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1. 发明申请

US20090130686A1 Method for the Microscopic Localization of a Selected, Intracellular DNA Segment with a Known Nucleotide Sequence 审中-公开
标题翻译：用已知核苷酸序列显微定位选定的细胞内DNA片段的方法
公开(公告)号：US20090130686A1
公开(公告)日：2009-05-21
申请号：US12294381
申请日：2007-02-21
申请人： Michael Hausmann , Christoph Cremer
发明人： Michael Hausmann , Christoph Cremer
IPC分类号： C12Q1/68 , C07H21/04
CPC分类号： C12Q1/6841 , C12Q2563/107 , C12Q2543/10 , C12Q2537/119
摘要： The method for the microscopic localization in situ of a selected intracellular native genome segment with a known nucleotide sequence is characterized by the nature and the sequence of the following measures: (1.) The target DNA is analyzed, via genome databases, for partial sequences which constitute a unique pattern within the genome. (2.) Single-stranded probe sequences are provided which are identical to these partial sequences or complementary thereto, and which are suitable for hybridizing with the single strands of these subsequences via a Watson-Crick binding. (3.) The probe sequences are coupled with marker molecules, where all units of probe sequence and marker molecule(s) have the same binding behavior or the same melting point as the single strand of the target DNA complementary thereto. (4.) The probe sequences are introduced into the cell and combined with the target DNA so that they hybridize to the corresponding partial sequences, of the target DNA, which are temporarily present as two single strands. (5.) The marker signals emitted are detected, and (6.) the locus of the target DNA on the genome is identified on the basis of the presence and/or intensity and/or the simultaneous occurrence of different marker signals.
摘要翻译：用已知核苷酸序列选择的细胞内天然基因组片段原位微观定位的方法的特征在于以下措施的性质和顺序：（1）通过基因组数据库分析目标DNA用于部分序列它们构成基因组内的独特模式。（2.）提供与这些部分序列相同或互补的单链探针序列，其适于通过Watson-Crick结合与这些亚序列的单链杂交。（3）探针序列与标记分子偶联，其中探针序列和标记分子的所有单元具有与其互补的靶DNA的单链具有相同的结合行为或相同的熔点。（4.）将探针序列引入细胞并与目标DNA组合，使得它们与作为两条单链暂时存在的靶DNA的相应部分序列杂交。（5.）检测发出的标记信号，（6）基于不同标记信号的存在和/或强度和/或同时发生的基因组上的靶DNA的位点被鉴定。

2. 发明授权

US06424421B1 Method and devices for measuring distances between object structures 有权
标题翻译：用于测量物体结构之间距离的方法和装置
公开(公告)号：US06424421B1
公开(公告)日：2002-07-23
申请号：US09331644
申请日：1999-08-25
申请人： Christoph Cremer , Michael Hausmann , Joachim Bradl , Bernd Rinke
发明人： Christoph Cremer , Michael Hausmann , Joachim Bradl , Bernd Rinke
IPC分类号： G01B904
CPC分类号： B82Y15/00 , G02B21/16 , G02B21/26 , G02B21/34
摘要： The invention concerns a method and devices for far field microscopy and flow fluorometry for geometric distance measurements between object structures, i.e. measurement structures, marked with fluorochromes, whereby the distances can be smaller than the half-intensity width of the principle maximum of the point spread function. In this method, the measurement structures are marked with fluorescent dyes with different or identical spectral signatures, according to their distances. Calibration targets with defined dimensions and arrays are marked with the same fluorescent dyes. Calibration targets and measurement structures are prepared separately or together on an object support and investigated microscopically or flow fluorometrically. In each case, two defined calibration targets with different spectral signatures are measured in consideration of the wavelength dependent imaging and localisation behaviour of the optical system used, the measurement values thus obtained are compared against the previously known real distance values and the difference is used as the calibration value for correcting the shift in the direction of the measurement structures caused by the optical system. In the case of the devices, these are calibration targets and an axial tomograph for undertaking the method described above.
摘要翻译：本发明涉及用于远场显微镜和流量荧光测量的方法和装置，用于在用荧光染料标记的物体结构之间进行几何距离测量，即测量结构，其距离可以小于点扩散原理最大值的半强度宽度功能。在该方法中，根据其距离，用不同或相同光谱特征的荧光染料标记测量结构。具有规定尺寸和阵列的校准目标用相同的荧光染料标记。校准目标和测量结构是单独地或一起在物体支撑物上制备的，并通过荧光测量法进行微观或流动测量。在每种情况下，考虑到所使用的光学系统的波长依赖成像和定位行为来测量具有不同光谱特征的两个定义的校准目标，将如此获得的测量值与先前已知的实际距离值进行比较，并将该差异用作用于校正由光学系统引起的测量结构的方向上的偏移的校准值。在这些装置的情况下，这些是用于进行上述方法的校准目标和轴向断层摄影机。

3. 发明授权

US07342717B1 Wave field microscope with detection point spread function 失效
标题翻译：波场显微镜具有检测点扩散功能
公开(公告)号：US07342717B1
公开(公告)日：2008-03-11
申请号：US09462435
申请日：1998-07-09
申请人： Michael Hausmann , Christoph Cremer , Joachim Bradl , Bernhard Schneider
发明人： Michael Hausmann , Christoph Cremer , Joachim Bradl , Bernhard Schneider
IPC分类号： G02B21/00
CPC分类号： G02B21/04 , C12Q1/6869 , G01N21/278 , G01N21/6458 , G01N2021/6441 , G02B21/06 , G02B21/16 , C12Q2565/601 , C12Q2563/107
摘要： The present invention relates to two new wave field microscopes, type I and type II, which are distinguished by the fact that they each have an illumination and excitation system, which include at least one real and one virtual illumination source, and at least one objective lens (in the case of type II), i.e., two objective lenses (in the case of type I), with the illumination sources and objective lenses being so positioned with respect to one another that they are suited for generating one-, two-, and three-dimensional standing wave fields in the object space. The calibration method in accordance with the present invention is adapted to this wave field microscopy and permits geometric distance measurements between fluorochrome-labeled object structures, whose distance can be less than the width at half maximum intensity of the effective point spread function. The invention relates moreover to a method of wave-field microscopic DNA sequencing.
摘要翻译：本发明涉及两种新型的I型和II型波场显微镜，其特征在于它们各自具有照明和激励系统，其包括至少一个实际和一个虚拟照明源，以及至少一个目标透镜（在II型的情况下），即两个物镜（在I型的情况下），其中照明源和物镜相对于彼此定位，使得它们适于产生一个，，以及对象空间中的三维驻波场。根据本发明的校准方法适用于这种波场显微镜，并且允许距离可以小于有效点扩散函数的半最大强度下的宽度的荧光染料标记物体结构之间的几何距离测量。本发明还涉及一种波场显微DNA测序方法。

4. 发明授权

US07298461B2 Far field light microscopical method, system and computer program product for analysing at least one object having a subwavelength size 有权
标题翻译：用于分析具有亚波长尺寸的至少一个物体的远场光显微镜方法，系统和计算机程序产品
公开(公告)号：US07298461B2
公开(公告)日：2007-11-20
申请号：US10492266
申请日：2002-10-09
申请人： Christoph Cremer , Antonio Virgilio Failla , Benno Albrecht
发明人： Christoph Cremer , Antonio Virgilio Failla , Benno Albrecht
IPC分类号： G01N21/00
CPC分类号： G01N21/6458 , G01N21/6428 , G01N2021/6421 , G01N2021/6439 , G01N2021/6441 , G02B21/00 , G02B21/002 , G02B21/0076 , G02B21/16
摘要： The present invention relates to a far field light microscopical method, respectively a system and a computer program product for analysing at least one object having a subwavelength size in at least one spatial direction to obtain spatial information of the object, in particular size and topology thereof, comprising the steps of:—labelling the object(s) with one or more suitable optical markers;—providing suitably structured illumination light to at least partially illuminate the object(s);—subjecting the object(s) to the structured illumination light;—detecting an optical response of the object(s);—obtaining the spatial information of the object(s) by comparing the obtained response with simulation data of an optical response of object(s) having known spatial information.
摘要翻译：本发明涉及远场光显微镜方法，分别是用于在至少一个空间方向上分析具有亚波长尺寸的至少一个物体的系统和计算机程序产品，以获得物体的空间信息，特别是其尺寸和拓扑结构包括以下步骤： - 用一个或多个合适的光学标记来描绘所述物体; - 提供适当结构的照明光以至少部分地照亮所述物体; - 使所述物体经受所述结构化照明光 ; - 检测对象的光学响应; - 通过将获得的响应与具有已知空间信息的对象的光学响应的仿真数据进行比较来获得对象的空间信息。

5. 发明申请

US20090237501A1 METHOD AND AN APPARATUS FOR LOCALIZATION OF SINGLE DYE MOLECULES IN THE FLUORESCENT MICROSCOPY 有权
标题翻译：用于荧光显微镜中单分子分子的定位的方法和装置
公开(公告)号：US20090237501A1
公开(公告)日：2009-09-24
申请号：US12404488
申请日：2009-03-16
申请人： Paul Lemmer , Christoph Cremer , David Baddeley , Heinz Eipel
发明人： Paul Lemmer , Christoph Cremer , David Baddeley , Heinz Eipel
IPC分类号： H04N7/18
CPC分类号： G01N21/6458 , G01N21/6428 , G01N2021/6441 , G02B21/0076 , G02B21/16 , G02B21/367 , G02B27/58
摘要： A method and apparatus are provided for obtaining a sub-resolution spatial information of a sample labeled with at least one type fluorescent label. The sub-resolution spatial information has localization information about the positions of fluorescent molecules of the at least one type fluorescent label in at least one spatial direction. The method acquires localization image data by employing fluorescence localization microscopy. The acquired localization image data is processed to obtain the localization information about the positions of fluorescent molecules of the at least one type fluorescent label in at least one spatial direction. The step of processing includes determining in each of the detected images of the series the positions of the barycenters of the detected fluorescence emission distributions from the single fluorescent molecules of the one or more fluorescent labels in at least one spatial direction.
摘要翻译：提供一种方法和装置，用于获得用至少一种类型的荧光标签标记的样品的亚分辨率空间信息。子分辨率空间信息具有关于至少一个类型的荧光标记在至少一个空间方向上的荧光分子的位置的定位信息。该方法采用荧光定位显微镜获取定位图像数据。处理获取的定位图像数据以获得关于至少一个类型的荧光标记物的荧光分子在至少一个空间方向上的位置的定位信息。处理步骤包括在至少一个空间方向上确定该系列的每个检测到的图像中的一个或多个荧光标记的单个荧光分子的检测的荧光发射分布的重心的位置。

6. 发明授权

US5922543A Detection as chromosomal translocations by extending and ligating differentially-labeled probes Hybridized on different sides of a break-point 失效
标题翻译：通过延伸和连接差异标记的探针作为染色体易位检测杂交在断点的不同侧面
公开(公告)号：US5922543A
公开(公告)日：1999-07-13
申请号：US818712
申请日：1997-03-14
申请人： Christoph Cremer
发明人： Christoph Cremer
IPC分类号： C12Q1/68 , C12P19/34
CPC分类号： C12Q1/6827 , C12Q1/6841
摘要： A composition and method of producing a composition which is directed to a single nucleic acid comprising a first section complementary to a sequence of a first chromosome, and comprising at least a first label, and a second nucleic acid section complementary to a sequence of a second chromosome, the second label being different from the first label. It is used for detecting translocations such that the single nucleic acid probe has different interactive labels on each side of a translocation break-point region.
摘要翻译：一种制备针对单一核酸的组合物的组合物和方法，所述组合物包含与第一染色体的序列互补的第一部分，并且包含至少第一标记和与第二染色体的序列互补的第二核酸部分染色体，第二标签不同于第一标签。它用于检测易位，使得单个核酸探针在易位断裂区的每一侧具有不同的交互式标记。

7. 发明授权

US08212866B2 Method and an apparatus for localization of single dye molecules in the fluorescent microscopy 有权
标题翻译：荧光显微镜中单染料分子的定位方法和装置
公开(公告)号：US08212866B2
公开(公告)日：2012-07-03
申请号：US12404488
申请日：2009-03-16
申请人： Paul Lemmer , Christoph Cremer , David Baddeley , Heinz Eipel
发明人： Paul Lemmer , Christoph Cremer , David Baddeley , Heinz Eipel
IPC分类号： H04N7/18
CPC分类号： G01N21/6458 , G01N21/6428 , G01N2021/6441 , G02B21/0076 , G02B21/16 , G02B21/367 , G02B27/58
摘要： A method and apparatus are provided for obtaining a sub-resolution spatial information of a sample labeled with at least one type fluorescent label. The sub-resolution spatial information has localization information about the positions of fluorescent molecules of the at least one type fluorescent label in at least one spatial direction. The method acquires localization image data by employing fluorescence localization microscopy. The acquired localization image data is processed to obtain the localization information about the positions of fluorescent molecules of the at least one type fluorescent label in at least one spatial direction. The step of processing includes determining in each of the detected images of the series the positions of the barycenters of the detected fluorescence emission distributions from the single fluorescent molecules of the one or more fluorescent labels in at least one spatial direction.
摘要翻译：提供一种方法和装置，用于获得用至少一种类型的荧光标签标记的样品的亚分辨率空间信息。子分辨率空间信息具有关于至少一个类型的荧光标记在至少一个空间方向上的荧光分子的位置的定位信息。该方法采用荧光定位显微镜获取定位图像数据。处理获取的定位图像数据以获得关于至少一个类型的荧光标记物的荧光分子在至少一个空间方向上的位置的定位信息。处理步骤包括在至少一个空间方向上确定该系列的每个检测到的图像中的一个或多个荧光标记的单个荧光分子的检测的荧光发射分布的重心的位置。

8. 发明授权

US08174761B2 Total internal reflection interferometer with laterally structured illumination 有权
标题翻译：具有横向结构照明的全内反射干涉仪
公开(公告)号：US08174761B2
公开(公告)日：2012-05-08
申请号：US12481927
申请日：2009-06-10
申请人： Roman Amberger , Christoph Cremer , Heinz Eipel
发明人： Roman Amberger , Christoph Cremer , Heinz Eipel
IPC分类号： G02B21/00
CPC分类号： G02B21/06 , G02B21/16 , G02B21/18 , G02B21/365
摘要： A total internal reflection microscope for epi-fluorescence illumination observations includes an objective through which an object to be observed is illuminated by an excitation illumination light at an angle to an observation axis of the microscope. The angle is adjustable to be within the range suitable for a total internal reflection observation. The microscope also has a source of collimated excitation light. An interferometer is arranged in the optical path of the collimated excitation light and is configured to produce an interference pattern. A focusing lens system focuses the interference pattern produced by the interferometer into the back focal plane of the objective. The objective and the focusing lens system image the interference pattern produced by the interferometer into the conjugated image plane of the objective, thereby producing excitation illumination light that modulated spatially in intensity in a plane orthogonal to the observation axis of the microscope.
摘要翻译：用于表面荧光照明观察的全内反射显微镜包括物镜，通过该物镜通过与显微镜的观察轴成一定角度的激发照明光照射被观察物体。该角度可调整在适合于全内反射观察的范围内。显微镜还具有准直激发光源。干涉仪布置在准直激发光的光路中并且被配置为产生干涉图案。聚焦透镜系统将由干涉仪产生的干涉图案聚焦到物镜的后焦平面中。目标和聚焦透镜系统将由干涉仪产生的干涉图案成像到目标的共轭像平面中，从而产生在垂直于显微镜的观察轴的平面中在空间上调制的激发照明光。

9. 发明申请

US20100315708A1 TOTAL INTERNAL REFLECTION INTERFEROMETER WITH LATERALLY STRUCTURED ILLUMINATION 有权
标题翻译：具有横向结构照明的总内部反射干涉仪
公开(公告)号：US20100315708A1
公开(公告)日：2010-12-16
申请号：US12481927
申请日：2009-06-10
申请人： Roman Amberger , Christoph Cremer , Heinz Eipel
发明人： Roman Amberger , Christoph Cremer , Heinz Eipel
IPC分类号： G02B21/06 , G02B21/36
CPC分类号： G02B21/06 , G02B21/16 , G02B21/18 , G02B21/365
摘要： A total internal reflection microscope for epi-fluorescence illumination observations includes an objective through which an object to be observed is illuminated by an excitation illumination light at an angle to an observation axis of the microscope. The angle is adjustable to be within the range suitable for a total internal reflection observation. The microscope also has a source of collimated excitation light. An interferometer is arranged in the optical path of the collimated excitation light and is configured to produce an interference pattern. A focusing lens system focuses the interference pattern produced by the interferometer into the back focal plane of the objective. The objective and the focusing lens system image the interference pattern produced by the interferometer into the conjugated image plane of the objective, thereby producing excitation illumination light that modulated spatially in intensity in a plane orthogonal to the observation axis of the microscope.
摘要翻译：用于表面荧光照明观察的全内反射显微镜包括物镜，通过该物镜通过与显微镜的观察轴成一定角度的激发照明光照射被观察物体。该角度可调整在适合于全内反射观察的范围内。显微镜还具有准直激发光源。干涉仪布置在准直激发光的光路中并且被配置为产生干涉图案。聚焦透镜系统将由干涉仪产生的干涉图案聚焦到物镜的后焦平面中。目标和聚焦透镜系统将由干涉仪产生的干涉图案成像到物镜的共轭像平面中，从而产生在与显微镜的观察轴正交的平面上的强度空间调制的激发照明光。

10. 发明授权

US06909105B1 Method and device for representing an object 有权
标题翻译：用于表示对象的方法和设备
公开(公告)号：US06909105B1
公开(公告)日：2005-06-21
申请号：US09914515
申请日：2000-03-02
申请人： Rainer Heintzmann , Christoph Cremer
发明人： Rainer Heintzmann , Christoph Cremer
IPC分类号： G02B21/00 , G02B21/36 , G02B27/46 , G01V8/00
CPC分类号： G02B21/367 , G02B21/00 , G02B27/46
摘要： A process for obtaining an object image of at least one object (40) is described, wherein at least two partial images of the object (40) are taken under differing object conditions which are formed on the object with spatial patterns, wherein a non-linear dependence of the light detectable from the object point on the object conditions given at the object point exists and the partial images contain different contributions of various space frequency components of the object structure, and the desired object image is determined from the partial images by reconstruction of the space frequency components. Optical systems for implementing this type of process are also described.
摘要翻译：描述了用于获得至少一个对象（40）的对象图像的处理，其中在具有空间图案的对象上形成的不同对象条件下拍摄对象（40）的至少两个部分图像，其中，存在可以从对象点检测到的物体在物体上给出的物体条件上的光的线性依赖性，并且部分图像包含对象结构的各种空间频率分量的不同贡献，并且通过重建从部分图像确定期望的对象图像的空间频率分量。还描述了用于实现这种类型的过程的光学系统。

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