Thieno[2,3-d]pyrimidine-3-acetic acids. A new class of nonpeptide endothelin receptor antagonists

On the basis of structural information for the cyclic hexapeptide endothelin (ET) receptor antagonist, TAK-044, a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives bearing a carboxyl group and aromatic rings that were important for receptor binding were designed, synthesized, and evaluated for ET receptor binding affinities and inhibitory activities against ET-induced vasoconstriction. Optimization of each substituent in the thieno[2,3-d]pyrimidine ring led to the discovery of a novel and potent nonpeptide ET receptor antagonist, 6-(4-methoxymethoxyphenyl)-5-methylsulfonylaminomethyl-1-(2- methylthiobenzyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]p yrimidine-3- acetic acid (32 g), which binded to human ETA and ETB receptor subtypes with affinities (IC50) of 7.6 and 100 nM, respectively. Compound 32 g effectively antagonized ET-induced vasoconstriction and the inhibitory effect mediated by the ETB receptor was more potent than that of bosentan, while the inhibitory effect mediated by the ETA receptor was slightly less potent than that of bosentan.     

Effect of the Chiral Center Position of an Optically Active Terminal Group on the Induction of Optical Activity in Polysilanes

Summary Polysilanes with an optically active alkoxy group, i.e., (S)-(+)-2-butoxy, (R)-(-)-2-butoxy, (S)-(-)-2-methyl-1-butoxy, and (S)-(+)-3,7-dimethyl-1-octoxy, at the terminal positions, the chiral carbon centers of which were located at the α, β, and γ positions relative to the oxygen, respectively, were prepared, and the effect of the position of chiral center of the terminal optically active group on the induction of optical activity in polysilanes was investigated. The circular dichroism (CD) spectra of these polymers showed positive Cotton signals around 340 nm at temperatures below -20 °C, but the intensities were small, indicating that the optically active groups at the terminal positions have some ability, albeit small, to induce optical activity to the polysilanes. Further, the optically active (S)-(+)-2-butoxy and (R)-(-)-2-butoxy groups did not control the helical sense direction of the polymers, despite the different chiral stimuli from the 2-butoxy groups introduced to the terminal positions. To control the helical structure of polysilanes by the use of optically active terminal groups, appropriate optically active groups are required.     

Accelerating sequential programs on commodity multi-core processors

A recently proposed pipelined multithreading (PMT) technique exhibits wide applicability in parallelizing general sequential programs on multi-core processors. However, significant inter-core communication overhead limits PMT performance and prevents its commercial utilization. A simple and effective clustered pipelined multithreading (CPMT) approach is presented to accelerate sequential programs on commodity multi-core processors. This CPMT technique adopts a clustered communication mechanism that can yield very low average communication overhead by eliminating false sharing as well as reducing communication operation and transit delays in the software-only approach. A single-producer/single-consumer concurrent lock-free clusteredQueue algorithm based on a two-level queue structure is also proposed. The accuracy of CPMT is theoretically demonstrated. The performances of the algorithm and CPMT are evaluated on a commodity AMD Phenom four-core processor. The number of enqueue and dequeue times of the algorithm are 20.8 and 23 cycles given an appropriate parameter, respectively. The speedup of CPMT ranges from 13.1% to 119.8% for typical loops extracted from the SPEC CPU 2000 benchmark suite.     

A coaxial pulsed plasma thruster using chemical propellants

Pulsed plasma thrusters (PPTs) have the advantages of mechanical simplicity and robustness compared to other electric propulsion systems. However the thrust power ratio of PPTs is lower than that of other electric propulsion systems. To enhance the thrust performance of the PPT, we propose to use several combustible solid chemicals as coaxial PPT propellants to replace Teflon^® (Polytetrafluoroethylene: PTFE). With the design, the force obtained thermodynamically is expected to augment the PPT thrust power ratio with the help of the chemical energy contained in the propellants. As a result, the thrust power ratio is increased using hydroxyl-terminated polybutadiene-ammonium perchlorate (HTPB-AP)-based propellants compared to the case of ordinary Teflon. The discharge current and voltage waveform does not change even when the propellant is changed. These findings could indicate that the impulse bits by gasdynamic contribution are lager in the case of chemical solid propellants than in the case of Teflon.     

HDPE膜预辐照接枝VBTAC制备阴离子交换膜

在氮气保护下,利用预辐照接枝技术在高密度聚乙烯(HDPE)膜上接枝苯乙烯三甲基氯化铵(VBTAC)单体,以甲基丙烯酸二甲氨基乙酯(DMAEMA)单体作为接枝辅助单体来提高VBTAC的接枝率,制备出阴离子交换膜,解决了在HDPE上难以直接接枝聚合VBTAC的问题.本文研究了接枝条件及接枝液的组分对接枝的影响,并用X射线显微分析方法研究了VBTAC的接枝进程和接枝分布.     

Development and Use of a Kinetical and Real-Time Monitoring System to Analyze the Replication of Hepatitis C Virus

In microbiological research, it is important to understand the time course of each step in a pathogen’s lifecycle and changes in the host cell environment induced by infection. This study is the first to develop a real-time monitoring system that kinetically detects luminescence reporter activity over time without sampling cells or culture supernatants for analyzing the virus replication. Subgenomic replicon experiments with hepatitis C virus (HCV) showed that transient translation and genome replication can be detected separately, with the first peak of translation observed at 3–4 h and replication beginning around 20 h after viral RNA introduction into cells. From the bioluminescence data set measured every 30 min (48 measurements per day), the initial rates of translation and replication were calculated, and their capacity levels were expressed as the sums of the measured signals in each process, which correspond to the areas on the kinetics graphs. The comparison of various HuH-7-derived cell lines showed that the bioluminescence profile differs among cell lines, suggesting that both translation and replication capacities potentially influence differences in HCV susceptibility. The effects of RNA mutations within the 5′ UTR of the replicon on viral translation and replication were further analyzed in the system developed, confirming that mutations to the miR-122 binding sites primarily reduce replication activity rather than translation. The newly developed real-time monitoring system should be applied to the studies of various viruses and contribute to the analysis of transitions and progression of each process of their life cycle.     

Self-assembly of three dimensional micro mechanisms using thermal shrinkage of polyimide

This paper describes three-dimensional microstructures fabricated using a simple self-assembly process involving the thermal shrinkage of polyimide. The proposed method enables hinged structures to be automatically rotated out of the wafer plane and to remain bent without the need to use any interlocking mechanisms. The hinged structures were fabricated using surface micromachining techniques involving heating in a furnace. An increase in the bending angle due to the shrinkage of polyimide was observed with increasing heating temperature, heating time, and length of the polyimide hinge. Of these three parameters, the heating time was found to be the most suitable for precise control of the bending angle. Furthermore, microcubes were fabricated by this method and the self-assembly process was successfully visualized using a CCD camera.     

Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia

KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting KIT mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients’ prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of KIT mutations in AML, (2) the data in AML with KIT mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting KIT mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common, KIT mutations are attractive novel molecular targets in AML.     

Stable and super‐low friction of amorphous carbon nitride coatings in nitrogen gas by using two‐step ball‐on‐disk friction test

Effect of running‐in process on friction behaviour of carbon nitride (CNx) coating in N₂ gas stream was investigated with a newly introduced two‐step ball‐on‐disk friction test, where the rubbed Si₃N₄ ball in the pre‐sliding (step 1) was replaced by a new CNx‐coated Si₃N₄ ball in the subsequent sliding stage under N₂ gas (step 2). The two‐step friction test is clarified to be a simple but effective technique for obtaining contact material combination of self‐mated CNx coatings and for achieving stable and low frictions of CNx coatings. Friction coefficients of CNx/CNx in N₂ gas stream decrease greatly from 0.07 without pre‐sliding to less than 0.025 in two‐step friction tests. The minimum friction coefficient of 0.004 was obtained by introducing 500 cycles of pre‐sliding in ambient air. These stable and low frictions are attributed to the generation of self‐mated CNx coatings and the formation of a lubricious layer on the disk surface. Copyright © 2014 John Wiley & Sons, Ltd.     

Terminal defined chain-growth polycondensation of 4-chloropyridine

This work examines the polycondensation of 4-chloropyridine derivatives using an N-(4-tert-butylbenzyl)-4-chloropyridinium (BPymCl) initiator and ion exchange reagents NaBPh₄, NaBF₄, and TBABF₄. The ¹H NMR spectra demonstrate that the product quantity is proportional to the total conversion of the monomer and the initiator. The MALDI-TOF MS spectrum shows that the product contains more than 9 monomer units. The polymerization was well-terminated via the addition of dimethylaminopyridine. These results indicate that the polycondensation proceeds in a chain-growth manner. This polycondensation could be a new example of a controlled polymerization with a well-defined end group.