reaction vessel

Abstract

The present invention provides a container for use in analyzing samples, the container comprising a housing, a lid closing a first end of the housing, a stator disposed within the housing for receiving a rotor, and a shaft having a first end to which a magnetic shaft drive is fixed and an opposing second end covered by the rotor, the rotor and stator spaced apart by a ring-shaped gap of constant radius, the shaft extending within a first bearing attached to the shaft at an axial portion disposed between the magnetic shaft drive and the rotor, the first bearing being fixed to the lid.

Description

Technical Field

[0001] The present invention relates to an apparatus which is a reaction vessel suitable for applying a predetermined shear force to a liquid sample, a method for manufacturing the reaction vessel, and a process for applying a predetermined shear force to a sample, preferably including an optical analysis of the sample passing through a part of the reaction vessel.

[0002] The reaction vessel includes a rotor extending on a bearing, preferably just one bearing, the rotor having a shaft with a drive part at one end and being suitable for receiving rotational torque from a drive motor which can be arranged adjacent to the drive part or at a distance from the drive part. Preferably, the bearing is arranged at a distance from the height of the liquid sample arranged in the container so that the bearing does not come into contact with the liquid.

[0003] The reaction vessel includes a stator arranged coaxially with the rotor, a predetermined gap being formed between the rotor and the stator, and it being possible to apply a predetermined shear stress to the liquid. The shear stress is proportional to the rotational frequency of the rotor, the radius of the rotor, and the viscosity of the liquid, and is inversely proportional to the gap width between the rotor and the stator.

[0004] The reaction vessel is such that when driven by the rotation of the rotor, the liquid sample can circulate. The shape of the container is designed such that the maximum shear stress is applied to the liquid at the part where the gap width between the rotor and the stator is the smallest.

[0005] The reaction vessel preferably comprises a detection part arranged at its lower end, which is at least partially light-transmissive, for example for light to irradiate the inner volume of the reaction vessel and for detecting radiation passing through the inner volume of the reaction vessel and / or radiation emitted from the inner volume of the reaction vessel.

Background Art

[0006] WO2012 / 110570A1 schematically illustrates a reaction vessel in which a rotor extends on an axle that extends on a bearing located on a lid covering the vessel and a second bearing located on the bottom of the lid, the rotor having a conical shape parallel to the vessel bottom which tapers to a conical shape. In an alternative example, the vessel extends on a single sleeve located in the upper half of a cylindrical vessel, the rotor extends within a tubular section that is open at both ends, the tubular section located in the lower half of the vessel, spaced apart from the rotor and spaced apart from the vessel bottom.

[0007] WO2016 / 001334A1 describes a reaction vessel in which the stator is inserted at a distance from the vessel wall and at a distance from the central rotor. The rotor is cylindrical with a chamfered periphery. The stator has an extension below the portion surrounding the rotor, and the light source and detector are oriented at 90° to each other and 45° to a common central axis, and directed into the space formed by the extension. [Overview of the project]

[0008] The object of the present invention is to provide an alternative reaction vessel suitable for applying shear stress to a liquid, and an alternative process for applying shear force to a liquid using the reaction vessel. Preferred objects are to provide a reaction vessel configured to effectively apply shear force to the entire volume of liquid contained in the vessel, and to provide a vessel that enables optical detection of a representative portion of the liquid.

[0009] The present invention, by the features of the claims, specifically aims to provide a reaction vessel suitable for subjecting the entire volume of liquid contained within a container to shear force, the container being configured for circulating the liquid passing through the container, A housing having a first end for connecting to a lid and an opposing second end closed by a bottom wall, wherein the second end includes a detection unit having at least one window portion, preferably two windows, in the housing wall, the windows being light-transmitting and preferably planar, and the detection unit preferably positioned adjacent to the bottom wall, the housing and A lid for closing the first end of a housing, preferably having a recess coaxial with the housing, and preferably having a cylindrical side wall that clamps to the cylindrical portion of the first end of the housing, A stator disposed within a housing and having a cylindrical inner surface for receiving a rotor at a certain interval, wherein the cylindrical surface has a first open end cross section and an opposing second end cross section, and the outer surface of the stator is spaced apart from the housing by at least three, preferably four, webs connecting the stator to the housing at intervals, the webs preferably extending only along the stator holding portion of the housing, and the stator and Optionally, the stator has an opening in its second end cross section, either directly adjacent to the detection unit or at a distance from the detection unit. Preferably, an extension pipe is connected to the second end cross section of the stator, the extension pipe having a constant cross section or a cross section that tapers toward the detection section, and having an end directly adjacent to the detection section or at a distance from the detection section, this distance may extend along the second portion of the nozzle holding section. A rotor having or composed of a cylindrical portion disposed within a stator, wherein the rotor and stator are separated by a ring-shaped gap of a certain radius, the rotor covers the second end of the shaft and has a flat front surface and a chamfered or rounded periphery, or has a second end having a rounded front surface, the rotor has a terminal peripheral collar at its first end that extends across the radius of the cylindrical rotor portion and extends across the cylindrical surface of the stator, and accordingly the collar extends across the ring-shaped gap formed between the rotor and the stator, A shaft having a first end to which a magnetic shaft drive is fixed and an opposing second end covered by a rotor, wherein the shaft extends into a first bearing disposed on the shaft in a shaft portion positioned between the magnetic shaft drive and the rotor, the first bearing being fixed to a cover, preferably the first end of the shaft being a free end and positioned in a recess of the cover, and the free end of the shaft and the recess of the cover forming a second bearing which is a friction bearing, the shaft and Equipped with, The shaft, magnetic shaft drive, first and second bearings on which the shaft extends, rotor, stator, preferably extension of the stator and / or detection unit, are arranged coaxially.

[0010] The ring-shaped gap of a certain radius between the cylindrical rotor and the cylindrical stator forms an annular gap with a certain cross-section.

[0011] Generally, the rotor, rotor periphery collar, stator, optional extension pipe, and first and optional second bearings, as well as the magnetic shaft drive, are coaxial with respect to the shaft, and preferably, all components of the vessel are coaxial with respect to a common longitudinal axis, for example, the longitudinal axis of the shaft.

[0012] In a detection unit having two window sections, the window sections are preferably arranged at a 90° angle, and more preferably arranged parallel to each other on opposing sides of the housing wall.

[0013] Generally, the stator is positioned at a distance from the housing, and this distance forms a channel through which the fluid flows from one end of the stator, e.g., its first end cross section, to the other end of the stator, e.g., its second end cross section, or to the opening of the extension pipe opposite the stator. Thus, the extension pipe is also positioned at a distance from the housing. Because there is no relative movement between the stator and the housing in the distance that forms the channel for the fluid, the shear force in this channel is significantly small, substantially negligible compared to, for example, the shear force generated between the rotor and the stator. Therefore, within the channel between the stator and the housing, the fluid can return to the gap between the rotor and the stator without being subjected to the associated shear force. Preferably, the distance from the housing to the stator is at least the same size as the radius of the ring-shaped gap between the rotor and the stator, in order to generate the maximum shear force between the rotor and the stator and to avoid large shear forces as the fluid passes through the distance between the stator and the housing. The extension pipe is positioned coaxially with the nozzle holder of the housing, and preferably, the extension pipe is positioned at a certain distance from the nozzle holder of the housing.

[0014] Preferably, the cross-sectional area of ​​the extension pipe is at least the same as the cross-sectional area of ​​the ring-shaped gap between the rotor and the stator. Preferably, the extension pipe is circular in its cross-section or height.

[0015] A web connecting the stator to the housing at a distance from the stator may be formed by one of the stator and the housing, and may involve clamp connections between the web and the other of the stator and the housing, respectively, or the web may be formed integrally with both the stator and the housing by additive manufacturing, for example, using a 3D printer or fused deposition modeling (FDM) technology. Embodiments in which the housing, including the stator, optionally an extension pipe connected to a second end of the stator, and a connecting web, are integrally formed have the advantage of less distortion and warping of the stator compared to, for example, a stator clamped within the housing by a web.

[0016] Preferably, the rotor is spaced apart from the first bearing so that the shaft is not covered in respect of this gap. The distance between the rotor and the first bearing reduces contamination of the first bearing by liquid contact with the rotor.

[0017] Preferably, the housing has a diameter smaller than the outer or inner diameter of the stator and / or smaller than the diameter of the rotor, and in particular smaller than the diameter of the peripheral collar of the rotor, in the portion between the height of the lid or the first bearing, for example, the first bearing located in the lid, and the height of the rotor. Such a small-diameter portion is also interchangeably referred to as the collar portion of the housing. Preferably, in the collar portion, particularly in the portion covering the lid or the first bearing of the housing, for example, the portion between the first bearing located in the lid and the rotor, the shaft is not covered by either the first bearing or the rotor. In a process using a container, preferably, the liquid is injected into the housing to a maximum of the minimum cross-section of the collar portion, preferably to a height that completely fills the annular gap between the rotor and the stator.

[0018] The housing preferably has a recess, preferably cylindrical in cross-section, for receiving the lid, which includes, for example, preferably friction fitting, optionally engaging grooves and ridges on the outer surface of the cylindrical side wall of the lid with grooves and ridges on the inner surface of the recess at the first end of the housing.

[0019] Optionally, the housing has an enlarged inner cross-section, for example, widened, in the portion at the height of the rotor's peripheral collar compared to the portion at the height of the stator's second end, and / or compared to the cross-section of the portion of the housing between the height of the lid or the height of the first bearing, e.g., the first bearing located within the lid, and the height of the rotor. The enlargement of the inner cross-section of the housing at the height of the rotor's peripheral collar has the advantage of guiding the fluid flow, which is moved radially outward by the rotating rotor, particularly by the rotating peripheral collar, into the space between the stator and the housing to generate a return flow of fluid, for example, to the cross-section of the stator's second end, or to the cross-sectional opening of an extension pipe located on the opposite side of the rotor and / or the opposite side of the stator.

[0020] The shaft is preferably a cylindrical stainless steel rod. Alternatively, the shaft may be a cylindrical rod made of high-performance plastic.

[0021] Preferably, the first bearing is fixed to the cover, for example by a clamp, and for example, the first bearing is clamped in a recess formed by the cylindrical side wall of the cover. The first bearing may be a bore in a plate, which optionally provides friction bearing to the shaft with radial guidance only and / or without axial guidance. The magnetic shaft drive preferably comprises or consists of a holder containing magnets, which is fixed to the shaft, for example by a clamp. The holder preferably has a recess for holding magnets, preferably a pair or two pairs of magnets. Along the shaft, the magnetic shaft drive is preferably positioned between a cover that forms a second bearing for a first end of the shaft and a first bearing fixed to the cover by a clamp in a recess formed by the side wall of the cover, so that the magnetic shaft drive holds the shaft between the first bearing and the second bearing, even if the first bearing is a bore that allows axial sliding of the shaft. To prevent axial movement of the shaft in the first bearing, the magnetic shaft drive can be fixed to the shaft in a position adjacent to the first bearing, for example, in a position where the magnetic shaft drive contacts the first bearing, in which case the first end of the shaft extends into the second bearing, and the front surface of the shaft contacts a recess in the cover with a sufficient clearance to allow rotation of the shaft. Preferably, the magnet is a neodymium magnet, for example, a cylindrical magnet placed in a hole in the holder. Alternatively, other high-performance magnets may be used, including high-performance composite magnets manufactured by injection molding.

[0022] Preferably, the shaft is a cylindrical metal rod, the magnets of the magnetic shaft drive are neodymium magnets, and all other components of the container are preferably made of a light-transmitting synthetic resin, such as polystyrene, polyethylene, polylactic acid, polyethylene terephthalate, polycarbonate, or acrylic nitrile-butadiene-styrene, or nylon.

[0023] Suitably, for example, components of synthetic resin that are fixed to each other by clamping on surfaces that slide relative to each other when attaching the components have grooves perpendicular to a common longitudinal axis, for example perpendicular to the longitudinal axis of a shaft. The grooves are produced, for example, by additive manufacturing, preferably by 3D printing, preferably liquid resin 3D printing, using, for example, high-precision fused deposition modeling (FDM) technology.

[0024] The magnetic shaft drive can be driven by a magnetic drive having correspondingly arranged magnets, preferably a pair of magnets of the same number as the shaft drive.

[0025] Suitably, the first bearing is connected to the lid, for example by clamping, preferably within a recess formed by the cylindrical side wall of the lid, and the lid is connected to the first end of the housing by clamping. Thereby, it is possible to provide a container as a separate element that is simply connected by clamping without the need for additional fixing means, for example without additional adhesives, sealants, or mechanical fixing devices.

[0026] The container is a housing having a detection part with at least one, preferably at least two, light-transmissive windows at its second end, including a stator, and having a recess for receiving a lid at its first end, and as a separate part, a lid connected to a first bearing including a shaft with a rotor fixed to its second end and a magnetic shaft drive fixed to its first end, the lid being clampable to the first end of the housing and can be provided as a combination.

[0027] The reaction vessel has the advantage of being configured such that a shear force is applied between the rotor and stator, causing the rotor to rotate and thus providing a pumping action to the liquid, resulting in homogeneous processing of the entire liquid in the vessel, and ensuring that a representative liquid of the entire liquid is present in the detection section of the housing. The peripheral collar, which extends along the radius of the cylindrical rotor during rotation, can generate sufficient centrifugal force in the liquid to pump it, causing it to circulate through the gap between the rotor and stator and return through the channel formed by the gap between the housing and stator.

[0028] The pumping action is brought about solely by the rotation of the rotor; therefore, the vessel's driving elements, such as the rotating elements, preferably consist of a rotor located at the second end of the shaft and a shaft drive located at the first end of the shaft. Furthermore, the vessel has the advantage that the shear force can be controlled by controlling only the rotational speed of the rotor, thereby exerting a large shear force on the liquid mainly between the rotor and the stator, and the vessel is configured to avoid the generation of relevant shear forces outside the ring-shaped gap defined between the rotor and the stator. Thus, the vessel is configured to subject the liquid to the maximum shear force only within the ring-shaped gap between the rotor and the stator. The vessel is configured to circulate the entire volume of liquid through the ring-shaped gap between the rotor and the stator when the rotor is rotated, and to convert the native structural prion protein to an aggregated state only within the ring-shaped gap between the rotor and the stator; the flow of liquid through the vessel outside this ring-shaped gap does not provide enough shear force to significantly affect the conversion from the native structural prion protein to an aggregated state.

[0029] The ring-shaped gap between the rotor and stator is preferably in the range of 0.2 to 0.5 mm and / or 5% to 30% of the rotor radius. The shear stress is proportional to the rotor rotation frequency, rotor radius, and fluid viscosity, and inversely proportional to the gap width between the rotor and stator.

[0030] Preferably, at least two containers are arranged in parallel and connected to one another, and the housing and the connecting portion between them are integral, for example, manufactured as a single unit, and more preferably, the material of the housing and the connecting portion between them is continuous. Here, the at least two parallel and connected containers are arranged such that their light-transmitting windows are in a common plane, for example, such that their windows are in a plane parallel to the straight line of the row in which the containers are arranged in the apparatus.

[0031] Furthermore, the present invention provides an analytical process in which a liquid sample is injected into a container, preferably by injecting the sample into a housing and / or stator, then positioning a rotor within the stator, preferably by positioning a rotor mounted on a shaft extending on a first bearing fixed to a lid, with the lid positioned at a first end of the housing, rotating a magnetic shaft drive to rotate the rotor, optically detecting the sample in a detection unit of the housing, and preferably by transmitting the detection result or a medical indication derived from the detection result to the sample provider. The sample provider may be a medical research institution, a physician, or the patient from whom the sample was taken. Furthermore, the analytical process may be used to determine the effect of a compound on the efficacy of inhibiting or reversing the formation of aggregated prion proteins by adding the compound to the sample or a certain amount of the sample and comparing the rate of formation of aggregated prion proteins during the process. Thus, the process may be used to analyze a patient-derived sample by adding a compound that is thought to have activity toward the formation of aggregated prion proteins to a sample derived from a specific patient in order to detect the efficacy of a compound that at least delays the formation of aggregated prion proteins in the provider's sample. The efficacy of compounds that delay the formation of aggregated prion proteins includes prevention, inhibition, suppression, and / or regression of aggregated prion protein formation. Here, the process may be used to select compounds with respect to efficacy in delaying, for example, inhibiting, suppressing, preventing, or regression of aggregated prion protein formation in a sample from a specific patient. Generally, the sample may be a liquid or solid biomaterial obtained from a patient, such as a solution, serum, or tissue. The patient may be a human patient, or, in particular for research purposes, an animal or tissue culture medium. The process may be an in vitro process or assay and may be used, for example, as a translational assay system in drug discovery.

[0032] The apparatus of the present invention can also be used to screen and select compounds for activity and efficacy in inhibiting, suppressing, or reversing the formation of aggregated prion proteins, the process comprising the steps of: injecting a liquid sample comprising a native prion protein and / or an aggregated prion protein to detect compounds having activity that delays the formation of aggregated prion proteins; adding at least one compound to be screened into the housing and positioning the rotor inside the stator; rotating the magnetic shaft drive to rotate the rotor; and optically detecting the sample in the detection section of the housing.

[0033] The present invention will be described in more detail below with reference to the drawings and using examples. [Brief explanation of the drawing]

[0034] [Figure 1] Figure 1A is a cross-sectional view of an embodiment of the container, Figure 1B is a cross-sectional view rotated 90° with respect to the horizontal at the indicated height B, Figure 1C is a cross-sectional view rotated 90° with respect to the horizontal at the indicated height C, and Figure 1D is a cross-sectional view of the housing of Figure 1A rotated 90° with respect to the vertical, with some components of the embodiment shown in Figure 2 removed from Figure 1A. [Figure 2] This is a cross-sectional view of a part of the embodiment. [Figure 3] This is an enlarged cross-sectional view of Figure 2. [Figure 4] Figure 1 shows the measurement results of the formation of aggregated prion proteins generated in the container. [Modes for carrying out the invention]

[0035] Generally, each feature described with reference to the drawings is an individual feature of the container of the present invention and is independent of other features.

[0036] Figures 1A to D show a housing 1 having a first end 2 and a second end 3 opposite it, and closed by a bottom wall 4. A detection unit 5 is located at the second end 3 of the housing 1, and this detection unit 5 has at least one, preferably two, opposing light-transmitting windows 6 (Figures 1C and 1D). Optionally, the bottom wall 4 has a bottom window 4a made of a light-transmitting material, and its central portion is surrounded by an opaque bottom wall that forms a bottom opening 4b.

[0037] A stator 10 is located inside the housing 1, extending from a first open end section 11 to an opposing second open end section 12, and having a cylindrical inner surface 15. An extension pipe 13, which tapers toward the second end 3 of the housing 1, is connected to the second end section 12. The extension pipe 13 functions to guide the liquid flowing through the detection section 5 along the extension pipe 13 and the stator 10.

[0038] Preferably, as shown with respect to the extension pipe 13, the extension pipe 13 tapers toward the second end 3 of the housing 1, forming a nozzle.

[0039] The stator 10 is positioned in the housing with spacing provided by the web 14. The stator 10 extends along the stator retaining portion 8 of the housing 1, and preferably the web 14 extends along the stator retaining portion 8 between the housing 1 and the stator 10.

[0040] The rotor 20 is coaxially positioned inside the stator 10, and the gap between the rotor 20 and the inner cylindrical surface of the stator 11 forms a ring-shaped gap where, as the rotor 20 rotates, a shear force is applied to the fluid. The rotor, as a cylindrical portion 21 located within the stator 10, and the cylindrical portion 21 at its first end 22, have a peripheral collar 23 that extends along the radius of the cylindrical rotor portion 21. In a preferred embodiment, the rotor collar 23 also extends into the ring-shaped gap between the rotor 20 and the stator 10.

[0041] The opposing second end 24 of the rotor has a flat front surface 25 with a circumferential slope 26.

[0042] The rotor 20 is positioned at the second end 32 of the shaft 30. Opposite the second end 32, the first end 31 of the shaft 30 carries a magnetic shaft drive 33 including at least two magnets 34. The magnetic shaft drive 33 is fixed to the shaft 30 extending into a first bearing 35, and optionally the shaft 30 is axially displaceable. In the shown embodiment, the magnetic shaft drive 33 has a flat front surface 36 that may extend with friction to an adjacent flat front surface 37 of the first bearing 35, thereby restricting the axial movement of the shaft 30. The first bearing 35 is held by a clamp inside a cylindrical portion 41 of the lid 40, which is clamped to the first end 2 of the housing 1. The lid 40 also closes the cross section of the first end 2 of the housing 1.

[0043] In the shown embodiment, all elements are arranged coaxially with respect to the longitudinal axis 39 of the shaft 30.

[0044] Preferably, Figures 1A and 1D show a housing 1 having a collar portion 82 between a first end 2 of the housing and a stator retaining portion 8. From the first end 2, the collar portion 82 tapers along a first portion 82a to a reduced cross-section of the housing 1, and from the stator retaining portion 8, the collar portion 82 tapers along a second portion 82b to a reduced cross-section of the housing 1. The collar portion 82 provides a threshold for the movement of liquid from the stator retaining portion 8 toward the first end 2 of the housing 1. Preferably, the liquid is injected into the housing up to the reduced cross-section of the collar portion 82, and at the reduced cross-section of the collar portion 82, for example, an approximate liquid filling level 91 is reached.

[0045] The portion of the housing 1 in which the extension pipe 13 is located is also referred to as the nozzle holding portion 83 of the housing. Preferably, the extension pipe 13 is connected only to the stator 10, that is, connected without a web extending between the extension pipe 13 and the nozzle holding portion 83. Preferably, the first portion 83a of the nozzle holding portion 83 extends for the axial extension of the extension pipe 13 and is spaced at a certain distance from the extension pipe 13, and the housing 1 adjacent to the first portion 83a in the second portion 83b of the nozzle holding portion 83 may taper toward the second end 3 of the housing 1. Here, the second portion 83b of the nozzle holding portion 83 connects the first portion 83a to the second end 3 of the housing 1 across the portion in which the extension pipe 13 does not extend.

[0046] Figure 2 shows an enlarged view of the lid 40, in which a first bearing 35 is clamped to the cylindrical portion 41 of the lid 40. The shaft 30 extends into the first bearing 35, and its first end 31 is attached to the magnetic shaft drive 33 by a clamp. In a preferred embodiment, the first end 31 of the shaft 30 terminates with a convex front surface 38 that extends into a corresponding recess 42 of the lid, and the front surface 38 of the shaft 30 forms a second bearing 50 with the corresponding recess 42 of the lid 40.

[0047] Figure 3 shows an enlarged cross-sectional view of Figure 2, which shows the second bearing 50.

[0048] Generally, the drawings show an embodiment of a vessel according to the present invention, in which the vessel is provided as two separate elements, each of which is pre-assembled to connect with one another to form a sealed reaction vessel by clamping a lid 40 to a second end 2 of a housing 1, thereby closing the cross section that opens and widens at the second end 2 of the housing 1, and coaxially positioning the rotor 20 within the stator 10.

[0049] With regard to the analysis process of the present invention, it is preferable to inject the liquid sample into the housing 1 before attaching the lid 40 to the housing.

[0050] Example: Analytical process for detecting the effect of shear force on a sample using optical detection. As a typical sample, recombinant aggregated prion protein derived from the shear force-induced reaction of recombinant native prion protein was mixed with postmortem brain homogenate samples from synuclein disease patients at a dilution of 1 / 100000 with 1.5 mg / ml of native structural human α-synuclein in PBS containing 1% Triton X-100 (positive control). The buffer composition and procedure details were similar to those in previous disclosures WO2012 / 110570A1 and WO2016 / 001334A1. Thioflavin T was used as the fluorescent agent for detecting the aggregated prion protein. The same reaction composition was used as a negative control without the addition of recombinant aggregated prion protein. The vessel generally corresponded to Figure 1. The gap width between the stator and rotor was 0.3 mm, and the rotor diameter was 3 mm. Corresponding to a shear rate of 12570 rpm and a shear stress of 11.2 Pascals, the processing frequency used was 400 revolutions per second (400 Hz), and the reaction temperature was set to 30°C. The reaction was tracked over 15 hours, corresponding to 180 processing and pause cycles. In each cycle, processing was applied for 3 seconds, followed by a 297-second pause. To detect the formation of aggregated prion proteins, the fluorescence signal of thioflavin T was accumulated during the pause phase of each cycle. Data traces were recorded for 15 replicas each of the positive and negative controls.

[0051] In the positive control, aggregated prion proteins formed after approximately 4 hours (±0.5 hours). In the negative control, aggregated prion proteins began to form after approximately 14 hours in some replicas, but in most replicas, there was no sign of aggregated prion formation during the observation period. The measurement results for the positive control (left) and negative control (right) are shown in Figure 4. Individual measurements overlap because the formation of aggregated structures occurred in a reproducible manner.

[0052] Generally, detection is measurable by the change in fluorescence of a fluorescent dye added to the mixture through the detection section of the container, and the dye is specific to the aggregated prion protein. Typical dyes include, for example, thiophene-based amyloid ligands such as thioflavin T, thioflavin S, Congo Red, luminescent conjugated polythiophene (LCP), polythiophene acetate (PTAA), and luminescent conjugated oligothiophene (LCO), Pittsburgh compound B, aminonaphthalene 2-cyanoacrylate (ANCA) probe, pegylated phenylbenzoxazole derivatives, pinacyanol, chrysamine G, and dyes containing at least one of the following scaffolds, chalcone, flavone, aurone, stilbene, diphenyl-1,2,4-oxadiazole, diphenyl-1,3,4-oxadiazole, benzothiazole, benzoxazole, benzofuran, imidazopyridine, benzimidazole, quinoline, and naphthalene.

[0053] As an alternative, native structural prion proteins can be labeled with fluorescent dyes, for example, by directly attaching the fluorescent dye to the native structural prion protein, or by attaching it via an intermediate spacer, such as isothiocyanate (which reacts with primary amines, e.g., lysine), succinylimide ester (which reacts with amino groups to form amide bonds, e.g., N-terminal amino acids), or maleimide (which reacts with free sulfhydryl groups, e.g., cysteine). Such fluorescent derivatives include cyanine, fluorescein, rhodamine, Alexa phosphors, Dylight phosphors, ATTO-Tec dyes, BODIPY dyes, SETA dyes, SeTau dyes, and DYOMICS dyes. The invention described in the original claims of this application is listed below. [1] A container for use in the analysis of a sample, A housing (1) having a first end (2) for connecting to a lid (40) and an opposing second end (3) closed by a bottom wall (4), wherein the second end (3) includes a detection unit (5) having at least one light-transmitting window (6) in the housing wall, A lid (40) that closes the first end (2) of the housing (1), A stator (10) is disposed inside the housing (1) and has a cylindrical inner surface (15) for receiving a rotor (20) at a certain interval, wherein the cylindrical surface (15) has a first open end cross section (11) and an opposing second end cross section (12), and the outer surface of the stator (10) is spaced apart from the housing (1) by at least two webs (14) that connect the stator (10) to the housing (1), The rotor (20) has a cylindrical portion (21) disposed within the stator (10), wherein the rotor (20) and the stator (10) are separated by a ring-shaped gap of a certain radius, and the rotor (20) has a second end (24) that covers the second end (32) of the shaft (30), and has a first end (22) having a circumferential end collar (23) that extends across the radius of the cylindrical rotor portion (21) and across the cylindrical surface (15) of the stator (10), A shaft (30) having a first end (31) to which a magnetic shaft drive (33) is fixed and an opposing second end (32) covered by the rotor (20), wherein the shaft portion positioned between the magnetic shaft drive (33) and the rotor (20) extends into a first bearing (35) positioned on the shaft (30), the first bearing (35) being fixed to a cover (40), and Equipped with, A container in which the shaft (30), the magnetic shaft drive (33), the first bearing (35), the rotor, the stator, and / or the detection unit are integrally formed. [2] The container according to claim 1, characterized in that the stator (10), the housing (1), and the web (14) that separates the stator (10) from the housing (1) are integrally formed. [3] The container according to claim 1 to 2, wherein the detection unit (5) has two window portions (6) in opposing walls, and the window portions (6) are light-transmitting and planar. [4] The container according to claim 1 to 3, wherein the detection unit (6) is arranged adjacent to the bottom wall (4). [5] The container according to claim 1 to 4, wherein the lid (40) has a cylindrical portion (41) of the side wall that forms a recess arranged coaxially with the housing (1), and the cylindrical side wall is clamped to the cylindrical portion (7) of the first end (2) of the housing (1). [6] The container according to claim 1 to 5, characterized in that the stator (10) has a second end section (12) opening (16) directly adjacent to the detection unit (5) or at a distance from the detection unit (5). [7] The container according to claim 1 to 6, characterized in that an extension pipe (13) is connected to the second end cross section (12) of the stator (10), and the extension pipe (13) has an end directly adjacent to the detection unit (5) or at a distance from the detection unit (5). [8] The container according to claim 7, characterized in that the extension pipe (13) has a cross-section that tapers toward the detection unit (5) or has a constant cross-section. [9] The container according to claim 1 to 8, characterized in that the rotor (20) has a flat front surface (25) and a chamfered or rounded periphery (26) at its second end (24), or has a rounded front surface (25).

[10] The container according to claim 1 to 9, characterized in that the collar (23) extends over the ring-shaped gap formed between the rotor (20) and the stator (10).

[11] The container according to claim 1 to 10, characterized in that the first end (31) of the shaft (30) is a free end disposed within the recess (42) of the lid (40), and the free end (31) of the shaft and the recess (42) of the lid (40) form a second bearing (50) which is a friction bearing.

[12] The container according to claim 1 to 11, comprising a housing (1), a stator (10) disposed inside the housing (1), a detection unit (5), and a lid (40) connected to the first bearing (35) as a separate element, wherein the shaft (30) extends into the first bearing (35), and a magnetic shaft drive (33) disposed between the first bearing (35) and the lid (40) is attached to the first end (31) of the shaft (30), the first end (31) of the shaft (30) is a free end disposed in a recess (42) of the lid (40), the free end (31) of the shaft and the recess (42) of the lid (40) form a second bearing (50), and the rotor (20) is attached to the second end (32) of the shaft (30).

[13] The container according to claim 12, wherein the housing (1) has a cylindrical portion at its first end (2) that is fitted to receive the lid (40) in a clamp-fit.

[14] A process for analyzing a patient-derived sample to detect the presence of aggregated prion protein using a container according to claim 1 to 13, comprising the steps of: injecting the sample and native prion protein into the housing; positioning the rotor in the stator; rotating the magnetic shaft drive to rotate the rotor; optically detecting the sample in the detection unit of the housing; and transmitting the detection result or a medical indication derived from the detection result to the provider of the sample.

[15] A process for analyzing a patient-derived sample according to claim 14, comprising adding the compound to the patient-derived sample in order to detect the efficacy of the compound in at least delaying the formation of aggregated prion proteins in the provider's sample.

[16] A process for screening compounds for activity that inhibits the formation of aggregated prion proteins using a container according to claim 1 to 13, comprising the steps of: injecting a liquid sample comprising a native prion protein and / or an aggregated prion protein to detect a compound having activity that delays the formation of the aggregated prion protein; adding at least one compound to be screened in the housing; positioning the rotor in the stator; rotating the magnetic shaft drive to rotate the rotor; and optically detecting the sample in the detection unit of the housing. [Explanation of symbols]

[0054] 1 Housing 2. First end of the housing 3. Second end of the housing 4 Bottom wall 4a Bottom window 4b Bottom opening 5. Detection Unit 6 Window section 7. Cylindrical section 8. Stator retaining part of the housing 10 staters 11 Cross section of the first end of the stator 12 Cross section of the second end of the stator 13 Extension pipes 14 Web 15. Inner surface of the stator cylinder 16 Opening 20 rotors 21. Cylindrical part of the rotor 22 First end of the rotor 23 Rotor Color 24 The second end of the rotor 25 Front of the rotor 26 Bevel 30 shafts 31 The first end of the shaft 32 The second end of the shaft 33 Magnetic shaft drive 34 Magnets 35 First bearing 36 Front view of the magnetic shaft drive 37 Front surface of the first bearing 38 Front of the shaft 39 Longitudinal axis 40 Lid 41. Cylindrical part of the lid 42 Recess in the lid 50 Second bearing 82 Housing color part 82a First part of the color section 82b Second part of the color section 83 Nozzle holding part of the housing 83a First end of nozzle holder 83b Second end of nozzle holder 91 Appropriate liquid filling level

Claims

1. A container for use in the analysis of a sample, A housing (1) having a first end (2) for connecting to a lid (40) and an opposing second end (3) closed by a bottom wall (4), wherein the second end (3) of the housing (1) is provided with a detection unit (5) having at least one light-transmitting window (6) in the housing wall, A lid (40) that closes the first end (2) of the housing (1), A stator (10) is disposed inside the housing (1) and has cylindrical surfaces (15) for receiving rotors (20) at regular intervals, wherein the cylindrical surfaces (15) have a first open end cross section (11) and an opposing second end cross section (12), and the outer surface of the stator (10) is disposed at a distance from the housing (1), The rotor (20) has a cylindrical portion (21) disposed within the stator (10), the rotor (20) and the stator (10) are separated by a ring-shaped gap of a certain radius, and the rotor (20) has a second end (24) that covers the second end (32) of the shaft (30), The shaft (30) has a first end (31) to which a shaft drive (33) is fixed, and a second end (32) of the shaft (30) that is opposite and covered by the rotor (20), wherein the shaft (30) extends into a first bearing (35) positioned on the shaft (30) in the shaft portion positioned between the shaft drive (33) and the rotor (20), and the first bearing (35) is fixed to a cover (40), and Equipped with, The shaft (30), the shaft drive (33), the first bearing (35), the rotor, the stator, and / or the detection unit are arranged coaxially. The container has at least two webs (14) that connect the stator (10) to the housing (1) at intervals, The rotor (20) has a first end (22) having an end circumferential collar (23) that extends across the radius of the cylindrical portion (21) and onto the cylindrical surface (15) of the stator (10), The shaft drive (33) is a container made of a magnetic material.

2. The container according to claim 1, characterized in that the stator (10), the housing (1), and the web (14) that separates the stator (10) from the housing (1) are integrally formed.

3. The container according to claim 1, wherein the detection unit (5) has two window portions (6) in opposing walls, and the window portions (6) are light-transmitting and planar.

4. The container according to claim 1, wherein the detection unit (5) is arranged adjacent to the bottom wall (4).

5. The container according to claim 1, characterized in that the lid (40) has a cylindrical portion (41) of its side wall that forms a recess arranged coaxially with the housing (1), and the cylindrical portion (41) is clamped to a cylindrical portion (7) of the first end (2) of the housing (1).

6. The container according to claim 1, characterized in that the stator (10) has a second end section (12) opening (16) directly adjacent to the detection unit (5) or spaced apart from the detection unit (5).

7. The container according to claim 1, characterized in that an extension pipe (13) is connected to the second end cross section (12) of the stator (10), and the extension pipe (13) has an end directly adjacent to the detection unit (5) or at a distance from the detection unit (5).

8. The container according to claim 7, characterized in that the extension pipe (13) has a cross-section that tapers toward the detection unit (5) or has a constant cross-section.

9. The container according to claim 1, wherein the rotor (20) has a flat front surface (25) and a chamfered or rounded periphery (26) at its second end (24), or has a rounded front surface (25).

10. The container according to claim 1, characterized in that the first end (31) of the shaft (30) is a free end disposed within the recess (42) of the lid (40), and the free end (31) of the shaft and the recess (42) of the lid (40) form a second bearing (50) which is a friction bearing.

11. The container according to claim 1, comprising the housing (1), the stator (10) disposed inside the housing (1), the detection unit (5), and the lid (40) connected to the first bearing (35) as a separate element, wherein the shaft (30) extends into the first bearing (35), and a magnetic shaft drive (33) disposed between the first bearing (35) and the lid (40) is attached to the first end (31) of the shaft (30), the first end (31) of the shaft (30) is a free end disposed in a recess (42) of the lid (40), the free end (31) of the shaft and the recess (42) of the lid (40) form a second bearing (50), and the rotor (20) is attached to the second end (32) of the shaft (30).

12. The container according to claim 11, wherein the housing (1) has a cylindrical portion at its first end (2) that is fitted to receive the lid (40) by clamp fitting.

13. A method for analyzing a patient-derived sample to detect the presence of aggregated prion protein using a container according to any one of claims 1 to 12, comprising the steps of: injecting the sample and native prion protein into the housing; positioning the rotor in the stator; rotating the shaft drive to rotate the rotor; optically detecting the sample in the detection unit of the housing; and transmitting the detection result or a medical indication derived from the detection result to the provider of the sample.

14. The method according to claim 13, further comprising adding the compound to the patient-derived sample in order to detect the efficacy of the compound in at least delaying the formation of aggregated prion proteins in the provider's sample.

15. A method for screening compounds for activity that inhibits the formation of aggregated prion proteins, using a container according to any one of claims 1 to 12, comprising the steps of: injecting a liquid sample comprising a native prion protein and / or an aggregated prion protein for detecting a compound having activity that delays the formation of the aggregated prion protein; adding at least one compound to be screened in the housing; positioning the rotor in the stator; rotating the shaft drive to rotate the rotor; and optically detecting the sample in the detection unit of the housing.

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