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    Neurofibrillary labels
    33.
    发明申请
    Neurofibrillary labels 有权
    神经原纤维标签

    公开(公告)号：US20080219929A1

    公开(公告)日：2008-09-11

    申请号：US12071693

    申请日：2008-02-25

    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： A61K49/00 ,  C07D277/62

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

    摘要： A method for determining the Braak stage of neurofibrillary degeneration associated with a tauopathy in a subject having neurofibrillary degeneration is disclosed. The method comprises the steps of (i) administering to the subject a conjugated, chelated or detectable chemical group-associated ligand that labels aggregated paired helical filament (PHF) tau protein and is capable of crossing the blood brain barrier; (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, and (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. Preferred ligands include sulphonated-benzothiazole-like compounds and diamonophenothiazines.

    摘要翻译： 公开了一种用于确定与具有神经原纤维变性的受试者中与tau蛋白病相关的神经原纤维变性的Braak阶段的方法。 该方法包括以下步骤：（i）向受试者施用标记聚集的成对螺旋丝（PHF）tau蛋白并能够穿过血脑屏障的共轭，螯合或可检测的化学基团相关配体; （ii）确定与受试者脑内侧颞叶中细胞外聚集的PHF tau结合的配体的存在和/或数量，以及（iii）将（ii）中确定的测定结果与神经原纤维的程度相关联 主题变性 优选的配体包括磺化苯并噻唑类化合物和二氨基吩噻嗪。

    Materials and methods relating to protein aggregation in neurodegenerative disease
    34.
    发明授权
    Materials and methods relating to protein aggregation in neurodegenerative disease 有权
    与神经退行性疾病中的蛋白质聚集相关的材料和方法

    公开(公告)号：US07335505B2

    公开(公告)日：2008-02-26

    申请号：US10451782

    申请日：2002-01-15

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

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

    IPC分类号： C12M1/20 ,  C12N1/14 ,  C12N5/06 ,  G01N33/53 ,  G01N33/567 ,  C12Q1/02 ,  A01N63/00 ,  A01N39/00 ,  A61K48/00

    CPC分类号： G01N33/6896 ,  A61K31/00 ,  A61K31/5415

    摘要： The present invention provides methods of proteolytically converting a precursor protein (e.g. tau) to a product fragment (e.g., a 12 kd fragment) in a stable cell line, wherein the precursor protein is associated with a disease state in which the precursor protein aggregates pathologically (e.g. a tauopathy), and the methods comprise: (a) providing a stable cell line transfected with nucleic acid encoding: (i) a template fragment of the precursor protein such that the template fragment is constitutively expressed in the cell at a level which is not toxic to the cell; and (ii) the precursor protein, which protein is inducibly expressed in the cell in response to a stimulus, whereby interaction of the template fragment with the precursor protein causes a conformational change in the precursor protein such as to cause aggregation and proteolytic processing of the precursor protein to the product fragment. The method is preferably used to screen for modulators of the aggregation process by monitoring production (or modulation of production) of the product band or bands. Also provided are materials for used in the assays, plus medicaments, and related uses and processes, based on compounds which show high activity in the assay of the invention e.g. reduced diaminophenothiazines.

    摘要翻译： 本发明提供了在稳定细胞系中将前体蛋白质（例如tau）蛋白水解转化成产物片段（例如，12kd片段）的方法，其中前体蛋白质与其中前体蛋白质在病理学上聚集的疾病状态相关联 （例如，tau蛋白病），并且所述方法包括：（a）提供用核酸转染的稳定的细胞系，编码：（i）前体蛋白的模板片段，使得模板片段在细胞中以 对细胞无毒性; 和（ii）前体蛋白质，该蛋白质响应于刺激而在细胞中可诱导表达，由此模板片段与前体蛋白质的相互作用导致前体蛋白质的构象变化，从而导致蛋白质的聚集和蛋白水解加工 前体蛋白到产物片段。 该方法优选用于通过监测产品带或带的生产（或调制生产）来筛选聚集过程的调制器。 还提供了用于测定中的材料，以及基于在本发明的测定中显示高活性的化合物的药物以及相关用途和方法，例如。 还原二氨基吩噻嗪。

    Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC)
    35.
    发明申请
    Methods of chemical synthesis and purification of diaminophenothiazinium compounds including methylthioninium chloride (MTC) 有权
    二氨基吩噻嗪鎓化合物的化学合成和纯化方法，包括甲基硫堇（MTC）

    公开(公告)号：US20060287523A1

    公开(公告)日：2006-12-21

    申请号：US11391675

    申请日：2006-03-29

    申请人： Claude Wischik ,  Janet Rickard ,  Charles Harrington ,  David Horsley ,  John Storey ,  Colin Marshall ,  James Sinclair ,  Han Tan

    发明人： Claude Wischik ,  Janet Rickard ,  Charles Harrington ,  David Horsley ,  John Storey ,  Colin Marshall ,  James Sinclair ,  Han Tan

    IPC分类号： C07D279/18

    CPC分类号： C09B19/02 ,  C07D279/18

    摘要： This invention pertains generally to the field of chemical synthesis and purification, and more specifically to methods of synthesizing and purifying certain 3,7-diaminophenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methythioninium Chloride (MTC) (also known as Methylene Blue). In one embodiment, the method comprises the steps of, in order: nitrosylation (NOS); nitrosyl reduction (NR); thiosulfonic acid formation (TSAF); oxidative coupling (OC); Cr(VI) reduction (CR); isolation and purification of zwitterionic intermediate (IAPOZI); ring closure (RC); chloride salt formation (CSF); one of: sulphide treatment (ST); dimethyldithiocarbamate treatment (DT); carbonate treatment (CT); ethylenediaminetetraacetic acid treatment (EDTAT); organic extraction (OE); and recrystallisation (RX). The present invention also pertains to the resulting (high purity) compounds, compositions comprising them (e.g., tablets, capsules), and their use in methods of inactivating pathogens, and methods of medical treatment and diagnosis, etc., for example, for tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral diseases, bacterial diseases, or protozoal diseases.

    摘要翻译： 本发明一般涉及化学合成和纯化领域，更具体地涉及合成和纯化某些3,7-二氨基吩噻嗪-5-肟化合物（本文中称为“二氨基吩噻嗪鎓化合物”）的方法，包括氯化铁偶氮（MTC）（ 也称为亚甲基蓝）。 在一个实施方案中，该方法包括以下步骤：按顺序：亚硝基化（NOS）; 亚硝酰还原（NR）; 硫代磺酸形成（TSAF）; 氧化偶合（OC）; Cr（VI）还原（CR）; 两性离子中间体（IAPOZI）的分离和纯化; 闭环（RC）; 氯化物盐形成（CSF）; 一种：硫化物处理（ST）; 二甲基二硫代氨基甲酸酯处理（DT）; 碳酸盐处理（CT）; 乙二胺四乙酸处理（EDTAT）; 有机萃取（OE）; 和重结晶（RX）。 本发明还涉及所得的（高纯度）化合物，包含它们的组合物（例如片剂，胶囊）及其在灭活病原体的方法中的用途，以及治疗和诊断方法等，例如对于tau蛋白病 ，阿尔茨海默病（AD），皮肤癌，黑素瘤，病毒性疾病，细菌性疾病或原生动物疾病。

    PWM-based measurement interface for a micro-machined electrostatic actuator
    36.
    发明授权
    PWM-based measurement interface for a micro-machined electrostatic actuator 有权
    用于微加工静电执行器的基于PWM的测量接口

    公开(公告)号：US06933873B1

    公开(公告)日：2005-08-23

    申请号：US10747875

    申请日：2003-12-29

    申请人： David Horsley ,  Robert Conant ,  William Clark

    发明人： David Horsley ,  Robert Conant ,  William Clark

    IPC分类号： G01R31/28 ,  H02N1/00 ,  H03M1/12 ,  G01R27/26

    CPC分类号： G01R31/2829 ,  H02N1/002

    摘要： Methods and apparatus for varying and measuring the position of a micromachined electrostatic actuator using a pulse width modulated (PWM) pulse train are disclosed. One or more voltage pulses are applied to the actuator. In each of the pulses, a voltage changes from a first state to a second state and remains in the second state for a time tpulse before returning to the first state. The position of the actuator may be varied by varying the time Δtpulse. A position of the actuator may be determined by measuring a capacitance of the actuator when the voltage changes state, whether the time t is varied or not. An apparatus for varying the position of a MEMS device may include a pulse width modulation generator coupled to the MEMS device an integrator coupled to the MEMS device and an analog-to-digital converter coupled to the integrator. The integrator may measure a charge transferred during a transition of a pulse from the pulse generator. The integrator may include an amplifier, an integrator capacitor, a hold capacitor, a compensation voltage generator and three switches. The hold capacitor and integrator capacitor may be coupled to a MEMS device. The integrator capacitor, hold capacitor, and compensation voltage generator may be selectively coupled to the amplifier by two of the switches. The MEMS device and hold capacitor may be selectively coupled to ground by a third switch.

    摘要翻译： 公开了使用脉冲宽度调制（PWM）脉冲串来改变和测量微加工静电致动器的位置的方法和装置。 一个或多个电压脉冲被施加到致动器。 在每个脉冲中，电压从第一状态变为第二状态，并且在返回到第一状态之前保持在第二状态一段时间t 。 致动器的位置可以通过改变时间差动脉冲来改变。 致动器的位置可以通过在电压改变状态时测量致动器的电容，时间t是否变化来确定。 用于改变MEMS器件的位置的装置可以包括耦合到MEMS器件的耦合到MEMS器件的积分器和耦合到积分器的模数转换器的脉宽调制发生器。 积分器可以测量在来自脉冲发生器的脉冲的转变期间传送的电荷。 积分器可以包括放大器，积分电容器，保持电容器，补偿电压发生器和三个开关。 保持电容器和积分电容器可以耦合到MEMS器件。 积分器电容器，保持电容器和补偿电压发生器可以通过两个开关选择性地耦合到放大器。 MEMS器件和保持电容器可以通过第三开关选择性地耦合到地。