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    Neurofibrillary labels
    2.
    发明申请
    Neurofibrillary labels 有权
    神经原纤维标签

    公开(公告)号：US20100285605A1

    公开(公告)日：2010-11-11

    申请号：US12662887

    申请日：2010-05-10

    申请人： Claude Michel Wischik ,  Charles Robert Harrington ,  Janet Elizabeth Rickard ,  David Horsley

    发明人： Claude Michel Wischik ,  Charles Robert Harrington ,  Janet Elizabeth Rickard ,  David Horsley

    IPC分类号： G01N33/566

    CPC分类号： C07D417/12 ,  C07D277/66 ,  C07D279/20 ,  G01N33/583 ,  G01N33/6896

    摘要： Disclosed are methods for determining the stage of neurofibrillary degeneration associated with a tauopathy in a subject believed to suffer from the disease, which methods comprise the steps of: (i) introducing into the subject a ligand capable of labelling aggregated paired helical filament (PHF) tau protein, (ii) determining the presence and\or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. The methods can be used for pre-mortem diagnosis and staging of tauopathies such as Alzheimer's Disease. Preferred ligands include sulphonated-benzothiazole-like compounds and diaminophenothiazines. Novel ligands (e.g. sulphonated-benzothiazole-like compounds) are also provided. The method may also include the use of “blocking ligands” to block competing binding sites. In other aspects the invention provides in vitro methods for identifying ligands capable of labeling aggregated PHF tau protein, the methods comprising the steps of: (i) providing a first agent suspected of being capable of labeling aggregated PHF tau protein, (ii) contacting (a) a tau protein or a derivative thereof containing the tau core fragment bound to a solid phase so as to expose a high affinity tau capture site, with (b) a liquid phase tau protein or derivative thereof capable of binding to the solid phase tau protein or derivative, and (c) said selected first agent and (d) a second agent known to be tau-tau binding inhibitor, (iii) selecting first agent which fully or partially relieves the inhibition of binding of the liquid phase tau protein or derivative of (b) to the solid phase tau protein or derivative of (a) by the inhibitor (d). Ligands may also be tested to confirm that they are not themselves inhibitors.

    摘要翻译： 公开了用于确定被认为患有疾病的受试者中与tau蛋白病相关的神经原纤维变性的阶段的方法，该方法包括以下步骤：（i）将能够标记聚集的成对螺旋丝（PHF）的配体引入受试者， tau蛋白，（ii）确定与受试者的脑内侧颞叶中细胞外聚集的PHF tau结合的配体的存在和/或量，（iii）将（ii）中确定的测定结果与 的神经原纤维变性。 这些方法可用于妊娠前诊断和分期的阿尔茨海默病等tau蛋白病。 优选的配体包括磺化苯并噻唑类化合物和二氨基吩噻嗪。 还提供了新的配体（例如磺化的苯并噻唑类化合物）。 该方法还可以包括使用“阻断配体”来阻止竞争结合位点。 在其它方面，本发明提供了用于鉴定能够标记聚集的PHF tau蛋白的配体的体外方法，所述方法包括以下步骤：（i）提供疑似能够标记聚集的PHF tau蛋白的第一药剂，（ii） a）包含与固相结合的tau核心片段的tau蛋白或其衍生物，以暴露高亲和力tau捕获位点，（b）能够结合固相tau的液相tau蛋白或其衍生物 蛋白质或衍生物，和（c）所述选择的第一试剂和（d）已知为tau-tau结合抑制剂的第二药剂，（iii）选择完全或部分缓解液相tau蛋白结合抑制的第一药剂，或 （b）衍生物与固相tau蛋白或（a）的抑制剂（d）的衍生物。 也可以测试配体以确认它们本身不是抑制剂。

    Neurofibrillary labels
    7.
    发明授权
    Neurofibrillary labels 有权
    神经原纤维标签

    公开(公告)号：US08097615B2

    公开(公告)日：2012-01-17

    申请号：US12662887

    申请日：2010-05-10

    申请人： Claude Michel Wischik ,  Charles Robert Harrington ,  Janet Elizabeth Rickard ,  David Horsley

    发明人： Claude Michel Wischik ,  Charles Robert Harrington ,  Janet Elizabeth Rickard ,  David Horsley

    IPC分类号： A61K31/54

    CPC分类号： C07D417/12 ,  C07D277/66 ,  C07D279/20 ,  G01N33/583 ,  G01N33/6896

    摘要： Disclosed are in vitro methods for identifying ligands capable of labeling aggregated PHF tau protein, the methods comprising the steps of: (i) providing a first agent suspected of being capable of labeling aggregated PHF tau protein, (ii) contacting (a) a tau protein or a derivative thereof containing the tau core fragment bound to a solid phase so as to expose a high affinity tau capture site, with (b) a liquid phase tau protein or derivative thereof capable of binding to the solid phase tau protein or derivative, and (c) said selected first agent and (d) a second agent known to be tau-tau binding inhibitor, (iii) selecting first agent which fully or partially relieves the inhibition of binding of the liquid phase tau protein or derivative of (b) to the solid phase tau protein or derivative of (a) by the inhibitor (d). Ligands may also be tested to confirm that they are not themselves inhibitors.

    摘要翻译： 公开了用于鉴定能够标记聚合的PHF tau蛋白的配体的体外方法，所述方法包括以下步骤：（i）提供疑似能够标记聚集的PHF tau蛋白的第一药剂，（ii）接触（a） 蛋白质或其衍生物，其含有与固相结合的tau核心片段以暴露高亲和力tau捕获位点，（b）能够结合固相tau蛋白或衍生物的液相tau蛋白或其衍生物， （c）所述选择的第一试剂和（d）已知为tau-tau结合抑制剂的第二药剂，（iii）选择完全或部分缓解液相tau蛋白或（b ）到固相tau蛋白或（a）的抑制剂（d）的衍生物。 也可以测试配体以确认它们本身不是抑制剂。

    Bi-directional mass air flow sensor having mutually-heated sensor elements
    10.
    发明授权
    Bi-directional mass air flow sensor having mutually-heated sensor elements 失效
    具有相互加热的传感器元件的双向质量空气流量传感器

    公开(公告)号：US5827960A

    公开(公告)日：1998-10-27

    申请号：US919644

    申请日：1997-08-28

    申请人： Michel Farid Sultan ,  Charles Robert Harrington ,  Michael James O'Rourke ,  Antonio Buddy Catalan

    发明人： Michel Farid Sultan ,  Charles Robert Harrington ,  Michael James O'Rourke ,  Antonio Buddy Catalan

    IPC分类号： G01F1/684 ,  G01F1/68

    CPC分类号： G01F1/6845 ,  G01F1/684

    摘要： A low cost, bi-directional manifold air flow sensing device based on sensed temperature differential due to airflow achieves improved sensitivity and frequency response by eliminating the heater element of the conventional sensor topology, and operating the sensor elements at a relatively higher current so that each temperature sensing element heats both itself and the other temperature sensing element. The sensitivity is significantly increased due to the increased current in the sensor elements, and the frequency response is significantly increased due to closer spacing of the sensor elements. With this new topology, the sensor elements are said to be mutually heated. In a particularly advantageous mechanization, the sensing device includes two separate pairs of upstream and downstream sensing elements, and the sensing elements are connected in the four legs of a Wheatstone bridge. The sensitivity is doubled since sensor elements are connected in each of the bridge legs, and performance and cost are improved through the elimination of off-chip bridge components. A simple, low cost, temperature compensation circuit compensates for ambient temperature variations.

    摘要翻译： 基于由气流感测到的温度差异的低成本双向歧管空气流量感测装置通过消除常规传感器拓扑的加热器元件来实现改善的灵敏度和频率响应，并以相对较高的电流操作传感器元件，使得每个 温度感测元件本身和另一温度感测元件加热。 由于传感器元件中的电流增加，灵敏度显着增加，并且由于传感器元件的间隔更近，频率响应显着增加。 通过这种新的拓扑结构，传感器元件被认为是相互加热的。 在特别有利的机械化中，感测装置包括两对独立的上游和下游感测元件，并且传感元件连接在惠斯通电桥的四条腿中。 传感器元件连接在每个桥脚中时，灵敏度增加了一倍，通过消除芯片外部桥式组件，可以提高性能和成本。 简单，低成本的温度补偿电路补偿环境温度变化。