A prefabricated panel for use in assembling swimming pools of the type employing a flexible liner for containing the water. The panel has a reinforcing frame on the back with pivotally mounted deck support members which can be moved out to support a deck on the swimming pool. A plurality of panels can be joined together in a closed configuration forming the sides of the swimming pool and with the bounded area forming the bottom. The pool liner is held along its top edge by a pool liner bead holder fastened along the edge of the assembled panels.. A decorative tile holder is supported about the upper edge of the swimming pool by the pool liner bead holder. The lower edge of the decorative tile holder is held against the side of the pool by a second pool liner bead which is inserted into and held by a channel along the lower edge of the decorative tile holder. The second pool liner bead depends from a flap of material on the pool liner and prevents water from moving behind the decorative tile holder. A complete swimming pool is also disclosed.

At the present time, in-ground swimming pools are generally made through either of two techniques. In the first technique a large hole is excavated in the ground where the swimming pool is desired. The hole is then lined with reinforcing rods and wire and a cement mixture is forced into the reinforcing structure to form the in-ground swimming pool. The top edge of the in-ground pool is usually covered with tile to enhance the overall appearance of the pool. After the pool is completed, a cement deck is usually laid around it to help keep the water clean. This is a very expensive construction technique.
In the second technique, a hole is excavated for the pool and a ledge is formed about two to four feet down from the top of the excavation. The ledge is lined with panels of fiberglass reinforced plastic, structural foam plastic, wood or metal which are joined together and then braced. Stakes are shipped separately from the pool walls and are secured to the pool walls on the job site. They extend perpendicularly away from the walls and have some type of stake receiving anchor at an end remote from the wall. A stake is driven into the ground, through the stake receiving anchor. The wall is usually aligned and the brace and anchor then fixed against relative movement. The walls are then back filled around the bracing. A flexible liner, usually of a vinyl plastic, is then drawn across the pool area confined within the walls. A concrete apron or wooden deck is then assembled around the top edge of the pool walls, extending away from the pool walls over the back fill area.
In an attempt to improve the appearance of the finished flexible lined pools, tile patterns have been printed on the pool liner. While this has an attractive appearance, it is not the same as having actual tile pieces mounted about the edge of the pool. In an attempt to accomplish the latter, U.S. Pat. No. 3,628,198, issued Dec. 21, 1971, to Katzman disclosed a panel which could be snap-fitted into a recess along the top edge of the swimming pool. The panel hung down into the water and substantially improved the appearance of the pool. A serious problem was found, however, in that motion in the pool caused the water to rise behind the panel causing it to flap or swing out away from the wall. This obviously presented a problem in that people going in and out of the pool had to be concerned about the decorative panel and the decorative panel itself was object to failure due to the uncontrolled motion. Children often played with the loose panels and occasionally pulled them free breaking the decorative tiles. The panel also tended to stick out into the pool where it passed over high spots on the inner wall. Also, dirt and algae tended to collect behind the decorative tile panel and extend down onto the pool wall below the tile panel.


A method for exploiting a natural gas hydrate reservoir includes drilling a borehole entering the natural gas hydrate reservoir; perforating the borehole to form perforations; fracturing the natural gas hydrate reservoir via the perforations by using a gas containing calcium oxide powder having a particle size 0.001 to 10 mm to generate a fracture; and collecting natural gas released by the natural gas hydrate. The method is easy to operate, cost-effective, and suitable for commercial applications.

Natural gas hydrate (gas hydrate), being a white solid substance and also known as "combustible ice" or "solid gas" or "steam ice", is an ice-like crystalline substance, has extremely strong combustibility, and is mainly composed of water molecules and hydrocarbon gas molecules (mainly methane). The natural gas hydrate is an ice-like, non-stoichiometric, cage crystalline compound formed by mixing water and a natural gas under medium-high pressure and a low temperature under certain conditions (an appropriate temperature, pressure, gas saturation, water salinity, pH, etc.), on the basis that the oxygen atom in a water molecule has relatively high electronegativity and can attract the hydrogen atom in a water molecule close thereto to form a hydrogen bond under high pressure, thus forming a cage structure. Once the temperature increases or the pressure decreases, a methane gas will escape and the solid hydrate will tend to disintegrate. The natural gas hydrate is widely distributed in continental permafrosts, island slope zones, active and passive continental margin uplifts, polar continental shelves, as well as deep-water environments of oceans and some inland lakes in nature, and can be expressed by mCH4.nH2O, in which m represents the number of gas molecules in the hydrate, and n is the hydration index, that is, the number of water molecules in the hydrate. In terms of the physical properties of the natural gas hydrate, its density is close to and slightly lower than that of ice. The components constituting the natural gas such as CH4, C2H6, C3H8, C4H10 and other homologues, as well as CO2, N2, H2S, etc., may form one or more natural gas hydrates.
In June to September 2013, a high-purity natural gas hydrate sample had been drilled and obtained for the first time in the eastern sea areas of Pearl River Mouth Basin along the coast of Guangdong in China, and considerable controlled reserves were obtained by drilling. In May 2017, trial production of the natural gas hydrate (combustible ice) in the sea areas has achieved a success for the first time in China. On Nov. 3, 2017, the natural gas hydrate was officially approved as a new mineral by the Chinese State Council. The natural gas hydrate is a new type of energy with huge reserves, and thus the trial production thereof has been conducted in countries such as Russia, the United States, Canada, Japan in addition to China. However, the average daily output of the natural gas obtained by various exploiting methods currently used is far from meeting the demands of commercialized development. Among the exploiting methods for a natural gas hydrate currently used, the highest natural gas production in trial production is achieved by a depressurization method, but for such a method, there are still problems such as a low gas production rate of the reservoir to be exploited, instability of the reservoir structure caused by the decomposition of the natural gas hydrate, and an insufficient contact volume.
Therefore, designing a more effective exploiting method for a natural gas hydrate so as to solve the above-mentioned defects in the exploitation of the natural gas hydrate, to further promote the exploitation process of the natural gas hydrate and to meet the demands of large-scale commercialized development, has become one of the focuses of many prospective researchers in the industry.

Exploiting structure for natural gas hydrate reservoir and exploiting method for natural gas hydrate by injecting hydraulic calcium oxide via gas fracturing

INSTITUTE OF GEOLOGY AND GEOPHYSICS, CHINESE ACADEMY OF SCIENCES


The disclosure generally relates to a modular printhead configured for ease of access and quick replacement of the printhead. In one embodiment, the disclosure is directed to an integrated printhead which includes: a printhead die supporting a plurality of micropores thereon; a support structure for supporting the printhead die; a heater interposed between the printhead die and the support structure; and an electrical trace connecting the heater to a supply source. The support structure accommodates the electrical trace through a via formed within it so as to form a solid state printhead containing all of the connections within and providing easily replaceable printhead.

1. Field of the Invention
The disclosure relates to printheads for evaporative printing of materials for organic light emitting device or diode (OLED). More specifically, the disclosure relates to a MEMS printhead fabricated from silicon material and assembled using backside support structure so as to define a modular printhead for ease of construction, attachment and assembly.
2. Description of Related Art
Organic optoelectronic devices, such as organic light emitting diodes (OLEDs) used for flat-panel displays, are fabricated by depositing layers of organic film onto a target substrate and coupling the top and bottom of the film stack to electrodes. Using advanced techniques, film layer thicknesses on the order of 100 nanometers can be achieved.
One such technique deposits OLED film layers onto substrate by thermal evaporation of the organic material from a thermal printhead. The organic ink material is first dissolved in a liquid carrier to form a liquid ink. The ink is transferred to the printhead, and the target substrate and printhead are drawn into close proximity. The ink is then heated in stages. The first stage evaporates the solvent. During the second stage, the ink is heated rapidly above its sublimation temperature until the organic ink materials evaporate to cause condensation of the organic vapor onto the target substrate. The process may be repeated until a desired film layer thickness is achieved. The composition of ink may be varied to achieve different colors and to optimize other properties such as viscosity and sublimation temperature.
In printing such films it also is important to deposit a dry film onto a surface so that the material being deposited forms a substantially solid film upon contact with the substrate. The solid film must have a uniform thickness. This is in contrast with ink printing where wet ink is deposited onto the surface and the ink then dries to form a solid film. Because ink printing deposits a wet film, it is commonly referred to as a wet printing method.
Wet printing methods have several significant disadvantages. First, as ink dries, the solid content of the ink may not be deposited uniformly over the deposited area. That is, as the solvent evaporates, the film uniformity and thickness varies substantially. For applications requiring precise uniformity and film thickness, such variations in uniformity and thickness are not acceptable. Second, the wet ink may interact with the underlying substrate. The interaction is particularly problematic when the underlying substrate is pre-coated with a delicate film. Finally, the surface of the printed film can be uneven. An application in which these problems are resolved is critical to OLED deposition.
The problem with wet printing can be partially resolved by using a dry transfer printing technique. In transfer printing techniques in general, the material to be deposited is first coated onto a transfer sheet and then the sheet is brought into contact with the surface onto which the material is to be transferred. This is the principle behind dye sublimation printing, in which dyes are sublimated from a ribbon in contact with the surface onto which the material will be transferred. This is also the principle behind carbon paper. However, the dry printing approach introduces new problems. Because contact is required between the transfer sheet and the target surface, if the target surface is delicate it may be damaged by contact. Furthermore, the transfer may be negatively impacted by the presence of small quantities of particles on either the transfer sheet or the target surface. Such particles will create a region of poor contact that impedes transfer.
The particle problem is especially acute in cases where the transfer region consists of a large area, as is typically employed in the processing of large area electronics such as flat panel televisions. In addition, conventional dry transfer techniques utilize only a portion of the material on the transfer medium, resulting in low material utilization and significant waste. Film material utilization is important when the film material is very expensive.
In addition, high resolution OLED displays may require pixel characteristic dimensions on the order of 100 microns or less. To achieve this degree of quality control, the printhead gap, that is, the gap between the printhead and the target substrate should be specified on an order of magnitude commensurate with the desired pixel characteristic dimensions. MEMS technology has been proposed for fabricating thermal printheads for evaporative deposition having this level of precision. One of the problems to be solved with this approach, and which is addressed by the present disclosure, is how to deliver thermal energy to the printing surface of a MEMS thermal printhead while enabling a sufficiently small print gap.


A game apparatus for playing a game in which the players simulate being waitpersons in a restaurant and in which the players take and remember lists of food dishes for later recitation and confirmation as to accuracy includes a board having a playing surface divided into segments, each segment assigned to a different player, each segment having table spaces marked thereon corresponding to tables in a restaurant. A set of table cards corresponding to each of the table spaces is provided and a plurality of order sheets for marking down food dishes being ordered is also provided. The order sheets are of a size smaller than the table cards so that they can be covered from view by the table cards during play of the game. A plurality of markers is provided, one marker associated with each player. The markers are moved around the playing surface to predetermined spaces marked on the playing surface. When the predetermined spaces are reached the player can begin taking and reciting orders in order to gain points sufficient to win the game. Preferably, two sets of action cards are provided, bearing messages that affect either the number of points of a player or the position of the player's marker on the playing surface. Preferably, points are kept in terms of dollars and token money, in the form of various denominations, is provided to the players to use in keeping track of the score.

This invention relates to an apparatus for playing a board game and, in particular, relates to an apparatus for playing a board game in which the players act as waitpersons taking orders for various food items, remembering them, and then later reciting the orders.
Games employing movement of playing pieces over a game board are popular and game boards with rectangular, circular, and abstract patterns have been developed for playing such games. However, game apparatus have not been provided that simulate a restaurant situation in which the players assume the roles of waitpersons and, in accordance with the movement of a marker piece on the board, achieve positions in which they are required to take orders for food items from other players and then, after another series of movements of the marker piece on the board, recite those orders from memory, being rewarded for a successful recitation.


An endoscope, particularly an arthroscope, preferably composed of an illumination module (17) and a viewing module (1) which can be connected together, with the viewing module (1) being provided with an optical system carrying shaft (2) which can be inserted into an interior cannula (18) in the viewing module (17), with the optical system carrying shaft (2) being part of a rotary optical system (3) that is surrounded by an optical system guide sleeve (5). The rotary optical system (3) is mounted in a manner secure against rotation and displacement within the optical system guide sleeve (5) and the viewing module includes a coupling device (9) which is connected with the optical system guide sleeve for connection with a removable optical funnel (12) on the side of the eyepiece.

The invention relates to an endoscope composed of an illumination module and a viewing module which are adapted to be connected with one another, the viewing module being provided with an optical system carrying shaft insertable into an interior cannula of the illumination module.
Such endoscopes are employed to examine body cavities and, in the form of arthroscopes, serve to examine and treat joints, usually the knee joints, in that, upon introduction of the arthroscope, the interior of the joint can be viewed. Preferably for the diagnosis of meniscus injuries arthroscopy is a frequently employed procedure.
Since the interior of the joint is not only viewed but also illuminated, endoscopes, such as, for example, the endoscope disclosed in German Utility Model Patent DE-GM 88/14,573, are provided with preferably separate illumination and viewing modules which can be plugged together. The viewing module includes a shaft carrying the optical system, an objective lens to be introduced into the interior of the joint at the distal end of the shaft and an eyepiece at the proximal viewing end of the shaft, and can be pushed into the light shaft of the illumination module.
However, the drawback of the prior art endoscopes is that the viewing component must always be replaced completely if an optical system having a different viewing angle is required for the further examination or must be replaced in the case of a defect. In particular, if the optical system is changed, manipulations are always required in the sterile region as well as in the non-sterile region so that a cover separating the respective regions must also always be replaced.

Modular endoscope having easily replaceable parts


The APPARATUSES, METHODS AND SYSTEMS FOR A RISK-ADJUSTED RETURN MAXIMIZING INVESTMENT STRUCTURE (“RAR-MAX”) transform market data, client's investment request inputs, and/or the like via RAR-MAX components into transaction record, investment return outputs, and/or the like). A method is disclosed, comprising: formulating a portfolio of a plurality of contract positions; determining hedge roll dates for each contract position in the portfolio; determining a first expiring financial instrument on a first hedge roll date; determining a first plurality of parameters for a first new financial instrument; rolling the first expiring financial instrument to the first new financial instrument associated with the determined first plurality of rollover parameters on the first hedge roll date; determining a second expiring financial instrument on a second hedge roll date; determining a second plurality of parameters for a second new financial instrument; and rolling the second expiring financial instrument to the second new financial instrument associated with the determined second plurality of rollover parameters on the second hedge roll date.

Different financial instruments have been utilized to provide investment options to investors. For example, bonds, forward contracts, futures, options, swaps and/or the like can be constructed to satisfy different investment objectives of investors. Investors may be interested in investing in different asset classes.
The leading number of each reference number within the drawings indicates the figure in which that reference number is introduced and/or detailed. As such, a detailed discussion of reference number 101 would be found and/or introduced in FIG. 1. Reference number 201 is introduced in FIG. 2, etc.

Apparatuses, methods and systems for a risk-adjusted return maximizing investment structure


A touchpad module includes a bracket member, a touch member, a supporting element and two elastic elements. The touch member is arranged between a first strip part and a second strip part of the bracket member. The supporting element is arranged between the elastic elements and the touch member. Each elastic element includes a swinging part, a fixing part and a shaft part. The fixing parts are installed on the first strip part and the second strip part, respectively. The swinging part and the fixing part are wider than the shaft portion. In response to an external force, the touch member is swung relative to the bracket member by using the shaft parts as fulcrums. While the touch member is swung, the shaft parts are subjected to deformation and the supporting element and the swinging parts are swung relative to the fixing parts.

With increasing development of science and technology, a variety of electronic devices are designed in views of convenience and user-friendliness. For helping the user well operate the electronic devices, the electronic devices are gradually developed in views of humanization. The common electronic devices include for example notebook computers, mobile phones, satellite navigation devices, or the like. Recently, the storage capacity and the processor's computing performance for these electronic devices are largely enhanced, and thus their functions become more powerful and complicated. For efficiently operating an electronic device, a touchpad is used as an input device of the electronic device for controlling the operations of the electronic device.
FIG. 1 schematically illustrates a conventional notebook computer with a touchpad module. As shown in FIG. 1, the touchpad module 1 is installed on a casing 21 of the notebook computer 2. Moreover, at least a portion of the touchpad module 1 is exposed outside so as to be touched by the user's finger. Consequently, the user may operate the touchpad module 1 to control the notebook computer 2. For example, in case that the user's finger is placed on the touchpad module 1 and slid on the touchpad module 1, a cursor 23 shown on a display screen 22 of the notebook computer 2 is correspondingly moved. Moreover, in case that the touchpad module 1 is pressed down by the user's finger, the notebook computer 2 executes a specified function. The use of the touchpad module 1 can implement some functions of the conventional mouse. In other words, the user may operate the notebook computer 2 through the touchpad module 1 without the need of additionally carrying or installing the mouse.
FIG. 2 is a schematic cross-sectional view illustrating the touchpad module as shown in FIG. 1, in which the touchpad module is not pressed down. FIG. 3 is a schematic cross-sectional view illustrating the touchpad module as shown in FIG. 2, in which the touchpad module is pressed down. As shown in FIGS. 2 and 3, a fixing frame 24 is concavely formed in a casing 21 of the notebook computer 2. The touchpad module 1 is installed in the fixing frame 24. The touchpad module 1 comprises a supporting structure 11, a triggering part 12 and a touch member 13. The supporting structure 11 and triggering part 12 are located at two opposite sides of the fixing frame 24. The touch member 13 of the touchpad module 1 is connected with the supporting structure 11. Consequently, the touch member 13 of the touchpad module 1 may be swung relative to the triggering part 12 by using the supporting structure 11 as a fulcrum. The touchpad module 1 further comprises a switch 14. The switch 14 is located under the touch member 13 and aligned with the triggering part 12.
While the touch member 13 is pressed down by the user, the touch member 13 is swung downwardly relative to the triggering part 12 by using the supporting structure 11 as a fulcrum. When the switch 14 of the touchpad module 1 is pushed by the triggering part 12 of the fixing frame 24, the switch 14 is triggered to generate a switch signal to the notebook computer 2. According to the switch signal, the notebook computer 2 executes a corresponding function. When the touch member 13 is no longer pressed by the user, the touch member 13 is swung upwardly relative to the triggering part 12 in response to the elastic force of the supporting structure 11. Consequently, the touch member 13 is returned to its original position.
However, the conventional touchpad module 1 still has some drawbacks. For example, the supporting structure 11 is connected with the upper component and the lower component through iron elements or plastic structures (e.g., sponge structures). Consequently, as the iron elements or plastic structures are subjected to deformation, the touch member 13 can be swung upwardly or downwardly. Due to the design of the supporting structure 11, the upward/downward swinging action of the touch member 13 is usually aslant and unstable.
Therefore, there is a need of providing an improved touchpad module in order to overcome the above drawbacks.

Touchpad module and computing device using same


The invention provides a compound of formula I:

5-Fluorouracil (5-FU) is well-established as a chemotherapeutic agent in the treatment of a variety of cancers (e.g. colon, pancreatic, breast). 5-FU irreversibly inhibits thymidylate synthase to block the synthesis of thymidine, an essential nucleotide required for DNA replication. 5-FU has been listed by the World Health Organization as one of the most important medications needed in a basic health system. However, there are many severe side effects associated with 5-FU treatment, including diarrhea, nausea, neutropenia, mouth sores, etc. Additionally, the resistance to 5-FU developed among patients also limits its clinical applications. Currently there is a need for new agents with a larger therapeutic window, lower toxicity, fewer side effects, increased solubility and/or improved pharmacokinetic profile that are useful for treating or preventing cancer.
Efficacy of active pharmaceutical ingredients (APIs) is known to be influenced by formulation methods. Among the formulation strategies being studied for solid form delivery of APIs, co-crystallization has been shown a promising means of improving physicochemical properties relative to effective drug delivery. Furthermore, a recent report on the use of a photodimer of 5-FU to function as a prodrug demonstrates the potential of delivering anticancer agents with excellent therapeutic efficacy to cancer cells, while avoiding side effects in normal cells (Q. Jin, F. Mitschang and S. Agarwal, Biomacromolecules, 2011, 12, 3684).

Abstract: wherein X, Y, Z have any of the values defined in the specification or a salt thereof. The compound is useful as anti-cancer agents. The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.


A differential gearing for a motor vehicle, comprising a drive gear, by means of which torque can be introduced into the gearing, a first output element and a second output element, by means of which the torque can be output from the gearing, a differential housing attached to the drive gear in a rotationally fixed manner, wherein the drive gear and the differential housing together form a differential cage for transmitting torque from the drive gear to the first output element, wherein the first output element is arranged in such a way that the first output element can be rotated in relation to the differential cage, and a first rolling-element bearing for supporting the differential hosing on a housing, wherein a bearing shell of a second rolling-element bearing is directly attached to the drive gear in a rotationally fixed manner.

German publication no. DE 10 2012 206 443 A1 (Biermann et al.) discloses a planetary gear differential transmission for a motor vehicle, the planetary gear differential transmission comprising a driving gear, by means of which the torque can be introduced into the transmission; comprising a first output member and a second output member, by means of which the torque can be outputted from the transmission; comprising a differential cage, which is designed to transmit the torque from the driving gear to the first output member, wherein the differential cage is attached to the driving gear in a rotationally fixed manner; and the first output member is arranged in such a way that it can be rotated in relation to the differential cage; and comprising a rolling bearing with a bearing shell, which is attached to the differential cage in a rotationally fixed manner.
For example, DE 10 2011 085 119 B3 (Martini et al.), discloses differential transmissions. Thus, this document discloses a spur gear differential, comprising a planetary gear carrier and two sun gears, which can be rotated relative to the planetary gear carrier, at least one friction disk and at least one spring means, which biases the sun gears relative to the planetary gear carrier. The spring means is spring-mounted, on the one hand, against a sun gear or the planetary gear carrier and, on the other hand, against an axial bearing. The geometrical and functional features, which are disclosed in DE 10 2011 085 119 B3 (Martini et al.), shall be incorporated by reference in its entirety.

Supporting assembly for a lightweight differential


A valve system enables use of a standard single line faucet with a water treatment system, protects water treatment systems and other fluid flow devices from unnecessary fluid pressure, and regulates or prevents fluid flow to a dispenser or outlet in response to a particular event, such as a leak. The valve system includes a housing having ports for: (1) receiving a supply fluid, (2) supplying the fluid to a device, such as a water treatment system, (3) receiving the fluid from the device and (4) supplying fluid to a dispenser. The valve system also includes an automatic shutoff device within the housing that prevents water from flowing into the housing and the water treatment system when the dispensing outlet is closed and that allows water to flow through the housing and into the water treatment system when the outlet is open. The valve system may also include a second actuator connected to the automatic shutoff that is capable of moving the automatic shutoff to a partially or fully closed position.

The present invention is directed to valve systems, and more particularly to a valve system for regulating flow and pressure in water treatment systems and other fluid flow systems.
Water treatment systems are well known for providing filtered, treated water. These systems typically include an inlet for receiving untreated water from a supply line, one or more filters for treating the water, and an outlet for the treated water. The treated water outlet may be connected to a outlet, such as a faucet, that can be opened (i.e. "turned on") to dispense the treated water. Currently, many water treatment systems can only be used with a "three-line" faucet that includes a first line for untreated water supply to the water treatment system, a second line that receives the treated water from the system, and a third line that receives untreated water from a supply source. This configuration serves to limit pressure on the water treatment system when 'waiting' to dispense water, because the water treatment system only experiences pressure when the valve on the faucet is open. Unfortunately, there are only a limited number of styles and options for three-line faucets, creating a need for a system that enables the use of a standard single-line faucet for dispensing treated water from a water treatment system while limiting the pressure on the system.
In addition to water treatment systems, a variety of other fluid flow systems, such as hot water heaters, beverage vending machines, and hydraulic and pneumatic cylinder systems suffer from disadvantages associated with the constant fluid pressure on the system. The high fluid pressure experienced by many of these systems places a strain on the connectors, housings, and other system components, and can make it difficult to conduct maintenance on the system without shutting off the fluid source at a separate, and sometimes remote, location. Even greater problems are caused when this high pressure causes the water treatment system or another type of fluid flow system to fail, causing the fluid to leak continuously until it is detected and can be shut off at its source.

This patent is subject to a terminal disclaimer.


In a method of annealing a workpiece which has a substrate and a light absorption film on the substrate, a laser beam is irradiated onto a workpiece to only heat the light absorption film without any temperature rise of the substrate and to anneal an internal stress of the light absorption film. A wavelength of the laser beam is selected so as to be absorbed into the light absorption film. The workpiece may be a photo mask blank (or a photo mask) or a phase shift mask blank (or a phase shift mask).

This invention relates to a method of manufacturing a mask blank and a mask each of which is used in a lithography process on fabricating a semiconductor device or the like and, in particular, to a mask blank and a method pertinent to KrF excimer laser, ArF excimer laser, or F2 excimer laser.
With fineness of a semiconductor circuit and the like, it is a recent trend that requirements have been directed to using an exposure source of a short wavelength in lithography and using lenses of a high numerical aperture (NA) in an exposure apparatus. However, it is to be noted that a high numerical aperture (NA) of the exposure lenses and a depth of focus reside in a trade-off relationship.
In order to attain a depth of focus, flatness required for a photo mask has become severe more and more and should be recently reduced to a range from 0.3 xcexcm to less than 0.5 xcexcm.
In the meanwhile, the flatness of the photo mask depends on bending strength of the transparent substrate, flatness of a substrate prior to deposition of any films, and internal stress of films that form a circuit pattern and the like. Among others, the internal stress of the films has raised a serious problem. Herein, flatness is defined by a difference between a highest point and a lowest one from an average plane determined on a surface used for exposure and can be given by measuring a configuration of a substrate by the use of an optical interferometer. The internal stress is given by the following formula (1):
xe2x80x83Eb2/[6(xcexdxe2x88x921)rd]xe2x80x83xe2x80x83(1)
where E is representative of Young""s modulus; b, a thickness of a substrate; xcexd, a Poisson""s ratio; r, a variable component of a radius of curvature of the substrate; and d, a thickness of a thin film.
In order to satisfy the flatness required for the photo mask, the film for forming the circuit pattern has the internal stress preferably not greater than 5xc3x97108 Pa when use is made of a synthetic quartz substrate of 6 inches square that has a thickness of 0.25 inch and that has films of 70 nm thick.
The internal stress of the films for the circuit pattern is generated during a process of manufacturing a photo mask blank that may be called a substrate with films and that serves to form a photo mask. Taking this into consideration, it has been found out that flatness should be improved in a photo mask blank so as to establish excellent flatness of the photo mask.
Herein, consideration is made about a method of controlling stress of the films for forming the circuit pattern. A method of controlling such stress can include a method of adjusting during a stage of depositing the film and a method of adjusting after deposition of the film.
In the method of adjusting during the deposition stage, a difficulty is present about making adjustment of the stress compatible with keeping characteristics necessary for the photo mask blank. Such characteristics may be an optical characteristic, chemical durability, and the like. Especially, it is often difficult to adjust the stress by deposition conditions in the case where the internal stress is compressive stress.
On the other hand, the instant has already filed Japanese Patent Application No. 2000-277215 and has proposed a method of reducing compressive stress in films for forming the circuit pattern. According to this method, a mask blank is manufactured by utilizing heat treatment carried out after deposition of films.
As any other conventional treatment methods, consideration is made about a method of using a clean oven, a method of using a hot plate, a method of using a lamp heater.
In Japanese Unexamined Patent Publication No. Hei 7-104457, namely, 104457/1995, disclosure is made about a method of manufacturing a half tone phase shift mask. Specifically, the method deposits a translucent film and thereafter forms a stabilization layer on the translucent film. The stabilization layer serves to protect a variation of characteristics in the translucent film that might occur due to irradiating light by a mercury lamp, heating, oxidizing, and due to irradiation of exposure light.
Alternatively, disclosure is also made in Japanese Unexamined Patent Publication No. Hei 8-220731, namely, 220731/1996 about a technique of stabilizing a translucent film of a half tone phase shift mask. According to this technique, the translucent film is irradiated by light, heat, an electromagnetic wave, a particle beam after deposition in an atmosphere of a vacuum, a rare gas, or a reactive atmosphere. In this case, a light source for irradiating light and the like may be, for example, either one of a heavy hydrogen lamp, a Xe lamp, and an excimer laser source, or a combination thereof.
Among the above-mentioned conventional methods, the heat treatment method should heat the transparent substrate to a high temperature not lower than 400xc2x0 C. with the film deposited on the transparent substrate, so as to reduce or alleviate the internal stress of the film. Such a high temperature inevitably lengthens heating and cooling time and lowers productivity.
When heat treatment is carried out by the use of the heat processing apparatus, there is a temperature limit. Consequently, a reduction effect of the internal stress is insufficient for flatness required for the photo mask.
In addition, the light irradiation for the above-mentioned stabilization is not enough to reduce the internal stress because the film can not be heated to a temperature sufficient to alleviate the internal stress.
It is a first object of this invention to provide a method of manufacturing a mask blank, wherein a time needed for improving an internal stress is very short and the internal stress is remarkably improved.
Especially, this invention makes it possible to improve an internal stress of a film that has a difficulty of improving the internal stress and provides the method of manufacturing the mask blank, wherein the internal stress of the film is largely improved.
It is another object of this invention to provide a method of manufacturing the mask blank, which can reduce the internal stress in the film and also improve optical characteristics of the film.
It is still another object of this invention to provide a mask blank or a mask that is not greater than 0.5 xcexcm in flatness.
In order to accomplish the above-mentioned objects, this invention has the following constitution.
(Constitution 1)
A method is for use in manufacturing a lithography mask blank on a transparent substrate. According to this invention, the method comprises the steps of depositing, on the transparent substrate, at least one light absorption film which has a property of absorbing a laser of a predetermined wavelength, and irradiating a laser beam of the predetermined wavelength onto the light absorption film to heat the light absorption film and to thereby alleviate its internal stress.
(Constitution 2)
The mask blank according to Constitution 1 is a phase shift mask blank and the light absorption film is formed by a translucent film which serves as a phase shift film of the phase shift mask blank so as to attenuate exposure light of predetermined intensity.
(Constitution 3)
The mask blank mentioned in Constitution 1 has at least one shield or opaque film and the light absorption film is formed by the opaque film.
(Constitution 4)
In the method according to either one of Constitutions 1 through 3, the laser beam is irradiated onto the mask blank so that the transparent substrate with the light absorption film has flatness not greater than 0.5 xcexcm.
(Constitution 5)
A lithography mask blank according to Constitution 5 is manufactured by the method mentioned in either one of Constitutions 1 through 4.
(Constitution 6)
A lithography mask according to Constitution 6 is manufactured by the use of the mask blank mentioned in Constitution 5.
In order to accomplish the above-mentioned objects, the transparent substrate after deposition of the light absorption film is irradiated by a laser beam in this invention to heat the light absorption film. A stress annealing or alleviating effect according to this invention might result from an effect similar to a heat treatment. However, the laser annealing according to this invention is featured by heating a film for an extremely short time of, for example, several tens of nanoseconds and by heating the film to a highest heating temperature of 1000xc2x0 C. or more. The above-mentioned features bring about a high annealing effect and high productivity that can not be accomplished by the conventional methods.
Specifically, the laser light or beam is transmitted through the transparent substrate but absorbed by the light absorption film. Taking this into consideration, the laser beam of sufficient intensity is irradiated onto the film for such a short time that any damage takes place in the film and heat is not conducted from the heated film to the transparent substrate. In this case, the light absorption film is effectively heated but the transparent substrate is scarcely heated.
Herein, it is to be noted that the thickness of the light absorption film is sufficiently thin in comparison with that of the transparent substrate. Therefore, the light absorption film heated by the laser beam is quickly cooled as compared with the transparent substrate that is not heated after the laser irradiation. Eventually, the temperature of the transparent substrate with the light absorption film is kept substantially invariable during the light irradiation.
The method according to this invention can remarkably shorten the heating and the cooling times and improve the productivity by the above-mentioned effect and is more advantageous in comparison with the conventional method of heating a whole of the transparent substrate with the film by using the oven or the hot plate.
In the method according to this invention, the light absorption film alone is selectively heated by irradiating the laser beam and the resultant transparent substrate is not damaged by the laser irradiation. This makes it possible to sufficiently strengthen the intensity of the laser beam and to sufficiently suppress the internal stress, such as the compressive stress, of the film that may be used for forming a circuit pattern, when the film is formed by the light absorption film. In addition, the internal stress is largely improved in this invention as compared with the conventional heat processing method. This is because the heat treatment is carried out at the temperature which is as high as 1000xc2x0 C. and which can not be accomplished in the conventional heating apparatus.
As mentioned before, irradiating the laser beam onto the transparent substrate with the light absorption film is effective to greatly shift the compressive stress of the light absorption film to a tensile stress side. Consequently, the method according to this invention can easily accomplish desired flatness of the photo mask for a very short time.
Herein, this invention will be described in detail.
It is necessary in this invention to deposit, on a transparent substrate, at least one light absorption film having a property of absorbing a laser beam. In other words, the light absorption films may be composed of a plurality of light absorption layers.
Alternatively, the light absorption film may also be formed by a stacked structure of a light absorption lamina having a light absorption property and an upper lamina that has no light absorption property and a thin thickness. In this case, since the upper lamina having no light absorption property is thin enough, the light absorption lamina is sufficiently heated indirectly via the upper lamina by the laser irradiation. Such absorbing the laser light can be accomplished when the light absorption lamina is located at an uppermost position of either of the transparent substrate or a multi-layer structure or may be placed at a position intermediate between the multi-layer.
The light absorption film which has the light absorption property may be a translucent film used in the half tone phase shift mask or an opaque film in the binary mask or a Levenson phase shift mask. In other words, the light absorption film may be used as a light translucent phase shift film in the half tone phase shift mask blank or an opaque film in the photo mask blank as it is, when exposure is made by using a laser, such as KrF excimer laser, ArF excimer laser, F2 excimer laser, as an exposure light source.
When deposition is made of a plurality of light absorption laminae or a stacked structure of a light absorption lamina and a light non-absorption lamina, the plural laminae may be operable as a light translucent phase shift film in the half tone phase shift mask blank or as an opaque film or a circuit pattern forming film in the photo mask blank.
As a material of the light absorption film operable as the translucent film in the phase shift mask blank, it is possible to exemplify nitrides or nitride oxides of metal and silicon (metal may be, for example, Mo, Ti, V, Zr, Nb, Ta, W, Hf, Cr and etc.), metal nitrides, and/or metals. In this event, the light absorption film is operable not only to absorb the laser beam irradiated on heating the film but also to transmit the laser beam irradiated from an exposure source to some extent. Herein, the light non-absorption film may be formed, for example, by SiO2, Si3N4, Al2O3, CaF2, CrOx, CrFx, and so on.
As regards the phase shift mask blank, it is preferable to carry out heat treatment due to laser irradiation of a laser that has the same wavelength as the laser light source used as the exposure light source. However, it should be considered that high power KrF, ArF, F2 excimer lasers seriously damage an optical system. Taking the above into account, XeCl laser may be practically used which has a wavelength of 308 nm comparatively near to a light source wavelength of the exposure light source.
The light absorption film which as an opaque film in the photo mask blank may be, for example, Si, Ti, V, Cr, Zr, Nb, Mo, Ta, W, Ru, Rh, Hf or the like. In this case, such a light absorption film acting as the opaque film is operable not only to absorb a laser beam used for heating by irradiation but also to shield or shade a laser beam or the like for exposure. This means that the light absorption film has a dense optical density for the laser beam or the like. On the other hand, a light non-absorption film usable for the photo mask blank may be, for example, Si3N4, CrOx, CrFx, or the like.
As for the photo mask blank, the laser irradiation for heating be preferably carried out by the same wavelength as that of the laser source used as the exposure light source but may be carried out by a wavelength which is longer than that of the exposure light source.
In general, the light absorption film according to this invention may be formed by a material that may have an absorption ability of a laser beam. At any rate, such a material may be used for an etching mask film, an antireflection film, or any other films used for any other purposes.
Herein, description will be made about an advantage of this invention in the following. As regards the phase shift mask blank, the conventional heat processing method of heats a whole of a transparent substrate with a translucent film which satisfies optical characteristics as the phase shift mask and can not often sufficiently reduce the internal translucent film of the translucent film. On the other hand, when a high power laser beam is irradiated for a short time in accordance with this invention, the internal stress of the translucent film is effectively and greatly reduced as compared with the conventional heat processing method mentioned above. Output power of the laser beam should be preferably increased within a range of giving no damage onto the film or the substrate. Such high power irradiation can shorten a process time (second unit). In any event, the output power of the laser beam is higher than that of the laser beam used for exposure.
Specifically, this invention can reduce the internal stress of the translucent film to zero or about zero, even when the translucent film is formed by a material that can not reduce the internal stress in the conventional methods. Such a translucent film that can not always reduce the internal stress by the use of the conventional methods may be, for example, nitrides or nitrided oxides of metals and silicon, or a multi-layer composed of a combination of Si3N4, and metal nitrides.
Furthermore, when this invention is applied to the phase shift mask blank, it is possible not only to reduce the internal stress of the translucent film but also to improve the optical characteristics of the translucent film required for the optical characteristics of the phase shift mask blank. Herein, the optical characteristics of the translucent film may be, for example, a desired transmittance and phase angle for exposure light, a required transmittance for test light, chemical durability, irradiation durability, and the like. According to the inventors"" experimental studies, it has been found out that a variation of the transmittance and phase angle due to the laser irradiation of this invention is improved in comparison with the conventional heat processing method. This shows that this invention can improve only the internal stress by the laser irradiation with the variation of the transmittance and phase angle suppressed.
Consideration will further be made about the wavelength of the laser beam in the following. The wavelength of the laser beam may be varied in dependency upon a film material and, therefore, can not be definitely determined. However, the wavelength of the laser beam preferably falls within a range between 157 and 633 nm, and more preferably within a range between 248 and 308 nm. In addition, laser intensity can not be definitely determined because it differs from each material of the translucent film but an energy density may be preferably between 100 mJ/cm2 and 500 mJ/cm2, more preferably between 200 mJ/cm2 and 400 mJ/cm2. At any rate, it is preferable that heating due to laser irradiation may be performed in a vacuum or an inert gas.
As regards the photo mask blank, this invention is also effective to efficiently reduce the internal stress of the opaque film by laser irradiation, in comparison with the conventional heat processing method.
Specifically, this invention can reduce the internal stress of the opaque film to zero or about zero, even when the opaque film is formed by a material that can not reduce the internal stress in the conventional methods. Such an opaque film that has a difficulty of reducing the internal stress by the use of the conventional methods may be, for example, Ta, Si, Nb, Mo, W, and so on.
Like in the translucent film, when this invention is applied to the photo mask blank, it is possible not only to reduce the internal stress of the opaque film but also to improve the optical characteristics of the opaque film required for the optical characteristics of the photo mask blank. Herein, the optical characteristics of the opaque film may be, for example, an optical density, chemical durability, irradiation durability and the like.
As regards the wavelength of the laser beam, it may be varied in dependency upon a film material of the opaque film and, therefore, can not be definitely determined. However, the wavelength of the laser beam preferably falls within a range between 157 and 633 nm, and more preferably within a range between 248 and 308 nm. In addition, laser intensity can not be definitely determined because it differs from each material of the opaque film but an energy density may be preferably between 50 mJ/cm2 and 500 mJ/cm2, more preferably between 100 mJ/cm2 and 300 mJ/cm2.
When the light absorption film is composed of a plurality of laminae, laser irradiation in this invention may be repeated plural times by selecting an optimum laser wavelength and laser intensity.
In the case of the phase shift mask blank, the light absorption film for the laser beam may preferably have flatness not greater than 0.5 xcexcm after laser irradiation of the transparent substrate, and more preferably, not greater than 0.4 xcexcm, 0.3 xcexcm, or 0.2 xcexcm.
Likewise, in the case of the photo mask blank, the light absorption film for the laser beam may preferably have flatness not greater than 0.5 xcexcm after laser irradiation of the transparent substrate, and more preferably, not greater than 0.4 xcexcm, 0.3xcexcm, or 0.2 xcexcm.
Thus, it is possible for this invention to highly improve the internal stress and to enhance an amount of improvement in the flatness to not smaller than 0.3 xcexcm. Such improvement can be established during a very short time (several seconds). Specifically, the flatness of 0.8 xcexcm or more can be achieved for a very short time and can not be accomplished by the heat treatment.
In the phase shift mask or mask blank and the manufacturing the same, no restriction is imposed on the transparent substrate, if the transparent substrate is transparent for an exposure wavelength. Such a transparent substrate may be, for example, a quartz substrate, a fluorite surface, and any other glass substrates or hardened substrates (formed by soda-lime glass, aluminosilicate glass, aluminoborosilicate glass, or the like.
Furthermore, a patterning process (patterning or masking process) of processing the film on the substrate may be carried out by the use of a known lithography technique (photo or electron beam lithography technique) that is used to coat resist, expose, develop, etch, peel the resist, and clean.
Eventually, the laser irradiation may be carried out after deposition of forming patterns.

Lithography mask blank and method of manufacturing the same


Process artifacts and elements in a business process model, such as a Business Process Modeling Notation (BPMN) compliant model, may be analyzed, converted into component model building blocks for developing applications, and enriched with technical metadata. The component model building blocks may be Service Component Architecture (SCA) Assembly Model building blocks, which may include artifacts, components, composites, and other elements. The building blocks may be structured in an output file, which may be a Simple Capabilities Description Language (SCDL) file, according to the Service Component Architecture (SCA) Assembly Model based on an order provided in the business process model. Business process model elements may be mapped to corresponding component model building blocks, such as SCA artifacts, composites, or components, through a lookup table or database.

Organizations rely on computing systems and applications to perform different business processes. For example, inventory control systems may be used to manage and track product distribution and task management systems may track progress to a goal. Although organizations often obtain different systems from different manufacturers, they nonetheless expect the different systems to interact with each other.
This is especially true when organizations develop new applications or functionality in existing applications to support new business processes. Aside from expecting interactivity between systems, organizations also seek to minimize costs when developing these new applications or functionalities. One way of minimizing development costs is to use business process modeling software to enable business analysts and those familiar with the organization's business processes to model those processes. However, development costs are not fully minimized because an experienced computer programmer may still be needed to convert the modeled processes into application code.
Business Process Modeling Notation (BPMN) may be used to graphically represent and model business processes. BPMN uses standardized symbols and flowcharts to visually describe processes intuitively to business users while also incorporating complex functions and semantics for technical users. This functionality makes BPMN useful to both business and technical users.
FIG. 1 shows an exemplary business process model 100 based on the BPMN specification. The model includes a pool 110 that may be subdivided into one or more lanes 120. A pool 110 may represent an entity involved in a process. An entity may include a technical system, business partner, corporate subsidiary, branch, or other division of systems or organizations. If multiple entities are involved in completing a process, then multiple pools may be included in the model. Each pool 110 may contain one or more lanes 120. A lane 120 may be used to organize and separate different functions or roles within an entity. Lanes may contain flow objects, connecting objects, and artifacts. Flow objects may include events 121, 123, 125, activities, or tasks 124. Connecting objects may include sequence flows 122 and message flows 131. Artifacts may include data objects 132.
An event 121, 123, 125 represents a synchronization between a business process and an external environment, which may occur by sending or receiving an event to a component of the external environment. An activity or task 124 represent something is performed. A start event 121 triggers the start of a process and is also known as a Catch Event because it may receive or "catch" an incoming message to begin the process. Intermediate events 123 represent actions, such as catch or throw events, that occur between the start and end of a process. End events 125 represent a concluding result of completing the process. End events 125 may also be known as Throw Events because they may send or "throw" the concluding result to another entity, process, or system.
Activities and tasks 124 may represent work that is to be performed by an entity or process. Sequence flows 122 may represent a chronological order in that steps of a process are executed. Message flows 131 may show the types of messages that may be exchanged between different business processes, that may, in some instances, be exchanged between different organizations, systems, or entities. Finally, data objects 132 may identify a local state of a business process.
While business process models, including BPMN-compliant models, may be used by business users to intuitively model business processes, application code may not be directly generated from these business process models. Furthermore, organizations with multiple systems from different vendors that expect interactivity between the systems may not be able to simply convert business process models to application code. Thus, the practicality of business process models has been limited to intuitive visualizations of business processes.
There is a need for converting business process models to programming and component models better suited for application delivery that conform with the principles of a technologically agnostic service-oriented architecture to support connectivity between different systems.

Converting business process models to component models in a service oriented architecture domain


Two-chain high molecular weight kininogen, and peptide analogs thereof having homology to sites within kininogen domain 5, are potent inhibitors of angiogenesis. The peptides have the formula X1-His-Lys-X-Lys-X2 wherein

The invention relates to therapeutic compounds and methods for inhibiting angiogenesis.
Angiogenesis
Angiogenesis is the process in which new blood vessels grow into an area which lacks a sufficient blood supply. Angiogenesis commences with the erosion of the basement membrane surrounding endothelial cells and pericytes forming capillary blood vessels. Erosion of the basement membrane is triggered by enzymes released by endothelial cells and leukocytes. The endothelial cells then migrate through the eroded basement membrane when induced by angiogenic stimulants. The migrating cells form a xe2x80x9csproutxe2x80x9d off the parent blood vessel. The migrating endothelial cells proliferate, and the sprouts merge to form capillary loops, thus forming a new blood vessel.
Angiogenesis can occur under certain normal conditions in mammals such as in wound healing, in fetal and embryonic development, and in the formation of the corpus luteum, endometrium and placenta. Angiogenesis also occurs in certain disease states such as in tumor formation and expansion, or in the retina of patients with certain ocular disorders. Angiogenesis can also occur in a rheumatoid joint, hastening joint destruction by allowing an influx of leukocytes with subsequent release of inflammatory mediators.
The evidence for the role of angiogenesis in tumor growth was extensively reviewed by O""Reilly and Folkman in U.S. Pat. No. 5,639,725, the entire disclosure of which is incorporated herein by reference. It is now generally accepted that the growth of tumors is critically dependent upon this process. Primary or metastatic tumor foci are unable to achieve a size of more than approximately 2 mm in the absence of neovascularization. Serial evaluation of transgenic mice predisposed to develop neoplasms has demonstrated that neovascularization of premalignant lesions precedes their evolution into tumors (Folkman et al., Nature 339:58-61, 1989), and that inhibition of angiogenesis delays the growth of such lesions, as well as their assumption of a malignant phenotype (Hanahan et al., Cell 86:353-364, 1996). In humans, several studies have demonstrated that increased density of microvessels within a tumor is associated with a poor clinical outcome (Weidner et al., J Natl Cancer Inst 84:1875-1887, 1992).
An emerging paradigm is that proteolytic fragments of plasma or extracellular matrix proteins regulate angiogenesis. To date, several polypeptides with such activities have been identified. These include angiostatin, which contains kringles 1-4 plasminogen (O""Reilly et al., Cell 79:315-328, 1994), endostatin, a 20 kD C-terminal fragment of collagen XVIII (O""Reilly et al., Cell 88:277-285, 1997), PEX, the hemopexin domain of matrix metalloprotease 2 (Brooks et al., Cell 92:391-400, 1998), the C-terminal 16 kD fragment of prolactin (Clapp et al., Endocrinol 133:1292-1299, 1993) and a 29 kD fragment of fibronectin (Homandberg et al., Am J Pathol 120:327-332; 1985). In addition, both intact thrombospondin 1 as well as peptides derived from its procollagen domain and properdin-like type-1 repeats express potent anti-angiogenic activity (Good et al., Proc Nat Acad Sci USA 87:6624-6628,1990); Tolsma et al., J Cell Biol 122:497-511, 1993. In preclinical models, several of these fragments inhibited tumor growth, and some induced tumor regression and dormancy (Boehm et al., Nature 390:404-407, 1997).
High Molecular Weight Kininogen
High molecular weight kininogen (HK) is a 120 kD glycoprotein containing heavy and light chains, comprised of domains 1 through 3, and 5 and 6, respectively (Kaplan et al., Blood 70:1-15, 1987). The heavy and light chains are linked by domain 4, which contains bradykinin, a nonapeptide which mediates several events including NO-dependent vasodilation (Weimer et al., J Pharm Exp Therapeutics 262:729-733, 1992). HK (also referred to as xe2x80x9csingle chain high molecular weight kininogenxe2x80x9d) binds with high affinity to endothelial cells, where it is cleaved to two-chain high molecular weight kininogen (HKa) by plasma kallikrein. Bradykinin is released from HK through cleavage mediated by plasma kallikrein (Kaplan et al., Blood 70:1-15, 1987). This event occurs on the surface of endothelial cells following the activation of prekallikrein to kallikrein by an endothelial cell protease (Motta et al., Blood 91:515-528, 1998). Cleavage of HK to form HKa and release bradykinin occurs between Lys(362) and Arg(363). HKa contains a 62 kD heavy chain and a 56 kD light chain linked by a disulfide bond.
Conversion of HK to HKa is accompanied by a dramatic structural rearrangement, which has been demonstrated using rotary shadowing electron microscopy (Weisel et al. J. Biol Chem 269:10100-10106, 1994). HKa, but not HK, has been shown to inhibit the adhesion of endothelial and other cell types to vitronectin (Asakura, J. Cell Biol 116:465-476, 1992).
Although the binding of HK to endothelial cells has been well characterized, comparatively little attention has been devoted to endothelial cell binding of Ha. Furthermore, although binding of bradykinin to endothelial cells induces well-defined responses, functional consequences of the direct binding of HKa have not been reported.
The compounds of the present invention are in the form of peptides which possess anti-angiogenic activity.
In all embodiments, the peptide may optionally comprise an amino-terminal and/or carboxy-terminal protecting group.
A compound of the formula X1-His-Lys-X-Lys-X2 (hereinafter xe2x80x9cX1-His-Lys-X-Lys-X2 peptidexe2x80x9d) is provided wherein
X is any amino acid,
X1 is from zero to twelve amino acids, more preferably from zero to six amino acids, most preferably from zero to three amino acids, and
X2 is from zero to twelve amino acids, more preferably from zero to six amino acids, most preferably from zero to three amino acids.
Preferably, X is an amino acid having a nonpolar side chain, i.e., Ala, Leu, Ile, Val, Pro, Phe, Trp, or Met; or X is an amino acid having a polar side group which is uncharged at pH 6.0 to 7.0, the zone of physiological pH, i.e., Ser, Thr, Tyr, Asn, Gln, Cys, or Gly. Most preferably, X is Asn, Phe or His.
Preferred compounds comprise fragments of HK. In one group of such preferred compounds,
X1 is
(i) zero amino acids, or
(ii) the segment His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly (SEQ ID NO:1) or N-terminal truncation fragment thereof containing at least one amino acid, and
X2 is
(i) zero amino acids, or
(ii) the segment Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:2), or C-terminal truncation fragment thereof containing at least one amino acid.
In another group of such preferred compounds,
X1 is
(i) zero amino acids, or
(ii) the segment Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys (SEQ ID NO:3) or N-terminal truncation fragment thereof containing at least one amino acid, and
X2 is
(i) zero amino acids, or
(ii) the segment Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:4) or C-terminal truncation fragment thereof containing at least one amino acid.
According to a further preferred embodiment of the invention, the compound has a substantial amino acid homology to either the amino acid sequence His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:5), or the amino acid sequence Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:6).
Exemplary and preferred compounds include:
(a) His-Gly-His-Glu-Gln-Gln-His-Gly-Leu-Gly-His-Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His-Val (SEQ ID NO:5);
(b) Gly-His-Lys-Phe-Lys-Leu-Asp-Asp-Asp-Leu-Glu-His-Gln-Gly-Gly-His (SEQ ID NO:7);
(c) Gly-His-Lys-His-Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:6);
(d) Lys-His-Gly-His-Gly-His-Gly-Lys-His-Lys-Asn-Lys-Gly-Lys-Lys-Asn (SEQ ID NO:8); and
(e) His-Lys-Asn-Lys-Gly-Lys-Lys-Asn-Gly-Lys-His-Asn-Gly-Trp-Lys-Thr (SEQ ID NO:9).
The invention also encompasses a method of inhibiting endothelial cell proliferation comprising contacting endothelial cells with HK, HKa or a X1-His-Lys-X-Lys-X2 peptide.
The invention also encompasses a method of inducing apoptosis of endothelial cells comprising contacting endothelial cells with HK, HKa or a X1-His-Lys-X-Lys-X2 peptide.
The invention is also a composition comprising a pharmaceutically effective carrier and HK, HKa or a X1-His-Lys-X-Lys-X2 peptide.
The invention is also a method of inhibiting angiogenesis in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a composition comprising a pharmaceutically effective carrier and HK, HKa or a X1-His-Lys-X-Lys-X2 peptide. The mammal treated is preferably a human being.
Other aspects and advantages of the present invention are described in the drawings and in the following detailed description of the preferred embodiments thereof.
Abbreviations and Short Forms
The following abbreviations and short forms are used in this specification.
xe2x80x9cBFGFxe2x80x9d is recombinant human basic fibroblast growth factor.
xe2x80x9cHKxe2x80x9d means the mature form of high molecular weight kininogen, and any allelic variations thereof. By xe2x80x9cmaturexe2x80x9d is meant the post-translationally-modified form of HK which results from cleavage of an eighteen amino acid leader from the initially translated molecule. All numbering with respect to amino acid positions of HK is from the N-terminus of the mature form as position 1. xe2x80x9cHKxe2x80x9d is synonymous with xe2x80x9csingle chain HKxe2x80x9d, the mature form of high molecular weight kininogen prior to cleavage by kallikrein and the formation of two chain high molecular weight kininogen.
xe2x80x9cHKaxe2x80x9d means two-chain high molecular weight kininogen, the product of kallikrein cleavage of mature high molecular weight kininogen, and any allelic variations thereof.
xe2x80x9cHDMVECxe2x80x9d means human dermal microvascular endothelial cells.
xe2x80x9cHGFxe2x80x9d means hepatocyte growth factor.
xe2x80x9cHUVECxe2x80x9d means human umbilical vein endothelial cell
xe2x80x9cPDGFxe2x80x9d is platelet-derived growth factor.
xe2x80x9cTGF-xcex2xe2x80x9d is transforming growth factor-xcex2.
xe2x80x9cVEGFxe2x80x9d means vascular endothelial cell growth factor.
xe2x80x9cX1-His-Lys-X-Lys-X2 peptidexe2x80x9d means a compound of the indicated formula wherein X, X1 and X2 are defined as above.
Amino Acid Abbreviations
The nomenclature used to describe polypeptide compounds of the present invention follows the conventional practice wherein the amino group is presented to the lest and the carboxy group to the right of each amino acid residue. In the formulae representing selected specific embodiments of the present invention, the amino- and carboxy-terminal groups, although not specifically shown, will be understood to be in the form they would assume at physiologic pH values, unless otherwise specified. In the amino acid structure formulae, each residue is generally represented by a one-letter or three-letter designation, corresponding to the trivial name of the amino acid, in accordance with the following schedule:
Definitions
The following definitions, of terms used throughout the specification, are intended as an aid to understanding the scope and practice of the present invention.
xe2x80x9cAngiogenesisxe2x80x9d means the generation of new blood vessels into a tissue or organ.
xe2x80x9cApoptosisxe2x80x9d means a process of programmed cell death.
A xe2x80x9cpeptidexe2x80x9d is a compound comprised of amino acid residues covalently linked by peptide bonds.
The expression xe2x80x9camino acidxe2x80x9d as used herein is meant to include both natural and synthetic amino acids, and both D and L amino acids. xe2x80x9cNatural amino acidxe2x80x9d means any of the twenty primary, naturally occurring amino acids which typically form peptides, polypeptides, and proteins. xe2x80x9cSynthetic amino acidxe2x80x9d means any other amino acid, regardless of whether it is prepared synthetically or derived from a natural source. As used herein, xe2x80x9csynthetic amino acidxe2x80x9d also encompasses chemically modified amino acids, including but not limited to salts, derivatives (such as amides), and substitutions. Amino acids contained within the peptides of the present invention, and particularly at the carboxy- or amino-terminus, can be modified by methylation, amidation, acetylation or substitution with other chemical groups which can change the peptide""s circulating half life without adversely affecting their activity. Additionally, a disulfide linkage may be present or absent in the peptides of the invention, as long as anti-angiogenic activity is maintained.
Amino acids have the following general structure:
Amino acids are classified into seven groups on the basis of the side chain R: (1) aliphatic side chains, (2) side chains containing a hydroxylic (OH) group, (3) side chains containing sulfur atoms, (4) side chains containing an acidic or amide group, (5) side chains containing a basic group, (6) side chains containing an aromatic ring, and (7) proline, an imino acid in which the side chain is fused to the amino group. Peptides comprising a large number of amino acids are sometimes called xe2x80x9cpolypeptidesxe2x80x9d. The amino acids of the peptides described herein and in the appended claims are understood to be either D or L amino acids with L amino acids being preferred.
xe2x80x9cHomologyxe2x80x9d means similarity of sequence reflecting a common evolutionary origin. Peptides or proteins are said to have homology, or similarity, if a substantial number of their amino acids are either (1) identical, or (2) have a chemically similar R side chain. Nucleic acids are said to have homology if a substantial number of their nucleotides are identical.
As used herein, xe2x80x9cprotectedxe2x80x9d with respect to a terminal amino group refers to a terminal amino group of a peptide, which terminal amino group is coupled with any of various amino-terminal protecting groups traditionally employed in peptide synthesis. Such protecting groups include, for example, acyl protecting groups such as formyl, acetyl, benzoyl, trifluoroacetyl, succinyl, and methoxysuccinyl; aromatic urethane protecting groups such as benzyloxycarbonyl; and aliphatic urethane protecting groups, for example, tert-butoxycarbonyl or adamantyloxycarbonyl. See Gross and Mienhofer, eds., The Peptides, vol. 3, pp. 3-88 (Academic Press, New York, 1981) for suitable protecting groups.
As used herein, xe2x80x9cprotectedxe2x80x9d with respect to a terminal carboxyl group refers to a terminal carboxyl group of a peptide, which terminal carboxyl group is coupled with any of various carboxyl-terminal protecting groups. Such protecting groups include, for example, tert-butyl, benzyl or other acceptable groups linked to the terminal carboxyl group through an ester or ether bond.
xe2x80x9cSubstantial amino acid sequence homologyxe2x80x9d means an amino acid sequence homology greater than about 30%, preferably greater than about60%, more preferably greater than about 80%, and most preferably greater than about 90%.
By xe2x80x9cN-terminal truncation fragmentxe2x80x9d with respect to an amino acid sequence is meant a fragment obtained from a parent sequence by removing one or more amino acids from the N-terminus thereof.
By xe2x80x9cC-terminal truncation fragmentxe2x80x9d with respect to an amino acid sequence is meant a fragment obtained from a parent sequence by removing one or more amino acids from the C-terminus thereof.

Inhibition of angiogenesis by high molecular weight kininogen and peptide analogs thereof

Abstract: X is any amino acid,

Abstract: X is preferably an amino acid having a nonpolar side chain, or a polar side chain which is uncharged at pH 6.0 to 7.0. X is most preferably Asn, Phe or His. Methods of inhibiting endothelial cell proliferation and angiogenesis are provided.

Temple University of the Commonwealth System of Higher Education


A process for the vapor-phase synthesis of non-adduct volatile fluorinated and non-fluorinated metal-ligand complexes comprising contacting a .beta.-diketone or .beta.-ketoimine ligand with an inert carrier gas to vaporize the ligand, reacting the vaporized ligand with a metal species at a temperature sufficient to form the metal-ligand complex and recovering the metal-ligand complex by sublimation. The process is conducted in the absence of solvent thereby providing pure non-adduct metal-ligand complexes. Such complexes are particularly suited for specialty applications requiring use of high purity compounds.

Volatile metal-.beta.-diketonate and metal-.beta.-ketoiminato complexes are used in a wide range of applications including trace metal analysis by gas chromatography, studies of the stereochemistry and isomerization of metal complexes, ligand exchange, gasoline antiknock additives and in the vapor deposition of metals.
Metal .beta.-diketonate complexes used as metal precursors in chemical vapor deposition processes must be of high purity and guaranteed volatility. The demand for high purity and guaranteed volatility is particularly acute in the electronics industry. Metal-ligand complexes are typically sold in the form of the hydrated or solvated adduct. While some specialty chemical manufacturers offer anhydrous metal-.beta.-ketonate complexes, these complexes are typically prepared by utilizing a non-aqueous solvent such as methanol wherein the complex is sold in the form of a solvated adduct (i.e., M(L).sub.2.MeOH). These adduct complexes often do not satisfy the stringent requirements imposed by some sensitive processes and are difficult to isolate requiring cumbersome purification schemes involving recrystallization.
Attempts have been made to effect the liquid-phase condensation of a primary amine or a primary diamine with a ligand represented by Formula I: ##STR1##
In substances in which R.sub.1 and R.sub.2 are not both fluorocarbon groups, the literature reports that one of the ketone oxygens can be replaced with a nitrogen atom from an amine group by direct Schiff-base liquid-phase condensation between an appropriate .beta.-diketone and an amine. Additionally, the corresponding metal complex can be synthesized by chelation to a metal species. See A. E. Martell, et al., J. Inorg. Chem., Volume 5, pp. 170-81 (1958).
As reported by Sievers, et al., in J. Inorg. Nucl. Chem., Volume 32, pp. 1895-906 (1970), ligands according to Formula I wherein both R.sub.1 and R.sub.2 are perfluoroalkyl and in which an oxygen atom has been replaced with an amine to form a ketoimine, have not been obtainable utilizing liquid-phase or vapor-phase conditions.
A need exists in the art for a process capable of preparing highly volatile metal-ligand complexes in high purity wherein the ligand is a .beta.-diketone or .beta.-ketoimine, each of which may also be partially or fully fluorinated. Unfortunately, typical liquid phase processes for preparing such metal-ligand complexes have fallen short of providing the broad range of structures and level of purity required in many current applications such as those employed in the electronics industry.

Synthesis of volatile fluorinated and non-fluorinated metal-beta-ketonate and metal-beta-ketoiminato complexes


A guide arrangement for guiding moving containers, includes at least one guide element which extends in a predefined extension direction at least in some sections along the transport path of the containers, and at least one holding device which holds the guide element at a predetermined position relative to the transport path. The holding device has a clamp element which clamps the guide element, wherein the clamp element bears against the guide element in a direction perpendicular to the extension direction, and the guide element has in its cross-section two holding sections and a wall section which is formed between these holding sections and in one piece with these holding sections, wherein these holding sections are curved at least by 90° and an outer circumference of the holding sections is in contact with the clamp element at least in some sections, and the guide element has a recess which is formed by the wall section and the hold sections and by which a further guide device can be held.

The present invention relates to a guide arrangement and more specifically to a guide railing for guiding moving containers. In the beverage-producing industry, transport belts which transport for example containers or else beverage crates or boxes and the like are used at many locations. In order to ensure lateral guidance at these transport belts, guide belts or guide railings are provided, along which the respective containers are transported. Depending on the respective containers, different rails are used, for example metal profiles, plastic profiles, profiles with rolling bodies and the like. These various railings are configured differently in each case.
A large number of different railing guides are known from the prior art. U.S. Pat. No. 3,325,131 describes a device for mounting railings. In this case, a railing with a semicircular cross-section is pushed into a guide device. DE 101 18 566 A1 discloses a holding device for a lateral guide of a continuous conveyor. In this case, a lateral guide which is composed of a plurality of rectilinear wall sections is held by the holding device.
DE 296 10 201 U1 describes a railing for a container conveyor. In this case, a holding clamp is provided which holds the railing. U.S. Pat. No. 6,105,757 discloses a guide system. This comprises a holding clamp in which a guide railing with rectilinear side faces is held.
DE 91 05 736 U1 describes a wear profile for guide railings in container conveying devices. Here too, a clamp is provided which clamps a guide element, wherein this guide element itself forms the actual guide device of the railing. DE 27 13 223 likewise discloses a railing guide. In this case, the actual railing is introduced into a guide clamp.
DE 24 39 804 A1 describes a guide railing for container conveyors. In this case, a guide element is carried centrally by a holding arm.


First party geolocation data is obtained along with data indicating one or more contact parties associated with the first party. A relevant contact party radius from the geolocation of the first party is defined such that any contact parties within the relevant contact party radius are considered relevant contact parties with respect to the first party. Contact party geolocation data indicating the geolocation of at least one of the contact parties is then obtained. The first party geolocation data and the contact party geolocation data is then analyzed to identify any relevant contact parties within the relevant contact party radius. When a relevant contact party is identified, contact data for the identified relevant contact party is obtained and/or accessed and provided to one or more applications associated with the first party computing system.

One popular feature now offered by many computing systems, and particularly mobile computing systems, is Point-to-Point data transfer.
Using Point-to-Point data transfer applications a first party can use a first party computing system to transfer funds/payments; image data; video data; audio data; text data; calendar data, and numerous other forms of data to one or more other, or "second", parties' computing systems, and/or network locations.
While incredibly convenient, Point-to-Point data transfer applications have a significant drawback in that in order to affect a data transfer from a first party to a second "contact" party, the first party must identify and designate the second party to the Point-to-Point data transfer application and provide contact data for the second party to the Point-to-Point data transfer application, typically a phone number, e-mail address, account data, or other contact data associated with the second party's computing system or accounts.
Currently, the first party designates the second party and provides contact data for the second party by one of two methods. If the second party is a new "contact" party, the first party must typically manually enter data indicating the identification of the second party and the second party's contact data into the Point-to-Point data transfer application through the first party computing system. This is often a difficult and time consuming task, particularly when the first party computing system is a mobile computing system with a typically limited screen and data entry capability.
In other cases, where the second party is a "known" contact entity, the second party's contact data may already exist and be accessible by the first party computing system and/or the Point-to-Point data transfer application. However, even in these cases, the first party must still identify the second party, typically via data entry in the form of manual character entry of data indicating the second party's identification, or, at best, by selecting the second party's identification from a pull down menu or listing. Again, this can be a difficult and time consuming task, particularly when the first party computing system is a mobile computing system with a typically limited screen and data entry capability.
In a mobile computing system dominated world, one of the most important goals is to minimize, or eliminate, manual data entry and to "auto-fill" as much required data as possible without requiring significant manual user data entry. As discussed above, currently available data transfer applications fail to meet this goal by requiring the first party to largely manually enter a second party's contact data in order to affect a data transfer. Consequently, currently available data transfer applications are not ideally optimized for today's computing environment.
What is needed is a method and system that allows a second party to be identified without significant data entry and for contact data associated with the identified second party to be obtained and provided to an application on a first party computing system with little or no manual first party data entry.

Method and system for identifying geolocationally relevant contacts and acquiring their contact data


In an abnormality monitoring apparatus of the present invention, a plurality of detectors (13, 14) are arranged at a plurality of positions in the axial direction of a pipeline (11) to detect respective sound waves (37) propagating from a position (B) of occurrence of abnormality. The aforementioned position is calculated from a sound wave detection time difference between the detectors (13, 14) and position between the detectors (13, 14). The apparatus further includes an abnormal waveform memory unit (28) for storing the waveforms of a plurality of kinds of typical abnormal sound waves generated from abnormality on the pipeline (11). A display device (19) displays, on the same image screen, the abnormal waveform stored in the abnormal waveform memory unit and that of the sound wave detected. It is, therefore, possible for a monitoring personnel to readily identify a kind of abnormality occurred.

A pipe of pipeline is usually laid beneath the surface of the ground, buried at a location between the walls of the adjacent buildings, or arranged in a place readily inaccessible by a maintenance personnel. There sometimes occurs an abnormal spot or an injury on the pipe upon impact from an external force or a leakage of an internal fluid resulting from a corroded pipe wall. It is very cumbersome or difficult to detect occurrence of abnormality on the pipe and locate it once the pipe has been buried or laid beneath the ground surface.
Published Unexamined Japanese Patent Application No. 60-49199 discloses a piping buried with an optical fiber spirally wound thereon. This optical fiber is connected at one end to a light emitting element and at the other end to a light receiving element, time differentiating circuit, alarm circuit, etc. A light signal emitted from the light emitting element is transmitted via the optical fiber to the light receiving element where it is converted to an electric signal, which is differentiated by the time differentiating circuit. An external lateral force on the buried piping causes microbends on the optical fiber. This leads to a greater transmission loss across the full length of the optical fiber and an abrupt variation in the output signal of the time differentiating circuit. The occurrence of abnormality is thus detected.
A piping, if newly buried beneath the ground surface, may be so done at a desired location with the wound optical fiber disposed on the piping. If, on the other hand, an optical fiber cable is provided on an already buried piping, digging-out has to be done at a location around the piping, involving an unpractically larger construction work expense.
The digging is effective to the situation in which the piping is deformed over a certain ground area due to the occurrence of earthquake, local ground subsidence or upheaval, etc., but a local impact by an excavating machine, etc., on the piping and resultant occurrence of a injured spot or spots on the piping do not correspond to the location of the optical fiber cable, sometimes failing to positively detect the occurrence of abnormality on the optical fiber.

Abnormality monitoring apparatus for a pipeline