dr. Richard Glynne Dr. Shifeng Pan Dr. Peter McNamara Dr. Valentina Molteni Dr. Jon Loren 《ChemMedChem》2020,15(16):1562-1570
Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation. 相似文献
3.
M. J. O’Sullivan C. G. Walker M. L. O’Sullivan T. D. Thompson A. B. Philpott 《Telecommunication Systems》2006,33(4):353-376
The problem of designing fibre-optic networks for local-access telecommunications generates (at least) three non-trivial subproblems.
In the first of these subproblems one must determine how many fibre-optic cables (fibres) are required at either end of a
street. In the next subproblem a minimum-cost network must be designed to support the fibres. The network must also provide
distinct paths from either end of the street to the central exchange(s). Finally, the fibre-optic cables must be placed in
protective covers. These covers are available in a number of different sizes, allowing some flexibility when covering each
section of the network. In this paper we describe a dynamic programming (DP) formulation for finding a minimum-cost (protective)
covering for the network (the third of the subproblems). This problem is a generalised set covering problem with side constraints
and is further complicated by the introduction of fixed and variable welding costs. The DP formulation selects covers along
each arc (in the network), but cannot exactly model the fixed costs and so does not guarantee optimality. We also describe
an integer programming (IP) formulation for assessing the quality of the DP solutions. The cost of the networks constructed
by the IP model is less than those designed using the DP model, but the saving is not significant for the problems examined
(less than 0.1%). This indicates that the DP model will generally give very good solutions. Furthermore, as the problem dimensions
grow, DP gives significantly better solution times than IP. 相似文献
4.
Sheldon H. Jacobson Julie L. Virta Jon M. Bowman John E. Kobza John J. Nestor 《IIE Transactions》2003,35(3):259-269
Aviation security protects vital national interests, as well as passengers and aircraft. Key components of an aviation security system include baggage and passenger screening devices and operations. Determining how and where to assign (deploy) such devices can be quite challenging. Moreover, even after such systems are in place, it can be difficult to measure their effectiveness. This paper describes how discrete optimization models can be used to address these questions, based on three performance measures that quantify the effectiveness of airport baggage screening security device systems. These models are used to solve for optimal airport baggage screening security device deployments considering the number of passengers on a set of flights who have not been cleared using a security risk assessment system in use by the Federal Aviation Administration (i.e., passengers whose baggage is subjected to screening), the number of flights in this set, and the size of the aircraft for such flights. Several examples are provided to illustrate these results, including an example that uses data available from the Official Airline Guide. 相似文献
5.
Life is pleasant--and memory helps to keep it that way! 总被引:1,自引:0,他引:1
Walker W. Richard; Skowronski John J.; Thompson Charles P. 《Canadian Metallurgical Quarterly》2003,7(2):203
People's recollections of the past are often positively biased. This bias has 2 causes. The 1st cause lies in people's perceptions of events. The authors review the results of several studies and present several new comparative analyses of these studies, all of which indicate that people perceive events in their lives to more often be pleasant than unpleasant. A 2nd cause is the fading affect bias: The affect associated with unpleasant events fades faster than the affect associated with pleasant events. The authors review the results of several studies documenting this bias and present evidence indicating that dysphoria (mild depression) disrupts such bias. Taken together, this evidence suggests that autobiographical memory represents an important exception to the theoretical claim that bad is stronger than good. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
6.
This paper focuses on a class of robot manipulators termed "continuum" robots - robots that exhibit behavior similar to tentacles, trunks, and snakes. In previous work, we studied details of the mechanical design, kinematics, path-planning and small-deflection dynamics for continuum robots such as the Clemson "tentacle manipulator". In this paper, we discuss the dynamics of a planar continuum backbone section, incorporating a large-deflection dynamic model. Based on these dynamics, we formulate a vibration-damping setpoint controller, and include experimental results to illustrate the efficacy of the proposed controller. 相似文献
7.
K-winner networks. 总被引:2,自引:0,他引:2
W J Wolfe D Mathis C Anderson J Rothman M Gottler G Brady R Walker G Duane G Alaghband 《Neural Networks, IEEE Transactions on》1991,2(2):310-315
A special class of mutually inhibitory networks is analyzed, and parameters for reliable K-winner performance are presented. The network dynamics are modeled using interactive activation, and results are compared with the sigmoid model. For equal external inputs, network parameters that select the units with the larger initial activations (the network converges to the nearest stable state) are derived. Conversely, for equal initial activations, networks that select the units with larger external inputs (the network converges to the lowest energy stable state) are derived. When initial activations are mixed with external inputs, anomalous behavior results. These discrepancies are analyzed with several examples. Restrictions on initial states are derived which ensure accurate K-winner performance when unequal external inputs are used. 相似文献
8.
9.
Olivier Merlin Jeffrey P. Walker Abdelghani Chehbouni Yann Kerr 《Remote sensing of environment》2008,112(10):3935-3946
A deterministic approach for downscaling ~ 40 km resolution Soil Moisture and Ocean Salinity (SMOS) observations is developed from 1 km resolution MODerate resolution Imaging Spectroradiometer (MODIS) data. To account for the lower soil moisture sensitivity of MODIS surface temperature compared to that of L-band brightness temperature, the disaggregation scale is fixed to 10 times the spatial resolution of MODIS thermal data (10 km). Four different analytic downscaling relationships are derived from MODIS and physically-based model predictions of soil evaporative efficiency. The four downscaling algorithms differ with regards to i) the assumed relationship (linear or nonlinear) between soil evaporative efficiency and near-surface soil moisture, and ii) the scale at which soil parameters are available (40 km or 10 km). The 1 km resolution airborne L-band brightness temperature from the National Airborne Field Experiment 2006 (NAFE'06) are used to generate a time series of eleven clear sky 40 km by 60 km near-surface soil moisture observations to represent SMOS pixels across the three-week experiment. The overall root mean square difference between downscaled and observed soil moisture varies between 1.4% v/v and 1.8% v/v depending on the downscaling algorithm used, with soil moisture values ranging from 0 to 15% v/v. The accuracy and robustness of the downscaling algorithms are discussed in terms of their assumptions and applicability to SMOS. 相似文献
10.
Jon T. Carter Paul E. Krajewski Ravi Verma 《JOM Journal of the Minerals, Metals and Materials Society》2008,60(11):77-81
The hot blow forming of magnesium sheet offers significant opportunity for forming complex, lightweight parts for automotive
applications. This paper characterizes the elevated-temperature formability of AZ31 magnesium sheet materials and the effect
of processing conditions on the performance of these materials. In addition, magnesium sheet application development at General
Motors Corporation is reviewed. 相似文献