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Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.

Graphical AbstractNVP-2 (1), a potent and selective inhibitor of cyclin-dependent kinase 9 (CDK9), showed potent antitumor activity in preclinical studies. In this work, we designed and adopted a convergent synthetic route to efficiently synthesize NVP-2 (1). The key intermediate (7) was synthesized from malononitrile (2) and 1-bromo-2-(2-bromoethoxy)ethane (3) by successive cyclization, reduction, nucleophilic substitution with 2-bromo-6-fluoropyridine, and Suzuki–Miyaura reaction with (5-chloro-2-fluoropyridin-4-yl)boronic acid. Another key intermediate (11) was synthesized from (S)-1-methoxypropan-2-ol (8) by reaction with TsCl, electrophilic substitution reaction with tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate, and then by deprotection of Boc. Finally, a substitution reaction by the key intermediates (7) and (11) to afford the target product NVP-2 (1). The reaction conditions of the whole synthesis process were simple and mild, free of harsh conditions such as the microwave reaction and dangerous reagents in the original patent, and realized the efficient synthesis of NVP-2. In addition, we analyzed the binding mode of NVP-2 in the active pocket of CDK9 to provide reasonable design ideas for subsequent discovery of novel CDK9 inhibitors.

Online popularity has a major impact on videos, music, news and other contexts in online systems. Characterizing online popularity dynamics is nature to explain the observed properties in terms of the already acquired popularity of each individual. In this paper, we provide a quantitative, large scale, temporal analysis of the popularity dynamics in two online video-provided websites, namely MovieLens and Netflix. The two collected data sets contain over 100 million records and even span a decade. We characterize that the popularity dynamics of online videos evolve over time, and find that the dynamics of the online video popularity can be characterized by the burst behaviors, typically occurring in the early life span of a video, and later restricting to the classic preferential popularity increase mechanism.

Based on the remanufacturing idea, taking the CH Company for the research case, the forward and reverse logistics processes of the household electrical appliances were simulated and optimized systemically through Flexsim. Through method study technique, the process for recovery, dismantling and remanufacturing of waste TV were analyzed qualitatively and quantitatively and the model of production logistics system was built. From this model, the bottlenecks of the total logistics system can be identified, and the corresponding improved program and a comprehensive evaluation can be suggested reasonably. The results indicate that, based on the simulation in this work, the system technical indexes, such as T, Q, C and S, can be improved greatly by optimizing household electrical appliances remanufacturing production logistics system.

With the shortening of product life cycle, and the constant increasing of End-of-life Electromechanical Products, the processing of waste products appears especially important and urgent. This paper, based on an existing recycle model, has established an economic evaluation model of end-of-life electromechanical products. Based on the collection of a large amount of data and tests, the research and evaluation of the engine has proved it is suitability for remanufacturing.

In order to solve production problems of X Company, such as capacity can't satisfy customer's need, low productivity, and high defective rate, the production line is analyzed and improved by Industrial Engineering method, Such as Work study, Facility planning, Human Factor and so on. Based on roundly analyzing product, quantity, route, layout, productivity, quality, and by improving material transportation way, optimizing key process, improving production line's layout, and improving quality, various waste are eliminated, and material handlings and work environment are optimized. It indicates that quality, productivity and cost is effectively optimized by the IE method.

Production system is a highly complex, discrete event dynamic system, so it is difficult to build mathematic model of it, and simulation has become one of good method for studying it. Flexsim, which has been widely used in manufacturing, logistics, transportation, service system and so on, is a DEDS simulation software based on Object-oriented idea. UML is a object-oriented modeling language, which can describe production system. A Modeling, Simulation and Optimization method of production system, which is based on UML and Flexsim, is proposed firstly. Then by this method, An air conditioner manufacturing company's production system is studied. The production system is simulated and improved, and finally the output is improved.

Today's society attach importance to low-carbon environmental protection, recycling waste home appliances emerge gradually under the constraints of the producer's lifetime responsibility system. Many large-scale household-manufacturers focus more on the appliance recycling reverse logistics system, and the recycling logistics model itself also attracts more and more attention in the aspect of modeling and simulation. Based on the analysis based on the principles of system dynamics, with the existing research appliance recycling reverse logistics model result, analyses the application of theory of system dynamics in reverse logistics modeling and simulation. Using the modeling software visualization tools--Vensim examples introduces the basic method of drawing the Flow Diagram which is the basic form of system dynamics modeling.

A method of reverse logistics network design, which is based on operation research method(i.e. set covering location model and mix-integer linear programming) and DEDS simulation method, is proposed in the paper. And take some home appliance product company which is located in Sichuan, china for example, Its reverse logistics network for television remanufacturing in Sichuan is established and optimized by the method.

With further developing of service economy, Boundary between service and manufacturing is more and more dim. Service-oriented manufacturing, which is presented by some Chinese scholars, is a new advanced manufacturing model for catering to integration and fusion of service and manufacturing. One of key problems in service-oriented manufacturing is operation mode. A mode of service-oriented manufacturing, which is by grid, is presented in this paper. And Architecture of service-oriented manufacturing system based on OGSA is also presented.

Choosing satisfactory cooperative partner, i.e. supplier or retailer, and constructing excellent supply chain are important for success of manufacturing enterprise in today's global highly competitive business environment. Grid, which stands for developing trend of next generation of Internet, make enterprise use global manufacturing resource more easily. Model of common supply chain construction is presented in this paper firstly, then method of searching for supplier based on OGSA, i.e. Open Grid Services Architecture, is proposed. Finally, algorithm of evaluating supplier is discussed. In this way, a model of supply chain construction based on OGSA and its key research topic is presented.

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The somatic Sertoli cells play an essential role in testis determination and spermatogenesis by providing nutrition and structural support. In the current study, we report on the novel Ankrd7 gene that contains five ankyrin repeat domains. This gene was specifically expressed in Sertoli cells and was regulated in a maturation-dependent manner. Its expression was restricted to testicular tissue, and its mRNA could be detected in testes at as early as 14 dpp (days post partum) using RT-PCR analysis. In both testicular tissue sections and in vitro cultured Sertoli cells, the Ankrd7 protein was localized to the nucleus of the Sertoli cell. Immuno-histochemistry and immunocytochemistry investigations showed that the protein was detectable in testicular tissues at 20 dpp, at which time Sertoli cells were gradually differentiating into their mature cellular form. These results suggest that Ankrd7 is probably involved in the process of Sertoli cell maturation and in spermatogenesis.