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

Humanized chimeric mouse models of hepatitis B virus infection

Hepatitis B virus (HBV) infection is associated with an increased risk of hepatic cirrhosis, hepatocellular carcinoma, fulminant hepatitis and end-stage hepatic failure. Despite the availability of anti-HBV therapies, HBV infection remains a major global public health problem. Developing an ideal animal model of HBV infection to clarify the details of the HBV replication process, the viral life cycle, the resulting immunoresponse and the precise pathogenesis of HBV is difficult because HBV has an extremely narrow host range and almost exclusively infects humans. In this review, we summarize and evaluate animal models available for studying HBV infection, especially focusing on humanized chimeric mouse models, and we discuss future development trends regarding immunocompetent humanized mouse models that can delineate the natural history and immunopathophysiology of HBV infection

A bus route evaluation model based on GIS and super-efficient data envelopment analysis

When compared to large cities in developed countries, the shares of public transportation in most Chinese cities are low. Increasing the competitiveness of urban public transportation remains an urgent problem. A capable evaluation method for public transportation is required to assist the development of urban transit systems. This paper focuses on the bus system. Being devoid of standard criteria, it is difficult to determine the efficiency of a transit system or any bus line using a single evaluation index. This paper proposes a comparative analysis to evaluate bus lines so as to filter out candidates for further optimization. From the viewpoints of transit planning, operation and quality of service, this paper establishes 10 subordinate evaluation indices and then uses geographical information system tools, global positioning system data and smart card data to assist the index definition and calculation. Super-efficient data envelopment analysis (DEA) method is adopted for the proposed single factor and comprehensive evaluation models. Finally, the bus system in Shenzhen, China is used as a case study. The comparable significant results validate the capability of the proposed model

Analyzing spatiotemporal congestion pattern on urban roads based on taxi GPS data

With the development of in-vehicle data collection devices, GPS trajectory has become a priority source to identify traffic congestion and understand the operational states of road network in recent years. This study aims to investigate the relationship between traffic congestion and built environment, including traffic related factors and land use. Fuzzy C-means clustering was used to conduct an exhaustive study on 24-hour congestion pattern of road segments in urban area, so that the spatial autoregressive moving average model (SARMA) was introduced to analyze the output from the clustering analysis to establish the relationship between built environment and the 24-hour congestion pattern. The clustering result classified the road segments into four congestion levels, while the regression explained 12 traffic-related factors and land use factors’ impact on road congestion pattern. The continuous congestion was found to mainly occur in the city center, and the factors, such as road type, bus station in the vicinity, ramp nearby, commercial land use and so on have large impact on congestion formation. The Fuzzy C-means clustering was proposed to be combined with quantitative spatial regression, and the overall evaluation process will assist to assess the spatial-temporal levels of service of traffic from the congestion perspective

Soliton microcombs in whispering gallery mode crystalline resonators with dispersive intermode interactions

Soliton microcombs have shown great potential in a variety of applications ranging from chip scale frequency metrology to optical communications and photonic data center, in which light coupling among cavity transverse modes, termed as intermode interactions, are long-existing and usually give rise to localized impacts on the soliton state. Of particular interest are whispering gallery mode based crystalline resonators, which with dense mode families, potentially feature interactions of all kind. While effects of narrow-band interactions such as spectral power spikes have been well recognized in crystalline resonators, that of broadband interactions remains unexplored. Here, we demonstrate soliton microcombs with broadband and dispersive intermode interactions, in home-developed magnesium fluoride microresonators with an intrinsic $\mathbf{Q}$-factor approaching 10 billion. Soliton combs with broadband spectral tailoring effect have been observed. Remarkably, footprints of both constructive and destructive interference on solitons have been observed, which as confirmed by simulations, are connected to the dispersive effects of the coupled mode family. The ultra-high-Q magnesium fluoride microresonator could also support high efficient soliton microcomb via intermode interactions, as well as rich Raman lasing dynamics. Our results not only contribute to the understanding of dissipative soliton dynamics in multi-mode or coupled resonator systems, but also extend the access to stable soliton combs in crystalline microresonators where mode control and dispersion engineering are usually challenging

Crystallinity and Sub-Band Gap Absorption of Femtosecond-Laser Hyperdoped Silicon Formed in Different N-Containing Gas Mixtures

Femtosecond (fs)-laser hyperdoped silicon has aroused great interest for applications in infrared photodetectors due to its special properties. Crystallinity and optical absorption influenced by co-hyperdoped nitrogen in surface microstructured silicon, prepared by fs-laser irradiation in gas mixture of SF6/NF3 and SF6/N2 were investigated. In both gas mixtures, nitrogen and sulfur were incorporated at average concentrations above 1019 atoms/cm3 in the 20–400 nm surface layer. Different crystallinity and optical absorption properties were observed for samples microstructured in the two gas mixtures. For samples prepared in SF6/N2, crystallinity and light absorption properties were similar to samples formed in SF6. Significant differences were observed amongst samples formed in SF6/NF3, which possess higher crystallinity and strong sub-band gap absorption. The differing crystallinity and light absorption rates between the two types of nitrogen co-hyperdoped silicon were attributed to different nitrogen configurations in the doped layer. This was induced by fs-laser irradiating silicon in the two N-containing gas mixtures

Soliton Microcomb on Chip Integrated <i>Si</i>₃N₄ Microresonators with Power Amplification in Erbium-Doped Optical Mono-Core Fiber

Soliton microcombs, offering large mode spacing and broad bandwidth, have enabled a variety of advanced applications, particularly for telecommunications, photonic data center, and optical computation. Yet, the absolute power of microcombs remains insufficient, such that optical power amplification is always required. Here, we demonstrate a combined technique to access power-sufficient optical microcombs, with a photonic-integrated soliton microcomb and home-developed erbium-doped gain fiber. The soliton microcomb is generated in an integrated Si3N4 microresonator chip, which serves as a full-wave probing signal for power amplification. After the amplification, more than 40 comb modes, with 115-GHz spacing, reach the onset power level of >−10 dBm, which is readily available for parallel telecommunications , among other applications

NIR-II bioluminescence for in vivo high contrast imaging and in situ ATP-mediated metastases tracing

Bioluminescence imaging has been widely used in life sciences and biomedical applications. However, conventional bioluminescence imaging usually operates in the visible region, which hampers the high-performance in vivo optical imaging due to the strong tissue absorption and scattering. To address this challenge, here we present bioluminescence probes (BPs) with emission in the second near infrared (NIR-II) region at 1029 nm by employing bioluminescence resonance energy transfer (BRET) and two-step fluorescence resonance energy transfer (FRET) with a specially designed cyanine dye FD-1029. The biocompatible NIR-II-BPs are successfully applied to vessels and lymphatics imaging in mice, which gives ~5 times higher signal-to-noise ratios and ~1.5 times higher spatial resolution than those obtained by NIR-II fluorescence imaging and conventional bioluminescence imaging. Their capability of multiplexed imaging is also well displayed. Taking advantage of the ATP-responding character, the NIR-II-BPs are able to recognize tumor metastasis with a high tumor-to-normal tissue ratio at 83.4