Petroleum residua are combined with water or an aqueous solution to form an emulsion which is then treated with ultrasound at a sufficient intensity and for a sufficient period of time to cause a conversion of the heavy hydrocarbon components of the residua to lighter components, thereby shifting the entire boiling point curve to lower boiling points. This allows one to draw a greater proportion of usable oil from the residua.

1. Field of the Invention
This invention resides in the field of crude oil and crude oil fractions, and particularly petroleum residuum fractions. In particular, this invention addresses reformation processes for deriving usable oil from, or increasing the usable oil that can be extracted from, petroleum residua.
2. Description of the Prior Art
Crude oil is the largest and most widely used natural resource in the world, serving as a source of a wide range of fuels for consumer and industrial use as well as chemicals for use as raw materials in products used every day worldwide. Petroleum residua (or "resids ") are the heavy fraction remaining after petroleum crudes are distilled at atmospheric pressure or at reduced pressure, i.e., the residue left after the most readily accessible components of the petroleum are extracted. Resids are highly complex in composition, including components of high molecular weight as well as polynuclear aromatics, coke, asphaltenes, resins, small ring aromatics, and saturates. Unfortunately, resids are of extremely limited utility. A variety of conversion processes have been developed to increase the utility of, or obtain useful products from, resids. These processes include separations, thermal conversion, hydroconversion or hydrotreating, and fluid catalytic cracking. The processes that are the most economical, however, result in a carbonaceous byproduct that is even heavier than the starting resid, including further formation of polynuclear aromatics. Processes that involve the use of catalysts are also costly due to the cost of the catalysts themselves and the expense of recovering and recycling the catalysts after use. Also, the petroleum industry is continually seeking ways to utilize resids of lower quality and lower cost due to a continual need for new sources of crude oil and to continuing pressure from the public and regulatory agencies to make use of these resids rather than to dispose of them. As a result, processes that can economically and effectively convert these resids to lighter components are continually needed.

This patent is subject to a terminal disclaimer.

Conversion of petroleum resid to usable oils with ultrasound


An information processing apparatus has a request determining part determining a request type for streaming contents from a communicating apparatus, a copy number managing part managing the number of copies permissible for the communicating apparatus, a stream number managing part managing the number of streams now in communication, a key-selection processing part selecting a first key corresponding to transfer of streaming contents permissible for one or more of copies or a second key corresponding to transfer of streaming contents for copies with generation management restriction or not permissible for copies, an encryption processing part generating encrypted streaming contents using the first or the second key, and a packet processing part generating a packet that includes the encrypted streaming contents and key information selected by the key-selection processing part and to include information on the number of copies to the packet when the first key is selected.

With the spread of computer networks such as broadband and wireless LAN, the products called as digital information equipment having a communication function (digital home appliances, hereinafter) have been gradually widespread. Moreover, with the start of terrestrial digital broadcasting and the halt of analog broadcasting, it is predicted that TVs, set-top boxes (STB), DVD recorders, etc., for digital broadcasting will be further widespread in the near future. If a plurality of digital home appliances are connected to a network, users can view or listen to contents via a network, thereby enhancing usability.
Here, contents intend to various types of digital data, i.e. moving-picture data such as MPEG2 or MPEG4, audio data, stream data, text data, still-picture data, etc. Contents composed of these types of data have a feature in that it can be easily copied with no degradation. Therefore, special care is needed for the copyright of contents. For example, a regulation of Japanese digital broadcasting stipulates that a recorder can record contents received via a broadcast wave in internal equipment up to ten times in total. This is commonly called "dubbing 10". Moreover, the current regulation stipulates that when equipments which received a broadcast wave output streaming contents to a network, "the number of streams to be simultaneously output be less than eight for each receiver" with respect to transmission of generation management information.
Incidentally, various proposals have been made in order to protect copyright of contents and enhance usability of contents.
As described above, according to the current regulation, equipment for receiving Japanese digital broadcasting can record streams in internal equipment up to ten times and output eight streams at the maximum to a network. Under the current regulation, if it is supposed to store eight streams output to a network in each of separated recording apparatuses, eight copies can be made, and the number of copies made in the equipment which received Japanese digital broadcasting under the regulation of dubbing 10 is added. As a result, 18 copies can be made in total at the equipment itself and the other equipment. As described above, under the current regulation, users cannot freely make 18 copies. More specifically there is a restriction on the storage place in that 10 copies at the maximum are permitted for the user's equipment and eight copies at the maximum are permitted for the other equipment. In this way, usability under the current regulation is not sufficient.

Information processing apparatus and information processing method


The invention relates to aircraft floor assemblies and to methods for their assembly. In one embodiment, an aircraft comprises at least one fuselage section and at least one floor section. At least one system component is installed to the floor section prior to installation of the floor section in the fuselage of the aircraft. In another embodiment, a floor section adapted to be installed in an aircraft includes at least one system component installed to the floor section while it is outside of the aircraft. In yet another embodiment, a method is disclosed for assembling an aircraft. The method comprises installing at least one system component to a floor section, and installing the floor section into a fuselage section of the aircraft.

Cabin floors for larger commercial and military aircraft typically comprise a number of individual, light weight panels that are assembled together while inside the aircraft. The panels are formed from composite material having a relatively low density core and may number in excess of 100 for a typical aircraft. Each panel has four edges that may be individually sealed to the edges of adjoining panels using sealing tape, as part of the assembly process. Because the panels use a low density core, they may have limited toughness and durability, and must be carefully handled during the assembly process in order to avoid deforming the face sheets, and particularly their edges. Additionally, each panel may require multiple fasteners to secure it to the framework in the aircraft, or to the adjoining panels.
The technique described above for forming a cabin floor is not only labor intensive, but requires a relatively large number of parts, and may also require rework of the panels during the installation process. Moreover, after the aircraft is placed in service, the sealing tape may need to be replaced from time-to-time, and/or individual panels may need to be repaired or replaced, for instance, when the cabin floor carpet is replaced or partially removed in order to service aircraft systems. Finally, a cabin floor of the type discussed may have less stand-alone structural strength than a monolithic, one-piece floor because it is formed from many individual panels.
Present aircraft floors also may make installation of certain aircraft system components more difficult because the floor is installed in the aircraft before installation of the system components. The floor may therefore obstruct areas of the aircraft such as, without limitation, cargo bays, where components such as electrical boxes, wiring, ducting, and other components, are commonly installed. Assembly personnel may be required to install these system components while inside the cargo bays, where space and clearances may be tight, due in part to a previously installed overhead cabin floor that includes supporting beams extending downward into the cargo area. Thus, the installation of the system components after the floor has been installed may be difficult, time consuming, labor intensive, require numerous parts, and may require mounting the components in areas that may be less than optimal for future service and/or maintenance of the components.
Accordingly, there is a need for an aircraft floor and related aircraft assembly method that overcomes one or more of the disadvantages and limitations mentioned above. There is also a need for a unitary aircraft floor that is self-supporting, in order to reduce or eliminate the need for underlying support beams.


According to one general aspect, a method of using an application may include receiving a request, from a user, to display at least a portion of a business service context regarding a business service. The method may also include receiving, from a database, an aggregated database result regarding the business service. The aggregated database result may include the requested business service context. The business service context may include information from a plurality of other applications. The method may further include displaying a graphical user interface element that displays at least a portion of the information included by the business service context.

Business service management (BSM) is generally a methodology for monitoring and measuring information technology (IT) services from a business perspective. Often, BSM includes a set of management software tools, processes and methods to manage the IT of a business or businesses. BSM tools are generally designed to help IT organizations view and manage technology environments, in order to better support and maintain the main services they provide to the business.
Generally, businesses execute or run a number of applications or systems (e.g., computers, etc.). Often these applications may collect or have access to different types of data. For example, an email system may include an email server application which is executed by one or more physical computers or servers. In such an example, a Help-Desk application may collect or access data referring to various user's experiences and troubles with an email system. Conversely, the email server application itself my collect or access data regarding how the email system processes emails (e.g., user not found errors, failure to deliver errors, number of emails sent, etc.). A third business application may monitor the system resources (e.g., processor load, memory utilization, network bandwidth, etc.) used by the physical computer or computes executing the email server application.
Traditionally, these pieces of information may be dispersed across various IT or business applications. As such, a traditional BSM set of management tools may not be able to provide a user or BSM software with a full view of the status or health of the email system. Generally, an application, even a BSM application, may only access data that is accessible by that application. Therefore, the Help-Desk application, in a traditional environment, would not be able to access the data collected by the email server application (e.g., user not found errors, etc.) or the system resource monitoring application (e.g., network load, etc.). As a result, a user of the Help-Desk application would have a limited view or understanding of the state or status of the email system. Such issues may occur for other IT applications.


An estate and gift tax estimator having a two-sided pocket part consisting of separate layers of semi-rigid material, whereby each layer is provided with a series of windows for viewing an insert card which is slideably engaged between the two layers defining the pocket. The insert card has a series of columns of numerical data corresponding in location to the windows on the outer layers, such that at least one column corresponds to taxable assets and the other column is a calculation of the estate tax applicable to that amount of taxable assets thereby allowing for the estimation of taxes between the calculated levels. The columns are adjacent to each other such that when a number corresponding to a taxable asset appears in a window, the corresponding estate tax estimate appears in the adjacent window. The insert card is interchangeable and may be oriented in any manner in the pocket part while providing accurate estimations of the estate tax.

1. Field of the Invention
The present invention relates to slide rule calculators, and more particularly, to a slide rule estimator having a pocket type cover and an insert card which allows for estimation of estate and gift tax corresponding to one's taxable assets for a broad range of asset figures.
Slide rule calculators having an insert card enclosed within a pocket type cover employing several windows for viewing numbers or calculations are well known in the art. These devices generally are bulky and inconvenient to carry due to their size. Moreover, they generally tend to calculate rather than estimate various figures ranging from taxes to personal data such as assets and net worth, requiring a large amount of comparative data necessary to provide accurate calculations, which consequently leads to a large and bulky calculator. Alternatively, smaller calculators may be available, but will have too large a range between calculations to accomodate the small size. Many of these devices employ one or more insert cards, or in an effort to reduce the size of the device employ a print font of a very small size, which often proves difficult to read. Many are single-sided, and those that are double-sided, generally require the insert card to correspond to one particular side of the calculator. Inserting the card in a backwards position, would result in inaccurate calculations, or inserting in an upside down position would result in the numbers failing to line up with their corresponding windows, making the device useless.
2. Discussion of the Prior Art
In the prior art, various types of slide rule calculators are disclosed, which reflect the various types of data to be calculated. These various devices, however, are subject to several disadvantages which, in many cases, inconvenience the user, and in some cases, require careful and specialized reading of the data to be calculated, since the device carries highly specialized numerical data.
Rees, U.S. Patent No. 4,324,975, discloses a hand held calculating device for calculating federal income taxes and various other tax information. The device comprises two sides secured together with a pocket therebetween, and each side is provided with a plurality of windows for calculating various tax numbers. An insert card is provided which slides up and down to reveal various numbers corresponding to various tax calculations. This device however, is a complicated device requiring precise input data to calculate the correct tax. In addition, the insert card must be properly fitted into the slot between the two outer layers and the card must be aligned with the proper side facing in a proper direction since the windows do not line up from one side to the other. Consequently, putting the insert card in backwards would either result in the numbers being only partially revealed, or worse, the calculation would be incorrect.
Murphy, U.S. Patent No. 3,933,305, discloses an asset value calculator, which comprises a two layer hand held calculator having a number of insert strips which are housed in the pocket between the two layers. Various windows are provided on one side of the outer layer, such that the strips align themselves with each other inside the pocket, and data along the bottom edge of one corresponds to data on the top edge of another. This device suffers similar disadvantages to the Rees device, as described above, and it is apparent that misaligning the insert strips will present inaccurate data, and presenting the wrong side of an insert strip at a window will reveal no data.
Bromberg, U.S. Patent No. 4,132,348, discloses a slide calculator having a single sheet construction which is detachable from itself and reassembled by a user to form a pocket and insert card. The piece forming the pocket part comprises a foldable sheet such that two sides are formed with a large window and a small window on each side. The second piece is foldable to form the insert card which is provided with a plurality of numbers on either side. The insert card is placed between the two sides of the pocket part, but must be placed in a specific configuration so that the numbers align with the windows. It is apparent that this device also suffers from the disadvantage that if the insert card is improperly positioned, the numerical data will either be inaccurate or will not be revealed to the user.
The novel slide estimator pursuant to the present invention obviates the disadvantage of the prior art and provides an accurate and easy-to-use tax estimator which eliminates the risk of inaccurate or incorrect calculation of the numerical data through the estimation of data, rather than precise calculation. A range of taxable asset levels are provided with the corresponding tax level, which is an accurate calculated tax for that particular asset. The device of the present invention allows for the accurate and fast estimation of taxes between asset levels provided for on the device.
The device has two sides forming a pocket with each side having at least two windows located an equal distance from each side edge that forms a length side of the device. The windows on the front side correspond in location to the windows on the back side and also correspond in size. An insert card is provided with columns of numbers on the front and on the back which correspond to the number of windows provided on the respective sides of the pocket part. The columns on the front also correspond in location to the columns of numbers on the back, thereby allowing the card to be inserted in any manner so that the numbers always align with the windows and are easily read by a user. The columns of numbers on the insert card always align with the windows on the front and back of the device so that the numerical data may always be accurately estimated regardless of how the insert card is positioned in the pocket part.


A method of removing a ceramic coating, such as a thermal barrier coating (TBC) of yttria-stabilized zirconia (YSZ), from the surface of a component, such as a gas turbine engine component. The method generally entails subjecting the ceramic coating to an aqueous solution of ammonium bifluoride, optionally containing a wetting agent, such as by immersing the component in the solution while maintained at an elevated temperature. Using the method of the invention, a ceramic coating can be completely removed from the component and any cooling holes, with essentially no degradation of the bond coat.

The present invention relates to methods for removing ceramic coatings. More particularly, this invention is directed to a method for removing a layer of thermal-insulating ceramic material, such as yttria-stabilized zirconia (YSZ) from the surface of a component intended for service at high temperatures, such as a component of a gas turbine engine.
Components located in certain sections of gas turbine engines, such as the turbine, combustor and augmentor, are often thermally insulated with a ceramic layer in order to reduce their service temperatures, which allows the engine to operate more efficiently at higher temperatures. These coatings, often referred to as thermal barrier coatings (TBC), must have low thermal conductivity, strongly adhere to the article, and remain adherent throughout many heating and cooling cycles.
Coating systems capable of satisfying the above requirements typically include a metallic bond coat that adheres the thermal-insulating ceramic layer to the component. Metal oxides, such as zirconia (ZrO2) partially or fully stabilized by yttria (Y2O3), magnesia (MgO) or other oxides, have been widely employed as the material for the thermal-insulating ceramic layer. The ceramic layer is typically deposited by air plasma spraying (APS), low pressure plasma spraying (LPPS), or a physical vapor deposition (PVD) technique such as electron beam physical vapor deposition (EBPVD), which yields a strain-tolerant columnar grain structure. Bond coats are typically formed of an oxidation-resistant diffusion coating such as a diffusion aluminide or platinum aluminide, or an oxidation-resistant alloy such as MCrAlY (where M is iron, cobalt and/or nickel). Aluminide coatings are distinguished from MCrAlY coatings, in that the former are primarily aluminide intermetallic while the latter are a metallic solid solution that contains a mixture of phases, including xcex2NiAl.
Though significant advances have been made with coating materials and processes for producing both the environmentally-resistant bond coat and the thermal-insulating ceramic layer, there is the inevitable requirement to remove and replace the ceramic layer under certain circumstances. For example, removal may be necessitated by erosion or impact damage to the ceramic layer during engine operation, or by a requirement to repair certain features such as the tip length of a turbine blade. Removal of the ceramic layer may also be necessitated during component manufacturing to address such problems as defects in the coating, handling damage and the need to repeat noncoating-related manufacturing operations which require removal of the ceramic, e.g., electrical-discharge machining (EDM) operations.
Current state-of-the-art repair methods often result in removal of the entire TBC system, i.e., both the ceramic layer and bond coat, after which the bond coat and ceramic layer must be redeposited. One such method is to use abrasives in procedures such as grit blasting, vapor boning and glass bead peening, each of which is a slow, labor-intensive process that erodes the ceramic layer and bond coat, as well as the substrate surface beneath the coating. With repetitive use, these procedures eventually destroy the component by reducing the wall thickness of the component. This disadvantage is particularly acute with diffusion aluminide bond coats, which have a diffusion zone that extends into the substrate surface of the component. Damage to diffusion aluminide bond coats generally occurs by the fracturing of brittle phases in the diffusion zone, such as PtAl2 phases of a platinum-aluminide bond coat, or in the additive layer, which is the outermost bond coat layer containing an environmentally-resistant intermetallic phase MAl, where M is iron, nickel or cobalt, depending on the substrate material. Damage is particularly likely when treating an air-cooled component, such as a turbine blade whose airfoil surfaces include cooling holes from which cooling air is discharged to cool the external surfaces of the blade.
Consequently, significant effort has been directed to developing nonabrasive processes for removing ceramic coatings. One such method is an autoclaving process in which the ceramic coating is subjected to elevated temperatures and pressures in the presence of a caustic compound. This process has been found to sufficiently weaken the chemical bond between the ceramic and bond coat oxide layers to permit removal of the ceramic layer while leaving the bond layer intact. However, suitable autoclaving equipment is expensive, and autoclaving techniques have been incapable of removing ceramic from the cooling holes of an air-cooled turbine blade.
Accordingly, what is needed is a process capable of removing a ceramic layer from a component without damaging an underlying substrate, including any bond coat used to adhere the ceramic layer.
The present invention provides a method of removing a ceramic coating, such as a thermal barrier coating (TBC) of yttria-stabilized zirconia (YSZ), from the surface of a component. Particularly notable examples are gas turbine engine components exposed to the hostile thermal environment of the turbine, combustor and augmentor sections of a gas turbine engine. The method is particularly suited for completely removing a thermal-insulating ceramic coating of a thermal barrier coating system without removing a metallic bond coat, such as a diffusion aluminide or MCrAlY coating, that adheres the ceramic coating to the surface of the component.
The method of this invention generally entails subjecting the ceramic coating to an aqueous solution of ammonium bifluoride. A preferred process for removing the ceramic coating further entails immersing the component in the solution while maintained at an elevated temperature, and subjecting the coating to ultrasonic energy. Using the method of this invention, a ceramic coating can be completely removed from the component and any cooling holes, with essentially no degradation of the bond coat. Accordingly, this invention allows the deposition of a new ceramic coating on components in production without refurbishment or replacement of the bond coat and without depositing additional ceramic in the cooling holes, which would be detrimental to the performance of the component. If the component has been in service, such that the bond coat has been partially depleted as a result of oxidation, the bond coat can be refurbished before replacing the ceramic coating.
A significant advantage of this invention is the reduced labor, equipment and processing costs required to remove a ceramic coating of a thermal barrier coating system. In addition to the simplified process and equipment that can be used, labor and process costs are further reduced by avoiding damage and removal of the bond coat. In addition, the service life of a component can also be extended by avoiding replacement of its entire thermal barrier coating system, since removal of a bond coat results in loss of wall thickness, particularly if the bond coat is a diffusion aluminide which inherently shares a significant diffusion zone with the component substrate. Importantly, prior art techniques for removing a ceramic layer of a TBC have typically been unable to remove ceramic from cooling holes, or have caused excessive damage to the bond coat in the process of removing the ceramic. By completely removing ceramic from the cooling holes of an air-cooled component, the performance of the component is improved by the restored uniform film cooling of its surfaces.
Other objects and advantages of this invention will be better appreciated from the following detailed description.


A camera photosensitive component, a camera, and a camera shooting terminal are provided in the field of camera shooting. The camera photosensitive component includes: a silicon substrate layer, a pixel array layer attached to one surface of the silicon substrate layer, and a microprism layer arranged in parallel with the pixel array layer. At least one microprism in the microprism layer is configured to decompose incident light into m color lights for emission. And n color lights in the emitted m color lights are respectively emitted into subpixels in corresponding colors of pixels corresponding to the microprisms, where n is not greater than m. The n color lights may be formed by decomposition with the microprisms, not obtained after part of color light is absorbed by an RGB filter, and transmittance of the color light emitted into the pixels may be improved, thereby reducing an exposure time required by imaging.

Light is emitted onto a photosensitive surface of a pixel in a camera photosensitive component to form an image. Therefore, transmittance of light is a key for imaging.
In a related technology, a camera photosensitive component includes a Red, Green and Blue (RGB) filter, and light is emitted onto a photosensitive surface of a pixel after being filtered through the RGB filter.

Camera photosensitive component, camera, and camera shooting terminal

Beijing Xiaomi Mobile Software Co., Ltd.


Evolutionary algorithms are used to find a global solution to the fitting of experimental X-ray scattering data to simulated models. A recombination operator combines two or more parameter vectors from one iteration of simulated scattering data to form a new parameter vector for the next iteration, in a manner such that there is a high probability that the new parameter will better fit the experimental data than any of the parent parameters. A mutation operator perturbs the value of a parent vector, to permit new regions of the error function to be examined, and thereby avoid settling on local minima. The natural selection guarantees that the parameter vectors with the best fitness will be propagated into future iterations.

In the manufacture of products, it is often necessary to conduct quality assurance measurements at various stages in the manufacturing process, to ensure that the ultimate product meets required specifications. Similarly, during research in the development of new products, it is necessary to be able to quantitatively characterize the structure of a prototype material. These requirements are particularly applicable in the field of advanced materials. In the context of the present invention, the term "advanced materials" encompasses a variety of different types of crystalline, polycrystalline and amorphous materials, including semiconductors, metallic thin films, glasses, coatings, superconductors, and the like. One example of a situation in which these types of measurement are particularly applicable is the manufacture of semiconductor products. Typically, a silicon wafer which forms the starting material for a semiconductor product has an appreciable cost associated with it. Each successive major processing step increases the cost of the overall process by a factor of about ten. Hence, it is necessary to be able to characterize the structure of the wafer during research and throughout the manufacturing process, to identify potential problems and correct them before significant waste occurs. Similar concerns apply in the processing of other types of advanced materials as well.
Originally, destructive testing methods were employed to determine characteristics such as the thickness of various layers of a structure, the roughness of their interfaces, their respective densities, strain and the tilt of crystalline layers. Over time, there has been a tendency to employ larger wafers in the process of manufacturing advanced materials. Because of the cost of each individual wafer, destructive testing methods have become quite uneconomical, and consequently undesirable. For this reason, non-destructive methods are employed.
One particularly useful category of non-destructive testing is X-ray metrology. In addition to being non-destructive, X-ray metrological methods provide several other advantages for both process development and process control of advanced material structures. For instance, they are capable of detecting unacceptable levels of internal defects generated by various processes. Furthermore, as individual material layers on such structures become thinner, traditional methods for measuring thickness and roughness become less accurate, relative to the results that can be achieved by X-rays. A variety of different X-ray metrological methods are known, for measuring different characteristics of a structure. Examples of these methods include X-ray absorption, diffraction, fluorescence, reflectivity, scattering, imaging and fringe analysis. In the context of the present invention, the term "X-ray scattering" is employed as a generic term which collectively encompasses any known X-ray technique that is applied to materials characterization.
The various types of X-ray metrological methods basically involve the projection of an X-ray beam onto a specimen being tested, and measurement of the intensity of the rays which are scattered by the specimen. If the crystallographic structure of a device is known, it is possible to calculate its X-ray scattering. For example, the equations for calculating X-ray diffraction are described by S. Takagi, Acta Cryst., Vol. 15, p. 1311 (1962) and J. Phys. Soc. Japan, Vol. 26, p. 1239 (1969), and by D. Taupin, Bull. Soc. Fr. Mineral Crystallogr., Vol. 87, p. 469 (1964). In addition, software programs for modeling and predicting experimental data are commercially available. Examples of such include the RADS program for modeling high resolution X-ray diffraction, and the REFS program for modeling X-ray reflectivity, both of which are distributed by Bede Scientific Instruments Ltd., Durham, UK.
While it is possible to predict the X-ray scattering data that can be obtained from a given structure, the inverse operation cannot be directly achieved. In particular, it is not possible to calculate the structure of a device from its X-ray scattering data. This limitation is due, at least in part, to the fact that the X-ray scattering data only provides a measurement of the intensity of the detected rays, but not their amplitude or phase. As a result, insufficient information is available from which to directly derive the parameters that characterize the structure, such as layer thicknesses, density, surface roughness, strain, etc.
Consequently, to characterize a structure on the basis of its X-ray scattering data, it is necessary to infer such structure by means of a trial-and-error technique. In the known techniques, an iterative procedure is employed, in which a structural model for a specimen is first suggested, on the basis of available information, such as the materials which were employed in the manufacture of the specimen being tested. The X-ray scattering data for this suggested model is then simulated, for example by means of one of the above-mentioned programs, and this simulated data is compared with the experimental, or measured, data from the specimen, either graphically or by using any suitable function which provides an indication of the differences or similarities between them. Based on this information, the suggested model is refined, i.e., certain parameters are changed. The X-ray scattering data for this revised model is then simulated, and compared against the measured data. This process is iteratively repeated until the difference between the simulation and the actual data converges to a minimum or falls below a predefined threshold.
This iterative procedure can be characterized as a non-linear data fitting problem. Given a particular curve, i.e., the experimental data, it is necessary to find a known curve which most closely matches the experimental curve. The parameters which define the known curve are then assumed to be those which characterize the tested specimen. In the past, various approaches have been applied to non-linear data fitting. In one approach, known as direct search, the parameter space is divided into small, but finite, regions. An error function is calculated for each region, and the region that produces the smallest error value is chosen as the best-fit parameter vector. In a related approach, known as the Monte Carlo method, the parameter space is again divided into small regions. The regions are selected at random, and the error function is evaluated for each. After a certain number of regions have been chosen, or when the error value is smaller than a specified value, the search is stopped. The region with the smallest error value is chosen as the best fit.
Other approaches to parameter optimization are also well known. In one approach, identified as Downhill Simplex, an initial guess for the best-fit parameters is made by the user. A geometrical construct known as a simplex then moves in directions that decrease the error value. The parameter vector that yields the smallest error value in the neighborhood of the initial guess is chosen as the best-fit parameter vector. In the Levenberg-Marquardt method, an initial guess for the best-fit parameters is again made by the user. This method combines linearization and gradient searching of the error function, to minimize the error in the neighborhood of the initial guess. The parameter vector which provides the smallest error value is selected as the best fit.
These latter methods have relatively limited usefulness, since they are highly dependent upon the accuracy of the initial estimate. In operation, they tend to settle upon a local minimum in the error function which is in the neighborhood of the initial estimate. An optimal solution, i.e., a global minimum, which is significantly different from the initial guess may never be found, because of the manner in which they operate. Hence, the fitting can only be carried out by a person having a high level of skill who is able to make an accurate initial estimate. Even then, it may take several hours to find the best solution.
To avoid the problem of having to start with an estimate that is close to the optimum solution, another approach known as simulated annealing has been employed. This approach uses the physical principles that govern annealing, namely the slow cooling of a liquid so that it forms a crystal, to obtain the best-fit parameters. While this approach provides improved results, in that it is capable of escaping from local minima, it can be quite difficult to design and set up the annealing schedule. The process also requires a considerable amount of time, since it does not search the parameter space in an efficient manner, and therefore is not well suited for on-line quality control for processes.
It is desirable, therefore, to provide a technique for fitting experimental X-ray scattering data to simulated data which operates in an efficient and robust manner to find a global solution, while avoiding the need to begin with an estimate that is close to the optimum, and which can therefore be practiced by non-skilled operators.

Fitting of X-ray scattering data using evolutionary algorithms


A solid state relay having an input circuit and a triac Darlington circuit coupled by a phototriac circuit. The input circuit having a bipolar indicator lamp for identifying the polarity and presence of an input voltage. The phototriac circuit and the triac Darlington circuit each having bipolar indicator lamps to indicate ON/OFF operation of respective triacs therein.

The present invention relates to relays, and more specifically to a solid state relay having bipolar indicator lamp incorporated therein.
A solid state relay (SSR) does not work if its power input terminal is connected reversely. Because an ordinary solid state relay does not have any indicator means for indication of correct connection, it may be regarded damaged when does no work.

High power solid state relay with input presence and polarity indication


Example embodiments are directed to an off-axis projection optical system including first and second mirrors that are off-axially arranged. The tangential and sagittal radii of curvature of the first mirror may be R1t and R1s, respectively. The tangential and sagittal radii of curvature of the second mirror may be R2t and R2s, respectively. The incident angle of the beam from an object point to the first mirror 10 may be i1, and an incident angle of the beam reflected from the first mirror 10 to the second mirror 30 is i2. The values of R1t, R1s, R2t, R2s, i1 and i2 may satisfy the following EquationR1t cos i1=R2t cos i2R1s=R1t cos2i1R2s=R2t cos2i2.

1. Field of the Invention
Example embodiments of the present invention relate to an off-axis projection optical system and an extreme ultraviolet (EUV) lithography apparatus using the same.
2. Description of the Related Art
In a photolithography process of a semiconductor manufacturing process, a light exposure technology used to realize a direct writing resolution of less than 100 nm may involve the use of a light exposure wavelength within the EUV band. In EUV lithography technology, extreme ultraviolet light having a very short wavelength of less than 100 nm, for example, a wavelength of about 13.5 nm, may be used.
Because most materials absorb light in the EUV band, it may be difficult and/or impossible to use a refractive optical device for EUV light. Therefore, a reflection mask may be required for the light exposure technology using the EUV light. In order for the EUV light reflected from the reflection mask to travel toward a wafer, a conventional projection optical system having a plurality of reflection mirrors may be used and/or required. The EUV light may be radiated to the reflection mask installed in a chamber. The EUV light reflected from the reflection mask may be incident on the wafer after being reflected by the plurality of reflection mirrors of the projection optical system, thereby forming a pattern corresponding to the mask on the wafer.
As described above, conventional EUV light lithography uses and/or requires a projection optical system having a plurality of reflection mirrors.
FIG. 1 schematically illustrates a conventional on-axis projection optical system, which may be used in a light exposure apparatus for performing a conventional EUV lithography process.
Referring to FIG. 1, EUV light 4 radiated from a EUV source onto a mask 1 may be reflected by the mask 1 and then incident on a light exposure apparatus 2.
First and second mirrors 3 and 5 for reflecting the EUV light 4 toward an image plane where a wafer 6 may be disposed may be included in the light exposure apparatus 2. First and second center holes 3a and 5a through which the EUV light 4 passes may be formed in the center of the first and second mirrors 3 and 5, respectively. The second mirror 5 may be disposed near the mask 1 while the first mirror 3 may be disposed relatively far from the mask 1.
The EUV light 4, which may be reflected from the mask 1 and incident on the second mirror 5 after passing through the second center hole 5a formed in the second mirror 5 is divergent. The EUV light 4 incident on the first mirror 3 may be reflected to the second mirror 5, which may reflect the EUV light 4 to form a convergent beam. Then, the EUV light 4 may be radiated to the wafer 6 onto the image plane after passing through the first center hole 3a formed in the first mirror 3.
In a conventional on-axis projection optical system, because the center holes 3a and 5a may be formed in the first and second mirrors 3 and 5, respectively, stray light 4′ traveling directly from the mask 1 toward the wafer 6 through the first and second center holes 3a and 5a of the respective first and second mirrors 3 and 5 may exist.
Therefore, a conventional light exposure apparatus 2 using a typical on-axis projection optical system requires a shielding member 7. An example of the shielding member 7 is illustrated in FIG. 2. The shielding member may reduce and/or prevent stray light from traveling directly toward the wafer 6. The shielding member 7 may be disposed at a location between the first and second mirrors 3 and 5 to block a central portion of the EUV light 4. That is, the stray light 4′ traveling toward the first center hole 3a through the second center hole 5a of the second mirror 5 may be partially or completely blocked by the shielding member 7.
The shielding member 7 may be supported by a narrow strip-shaped support 8 so the shielding member 7 may block the central portion of the EUV light 4. Referring to FIG. 2, the support 8 for supporting the shielding member 7 may be cross-shaped, for example.
A drawback of conventional on-axis projection optical systems is that the shielding member 7 for blocking the stray light 4′ is necessary. Further, the shielding member 7 may cause diffraction, scattering and flare, for example.

Off-axis projection optical system and extreme ultraviolet lithography apparatus using the same


Described embodiments enable display of graphical reports based on multi-category data. A graphical report is generated and displayed on the device. The graphical report includes data corresponding to selected values from multiple categories. All values for some categories are displayed near the chart, for example, using a textual representation. A graphical representation of the relative magnitude of each value in some categories is also displayed near the chart. When appropriate user input is received, the categories displayed as magnitudes are displayed textually, and categories displayed textually are displayed as magnitudes. When appropriate user input is received, the categories for which values are displayed are changed.

1. Field of the Invention
This disclosure relates generally to displaying and navigating between reports of multi-category data on a device having a display area that is small relative to the amount of data that is being displayed.
2. Description of Related Art
Frequently there is desire to display on a display screen of a computing device data having multiple dimensions, for example, multi-dimensional charts or graphs. On a mobile device such as a handheld computer, cell phone, tablet computer, netbook, or personal digital assistant (PDA), such graphs and charts have to be displayed on small display screens. Because of the limited display area, only information related to either a single data point or a small subset of data points can be displayed at a time. Users inspect various portions of the charts, for example by using a scroll bar or by viewing the data a page at a time. Users navigate through the data using a pointing device or keys to move through the data set.

Presentation of multi-category graphical reports


The invention is directed to a method for the preparation of a multiring engineered heart tissue construct suitable for use in cardiac tissue augmentation and/or replacement therapy. The invention further refers to multiring EHT constructs which comprise at least two force-generating engineered heart tissue rings fused with each other and a device for preparing the same. Finally, the invention relates to force-generating engineered heart tissue rings derived from human cells and their use in drug screening and target validation assays.

Myocardial infarction and heart failure represent the main cause of death in industrialized countries. The loss of terminally differentiated cardiac myocytes which is associated with these pathologies accounts for a decrease in myocardial function which can lead to total organ failure or trigger compensatory mechanisms like hypertrophy of the remaining myocardium, activation of neurohumoral systems, and autokrine/parakrine stimulation by various growth factors/cytokines.
It has been shown that endogenous regenerative mechanisms do not suffice to compensate for cardiac myocyte death after myocardial infarction. Modern pharmacotherapy can delay, but not reverse the natural course of the disease. Thus, exogenous regenerative strategies including cardiac implantation or coronary transfusion of cells, activation of endogenous cardiac regeneration by pharmacological means, or implantation of performed, engineered cardiac tissues have gained increasing attention (Reinlib, L. & Field, L., Circulation 101, E182-7 (2000); Zimmermann, W. H. & Eschenhagen, T., Heart Fail Rev 8, 259-69 (2003); Olson, E. N., Nat Med 10, 467-74 (2004); Orlic, D. et al., Proc Natl Acad Sci USA 98, 10344-9 (2001)).
So far, cells of various origins and developmental stages have been grafted into healthy and diseased hearts, including immature cardiac myocytes (Reinecke, H., Zhang, M., Bartosek, T. & Murry, C. E.; Circulation 100, 193-202 (1999); Muller-Ehmsen, J. et al., Circulation 105, 1720-6 (2002); Li, R. K. et al., Circulation 96, II-179-86; discussion 186-7 (1997)), skeletal myoblasts (Taylor, D. A. et al., Nat Med 4, 929-33 (1998); Menasche, P. et al., Lancet 357, 279-80 (2001)), fibroblasts (Etzion, S. et al., Circulation 106, I125-30 (2002); Sakai, T. et al., J Thorac Cardiovasc Surg 118, 715-24 (1999)), endothelial cells (Condorelli, G. et al., Proc Natl Acad Sci USA 98, 10733-8 (2001)), embryonic stem cell-derived cardiac myocytes (Soonpaa, M. H., Koh, G. Y., Klug, M. G. & Field, L. J., Science 264, 98-101 (1994)), and a number of potential cardiac progenitors from peripheral blood (Assmus, B. et al., Circulation 106, 3009-17 (2002)) or bone marrow (Orlic, D. et al., Nature 410, 701-5 (2001); Stamm, C. et al., Lancet 361, 45-6 (2003); Strauer, B. E. et al., Circulation 106, 1913-8 (2002)). Even though the evidence for the formation of true cardiac muscle tissue, electrically coupled to the host myocardium is sparse, most studies reported procedure-induced improvement of contractile function after cryo-injury or myocardial infarction.
A different concept in cardiac regeneration is to graft heart muscle produced ex vivo by tissue engineering. Tissue engineering aims at generating functional 3-dimensional tissues outside of the body that can by tailored in size, shape and function according to the respective needs before implanting them into the body. In contrast to cell implantation in preexisting structures, this approach may allow for complete replacement of diseased myocardium or reconstitution of missing cardiac structures in individuals with cardiac malformations.
Despite its potential, cardiac tissue engineering is still in its infancy for several reasons: (i) Postnatal cardiac myocytes do not or not sufficiently replicate. Given the high absolute numbers of cells needed for cardiac regeneration (Gepstein, L., Circ Res 91, 866-76 (2002)), utilisation of primary cardiac myocytes will not be feasible. (ii) To repair myocardial infarctions or correct heart defects, heart tissue patches need to be engineered at a size and with contractile features that have a realistic chance to lend significant support to failing hearts. Size as well as function and in vivo survival depend crucially on metabolic supply. Thus, vascularization is likely to be a prerequisite for successful creation and grafting of large cardiac tissue patches. (iii) The heart not only needs systolic strength, but also depends on unimpeded diastolic relaxation. Consequently, engineered heart muscle must exhibit a large compliance, a feature often neglected in classical, scaffold-based tissue engineering approaches. (iv) Finally, any successful tissue engineering concept will depend on structural and electrical integration of implanted tissue into the host myocardium. Recent progress in stem cell research has opened new perspectives for cell sourcing, e.g. from embryonic (Kehat, I. et al., J Clin Invest 108, 407-14 (2001)) or adult stem cells (Beltrami, A. P. et al., Cell 114, 763-76 (2003); Messina, E. et al., Circ Res (2004)).
Several publications describe the generation of engineered heart tissue in different geometrical sizes and shapes (Zimmermann, W. H. et al., Circ Res 90, 223-30 (2002); Fink, C. et al., Faseb J 14, 669-79 (2000); see also published International Application WO 01/55297). It was shown that engineered heart tissue can be reconstituted by mixing heart cells from rat (including cardiac myocytes, fibroblasts, smooth muscle cells, endothelial cells, macrophages and other cells of leukocytic origin, etc.) with collagen type I, matrigel and serum-containing culture medium (the complete mixture is referred to as reconstitution mix). Specifically, ring-shaped casting molds were used to form ring-shaped EHTs. The engineered tissue rings resemble intact heart tissues in terms of force-frequency behaviour, force-length relationship (FrankStarling mechanism) and response to extracellular calcium (Eschenhagen T, et al., Faseb J. 11, 683-94 (1997); Zimmermann W H et al., Biotechnol Bioeng. 68, 106-14 (2000). These data support the conclusion of true heart tissue-development in vitro from a functional point of view. However, differences exist as well. For example, absolute contractile forces of EHTs remain lower than in the intact heart. In the literature, maximal twitch tensions of about 1-2 mN/mm2 are reported in artificial heart muscle (overview in Zimmermann W H, et al., Heart Fail Rev. 8, 259-69 (2003)). In comparison, papillary muscles from rat develop 4-10 mN/mm2. The difference of EHT force generation as compared to mature heart muscles most likely reflects both a quantitative and a qualitative aspect, as for example a lower fractional occupancy of the EHT tissues by cardiac myocytes and the lower degree of sarcomere development. In fact, single adult cardiac myocytes develop up to 56 mN/mm2. These ideal forces are unlikely to be reached in intact muscle preparations due to the lack of oxygen and metabolite supply in the absence of blood perfusion.
It has been demonstrated that a simple scale-up of the preparation approach, e.g. by use of larger casting molds than those described in International Application WO 01/55297 cannot solve the problem, since size of the engineered tissue constructs appears to be limited by maximum diffusion distances for nutrients and oxygen. Indeed, none of the various tissue engineering approaches developed today generate cardiac tissue-like, contracting constructs of a thickness of more than 0.8 mm (Zimmermann, W. H. et al., Circ Res 90, 223-30 (2002)). Yet, so far developed artificial heart tissues do not represent homogeneous myocardium, but consists of a large fraction of cell-free matrix and interconnected cardiac muscle strands that do not exceed 20-100 μm in thickness. Interconnected muscle strands can be observed and evaluated by confocal laser scanning microscopy e.g. after actin or actinin staining as outlined in Zimmermann et al. (Circ Res 90, 223-30 (2002)).
Therefore, a need exists for the provision of improved heart tissue grafts of larger size which overcome the above shortcomings. It has been an object of the present invention to provide heart tissue grafts having a size and contractile strength which allows for the effective support of failing hearts in a mammal, such as a human. The present invention provides for a solution of this problem and offers other related benefits as well.
It has surprisingly been found in course of the invention that large three dimensional tissue grafts which consist of a well-organized and highly differentiated cardiac muscle syncytium can be produced by fusing two or more engineered heart tissue rings with each other. Fusing, as used herein, means that single EHT units or stripes grow together at a region where sustained physical contact is established to form a contiguous cell assembly. The assembly represents a structurally, electrically and functionally syncytium that may be finally used as a cardiac tissue graft in vivo. Such graft constructs are designated "multiring engineered heart tissue construct" herein. Specifically, it has been found that several engineered heart tissue rings or comparable geometric forms can be woven together, thus forming a network in which each individual construct remains accessible for unlimited diffusion and exchange of nutrients. As a consequence, these constructs do not exhibit the typical size limitations known from the prior art. Multiring engineered heart tissue constructs of the invention can be produced by using a plurality of distinct engineered heart tissue rings as those described in the prior art. The rings can be fused in any suitable manner to provide "chain-mail"-like constructs. By this technique, the form of the multiring constructs can be adjusted dependent on the specific therapeutic approach. For example, large multiring net-like patches can be generated for replacing dysfunctional areas of the heart of a mammal. Alternatively, bag-like forms may be generated which surround the complete organ. The size of the multiring construct patches can be varied dependent on the size of the area to be treated. The multiring engineered heart tissue construct of the invention can be comprised of force-generating engineered heart tissue rings derived from any mammal. In view of its intended use in the field of tissue augmentation, it is preferred that the engineered heart tissue rings are derived from human cells.
Thus, according to a first aspect of the invention, an ex vivo method for the preparation of a multiring engineered heart tissue construct suitable for use in cardiac tissue augmentation and/or replacement therapy is provided, which method comprises the steps of                a) providing force-generating engineered heart tissue rings;        b) placing into contact at least two force-generating engineered heart tissue rings so that each force-generating engineered heart tissue ring has one or more contact points to an adjacent force-generating engineered heart tissue ring; and        c) culturing the force-generating engineered heart tissue rings under conditions which allow fusion of the at least two force-generating engineered heart tissue rings at the one or more contact points to form a multiring heart tissue construct.
As used herein, the term "multiring engineered tissue construct" means an ex vivo produced tissue construct comprised of at least two, and preferably more than two distinct force-generating engineered heart tissue rings, which may have been produced by tissue engineering techniques, such as those described in Zimmermann, et al., Circ Res 90, 223-30 (2002) and International Application WO 01/55297. The term "tissue" refers to a group of similar cells united to perform a specific function or a grouping of cells that are similarly characterized by their structure and function. The constructs of the invention consist of at least two distinct engineered heart tissue rings. In this context, the expression "multiring" is meant to emphasize that the fused construct comprises a plurality of loop structures originating from the essentially circular shape of the force-generating engineered heart tissue rings that serve as a basis material for the construct of the invention. Such loop structures have been proven very useful for the handling of the tissue construct, for example when surgically fixing the construct to the recipient organ or tissue. Additionally, the term multiring is also intended to comprise embodiments in which tissue constructs are formed which consist of tube- or stripe-like structures. The former might be obtained by establishing side-to-side connections between two or more rings (FIG. 8b). The latter might be obtained by forming a ring structure and subsequently cut the latter in two or more pieces for further use. An example of such tissue construct is provided in FIG. 8(c).
The multiring construct according to the present invention comprises force-generating engineered heart tissue rings. The production of such contractile engineered heart tissue in circular/annular shape has been described in detail in the prior art, for example in published International Application WO 01/55297 and in Zimmermann et al., 2000, Biotechnology and Bioengineering Vol. 68, pages 106 to 114. Cardiac myocytes such as those obtained from tissue samples of neonatal hearts of different mammals may be used for preparing the EHT rings, as described in Zimmermann, et al., Circ Res 90, 223-30 (2002) and International application WO 01/55297. As can be taken from these publications, engineered heart tissue rings can be obtained by culturing cardiac myocytes in ring-shaped molding devices. It has been shown that mixed populations consisting of almost identical portions of cardiac myocytes and non-cardiac myocytes result in EHTs with increased contractile properties compared to selected cardiac myocytes (Zimmermann et al. (2003), Heart Failure Rev., 8, 259-269). Fetal or neonatal cardiac myocytes from mammals, such as rat, mouse or primates are a suitable source for obtaining EHT rings. In contrast to differentiated cardiac myocytes, these cells still have the capability to divide as well as to redifferentiate after dedifferentiation. Briefly, a solution of a scaffold substance (such as collagen type I) is mixed with culture medium (final concentration in the mixture: 1×DMEM; 2% chicken embryo extract; 10% horse serum; 100 μg/ml Streptomycin; 100 U/ml penicillin). The pH of the mixture is adjusted to physiologic values ˜7.4 with 0.1 N NaOH. Engelbreth-Holm-Swarm tumor exudate (also known as "Matrigel") is added to give a final concentration of 5-15%. This mixture is added to a cell suspension of fetal or neonatal cells (for example, 2.5×106 cells/EHT). Alternatively, serum-free media may be used. A serum-free medium suitable for culturing the cardiac myocytes is exemplified in FIG. 12. The person skilled in the art will appreciate that several modifications as to the components of the medium can be performed. Moreover, Matrigel may be substituted against insulin and triiodothyronine, as described in more detail below.
Alternatively, mammalian cardiac myocyte progenitor cells, such as pluripotent stem cells, adult or embryonic, provide a source for preparing the EHT rings. Preferably, the EHT rings to be used in the method according to the invention are derived from human cells. Human engineered heart tissue rings may be obtained by use of circular-shaped casting molds. In this case, cardiac myocyte progenitor cells, such as stem cells, more preferably pluripotent embryonic stem cells, may be used for preparing the force-generating engineered heart tissue rings. However, also other types of stem cells, such as pluripotent adult stem cells may be used. The preparation of contractile EHT rings derived from human stem cells is particularly described in example 6 of the present invention.
The force-generating engineered heart tissue rings produced from human or non-human mammalian cells comprise cardiac myocytes. However, they are usually not composed purely of cardiac myocytes but comprise almost all cells species that are normally found in the heart including cardiac myocytes, fibroblasts, smooth muscle cells, endothelial cells, macrophages and other cells of leukocytotic origin. Typically, the presence of cardiac cells within a given EHT ring can be confirmed by positive staining with anti-cardiac myosin heavy chain, anti-α-actinin, anti-desmin and/or anti-cardiac troponin I antibodies (see Kehat I. et al, supra). If cells are derived from human cells, this can readily be confirmed by well known methods, such as PCR analysis based on typically conserved regions of the genome.
The term "ring" as used in the context of the present invention is meant in a broad sense to comprise also geometric forms which do not represent a perfect geometric ring. For example, it may also comprise other forms which consists of annularly closed tissue tube structures. It has been found that a circular geometry of the EHT is ideal for several technical and biological reasons. For example, circular heart tissue structures allow large scale production with minimal handling. Most importantly, circular engineered heart tissue structures can be easily miniaturized for high-throughput screening and they exhibit better tissue formation than the non-circular designs, since the circular form causes homogeneous force distribution throughout the tissues. Furthermore, nutrient distribution is facilitated in circular-shaped tissues. Also not being particularly restricted to a specific limited size, it has been shown that engineered heart tissue rings having an outer diameter of 8-12 mm have particularly preferred characteristics. The inner diameter of these rings should be in the range of 6-10 mm. Particularly preferred are EHT rings with an outer diameter of about 10 and an inner diameter of about 8 mm (see International Application WO 01/55297).
As used herein, the term "force-generating" means that the engineered heart tissue rings are able to actively contract against a given mechanical load. The intrinsic property of heart cells to form contractile aggregates has been known in the field for years. Several publication reported that contractile properties are maintained when three dimensional EHTs, such as EHTs of circular shape, are constructed. Contraction of the tissue constructs are triggered by addition of Ca2+ ions or isoprenaline to the culture medium. Zimmermann, W. H. et al., Circulation 106, I 151-7 (2002), reported determination of contractile functions of engineered tissue rings by isometric force measurements in organ baths before implantation (see FIG. 2a of the above publication). Maximal twitch tension (TT) values of about 0.4 mN to 0.7 mN were measured.
According to a first step of the method for the preparation of the multiring engineered heart tissue construct of the invention, distinct force-generating engineered heart tissue rings are provided. These rings are, for example, obtainable by culturing suitable cells in ring-shaped molding devices. The preparation of such rings from mammalian cell sources is described in the art, for example, in Zimmermann, et al., Circ Res 90, 223-30 (2002), in International Application WO 01/55297 and in Example 1. Using the same casting molds, engineered heart tissue rings may also be prepared from human stem cells, for example, as described in Example 6.
Subsequently, at least two force-generating engineered heart tissue rings are positioned into contact, so that each of these force-generating engineered heart tissue rings has one or more contact points with at least one further EHT ring in its vicinity. This means, each of the engineered heart tissue rings used for preparing the multiring heart muscle construct is tangent to at least a further engineered heart tissue ring. Preferably, the distinct EHT rings are held via suspension points of a holding device. According to a very simple embodiment of the invention, several force-generating engineered heart tissue rings as defined herein are stacked, i.e. laid upon each other to form a stack with a plurality of loops extending in different directions (see for example FIG. 8a). It is particularly preferred that the force-generating EHT rings are placed into contact by stacking of the distinct rings to form a central region in which the force-generating engineered heart tissue rings overlap with each other as shown in FIG. 8a). According to an alternative embodiment several rings are placed into contact as shown in FIG. 8 (b). Apart from that, any other random distribution of the tissue rings in which each ring is in contact with at least another one are possible. It has been found in course of the invention, that the tissue rings which have been positioned into contact in this manner fuse and form a complex in-unison contracting construct which is synchronized with respect to its contracting activity. This finding allows for the generation of large tissue-like structures by fusing distinct contractile EHT rings (or prefused multiring structures comprising several of theses EHT rings).
In a further step, the force-generating engineered heart tissue rings, which are in contact with each other, are cultured under conditions which allow the fusion of the contacted ring structures to form an artificial heart muscle construct. For this purpose, the engineered heart tissue rings are normally incubated in culture dishes, wherein the rings are submersed in appropriate culture medium. If a holding device is used for culturing, the device should be designed to allow the tissue rings to stay in continuous contact with the culture medium. The choice of the culture medium is not critical. Conventional media for culturing cardiac myocytes may be used. Such media are known in the art and described, for example, in Zimmermann, W. H. et al., Circulation 106, I 151-7 (2002) and published International Application WO 01/55297. These media may further be modified, i.e. by substituting Matrigel against a mixture of Insulin (10 μg/ml) and triiodothyronine (1 nM). It was found that the addition of insulin and triiodothyronine allowed for the generation of strongly contracting EHTs. Simultaneous addition of both factors for only 24 h at the beginning of the EHT culture was sufficient. By using insulin and triiodothyronine during EHT construction, improved EHT contractility was achieved. These effects did not stem from enhanced overall EHT cell number, since no difference in the DNA content and no apparent structural differences were observed. Rather, the effects may be the result of enhanced protein content or improved survival of cardiomyocytes leading to a higher cardiomyocyte fraction without an apparent change of the overall cell number (standard EHTs on culture day 12 contain roughly 100.000 cardiomyocytes and a total cell number of 600.000; a fractional increase in cardiomyocyte number may have significant effects on force of contraction, may lead to an increase in overall "cardiomyocyte" protein [e.g. sarcomeric actin] but may not lead to a measurable [by total DNA quantification and cell counting after enzymatic digestion of EHTs] increase in total cell number in EHTs treated with insulin and triiodothyronine. Furthermore, the media as used herein for culturing stem cells in example 6 can be used as well.
According to a more preferred embodiment of the invention, the same media which has been used for casting the EHT rings are used during incubation of the force-generating engineered heart tissue rings for fusion (see examples 1 and 6 for neonatal cardiomyocyte and stem cells, respectively). Suitable culturing conditions are described in the art and comprise a physiological temperature range of 30-40° C., preferably 36-38° C., and more preferably 37° C. The percentage of O2 in the ambient air should range from 21-80%, preferably 70%, 60% 50%, and more preferably 40%. Culturing may be performed for 3 to days, preferably 10-30 days, and more preferably 15-20 days.
According to preferred embodiment of the present invention a plurality of distinct force-generating engineered heart tissue rings are placed into contact to form the fused multiring EHT construct. Preferably, five or more tissue are placed into contact, for example six, seven, eight, nine, ten, eleven, twelve or more. More preferably, more than 15, 20, 30, 40, 50, or even up to 100 force-generating engineered heart tissue rings are placed into contact to form the fused multiring EHT construct. It has to be understood that larger multiring EHT constructs can also be formed in several steps, for example by forming several constructs of 5-10 EHT rings in a first step and fusing these different constructs in a subsequent step. In any case, care should be taken that the resulting multiring EHT construct is cultured for a further period of time to allow synchronization of contractile activities.
According to preferred embodiment of the present invention, the force-generating engineered heart tissue rings used for preparing the multiring heart muscle construct of the invention are subjected to tensile stress prior to or simultaneously with placing into contact the at least two force-generating engineered heart tissue rings. For example, when using a device of the invention as described in more detail below, placing into contact of the EHT rings and subjecting to tensile stress can be performed in one step. Subjecting to tensile stress can for example be performed by actively stretching the tissue rings, for instance by use of a mechanical stretching device like the one described in Zimmermann, W. H. et al., Circulation Res 90, 223-30 (2002). Such device can provide for a "static" load, i.e. a permanent load produced by expanding the ring by 3 to 20%, preferably 10% of its original length (original length determined in the absence of any load) as described in WO 01/55297. Alternatively, a "phasic" load can be applied by periodically expanding the ring by 3 to 20%, preferably 10% of its original length, for example at a frequency of 0.1-10 Hz, preferably 1-5 Hz. Such stretching can be regarded as a static or phasic manner, respectively.
In several publications, it was demonstrated that contractile properties of artificially synthesized heart tissue rings can be improved by mechanically stretching the rings after there casting (see Eschenhagen et al., 2002; Fink et al., 2000; Zimmermann et al., 2002b). It has been demonstrated that mechanical load improves both orientation and differentiation of muscle cells in EHT rings. Tensile stress can be applied for a period of time ranging from several hours to more than 40 days. Preferably, tensile stress is applied for 5-9, more preferably 7 days. During imposing tensile stress, the EHT rings are cultured under the conditions recited above.
According to a preferred embodiment of the invention, tensile stress is applied by a static, phasic or auxotonic manner or a combination thereof. According to a particularly preferred embodiment of the invention, tensile stress is applied by a auxotonic manner. An "auxotonic manner", as used herein, means that the engineered heart tissue rings are kept under conditions so that they have to contract against a defined force and are reexpanded during relaxation of the EHT ring by another force or, preferably, the same force. For example, if the tissue ring is held under tension by using a spring, this spring will provide a defined force against which the EHT must contract. Upon relaxation of the EHT ring, the spring will expand the EHT ring again. It has been found that culturing the EHT rings in this manner leads to a considerable increase of contractile properties compared to phasic and static processes (see FIG. 1b). Therefore, both the single engineered heart tissue rings as well as the artificial multiring heart muscle construct consisting of the distinct heart tissue rings show improved maximal active forces during contraction. Under auxotonic load, the EHT rings have to perform contraction under conditions which resemble the systole and diastole phase of the heart cycle. In other words, the engineered heart tissue rings are held under conditions which corresponds to the native environment of active heart tissue.
Auxotonic tensile stress can be applied, for example, by elastically suspending each of the at least two force-generating engineered heart tissue rings between at least two associated suspension means wherein at least one of said associated suspension means is resiliently biased (i.e. mounted to be movable against a bias force) so that the individual force-generating EHT rings are able to contract against the bias force provided by the suspension means and are reexpanded during relaxation of the EHT ring. Preferably each of the force-generating engineered heart tissue rings is suspended between two associated suspension means. Preferably, the two suspension means can be variably adjusted to be used with rings of different diameters. The suspension means may be part of a device as explained in detail below. Such device comprises a pair of suspension means for each EHT ring. According to a further embodiment, all of the associated suspension means are resiliently biased.
Preferably, the at least one suspension means can be adjusted to vary the tensile stress. This means, the load applied to the EHT rings can be easily adjusted to a specific strength by modulating the tension provided by the resilient means. For example, springs can be used as resilient means comprising spring coils which can be adjusted in order to modulate the resilient tension of the spring.
As already mentioned, "auxotonic" tensile stress can be applied simultaneously with placing into contact of the at least two force-generating engineered heart tissue rings. For example, the different EHT rings can be suspended in a device as explained in detail below so that the tissue rings are held in a position that provides for a plurality of contact points between the different heart tissue rings. It has been found that the fusion of the different rings at their contact points occurs also during the different rings are subjected to the tensile stress. Surprisingly, subjecting the heart tissue rings to tensile stress in terms of auxotonic (or phasic or static) load obviously does not hamper formation of a fused multiring construct. Therefore, the culturing which allows fusion of the at least two engineered heart tissue rings to form an artificial heart muscle construct can be performed while the heart tissue rings are held under tensile stress.
According to a further aspect, the invention refers to multiring EHT constructs which comprise at least two force-generating engineered heart tissue rings fused with each other to form an interconnected tissue construct. The multiring engineered heart tissue construct is obtainable according to a method described above. As already explained, the multiring constructs can comprise more than 5 EHT rings, for example 15, 20, 30, 40, 50, or even up to 100. Preferably, each of the EHT rings has an outer diameter of 8-12 mm.
Preferably, the multiring EHT constructs of the invention are comprised of fused engineered heart tissue rings which are stacked to form a central region in which the force-generating engineered heart tissue rings overlap with each other. A construct, which results from stacking of five different tissue rings is depicted in FIG. 8(a). Further examples of multiring EHT construct structures are provided in FIGS. 8(b) and (c). FIG. 8(b) shows a plurality of ring structures which are suspended by a flexible lateral suspension device wherein the distinct ring structures are in contact with each other in the region of contact with the suspension means. It has to be understood by the person ordinary skilled in the art that these examples of ring assemblies are not limiting. A large number of further geometric structures are conceivable for example bag- or net-shaped structures or different forms of stackings.
The multiring heart muscle constructs provided by the present invention show properties which makes them particularly useful for tissue grafts in heart tissue augmentation and/or replacement therapy. In animal models, it has been shown that multiring heart muscle constructs generated from neonatal myocard cells of rats were suitable to provide functional tissue grafts which could be successfully transplanted to infarcted rat hearts and support dysfunctional tissue damaged after myocard infarct (see examples). The multiring engineered heart tissue construct comprise cardiac myocytes, i.e. cells comprising one or more of the following proteins: cardiac myosin heavy chain, α-actinin, desmin and/or cardiac troponin I. It is clear that tissue grafts which are intended to be used in human therapy should be derived from cells of human origin. Therefore, according to preferred embodiment of the present invention, the multiring heart muscle constructs are comprised of force-generating engineered heart tissue rings derived from human cells. The human origin of the EHT can be confirmed by a plurality of different methods known in the art, for example by amplification of species-specific DNA sequences and/or the antibody-based detection of species-specific antigens, such as polypeptides. The preparation of the engineered heart tissue rings starting from human stem cells is exemplified in detail in example 6 of the present invention.
It is preferred that the multiring EHT construct of the invention has a overall twitch tension of more than 2.5 mN, more preferably more than 3 mN, for example 3.5 mN, 4 mN, 4.5 mN, 5 mN, 5.5 mN, 6 mN, 10 mN, 15 mN or more. The capability of the multiring construct to contract can be determined in accordance with methods as described in the prior art, for example, by monitoring the constructs in standard organ baths (see Zimmermann et al., Biotech. Bioeng., 68, (2000)).
According to a further aspect, the invention relates to the use of the multiring EHT construct of the invention for drug target validation and drug development. According to a preferred embodiment, the multiring EHT construct is used in drug screening or target validation assays. In this context, it is preferred that the multiring EHT construct used is derived from a mammal, such as a human. For example, the multiring construct can be used to analyze the capability of candidate drugs to interfere with the physiological function of the native cardiac tissue of a mammal. For this, the capability of said candidate drug to enhance or reduce contractile functions of the multiring EHT construct is determined. Moreover, the multiring EHT construct may be used in determining the influence of the activity of certain genes on the physiological function of the native cardiac tissue of a mammal (referred to herein as target validation). For this purpose, genes of the cells within the distinct EHT rings (or cells which are used for preparing the same) may be knocked-out or overexpressed or otherwise influenced in view of their expression rate (e.g. by addition of inhibitory molecules, such as small interfering RNAs). Genes may be selectively switched on or off, and the alterations in the contractile functions of the multiring EHT construct are determined.
The invention provides a method for providing force-generating engineered heart tissue rings derived from human cells comprising the steps of:    a) providing undifferentiated human embryonic stem cells;    b) culturing said undifferentiated human embryonic stem cells under conditions which allow for propagating the cells;    c) mixing the cells with a suitable scaffold material in a circular casting mold;    d) culturing the human embryonic stem cells under conditions which allow for differentiation of the cells into cardiac myocytes and formation of a tissue ring structure.
The method can be performed by using the cell lines, media and conditions described in example 6 of the present invention. Particularly, the embryonic stem cells may comprise a selection system and may be subjected to selection before or simultaneously with reconstitution of the EHTs. As explained in more detail below, a suitable scaffold material may be collagen type I. As a matter of course, the human force-generating engineered heart tissue rings resulting from the method may also be subjected to tensile stress as described above with respect to the multiring constructs.
Accordingly, the invention further provides a force-generating engineered heart tissue ring derived from human cells, preferably human stem cells. The tissue ring essentially consists of differentiated human cardiac myocytes and other cell types usually found in heart tissue, such as fibroblasts, smooth muscle cells, endothelial cells, cells of leukocytic origin, like macrophages, etc.) which are embedded by a non-cellular matrix. The presence of cardiac myocytes may be confirmed by detecting one or more of the following proteins: cardiac myosin heavy chain, α-actinin, desmin and/or cardiac troponin I.
According to a preferred embodiment, the force-generating engineered heart tissue ring derived from human cells is used in drug screening assays. For example, the EHT ring derived from human cells can be used to analyze the capability of candidate drugs to interfere with the physiological function of the native cardiac tissue of a mammal. For this, the capability of said candidate drug to enhance or reduce contractile functions of the human EHT is determined. Moreover, the force-generating engineered heart tissue ring derived from human cells may be used in determining the influence of the activity of certain genes on the physiological function of the native cardiac tissue of a mammal (referred to herein as target validation). For this purpose, genes of the cells within the EHT ring (or cells which are used for preparing the same) may be knocked-out or overexpressed or otherwise influenced in view of their expression rate (e.g. by addition of inhibitory molecules, such as small interfering RNAs). Genes may be selectively switched on or off, and the alterations in the contractile functions of the human EHT are determined.
According to a further aspect, the invention provides a device for preparing a multiring engineered heart tissue construct, comprising a plurality of associated suspension means for suspending force-generating engineered heart tissue rings under tensile stress, wherein at least one of each of the associated suspension means is resiliently biased so that the suspended force-generating engineered heart tissue ring is able to contract against the bias force provided by the suspension means, wherein the suspension means are arranged to each other so that each force-generating engineered heart tissue ring has one or more contact points to an adjacent force-generating engineered heart tissue ring when suspended in the device. A preferred embodiment of a device according to the invention is depicted in FIG. 10.
Preferably, two suspension means are associated to each other to form a pair of associated suspension means. It is preferred that the device comprises more than two pairs of associated suspension means so that more than two EHT rings can be suspended in the device. Preferably, the device is design for more than 5 EHT rings, for example 15, 20, 30 or even more.
According to a further embodiment, the associated suspension means of the device are arranged to each other so that the force-generating engineered heart tissue rings can be suspended by stacking to form a central region in which the force-generating engineered heart tissue rings overlap with each other.
According to a particularly preferred embodiment, all associated suspension means are resiliently biased. Preferably, at least one suspension means which is resiliently biased can be adjusted to vary the tensile stress.

Multiloop engineered heart muscle tissue


Provided is a handgun recoil spring guide rod having an elongated rod body configured to fit within a compression recoil spring. An axially elongated slot is formed transversely through the body and a blocking member that is configured to fit entirely within the slot and pivotably movable between a first position entirely within the slot and a second position partially protruding from the slot, such that it engages the recoil spring to hold the spring in a more compressed condition.

Handguns must be disassembled from time to time for routine maintenance and periodic cleaning. In a semi-automatic pistol, this entails removing the slide assembly from the frame. In a Model 1911 pattern handgun, it requires removing a barrel pin from the frame while the slide is in a partially retracted position. In order to then remove the recoil spring and guide rod assembly from the slide, the spring must be held in a compressed condition. Various tools have been created to facilitate this, including what may be the simplest: compressing the spring and then inserting a small wire or bent paperclip into a small transverse hole formed in the guide rod near a midpoint. But even this method requires having available some additional item to use as a tool.
A tool-less guide rod is available from Dawson Precision, Inc. of Florence Tex. (http://dawsonprecision.com). The Dawson guide rod includes a lever mounted in a longitudinal trough formed in the guide rod. The lever pivots at a midpoint and, when the forward end is depressed against a spring, a rearward end of the lever is raised to block the recoil spring guide plug and compressed recoil spring. This device functions well, but is expensive to manufacture because it requires precision machining and skill to assemble, and could accumulate difficult-to-remove debris in the trough under the teeter-totter lever.


Compositions having high fluoride ion recovery comprising a hydrocolloid, a heteropolysaccharide, a PVME/MA copolymer, and a fluoride ion source and use thereof, e.g., in the treatment of xerostomia and/or sensitive teeth.

Dental caries is a major dental disease that affects the majority of the population. In the early part of the 20th century, investigators discovered that fluoride was effective in reducing the incidence of caries. Since that time, fluoride research has developed, and it is now well accepted that fluoride treatments benefit dental health.
Most dentifrice compositions contain fluoride ions in the range of 1,000 to 1,500 ppm. However, for some segments of the population, higher amounts of fluoride may be even more beneficial. Some patients often suffer from either aggressive caries, or are otherwise at a higher risk of dental decay than the general population. Other patients suffer from xerostomia, or tooth sensitivity. These patients may benefit from special dentifrices that incorporate high levels of fluoride ions. For example, some such dentifrices incorporate sodium fluoride as a fluoride ion source, in amounts of over 1,500 ppm, such as around 2,000 ppm or around 5,000 ppm.
However, it may be difficult to maintain the effective properties of high levels of fluoride in oral care compositions. Fluoride ion sources may have low solubility, fluoride ions may precipitate out of a dentifrice composition and fluoride ions may react with other ingredients in a dentifrice composition. On the other hand, if more solvent is added to the composition to increase fluoride ion availability, the composition changes and tends to lose the desirable physical characteristics associated with an acceptable dentifrice, e.g., the viscosity of the compositions may be too thin and runny.
The use of mucoadhesive polymers in combination with fluoride is known in the art. However, ionic salts, including fluoride ions known to interact and become entrapped in multiple polymers, causes a reduction of available fluoride ions. Additionally, typical toothpaste compositions containing mucoadhesive polymers may experience undesirable "stickiness" or "tackiness" in the mouth following use.
Thus, there is a need in the art for a high-fluoride content oral care compositions, e.g., for patients who need high levels of fluoride, e.g., those suffering from xerostomia and/or tooth sensitivity. It is further desirable to develop such a composition in which the anticaries activity of the fluoride ion is maintained successfully over time. It is also desirable to develop compositions which do not result in a sticky or tacky sensation following use, and provides a smooth feel during and after brushing.


Provided is an alignment tool for a cutting arrangement including a cutting apparatus with a cutting edge for treatment of a workpiece, especially a rotor blade of a wind turbine, in which the alignment tool includes at least one fixation means for fixing the alignment tool to the workpiece and at least one guiding structure to guide the cutting edge of the cutting tool.

Leading edges of wind turbine blades are protected against rain and erosion by providing a protection layer consisting of ductile and robust material to avoid for instance penetration of rain. However, due to the ductility and the robustness of the material, repair or replacement of the material is difficult due to fraying of the material during cutting. The fraying counteracts the necessity of providing precise cuts in the material for repair or replacement of damaged material at all areas of the wind turbine blade, which are covered by such a leading edge protection material, independently of the local geometry or contour of the rotor blade.

Alignment tool, cutting arrangement and method for treatment of a workpiece


A tunable fluid flow control system for controlling combustion dynamics in a combustor is disclosed. The control system includes a fuel supply path having an inlet portion, a first diverted portion, a second diverted portion, and an exit portion. A first diverted portion has a first length and a first diameter. A second diverted portion has a second length and a second diameter and spaced apart from the first diverted portion. The first and second diverted portions converge at a merging location. The exit portion is coupled to the merging location of the first and second diverted portions. At least one flow regulation device is coupled to the inlet portion and configured to divert fuel flow to the first and second diverted portions alternately to generate fuel flow perturbations at the merging location.

The invention relates generally to control of combustion dynamics in a combustor, and more particularly to a fail-safe and tunable system and method for controlling combustion dynamics in a combustor.
Rotary engines, such as gas turbines, extract energy from a flow of combustion gas. A gas turbine typically includes a compressor coupled to a downstream turbine through a combustor. Combustion gas is generated by combusting a mixture of air and fuel in the combustor. Combustion increases the temperature, velocity and volume of the gas flow. The combustion gas is directed through a nozzle over the turbine's blades, spinning the turbine and powering the compressor.
Lean premixed combustion (LPC) is currently one of the most promising concepts for substantial reduction of emissions while maintaining high efficiency for gas turbine combustors. This mode of combustion is operated with excess air to reduce flame temperatures in combustors to acceptable levels typically less than 1800 Kelvin. At these flame temperatures, the production of thermal NOX (oxides of nitrogen) is virtually eliminated; the production of prompt NOX is negligible. This intrinsic benefit can be offset by several potential disadvantages. LPC systems can have problems with flame stability, noise, and can exhibit system dynamic responses (combustion instabilities).
Combustion dynamics (or instability) is well known problem encountered by the lean premixed combustion systems leading to operational restrictions and even to potential hardware downtime. Fluctuations in fuel-air-ratio may play a vital role in driving the combustion dynamics. There may be primarily two approaches to control combustion dynamics. The first approach may be to control the generating mechanism itself by using fuel-flow fluctuations to drive the stability, for example. A second approach may be to suppress the dynamics generated by using resonators inside combustors, for example, to suppress combustion dynamics. The approaches so far to obtain the fuel flow fluctuations have been to either use high-frequency mechanical modulator valves or fluidic oscillators. The usage of modulator valves or fluidic oscillators has a drawback that a failure of the modulator valve or fluidic oscillator can lead to a disruption of fuel supply to gas turbine causing shutdown. The characteristic response frequency and the amplitude of the fluidic oscillator cannot be controlled.
It is desirable to have a fail-safe and tunable system and method for controlling combustion dynamics in a combustor.

System and method for controlling combustion dynamics