Control device, control method, and control program

Abstract

To stably optimize resolution obtained by up-sampling based on a perturbation factor of resolution improvement.SOLUTION: A relative position control unit 214 that controls a plurality of relative positions by moving and stopping the beam or the detector with a movement width smaller than a pixel size, a measurement data storage unit 217 that stores X-ray scattering data acquired by the detector at each controlled relative position, a data conversion unit 223 that generates an intensity profile based on the acquired X-ray scattering data, an index calculation unit 232 that calculates a parameter based on a wave number of a smallest scattering vector in which statistically significant data exists on each generated intensity profile as a formal qmin, and a setting specifying unit 234 that specifies a relative position giving a maximum value among the calculated formal qmin as a matching position.SELECTED DRAWING: Figure 5

Description

[Technical Field]

[0001] The present invention relates to a laboratory-use control device, a control method, and a control program for controlling an X-ray analysis device that can acquire X-ray scattering images for molecules on the order of 1000 Å. [Background technology]

[0002] X-ray scattering is a method in which X-rays are incident on a sample and the scattered X-rays are detected by a detector. Unlike imaging, this method obtains measurement data of the reciprocal lattice in the real space measured by the detector. Therefore, measurement data in the region with a large scattering angle contains information about the fine structure of the sample. Furthermore, because the atomic size of the sample is finite, the larger the scattering angle, the lower the obtained scattering intensity, and the information density decreases dramatically.

[0003] On the other hand, the smaller the scattering angle, the greater the information density contained in the scattering image on the detector (hereinafter, low and high scattering angles will be abbreviated to "low angle" and "high angle"). However, unlike visible light cameras, X-ray measurements require detectors with low sensitivity and complex structures, so the pixel size cannot be made smaller than a certain size due to the detection configuration. Due to these limitations on the detector configuration, there is a limit to the spatial resolution in the low-angle region on the detector.

[0004] The scattering angle is equivalent to the wave number of the scattering vector, and conversion between the two is possible. Therefore, the expression "high-angle or low-angle wave number" means "the wave number corresponding to the high-angle or low-angle scattering angle." [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Y. Chushkin and F. Zontone, “Upsampling speckle patterns for coherent X-ray diffraction imaging”, J. Appl. Cryst. (2013). 46, 319-323 [Non-patent document 2] Fruchter, “Drizzle: A method for the linear reconstruction of undersampled images”, AS & Hook, RN (2002). Publ. Astron. Soc. Pac. 114,144-152. Summary of the Invention [Problem to be solved by the invention]

[0006] Although not an X-ray diffraction method, X-ray imaging methods are similarly limited by the spatial resolution of X-ray detectors. To solve the above problem, attempts have been made to apply upsampling, which involves sampling at a width smaller than the pixel size when processing measurement data, thereby improving the resolution of the resulting image (Non-Patent Document 1).

[0007] Similarly, not only in X-ray imaging but also in ordinary X-ray diffraction experiments, there are measurements in which the detector sensitivity itself is the rate-limiting factor. In such measurements, pixel binning is often used to improve sensitivity by processing the number of photons detected by multiple pixels together, thereby increasing the number of photons received per pixel. In this case, the obtained spatial resolution is significantly reduced, and image degradation due to coarse pixels becomes severe. Various countermeasures have been devised and used (Non-Patent Document 2). However, in X-ray diffraction experiments, even with these methods, the improvement in resolution at low angles is not stable from measurement to measurement, and the resulting resolution is not reproducible.

[0008] The present invention has been made in consideration of the above circumstances, and aims to provide a control device, a control method, and a control program that can stably optimize the resolution obtained by upsampling based on perturbation factors of the resolution improvement rate. [Means for solving the problem]

[0009] (1) In order to achieve the above object, the control device of the present invention is a control device for controlling a laboratory X-ray analysis device capable of acquiring X-ray scattering images of molecules on the order of 1000 Å, and is characterized by comprising: a relative position calculation unit that calculates multiple relative positions between the beam and the detector, which are marked with a movement width smaller than the pixel size; a relative position control unit that controls the multiple relative positions by moving and stopping the beam or the detector; a measurement data memory unit that stores X-ray scattering data acquired by the detector at each of the controlled relative positions; a data conversion unit that generates an intensity profile based on the acquired X-ray scattering data; an index calculation unit that calculates, in the form qmin, a parameter based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; and a setting identification unit that identifies the relative position that gives the maximum value of the calculated form qmin as the suitable position.

[0010] (2) Furthermore, in the control device described in (1) above, the index calculation unit calculates the format qmin for multiple optical system settings, and the setting identification unit identifies the optical system setting that gives the maximum value among the calculated formats qmin as the suitable setting.

[0011] (3) Furthermore, the control device according to (1) or (2) above is characterized in that it further comprises a measurement control unit that aligns the relative position with the suitable position and performs X-ray scattering measurement on the sample.

[0012] (4) Furthermore, the control device described in (3) above further includes a setting memory unit that stores the suitable position, and an input / output control unit that receives input regarding whether or not to use the stored suitable position, and the measurement control unit is characterized in that it performs X-ray scattering measurement using or without using the stored suitable position depending on the received input.

[0013] (5) In the control device according to (3) or (4) above, the sample is a biopolymer in a solution.

[0014] (6) In the control device according to any one of (3) to (5) above, the data conversion unit generates a profile with a sampling width smaller than the pixel size.

[0015] (7) In addition, in the control device according to any one of (1) to (6) above, the movement width is between 1 μm and 100 μm.

[0016] (8) Furthermore, the control device of the present invention is a control device for controlling a laboratory X-ray analysis device capable of acquiring X-ray scattering images for molecules on the order of 1000 Å, and is characterized in that it comprises a relative position calculation unit that calculates multiple relative positions between the beam and the detector, which are marked with a movement width smaller than the pixel size, a relative position control unit that controls the multiple relative positions by moving and stopping the beam or the detector, a measurement data memory unit that stores X-ray scattering data acquired by the detector at each of the controlled relative positions, and a data conversion unit that generates an intensity profile based on the acquired X-ray scattering data, wherein the movement width is a predetermined value determined before measurement.

[0017] (9) Furthermore, the control method of the present invention is a control method for controlling a laboratory X-ray analysis device capable of acquiring X-ray scattering images for molecules on the order of 1000 Å, and is characterized by including the steps of calculating multiple relative positions between the beam and the detector, each of which is marked with a movement width smaller than the pixel size; controlling the multiple relative positions by moving and stopping the beam or the detector; storing X-ray scattering data acquired by the detector at each of the controlled relative positions; generating an intensity profile based on the acquired X-ray scattering data; calculating, in the form qmin, a parameter based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; and identifying the relative position that gives the maximum value of the calculated form qmin as the matching position.

[0018] (10) Furthermore, a control program of the present invention is a control program for controlling a laboratory X-ray analysis device capable of acquiring X-ray scattering images of molecules on the order of 1000 Å, and is characterized in that it causes a computer to execute the following processes: a process of calculating multiple relative positions between a beam and a detector, each of which is marked with a movement width smaller than the pixel size; a process of controlling the multiple relative positions by moving and stopping the beam or the detector; a process of storing X-ray scattering data acquired by the detector at each of the controlled relative positions; a process of generating an intensity profile based on the acquired X-ray scattering data; a process of calculating, in the form qmin, a parameter based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; and a process of identifying the relative position that gives the maximum value of the calculated form qmin as the matching position. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is a schematic diagram showing the relationship between the beam and the detector. [Figure 2]Graphs showing (a) and (b) the absolute position of the beam relative to the detector and the resolution relative to the position within a unit pixel, respectively. [Figure 3] 1 is a schematic diagram illustrating a control system according to the present invention. [Figure 4] FIG. 1 is a perspective view showing an X-ray analysis device. [Figure 5] 1 is a block diagram showing a configuration of a control system according to the present invention. [Figure 6] 4 is a flowchart showing the operation of the control device. [Figure 7] (a) to (c) are the scattering image, the β-direction profile, and the q-direction profile, respectively. [Figure 8] 10 is a table showing the attainable resolution for each optical system setting and relative position. [Figure 9] 1 is a flowchart showing the process from sample measurement to analysis. [Figure 10] FIG. 1 is a schematic diagram showing the process from acquiring a scattering image to analyzing it. DETAILED DESCRIPTION OF THE INVENTION

[0020] Next, an embodiment of the present invention will be described with reference to the drawings. To facilitate understanding of the description, the same reference numerals are used to designate the same components in the drawings, and duplicated descriptions will be omitted.

[0021] [principle] In this invention, a parameter based on the wave number of the smallest scattering vector for which statistically significant data exists on the intensity profile is calculated as a formal qmin, and the relative position that gives the maximum value of the calculated formal qmin is identified as the suitable position. Therefore, depending on the degree of exposure of a pixel exposed from the edge of the beam stopper (the exposed pixel closest to the center position of the X-ray beam), the statistically significant resolution obtained at that pixel changes, and the formal qmin changes.

[0022] The form qmin is defined as 2π / qa, where qa is the wavenumber of the smallest scattering vector with a statistically significant intensity standard deviation σ, which is determined formally by plotting a graph. For example, a "statistically significant" intensity standard deviation σ can be defined as a standard deviation σ where the intensity standard deviation σ is 5% or less of the intensity.

[0023] To verify this principle, a standard material was used, and the relative position between the beam position and the detector was changed to measure the form qmin. Figure 1 is a schematic diagram showing the relationship between the beam and the detector. In the example shown in Figure 1, the center position C0 of the direct X-ray beam is fixed on the beam stopper 127, and the detector 130 can be moved relative to the beam stopper 127. Note that the direction of the X-ray beam may also be moved relative to the detector 130. Note that one pixel is formed as a square with a side length of 100 μm. Currently, the pixel size technically achievable is approximately 100 μm. The movement range when verifying the relative position is 1 to 100 μm. The movement range is preferably between 100 and 5 divisions of the pixel size.

[0024] The detector 130 has an area 130a exposed from the beam stopper 127 and an area 130b hidden behind the beam stopper 127. As the detector 130 moves in the direction D1 away from the center position of the X-ray beam, the exposed area 130a increases. The numerical value displayed for each pixel indicates the intensity detected at that pixel. The edge position x of the beam stopper 127 is 9.0, and the pixel exposed from the edge of the beam stopper 127 (the pixel located between 9.0 and 10.0) is 100% exposed from the beam stopper 127. The format qmin varies depending on the exposure rate of this pixel, resulting in different resolutions. The relative position may be considered as the position of the edge of the beam stopper 127 relative to the pixel. Note that the movement direction D1 of the detector 130 is preferably vertically upward to reduce mechanical errors.

[0025] The occurrence of this change depends on the position of the beam stopper edge. When the detector 130 is moved in the direction D1 shown in Figure 1, the usable area within the pixel increases as the top edge of the beam stopper approaches the pixel boundary. As a result, the standard deviation σ of the intensity data corresponding to that portion decreases, making it more reliable as a data point. However, if the detector 130 moves beyond the boundary value (cliff), the data becomes unusable. This causes the value of the formula qmin to decrease discontinuously with the movement of the detector 130. In this specification, we assume that the relative positions of the top edge of the beam stopper and the beam center are fixed, and for convenience, we use the pixel coordinates of the direct beam instead of the pixel coordinates of the top edge of the beam stopper. Note that the positional relationship between the top edge of the beam stopper and the direct beam can be uniquely determined based on the desired wavenumber resolution.

[0026] Figures 2(a) and (b) are graphs showing the resolution for the absolute position of the beam relative to the detector and the position within a unit pixel, respectively. In both cases, the vertical axis represents the attainable resolution (Å), which corresponds to the format qmin. As shown in Figure 2(a), the resolution for the absolute position of the X-ray beam gradually increases in the range of decimal points from 0 to 8 for the beam position expressed in pixels, and then drops sharply at a boundary value (cliff) around 9 decimal points. This trend can be clearly seen by enclosing the group of plots with a rectangular frame for each unit pixel size movement. Each time the relative position moves by the pixel size, the attainable resolution increases from 2000 to 2800, then suddenly decreases to 2000, and then increases again, repeating this cycle of increase and decrease.

[0027] On the other hand, Figure 2(b) shows the results of overlaying the absolute beam position on the horizontal axis shown in Figure 2(a) as a position within a unit pixel. It can be seen that within a unit pixel, all plots show the same trend, with the resolution increasing at a constant rate from 0.0 to 0.8 on the horizontal axis, before decreasing significantly at 0.9. Therefore, it can be seen that moving the relative position by just one pixel and searching is sufficient to determine the maximum value of the formal qmin (maximum attainable resolution). Furthermore, as can be seen from Figure 2(b), even if the movement width is reduced to less than 1 μm, the formal qmin remains almost unchanged, and no effect is obtained.

[0028] [First embodiment] (Control System) FIG. 3 is a schematic diagram illustrating a control system 10. The control system 10 includes an X-ray analysis device 100 and a control device 200. The X-ray analysis device 100 irradiates a sample S0 with X-rays and detects small-angle scattered X-rays. The sample S0 to be measured may be a polymer used for industrial applications, such as a crystalline polymer in an amorphous state, but a polymer in solution, particularly a biopolymer, is preferred. This is particularly effective for pharmaceutical molecules, molecular complexes, or structures in solution that require structural analysis with a resolution of 30 Å or less. Note that biopolymers are basically natural polymers produced by biological cells, but here they also include not only artificially synthesized molecules and complex molecules, but also molecular complexes such as viruses, gene vectors with similar structures, and LNPs.

[0029] Solutions to be irradiated with X-rays include sample solutions and buffer solutions. A sample solution is a solution containing a sample, such as a biopolymer and a special component for retaining the biopolymer. A buffer solution is a solution obtained by removing the sample from the sample solution. For example, the buffer solution in the above example does not contain a biopolymer but contains a special component. A buffer solution may be prepared separately with components similar to those of the sample solution, but it is preferable to use a solution obtained by separating the sample from the sample solution.

[0030] The control device 200 is composed of a computer 210, an input device 280, and an output device 290, and controls the operation of the X-ray analysis device 100 and acquires and processes measurement data from the X-ray analysis device 100. Note that the control of the measurement device and the processing of the measurement data may be performed by separate computers.

[0031] The X-ray analysis apparatus 100 includes an X-ray generation unit 110, a sample loading mechanism 120, a detector 130, and a control unit 140. The X-ray generation unit 110 has an X-ray source 111 and irradiates X-rays onto a sample S0. The target of the X-ray source 111 is preferably Cu, but Co may also be used. The sample loading mechanism 120 sends a sample solution containing a sample or a buffer solution without a sample, along with the sample holding tube, to the X-ray irradiation position. The detector 130 detects X-rays scattered by the sample S0 and transmits the resulting measurement data to a computer 210.

[0032] In the above configuration, one detector 130 is provided for one X-ray beam emitted from the X-ray source 111, but other configurations may also be employed. For example, the X-ray analysis apparatus 100 may be configured to emit two equal beams in the same direction using a mirror or a slit, and detect the scattered rays thereof with one detector. Alternatively, the X-ray analysis apparatus 100 may be configured to emit two equal beams in opposite directions, and detect the scattered rays thereof with two detectors, respectively.

[0033] The computer 210 is, for example, a PC, and is configured with a processor that executes processing, and a memory or hard disk that stores programs and data, etc. The computer 210 receives user input from an input device 280 such as a keyboard or mouse.

[0034] The computer 210 may be a server device placed on the cloud. In addition, from the viewpoint of processing load, the function of controlling the operation of the X-ray analysis apparatus 100 and the function of processing the measurement data may be separated, with the control being performed by a PC installed on-site and the data processing being performed by a server device.

[0035] (X-ray analyzer) FIG. 4 is a perspective view showing an X-ray analysis apparatus 100. The X-ray analysis apparatus 100 is a measurement device that irradiates a sample S0 with X-rays and detects the scattered X-rays to obtain measurement data. The X-ray analysis apparatus 100 includes an X-ray source 111, an optical system 115, a Kratsky block 117, a sample holding tube 125, and a detector 130. The X-ray source 111 is a line radiation source or a point radiation source, and emits a diverging beam. The optical system 115 is, for example, a KB parallel or serial optical system.

[0036] The pair of Kratky blocks 117 interact with the X-rays with their respective edges to define one side of the X-ray beam, thereby eliminating parasitic scattering from the irradiated X-rays. The sample holding tube 125 delivers and holds 5 to 10 μl of solution.

[0037] The detector 130 detects the X-rays scattered by the solution. The X-ray analysis device 100 transmits the detected scattered image to the control device 200. The detected scattered image is transmitted as measurement data every predetermined time t.

[0038] The relative position can basically be moved by fixing the X-ray irradiation side and moving the detector 130. However, the detector 130 may be fixed and the X-ray irradiation direction may be changed. For example, the X-ray irradiation direction can be changed by changing part or all of the arrangement of the X-ray source 111, the optical system 115, and the Kratsky block 117.

[0039] (Control device) 5 is a block diagram showing the control system. The control device 200 controls the X-ray analysis device 100 and adjusts the relative position before sample measurement. The control device 200 also controls the X-ray analysis device 100 during sample measurement, and can acquire and profile X-ray scattering data for analysis. The functions of the control device 200 are mainly realized by a computer 210.

[0040] The computer 210 includes an input / output control unit 211, a relative position calculation unit 213, a relative position control unit 214, a measurement control unit 215, a measurement data storage unit 217, a data conversion unit 223, an index calculation unit 232, a setting specification unit 234, a setting storage unit 236, and an analysis data generation unit 242. Each unit can send and receive information via a control bus L.

[0041] The input / output control unit 211 accepts input from the input device 280 and controls output to the output device 290. The input / output control unit 211 accepts input as to whether or not to use the stored suitable position. When input to use the stored suitable position is accepted, the measurement control unit 215 instructs sample measurement using the stored settings. This allows the settings that achieve the maximum achievable resolution identified the previous day to be stored, and sample measurement to be performed immediately the next day using those settings.

[0042] The input / output control unit 211 can also accept input of measurement conditions, for example. Measurement conditions include the intensity of the generated X-rays, the position of the Kratky block, the initial position where the X-rays are irradiated, the position of the solution, the arrangement of the detector, and the measurement time t when the scattering image is acquired. The input / output control unit 211 can also output each index and the determination result.

[0043] The relative position calculation unit 213 calculates multiple relative positions between the beam and the detector, each of which is marked with a movement width smaller than the pixel size. Note that the relative position basically refers to the position of the detector relative to the center position of the X-ray beam, but is a relative position and is equivalent to the center position of the X-ray beam relative to the position of the detector. Therefore, in reality, movement of the relative position often refers to movement of the detector relative to the center position of the X-ray beam, but it may also refer to movement of the center position of the X-ray beam relative to the detector, or movement of both.

[0044] The relative position control unit 214 controls multiple relative positions by moving and stopping the beam or detector. Specifically, the detector position is moved relative to the beam position in increments smaller than the pixel size, and is stopped and positioned at multiple locations.

[0045] The controlled detector or beam movement range is preferably 1 μm to 100 μm, and more preferably 5 μm to 15 μm. This allows for improved resolution even when there are limitations on mechanical positional accuracy due to backlash or fluctuations in the resolution boundary (cliff) caused by the profiling routine that integrates the intensity of pixel images. The movement range can also be set to 20 divisions of the pixel size. This is particularly effective when future improvements in resolution boundary fluctuations and mechanical positional accuracy limitations are realized.

[0046] When moving the detector for positioning, it is preferable to move it vertically upward in increments of the movement width, vertically above the center position of the direct beam. If positioning is performed by moving it vertically downward, the direction of gravity and the movement direction will match, and the detector will not be able to stop at the intended position due to mechanical margins such as gear meshing. It is easier to control the detector's stopping position by moving it in a direction that resists gravity.

[0047] The measurement control unit 215 controls the operation of the X-ray analysis apparatus 100. The controlled operations include sending out the sample, generating X-rays, and moving the sample position and detector. Control instructions are sent to the control unit 140 in the X-ray analysis apparatus 100, which controls each part of the X-ray analysis apparatus 100. The measurement control unit 215 adjusts the relative position between the beam and the detector to an appropriate position and performs X-ray scattering measurement on the sample.

[0048] The measurement data storage unit 217 stores, as measurement data, X-ray scattering data (scattered images) detected by the X-ray analysis device 100. The measurement data storage unit 217 stores not only X-ray scattering data acquired during sample measurement but also X-ray scattering data acquired at relative positions determined during adjustments prior to sample measurement. The stored measurement data is used for conversion into a scattering profile, optimization of measurement conditions, generation of analysis data, etc.

[0049] The data conversion unit 223 generates an intensity profile based on the acquired X-ray scattering data. When profiling, it is preferable to generate the profile by sampling (upsampling) with a width smaller than the pixel size. This improves the resolution of structural analysis. Specifically, the measurement data is converted into a scattering profile using the following method. That is, the intensity is integrated along the circumferential direction (β direction) around the center of the scattering image to calculate the scattering profile. The data conversion unit 223 also calculates the standard deviation σ of the intensity in the β direction for a certain wave number q.

[0050] The index calculation unit 232 calculates a parameter of the form qmin based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each generated intensity profile. The index calculation unit 232 may calculate the parameter of the form qmin not only for multiple relative positions but also for multiple optical system settings. The optical system settings refer to parameters such as the placement of the radiation source and the Kratkey block.

[0051] The setting specification unit 234 specifies the relative position that gives the maximum value of the calculated form qmin as the suitable position. In this way, X-ray scattering data can be acquired at each determined relative position, and the relative position with the maximum form qmin can be automatically specified. As a result, the resolution obtained by adaptive hypersampling after measuring the sample can be stably optimized. Note that adaptive hypersampling refers to sampling set at arbitrary intervals rather than at fixed intervals, and includes upsampling.

[0052] The setting specifying unit 234 can specify the setting of the optical system that gives the maximum value of the calculated form qmin as the suitable setting, thereby optimizing not only the position adjustment of the detector but also the calibration of the entire apparatus.

[0053] The setting storage unit 236 stores the measurement conditions that give the maximum value of the obtained form qmin. Storing the relative position thus identified allows measurements to be performed with stable, high resolution. For example, the settings that lead to the maximum achievable resolution obtained that day can be stored, and the sample measurement can be started immediately the next day using the stored settings.

[0054] The analytical data generating unit 242 subtracts the profile of the buffer solution, which has been scaled as a background, from the profile of the sample solution, and outputs the profile of the sample solution from which the background has been subtracted as analytical data.

[0055] (Control method (relative position adjustment method)) Next, a method for controlling the X-ray analysis apparatus 100 and adjusting the relative position, etc., during measurement preparation using the control apparatus 200 configured as described above will be described. Fig. 6 is a flowchart showing the operation of the control apparatus 200. A standard material is placed in advance in the X-ray analysis apparatus 100 in place of the sample S0. The standard material can be, for example, AgBh.

[0056] First, the control device 200 sets up the optical system (step S1). For example, if parameter sets A, B, and C, such as the position of the radiation source and the arrangement of the Kratsky block, depend on the type of sample, such as recombinant protein preparations, gene therapy vectors, or antibody drugs, the optical system can be set by determining the parameter sets. Next, the relative position of the detector with respect to the beam is calculated and set (step S2). By setting the pixel division number N, the movement width of 1 / N pixels for moving the detector is determined.

[0057] Based on the above settings, the optical system is controlled to the settings for the current sequence (step S3). Similarly, based on the above settings, the position of the detector is moved to the settings for the current sequence and positioning is controlled (step S4). The device is controlled with the determined optical system and relative position, and X-ray scattering data is acquired (step S5).

[0058] The acquired X-ray scattering data is sampled and integrated in the β direction to generate a profile (step S6). Details of this data conversion to create a profile will be described later. qmin is calculated for the profile (step S7). Then, the set relative position and qmin are stored (step S8). qmin is equivalent to the attainable resolution, and the attainable resolution may be stored instead of qmin. Details of storing the measurement results will be described later.

[0059] Here, it is determined whether data acquisition has been completed for all relative positions (step S9). If data acquisition has not been completed for all relative positions, the process returns to step S4. On the other hand, if data acquisition has been completed for all relative positions, the process proceeds to step S10.

[0060] Next, it is determined whether data acquisition for all optical system settings has been completed (step S10). If data acquisition for all optical system settings has not been completed, the process returns to step S3. If data acquisition for all relative positions has been completed, the optical system settings and relative positions that give the minimum value of qmin are identified (step S11), and the series of processes is terminated.

[0061] By specifying the optimal optical system settings and relative position in this way, the achievable resolution can be optimized. For example, when the present invention is applied to MAXS (Middle Angle X-ray Scattering), a resolution of up to 3000 Å can be achieved. The scattering image is obtained by Fourier transform of real space, and the scattering image is obtained by Fourier transform within an integration range that allows for a margin relative to the observable size. Therefore, the size of the target molecule that can actually be analyzed is smaller than the achievable resolution. However, even in this case, it is possible to distinguish the state of biopolymers such as lentiviruses, coronaviruses, and adenoviruses that are approximately 1000 Å in size.

[0062] (Data conversion) Figures 7(a) to (c) show a scattering image, a β-direction profile, and a q-direction profile, respectively. When a solution is irradiated with X-rays, a scattering image such as that shown in Figure 7(a) is obtained. When the intensity I in this scattering image is plotted in the circumferential direction (β-direction) around the center at the wave number q of a given scattering vector, a graph such as that shown in Figure 7(b) is obtained. Furthermore, when the intensity I in the β-direction of the scattering image is integrated and the integrated intensity I is plotted against the wave number q of each scattering vector, a scattering profile such as that shown in Figure 7(c) is obtained.

[0063] (Each measurement result) Figure 8 is a table showing the settings of each optical system and the achieved resolution for the relative position. As shown in the example table in Figure 8, the settings of each optical system, relative position, and achieved resolution (= qmin) are stored for each measurement. For each of the optical system settings A to C, movement of 1 / (N+1) pixels is performed N+1 times, and the achieved resolution measured for each is stored. The optimal relative position is identified by the above control method, so the relative position is adjusted to that position before measuring the sample.

[0064] (Sample measurement and analysis methods) After the optical system is set and the relative position is adjusted as described above, further sample measurement and analysis can be performed using the control system 10. Fig. 9 is a flowchart showing the process from sample measurement to analysis. First, the X-ray analysis apparatus 100 sets the measurement conditions based on information input by the user (step T1).

[0065] Upon receiving a command to start measurement input by the user, the X-ray analysis device 100 starts measurement (step T2). The X-ray analysis device 100 sends the buffer solution to a predetermined position, irradiates X-rays, and acquires scattering data using a detector (step T3). Next, scattering data of the sample solution is acquired in the same manner (step T4). The X-ray analysis device transmits the acquired scattering image data to the computer 210 as measurement data.

[0066] The computer 210 stores the received measurement data and converts the measurement data into a scattering profile (step T5), then calculates the difference between the obtained profiles to generate analytical data (step T6), and performs analysis using the data (step T7).

[0067] (Acquisition and analysis of scattering images) Figure 10 is a schematic diagram showing the process from acquiring scattering images to analyzing them. X-rays are alternately irradiated onto a buffer solution and a sample solution, and scattering images are detected at predetermined intervals t. The sample loading mechanism switches the sample holding tube 125, enabling alternate irradiation of each solution.

[0068] The scattering image is converted into a profile, and the data for analysis is obtained by subtracting the intensity profile obtained by integrating the measurement data of the buffer solution from the intensity profile obtained by integrating the measurement data of the sample solution over the entire measurement time.

[0069] In this case, in order to properly process the high-angle data used in structural analysis with a resolution of 30 Å or less, it is necessary to adjust the relative scale of the sample solution profile and the buffer solution profile, i.e., perform scaling before subtraction.

[0070] The obtained analytical data can be used for structural analysis as an actually measured X-ray scattering profile. The cubic volume of the real space containing the particle is represented by cubic voxels discretized into an N × N × N grid, and an electron density map can be calculated by searching for structure factors based on the actually measured X-ray scattering profile.

[0071] Specifically, multiple structural models are generated from the measured X-ray scattering profile, and a calculated X-ray scattering profile is calculated from each of the multiple structural models. An index representing the degree of agreement between the calculated X-ray scattering profile and the measured X-ray scattering profile is calculated, and a representative structural model is selected from the multiple structural models based on the calculated index. Multiple structural models can also be used as an ensemble to evaluate the molecular shape and mobility. In this way, the electron density of a polymer in solution with a dynamically fluctuating structure can be reproduced, and a variety of information can be obtained. [Explanation of symbols]

[0072] 10. Control System 100 X-ray analyzer 110 X-ray generation section 111 X-ray source 115 Optical system 117 Kratsky Block 120 Sample Loading Mechanism 125 Sample holding tube 127 Beam Stopper 130 detector 130a Exposed area 130b Hidden Area 140 Control Unit 200 control device 210 Computer 211 Input / Output Control Unit 213 Relative position calculation unit 214 Relative position control unit 215 Measurement control section 217 Measurement data storage unit 223 Data Conversion Unit 232 Indicator calculation section 234 Setting specific part 236 Setting memory section 242 Analysis data generation unit 280 Input Device 290 Output Device C0 Center position L control bus q wavenumber

Claims

1. A control device for controlling a laboratory X-ray analysis device capable of acquiring an X-ray scattering image for molecules on the order of 1000 Å, a relative position calculation unit that calculates a plurality of relative positions between the beam and the detector, the relative positions being marked with a movement width smaller than the pixel size; a relative position control unit that controls the plurality of relative positions by moving and stopping the beam or the detector; a measurement data storage unit that stores X-ray scattering data acquired by the detector at each of the controlled relative positions; a data conversion unit that generates an intensity profile based on the acquired X-ray scattering data; an index calculation unit that calculates a parameter in the form qmin based on the wave number of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; a setting specifying unit that specifies, as an appropriate position, a relative position that gives a maximum value among the calculated forms qmin.

2. The index calculation unit calculates the formula qmin for a plurality of optical system settings, 2. The control device according to claim 1, wherein the setting specifying unit specifies, as the suitable setting, the setting of the optical system that gives the maximum value among the calculated forms qmin.

3. 3. The control device according to claim 1, further comprising a measurement control unit that adjusts the relative position to the suitable position and performs X-ray scattering measurement on the sample.

4. a setting storage unit that stores the matching position; an input / output control unit that receives an input indicating whether or not the stored matching position is to be used; 4. The control device according to claim 3, wherein the measurement control unit performs the X-ray scattering measurement using or without using the stored suitable positions depending on the received input.

5. 4. The control device according to claim 3, wherein the sample is a biopolymer in a solution.

6. 4. The control device according to claim 3, wherein the data conversion unit generates a profile with a sampling width smaller than a pixel size.

7. 3. The control device according to claim 1, wherein the movement width is between 1 μm and 100 μm.

8. A control device for controlling a laboratory X-ray analysis device capable of acquiring an X-ray scattering image for molecules on the order of 1000 Å, a relative position calculation unit that calculates a plurality of relative positions between the beam and the detector, the relative positions being marked with a movement width smaller than the pixel size; a relative position control unit that controls the plurality of relative positions by moving and stopping the beam or the detector; a measurement data storage unit that stores X-ray scattering data acquired by the detector at each of the controlled relative positions; a data conversion unit that generates an intensity profile based on the acquired X-ray scattering data, The control device is characterized in that the movement width is a predetermined value that is determined before measurement.

9. 1. A control method for controlling a laboratory X-ray analysis device capable of acquiring an X-ray scattering image for molecules on the order of 1000 Å, comprising: calculating a plurality of relative positions between the beam and the detector, each of which is inscribed with a movement step smaller than the pixel size; performing control of the plurality of relative positions by moving and stopping the beam or detector; storing X-ray scattering data acquired by the detector at each of the controlled relative positions; generating an intensity profile based on the acquired X-ray scattering data; calculating a parameter of the form q based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; and specifying the relative position that gives the maximum value of the calculated form qmin as the suitable position.

10. A control program for controlling a laboratory X-ray analysis device capable of acquiring an X-ray scattering image of a molecule on the order of 1000 Å, calculating a plurality of relative positions between the beam and the detector, each of which is inscribed with a movement step smaller than the pixel size; performing control of the plurality of relative positions by moving and stopping the beam or detector; storing the x-ray scattering data acquired by the detector at each of the controlled relative positions; generating an intensity profile based on the acquired X-ray scattering data; calculating a parameter of the form qmin based on the wavenumber of the smallest scattering vector for which statistically significant data exists on each of the generated intensity profiles; and specifying, as a suitable position, the relative position that gives the maximum value of the calculated form qmin.

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