HBV infection-induced liver cirrhosis development in dual-humanized mice with human bone mesenchymal stem cell transplantation

疾病动物模型是现代医学发展的基石，尤其是重大、突发传染病暴发时，适宜的疾病动物模型可为及时发现病原体、制定防控策略提供强大保障，原创的疾病动物模型已成为衡量一个国家生物医药科研水平的标志。我校夏宁邵教授团队和浙江大学附属第一医院李君教授团队历经5年的协同攻关，终于建立了国际上首个高度模拟人类乙肝病毒（HBV）自然感染诱发的慢乙肝肝硬化小鼠模型。厦门大学公共卫生学院袁伦志博士生、浙江大学医学院附属第一医院江静博士和厦门大学公共卫生学院刘旋博士生为该论文共同第一作者。厦门大学夏宁邵教授、浙江大学附属第一医院李君教授和厦门大学程通副教授为该论文共同通讯作者。【Abstract】Objective： Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs). Design： Transplantation of hBMSCs into Fah -/- Rag2 -/- IL-2Rγc -/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanized (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterize the progression of chronic hepatitis and cirrhosis after HBV infection. Results： The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and immune cell lineages, including B cells, T cells, NK cells, dendritic cells (DCs) and viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks. Conclusion： This new humanized mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.this work was supported by the national Science and technology Major Project (grant nos. 2017ZX10304402, 2017ZX10203201 and 2018ZX09711003-005-003), the national natural Science Foundation of china(grant nos. 81672023, 81571818 and 81771996), the Scientific research Foundation of the State Key laboratory of Molecular Vaccinology and Molecular Diagnostics (grant no 2016ZY005), Zhejiang Province and State's Key Project of the research and Development Plan of china (grant nos 2017c01026 and 2016YFc1101304/3).该研究获得了传染病防治国家科技重大专项、新药创制国家科技重大专项和国家自然科学基金的资助

A new constraint handling method for wind farm layout optimization with lands owned by different owners

For wind farm optimizations with lands belonging to different owners, the traditional penalty method is highly dependent on the type of wind farm land division. The application of the traditional method can be cumbersome if the divisions are complex. To overcome this disadvantage, a new method is proposed in this paper for the first time. Unlike the penalty method which requires the addition of penalizing term when evaluating the fitness function, it is achieved through repairing the infeasible solutions before fitness evaluation. To assess the effectiveness of the proposed method on the optimization of wind farm, the optimizing results of different methods are compared for three different types of wind farm division. Different wind scenarios are also incorporated during optimization which includes (i) constant wind speed and wind direction; (ii) various wind speed and wind direction, and; (iii) the more realisticWeibull distribution. Results show that the performance of the new method varies for different land plots in the tested cases. Nevertheless, it is found that optimum or at least close to optimum results can be obtained with sequential land plot study using the new method for all cases. It is concluded that satisfactory results can be achieved using the proposed method. In addition, it has the advantage of flexibility in managing the wind farm design, which not only frees users to define the penalty parameter but without limitations on the wind farm division

Geometrical Optimization of Pump-As-Turbine (PAT) Impellers for Enhancing Energy Efficiency with 1-D Theory

This paper presents a multi-objective optimization strategy for pump-as-turbines (PAT), which relies on one-dimensional theory and analysis of geometrical parameters. In this strategy, a theoretical model, which considers all possible losses incurred (mainly by the components of pipe inlet, impeller and volute), has been put forward for performance prediction of centrifugal pumps operating as turbines (PAT). With the established mathematical relationship between the efficiency of PAT (both at pump and turbine mode) and the impeller controlling variables, the geometric optimization of the PAT impeller is performed with constant rotational speed. Specifically, the optimization data consist of 50 sets of impellers generated from Latin Hypercube Sampling method with its corresponding efficiencies calculated. Subsequently, the pareto-based genetic algorithm (PBGA) was adopted to optimize the geometic parameters of the impellers through the theoretical model. To validate the theoretical optimization results, the high-fidelity Computational Fluid Dynamics (CFD) simulation and the experimental data are employed for comparison of the PAT performance. The findings show that the efficiencies of both the pump and PAT optimized variables increased by 0.27% and 16.3% respectively under the design flow condition. Based on the one-dimensional theoretical optimization results, the geometry of the impeller is redesigned to suit both pump and PAT mode operations. It is concluded that the chosen design variables (b2, β1, β2, and z) have a significant impact on the PAT efficiency, which demonstrates that the optimization scheme proposed in this study is practicable

Effectiveness of optimized control strategy and different hub height turbines on a real wind farm optimization

Highlights • An optimized control strategy approach and different hub height turbines are studied. • Means of handling irregular boundaries and wind speed variations over non-flat terrain are developed. • Optimized control strategy yields 9 kW more power per turbine than self-optimum control strategy. • Optimized control strategy reduces cost of energy by 0.08 million dollars per megawatt. • Different hub height turbines are more able to alleviate wake interactions than constant hub height

The Impact of Surrogate Models on the Multi-Objective Optimization of Pump-As-Turbine (PAT)

Pump-as-turbine (PAT) technology permits two operating states—as a pump or turbine, depending on the demand. Nevertheless, designing the geometrical components to suit these operating states has been an unending design issue, because of the multi-conditions for the PAT technology that must be attained to enhance the hydraulic performance. Also, PAT has been known to have a narrow operating range and operates poorly at off-design conditions, due to the lack of flow control device and poor geometrical designs. Therefore, for the PAT to have a wider operating range and operate effectively at off-design conditions, the geometric parameters need to be optimized. Since it is practically impossible to optimize more than one objective function at the same time, a suitable surrogate model is needed to mimic the objective functions for it to be solvable. In this study, the Latin hypercube sampling method was used to obtain the objective function values, the Adaptive Neuro-Fuzzy Inference System (ANFIS), Artificial Neural Network (ANN) and Generalized Regression Neural Network (GRNN) were used as surrogate models to approximate the objective functions in the design space. Then, a suitable surrogate model was chosen for the optimization. The Pareto-optimal solutions were obtained by using the Pareto-based genetic algorithm (PBGA). To evaluate the results of the optimization, three representative Pareto-optimal points were selected and analyzed. Compared to the baseline model, the Pareto-optimal points showed a great improvement in the objective functions. After optimization, the geometry of the impeller was redesigned to suit the operating conditions of PAT. The findings show that the efficiencies of the optimized design variables of PAT were enhanced by 23.7%, 11.5%, and 10.4% at part load, design point, and under overload flow conditions, respectively. Moreover, the results also indicated that the chosen design variables (b2, β2, β1, and z) had a substantial impact on the objective functions, justifying the feasibility of the optimization method employed in this study

Dynamic Analysis of Cavitation Tip Vortex of Pump-Jet Propeller Based on DES

When a pump-jet propeller rotates at high speeds, a tip vortex is usually generated in the tip clearance region. This vortex interacts with the main channel fluid flow leading to the main energy loss of the rotor system. Moreover, operating at a high rotational speed can cause cavitation near the blades which may jeopardize the propulsion efficiency and induce noise. In order to effectively improve the propulsion efficiency of the pump-jet propeller, it is mandatory to research more about the energy loss mechanism in the tip clearance area. Due to the complex turbulence characteristics of the blade tip vortex, the widely used Reynolds averaged Navier–Stokes (RANS) method may not be able to accurately predict the multi-scale turbulent flow in the tip clearance. In this paper, an unsteady numerical simulation was conducted on the three-dimensional full flow field of a pump-jet propeller based on the DES (detached-eddy-simulation) turbulence model and the Z-G-B (Zwart–Gerber–Belamri) cavitation model. The simulation yielded the vortex shape and dynamic characteristics of the vortex core and the surrounding flow field in the tip clearance area. After cavitation occurred, the influence of cavitation bubbles on tip vortices was also studied. The results revealed two kinds of vortices in the tip clearance area, namely tip leakage vortex (TLV) and tip separation vortex (TSV). Slight cavitation at J = 1.02 led to low-frequency and high-frequency pulsation in the TLV vortex core. This occurrence of cavitation promotes the expansion and contraction of the tip vortex. Further, when the advance ratio changes into J = 0.73, a third type of vortex located between TLV and TSV appeared at the trailing edge which runs through the entire rotational cycle. This study has presented the dynamic characteristics of tip vortex including the relationship between cavitation bubbles and TLV inside the pump-jet propeller, which may provide a reference for the optimal design of future pump-jet propellers