Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

认知无线电网络中基于信道跳频序列的异步交汇算法研究

认知无线电技术被公认为是未来通信网络中解决频谱资源稀缺和提高频谱利用率的关键技术。认知无线电用户以频谱共享方式机会式地接入授权用户的频段。异步认知无线电网络中的认知无线电用户在相互通信之前,首先需要完成交汇(Rendezvous)和信道协商。对近几年来基于信道跳频序列的异步交汇算法进行了综述,对文献中提出的三类算法进行理论分析,并通过Matlab仿真验证这三类中的八个算法在ETTR、MTTR和公平性三方面的性能表现,对比分析了这八个算法的优缺点。     

A modernized and versatile startup reactivity measuring system installed at NPP Paks and its application for subcritical systems

In 2004 the Hungarian Paks NPP completed a project for upgrading the reactivity measuring system applied during reactor startup experiments. Almost all components of the previous system were replaced, only ex-core ionisation chambers remained unaltered. New hardware and software components were introduced for neutron flux signal handling, for data acquisition, as well as for measurement evaluation and data presentation. High-precision picoamper meters were installed at each reactor unit, current signals are handled by a portable signal processing unit. The system applies an accurate on-line reactivity calculation algorithm based on the point-kinetic model with six delayed neutron groups. Detailed off-line evaluation and analysis of startup measurements can be performed on the portable unit, as well.The paper describes the architecture, data acquisition modules, services and man–machine interface of the new system. Functions and results are illustrated with measured data recorded during a startup of Unit 3. In 2003 and 2004 the RMR was installed and tested at all Paks NPP units successfully and now it is in regular use during unit startups.The second part of the paper illustrates an extension of the new system to perform reactivity measurements using the well-known Rossi-α and Feynman-α statistical methods. The modified system was needed to estimate the reactivity of a subcritical system formed by damaged fuel assemblies stored at the fuel service pit of Paks Unit 2. Theoretical background of the applied algorithms is outlined, then results of validation tests and on site measurements are treated. The measurements have shown that the subcriticality of the damaged fuel was sufficiently deep if the high boron concentration in the fuel service pit was maintained.     

Exposure and effects assessment of persistent organohalogen contaminants in arctic wildlife and fish

Persistent organic pollutants (POPs) encompass an array of anthropogenic organic and elemental substances and their degradation and metabolic byproducts that have been found in the tissues of exposed animals, especially POPs categorized as organohalogen contaminants (OHCs). OHCs have been of concern in the circumpolar arctic for decades. For example, as a consequence of bioaccumulation and in some cases biomagnification of legacy (e.g., chlorinated PCBs, DDTs and CHLs) and emerging (e.g., brominated flame retardants (BFRs) and in particular polybrominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs) including perfluorooctane sulfonate (PFOS) and perfluorooctanic acid (PFOA) found in Arctic biota and humans. Of high concern are the potential biological effects of these contaminants in exposed Arctic wildlife and fish. As concluded in the last review in 2004 for the Arctic Monitoring and Assessment Program (AMAP) on the effects of POPs in Arctic wildlife, prior to 1997, biological effects data were minimal and insufficient at any level of biological organization. The present review summarizes recent studies on biological effects in relation to OHC exposure, and attempts to assess known tissue/body compartment concentration data in the context of possible threshold levels of effects to evaluate the risks. This review concentrates mainly on post-2002, new OHC effects data in Arctic wildlife and fish, and is largely based on recently available effects data for populations of several top trophic level species, including seabirds (e.g., glaucous gull (Larus hyperboreus)), polar bears (Ursus maritimus), polar (Arctic) fox (Vulpes lagopus), and Arctic charr (Salvelinus alpinus), as well as semi-captive studies on sled dogs (Canis familiaris). Regardless, there remains a dearth of data on true contaminant exposure, cause-effect relationships with respect to these contaminant exposures in Arctic wildlife and fish. Indications of exposure effects are largely based on correlations between biomarker endpoints (e.g., biochemical processes related to the immune and endocrine system, pathological changes in tissues and reproduction and development) and tissue residue levels of OHCs (e.g., PCBs, DDTs, CHLs, PBDEs and in a few cases perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonates (PFSAs)). Some exceptions include semi-field studies on comparative contaminant effects of control and exposed cohorts of captive Greenland sled dogs, and performance studies mimicking environmentally relevant PCB concentrations in Arctic charr. Recent tissue concentrations in several arctic marine mammal species and populations exceed a general threshold level of concern of 1 part-per-million (ppm), but a clear evidence of a POP/OHC-related stress in these populations remains to be confirmed. There remains minimal evidence that OHCs are having widespread effects on the health of Arctic organisms, with the possible exception of East Greenland and Svalbard polar bears and Svalbard glaucous gulls. However, the true (if any real) effects of POPs in Arctic wildlife have to be put into the context of other environmental, ecological and physiological stressors (both anthropogenic and natural) that render an overall complex picture. For instance, seasonal changes in food intake and corresponding cycles of fattening and emaciation seen in Arctic animals can modify contaminant tissue distribution and toxicokinetics (contaminant deposition, metabolism and depuration). Also, other factors, including impact of climate change (seasonal ice and temperature changes, and connection to food web changes, nutrition, etc. in exposed biota), disease, species invasion and the connection to disease resistance will impact toxicant exposure. Overall, further research and better understanding of POP/OHC impact on animal performance in Arctic biota are recommended. Regardless, it could be argued that Arctic wildlife and fish at the highest potential risk of POP/OHC exposure and mediated effects are East Greenland, Svalbard and (West and South) Hudson Bay polar bears, Alaskan and Northern Norway killer whales, several species of gulls and other seabirds from the Svalbard area, Northern Norway, East Greenland, the Kara Sea and/or the Canadian central high Arctic, East Greenland ringed seal and a few populations of Arctic charr and Greenland shark.     

基于小波变换的顶张力立管涡激振动规律实验研究

为研究顶张力立管在海流作用下的涡激振动规律,在大型波浪流水槽中进行涡激振动模型实验。实验中立管竖直固定于实验支架上,外部承受不同速度的流体作用,上端施加变化的顶张力。立管模型上均匀布置六个测点,根据每个测点布置的两个应变计,分别测得来流向和横向两个方向振动响应。通过小波变换方法对实验数据进行时间频域分析,得到立管涡激振动频率和振动幅值以及来流向与横向的耦合振动规律,考察顶张力变化对立管自振频率以及涡激振动的影响。     

羟基多溴二苯醚生物活性的QSAR研究

采用VSMP方法从大量的分子结构描述符中筛选最优子集,用多元线性回归方法分别构建了羟基多溴二苯醚（hydroxylated polybrominated diphenyl ethers,OH-PBDEs）对细胞色素CYP19介导类固醇生成的抑制活性,甲状腺受体-β（thyroid receptors,TR-β）的激素活性以及与甲状腺素结合球蛋白（thyrox-ine-binding globulin,TBG）和甲状腺转运蛋白（transthyretin,TTR）之间结合能力的定量构效关系（quantita-tive structure-activity relationship,QSAR）模型。模型的留一法交叉验证（leave-one-out cross validation,LOO-CV）相关系数Q2和拟合相关系数R2均高于0.95和0.97,表明模型具有良好的稳健性、拟合能力和预测能力。QSAR模型表明OH-PBDEs的分子三维结构和芳香性是其活性的重要影响因素。另外,分子中溴原子数量和取代位置对OH-PBDE生物活性具有重要影响。     

A framework to practical predictive maintenance modeling for multi-state systems

A simple practical framework for predictive maintenance (PdM)-based scheduling of multi-state systems (MSS) is developed. The maintenance schedules are derived from a system-perspective using the failure times of the overall system as estimated from its performance degradation trends.

The system analyzed in this work is a flow transmission water pipe system. The various factors influencing PdM-based scheduling are identified and their impact on the system reliability and performance are quantitatively studied. The estimated times to replacement of the MSS may also be derived from the developed model.

The results of the model simulation demonstrate the significant impact of maintenance quality and the criteria for the call for maintenance (user demand) on the system reliability and mean performance characteristics. A slight improvement in maintenance quality is found to postpone the system replacement time by manifold. The consistency in the quality of maintenance work with minimal variance is also identified as a very important factor that enhances the system's future operational and downtime event predictability.

The studies also reveal that in order to reduce the frequency of maintenance actions, it is necessary to lower the minimum user demand from the system if possible, ensuring at the same time that the system still performs its intended function effectively.

The model proposed can be utilized to implement a PdM program in the industry with a few modifications to suit the individual industrial systems’ needs.     

In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.     

Manufacturing of composite parts reinforced through-thickness by tufting

The paper aims at providing practical guidelines for the manufacture of composite parts reinforced by tufting. The need for through-thickness reinforcement of high performance carbon fibre composite structures is reviewed and various options are presented. The tufting process is described in detail and relevant aspects of the technology are analysed such as: equipment configuration and setup, latest advances in tooling, thread selection, preform supporting systems and choice of ancillary materials. Effects of the process parameters on the preform fibre architecture and on the meso-structure of the reinforced component are discussed. Special emphasis is given to the different options available in terms of tuft insertion and loops management.Potential fields of application of the technology are investigated as well as the limitations of its applicability in relation to preform nature and geometry. Critical issues which may arise during the manufacturing process concerning thread insertion, loops formation, alteration to the fabric fibres layout or local volume fraction are identified.