Modulation of the Rev-RRE interaction by aromatic heterocyclic compounds

The HIV-1 Rev protein regulates the nucleocytoplasmic distribution of viral precursor RNAs that encode HIV-1 structural proteins. Rev-mediated viral RNA expression requires a sequence-specific interaction between Rev and a viral RNA sequence, the Rev responsive element (RRE). Because the Rev-RRE interaction is essential for HIV-1 replication, anti-viral agents that selectively block this interaction may be effective anti-HIV-1 therapeutics. Here, we show that certain aromatic heterocyclic compounds, in particular, a tetracationic diphenylfuran, AK.A, can block binding of Rev to its high-affinity viral RNA binding site. AK.A abolishes Rev-RRE interactions at concentrations as low as 0.1 microM. Inhibition appears to be selective and results from competitive binding of the drug to a discrete region within the Rev binding site. Interestingly, the molecular basis for the AK.A-RNA interaction, as well as the mode of RNA binding differs from previously described aminoglycoside Rev inhibitors. Analysis of a variety of aromatic heterocyclic compounds and their derivatives reveals stereo-specific features required for the inhibition. Our results further demonstrate the feasibility of identifying and designing small molecules that selectively block viral RNA-protein interactions.     

Powernet — das neue EIB-Medium

Powernet EIB is a powerline-based information transmission system using the powerline medium to exchange information for communication purposes. The first implementation of the EIB makes use of the twisted pair transmission medium only. Introducing Powernet EIB, the new transmission medium powerline opens new application fields for the EIB. Powerline is a very hostile medium for carrier based data transmission. Powernet EIB presents a reliable data transmission with considerable speed. Half duplex transceiver technology enables two-way communication in Powernet EIB. The transmission method is based on spread frequency shift keying (SFSK).     

Obstacles to Regional Housing Solutions: A Comparison of Four Metropolitan Areas

Abstract: Studies of regionalism continue to appear in the scholarly literature. Research specifically on regional housing policies, however, appears far less frequently, most likely a reflection of the absence of regional housing initiatives in practice. Two leading explanations for the lack of regional housing solutions include: 1) intercity competition as asserted by public choice theorists; and 2) NIMBY attitudes expressed by community residents. This research uses a multiple case study design to examine the development of regionalism, and the status of regional housing efforts, in the Portland, Minneapolis‐St. Paul, Louisville, and New Orleans metropolitan areas. We examine the public choice and NIMBY explanations as well as other factors emerging from the research as obstacles to regional housing solutions. The results indicate that regionalism varies in degree across the four study areas. However, in all cases, regional housing solutions are either absent or ineffective. Our data do not strongly support the public choice hypothesis, but do provide evidence that NIMBY attitudes about race and growth are barriers to regional housing policies. Furthermore, context‐specific circumstances, such as population characteristics and health of the regional economy, result in dominance of economic development in approaches to regionalism. The article concludes with implications based on the findings.     

Materials integrity in microsystems: a framework for a petascale predictive-science-based multiscale modeling and simulation system

Microsystems have become an integral part of our lives and can be found in homeland security, medical science, aerospace applications and beyond. Many critical microsystem applications are in harsh environments, in which long-term reliability needs to be guaranteed and repair is not feasible. For example, gyroscope microsystems on satellites need to function for over 20 years under severe radiation, thermal cycling, and shock loading. Hence a predictive-science-based, verified and validated computational models and algorithms to predict the performance and materials integrity of microsystems in these situations is needed. Confidence in these predictions is improved by quantifying uncertainties and approximation errors. With no full system testing and limited sub-system testings, petascale computing is certainly necessary to span both time and space scales and to reduce the uncertainty in the prediction of long-term reliability. This paper presents the necessary steps to develop predictive-science-based multiscale modeling and simulation system. The development of this system will be focused on the prediction of the long-term performance of a gyroscope microsystem. The environmental effects to be considered include radiation, thermo-mechanical cycling and shock. Since there will be many material performance issues, attention is restricted to creep resulting from thermal aging and radiation-enhanced mass diffusion, material instability due to radiation and thermo-mechanical cycling and damage and fracture due to shock. To meet these challenges, we aim to develop an integrated multiscale software analysis system that spans the length scales from the atomistic scale to the scale of the device. The proposed software system will include molecular mechanics, phase field evolution, micromechanics and continuum mechanics software, and the state-of-the-art model identification strategies where atomistic properties are calibrated by quantum calculations. We aim to predict the long-term (in excess of 20 years) integrity of the resonator, electrode base, multilayer metallic bonding pads, and vacuum seals in a prescribed mission. Although multiscale simulations are efficient in the sense that they focus the most computationally intensive models and methods on only the portions of the space–time domain needed, the execution of the multiscale simulations associated with evaluating materials and device integrity for aerospace microsystems will require the application of petascale computing. A component-based software strategy will be used in the development of our massively parallel multiscale simulation system. This approach will allow us to take full advantage of existing single scale modeling components. An extensive, pervasive thrust in the software system development is verification, validation, and uncertainty quantification (UQ). Each component and the integrated software system need to be carefully verified. An UQ methodology that determines the quality of predictive information available from experimental measurements and packages the information in a form suitable for UQ at various scales needs to be developed. Experiments to validate the model at the nanoscale, microscale, and macroscale are proposed. The development of a petascale predictive-science-based multiscale modeling and simulation system will advance the field of predictive multiscale science so that it can be used to reliably analyze problems of unprecedented complexity, where limited testing resources can be adequately replaced by petascale computational power, advanced verification, validation, and UQ methodologies.     

Investigation of the decomplexation of polyamide/CaCl2 complex toward a green,nondestructive recovery of polyamide from textile waste

The ‘circular economy’ concept envisages deriving the maximum value out of resources and reducing waste to a minimum. In textiles, that includes the recovery of fiber materials out of used clothing and reusing them in the construction of new clothes. Processes such as mechanical separation, depolymerization treatment, and selective dissolutions of individual polymers are applied. We investigate the approach of selective nondestructive dissolution and recovery of polyamide fiber from mixed textile waste by using the solvent system CaCl₂/ethanol/water (CEW) based on complexation and decomplexation of polyamide (PA). The results show that PA is precipitated and decomplexed by simple addition of water and a substantial amount of previously incorporated calcium by complexation, is removed. The recovered polyamide shows properties similar to pristine polyamide. Investigation on a mixed textile waste model of polyamide/wool demonstrates that CEW treatment can successfully separate different fiber materials. The nondestructive approach in dissolving PA using CEW, clearly shows the benefit, that PA fiber can be separated by controlled complexation/decomplexation without degradation, thus avoiding the repolymerization step. Furthermore, the solvent system is made of abundantly available materials that are inexpensive and used widely in industrial-scale operations. Thus, the concept will make significant contribution to a green textile recycling approach.     

Photoswitchable Azo- and Diazocine-Functionalized Derivatives of the VEGFR-2 Inhibitor Axitinib

In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)-2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene-like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]-cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z-isomer usually is bioinactive, and back isomerization from the bioactive E-isomer occurs thermally. Here, we report on the development of different sulfur–diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR-2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR-2 kinase assay that the Z-isomer is biologically inactive (IC₅₀ >> 10,000 nM), while significant VEGFR-2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC₅₀ value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40-fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.     

采用非浸润模板制作纳米颗粒基因药物

近年来,RNA(Ribonucleic Acid,核糖核酸)干扰现象在癌症、病毒感染治疗方面展现出巨大潜力。RNA干扰药物可以直接作用于致病基因,治疗作用更加彻底,治疗范围更加广泛,同时降低了的副作用。RNA药物研究工作中遇到的最大困难就是将敏感易分解的基因药物传输到哺乳动物细胞中。美国北卡罗来纳大学实验组致力于采用PRINT(Particle Replication in Non-wetting Templates,在非浸润模板中制作纳米颗粒)技术制作大小形状均一可控的纳米级颗粒来运载基因药物。实验中通过测定HeLa癌症细胞中的荧光素酶降低率以及细胞存活率来评价PRINT颗粒的运载效果。最终制得运载效率为65%的PVP(Poly(N-vinyl pyrrolidone,聚乙烯吡咯烷酮)PRINT颗粒。