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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.
Co-browsing is an activity in which a group of users navigate their way through of a set of Web pages together for a shared
purpose. Effective co-browsing among users with different device capabilities requires a shared understanding of those Web
pages. This paper demonstrates the concept of shared viewpoints (SVPs), and personal viewpoints (PVPs), for co-browsing, before
detailing a framework for implementing these concepts. Finally, the effectiveness of the framework is presented through a
perceptual experiment. 相似文献
4.
Multimodality image registration via pixel migration is a powerful approach. However, it suffers from a serious problem--the global maximum on the sum of squared gradient magnitude (SSG) surface does not correspond to the correct solution of registration. To solve the problem, we partition the search space into feasible and infeasible regions. The genetic algorithm (global optimizer) is used to obtain a good initial estimate of registration parameters and followed by a fast refining with Powell's approach (local optimizer). The experimental results demonstrate that the use of this modified pixel migration algorithm on multisensor image registration is very effective. 相似文献
5.
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
6.
Baeyens Y. Georgiou G. Weiner J.S. Leven A. Houtsma V. Paschke P. Lee Q. Kopf R.F. Yang Yang Chua L. Chen C. Liu C.T. Young-Kai Chen 《Solid-State Circuits, IEEE Journal of》2002,37(9):1152-1159
The combination of device speed (f/sub T/, f/sub max/ > 150 GHz) and breakdown voltage (V/sub bceo/ > 8 V) makes the double heterojunction bipolar InP-based transistor (D-HBT) an attractive technology to implement the most demanding analog functions of 40-Gb/s transceivers. This is illustrated by the performance of a number of analog circuits realized in an InP D-HBT technology with an 1.2- or 1.6-/spl mu/m-wide emitter finger: a low phase noise push-push voltage-controlled oscillator with -7-dBm output power at 146 GHz, a 40-GHz bandwidth and low-jitter 40-Gb/s limiting amplifier, a lumped 40-Gb/s limiting driver amplifier with 4.5-V/sub pp/ differential output swing, a distributed 40-Gb/s driver amplifier with 6-V/sub pp/ differential output swing, and a number of distributed preamplifiers with up to 1.3-THz gain-bandwidth product. 相似文献
7.
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
8.
Kubat M. Hafez A. Raghavan V.V. Lekkala J.R. Wei Kian Chen 《Knowledge and Data Engineering, IEEE Transactions on》2003,15(6):1522-1534
Association mining techniques search for groups of frequently co-occurring items in a market-basket type of data and turn these groups into business-oriented rules. Previous research has focused predominantly on how to obtain exhaustive lists of such associations. However, users often prefer a quick response to targeted queries. For instance, they may want to learn about the buying habits of customers that frequently purchase cereals and fruits. To expedite the processing of such queries, we propose an approach that converts the market-basket database into an itemset tree. Experiments indicate that the targeted queries are answered in a time that is roughly linear in the number of market baskets, N. Also, the construction of the itemset tree has O(N) space and time requirements. Some useful theoretical properties are proven. 相似文献
9.
The continuous reduction of chip size driven by the market demand has a significant impact on circuit design and assembly process of IC packages. Shrinking chip size and increasing I/O counts require finer bond pad pitch and bond pad size for circuitry layout. As a result, serious wire deflection during transfer molding process could make adjacent wires short, and this issue becomes more critical as a smaller wire diameter has to be applied for the finer pitch wire bonded IC devices.This paper presents a new encapsulation process development for 50 μm fine pitch plastic ball grid array package. Since reduced wire diameter decreases the bending strength of bonded wires significantly, wire deflection during molding process becomes quite serious and critical. Experiments on conventional transfer molding were conducted to evaluate wire span threshold with 23.0 μm diameter gold wire. The results show that the wire span threshold is about 4.1 mm, which is much shorter than the wire span threshold of over 5.0 mm for wire with 25.4 μm diameter. Finite element analysis shows there is a significant difference in the wire deflection between 23.0 μm gold wire and 25.4 μm gold wire diameter under the same action of mold flow. A novel encapsulation method is introduced using non-sweep solution. The wire span could be extended to over 5.0 mm with wire sweep less than 1%. Reliability tests conducted showed that all the units passed 1000 temperature cycles (−55 to 125 °C) with JEDEC moisture sensitivity level 2a (60 °C/60% relative humidity for 120 h) and 3 times reflow (peak temperature at 220–225 °C). It is believed that this solution could efficiently overcome the risk of wire short issues and improve the yield of ultra fine pitch wire bonds in high-volume production. 相似文献
10.
The Asia-Pacific region is one of the fastest growing regional economies in the world today. The region is home to over half of the global population and is one of the most important markets for multinational corporations to penetrate. The wind power sector is no exception. Wind resources remain untapped and the demand for electricity continues to grow as a result of expanding and modernizing economies. Godfrey Chua, Emerging Energy Research USA reports on the current status and development of the wind industry in the region. 相似文献