Alzheimer’s disease (AD) is a neurodegenerative disease that accounts for more than 60% of dementia cases worldwide (Alzheimer’s Association, 2017). The exact underlying mechanisms of the disease pathogenesis are not yet understood and effective treatments that stop or even reverse AD are badly needed. Among hypotheses proposed to explain the pathogenesis of AD, amyloid cascade hypothesis is a dominant one, and an extensive amount of research is conducted on the investigation into the infamous extracellular amyloid-β (Aβ). Aβ is the main component of the amyloid plaques, a hallmark of AD, and is believed to be the major cause that leads to the neurodegeneration of AD (Hardy and Selkoe,2002; Karran et al., 2011). Most clinical trials target relatively late phase of the disease by reducing the Aβ accumulation in the brain. However, the continued failures of clinical trials of anti-amyloid suggest that the need for new approaches for the prevention of disease progression is urgent. Accumulating experimental evidence suggests that the aggregation of Aβ induces the intracellular Ca2+ dysregulation, which is an early event prior to the presence of clinical symptoms of AD and is believed to be crucial to its pathogenesis (Bezprozvanny and Mattson, 2008; Berridge, 2010). Numerous research has been conducted to study the mechanisms through which Aβ causes the Ca2+ dysregulation leading to neurodegeneration in AD, to offer new therapeutic strategies. Therefore, treatments of Ca2+ dysregulation provide an alternative direction in addition to the anti-amyloid approach. Attenuation of the dysfunctions of intracellular organelles, endoplasmic reticulum (ER)and mitochondria, and modulation or stabilisation activities of Ca2+ channels in plasma membrane or ER are potential therapeutic strategies for early stage of AD(Popugaeva and Bezprozvanny, 2013; Popugaeva et al.,2017).

Under experimental conditions, the disturbances in AD are mostly studied in transgenic animal models of AD or by injecting certain compunds, such as Aβ, into healthy animals or cells. The research generally focuses on the individual disturbances and effects. Aβ is reported to interact with multiple key proteins in various pathways (Berridge, 2010), therefore, it is difficult to isolate the individual effects or study the complex interactions across different pathways because of the limitations of currently available technology. Besides, due to the selection of experiment materials or/and methods by different research groups, controversial results and con fl icting interpretations exist.

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Computational biology offers great opportunities to study this kind of problem. Basing on conceptual models which integrate different components and pathways, disturbances or alterations in AD can be investigated both individually or comprehensively. Through thoughtfully-designed computational experiments,insights can be obtained by proper interpretation of the simulation results.

Computational modeling approach is a powerful tool that provides great opportunities to investigate and predict Ca2+ signaling through the simulation of the interaction of multiple Ca2+-dependent pathways. Cytosolic Ca2+ oscillations and waves in a variety of cell types have been extensively modelled. Details of modeling on cytoplasmic Ca2+ signaling are well reviewed by Schuster et al. (2002) and Blackwell (2013). During the past twothree decades, computational modeling of intracellular signaling has become an increasingly valuable approach in neuroscience to study the temporal and spatial complexities of nerve system. Computational models with Ca2+-dependent mechanisms are constructed at different biological scales, ranging from single ion channels to neurons and neural networks. The levels of detail for these models are diverse and depend on the research questions to be answered. They contain mechanisms such as influx of Ca2+ through membrane channels,extrusion by membrane Ca2+ pumps, intracellular diffusion of Ca2+, interaction of Ca2+ with other molecules and Ca2+ handling by intracellular organelles.

Financial support: None.

There are numerous simulation tools available for scientists with different backgrounds and for different research purposes (reviewed in Brette et al., 2007;Blackwell, 2013). There are two types tools: general purpose tools and biological simulation tools. The former generally have command-line interfaces or use scripting languages for modeling, therefore, requires users to have certain programming capability. At the same time,they offer users high degree of freedom in model analysis. Most popular tools belong to the former category are MATLAB, Mathematica, Python and R. The latter are tools that have built-in capabilities for simulation biological processes and mostly have friendly graphical user interfaces. They are suitable for sceintists who do not have programming backgrounds. This category includes the tools for general biological simulation(such as CellDesigner, MCell and COPASI) and speci fi c software packages particularly for neuronal simulation(such as NEURON and GENESIS).

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In spite of an extensive amount of research that carried on studying the dysregulation of Ca2+ signaling pathways in AD both in vitro and in vivo, the computational modeling on this fi eld is still in its infancy. Tiveci et al. developed a computational model that integrated a hemodynamic model with Ca2+ signaling pathway to study the brain energy metabolism (Tiveci et al., 2005).They used this model to investigate the effects of Ca2+dynamics on the blood oxygenation level-dependent signal under healthy and AD conditions. The simulation results revealed that the alteration in cerebral blood fl ow reported in AD leads to a negative effect on the blood oxygenation level-dependent signal and an increase in the intracellular Ca2+ concentration. In another study carried by Toivari et al., they developed a stochastic model of Ca2+ signaling in astrocyte, the predominant glial cells in the central nervous system (Toivari et al.,2011). The simulation results confirmed the effects of Aβ and neuron transmitters on inducing Ca2+ transients in astrocyte, which was consistent with their experimental observations.

Due to the challenges in quantitative studies of Aβ-mediated alteration in Ca2+ signaling, Aβ under the experimental conditions usually are given at a much higher concentration compared to the concentration in human brains with AD. This creates difficulties in studying the concentration dependence of Aβ disturbances. Therefore, a compromise solution in computational modeling study is to mimic the disturbances of Aβ by perturbing the related key parameters (Liang et al., 2017). Liang et al. (2017) developed a computational model according to the characteristic of a typical neuron to represent the healthy condition. The key parameters which reflect the Aβ-induced alterations are selected based on the experimental observations.When simulating the AD condition, the perturbations in these parameters are imposed to represent the degree of Aβ disturbances at different stages of AD. Another option is to develop highly conceptual models to study Aβ-mediated alterations in Ca2+ signaling. De Caluwé and Dupont proposed a simple mathematical model which models the interplay between Aβ-mediated neuronal Ca2+ level and the production of amyloids (De Caluwé and Dupont, 2013). This minimal qualitative model contained a positive feed-forward loop between intracellular Ca2+ and Aβ, and excluded the detailed molecular mechanisms. Simulation results showed an Aβ-dependent bistable switch between the healthy and pathological states. The model suggested that AD onset can be induced by a large enough perturbation in amyloid metabolism or upregulation of Ca2+ homeostasis, bringing insights into therapeutic research on the inhibition of disease onset and deceleration of its progression.

The developments in computational neuroscience,especially on Ca2+ signaling, provide a useful framework and foundation for modeling studies of AD and other neurodegenerative diseases. There are a few computational models that partially capture the Ca2+ dysregulation related to AD. For example, Good and Murphy developed a mathematical model of Aβ-mediated blockages of fast-inactivating K+ channels in neuronal plasma membranes, based on their experimental result:Aβ induced a voltage-dependent decrease in membrane conductance (Good and Murphy, 1996). They proposed an Aβ concentration-dependent effect in the membrane current and simulated this effect by fitting experimental data to a simple inhibition function. Their simulation results are consistent with the experimental observations and suggest that the blockage by Aβ of the fast-inactivating K+ current is one of the most feasible mechanisms that cause the intracellular Ca2+ overload and consequently leads to neurotoxicity. In a study carried by Morse et al., a realistic multi-compartment model was developed to investigate the Aβ-mediated block of A-type K+ currents and its hyperexcitability effects in proximal dendrites in AD (Morse et al., 2010).The simulation results predicted that the oblique branch is the most vulnerable target of Aβ to disrupt the A-type K+ currents and signal integration. They also suggested that the above alterations may account for the decline of cognitive function in the early phase of AD.

Acknowledgments: We would like to acknowledge Lincoln University for facilitation of the research mentioned here.

In conclusion, computational modeling has been applied to study the general Ca2+ dynamics. Current computational models provide a good foundation to help scientists to study the underlying mechanisms of Ca2+dysregulation in AD. Most current models are relatively simple, but they still can provide useful insights on Ca2+dysregulation in AD. However, comprehensive disease-speci fi c models of Ca2+ dysregulation are yet to be developed in order to study how different factors lead to intracellular Ca2+ dysregulation. Besides, future models should include downstream factors to explain how Ca2+dysregulation contribute to other neuronal alterations in AD. Moreover, models for therapeutic purposes should be able to directly test the medication effects, to provide potentials in drug discovery for AD.

中西方因历史和社会因素不同，英国偏向直线思维方式，我国则偏向曲线思维，因此中西方人认识事物的出发点不同，语言表达习惯也有所不同，这也是商务英语翻译中易出问题的关键。

其中政治生活参与者的素养包括，政治素养，思想素养，心理素养等，想要切实合法参与我国的政治生活，首先参与者要具备一定素养，最基本的就是对于政治生活的兴趣以及想要创造美好社会的愿望，以此才能保证公民在参与政治的过程中，思想是积极正确的，能够切实为社会发展、祖国进步作出自己的贡献。

1.环境的影响。当前，社会环境中各种享乐主义、拜金主义思想不断冲击着职工队伍，在挑战和考验面前，一些党员干部、项目管理人员的世界观、人生观、价值观、利益观发生扭曲，进而导致行为失范。

Author contributions: The fi rst author wrote the fi rst draftwith inputs from the second author, and the second author edited the content.

（六）生态安全压力较大。渝黔边界地区地处武陵山区和大娄山脉，是长江上游地区重要的生态屏障。受多年来资源的开发、自然灾害等多重因素影响，生态环境持续恶化，区域内形成煤炭采空区面积达400多平方公里，是全国8个熔岩石漠化地区之一。石漠化面积超过200平方公里，严重影响长江上游地区生态安全，亟需加强生态保护、加快生态修复。

Con fl icts of interest: None declared.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open access statement: This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License,which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Open peer reviewer: Matin Ramezani, Arak University,Iran.

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