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    Separation of charged particles by a spatially and temporally varying electric field
    1.
    发明授权
    Separation of charged particles by a spatially and temporally varying electric field 失效
    通过空间和时间变化的电场分离带电粒子

    公开(公告)号：US06193866B1

    公开(公告)日：2001-02-27

    申请号：US09212622

    申请日：1998-12-16

    申请人： Joel S. Bader ,  Jonathan M. Rothberg ,  Michael W. Deem ,  Gregory T. Mulhern ,  Gregory T. Went ,  John Simpson ,  Steven Henck

    发明人： Joel S. Bader ,  Jonathan M. Rothberg ,  Michael W. Deem ,  Gregory T. Mulhern ,  Gregory T. Went ,  John Simpson ,  Steven Henck

    IPC分类号： G01N2726

    CPC分类号： B82Y30/00 ,  G01N27/44773

    摘要： This invention relates to a method and device for separating charged particles according to their diffusivities in a separation medium by means of a spatially and temporally varying electric potential. The method is particularly suited to sizing and separating DNA fragments, to generating DNA fragment length polymorphism patterns, and to sequencing DNA through the separation of DNA sequencing reaction products. The method takes advantage of the transport of charged particles subject to an electric potential that is cycled between an off-state (in which the potential is flat) and one or more on-states, in which the potential is preferably spatially periodic with a plurality of eccentrically shaped stationary potential wells. The potential wells are at constant spatial positions in the on-state. Differences in liquid-phase diffusivities lead to charged particle separation. A preferred embodiment of the device is microfabricated. A separation medium fills physically defined separation lanes in the device. Electrodes deposited substantially transverse to the lanes create the required electric potentials. Advantageously, injection ports allow sample loading, and special gating electrodes focus the sample prior to separation. The effects of thermal gradients are minimized by placing the device in contact with a thermal control module, preferably a plurality of Peltier-effect heat transfer devices. The small size of a microfabricated device permits rapid separation in a plurality of separation lanes.

    摘要翻译： 本发明涉及一种通过空间和时间上变化的电势根据其在分离介质中的扩散性分离带电粒子的方法和装置。 该方法特别适用于分选DNA片段，产生DNA片段长度多态性模式，并通过分离DNA测序反应产物对DNA进行测序。 该方法利用带电粒子的传输，该带电粒子经历在关闭状态（其中电位为平坦）和一个或多个导通状态之间循环的电位，其中电位优选为空间周期性的多个 偏心固定势阱。 势阱在导通状态下处于恒定的空间位置。 液相扩散性的差异导致带电粒子分离。 装置的优选实施例是微制造的。 分离介质填充设备中物理定义的分离通道。 基本横向于通道沉积的电极产生所需的电位。 有利地，注射端口允许样品加载，并且特殊门电极在分离之前聚焦样品。 通过将设备与热控制模块（优选多个珀耳帖效应传热装置）接触来使热梯度的影响最小化。 微型加工装置的小尺寸允许在多个分离通道中快速分离。

    Separation of charged particles by a spatially and temporally varying electric field
    2.
    发明授权
    Separation of charged particles by a spatially and temporally varying electric field 失效
    通过空间和时间变化的电场分离带电粒子

    公开(公告)号：US5938904A

    公开(公告)日：1999-08-17

    申请号：US623346

    申请日：1996-03-27

    申请人： Joel S. Bader ,  Jonathan M. Rothberg ,  Michael W. Deem ,  Gregory T. Mulhern ,  Gregory T. Went

    发明人： Joel S. Bader ,  Jonathan M. Rothberg ,  Michael W. Deem ,  Gregory T. Mulhern ,  Gregory T. Went

    IPC分类号： B01D57/02 ,  G01N27/26 ,  G01N27/447

    CPC分类号： B82Y30/00 ,  G01N27/44773

    摘要： This invention relates to a method and device for separating charged particles according to their diffusivities in a separation medium by means of a spatially and temporarily varying electric potential. The method is particularly suited to sizing and separating DNA fragments, to generating DNA fragment length polymorphism patterns, and to sequencing DNA through the separation of DNA sequencing reaction products. The method takes advantage of the transport of charged particles subject to an electric potential that is cycled between an off-state (in which the potential is flat) and one or more on-states, in which the potential is preferably spatially periodic with a plurality of eccentrically shaped stationary potential wells. The potential wells are at constant spatial positions in the on-state. Differences in liquid-phase diffusivities lead to charged particle separation. A preferred embodiment of the device is microfabricated. A separation medium fills physically defined separation lanes in the device. Electrodes deposited substantially transverse to the lanes create the required electric potentials. Advantageously, injection ports allow sample loading, and special gating electrodes focus the sample prior to separation. The effects of thermal gradients are minimized by placing the device in contact with a thermal control module, preferably a plurality of Peltier-effect heat transfer devices. The small size of a microfabricated device permits rapid separation in a plurality of separation lanes.

    摘要翻译： 本发明涉及一种通过空间和暂时变化的电位根据其在分离介质中的扩散性分离带电粒子的方法和装置。 该方法特别适用于分选DNA片段，产生DNA片段长度多态性模式，并通过分离DNA测序反应产物对DNA进行测序。 该方法利用带电粒子的传输，该带电粒子经历在关闭状态（其中电位为平坦）和一个或多个导通状态之间循环的电位，其中电位优选为空间周期性的多个 偏心固定势阱。 势阱在导通状态下处于恒定的空间位置。 液相扩散性的差异导致带电粒子分离。 装置的优选实施例是微制造的。 分离介质填充设备中物理定义的分离通道。 基本横向于通道沉积的电极产生所需的电位。 有利地，注射端口允许样品加载，并且特殊门电极在分离之前聚焦样品。 通过将设备与热控制模块（优选多个珀耳帖效应传热装置）接触来使热梯度的影响最小化。 微型加工装置的小尺寸允许在多个分离通道中快速分离。

    Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments
    3.
    发明授权
    Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments 失效
    用于产生，分离，检测和识别生物聚合物片段的装置和方法

    公开(公告)号：US06485625B1

    公开(公告)日：2002-11-26

    申请号：US09336848

    申请日：1999-06-21

    申请人： John W. Simpson ,  Jonathan M. Rothberg ,  Gregory T. Went ,  Marie Carmen Ruiz-Martinez ,  Gregory T. Mulhern

    发明人： John W. Simpson ,  Jonathan M. Rothberg ,  Gregory T. Went ,  Marie Carmen Ruiz-Martinez ,  Gregory T. Mulhern

    IPC分类号： G01N2326

    CPC分类号： B01J19/0093 ,  G01N27/44708 ,  G01N27/44721 ,  G01N27/44782 ,  G01N27/44791

    摘要： This invention is an integrated instrument for the high-capacity electrophoretic analysis of biopolymer samples. It comprises a specialized high-voltage, electrophoretic module in which the migration lanes are formed between a bottom plate and a plurality of etched grooves in a top plate, the module permitting concurrent separation of 80 or more separate samples. In thermal contact with the bottom plate is a thermal control module incorporating a plurality of Peltier heat transfer devices for the control of temperature and gradients in the electrophoretic medium. Fragments are detected by a transmission imaging spectrograph which simultaneously spatially focuses and spectrally resolves the detection region of all the migration lanes. The spectrograph comprises a transmission dispersion element and a CCD array to detect signals. Signal analysis comprises the steps of noise filtering, comparison in a configuration space with signal prototypes, and selection of the best prototype. Optionally post-processing is done by a Monte-Carlo simulated annealing algorithm to improve results. Optionally, an array of micro-reactors can be integrated into the instrument for the generation of sequencing reaction fragments directly from crude DNA samples.

    摘要翻译： 本发明是用于生物聚合物样品的高容量电泳分析的综合仪器。 它包括专门的高压电泳模块，其中迁移通道形成在顶板和顶板中的多个蚀刻凹槽之间，该模块允许同时分离80个或更多个单独的样品。 与底板热接触的是热控制模块，其包含多个用于控制电泳介质中的温度和梯度的珀尔帖传热装置。 通过透射成像光谱仪检测片段，其同时空间聚焦并光谱地解析所有迁移通道的检测区域。 该光谱仪包括用于检测信号的透射色散元件和CCD阵列。 信号分析包括噪声滤波，配置空间与信号原型的比较以及最佳原型的选择。 可选地，后处理通过蒙特卡罗模拟退火算法完成以改善结果。 任选地，可以将微反应器阵列整合到仪器中，以直接从粗DNA样品产生测序反应片段。

    Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments
    4.
    发明授权
    Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments 失效
    用于产生，分离，检测和识别生物聚合物片段的装置和方法

    公开(公告)号：US5993634A

    公开(公告)日：1999-11-30

    申请号：US644073

    申请日：1996-05-09

    申请人： John W. Simpson ,  Jonathan M. Rothberg ,  Gregory T. Went

    发明人： John W. Simpson ,  Jonathan M. Rothberg ,  Gregory T. Went

    IPC分类号： B01J19/00 ,  G01N27/447 ,  G01N27/26

    CPC分类号： B01J19/0093 ,  G01N27/44708 ,  G01N27/44782 ,  G01N27/44791 ,  B01J2219/00783 ,  B01J2219/00828 ,  B01J2219/00831 ,  B01J2219/00833 ,  B01J2219/00873 ,  B01J2219/00995 ,  G01N27/44721 ,  Y10S436/80 ,  Y10T436/143333

    摘要： This invention is an integrated instrument for high-capacity electrophoretic analysis of biopolymer samples. It comprises a specialized high-voltage, electrophoretic module in which the migration lanes are formed between a bottom plate and a plurality of etched grooves in a top plate, the module permitting concurrent separation of 80 or more separate samples. In thermal contact with the bottom plate is a thermal control module incorporating a plurality of Peltier heat transfer devices for the control of temperature and gradients in the electrophoretic medium. Fragments are detected by a transmission imaging spectrograph which simultaneously spatially focuses and spectrally resolves the detection region of all the migration lanes. The spectrograph comprises a transmission dispersion element and a CCD array to detect signals. Signal analysis comprises the steps of noise filtering, comparison in a configuration space with signal prototypes, and selection of the best prototype. Optionally post-processing is done by a Monte-Carlo simulated annealing algorithm to improve results. Optionally, an array of micro-reactors can be integrated into the instrument for the generation of sequencing reaction fragments directly from crude DNA samples.

    摘要翻译： 本发明是用于生物聚合物样品的高容量电泳分析的集成仪器。 它包括专门的高压电泳模块，其中迁移通道形成在顶板和顶板中的多个蚀刻凹槽之间，该模块允许同时分离80个或更多个单独的样品。 与底板热接触的是热控制模块，其包括用于控制电泳介质中的温度和梯度的多个珀尔贴热传递装置。 通过透射成像光谱仪检测片段，其同时空间聚焦并光谱地解析所有迁移通道的检测区域。 该光谱仪包括用于检测信号的透射色散元件和CCD阵列。 信号分析包括噪声滤波，配置空间与信号原型的比较以及最佳原型的选择。 可选地，后处理通过蒙特卡罗模拟退火算法完成以改善结果。 任选地，可以将微反应器阵列整合到仪器中，以直接从粗DNA样品产生测序反应片段。

    Method for distance measurements with solid-state NMR
    5.
    发明授权
    Method for distance measurements with solid-state NMR 失效
    使用固态NMR进行距离测量的方法

    公开(公告)号：US6027941A

    公开(公告)日：2000-02-22

    申请号：US648609

    申请日：1996-05-15

    申请人： Thomas P. Jarvie ,  Joel S. Bader ,  Gregory T. Went

    发明人： Thomas P. Jarvie ,  Joel S. Bader ,  Gregory T. Went

    IPC分类号： G01R33/32 ,  G01N24/08 ,  G01N33/483 ,  G01R33/46 ,  G01N24/00 ,  G01V3/00

    CPC分类号： G01R33/4625 ,  G01R33/4641 ,  Y10T436/24

    摘要： This invention includes methods for analyzing data generated by various solid-state NMR experiments, including rotational echo double resonance (REDOR), transferred echo double resonance (TEDOR), dipolar recoupling at the magic angle (DRAMA), dipolar recoupling with a windowless sequence (DRAWS), and melding of spin-locking and DRAMA (MELODRAMA). The methods are based alternately on a new analytical transform or the maximum entropy method and their multi-dimensional extensions. They permit simultaneous, multiple distance measurements of high accuracy and precision, even from nuclei with identical chemical shifts. By providing high quality easily obtained distance measurement from disordered solid state materials, this invention also improves drug discovery and design through fast determination of structures of pharmaceutical lead compounds, drug molecules, or their targets.

    摘要翻译： 本发明包括用于分析由各种固态NMR实验产生的数据的方法，包括旋转回波双共振（REDOR），传输回波双共振（TEDOR），魔角（DRAMA）的偶极重耦合，无窗序列的偶极重耦合 DRAWS），以及自旋锁定和DRAMA（MELODRAMA）的融合。 该方法交替地基于新的分析变换或最大熵方法及其多维扩展。 它们允许同时进行高精度和高精度的多距离测量，即使是具有相同化学位移的原子核。 通过从无序固体材料提供高质量的容易获得的距离测量，本发明还通过快速测定药物铅化合物，药物分子或其靶标的结构来改进药物发现和设计。

    Consensus configurational bias Monte Carlo method and system for pharmacophore structure determination
    6.
    发明授权
    Consensus configurational bias Monte Carlo method and system for pharmacophore structure determination 失效
    共同配置偏差蒙特卡罗方法和药效团结构测定系统

    公开(公告)号：US06341256B1

    公开(公告)日：2002-01-22

    申请号：US08418992

    申请日：1995-03-31

    申请人： Michael W. Deem ,  Jonathan Marc Rothberg ,  Gregory T. Went

    发明人： Michael W. Deem ,  Jonathan Marc Rothberg ,  Gregory T. Went

    IPC分类号： G06F1900

    CPC分类号： G01N33/6803 ,  B01J2219/007 ,  C07K1/00 ,  C40B40/10 ,  G01N33/542 ,  G01N33/54326 ,  G01N33/5748 ,  Y10S977/808 ,  Y10S977/839 ,  Y10S977/906 ,  Y10S977/953 ,  Y10T436/24

    摘要： In a specific embodiment, this invention includes a method for determining an accurate, consensus pharmacophore structure shared by compounds that bind selectively to a target molecule. Optionally, the method begins with screening a diversity library against the target molecule of interest to pick the selectively binding members. Next the structure of the selected members is examined and a candidate pharmacophore responsible for the binding to the target molecule is determined. Next, preferably by REDOR nuclear magnetic resonance, several highly accurate interatomic distances are determined in certain of the selected members which are related to the candidate pharmacophore. A highly accurate consensus, configurational bias, Monte Carlo method determination of the structure of the candidate pharmacophore is made using the structure of the selected members and incorporating as constraints the shared candidate pharmacophore and the several measured distances. This determination is adapted to efficiently examine only relatively low energy configurations while respecting any structural constraints present in the organic diversity library. If the diversity library contains short peptides, the determination respects the known degrees of freedom of peptides as well as any internal constraints, such as those imposed by disulfide bridges. Finally, the highly accurate pharmacophore so determined is used to select lead organics for drug development targeted at the initial target molecule.

    摘要翻译： 在具体实施方案中，本发明包括用于确定由选择性结合靶分子的化合物共享的准确的，一致的药效团结构的方法。 任选地，该方法开始于针对感兴趣的靶分子筛选多样性文库以选择性结合成员。 接下来，检查所选成员的结构，确定负责与靶分子结合的候选药效团。 接下来，优选地通过REDOR核磁共振，在与候选药效团相关的某些选定的成员中确定几个高度准确的原子间距离。 使用所选择的成员的结构并将作为约束的共同候选药效基团和几个测量距离并入，来确定候选药效团的结构的高度准确的共识，构型偏差，蒙特卡罗方法确定候选药效团的结构。 该确定适于在尊重有机分集库中存在的任何结构约束的同时仅有效地检查相对较低的能量构型。 如果多样性文库包含短肽，则确定方面取决于肽的已知自由度以及任何内部约束，例如由二硫键施加的约束。 最后，如此确定的高度精确的药效团用于选择靶向初始靶分子的药物开发的铅有机物。