A monitoring control system includes: a safety control device that includes a state monitoring unit that monitors a state of a plant after emergency shut-down of the plant, and a work progress monitoring unit that monitors a work progress after the emergency shut-down of the plant; and a display device that displays, in a case where the emergency shut-down of the plant is performed by the safety control device, an emergency shut-down screen including a monitoring result of the state monitoring unit and a monitoring result of the work progress monitoring unit.

Field of the Invention
The present invention relates to a monitoring control system and a work support method.
Priority is claimed on Japanese Patent Application No. 2016-006086, filed Jan. 15, 2016, the content of which is incorporated herein by reference.
Description of Related Art
All patents, patent applications, patent publications, scientific articles, and the like, which will hereinafter be cited or identified in the present application, will hereby be incorporated by reference in their entirety in order to describe more fully the state of the art to which the present invention pertains.
In the related art, in a plant, a factory, or the like (which may be generally referred to as a "plant", hereinafter), a monitoring control system is provided, and an advanced automatic operation is realized. In order to perform an advanced control while securing safety, such a monitoring control system includes a distributed control system (DCS) which is a process control system that performs a control of an industrial process realized in the plant, and a safety system such as a safety instrumentation system (SIS).
The distributed control system is a system in which a field device (measurer or manipulator) and a controller that controls the field device are connected to each other through communication means and the controller collects measurement data obtained by the field device and manipulates (controls) the field device according to the collected measurement data to control various state amounts in an industrial process. The safety instrumentation system is a system that causes a plant to reliably stop in a safe state in an emergency in order to prevent an explosion accident, an injury accident, or environmental contamination before it occurs, to thereby protect an expensive facility.
During operation of a plant, in a case where an abnormality that may cause an accident occurs (for example, device failure, response abnormalities, explosive gas limit being exceeded, or the like), emergency shut-down (ESD) of the plant is performed by the safety instrumentation system as a primary action for securing safety. For example, in a chemical plant, an action of stopping supply of raw materials to a reactor to stop chemical reaction in the reactor is performed. By performing such an action, it is possible to prevent the occurrence of accidents, to thereby secure safety of the plant.
Japanese Patent Publication No. 4671131 discloses a safety instrumentation system that can manipulate a device which is provided in the safety instrumentation system through a distributed control system while reducing a workload of engineering. Specifically, in the safety instrumentation system, a manipulation according to an instruction with respect to the safety instrumentation system is executed, and an instruction with respect to the distributed control system is converted into an instruction with a format suitable for the safety instrumentation system for execution. Further, in a case where the respective instructions conflict with each other, the instruction with respect to the safety instrumentation system is preferentially executed.
However, in a case where the above-described ESD of the plant is performed, it is necessary to determine a situation of the plant, to perform a suitable action (secondary action) according to the determined situation, and then, to restart the plant. However, in the monitoring control system in the related art, the ESD of the plant which is the primary action is considered, but an action after the ESD of the plant is performed (an action before the plant is restarted) is not considered, and is left for determination of an operator of the plant. Thus, in the related art, a workload of the operator becomes large after the ESD of the plant is performed, and there may be a long period of time until the restart. Specifically, for example, the following problems are caused.
(1) Time Necessary for Determining Situation of Entire Plant
Most of a plant operation screen displays a part of a plant (a part of devices, apparatuses, and facilities installed in the plant), whereas important portions (for example, an important sensor or an emergency shut-down valve) to be checked by an operator of the plant after emergency shut-off of the plant is performed are scattered over the entire plant. Thus, in order to determine situations of the entire plant, the operator of the plant needs to collect information while changing the plant operation screen, and thus, time is necessary for determining the situations of the entire plant.
Further, while the emergency shut-down of the plant is being performed, in a case where an abnormality occurs in a device installed in the plant, it is necessary to specify the device where the abnormality occurs, but in an information collecting method in the related art for collecting information while changing the plant operation screen, time is necessary for the specification. In this way, in the information collecting method in the related art, since the operator needs to perform complicated manipulations in order to collect necessary information, this may lead to wrong recognition and an erroneous operation.
(2) Difficulties in Recognition of Work Progress and Plant State Transition after Emergency Shut-Down
As described above, in the monitoring control system in the related art, an action after emergency shut-down of a plant is performed is not considered. Thus, in the related art, the operator of the plant needs to collectively consider information displayed on a plant operation screen to determine work progress, and thus, it is difficult to determine the work progress. Further, since the determination of the work progress and determination of the plant state transition greatly depend on the performance or experience of an operator of the plant, there is a concern that variations in operation quality, and reduction in overall work safety and efficiency may occur.
(3) Time Taken for Specification of Cause of Emergency Shut-Down
There are rare cases where the number of causes of emergency shut-down of a plant is only one, and instead, there are many cases where the number of causes of emergency shut-down is plural. In particular, in a large-scale plant, the number of causes of emergency shut-down of the plant is plural, in most cases. In the related art, causes of emergency shut-down have been determined by analyzing time series information such as an alarm summary or an event log, but in a case where there are plural causes of emergency shut-down of the plant, time is taken for analysis.
(4) High Degree of Freedom of Manipulation
As described above, since an action after emergency shut-down of a plant is performed is left for determination of an operator of the plant, in a monitoring control system in the related art, the degree of freedom of a manipulation is set to be high to some extent. For example, it is possible to avoid (bypass or reset) interlock (for example, emergency shut-off valve, or the like) by a manipulation of the operator, regardless of states (during emergency shut-down, during shut-down, and during operation) of the plant. If such a manipulation is performed under calm determination of a skilled operator, it does not cause problems. However, if such a manipulation is performed by wrong determination in an emergency when emergency shut-down of a plant is performed, it may cause problems. Thus, in an emergency when emergency shut-down of the plant is performed, for example, if a manipulation for avoiding interlock is limited until appropriate conditions (for example, conditions that the plant can be restarted) are satisfied, it can be considered that it is possible to reduce a workload of an operator and to enhance safety.

Monitoring control system and work support method


Support and positioning means (10) and a cutting head (13) supported on them extend in the operating position of the area of the edge part (14′) of a paper web (14). In the cutting head (13), there is a support surface (16) and at least one nozzle (17), which is set in such a way that the edge part (14′) travels between the support surface (16) and the nozzle (15). The equipment includes mechanical cleaning means (20) and/or a cleaning construction (21) for keeping the support surfaces (16) clean. The cleaning means (20) and/or cleaning construction (21) are arranged on the opposite side of the paper web (14) to the nozzle (17).

The present invention relates to equipment for cutting particularly a paper web with a water jet, which equipment includes support and positioning means and a cutting head supported on them extending in the operating position to the edge part of the paper web, in which there is a support surface arranged at least beneath the edge part and, above it, at least one nozzle for forming a cutting jet with the aid of high-pressure water, which nozzle is set in such a way that the edge part travels between the support surface and the nozzle, in order to cut an edge strip from the paper web.
Finnish publication print number 98346 discloses equipment for cutting the edge of a paper web. In this case, for the actual cutting, the equipment includes a nozzle for forming a cutting jet with the aid of high-pressure water, and a surface arranged beneath the nozzle. In the cutting situation, the paper web travels between the nozzle and the surface, so that the water jet cuts the paper web. There is a hole in the surface for the cutting jet and, at this point beneath the surface, there are outlet connections for removing the cutting water from the equipment. The surface is also termed a table, the location of which together with the nozzle can be adjusted in the cross direction of the paper web.
Despite the hole in the surface and blasts of air direction towards the cutting point and the outlet connections, a lump of paper fibers and fillers accumulates very quickly on the surface after the cutting point. The problem appears particularly when cutting paper grades with a high filler content. The problem is the same, both in the above and in other known equipment. In principle, the equipment is designed in such a way that the paper web is only just separated from the surface by an air cushion. In practice, either the edge strip that has just been cut, or even the entire paper web can touch or catch on the lump, which usually results in a web break. The lump also interferes with the creation of the air cushion. The surface can be manually cleaned during a maintenance shutdown, but when the equipment is operating, the surface cannot be kept clean by means of the known art, despite the air blasts. Reliably operating cutting would, however, be a precondition for successful continuous paper production.

Equipment for cutting particularly a paper web with a water jet


A fuel supply adapter for pumping fuel out of fuel cans through a pump. The adapter is shaped to fit in the pouring neck of the fuel can and be secured therein. The adapter has a U-shaped cross-section with a thick bottom portion and a hollow top portion, and a connector is located inside the top portion so it does not interfere with the closing of the cap of the fuel can. Radial gripping pins are provided inside the bore the handle the adapter.

Fuel cans are used to transport fuel to remote locations, for example for military or fire fighting applications. Cans known in the art are made of metal or plastic, and have pouring necks with inner threads adapted to receive a pouring spout, and outer threads for receiving a closing cap. To deliver fuel to an engine having a fuel supply pump, it is necessary to either transfer the fuel to a can already provided with the appropriate adapter, drill a hole in the top surface of the fuel transport can and install an adapter in the hole, or install a separate adapter over the pouring neck of the can. This latter type of adapters is usually fitted on the outer threads of the pouring neck, and thereby need to be transported apart from the can and installed after the cap has been removed. In each of the above cases, accessories need to be carried apart from the can and the fuel cannot be readily supplied in case of an emergency.


A method comprising: providing a powder composition including at least one ultrafine, spherical thermoplastic polymer powder having a glass transition temperature (Tg) of at least 150 degrees C.; and powder bed fusing the powder composition to form a three-dimensional article.

Additive Manufacturing (AM) is a production technology that is transforming the way all sorts of things are made. AM makes three-dimensional (3D) solid objects of virtually any shape from a digital model. Generally, this is achieved by creating a digital blueprint of a desired solid object with computer-aided design (CAD) modeling software and then slicing that virtual blueprint into very small digital cross-sections. These cross-sections are formed or deposited in a sequential layering process in an AM machine to create the 3D object. AM has many advantages, including dramatically reducing the time from design to prototyping to commercial product. Running design changes are possible. Multiple parts can be built in a single assembly. No tooling is required. Minimal energy is needed to make these 3D solid objects. It also decreases the amount waste and raw materials. AM also facilitates production of extremely complex geometrical parts. AM also reduces the parts inventory for a business since parts can be quickly made on-demand and on-site.
Several different techniques that use polymers have been developed for AM. These include material extrusion processes such as fused filament fabrication as well as powder bed fusing processes such as laser sintering.
Laser sintering is a process by which a three dimensional article may be formed in a layer-wise fashion by selectively projecting a laser beam having the desired energy onto a bed of resin particles. Prototype or production parts may be efficiently and economically produced by this process, which is often times referred to as selective laser sintering. This process has been described in U.S. Pat. Nos. 4,944,817; 5,516,697 and 5,382,308 to Bourell, et al.; U.S. Pat. Nos. 5,304,329 and 5,342,919 to Dickens, Jr. et al. and U.S. Pat. No. 5,385,780 to Lee.
In the laser sintering process, a high power laser is used to fuse polymer powders of the required material type together into the desired three-dimensional shape. SLS processes require a polymer powder of well-defined shape, size and composition in order to make high quality part. The preferred size of the particles is usually below 100 um (Ref: Proceedings of the Institution of Mechanical Engineers, Part L: Journal of Materials: Design and Applications Jul. 1, 2004 vol. 218 no. 3 247-252) and a narrow distribution of particle sizes is also preferred to get optimum precision and density of the sintered part. In addition, for good stacking of the powder particles, it is important that they have a regular, reproducible shape, like spherical morphology. However, the preparation of such powders from thermoplastic resins on an economic, large scale is not straightforward.
Most of the thermoplastic powders used for powder bed fusion processes such as laser sintering are made by (cryogenic) milling and subsequent sieving. This method has the disadvantage that the distribution in particle size is relatively high and that it is difficult to control the exact size of the powder. Also, fines are generated that cannot be used in the SLS process. Finally, the shape of the powder particles is very irregular.
Recently, Sumika Enviro Science has published a patent (Japanese published patent No. JP05288361B2) that describes a method to make spherical polyamide particles for laser sintering. The spherical polyamide particles are polymerized in an aqueous medium maintaining the shape of the spherical particles. Disadvantage of this method is that it seems not possible to add additives such as colorants, flow agents and the like into the particles. However, this reference does not teach or suggest this process would be useful with any thermoplastic polymers that have high glass transition temperatures (Tg). Also, polyamides have low glass transition temperatures (i.e., below 100 degrees C.)
There is still a need to provide suitable thermoplastic polyetherimide powder that can be used in powder bed fusion processes. The present invention offers a solution to that problem.

Powder bed fusing thermoplastic polymers


A support material for thermal dye transfer processes of a polyolefin coated base paper in which the base paper has a roughness of 4 .mu.m or less and the polyolefin coating is applied to the base paper in an amount of 30 g/m.sup.2 or less.

This invention concerns polyolefin coated support material for thermal dye transfer processes, as well as a process for producing same.
The system of thermal dye transfer (dye diffusion thermal transfer "D2T2") makes it possible to reproduce an electronically generated image in the form of a "hard copy". The principle of thermal dye transfer consists of the fact that a digital image is processed with regard to the primary colors cyan, magenta, yellow and black and is converted to corresponding electric signals. These signals are then relayed to a thermal printer and converted into heat. The influence of heat causes the dye to sublime out of the donor layer of an ink ribbon (ink sheet) that is in contact with the receiving material so that it diffuses into the receiving layer.
A receiving material for thermal dye transfer usually consists of a base with a receiving layer applied to the front side of the base. The base may be a plastic film, e.g. polyester film, or a synthetic or resin-coated paper. The main component of the receiving layer is usually a thermoplastic resin with an affinity for the dye from the ink ribbon, such as polyester or acrylic resins. In addition to a receiving layer, other layers are frequently also applied to the front side of the base, such as barrier layers, separation layers, adhesion layer and protective layers.
High demands are made of a dye receiving material so that when they are met a high color density and image sharpness (line sharpness) in the transferred image should be assured. Various methods of optimizing the dye receiving material are known from the state of the art, e.g. by means of the support material or by applying various functional layers and/or by means of a specific choice and composition of the receiving layer.
U.S. Pat. No. 4,774,224 discloses a receiving material whose polyethylene coated paper base must have a surface roughness (Ra) of at most 7.5 .mu.inch.
In Japanese patent application No. 02 229 082 a receiving material is described whereby the polyethylene coated paper support material has a roughness value in the amount of 8 to 160 .mu.inch.
A disadvantage of both of these receiving materials is that not all polyethylene coated paper bases with the claimed roughness values in the polyethylene surface either below or above 7.5 .mu.inch guarantee good results with regard to the color density and image sharpness of the image transferred.
The present invention is based on the problem of developing a support material for thermal dye transfer processes which should assure a receiving material that will permit the production of images with a high resolution (line sharpness) and color density after application of a receiving layer.
This problem is solved by using a base paper with a surface roughness (Ra) of 4 .mu.m or less and applying a polyethylene coating to it in a maximum amount of 30 g/m.sup.2 to receive the support material for thermal dye transfer.
It has surprisingly been found that contrary to the claims made in the state of the art, the roughness of the base paper of a support material for thermal dye transfer processes does play a role in determining the quality of the image transmitted later. It has been found that maintaining a base paper roughness of <4 .mu.m and applying the polyolefin coating in an amount of <30 g/m.sup.2 make it possible to achieve a high color density and resolution (line sharpness) of the transmitted image. This is true not only for high gloss surfaces of the polyolefin coated support material (Ra<0.2 .mu.m), but also for polyethylene surfaces with a greater surface roughness (>0.2 .mu.m).
In a preferred embodiment of this invention, the roughness of the base paper is 2.5 .mu.m or less.
In another preferred embodiment, the amount of polyolefin coating applied is less than 15 g/m.sup.2.
The polyolefin coating may consist of high density polyethylene (HDPE) and/or low-density polyethylene (LDPE) or polypropylene. In addition, the polyolefin coating may contain pigments such as TiO.sub.2 and other additives.
According to this invention, the polyolefin coating contains at least 30% HDPE, preferably 40-80% HDPE.
This invention will be illustrated in greater detail with the help of the following examples.

Support material for thermal dye transfer


The invention relates to a device which changes the Mach number capability of a wind tunnel without permanently altering the existing nozzle of the tunnel. An insert (14) is removably attached to the wall (17) of the existing nozzle expansion area (22) thereby creating a second minimum section (15) upstream of the model test section (21). The added insert (14) may be removed without complicated and expensive changes to the basic wind tunnel. In the embodiment illustrated in FIG. 2, a removable insert (25) is disposed within wind tunnel nozzle walls (17) with a portion of the flow boundary layer being bled off from the tunnel via passageway (29) and tunnel exit (28) to thereby reduce the extent of separated flow normally occuring upstream of the insert contraction section.

Wind tunnels are tubelike structures or passages in which a high-speed wind or gas stream is produced and within which objects such as engines, aircraft, airfoils, rocket missiles or scale models of these objects are placed to investigate the air flow about them and the aerodynamic forces acting upon them. Wind tunnels are designed to simulate forces acting on the test object to which the full size object would be subjected if it were in actual flight.
Most wind tunnel nozzles create a high speed gas stream by supplying a compressed gas, usually air, to a converging-diverging nozzle which accelerates and expands the pressurized gas and forms it into a high speed gas stream. The converging-diverging nozzle usually comprises an inlet section whose cross-sectional area decreases in the direction of flow through the nozzle, and a diverging outlet section, usually of relatively great length, whose cross-sectional area increases in the direction of flow through the nozzle, with a "throat" joining the converging and diverging sections.
As is well known in the high speed gas dynamic art, the speed ultimately attained by the gas accelerated in a well-designed converging-diverging nozzle depends upon the "area ratio" of the nozzle, that is, the ratio of the cross-sectional area of the nozzle passageway at its exit to the cross-sectional area at its throat. Thus, by preselecting the area ratio of the nozzle, the ultimate speed of the gas can be made "transonic" (slightly greater or less than Mach 1, or the speed of sound in air), or "supersonic" (substantially greater than Mach 1), or "hypersonic" (very much greater than Mach 1).
The construction of wind tunnels is expensive and involves elaborate and sophisticated technology. With the supersonic and hypersonic tunnels, the area ratio of the nozzle must be made extremely large in order to produce the desired wind speeds. A large area ratio usually is attained by making the throat area as small as possible rather than by making the exit area larger. This is done in order to make the wind tunnel test section of reasonable size and as inexpensive as possible, and in order to minimize the quantity of gas flow through the nozzle and thus minimize the required capacity of the system used to supply compressed gas to the wind tunnel.
To maximize the area ratio of the nozzle, the cross-sectional area at the throat can be minimized. The throat area is minimized by making the passage connecting the converging and diverging sections as small as possible. Often, the throat height or spacing will be only a few hundredths of an inch. With such minute spacings, the slightest deformation of the throat structure is likely to cause substantial distortion of the gas stream. Consequently, most wind tunnels are designed with nozzles which are relatively immutable.
If the cross-sectional area of the throat section cannot be changed, then the ultimate Mach number capability of the wind tunnel cannot be varied. However, researchers often wish to test aerodynamic models at variable Mach numbers. Thus, designers have sought ways to change the cross-sectional area of the throat section to provide supplementary Mach numbers without sacrificing the precision of the wind tunnel performance characteristics.

Wind tunnel supplementary Mach number minimum section insert

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration


A method, system and computer program product for managing and deploying physical and virtual environments across multiple hardware platforms. A single unit, referred to herein as a cloud construction block, contains both the hardware and software components used to build a cloud computing environment. By having such a single unit contain both the hardware and software components needed to build a cloud computing environment, the user no longer needs to purchase and integrate different hardware and software components. Furthermore, the cloud construction block contains modular pieces of hardware, such as compute hardware, memory hardware, storage hardware and network hardware, that are integrated with management software configured to manage both the hardware and the cloud computing environment in a seamlessly integrated package. Since there is a single management system, the management software allows the user to manage the modular pieces of hardware via a single user interface.

In a cloud computing environment, computing is delivered as a service rather than a product, whereby shared resources, software and information are provided to computers and other devices as a metered service over a network, such as the Internet. In such an environment, computation, software, data access and storage services are provided to users that do not require knowledge of the physical location and configuration of the system that delivers the services.
Currently, if a user desires to build a cloud computing environment, the user has to purchase different hardware and software components which are then integrated amongst each other. For example, in an x86 environment, the user purchases individual physical machines, where each physical machine would either have internal storage or require the user to purchase and configure external storage. Furthermore, switches would have to be purchased to connect the network devices in the cloud computing environment and separately configured in order to network them together.
Such a process in building a cloud computing environment is inefficient and time consuming.

Unified cloud computing infrastructure to manage and deploy physical and virtual environments

International Business Machines Corporation


Among other things, assays and methods of diagnosis and treatment of disease (e.g., Alzheimer""s disease) based on the surprising observation of an interaction between amyloid xcex2 or its aggregates with the sodium channel are provided. In particular, methods to identify compounds that modulate this interaction are provided, as well as methods of diagnosis and treatment that are based on this interaction.

The present invention provides, among other things, assays and methods of diagnosis and treatment that are based on the surprising observation of an interaction between amyloid xcex2 or its aggregates with sodium channels. In particular, the present invention provides methods to identify compounds that modulate this interaction, and methods of diagnosis and treatment that are based on this interaction.
Certain neurodegenerative diseases such as Alzheimer""s disease and Down""s syndrome are characterized by the presence of insoluble aggregates of amyloid xcex2 (Axcex2). This 39-43 amino acid peptide is derived by abnormal proteolysis from the Amyloid Precursor Protein (APP). It is well known that the amyloid xcex2 aggregates/plaques widely found in the brain and intraneuronal neurofibrillary tangles of Alzheimer""s disease patients can modulate neurite outgrowth, synaptogenesis, synaptic plasticity or cause neuronal death (Mattson et al, Trends Neurosci., 16, 406-415 (1993)). The mechanism(s) by which these effects are accomplished remain elusive, however (Frazer et al, Trends Neurosci., 20, 67-72 (1997)).
Presently, one theory maintains that these deleterious effects may originate from amyloid xcex2""s ability to promote chronic calcium influx into neurons through modulation of neuronal calcium ion channels (Daidson et al., Brain Res., 643, 324-327 (1994)), or to form transmembrane cation-permeable channels (Kawahara et al., Biophysiol. J., 73, 67-75 (1997)) that indiscriminately allow calcium, sodium, and other cations to flood a cell""s interior and destroy its calcium homeostasis. Calcium channel blockers such as nimodipine that can cross the blood-brain barrier have been shown to slow the progression of Alzheimer""s disease in some patients (Tollefson, Biol. Psychiatry, 27, 1133-1142 (1990)). Similarly, zinc cation, which is known to bind at specific amyloid xcex2 1-40 sites (Bush et al, Science, 265, 1464-1467 (1994)), can block the calcium influx through amyloid xcex2 1-40 channels (Arispe et al., Proc. Natl. Acad. Sci., 93, 1710-1715 (1996)).
In addition, amyloid xcex2 aggregates have been shown to induce abnormal potassium ion channel activity. In cultured hippocampal neurons, amyloid xcex2 opens a calcium-sensitive, large conductance potassium channel (i.e., iberitoxin-sensitive BK) (Furukawa et al., Nature, 379, 74-78 (1996)), which could lead to chronic loss of cytoplasmic potassium and destroy the ability of the neurons to generate and propagate action potentials critical for brain signaling functions. Such aberrant potassium channel activity has in fact been noted in Alzheimer""s disease patients (Etchebemgaray et al., Proc. Natl. Acad. Sci., 90, 8209-8213 (1993)). Likewise, in the cultured cholinergic septal cell line SN56, amyloid xcex2 (e.g., amyloid xcex2 1-40) causes cell death by impacting a TEA-sensitive potassium channel (Colom et al., J. Neurochemistry, 70, 1925-1934 (1998)).
These studies suggest that amyloid xcex2 aggregates exert their effects through multiple targets. None of the targets that have been described, however, would result in the rapid and complete inhibition of neuronal electrical impulses critical for brain function that is observed with advanced stage Alzheimer""s disease. Furthermore, the ion channel studies described above were performed on cultured neurons, whose properties may have been changed significantly through dedifferentiation in culture conditions. Therefore, the data currently available likely does not represent the true response of native neurons.
Recent genetic studies have shown that mutations in the amyloid protein precursor and presenilin genes affect the processing and production of amyloid xcex2 and thus are related to age of onset and susceptibility to Alzheimer""s disease. Additional studies have shown that variants in ApoE genes also affect susceptibility and age of onset for Alzheimer""s disease. Spontaneous Alzheimer""s disease is hypothesized to be under the control of other genes and environmental factors that have yet to be identified.
Additionally, inhibition of amyloid xcex2 aggregation, and hence toxicity, is believed to be beneficial therapeutically in the treatment of Alzheimer""s disease. Several reports have appeared providing evidence that small, diffusable aggregates (Lambert et al., Proc. Natl. Acad. Sci., 95, 6448-6453 (1998); PCT International Application WO 98/33815), and protofibrils (Harper et al., Chem. Biol., 4, 119-125 (1997); Harper et al., Chem. Biol., 4, 951-959 (1997); Walsh et al., J. Biol. Chem., 272, 22364-22374 (1997)), and not the completely fibrillar peptide, might be the Axcex2 species toxic to living cells. The physical differences in the alleged toxic species identified by these different research groups xe2x80x9csupports the concept that different Axcex2 assemblies have distinct neurobiological activities, which may be manifested differently using an electrophysiological readoutxe2x80x9d (Hartley et al., J. Neuroscience, 19, 8876-8884 (1999)). Thus, the etiology of Alzheimer""s disease may be quite complex, and may warrant a variety of different avenues of diagnosis and treatment.
Along these lines, U.S. Pat. No. 5,876,948 describes screening methods to identify inhibitors of the neurotoxic effect of amyloid xcex2. In particular, the ""948 patent purportedly provides a method of screening candidate compounds, wherein the method comprises obtaining a cell such as a primary neuron, a neuronal cell, or a cell developmentally derived from neuronal tissue. The cell is contacted with a candidate compound in the presence of a neurotoxin selected from the group consisting of amyloid xcex21-38, xcex21-40, xcex21-43, and xcex229-35, and it is determined whether the compound reduces the effect of the neurotoxin (e.g., reduces cell death), or reduces accumulation of amyloid xcex2 on the cell surface. Accordingly, this patent provides no information on how to screen for compounds that target cell events that precede cell death, apart from accumulation of the peptide on the cell surface. A need thus remains for useful assays to screen for compounds that exert protective effects at a stage prior to cell death mediated by amyloid xcex2, and for compounds that exert their effect apart from interference with amyloid xcex2 deposition on the cell surface. Furthermore, the ""948 patent does not appear to consider any effect of the aggregation state of amyloid xcex2 on neurotoxicity. A related patent, U.S. Pat. No. 5,137,873, claims a method for treating a disease that is characterized by accumulation of amyloid xcex2, which comprises administration of a therapeutically effective amount of a tachykinin agonist such as substance P.
U.S. Pat. No. 5,892,018 pertains to DNA sequences encoding a novel subfamily of amiloride-sensitive sodium channel proteins from the human central nervous system. PCT International Application WO 98/54316 describes a new class of sodium channel protein that may function as a receptor for endogenous transmitters. Both the ""018 patent and the ""316 application suggest that ion channels may play some role in the pathogenesis or treatment of Alzheimer""s disease (see, ""316 application, pages 1 and 15; see, ""018 patent, column 1, lines 50-54). However, neither document presents any assay for diagnosis of Alzheimer""s disease, much less any methods for its treatment.
Thus, there remains a need for further understanding of the functioning of amyloid xcex2 or its aggregates, and means to diagnose, predict, prevent and treat diseases, disorders, and conditions that result from amyloid xcex2 or its aggregates. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention relates to a surprising observation of an interaction between amyloid xcex2 or its aggregates with sodium channels. Based on this novel and unexpected interaction, the present invention provides a method for identifying compounds that modulate the interaction of amyloid xcex2 or its aggregates with a sodium channel, wherein the method preferably comprises contacting a cell which comprises a sodium channel with amyloid xcex2 or its aggregates in the presence and in the absence of a test compound, and then determining whether there is any impact on the sodium channel in the presence of the test compound as compared with in the absence, with a compound that exhibits an impact being considered a modulator of the interaction of amyloid xcex2 or its aggregates with said sodium channel. In preferred embodiments, the impact on the sodium channel is assessed by either examining resting membrane potential, action potential, or measuring the fast inward sodium current. Preferably as employed in the invention, the cell is a neuronal cell, or is a non-neuronal cell, as described herein.
The method of identifying compounds that modulate the interaction of amyloid xcex2 or its aggregates with a sodium channel also can be carried out according to the invention wherein the method comprises obtaining a first cell that produces amyloid xcex2 or its aggregates, obtaining a second cell comprising a sodium channel, contacting the second cell with the first cell in the presence and absence of a test compound, and determining the activity of the sodium channel in the presence of said test compound as compared with in the absence, wherein a test compound that impacts activity is considered a modulator of the interaction of amyloid xcex2 or its aggregates with said sodium channel. Preferably one of the first and second cells is a neuronal cell and the other is a non-neuronal cell, or both of the first and second cells are either a neuronal cell or a non-neuronal cell.
Also, preferably the method of identifying compounds that modulate the interaction of amyloid xcex2 or its aggregates with a sodium channel can be carried out according to the invention wherein the method comprises the steps of obtaining a composition comprising a purified sodium channel, contacting the sodium channel with amyloid xcex2 or its aggregates in the presence and absence of a test compound, and determining the activity of the sodium channel in the presence of the test compound as compared with in the absence, wherein a test compound that impacts activity is considered a modulator of the interaction of amyloid xcex2 or its aggregates with the sodium channel.
The invention also provides a method for diagnosing Alzheimer""s disease (or prion disease) in a mammal suspected of having Alzheimer""s disease (or prion disease), the method comprising the step of measuring the activity of a sodium channel in a cell of the mammal, wherein reduced activity of the sodium channel is correlated with the existence of an Alzheimer""s disease state (or a prion disease state).
The invention further provides a method of screening a mammal for susceptibility to Alzheimer""s disease, comprising the steps of:
(a) isolating a cell from the mammal, the cell comprising a sodium channel; and
(b) measuring activity of the sodium channel in the absence and in the presence of amyloid xcex2 protein;
wherein reduced activity of the sodium channel in the presence of amyloid xcex2 as compared to in the absence is correlated with a susceptibility to developing Alzheimer""s disease.
Additionally, the invention provides a method for preventing, treating, or reversing diseases such as Alzheimer""s disease and prion disease in a mammal, wherein the method preferably comprises contacting a sodium channel of the mammal with a compound that protects the sodium channel from a negative impact of amyloid xcex2 or its aggregates. This method optionally is carried out with use of a compound that opens the sodium channel.
Furthermore, the invention provides for the use of a compound that modulates the interaction of amyloid xcex2 or its aggregates with cellular sodium channels for the manufacture of a medicament for the treatment of a neurological disorder (e.g., Alzheimer""s disease).
Additional features and variations of the invention will be apparent to those skilled in the art from the entirety of this application, including the detailed description, and all such features are intended as aspects of the invention. Likewise, features of the invention described herein can be recombined into additional embodiments that also are intended as aspects of the invention, irrespective of whether the combination of features is specifically mentioned above as an aspect or embodiment of the invention. Also, only such limitations which are described herein as critical to the invention should be viewed as such; variations of the invention lacking limitations which have not been described herein as critical are intended as aspects of the invention.
In addition to the foregoing, the invention includes, as an additional aspect, all embodiments of the invention narrower in scope in any way than the variations specifically mentioned above. Although the applicant(s) invented the full scope of the claims appended hereto, the claims appended hereto are not intended to encompass within their scope the prior art work of others. Therefore, in the event that statutory prior art within the scope of a claim is brought to the attention of the applicants by a Patent Office or other entity or individual, the applicant(s) reserve the right to exercise amendment rights under applicable patent laws to redefine the subject matter of such a claim to specifically exclude such statutory prior art or obvious variations of prior art from the scope of such a claim. Variations of the invention defined by such amended claims also are intended as aspects of the invention.

Method for identifying compounds that modulate the interaction of amyloid beta or its aggregates with a voltage gated sodium channel


An apparatus for testing an electrical component, having a simulation unit for producing a simulation signal, a plurality of test units, and at least one electrical connecting device, whereby the simulation unit and the plurality of test units are connected or connectable to each other in an electrically conductive fashion via the at least one connecting device, and the at least one connecting device has at least one electrical switch device, which is situated to make or break an electrical connection between the plurality of test units.

Field of the Invention
The present invention relates to an apparatus for testing an electrical component having a simulation unit for producing a simulation signal, a plurality of test units, and at least one electrical connecting device. The simulation unit and the plurality of test units are connected or connectable to each other in an electrically conductive fashion via the at least one electrical connecting device.
Description of the Background Art
An apparatus for testing an electrical component is frequently referred to as a "testing apparatus" or a "simulator system."
An extremely wide range of embodiments of apparatuses for testing electrical components such as a control system for a motor vehicle or an automation unit are known from the conventional art and are primarily used in applied research, industrial development, and other application areas, in particular the fields of mechatronics, automotive applications, aerospace engineering, systems and process engineering, and other technical fields that require the execution of process control tasks. In this context, therefore, a "control system" can be understood to mean a technical apparatus that essentially can be used for measurement, control, and/or regulation. In the broadest sense, it is generally an electrical, for example program-controllable system that is usually referred to as a "control unit," particularly in the field of automotive applications. In this regard, a control system is not restricted only to the system theory definition of a control, but is also usually used to carry out regulation procedures.
Apparatuses for testing a control system that are known from the conventional art frequently have a simulation unit for producing, measuring, and/or analyzing a simulation signal, a plurality of test units for connecting the control system, and at least one connecting device such as a bus bar or bus system. In the conventional art, there are known bus bars that have one or more electrical conductors that is/are separated from other electrical conductors by an insulator such as an insulating plastic and/or an air gap. In this case, the bus bar can be a component of a printed circuit board. A printed electrical conductor path of the printed circuit board can, for example, on the one hand be partially enclosed in plastic and on the other hand, can be partially insulated from other electrical conductors by an air gap. A connecting device can, for example, be provided with two separate conductors.
In such apparatuses, it is disadvantageous that parasitic properties of the connecting device interfere with and/or alter the simulation signals. In other words, the parasitic properties of the bus bar or bus system cause a distortion of the simulation, which in the end can result in an error-encumbered test of the control system. In this regard, test results can be distorted and lead to incorrect results.
For purposes of error simulation, many components can be connected to the connecting device, which promotes the distortion of test results. Parasitic capacitances increase with the number of components connected and can have an effect across various switch cabinets over which the apparatus is distributed. It can also be necessary for high currents to be supported in the connecting device, which is why sufficient conductor cross-sections and/or sufficient conductor path widths (e.g. in printed circuit boards) must be selected for the connecting device. Furthermore, the use of power semiconductors is on the rise; these have switching behaviors whose timing is defined in a comparatively precise way. Both of these approaches, i.e. conductor paths for high currents and power semiconductors, promote the occurrence of parasitic capacitances that can have an interfering impact on sensitive signals. As a rule, the parasitic capacitance of bus bars increases with the number of interconnected components.
An error simulation can be desirable both at the level of a single control unit and also at the level of the combination. In this context, the design of the apparatus must be adapted to the respective test. A generic test design is only possible to a limited degree since the design itself, particularly the connecting device, can further distort the test results. In addition, testing a plurality of separate control units simultaneously and independently of one another is only possible with such a design after a corresponding configuration. For example, components in different racks can be connected to produce a test setup.
In this case, simultaneous and independent error simulations in the different racks are not possible.
Examples of a rack include a switch cabinet or a so-called 19-inch cabinet. As a rule, a rack can include a plurality of so-called sub-racks, where the sub-racks can be embodied, for example, as so-called subassembly supports, for example, as so-called 19-inch subassembly supports.
Various simulation signals can be used for testing an electrical component. For this reason, signals that are to be conveyed via the connecting device can be almost arbitrarily embodied and range from small sensor signals, also referred to as "low-level" below to large actuator signals, also referred to as "high-level" below.
A conceptual assignment of sensor signals to the high-level or low-level categories can differ depending on the embodiment of the test device. For example, it is possible to define all signals that have a maximum electrical voltage amount Umax≤10 mV and/or that have a maximum electrical current amount of Imax≤10 mA for assignment to the group of low-level signals. An exemplary determination for the group of high-level signals can define that all signals that have a maximum electrical voltage amount of Umax≥5 V and/or that have a maximum electrical current amount of Imax≥100 mA must be assigned to the group of high-level signals.
In this illustrated example, the signals that are quantitatively larger than the low-level signals, but quantitatively smaller than the high-level signals are, according to the above mentioned exemplary determination, nevertheless assigned to the group of high-level signals. The high-level range and low-level range can in principle be arbitrarily defined, but the high-level range always has larger values (voltage, current, and/or power) than the low-level range.
As a rule, a technical separation of the signals according to high and low level is not practically possible, for example, because at the time of the project planning for the apparatus, the boundary conditions are not known or a temporary implementation of a short circuit of a high-level signal to the low-level signal is explicitly required for testing purposes, for example in order to use the testing apparatus to simulate, for an electrical component to be tested, appropriate technical boundary conditions in the event of an error.

Apparatus having simulation unit for producing simulation signal for testing an electrical component

dSPACE digital signal processing and control engineering GmbH


An aircraft traffic pattern computer employing a slotted frame having a window surrounded by a compass rose which is movable in relation to the frame about a pivot point, the slotted frame being adapted for holding a placard having a pair of surfaces upon which various aircraft movement patterns are shown about a reference point and a reference line such that alignment of the reference point with the center of the compass rose and alignment of the reference line with the compass rose proper provides at least one selected course heading for an aircraft.

The present invention relates to a novel aircraft traffic pattern computer for aiding a pilot during aircraft maneuvers requiring specific course headings.
Piloting an aircraft demands exacting coordination between hand and foot, and the senses, particularly the sense of sight. During steady flight operations the pilot may easily read a map or use other means of obtaining the position, course, and heading of the aircraft. However, during the most exacting maneuvers such as takeoff, landing, confinement within a holding pattern and the like, the pilot is hard pressed to quickly calculate the values for course headings with great exactitude.
There have been devices in the form of computers which are able to calculate to air speed, duration of flight, and the effective wind on air speed and course of the aircraft. Certain devices have been provided which visually indicate holding patterns in relation to a pivot point. In this regard, the "Holding Pattern Computer" manufactured by Jeppesen and Co., Denver, Colo. is an example of such a device.
There is a need for a air traffic pattern computer which may be quickly set and easily interpreted for the purposes of providing information concerning flight patterns of an aircraft.


Metal powder Ta and/or Nb, with or without one or metals from the group Ta, Nb, Ti, Mo, W, V, Zr and Hf, is made in a fine powder form by reduction of metal oxide by contact with a gaseous reducing agent, preferably an alkaline earth metal, to near complete reduction, leaching, further deoxidation and agglomeration, the powder so produced being sinterable to capacitor anode form and processable to other usages.

This invention relates to the production of tantalum, niobium and other metal powders and their alloys by the reduction of the corresponding metal oxide with gaseous active metals such as Mg, Ca and other elemental and compound reducing materials, in gaseous form.
Tantalum and niobium are members of a group of metals that are difficult to isolate in the free state because of the stability of their compounds, especially some of their oxides. A review of the methods developed to produce tantalum will serve to illustrate the history of a typical manufacturing process for these metals. Tantalum metal powder was first produced on a commercial scale in Germany at the beginning of the 20th Century by the reduction of the double salt, potassium heptafluorotantalate (K2TaF7) with sodium. Small pieces of sodium were mixed with the tantalum containing salt and sealed into a steel tube. The tube was heated at the top with a ring burner and, after ignition, the reduction proceeded quickly down the tube. The reaction mixture was allowed to cool and the solid mass, consisting of tantalum metal powder, unreacted K2TaF7 and sodium, and other products of the reduction was removed by hand using a chisel. The mixture was crushed and then leached with dilute acid to separate the tantalum from the components. The process was difficult to control, dangerous, and produced a coarse, contaminated powder, but nevertheless pointed the way to what became the principal means of production of high purity tantalum in later years.
Commercial production of tantalum metal in the United States began in the 1930""s. A molten mixture of K2TaF7 containing tantalum oxide (Ta2O5) was electrolyzed at 700xc2x0 C. in a steel retort. When the reduction was completed, the system was cooled and the solid mass removed from the electrolysis cell, and then crushed and leached to separate the coarse tantalum powder from the other reaction products. The dendritic powder was not suitable for use directly in capacitor applications.
The modern method for manufacturing tantalum was developed in the late 1950""s by Hellier and Martin (Hellier, E. G. and Martin, G. L., U.S. Pat. No. 2,950,185, 1960). Following Hellier and Martin, and hundreds of subsequently described implementations or variations, a molten mixture of K2TaF7 and a diluent salt, typically NaCl, is reduced with molten sodium in a stirred reactor. Using this system, control of the important reaction variables, such as reduction temperature, reaction rate, and reaction composition, was feasible. Over the years, the process was refined and perfected to the point where high quality powders with surface area exceeding 20,000 cm2/gm are produced and materials with surface area in the 5000-8000 cm2/gm range being typical. The manufacturing process still requires the removal of the solid reaction products from the retort, separation of the tantalum powder from the salts by leaching, and treatments like agglomeration to improve the physical properties. Most capacitor grade tantalum powders are also deoxidized with magnesium to minimize the oxygen content (Albrecht, W. W., Hoppe, H., Papp, V. and Wolf, R., U.S. Pat. No. 4,537,641, 1985). Artifacts of preagglomeration of primary particles to secondary particle form and doping with materials to enhance capacitance (e.g. P, N, Si, and C) are also known today.
While the reduction of K2TaF7 with sodium has allowed the industry to make high performance, high quality tantalum powders thus, according to Ullmann""s Encyclopedia of Industrial Chemistry, 5th Edition, Volume A 26, p. 80, 1993, the consumption of tantalum for capacitors had already reached a level of more than 50% of the world production of tantalum of about 1000 tons per annum, whereas there had essentially been no use of niobium for capacitors, even through the raw material base for niobium is considerably broader than that for tantalum and most of the publications on powder preparation and capacitor manufacturing methods mention niobium as well as tantalum.
Some of the difficulties of applying that process to niobium are as follows:
While the manufacturing process of the type shown in Hellier and Martin (U.S. Pat. No. 2,950,185) for the reduction of potassium heptaflorotantalate by means of sodium in a salt melt is available in principle for the production of high purity niobium powders via potassium heptafluoroniobate, it doesn""t work well in practice. This is due, in part, to the difficulty of precipitating the corresponding heptafluoroniobate salts and is due, in part, to the aggressively reactive and corrosive nature of such salts, such that niobium produced by that process is very impure. Further, niobium oxide is usually unstable. See, e.g., N. F. Jackson et al, Electrocomponent Science and Technology, Vol. 1, pp. 27-37 (1974).
Accordingly, niobium has only been used in the capacitor industry to a very minor extent, predominantly in areas of with lower quality requirements.
However, niobium oxide dielectric constant is about 1,5 times as high as that of a similar tantalum oxide layer, which should allow in principle, for higher capacitance of niobium capacitors, subject to considerations of stability and other factors.
As for tantalum itself, despite the success of the K2TaF7/sodium reduction process, there are several drawbacks to this method.
It is a batch process subject to the inherent variability in the system; as a result, batch to batch consistency is difficult. Post reduction processing (mechanical and hydro-metallurgical separations, filtering) is complex, requiring considerable human and capital resources and it is time consuming. The disposal of large quantities of reaction products containing fluorides and chlorides can be a problem. Of fundamental significance, the process has evolved to a state of maturity such that the prospects for significant advances in the performance of the tantalum powder produced are limited.
Over the years, numerous attempts were made to develop alternate ways for reducing tantalum and similar metal compounds, including Nb-compounds, to the metallic state (Miller, G. L. xe2x80x9cTantalum and Niobium,xe2x80x9d London, 1959, pp. 188-94; Marden, J. W. and Rich, M. H., U.S. Pat. No. 1,728,941, 1927; and Gardner, D., U.S. Pat. No. 2,516,863 1946; Hurd, U.S. Pat. No. 4,687,632). Among these were the use of active metals other than sodium, such as calcium, magnesium and aluminum and raw materials such as tantalum pentoxide and tantalum chloride. As seen in Table I, below, the negative Gibbs free energy changes indicate that the reduction of the oxides of Ta, Nb and other metals with magnesium to the metallic state is favorable; reaction rate and method determine the feasibility of using this approach to produce high quality powders on a commercial scale. To date, none of these approaches were commercialized significantly because they did not produce high quality powders. Apparently, the reason these approaches failed in the past was because the reductions were carried out by blending the reducing agents with the metal oxide. The reaction took place in contact with the molten reducing agent and under conditions of inability to control the temperature of highly exothermic reactions. Therefore, one is unable to control morphology of the products and residual reducing metal content.
The use of magnesium to deoxidize or reduce the oxygen content of tantalum metal is well known. The process involves blending the metal powder with 1-3 percent magnesium and heating to achieve the reduction process. The magnesium is in the molten state during a portion of the heating time. In this case, the objective is to re-move 1000-3000 ppm oxygen and only a low concentration of MgO is produced. However, when a much greater quantity of tantalum oxide is reduced a large quantity of magnesium oxide is generated. The resulting mixture of magnesium, tantalum oxide and magnesium oxide can under conditions of poorly controlled temperature, form tantalum-magnesium-oxygen complexes that are difficult to separate from the tantalum metal.
It is a principal object of the invention to provide a new approach to production of high performance, capacitor grade tantalum and niobium powders that provides a means of eliminating one or more, preferably all, the problems of traditional double salt reduction and follow on processing.
It is further object of the invention to enable a continuous production process.
It is a further object of the invention to provide improved metal forms.
Another object is to provide niobium/tantalum alloy powders of capacitor grade quality and morphology.
We have discovered that the prior art problems can be eliminated when metal oxides such as Ta2O5 and Nb2O5 and suboxides in massive amounts are reduced with magnesium in gaseous form, substantially or preferably entirely. The oxide source should be substantially or preferably entirely in solid. The oxide is provided in the form of a porous solid with high access throughout its mass by the gaseous reducing agent.
The metals that can be effectively produced singly or in multiples (co-produced) through the present invention are in the group of Ta, Nb, and Ta/Nb alloy, any of these alone or with further inclusion of added or co-produced Ti, Mo, V, W, Hf and/or Zr. The metals can also be mixed or alloyed during or after production and/or formed into useful compounds of such metals. The respective stable and unstable oxide forms of these metals can be used as sources. Metal alloys may be produced from alloyed oxide precursors, e.g. resulting from coprecipitation of a suitable precursor for the oxide.
Vapor pressures of some of the reducing agents are given as follows:
The temperature of reduction varies significantly depending on the reducing agent used. The temperature ranges for reduction of (Ta, Nb) oxide are: with Mg(gas)xe2x88x92800-1,100xc2x0 C., Al(gas)xe2x88x921,100-1,500xc2x0 C., Li(gas)xe2x88x921,000-1,400xc2x0 C., Ba(gas)xe2x88x921,300-1,900xc2x0 C.
Different physical properties as well as morphology of the metal powder produced by reduction can be achieved by variations of temperature and other conditions of processing within the effective reduction range.
One embodiment of the invention includes a first step of reducing an oxide source of selected metal(s) substantially to free 80-100% (by weight) of the metal values therein as primary powder particles, then leaching or other steps of hydrometallurgy to separate the metal from residual reducing agent oxide and other byproducts of the reduction reaction and from residual condensed reducing agent (optionally), followed by one or more deoxidation steps under less concentrated reagent conditions than in the first gross reduction step (and with better tolerance of molten state of the reducing agent), then further separation as might be needed.
In accordance with this first embodiment the invention provides for a single stage reduction process for the production of metal powders as cited above, comprising the steps of:
(a) providing an oxide or mixed oxides of the metal(s), the oxide itself being in a form that is traversable by gas,
(b) generating a gaseous reducing agent at a site outside the oxide mass and passing the gas through the mass at an elevated temperature,
(c) the reactants selection, porosity of the oxide, temperature and time of the reduction reaction being selected for substantially complete reduction of the oxide(s) to free the metal portion thereof, the residual oxide of reducing agent formed in the reaction being easily removable,
whereby a high surface area, flowable metal powder is formed in a process that essentially avoids use of molten state reducing agent in production of metal or alloy powder.
Preferred reducing agents used in this reduction process of the first embodiment are Mg, Ca and/or their hydrides. Particularly preferred is Mg.
Preferred is the production of Nb and/or Ta metals, optionally alloyed with each other and/or with alloying elements, selected from the group consisting of Ti, Mo, W, Hf, V and Zr.
A second embodiment of the invention provides for a two-stage reduction process, comprising the steps of:
(a) providing an oxide or mixed oxide of the metal(s), the oxide being in a form that is traversible by gas,
(b) passing a hydrogen containing gas, alone or with gaseous diluent, through the mass at an elevated temperature in a manner for partial reduction of the oxide(s),
(c) the porosity of the oxide, temperature and time of reduction reaction being selected to remove at least 20% of the oxygen contained in the oxide to produce a suboxide,
(d) reducing the suboxide with reducing metal(s) and/or hydrides of one or more reducing metals, thereby substantially completely reducing the oxide to free the metal portion thereof.
Preferrably the reducing metals and/or metal hydrides are brought into contact with the suboxide in gaseous form.
Preferred reducing metals in the second reduction step of this second embodiment are Mg and/or Ca and/or their hydrides. Particularly preferred is Mg.
Reduction temperature preferably (for Mg) is selected between 850xc2x0 C. up to normal boiling point (1150xc2x0 C.)
The process according to the present invention (both embodiments) specifically has been developed to provide capacitor grade tantalum and niobium and tantalum nio-bium alloy powders and Ta/Nb materials or application of equivalent purity and/or morphology needs. The greatest gap of the state of the art is filled in part by the availability of capacitor grade niobium enabled by this invention, but a segment of the tantalum art is also enhanced thereby. In all cases the tantalum and/or niobium may be enhanced by alloying or compounding with other materials during the reduction reaction production of the tantalum/niobium or thereafter. Among the requirements for such powders is the need for a high specific surface presintered agglomerate structure of approximately spherical primary particles which after pressing and sintering results in a coherent porous mass providing an interconnected system of pore channels with gradually narrowing diameter to allow easy entrance of the forming electrolyte for anodization and manganese nitrate solution [Mn(NO3)2] for manganization.
The reduction of oxides with gaseous reducing agents at least during the initial reduction phase allows for easy control of temperature during reduction to avoid excessive presintering. Furthermore, as compared to prior art proposals using liquid reducing metals, the controlled reduction with gaseous reducing metals does not lead to contamination of the reduced metal with the reducing metal by incorporation into the reduced metal lattice. It has been found that such contamination mainly occurs during the initial reduction of (in case of Nb) Nb2O5 to NbO2. This at first appeared surprising because niobium suboxide (NbO2) contains only 20% less oxygen than niobium pentoxide (NbO2.5). This effect was traced back to the fact that the suboxide forms a considerably more dense crystal lattice than the pentoxide. The density of NbO2.5 is 4.47 g/cm3, whilst that of NbO2 is 7.28 g/cm3, i.e., the density is increased by 1.6 times by the removal of only 20% of the oxygen. Taking into account the different atomic weights of niobium and oxygen, a reduction in volume of 42% is associated with the reduction of NbO2.5 to NbO2. Accordingly, Applicants state (without limiting the scope of the invention thereby) that the effect according to the invention can be explained in that during the reduction of the pentoxide magnesium in contact with the oxide is able to diffuse relatively easily into the lattice, where it has a high mobility, whereas the mobility of magnesium in the suboxide lattice is significantly reduced. Accordingly, during the reduction of the suboxide the magnesium substantially remains on the surface and remains accessible to attack by washing acids.
This even applies in case of a controlled reduction with gaseous magnesium. Obviously in this case reduction occurs also during the critical initial reduction to suboxide only at the surface of the oxide, and magnesium oxide formed during reduction does not enter the oxide or suboxide powder. Preferred temperature during reduction with magnesium gas is between 900 and 1100xc2x0 C., particularly preferred between 900 and 1000xc2x0 C.
Temperature may be increased up to 1200xc2x0 C. after at least 20% of the oxygen is removed to improve presintering.
The reduction of the pentoxide with hydrogen produces a suboxide which is already sintered with the formation of agglomerates comprising stable sintered bridges, which have a favorable structure for use as a capacitor material.
Lower temperatures necessitate longer times of reduction. Moreover, the degree of sintering of the metal powders to be produced can be adjusted in a predeterminable manner by the choice of reduction temperature and reduction time. The reactors are preferably lined with molybdenum sheet or by a ceramic which is not reduced by H2, in order to prevent contamination.
Furthermore, the reduction time and reduction temperature should be selected so that at least 20% of the oxygen is removed from the pentoxide. Higher degrees of reduction are not harmful. However, it is generally not possible to reduce more than 60% of the oxygen within practicable time scales and at tolerable temperature.
After a degree of reduction of 20% or more has been reached, the suboxide is present. According to this process embodiment the reduction product is preferably still held (annealed) for some time, most preferably for about 60 to 360 minutes, at a temperature above 1000xc2x0 C. It appears that this enables that the new, dense, crystal structure can be formed and stabilized. Since the rate of reduction decreases very considerably with the degree of reduction, it is sufficient to heat the suboxide at the reduction temperature under hydrogen, optionally with a slight decrease in temperature. Reduction and annealing times of 2 to 6 hours within the temperature range from 1100 to 1500xc2x0 C. are typically sufficient. Moreover, reduction with hydrogen has the advantage that impurities such as F, Cl and C, which are critical for capacitor applications, are reduced to less than 10 ppm, preferably less than 2 ppm.
The suboxide is subsequently cooled to room temperature ( less than 100xc2x0 C.) in the reduction apparatus, the suboxide powder is mixed with finely divided powders of the reducing metals or metal hydrides and the mixture is heated under an inert gas to the reduction temperature of the second stage. The reducing metals or metal hydrides are preferably used in a stoichiometric amount with respect to residual oxygen of the acid earth metal suboxide, and are most preferably used in an amount which is slightly in excess of the stoichiometric amount.
One particularly preferred procedure consists of using an agitated bed in the first stage and of carrying out the second stage, without intermediate cooling, in the same reactor by introducing the reducing metals or metal hydrides. If magnesium is used as the reducing metal, the magnesium is preferably introduced as magnesium gas, since in this manner the reaction to form metal powder can readily be controlled.
After the reduction whether according to the one-stage or to the two-stage reduction process to metal is complete, the metal is cooled, and the inert gas is subsequently passed through the reactor with a gradually increasing content of oxygen in order to deactivate the metal powder. The oxides of the reducing metals are removed in the manner known in the art by washing with acids.
Tantalum and niobium pentoxides are preferably used in the form of finely divided powders. The primary grain size of the pentoxide powders should approximately correspond to 2 to 3 times the desired primary grain size of the metal powders to be produced. The pentoxide particles preferably consist of free-flowing agglomerates with average particle sizes of 20 to 1000 xcexcm, including a specific preference of a narrower range of most preferably 50 to 300 xcexcm particle size.
Reduction of niobium oxide with gaseous reducing agents can be conducted in an agitated or static bed, such as a rotary kiln, a fluidized bed, a rack kiln, or in a sliding batt kiln. If a static bed is used, the bed depth should not exceed 5 to 15 cm, so that the reducing gas can penetrate the bed. Greater bed depths are possible if a bed packing is employed through which the gas flows from below. For tantalum, preferred equipment choices are described in Example 2 and the paragraph between Examples 2 and 3, below, with reference to FIGS. 1-4.
Niobium powders which are particularly preferred according to the invention are obtained in the form of agglomerated primary particles with a primary particle size of 100 to 1000 nm, wherein the agglomerates have a particle size distribution as determined by Mastersizer (ASTM-B822) corresponding to D10=3 to 80 xcexcm, particularly preferred 3 to 7 xcexcm, D50=20 to 250 xcexcm, particularly preferred 70 to 250 xcexcm, most preferably 130 to 180 xcexcm and D90 =30 to 400, particularly preferred 230 to 400 xcexcm, most preferably 280 to 350 xcexcm. The powders according to the invention exhibit outstanding flow properties and pressed strengths, which determine their processability to produce capacitors. The agglomerates are characterized by stable sintered bridges, which ensure a favorable porosity after processing to form capacitors.
Preferably niobium powder according to the invention contains oxygen in amounts of 2500 to 4500 ppm/m2 surface and is otherwise low in oxygen, up to 10,000 ppm nitrogen and up to 150 ppm carbon, and without taking into account a content of alloying metals has a maximum content of 350 ppm of other metals, wherein the metal content is mainly that of the reducing metal or of the hydrogenation catalyst metal. The total content of other metals amounts to not more than 100 ppm. The total content of F, Cl, S is less than 10 ppm.
Capacitors can be produced from the niobium powders which are preferred according to the invention, immediately after deactivation and sieving through a sieve of mesh size 400 xcexcm. After sintering at a pressed density of 3,5 g/cm3 at 1100xc2x0 C. and forming at 40 V these capacitors have a specific capacitance of 80,000 to 250,000 xcexcFV/g (as measured in phosphoric acid) and a specific leakage current density of less than 2 nA/xcexcFV. After sintering at 1150xc2x0 C. and forming at 40 V, the specific capacitor capacitance is 40,000 to 150,000 xcexcFV/g with a specific leakage current density of less than 1 nA/xcexcFV. After sintering at 1250xc2x0 C. and forming at 40 V, capacitors are obtained which have a specific capacitor capacitance (as measured in phosphoric acid) of 30,000 to 80,000 xcexcFV/g and a specific leakage current density of less than 1 nA/xcexcFV.
The niobium powders which are preferred according to the invention have a BET specific surface of 1.5 to 30 m2/g, preferably of 2 to 10 m2/g.
Surprisingly it has been found that capacitors can be made from Nb/Ta-alloy powders in way that the capacitors have an appreciably higher specific capacitance obtained from capacitors made from pure Nb-and pure Ta-powers or anticipated for an alloy be simple linear interpolation. Capacitances (xcexcFV) of capacitors with sintered Nb-powder anodes and sintered Ta-powder anodes having the same surface area are approximately equal. The reason is that the higher dielectric constant of the insulating niobium oxide layer (41 as compared to 26 of tantalum oxide) is compensated by the larger thickness of the oxide layer per volt (anodization voltage) formed during anodization. The oxide layer thickness per volt of Nb is about twice as thick as that formed on Ta (about 1.8 nm/V in the case of Ta and about 3.75 nm/V in the case of Nb). The present invention can provide a surface related capacitance (xcexcFV/m2) of alloy powder capacitors which is up to about 1.5 to 1.7 higher than the expected value from linear interpolation between Nb powder capacitors and Ta powder capacitors. This seems to indicate that oxide layer thickness per volt of anodization voltage of alloy powders of the invention is closer to that of Ta, whereas the dielectric constant of the oxide layer is closer to that of Nb. The foregoing surprisingly high capacitance of the alloy may be associated with a different structural form of oxide of alloy components compared to structure of oxides on surfaces of pure Nb powders. Indeed, preliminary measurements have revealed that oxide layer growth of a 15 at.-%Taxe2x80x9485 at.-% Nb alloy is almost 2.75 nm/volt.
The present invention accordingly further comprises an alloy powder for use in the manufacture of electrolyte capacitors consisting primarily of niobium and containing up to 40 at.-% of tantalum based on the total content of Nb and Ta. Alloy powder in accordance with the present invention shall mean that the minor Ta-component shall be present in an amount greater than the amount of ordinary impurity of niobium metal, e.g. in an amount of more than 0.2% by weight (2000 ppm, corresponding to 2 at.-% for Ta).
Preferrably, the content of Ta is at least 2 at.-% of tantalum, particularly preferred at least 5 at.-% of tantalum, most preferably at least 12 at.-% of tantalum, based on the total content of Nb and Ta.
Preferably the content of tantalum in the alloy powders in accordance with the invention is less than 34 at.-% of tantalum. The effect of capacitance increase is gradually increasing up to a ratio of Nb- to Ta-atoms of about 3. Higher than 25 at.-% Ta based on the total content of Nb and Ta does only slightly further increase the effect.
The alloy powders according to the invention preferably have BET-surfaces multiplied with the alloy density of between 8 and 250 (m2/g)xc3x97(g/cm3), particularly preferred between 15 and 80 (m2/g)xc3x97(g/cm3). The density of the alloy material may be calculated from the respective atomic ratio of Nb and Ta multiplied by the densities of Nb and Ta respectively.
The effect of capacitance increase of alloying is not limited to powders having the structure of agglomerated spherical grains. Accordingly the alloyed powders in accordance of the invention may have a morphology in the form agglomerated flakes preferably having have a BET-surface times density of between 8 and 45 (m2/g)xc3x97(g/cm3).
Particularly preferred alloy powders are agglomerates of substantially spherical primary particles having a BET-surface times density of 15 to 60 (m2/g)xc3x97(g/cm3). The primary alloy powders (grains) may have mean diameters of between 100 to 1500 nm, preferrably 100 to 300 nm. Preferrably the deviation of diameter of primary particles from mean diameter is less than a factor 2 in both directions.
The agglomerate powders may have a mean particle size as determined in accordance with ASTM-B 822 (Mastersizer) as disclosed for niobium powders above.
Particularly preferred alloy powders have a ratio of Scott density and alloy density of between 1.5 and 3 (g/inch3)/(g/cm3).
Any production method known in the art for the production of capacitor grade tantalum powder may be used, provided that a precursor is used which is an alloyed precursor containing niobium and tantalum approximately at the atomic ratio of Nb and Ta desired in the metal powder alloy instead of precursor containing tantalum alone.
Useful alloy precursors may be obtained from coprecipitation of (Nb,Ta)-compounds from aqueous solutions containing water soluble Nb- and Ta-compounds e.g. coprecipitation of (Nb, Ta)-oxyhydrate from aqueous solution of heptafluoro-complexes by the addition of ammonia and subsequent calcination of the oxhydrate to oxide.
Flaked powders may be obtained by electron beam melting of a blend of high purity tantalum and niobium oxides, reducing the molten ingot, hydriding the ingot at elevated temperature, and comminuting the brittle alloy, dehydriding the alloy powder and forming it into flakes. The flakes are thereafter agglomerated by heating to 1100 to 1400xc2x0 C. in the presence of a reducing metal such as Mg, optionally with doping with P and/or N. This process for the manufacture of xe2x80x9cingot derivedxe2x80x9d powder is generally known from U.S. Pat. No. 4,740,238 for the production of tantalum flaked powder and from WO 98/19811 for niobium flaked powder.
Particularly preferred Nb-Ta-alloy powders having the morphology of agglomerated spherical grains are produced from mixed (Nb, Ta)-oxides by reduction with gaseous reducing agent as described herein.
The metal powders produced are suitable for use in electronic capacitors and other applications including, e.g. the production of complex electro-optical, superconductive and other metal and ceramic compounds, such as PMN structures and high temperatures form metals and oxide.
The invention comprises the said powders, the methods of producing such powders, certain derivative products made from such powders and methods for making such derivative products.
The capacitor usage can be accompanied by other known artifacts of capacitor production such as doping with agents to retard sinter densification or otherwise enhance end product capacitance, leakage and voltage breakdown.
The invention enables several distinct breakthroughs in several of its various fields of application.
First, the well known high performance tantalum powders for making computer/telecommunications grade solid electrolyte, small size capacitors (high capacitance per unit volume and stable performance characteristics) can now be made with substantial net savings of cost, complexity and time.
Second, other reactive metalsxe2x80x94especially Nb and alloys, e.g. Taxe2x80x94Nb, Taxe2x80x94Ti, Nbxe2x80x94Ti, can be introduced as replacement for Ta in capacitors in certain applications with a cost saving or as replacement for the high end Al market with much better performance, particularly enabling much smaller sizes for equivalent capacitance and use of solid electrolyte. Commercial aluminum electrolytic capacitors use wet electrolyte systems.

Metal powders produced by the reduction of the oxides with gaseous magnesium


A unitary shingling apparatus prepares uniformly shingled sets of forms from a continuous, preprinted roll. The apparatus numbers the individual forms in groups of predetermined count, wherein the forms in each group receive identical numbers. Each group is then shingled into its own set. The forms are numbered while still on the web, then separated from the web by a reciprocating knife, transported individually to a predetermined indexing position, and then transferred, glued and shingled onto a shingling conveyor in the shingled, overlapped sets.

This invention relates to machines for assembling and fastening forms in shingled sets, and more particularly to a machine which is especially adapted for rapidly and continuously numbering, assembling, and fastening forms from a continuous web thereof into shingled sets of predetermined count. The forms in each set are numbered with related, usually identical numbers, while the number printed on the forms in one set differs from that on any other set.
Such shingled sets of forms, often called "controlled" sets, are becoming increasingly popular. The positive numbering of the forms provides for precise control and accounting for every form which is issued. For example, such sets are used in hospitals in connection with controlled substances such as narcotics. A certain initial quantity of the substance may be "assigned" to a given set of the forms (for instance 20 forms), and each time a dose of the substance is administered, a precise record is entered on one of the forms in the set. The shingled forms are usually attached to the front of a large receipt or control ledger onto which the information entered on the individual sheets or forms is copied. Further, that initial quantity of the controlled substance, and the corresponding particular controlled set of forms, become the responsibility of one individual (for example, a particular nurse). Thus "phantom" forms, perhaps stolen from a supply room, cannot be used to obtain unauthorized material because the forms are numbered and identifiable.
In prior art shingling machines, the individual forms are commonly supplied in stacks of discrete sheets which have been pre-numbered in groups of predetermined count. The forms in each group have identical numbers so that they can be shingled into corresponding sets as described. The stacks are prepared in several phases, each of which requires operator intervention, thereby interrupting the continuity of the preparation thereof. For example, a printing press may typically be equipped with a sheeter to separate the individual forms from the continuous web as it comes out of the printing press. The stacks of individual sheets are then transferred to another machine where they are numbered in their groups and re-stacked. These in turn are transferred to and fed into a sheet shingling machine.
It might be thought that the forms could be directly numbered on the printing press itself. Prior experience, however, has shown that as a practical matter this is mechanically too difficult. It is true that consecutive numbering is commonly done in which each form is numbered one higher than the last. This is an entirely different matter, however, from numbering the forms in groups in which the forms in each group receive identical or related numbers.
Known numbering presses which number consecutively have press speeds, for example, of 500 feet per minute, which is substantially slower than presses which do not require printing this variable information. Every time such a press is started, there are potential registration problems between the fixed information and the printing of the variable (number) information. Further, every time one roll is spliced to another (which is usually done while the press continues operating at or near full speed), a form must be rejected due to the splice therein. Also, the individual rolls themselves commonly have one or two mill splices in them, leading to additional rejected forms.
These problems are serious enough on presses which number consecutively. In the preparation of controlled sets, in which exact numbers of splice-free forms must be provided, it is impractical to try to number these forms on the initial printing press. The frequent interruptions and restarting which would be occassioned by the splices would be intolerable. Not unimportant, also, is the lack of numbering equipment which can satisfactorily advance intermittently (for example, once every twenty forms) at these press speeds.
A need therefore remains for a method and apparatus compatible with continuous full speed operation of printing presses for the production of controlled sets of shingled forms. Preferably, such a method and apparatus will allow the individual forms as they first come from the printing press to be rewound onto a roll at full speed, as a continuous web, rather than requiring the web of forms to be fed more slowly directly into a sheeter. Then, in a single operation, these rolls should be transferable to a machine which, in a unitary apparatus, will number and process the forms into the shingled, overlapped, controlled sets.

Roll fed shingling machine with predetermined numbering


A self-regulating PTC heater assembly and a method of manufacturing the heater assembly is disclosed. PTC heater assembly includes a plurality of positive temperature coefficient devices, a plurality of spacers located between the positive temperature coefficient devices, a pair of metallic electrodes and a heat shrink tubing surrounding the pair of electrodes, PTC elements and spacers to hold the PTC elements and electrodes in place during assembly. A metallic sheath is compressed about the heat shrink tubing to establish uniform electrical contact between the PTC elements and the electrodes, to increase the thermal efficiency of the heater and to protect the heater assembly from physical damage.

PTC heater assemblies are well known in the art. A PTC or positive temperature coefficient device is a semiconductor which has an electrical resistance which is temperature sensitive. The electrical resistance of the PTC device varies proportionately with temperature. PTC devices are available as ceramics or polymers and are well known for use in temperature sensors, current limiters and heaters. Their usefulness as a heater is particularly attractive due to the fact that a self regulating heater can be constructed. When a current is passed through a PTC device, it produces heat by virtue of the internal resistance of the PTC device and the resultant current is similar to that of other resistance heaters except that at a certain predetermined temperature (curie point or autostabilizing temperature), the resistance begins to increase virtually exponentially causing the power to decrease thereby autostabilizing the PTC device at a particular predetermined temperature. The temperature at which the PTC device autostabilizes will vary depending upon the specific PTC device. In the present invention, the autostabilizing temperature of the PTC device is useful because it can be established at a temperature which is below the ignition temperature of the heaters environment.
PTC heaters have not been particularly successful in the prior art when used in hostile environments such as in the chemical processing industry. In such hostile environments, strong oxidizers, free halogen ions and strong reducing acids contribute to the degregation of PTC assemblies.
In conventional resistance heaters utilized in hostile environments, the use of plastics and in particular fluoropolymers has proven successful but such plastics were unpractical with respect to their use in protecting PTC devices because a plastic with sufficient thickness to resist the hostile environment generally produces sufficient thermal resistance to increase the temperature of the PTC device above its autostabilizing temperature rendering it ineffective as a heating device.


A method of treating an aqueous system is disclosed. The method may be used to treat sewage streams as well as aqueous streams in pulp and paper mill processing. The method includes the steps of adding a polymeric composition to an aqueous stream. The composition is an anionically modified acrylamide polymer in an aqueous medium. The polymer is formed by reacting an acrylamide polymer with phosphorous acid, and has at least 5 mole percent phosphonate groups based on the acrylamide content of the polymer, and has a molecular weight of at least about 40,000. the pH of the composition is adjusted to at least about 7.7.

1. Field of the Invention
The invention relates generally to water treatment polymers and, more particularly, the invention relates to anionic polymers useful as flocculants and methods of preparing and using the same.
2. Description of Related Technology
Considerable expenditures are made each year for materials used in water treatment, such as flocculants and coagulants used to clarify raw waters for potable and industrial use. Flocculants are used to clarify municipal and industrial effluents to remove pollutants and to improve the efficiency of papermaking processes by increasing the first pass retention of fiber and filler when paper is formed on a paper machine and for other process clarification needs. Therefore, the demand for more efficient, inexpensive water treatment compositions for use as flocculants is increasing.
Anionic high molecular weight polymers are widely used as flocculants to clarify waters for potable and industrial use. Some commercially available anionic polymers include pendant carboxyl units connected to a backbone chain. These units function as active sites for linking with solid particles suspended in the water to be treated. The active carboxyl units along the chain begin to become deprotonated at about pH 4.6 and deprotonation increases as pH increases. Accordingly, the deprotonated sites become anionic, exhibiting a single negative charge per carboxyl pendant. In the flocculant-type applications described above, it would therefore be advantageous to increase the negative charges per active pendant unit to increase polymer activity and efficiency.
In water stabilization applications, the use of phosphono-methylated amine compounds to sequester polyvalent metal ions, especially calcium and magnesium, has been the subject of investigation for many years. It has been found that four phosphono units can be attached to a diamine base while five phosphono units may be attached to a triamine base to provide additional sequestering ability. Amine-based phosphonates have enjoyed commercial success as sequesterants and chelating agents in industrial systems needing control over such metal ions as calcium, magnesium, iron, and manganese.
In the past, a Mannich-type reaction has been used to prepare phosphono-methylated amines using phosphorous acid, formaldehyde and ammonia or amine compounds. See Moedritzer & Irani, J. Org. Chem., 31, 1603-1607 (1966). It has also been disclosed that certain polymers containing phosphonate units may be copolymerized with other materials such as acrylamide, acrylic acid and acrylates to produce scale and corrosion inhibitors for water systems such as cooling, boiler and gas scrubbing systems. See Becker, U.S. Pat. No. 4,446,028 (May 1, 1984) and Hoots et al., U.S. Pat. No. 4,904,413 (Feb. 27, 1990).

Method of water treatment using polyacrylamide-phosphonate flocculants


The present invention relates to the field of protein display libraries and library screening. In preferred embodiments, the present invention provides a three component system for display comprising a cell surface molecule, an adapter molecule and a display molecule.

Protein binding domains can be predicted from sequence data, however redesigning proteins with improved or altered binding affinities often requires testing of a number of variants of the re-designed protein. Currently the best method for obtaining proteins with desired binding affinities is to generate and screen a protein library including such variants that can include rationally redesigned proteins, randomly altered proteins, or a combination thereof. Libraries of many types of protein, such as immunoglobulins and scaffold proteins and receptors or receptor ligands have successfully been constructed and screened for binding affinity.
There are many methods to screen libraries, but one of the most common methods is the phage display method, which comprises fusion of a protein library to the coat proteins of filamentous phage (e.g., Huse et al. '89; Clackson et al., '95; Marks et al., '92). Fusions are made most commonly to a minor coat protein, called the gene III protein (pIII), which is present in three to five copies at the tip of the phage. The fused library is then displayed on the surface of the viral particle. The page display library can then be screened against, an immobilized target protein. However, one major drawback of this method is that target proteins that bind the library with very high affinity are not always identified because the conditions required to elute the bound phase usually denature the phage particle such that it becomes impossible to identify the protein of interest. Another draw back of phage display libraries is the requirement that the target protein be immobilized on a solid surface, which can lead to difficulties in determining the actual affinity of a target protein for the phage display protein. Furthermore, some proteins of interest require post-translational modifications, such as glycosylation, methylation, or disulfide binding, that cannot be achieved when expressed in a phage particle.
An alternative method for screening protein libraries is to display the library on the surface of bacterial cells. This method solves many of the drawbacks associated with phage display, but has its own problems. One problem with bacterial display is that the bacterial capsule can cause steric hindrance to proteins displayed on the bacterial surface. Also, bacteria do not contain the machinery to properly fold eukaryotic proteins, so the protein of interest may not always be expressed within the bacterium. Similar to the problem in phage, bacteria cannot provide post-translational modifications, like disulfide binding, to a eukaryotic protein.
Wittrup et al. (U.S. Pat. Nos. 6,699,658 and 6,696,251) have developed a method for a yeast cell display library. This is a two component system, wherein the first component involves expressing one subunit of the yeast mating adhesion protein, agglutinin, which is anchored to the yeast cell wall. The second component involves expressing a protein library fused to a second subunit of the agglutinin protein which forms high affinity disulfide bonds to the first agglutinin subunit. The protein library fused to the agglutinin is thus displayed on the surface of the cell. The library can then be screened. This method allows for the proper folding and post-translational modification of eukaryotic proteins.
Rakestraw et al. (PCT/US2008/003978) have developed a three component system for displaying a protein library on the surface of yeast cells. The first component involves expressing a protein library fused to a biotin-binding peptide, the second component involves modifying the yeast cell wall to express biotin, and the third component involves binding avidin to the biotin expressed on the cell surface. The fused protein library is then biotinylated and secreted from the yeast cell and binds to the avidin on the yeast cell surface, thus displaying the protein library on the surface of the yeast cell. One potential drawback of this system is that avidin non-specifically binds all biotin. Another potential drawback is that avidin contains four binding sites, which may cause steric hindrance thus preventing the biotinylated protein library from binding to the cell surface bound avidin. Similarly, the avidin molecule may bind the biotinylated protein library before binding the biotinylated yeast cell wall, thereby hindering the binding of the avidin to the yeast cell wall. Additionally, this method contains the added complication of having to biotinylate the protein library within the yeast cell. This necessary extra step requires further modification to the yeast cell. It is well established that the more modifications are made to a biological system, the less likely it is that the system will behave as designed. In addition, since avidin/streptavidin is multivalent, care must be taken to not cross-link the biotinylated cells. Finally, biotin/streptavidin and biotin/avidin are used in a number of commercially available labeling kits. Such kits would be difficult to use in such a biotin/avidin display system.
The prior art lacks a simple, efficient system capable of specifically binding a secreted protein library using an adapter molecule that binds to the protein library and to the surface of a eukaryotic cell through different binding moieties.