Ion channels in cultured microglia

Inward and, depending on activation state, outward potassium currents are the dominant ion channels in microglial cells in culture. During transition between resting and activated phases, there is also an upregulated expression of stretch/swelling-activated chloride currents. Pharmacological blockade of the specific potassium channels does not prevent the transition, whereas blockade of chloride channels does, suggesting that this current may be involved in phase changes. Interestingly, this chloride current is far less studied than the potassium currents with regard to the different microglial phases. One puzzling finding when studying microglial state is that despite changes in current densities and membrane oscillations during transition, there is no evidence of an accompanying change in membrane potential. In other cells of the immune system, membrane oscillations and alterations in membrane potential are correlated with transitions in cellular phases. This discrepancy in microglia may be a result of the fact that almost all ion channel and membrane potential studies in culture are undertaken with concomitant dialysis of cytoplasm with pipette solution. Further complicating matters is that the few studies that use microglia in situ, find fundamental differences in ion channel current patterns of "resting" microglia as well as different temporal changes to pathological events or stimuli.     

Microglia in neuroregeneration

Microglia has the potential to produce and release a range of factors that directly and/or indirectly promote regeneration in the injured nervous system. The overwhelming evidence indicates, however, that this potential is generally not expressed in vivo. Activated microglia may enhance neuronal degeneration following axotomy, thereby counteracting functional recovery. Microglia does not seem to contribute significantly to axonal outgrowth after peripheral nerve injury, since this process proceeds uneventful even if perineuronal microglia is eliminated. The phagocytic phenotype of microglia is highly suppressed during Wallerian degeneration in the central nervous system. Therefore, microglia is incapable of rapid and efficient removal of myelin debris and its putative growth inhibitory components. In this way, microglia may contribute to regeneration failure in the central nervous system. Structural and temporal correlations are compatible with participation by perineuronal microglia in axotomy-induced shedding of presynaptic terminals, but direct evidence for such participation is lacking. Currently, the most promising case for a promoting effect on neural repair by activated microglia appears to be as a mediator of collateral sprouting, at least in certain brain areas. However, final proof for a critical role of microglia in these instances is still lacking. Results from in vitro studies demonstrate that microglia can develop a regeneration supportive phenotype. Altering the microglial involvement following neural injury from a typically passive or even counterproductive state and into a condition where these cells are actively supporting regeneration and plasticity is, therefore, an exciting challenge and probably a realistic goal.     

Microglia-precursor cell interactions in health and in pathology

Until recently, microglia were mainly known as the resident phagocytes of the brain, i.e. the ‘immunological warriors’ of the brain. However, extensive knowledge is being accumulated about the functions of microglia beyond immunity. Nowadays, it is well accepted that microglial cells are highly dynamic and responsive, and that they intervene in a dual manner in many developmental processes that shape the central nervous system, including neurogenesis, gliogenesis, spatial patterning, synaptic formation and elimination, and neural circuit establishment and maturation. The differentiation and the pool of precursor cells were also shown to be under microglia regulation via bidirectional communication. In this concise review, I discuss our recent work in microglia-Pax6⁺ cell interactions in one of the circumventricular organs, the pineal gland. An analogy with the rest of the central nervous system is also presented. In addition, I briefly examine mechanisms of interaction between microglia and non-microglial cells in both health and disease. New avenues are also introduced, which may lead us to better comprehend the impact of microglia in physiological and pathological conditions.     

Microglia and prion disease.

Gliosis is one of the hallmarks of the prion diseases. Prion diseases are fatal neurodegenerative conditions of low incidence made famous by both the hypothesis that a protein acts as the infectious agent without involvement of nucleic acid and the speculative idea that a disease of cattle, BSE, has spread to humans from the ingestion of prion-infected beef. Despite these unproved hypotheses, the aetiology of the prion diseases remains unsolved. The rapid degenerative course of the disease is preceded by a long incubation period with little or no symptoms. The rapid neurodegeneration in the disease follows from increased deposition of an abnormal isoform of a normal neuronal protein. Co-incident with the appearance of this abnormal protein is the activation of large numbers of microglia. Studies in cell culture with both the abnormal prion protein and a peptide-mimic suggest that neuronal degeneration occurs because of two concurrent effects. First, there is a reduction in neuronal resistance to toxic insults and, second, there is an increase in the production of toxic substances such as reactive oxygen species by microglia and a decrease in glutamate clearance by astrocytes. Microglia activated by the abnormal form of the prion protein also release cytokines, which stimulate changes in astrocytes such as proliferation. The implication of this is that microglia may play a major role in initiating the pathological changes in prion disease. This review discusses the role of microglia in these changes.     

Immunoregulation of microglial functional properties

Microglia are the resident tissue macrophages of the central nervous system (CNS) parenchyma and are key players in the initiation of an inflammatory response. Microglia rapidly transform from a resting to an activated morphology in response to a variety of disease states. However, they can also be the target of infections, as in the case of HIV. Many of the effector properties of microglia can be attributed to the array of substances they secrete in response to stimuli such as bacterial lipopolysaccharide, cytokines, and chemokines. The products of activated microglia include: cytokines (pro- and anti-inflammatory), chemokines, nitric oxide, superoxide radicals, and proteases. Furthermore, microglia have the ability to present antigen to T cells, migrate in response to chemotactic stimuli, and phagocytose cell debris. This report focuses on the immunomodulatory functions of microglia, with particular attention to chemokines, and highlights their pivotal role in the CNS.     

Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE.

The microglial cell, after many years of neglect, has become recognized as the sole representative cell of the immune system that resides in the normal central nervous system. While normally dormant, microglia can be activated by secretory substances or signals associated with disease or injury, and becomes a phagocytic cell, which also produces its own injurious molecules. In the activating process, its morphology is changed from a resting process-bearing cell, into a rounded amoebic form, and displays new or increased amounts of functional markers, such as receptors and Class I and Class II MHC molecules. Microglia prepared from newborn mice or rats for tissue culture are already activated, and can be used for studies of their phagocytic properties. Although they can phagocytize foreign substances, their uptake and metabolism of myelin are emphasized here, in keeping with their role in demyelinating diseases. A number of receptors have been implicated and appear to be important in the attachment to, and ingestion of, myelin particles in vitro, including the Fc, complement, macrophage scavenger, and the Galectin-3/MAC-2 receptors, although the alpha2-macroglobulin/low-density lipoprotein receptor and mannose receptors have also been suggested as participants in myelin phagocytosis. Certain cytokines and adhesion molecules also regulate the phagocytic activity of microglia. Comparative in vitro studies of phagocytosis by peritoneal macrophages and microglia have shown that the two kinds of cells respond differently to regulatory molecules, and it is concluded that they have different innate properties. The role of microglia in the demyelinative diseases experimental autoimmune encephalomyelitis and multiple sclerosis is emphasized here, and the possible means of intervention in the process leading to myelin destruction is discussed. Published 2001 Wiley-Liss, Inc.     

Role of microglia in glioma biology.

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors or malignant gliomas. Although the function of these cells in CNS inflammatory processes is being studied, their role in malignant glioma biology remains unclear. On one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors.     

From theory to therapy: implications from an in vitro model of ramified microglia

Microglia are the principal immune cells in the central nervous system (CNS), characterized by a highly specific morphology and unusual antigenic phenotype. An increasing number of studies have focused on the role of microglia in the pathogenesis of neurodegenerative diseases. To elucidate the function of microglial cells under several neuropathological conditions, we have studied and established a cell culture model that allows us to cultivate microglial cells in their inactive, resting (ramified) phenotype. In the first part of this work, we describe the interaction of microglia cells with their epithelial (astrocytic) microenvironment. The second part reviews experiments with microglia cell cultures to elucidate underlying signalling pathways and summarizes recent advances of our knowledge in microglial molecular pathways that may ultimately lead to neurodegeneration.     

锅炉受热面动态过程的一套显式解析特解

对锅炉省煤器受热面的动态过程偏微分方程组导出了一套代数显式解析特解。它仅由时间与几何坐标的常数项、线性项与负指数项组成,比较简单明了,而且有典型的物理意义。另外,在推导这些解时用了作者建议的一些新的办法,例如加法分离变量法。它把未知多元变量视为多个单元变量之和,而非如经典办法那样视为单元变量之积。这些办法可推广到其他的学科领域中去。     

Microglial interaction with beta-amyloid: implications for the pathogenesis of Alzheimer's disease.

The etiology of Alzheimer's disease (AD) involves a significant inflammatory component as evidenced by the presence of elevated levels of a diverse range of proinflammatory molecules in the AD brain. These inflammatory molecules are produced principally by activated microglia, which are found to be clustered within and adjacent to the senile plaque. Moreover, long-term treatment of patients with non-steroidal anti-inflammatory drugs has been shown to reduce risk and incidence of AD and delay disease progression. The microglia respond to beta-amyloid (Abeta) deposition in the brain through the interaction of fibrillar forms of amyloid with cell surface receptors, leading to the activation of intracellular signal transduction cascades. The activation of multiple independent signaling pathways ultimately leads to the induction of proinflammatory gene expression and production of reactive oxygen and nitrogen species. These microglial inflammatory products act in concert to produce neuronal toxicity and death. Therapeutic approaches focused on inhibition of the microglial-mediated local inflammatory response in the AD brain offer new opportunities to intervene in the disease.     

RECONSTRUCTION STABILITY OF NEARFIELD ACOUSTIC HOLOGRAPHY

The distributed source boundary point method (DSBPM) is used as the spatial transform algorithm for realizing nearfield acoustic holography (NAH),the sensitivity of the reconstructed solution to the measurement errors is analyzed,and the regularization method is proposed to stabilize the reconstruction process,control the influence of the measurement errors and get a better approximate solution.An oscillating sphere is investigated as a numerical example,the influence of the measurement errors on the reconstruction solution is demonstrated,and the feasibility and validity of the regularization method are validated.     

含湿毛细多孔介质传热与传质基本方程的一组代数显式解析解

对含湿毛细多孔介质传热与传质过程的基本主控方程,以建议使用的加法分离变量法导出了一套代数显式解析特解。它仅由时间的线性项与几何坐标的二次项组成,比较简单明了,具有一定的物理意义。这个特解尤其适合作为标准解发展计算传热传质学。     

平面曲柄滑块机构函数综合的LINGO求解方法

对平面曲柄滑块机构的求解方法分析后,提出了一种用LINGO9.0软件求出全部解的方法。该方法是用LINGO10.0求出一个解后,将该解作为一个约束,使新解与该不同,直至求出全部解。该方法简单、实用,为实际机构的设计提供了多种选择方案,为机构学设计提供了全新的方法。     

激光粒度测量的综合反演及参数选择

本论文提出了一种应用于激光粒度测量的无模式综合反演算法,即,二阶段迭法算法。该算法综合采用了改进共轭梯度法和松弛迭代法各自的优点,使用了共轭梯度法作为第一步预迭代,利用其快速收敛性和解的平滑性得到第二步迭代的初始解,而后,采用了改进的松弛迭代法对第一步的初始解进行改进。使用该方法能使解在稳定性和准确性方面得到了一定程度的改进。对算法进行了分块操作,并对所有模块如共轭迭代法,正则化法,松弛迭代法进行分析,指出模块的可行性与必要性,同时进行参数的最优化选择。     

Microglia in HIV-associated neurological diseases.

Human immunodeficiency virus type-1 (HIV-1) is a neurotropic virus linked to a variety of progressive neurologic disorders. This review describes our current understanding of how HIV-1 enters the nervous system and interacts with neuronal and non-neuronal cells to initiate and sustain neurologic dysfunction. The overwhelming majority of cells infected with HIV-1 in the nervous system are microglia/macrophages. Microglial/macrophage infection leads to immune dysregulation as well as production and release of cytotoxic molecules. Interaction of these infected cells with astrocytes may accelerate neurotoxic mechanisms. A hypothetical scenario for how HIV-1 infection leads to neurologic disease is presented.     

A mesh-less method to solve electrical resistance tomography forward problem using singular boundary distributed source method

This paper presents a novel mesh-less method called singular boundary distributed source (SBDS) method to solve the electrical resistance tomography (ERT) forward problem. Mesh-less methods are mathematically simple and computationally efficient i.e. same accuracy that of mesh or domain based methods can be achieved with less computation time. The domain boundary is discretized such that the source and field points coincide on the same boundary and the solution is expressed as a linear combination of fundamental solution of governing equation. The singularity appearing due to coinciding of source and field points is addressed using a hybrid approach. The coefficients corresponding to Neumann boundary are evaluated using the improved distributed source method (IBDS) while the coefficients corresponding to Dirichlet boundary conditions are evaluated using inverse interpolation technique. The hybrid SBDS with complete electrode model is formulated for ERT forward problem. The proposed SBDS method has better accuracy and convergence as compared to other mesh-less methods. Especially, the SBDS method solution is not dependent on distributed source radius therefore is stable compared to the IBDS method. The proposed SBDS method is tested with numerical experiments and the performance is compared against boundary discretization methods such as the IBDS and boundary element methods.     

基于矩阵算式和蚁群算法的元功能链设计方案优化方法*

为解决矩阵算式求解元功能链设计方案过程中缺乏优化工具的问题,提出了一种矩阵算式结合蚁群算法的优化方法。分析了相似性理论,用相似度和广义距离表征两个相邻元件的兼容性;定义了相似度矩阵,并使之与设计方案矩阵关联计算,获得了蕴含元件相似度信息的设计方案矩阵;定义了设计方案的评价模型和基于蚁群算法的优化模型,给出了评价参数、权重以及评价值的计算方法;以元件的评价得分作为信息素,以广义距离作为相邻节点路径的长度,构建了信息素矩阵和概率矩阵;将方案求解问题转化为组合优化的最优路径问题,用蚁群算法直接优化蕴含在设计方案矩阵中的方案,得到了同时满足结构需求、功能需求、评价需求的设计方案。通过某三轴伺服传送机构设计方案优化的实例,验证了方法的有效性。     

基于灰色聚类法的港口移动式高架起重机变幅系统多目标优化设计

以变幅系统为研究对象,建立了变幅过程中吊钩运动轨迹高度差值、臂架强度应力和变幅液压缸力差值为目标的多目标优化模型。采用遗传算法获得问题的理想解和若干有效解,并基于灰色聚类法确定各有效解的优劣次序,从而确定最有效解。应用表明,这种多目标优化问题的解决方法能够为决策提供更趋于实际的方法和依据,提高了设计的可靠性和有效性。     

一种机床动态特性的模糊评价方法

基于模拟数学的原理,提出一种机床整机动态特性的评价方法,该方法可以同时考虑多项动态性能评价指标,定量、客观地区分多个方案之间的优劣,例于实现机床方案评价的自动化。算例比较表明本方法是有效的,可以为实现机床多方案动态特性评价决策提供依据。