Huntington's disease (HD) 1 is a dominant inherited neurodegenerative disorder characterized by choreiform movement, psychiatric disturbance, and cognitive decline (2). The HD gene encodes a 350-kDa protein designated as huntingtin (3), which is richly expressed in dendrites and nerve terminals, where huntingtin is associated with synaptic vesicles and microtubule complexes (4 -5). The defect of the HD gene is the expansion of a CAG repeat encoding polyglutamine at its 5Ј end, and the length of the repeat is correlated with the age of onset and the severity of the disease (6).Although the HD gene has been identified for many years, how polyglutamine-expanded huntingtin causes neurons to die remains unclear. Increased glutamate-mediated excitotoxicity in HD has been a very popular hypothesis for the last 25 years (1). The hypothesis is generated from findings that the intrastriatal injection of glutamate or kainic acid in rat causes selective loss of medium spiny neurons that are also selectively affected in HD (7-8). This hypothesis is supported further by the findings that NMDA receptors are hyperactive, and excitotoxicity mediated by these receptors is enhanced significantly in HD transgenic mice (9 -10). These results suggest that overactivation of glutamate receptors may play a significant role in the pathogenesis of HD. However, over 95% of normal or polyglutamine-expanded huntingtin is located in the cytoplasm (6 -7), whereas glutamate receptors are cell surface receptors. How a cytoplasmic protein alters glutamate receptors on the cell surface membrane is an intriguing question.PSD-95 is a scaffold protein that contains an SH3 domain, a GK domain, and three PDZ domains that bind to the NMDA receptor NR2 subunits and kainate receptor GluR6 subunit (11)(12). The binding of PSD-95 to NMDA or kainate receptors causes the clustering of the receptors in the postsynaptic membrane and regulates NMDA-dependent long term potentiation and long term depression (12). PSD-95 also binds to cytoplasmic signaling proteins and links the receptors to cellular signaling cascades (13)(14). In transgenic mice lacking PSD-95, the frequency function of NMDA-dependent long term potentiation and long term depression is shifted, and spatial learning is impaired severely (15). Suppression of PSD-95 expression inhibits NMDA receptor-mediated activation of nitric-oxide synthase and excitotoxicity (16). These studies suggest that PSD-95 regulates glutamate receptor-mediated excitotoxicity and plays an important role in spatial learning, which is severely impaired in HD patients and HD transgenic mice (17)(18)(19). In previous studies, we observed that the overexpression of polyglutamine-expanded huntingtin caused neuronal apoptosis via activation of the mixed lineage kinase/c-Jun N-terminal kinase signaling pathway (20 -21), and mixed lineage kinase is also involved in neuronal toxicity mediated by GluR6 receptors via interaction with . The present study is intended to investigate the "missing link" protein between glutamate receptor...

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Abstract:The economic, social and environmental benefits generated by the use of urban public transportation infrastructure constitute a complex dynamic urban public transportation infrastructure utilization benefit system. This paper evaluates the coupling coordination among these three benefits taking four Chinese autonomous municipalities as an example. These four cities have large-scale urban public transportation infrastructures but their utilization has many serious problems. The basic function of urban public transportation infrastructure has not been fully played in these cities. Whether the different benefits of urban public transportation infrastructure have been developed in harmony or not is unclear. We analyzed the coordinated development among three benefits by constructing coupling coordination degree model and used Gini coefficient to study the difference of coordinated development among three benefits of four cities. The result shows that the levels of coordinated development among three benefits of urban public transportation infrastructure were lower in these four cities and have positive correlation with it of urban public transportation infrastructure utilization benefit. Raising the level of urban public transportation infrastructure utilization benefit is the most crucial solution of promoting the coordinated development among three benefits.

The zero-markup drug policy is an important component of the new round of Chinese health care reform that began in 2009 to promote the separation between medical and pharmaceutical services, reduce patients' medical burden, and improve the medical supply security system. Over the past 8 years, the zero-markup drug reform policy has been carried out in 4 pilot rounds (a policy diffusion model with Chinese characteristics) and has been promoted throughout the mainland China. At this critical point, it is necessary to review this policy systematically. Therefore, based on the literature, government documents, and interview records, this study analyzed the characteristics, progress, achievements, challenges, and recommendations of zero-markup drug reform by using the policy diffusion theory. The study found that zero-markup drug reform has completed its initial diffusion by use of the "policy experiment" method and has reduced drug prices and patients' burden to a certain extent. However, in the next phase of policy diffusion, the reform still requires adjustment and innovative measures to respond to future challenges. Generally speaking, as China's unique health care reform practice, the experience of zero-markup drug reform could be used as a reference for other countries to control drug prices, separate medical and pharmaceutical services, and establish a modern system of hospital operation.

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