A method of making a microelectronic assembly includes providing a starting subassembly having a microelectronic component with a top surface and having electrical contacts, the subassembly further including a plurality of terminals over the top surface of the component, each terminal being connected to at least one contact of the component but moveable with respect to the component; positioning a plurality of joining units each having a solid core on the terminal; providing a unit bonding material at interfaces between each core terminal; and bonding the joining units to the terminals by heating the joining units and terminals so as to convert the unit bonding material to a liquid phase without melting the cores and solidifying the unit bonding material.

The present invention relates to the art of electronic packaging, and more specifically to assemblies incorporating microelectronic components and to methods of making such assemblies.
Modem electronic devices utilize microelectronic components, commonly referred to as "integrated circuits" which incorporate numerous electronic elements. These chips are mounted on substrates which physically support the chips and electrically interconnect each chip with other elements of the circuit. The substrate may be a part of a discrete chip package used to hold a single chip and equipped with terminals for interconnection to external circuit elements. Such substrates may be secured to an external circuit board or chassis. Alternatively, in a so-called "hybrid circuit" one or more chips are mounted directly to a substrate forming a circuit panel arranged to interconnect the chips and the other circuit elements mounted to the substrate. In either case, the chip must be securely held on the substrate and must be provided with a reliable electrical interconnection to the substrate. The interconnection between the chip itself and the supporting substrate is commonly referred to as "first level" assembly or chip interconnection, as distinguished from the interconnection between the substrate and the larger elements of the circuit, commonly referred to as "second level" interconnection.
The first level interconnection structures connecting a chip to a substrate ordinarily are subject to a substantial stress caused by thermal cycling as temperatures within the device change during operation. The electrical power dissipated within the chip tends to heat the chip and substrate, so that the temperature of the chip and the substrate rises each time the device is turned on and falls each time the device is turned off. As the chip and the substrate ordinarily are formed from different materials having different coefficients of thermal expansion, the chip and the substrate ordinarily expand and contract by different amounts. This causes the electrical contacts on the chip to move relative to the electrical contact pads on the substrate as the temperature of the chip and the substrate changes. This relative movement deforms the electrical interconnection between the chip and the substrate and places them under mechanical stress. These stresses are applied repeatedly with repeated operation of the device, and can cause breakage of the electrical interconnections. Thermal cycling stresses may occur even when the chip and substrate are formed from like materials having similar coefficients of thermal expansion, because the temperature of the chip may increase more rapidly than the temperature of the substrate when power is first applied to the chip.
Flip-chip bonding provides a method for interconnection. In flip-chip bonding, contacts on the surface of the chip are provided with bumps of solder. The substrate has contact pads arranged in an array corresponding to the array of contacts on the chip. The chip, with the solder bumps, is inverted so that its front surface faces towards the top surface of the substrate, with each contact and solder bump on the chip being positioned on the appropriate contact pad of the substrate. The assembly is then heated so as to liquefy the solder and bond each contact on the chip to the confronting contact pad of the substrate. Because the flip-chip arrangement does not require leads arranged in a fan-out pattern, it provides a compact assembly. The area of the substrate occupied by the contact pads is approximately the same size as the chip itself. Moreover, the flip-chip bonding approach is not limited to contacts on the periphery of the chip. Rather, the contacts on the chip may be arranged in a so-called "area array" covering substantially the entire front face of the chip. Flip-chip bonding therefore is well-suited to use with chips having a large number of I/O contacts.
Early flip-chip connections, as shown in U.S. Pat. No. 3,303,393, incorporated copper core solder balls, each including a sphere of copper coated with a solder. One such solder ball was provided between each contact on the chip and each contact pad on the substrate. These connections worked well for small devices. With larger devices having greater differential thermal expansion, the rigid connections provided by the solid core solder balls tended to crack. Warpage or distortion of the chip or substrate made it difficult to engage all of the solid core solder balls between the chip and substrate simultaneously, or to engage all of the solid core solder balls between the chip and a test fixture.
Other flip-chip bonding techniques, commonly referred to as "controlled collapse chip connection" or "C4" bonding, utilized masses of relatively soft, high-lead solder, typically containing between 90 and 97 percent lead. The high lead solder forms a somewhat less rigid connection than the solid core solder balls, Deformation of the solder connection relieves the stresses caused by differential thermal expansion to some degree. However, assemblies made by flip-chip bonding with the C4 process are still susceptible to thermal stresses. The degree of flexibility provided by the high-lead solder connections is limited. The solder joints and may be subject to very high stress upon differential expansion of the chip and substrate. These difficulties are particularly pronounced with relatively large chips. An article entitled "Flip Chip Solder Bump (FCSB) Technology: An Example" by Karl J. Puttlitz, Sr., describes these problems. Moreover, it is difficult to test and operate or "burn-in" chips having an area array of contacts before attaching the chip to the substrate. Where the chips are provided with high-lead solder balls suitable for the C4 process and then clamped to a socket to engage the solder balls with test contacts, the solder creeps and deforms rapidly. It is also difficult to rework a chip bonded using the C4 process. Parts of the solder masses are removed from the contacts if the chip is separated from the substrate, leaving non-uniform partial solder masses on the chip contacts.
Commonly assigned U.S. Pat. Nos. 5,148,266 and 5,148,265, the disclosures of which are hereby incorporated by reference herein, provide substantial solutions to the problem of thermal stresses. Nonetheless, still further improvements would be desirable.

Methods of making microelectronic assemblies


A linear measuring device including a housing fastened to a first machine element and a scale within the housing, wherein the scale is fastened extending along the housing in a measuring direction. A scanning device for scanning a scale. A linear guide device including a guide rail, which is rigidly assigned to the housing; and a guide carriage, which is guided on the guide rail along the housing in the measuring direction, and includes a fastener to fasten the guide carriage rigidly on a second machine element. The housing is structured so that during measuring operations it is deflected perpendicular to the measuring direction, so that in the course of movement of the guide carriage in a direction perpendicular to the measuring direction the housing is taken along in the direction perpendicular to the measuring direction.

1. Field of the Invention
The present invention relates to a linear measuring device for measuring the relative position of a first machine element with respect to a second machine element. The first machine element is a base of a machine tool, for example, and the second machine element is the machine carriage which can be displaced with respect to the base.
2. Description of the Related Art
For the exact position measurement in connection with machine tools and coordinate measuring machines, the scales, or the scale supports, are elaborately fastened, aligned parallel with the measuring direction, wherein the measuring direction is predetermined by the guide system of the machine tool or the measuring machine. A step for alignment is described in DE 199 14 311 A1 and DE 197 00 367 A1, for example.
However, in connection with linear measuring devices, wherein the scale has been protectively arranged in a housing, these steps cannot be taken at all, or only with difficulty.


An apparatus for making waffles with customized shapes having a top plate with a top lid having a plurality of variable length protrusions in a shape that fits a round recess on the bottom plate. The apparatus can be used to make the top of a sandwich bun and/or the bottom of a sandwich bun in the same or different waffle irons. Variable shaped protrusions allow for even distribution of heat to a mixture for making shaped edible items.

Field of the Invention
This invention relates primarily to an apparatus and a method to facilitate the preparation of a batter-type food customized waffle product. More particularly, the invention is directed to an apparatus for the manufacture of sandwich bun style shaped waffles.
Background
Waffle irons are well-known in the art. Typically, a waffle iron maintains a honeycomb pattern on both sides of the waffle. In some instances, a waffle iron is designed to change the profile shape of the waffle as shown, for example, in U.S. Pat. No. D570,157. Adjusting the profile shape of the waffle does not address the problem that the resulting waffles cannot be used effectively as a sandwich bun. The inherent shape of the waffle with its honeycomb pattern on both sides breaks apart under normal pressure from holding a sandwich during consumption. U.S. Pat. No. 5,983,784 creates a waffle with the honeycomb pattern on one side and a smooth flat profile on the opposite side. However, the design produces a thick waffle profile that creates a waffle with an undesirable thickness inconsistent with traditional waffles. In addition, the thick profile lengthens cook times in order to cook the batter thoroughly. This prevents the waffle from attaining proper texture and consistency and will burn the waffle exterior. Such design does not achieve the desired waffle product.
U.S. Pat. No. 1,854,244 attempts to address the stated problem. However the design produces an inner concave side that, while appropriate for use with a hotdog or sausage, is not appropriate for use with flat ingredients such as formed hamburger patties or chicken. The shaped waffle would collapse under slight hand pressure from holding the sandwich during consumption. Additionally, the design creates waffles with the honeycomb pattern on the outer convex side making it less comfortable to hold in a person's hands. In addition, the waffle irons of the prior art, typically comprise recessed cavities of uniform depth to create the waffle.

Waffle-iron type cooking apparatus for cooking and forming rounded bun shaped waffles


According to a method of programming a TV-game of the present invention, the event variation process 40 is added between processes of the TV-game program. Therefore, one of the processes of the TV-game program or the event variation process 40 is selected according to a situation of a TV-game scenario. Namely, the event variation process 40 is executed only when the event variation process 40 is selected. The event variation process 40 is not executed when anther process is selected. Therefore, the CPU load is light, because the event variation process 40 is not executed at each time. Further, even if the characters of the TV-game are many, the character motion is not paused. Therefore, the TV-game can include a variety of situations, because the steps in the TV-program are not cut off.

A game unit comprises a CPU, one or more memories, output/input (I/O) interfaces and an image processing unit.
The image processing unit comprises a VRAM (Video Random Access Memory), a VDC (Video Displaying Controller) and a VDE (Video Displaying color Encoder). The game unit is connected with a home TV by using the I/O interface. The VDE has a color pallet table which relates to a color code for outputting an image data and a color code for a game program.
In the game unit, the image data is processed and then outputted to the home TV through the I/O interface. The processed image data is displayed on the home TV by using scanning lines. It takes 1/60 second to display one image by the scanning lines (namely, an image displaying cycle is 1/60 second). Therefore, a neat image must be prepared within 1/60 second.
In a conventional method for programming a TV-game, when the next image is not prepared in the VRAM within a predetermined time such as the image displaying cycle, a programmer modifies a TV-game program. Further, if a next image processed by the modified TV-game program us not prepared in the VRAM within the predetermined time, a programmer must cut off one or more steps of the TV-game program.
In the conventional method for programming a TV-game, however, there are disadvantages in that a TV-game becomes very simple and rough, because the steps of the TV-game program are cut off.


A fish sauce is treated for (2) to (16) hours at a pH of (9.0) to (10.0), under a temperature of (40° C.) or lower and under a reduced pressure of (80) to (180) Torr, and the pH is then adjusted, if required, to be (4.5) to (7.0), to thereby obtain a final fish sauce which contains specific odor components having specific values or less as determined by gas chromatography, and which thus contains an acceptable level of undesirable odor components.

This invention relates to a fish sauce for use as a seasoning or taste enhancer, in which no peculiar or undesirable odor is present. There are a number of fish sauces available, prepared from a variety of fish and shell fish, which are used as seasonings or taste enhancers. Among the more well-known are nuoc mam, nampla (nom pla) and patis, used in Southeast Asia; and Ishiri (derived from squid organs during the production of dried squid), Shottsuru (derived from stand fish, and others), and Ikanago (derived from sand eel) which are all used in Japan. Each of these seasonings has its own characteristic flavor (referred to as 'umami' in Japanese) and they are useful for enhancing the taste of foods or imparting a new taste to foods. Fish sauces have been drawing attention for their characteristic flavor and they are used in various foods. However, the use of fish sauces are limited to certain food groups, since in other food groups, any underlying undesirable odor existing in fish sauce tends to impair the taste of the food rather than enhance the taste or induce a new taste.
To overcome the problems of undesirable odors in fish sauces, various methods for their removal have been proposed. These include a method using ultrafiltration (Japanese Unexamined Patent Publication No. 346767/1992); a method in which the pH of the fish sauce is adjusted and the resulting sauce is subsequently subjected to steam distillation (Japanese Unexamined Patent Publication No. 64563/1993); and a method comprising adsorbing volatile amines to undecomposed products of koji (malted rice) (Japanese Unexamined Patent Publication No. 47051/1991). However, each of these methods is subject to problems. The ultra-filtration method, while being useful for removing certain undesirable odor components, is not able to remove all of the undesirable odor components liable to produce unpleasant, fermentation and briny odors, and there is a tendency to also remove palatable odor components along with those which are not desirable. In the method comprising adjusting the pH of a fish sauce and subsequently subjecting it to steam distillation, whereby undesirable odor components tend to remain in the sauce; and, in particular, it is not possible to remove briny and fermentation odor components using the said method. Also, in using the method whereby volatile amines are adsorbed by undecomposed products of koji, an undesirable koji-type odor is imparted to the sauce, and it is also not possible to remove fully those substances which give rise to undesirable odors, other than amines.

Fish sauce and method for producing same


A method and apparatus for generating and selecting therapies, or hierarchies of therapies, that may be used to treat episodes of atrial or ventricular tachycardia. A characteristic of a detected tachycardia event is determined, and a hierarchy of therapies to treat the detected tachycardia event is selected in response to the determined characteristic.

Tachycardia is an abnormal heart rhythm characterized by rapid activation of one or more chambers of the heart of a patient. Tachycardia is often qualified by the locus of origin: a tachycardia that originates in the ventricles of the heart is called a ventricular tachycardia (VT) and a tachycardia that originates in the atria of the heart is called an atrial tachycardia (AT) or a supraventricular tachycardia (SVT). Some VTs, if untreated, may accelerate into ventricular fibrillation, in which the pumping ability of the heart is seriously impaired.
In a single patient, two episodes of tachycardia may be different. The causes for these differences could be many, such as disease progression, changes in medication, presence of multiple reentrant circuits and differences in site of origin. Hence, a single patient may experience distinct VTs or ATs over time.
Some tachycardias respond well to medication, and others may be treated with surgery such as radio frequency (RF) ablation. In some patients, VT or AT may respond well to antitachycardia pacing (ATP), in which small electric stimulations from an implantable pulse generator (IPG) in an implantable medical device (IMD) disrupt the propagation of electrical signals that cause the tachycardia. The IMD may be programmed to administer several forms of ATP therapies, and may apply one ATP therapy after another until the tachycardia terminates.
In some circumstances, a tachycardia may fail to terminate in response to ATP, and therefore certain IMDs include the capability of delivering a higher energy cardioversion shock to terminate the tachycardia. In addition, some IMDs may be programmed to administer several cardioversion shocks of progressively increasing energy. Cardioversion therapies tend to be painful compared with ATP therapies, which tend to go unnoticed by the patient. As a result, since ATP therapies may be just as effective for a given episode as cardioversion shock therapies, some patients are treated with one or more ATP therapies prior to being treated with one or more cardioversion therapies in an attempt to avoid the discomfort associated with cardioversion.

Method and apparatus for generation and selection of tachycardia therapy hierarchy


There is provided a polyester resin composition excellent in mechanical properties, heat deformation temperature, surface appearance, dimensional stability and mold releasing ability, and a process for preparing the same. The polyester resin composition contains a thermoplastic polyester resin and layered phyllosilicate, wherein the layered phyllosilicate in the resin composition satisfies at least one of the following conditions (a) to (c):

Thermoplastic polyester resins such as poly(ethylene terephthalate) are used for various industrial purposes in the form of fiber or film since they are excellent in heat resistance, chemical resistance, weatherability, mechanical properties, electric properties, molding flowability and the like. However, higher mechanical properties and heat resistance are further required. Attempts have been made to mix various fillers, examples of which are inorganic fiber such as glass fiber, carbon fiber and potassium titanate whisker, and inorganic particles such as glass flakes, glass beads, talc, mica and kaolin. Though mechanical properties and the like are actually improved by mixing the above inorganic materials, there is a problem that appearance is lost due to the emergence of fibrous reinforcements and specific gravity is increased. There is also a problem that anisotropy occurs due to orientation of inorganic fibers.
It is generally thought that these defects in mixing inorganic fiber and inorganic particles are caused by the fact that dispersion of inorganic materials is insufficient and dispersion particle size thereof is too large.
As an attempt to disperse layered phyllosilicate among inorganic materials into a thermoplastic resin, there is disclosed (1) invention relating to a resin composition containing a layered inorganic filler and a thermoplastic polyester resin, wherein the layered inorganic filler has 0.2 to 1.0 of a charge on the layers and basal space expanded at least five times the initial value (Japanese Unexamined Patent Publication No. 26123/1995). Specifically, the disclosed technology is such that swellable mica is used as layered phyllosilicate and that a polyester resin composition is obtained by polymerization after ester exchange reaction of ethylene glycol and dimethyl terephthalate in which the above mica is dispersed. However, a polyester resin composition having desired properties cannot be prepared according to the above invention.
In addition, there are disclosed (2) invention relating to a resin composition obtained by dispersing layered phyllosilicate in a crystalline thermoplastic resin as a crystalline nucleus at molecular level under aspect ratio of at least 20 (Japanese Unexamined Patent Publication No. 183910/1997); and (3) invention relating to a resin composition obtained by dispersing, in a thermoplastic resin, layered phyllosilicate having average layer thickness of 25 to 1,000 Å and aspect ratio of 20 to 200 (Japanese Unexamined Patent Publication No. 124836/1997). Specifically, the disclosed technology is such that swellable mica is used as layered phyllosilicate and that a resin composition is obtained by extruding swellable mica swelled in water or alkyl ammonium-treated swellable mica swelled in xylene with polypropylene or the like by using a twin-screw extruder. However, it was impossible to prepare a polyester resin composition having desired properties even by the above inventions.
The reason why a polyester resin composition having desired properties cannot be prepared by the above prior arts (1), (2) and (3) is insufficient dispersion of layered phyllosilicate. Though the basal space of swellable mica is actually expanded from the initial value, the layered phyllosilicate is not finely dispersed into the thermoplastic polyester resin but only in the state of coagulation according to the prior art (1). In addition, even if the prior arts (2) and (3) are directly applied to a thermoplastic polyester resin, dispersion of layered phyllosilicate is still incomplete and inhomogeneous though fine dispersion is partly observed.
Having excellent mechanical properties and heat resistance, reinforced polyester resins containing a thermoplastic polyester resin and a fibrous filler are used for various purposes including electronic or electric parts, exterior materials for automobiles, household electric appliances, mechanical or machinery parts and the like. However, there were problems with the above polyester resin such that dimensional accuracy of the obtained molded article significantly decreased due to orientation of the fibrous filler during injection molding. As a means for improving the above problems, processes for combining glass fiber with other inorganic fillers have been attempted. Examples thereof include (4) adding a non-fibrous inorganic substance to poly(ethylene terephthalate) and glass fiber (Japanese Unexamined Patent Publication No. 74852/1979); (5) combining fragmentized mineral fiber with poly(butylene terephthalate) and glass fiber (GF) (Japanese Unexamined Patent Publication No. 254655/1986); (6) combining mica with poly(ethylene terephthalate) and glass fiber (Japanese Unexamined Patent Publication No. 59661/1987); and the like.
However, the above prior arts (4) to (6) did not show sufficient improving effect on dimensional accuracy when the amount of the inorganic filler was small. On the contrary, when a large amount of the inorganic filler was used in order to improve dimensional accuracy, there arise different problems with increase in specific gravity, deterioration in appearance of a molded article, decrease in strength and the like.
It is thought that these defects in mixing the above inorganic filler are caused by the fact that dispersion of inorganic materials is insufficient and dispersion particle size thereof is too large. Though there are disclosed the above prior arts (1) to (3) as an attempt to finely disperse layered phyllosilicate out of organic materials into a thermoplastic resin, improvement effect on dimensional accuracy was insufficient even in the reinforced polyester resins because uniform dispersion of the layered phyllosilicate was impossible as mentioned above.
Besides, thermoplastic polyester resins have disadvantages of inferior impact resistance and dimensional stability though it shows the above characteristics. Meanwhile, aromatic polycarbonate resins are widely used, as thermoplastic resins excellent in heat resistance, impact resistance, toughness and the like, for parts of machines, automobiles, electric and electronic devices. However, relatively high processing temperature of about 300° C., high injection speed and high injection pressure are normally required for ensuring molding flowability. In addition, aromatic polycarbonate resins have problems with chemical resistance such that the surface of the molded article is cracked, deformed or dissolved due to various organic solvents or gasoline. There are also weatherability problems such as crack propagation and discoloration into yellow on the surface of the molded article in case of long exposure to ultraviolet ray.
In order to overcome these defects by making use of the respective features, resin compositions comprising a polyester resin and a polycarbonate resin are disclosed, for example, in Japanese Examined Patent Publication No. 14035/1961, Japanese Examined Patent Publication No. 20434/1964, Japanese Unexamined Patent Publication No. 176345/1984, Japanese Examined Patent Publication No. 94350/1980, Japanese Unexamined Patent Publication No. 83158/1988 and the like.
In case of forming a composition by mixing a polyester resin and a polycarbonate resin, impact resistance and dimensional stability of a polyester resin and molding flowability and chemical resistance of a polycarbonate resin are actually improved, but improvement effect on mechanical properties such as flexural modulus and heat resistance is insufficient. It is said that this is because crystallization of the polyester resin is prevented and crystallinity is lowered since the polycarbonate resin and the polyester resin are partly compatibilized or reacted with each other. Due to these phenomena, the obtained composition did not have satisfactory chemical resistance.
It has been attempted to promote crystallization of polyester resins for the purpose of improving mechanical properties and heat resistance. However, there was a problem that the polycarbonate resin is decomposed and foamed in case of using an organic carboxylate salt nuclear agent (Japanese Examined Patent Publication No. 29977/1971, Japanese Unexamined Patent Publication No. 158452/1979 and the like). Also, effects were insufficient in case of using an inorganic nuclear agent (Japanese Examined Patent Publication No. 38707/1971, Japanese Examined Patent Publication No. 27142/1972 and the like).
Though the above prior art (3) is disclosed as a different method, the layered phyllosilicate is not uniformly dispersed in the whole system but only in some part as mentioned above, making it impossible to obtain a resin composition having desired properties even if the thermoplastic resin composition contains a polycarbonate resin. In addition, when swellable mica treated with alkyl ammonium or the like is used, there arise other problems with lowering in properties and coloring due to deterioration of the polyester resin and the polycarbonate resin. Therefore, no technology is available yet at present as to obtaining a resin composition excellent in mechanical properties and heat resistance by finely dispersing layered phyllosilicate into a polyester resin and a polycarbonate resin.
An object of the present invention is to solve these conventional problems and to provide a thermoplastic resin composition and a process for preparing the thermoplastic resin composition, wherein mechanical properties, heat deformation temperature, dimensional stability and moldability are improved without losing surface properties and appearance by separating and exfoliating each unit layer of layered phyllosilicate to divide one coagulated particle of the layered phyllosilicate into numerous, extremely fine laminar particles and by dispersing the same in a thermoplastic polyester resin independently and uniformly. Another object of the present invention is to provide a reinforced thermoplastic resin composition having improved dimensional accuracy and a thermoplastic resin composition having improved mechanical properties and heat resistance without deterioration of resins, foaming, lowering of surface properties and decrease in dimensional stability.

Thermoplastic resin composition and process for preparing the same

Abstract: (a) ratio of layered phyllosilicate having equivalent area circle diameter [D] of at most 3,000 Å is at least 20%;

Abstract: (b) a mean value of equivalent area circle diameter [D] is at most 5000 Å;

Abstract: (c) the number of particles [N] per unit ratio of layered phyllosilicate present in 100 μm2 of a resin composition is at least 30.


A system for in-situ bioremediation includes a well extending into a saturated zone. The well includes a casing having two permeable sections in the saturated zone. Groundwater may be recirculated through the well and the saturated zone between the two permeable sections. Nutrients, such as oxygen and methane, may be added to the groundwater as it flows in the well. A venturi transfer device may be used to supply the nutrients.

The present invention relates in general to remediation of contaminated groundwater. It relates in particular to an in-situ method of bioremediation, including adding biological nutrients to the groundwater.
Existing methods for bioremediation of contaminated groundwater involve bringing the contaminated groundwater from an aquifer to ground level for treatment. The treated groundwater is then returned to the aquifer. The treatment may include adding gaseous nutrients, such as oxygen and methane, to the groundwater to accelerate the biological decomposition of contaminants in the groundwater.
Bringing contaminated groundwater to the surface for treatment may, however, present certain problems. For example, the nature of the contamination may be such that, for safety reasons, it may be preferable not to even bring the contaminated groundwater to the surface. Additionally, temporary storage must be provided on the surface for groundwater while it is being treated. Bureaucratic problems in obtaining permits to bring the water to the surface may also be significant. Such problems may add considerably to the treatment cost. Further, nutrients may not be easily added to the groundwater under standard conditions of temperature and atmospheric pressure. This may further increase the time and cost of the treatment.
Accordingly, it is an object of the present invention to provide a system for in situ treatment of contaminated groundwater.
It is a further object of the present invention to provide an in situ system for efficiently adding nutrients, such as oxygen, to contaminated groundwater.

Method and apparatus for in situ groundwater remediation

The Board of Trustees of the Leland Stanford Junior University


A fragrance container with a container body provided with a bottom bracket permeable to interior air of the container near a bottom opening. A top cover having a shutter within an interior of the container body near a top opening with a fragrance substance contained in the container body between the bottom bracket and the top cover. An outer peripheral portion of the container body near the bottom opening is covered with an indexing collar for adjusting the degree of opening of an intake port of the container body. A fragrance diffuser includes an air pump, a fragrance container retainer connected to the air pump, and at least one fragrance container received in the retainer. The fragrance containers communicate with each other, wherein each of the fragrance containers contains the same type of fragrance substance with the same smell or a different type of fragrance substance with a different smell.

In daily life, people often selectively use fragrance substances or deodorant to generate sweet smell indoor, in order to eliminate stress and fatigue or to eliminate unpleasant smell in toilets and other places. Traditional fragrance diffusers generally realize diffusion of fragrance substances or deodorant by means of heat, wind or ultrasonic atomization. But, they have the following drawbacks. For example, heat sources of diffusers such as scented candles, tea lights, etc., are dangerous due to their open flames. Most wind diffusers are of open-typed, and it is difficult to control the volatilization degree of essential oil in such kind of diffusers. Atomization diffusers need water, and should be cleaned frequently. The above open-typed fragrance diffusers are subject to oil leakage and are not easy to be stored, and cannot control the degree of volatilization and mixing ratio of fragrant smells. Most of the existing closed fragrance diffusers require complicated control methods and complex devices to adjust fragrant smell concentration and mixing ratio, and therefore are expensive and are difficult to operate.

Fragrance container and fragrance diffuser


A method of improving adhesion between layers in the formation of a semiconductor device and integrated circuit, and the resultant intermediate semiconductor structure, which include a substrate layer with a low k insulating layer thereover. The low k insulating layer includes a treated surface area of adsorbed gaseous particles. This treated surface area is formed by flowing a gas, preferably, silane, disilane, dichlorosilane, germane or combinations thereof, over a surface of the heated low k insulating layer for adsorption of such gaseous particles onto the heated surface, wherein the insulating layer maintains its original thickness. A capping layer is then deposited directly over the insulating layer wherein the treated surface area of the insulating layer significantly improves adhesion between the insulating layers and the capping layers to prevent delamination therebetween during subsequent processing steps of forming the integrated circuit.

1. Field of the Invention
The present invention relates to manufacturing of integrated circuits on semiconductor substrates and, in particular, to a method of improving adhesion between an insulating layer and a cap layer within such integrated circuits.
2. Description of Related Art
In semiconductor fabrication processes, layers of insulating, conducting and semiconductor materials are commonly deposited and patterned to form integrated circuits (IC). These multilayer electronic components may further be provided with contact vias and line wirings formed in the insulating materials of such ICs, which, are referred to as interlevel dielectrics (ILDs). Typically, ILDs are made by damascene and dual damascene processing techniques.
In damascene processing, multilayer electronic components are made by depositing a dielectric material on a surface of a substrate to form an insulating layer and then patterning the insulating layer to form openings for trenches therein such insulating layer. Once trenches are formed, a conductive material is deposited into the trenches and then any excess conductive material may be removed from the structure surface to form damascene regions within the insulator layer.
Dual damascene processing similarly involves etching trenches within the insulating layer of the IC and further etching vias at the bottom of these trenches. In ICs where contact vias also extend downwardly from the bottom of the trenches, both the trenches and the downwardly extending vias are simultaneously filled with conductive material. This process forms both contact vias and integrated wires for interconnecting electrical devices and wiring at various levels within the IC.
Thus, in the process of forming multilayer electronic components, using both damascene and dual damascene processes, several layers are required to form the contact vias and integrated wires. For example, a typical multilayer electronic component may be built up from a first insulating layer on a substrate by forming an opening therein and then filling the opening with a conductive fill material to form conductive lines. However, prior to metallization, a barrier layer is typically provided within the openings in the first insulating layer to avoid metal diffusion between the conductive fill and the first insulating layer.
A second insulating layer is deposited over the first insulating layer and the metallization. Trenches and contact vias are then formed in this second insulating layer to form the line wirings and contact vias of the multilayer electronic component. Again, prior to metallization, a barrier layer may be deposited into the trenches and vias so as to coat the sidewalls of the openings in order to prevent any metal diffusion. The trenches and vias are then filled with metallization and the surface area of the substrate planarized, such as, by chemical mechanical polishing.
However, during the polishing process, the barrier layer may delaminate from the insulating layer resulting in interruption of polishing process as well as damage to the multilayer electronic component. This delamination problem is particularly severe in those devices having low k dielectric constant insulating layers. One method to decrease the problem of delamination between low k dielectric constant insulating layers and barrier layers has been to deposit a cap layer between the insulating layer and the barrier layer. However, the use of cap layers is ineffective as delamination occurs between the insulating and cap layers, and in particular, between low k dielectric constant insulating layers and cap layers.
Therefore, a need exists in the art for preventing delamination between insulating layers and cap layers, particularly, those insulating and cap layers used in single and dual damascene processes.

Method of improving adhesion between two dielectric films


An object is to obtain a low-frequency circuit breaker which has a simple configuration and a small size as a whole and is advantageous in view of costs. There is provided a low-frequency circuit breaker, in which a semiconductor switch and a mechanical switch are connected in parallel with each other. The semiconductor switch is configured by connecting a thyristor and a thyristor in anti-parallel with each other. These members are controlled by the circuit breaker control circuit.

1. Field of the Invention
The present invention relates to a low-frequency circuit breaker (low-frequency-current circuit breaker) which is applied to, for example, a wind generator system and cuts off a current having a frequency of about 10 to 20 Hz.
2. Description of the Related Art
Conventionally, as an example of a wind generator system, there is a system configured to convert three-phase alternating-current power generated by a permanent-magnet-type wind generation installation into direct current by a converter to which, for example, an IGBT element is bridge-connected. This current is converted into alternating-current power by an inverter to which, for example, an IGBT element is bridge-connected, and is supplied to an alternating-current load.
In a system configured as described above, a short-circuit accident can be considered to occur in an IGBT element which forms part of a converter due to some reason. When an IGBT element short-circuits, a short-circuit current continues to flow through a diode connected in anti-parallel to the IGBT element. However, at present, there is no circuit breaker for general purpose use, which can cut off a fault current caused by a short-circuit accident, and therefore, development of a circuit breaker for general purpose use is demanded.
A permanent-magnet-type wind generator installation cannot control a field current and hence needs to cut off a current flowing through a line between stators. Unless the fault current is cut off, a properly working semiconductor device such as an IGBT forming part of a main circuit of a converter may be broken.
A synchronous power generator which is used in the permanent-magnet-type wind generator installation has a high internal impedance. There exists a situation that only a short-circuit current which is at most approximately twice greater than a normal current flows even when an IGBT element causes a short circuit Therefore, a current limiting means such as a fuse cannot be used.
Conventionally, an alternating current which is generated by a wind generator installation and flows through an alternating-current path is, for example, a low-frequency current of 10 to 20 Hz. There is a demand for development of a circuit breaker which is advantageous in view of costs, with a simple configuration capable of cutting off the low-frequency current.
At present, a circuit breaker for a direct current is used in a wind generator system. An example of the circuit breaker for a direct current is configured by connecting a thyristor bulb in parallel with a bypass switch such as a gas circuit breaker, as disclosed in Patent Document 1.
Patent Document 1: Jpn. Pat. Appln. KOKAI Publication No. 7-105789
However, in a direct-current circuit breaker according to Patent Document 1, a thyristor bulb and a gas circuit breaker which form part of the circuit breaker both have large sizes and are disadvantageous in view of costs.
A circuit breaker comprising only a thyristor switch naturally causes conduction loss due to conduction.

Toshiba Mitsubishi-Electric Industrial Systems


Diagnostic and therapeutic compositions in the form of complexes for enhancing transmembrane transport of a diagnostic or therapeutic agent and methods for their use. The complexes contain the α, γ, or bis isomers of folate receptor-binding analogs of folate, a metal chelated by a ligand, and in one embodiment, a chemotherapeutic agent.

1. Field of the Invention
The present invention relates to diagnostic and therapeutic compositions, methods of their use, and processes of their preparation.
More particularly, the invention relates to:    a) Magnetic resonance diagnostic compositions for visualization of tissues that over-express folate binding protein, comprising ligands chelated to superparamagnetic or paramagnetic metals and coupled to folate-receptor binding ligands;    b) Radiodiagnostic compositions for visualization of tissues, comprising ligands chelated to radioactive gamma-emitting metals and coupled to folate-receptor binding ligands;    c) Compositions for radiotherapy or for neutron capture therapy, comprising ligands chelated to radioactive alpha or beta-emitting metals or to metals suitable for neutron capture therapy and coupled to folate-receptor binding ligands; and    d) Compositions for chemotherapy, comprising certain derivatives of folic acid coupled to a cancer chemotherapy drug through the alpha carboxylate of folic acid or coupled through both the alpha and gamma carboxylates.
2. Reported Developments
The folate-based diagnostic and therapeutic agents of the present application are designed for use in Nuclear Medicine, Magnetic Resonance Imaging (MRI), and neutron capture therapy applications. Magnetic resonance (hereinafter sometimes referred to as MR) imaging is well known and widely used by the prior art for obtaining spatial images of parts of a patient for clinical diagnosis. The image is obtained by placing the patient in a strong external magnetic field and observing the effect of this field on the magnetic properties of protons contained in and surrounding the organ or tissue of the patient. The proton relaxation times, called T1 or spin-lattice or longitudinal relaxation time, and T2 or spin-spin or transverse relaxation time depend on the chemical and physical environment of the organ or tissue being imaged. In order to improve the clarity of the image, a diagnostic agent is administered intravenously (hereinafter sometimes referred to as I.V.) and is taken up by the organs, such as the liver, spleen, and lymph nodes to enhance the contrast between healthy and diseased tissues.
The contrast agents used in MR imaging derive their signal-enhancing effect from the inclusion of a material exhibiting paramagnetic, ferrimagnetic, ferromagnetic or superparamagnetic behavior. These materials affect the characteristic relaxation times of the imaging nuclei in the body regions into which they distribute causing an increase or decrease in MR signal intensity. There is a need for contrast agents such as those of the present invention, that selectively enhance signal intensity in particular tissue types, as most MR contrast agents are relatively non-specific in their distribution.
Nuclear medicine procedures and treatments are based on internally distributed radioactive materials, such as radiopharmaceuticals or radionuclides, which emit electromagnetic radiations as gamma rays or photons. Following I.V., oral or inhalation administration, the gamma rays are readily detected and quantified within the body using instrumentation such as scintillation and gamma cameras. The gamma-emitting agents of the present invention are designed to selectively localize in particular targeted tissues by transmembrane transport, yielding either high signal intensity in these tissue types for imaging purposes, or high radiation dose, for radiotherapy purposes.
Transmembrane transport of exogenous molecules, such as diagnostic agents, is also known by the prior art. One method of transmembrane delivery, receptor-mediated endocytosis, is the movement of extracellular ligands bound to cell surface receptors into the interior of the cells through invagination of the membrane. This process is initiated by the binding of a ligand to its specific receptor. Folates, which are required for the survival and growth of eukaryotic cells, are taken up into cells by receptor-mediated transport after binding to folate binding protein on the cell membrane. The cellular uptake of exogenous molecules can be enhanced by conjugation of these molecules to folate. Such conjugates have been used to target folate receptors to enhance cellular uptake of exogenous molecules, including some diagnostic agents. The uptake of substances by receptor-mediated endocytosis (hereinafter sometimes termed RME) is a characteristic ability of some normal, healthy cells. RME transport systems have been found on normal macrophages, hepatocytes, fibroblasts and reticulocytes. On the other hand, conversion of normal cells into tumor cells can be associated with an increase or decrease in the activity of receptors performing RME or, sometimes, with changes in the levels of receptor expression.
The use of neutron capture therapy for the treatment of cancer is well known to those skilled in the art. Briefly the system comprises administering a target substance that emits short-range radiation when it is irradiated with neutrons. Boron-10 has traditionally been used for neutron capture therapy, but more recently Gadolinium-157, which has a very high cross section for neutrons and emits short range Auger-electrons, has been used. [Brugger, R. M. and Shih, J. A., Strahlentherapie Und Onkologie, 165, 153-156, 1989; Brugger, R. M. and Shih, J. A., Medical Physics, 19, 733-744, 1992]. Specificity is achieved by using neutrons of appropriate energy and the selective distribution of the gadolinium within the tumor tissue. In the past, neutron capture therapy has suffered from insufficient concentration of target substance in the desired cells and in the case of gadolinium, has suffered from the exclusion of the gadolinium from the inside of the cell. The use of the folate-containing gadolinium compounds of this invention is advantageous because of the large amounts of gadolinium that are specifically taken up by the desired cells. The internalization of the compounds of this invention following binding to folate binding protein is beneficial because of the short range of the Auger electrons. In addition, the gadolinium compounds of this invention can be used as MRI contrast agents that selectively target the cells that are to be treated by neutron capture therapy. The imaging data can provide the radiotherapist with spatial information beneficial for planning the radiotherapy procedure, using the same gadolinium atoms as are used as the target for the neutrons.
The following illustrative studies describe relevant properties of the folate receptor.
Folic acid or pteroyl glutamic acid is a vitamin consisting of a pteridine ring linked by a methylene bridge to a para-aminobenzoic acid moiety, which is joined through an amide linkage to a glutamic acid residue. Folic acid and folates are well absorbed from the diet primarily via the proximal portion of the small intestine. Following their absorption from the digestive system, dietary folates are rapidly reduced by dihydrofolate reductase and other enzymes to tetrahydrofolic acid and derivatives thereof.
Folates are required for the survival and growth of eukaryotic cells, so their cellular uptake is assured by at least two independent transport mechanisms. Reduced folates are internalized via a carrier-mediated low affinity (Km 1-5 μM) anion-transport system that is found in nearly all cells. Folic acid and 5-methyl tetrahydrofolate can also enter cells via a high affinity (Kd values in the nanomolar range) membrane-bound folate-binding protein (hereinafter sometimes referred to as FBP) that is anchored to the cell membrane via a glycosylphosphatidylinositol (hereinafter sometimes referred to as GPI) moiety. This process has been studied in MA104 cells, where experiments have shown that 5-methyltetrahydrofolate is taken up into the cell after binding to glycosylphosphatidylinositol (GPI)-anchored FBP that has clustered in cell structures known as caveolae. The caveolae then seal the folate binding protein-folate complex off from the extracellular space and transport folate into the cell. Once inside, the folate dissociates from FBP and diffuses into the cytoplasm, where it is rapidly coupled to one or more glutamic acid residue, slowing diffusion out of the cell. The caveolae and FBP then migrate to the membrane surface for another round of folate uptake.
There are two major isoforms of the human membrane folate binding proteins, α and β. The two isoforms have ˜70% amino acid sequence homology, and differ dramatically in their stereospecificity for some folates. Both isoforms are expressed in both fetal and adult tissue; normal tissue generally expresses low to moderate amounts of FR-β. FR-α is expressed in normal epithelial cells and is frequently strikingly elevated in a variety of carcinomas, with the exception of squamous cell carcinomas of the head and neck. Several papers have reported the overexpression of folate binding protein in cancer, See for example:    Ross J F, Chaudhuri P K, Ratman M, "Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications", Cancer, 1994, 73(9), 2432-2443;    Rettig, W, Garin-Chesa P, Beresford H, Oettgen H, Melamed M. Old L., "Cell-surface glycoproteins of human sarcomas: differential expression in normal and malignant tissues and cultured cells", Proc. Natl. Acad. Sci U.S.A., 1988, 85, 3110-3114;    Campbell I G, Jones T A, Foulkes W D, Trowsdale J., "Folate-binding protein is a marker for ovarian cancer", Cancer Res., 1991, 51, 5329-5338;    Coney L R, Tomassetti A, Carayannopoulos L, Frasca V, Kamen B A, Colnaghi M I, Zurawski V R Jr, "Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein", Cancer Res. 1991, 51, 6125-6132;    Weitman S D, Lark R H, Coney L R, Fort D W, Frasca V, Zurawski V R Jr, Kamen B A, "Distribution of the folate receptor (GP38) in normal and malignant cell lines and tissues", Cancer Res., 1992, 52, 3396-3401;    Garin-Chesa P, Campbell I, Saigo P, Lewis J, Old L, Rettig W, "Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein", Am. J. Pathol., 1993, 142, 557-567;    Holm J, Hansen S I, Hoier-Madsen M, Sondergaard K, Bzorek M, "Folate receptor of human mammary adenocarcinoma", APMIS, 1994, 102, 413-419;    Franklin W A, Waintrub M., Edwards D, Christensen K, Prendergrast P, Woods J., Bunn P A, Kolhouse J F, "New anti-lung cancer antibody cluster 12 reacts with human folate receptors present on adenocarcinoma", Int. J. Cancer, 1994, 8 (Suppl.) 89-95.    Miotti S, Canevari S, Menard S, Mezzanzanica D, Porro G, Pupa S M, Regazzoni M, Tagliabue E, and Colnaghi M I, "Characterization of human ovarian carcinoma-associated antigens defined by novel monoclonal antibodies with tumor-restricted specificity", Int. J. Cancer, 1987, 39, 297-303; and    Vegglan R, Fasolato S, Menard S, Minucci D, Pizzetti P, Regazzoni M, Tagliabue E, Colnaghi M I, "Immunohistochemical reactivity of a monoclonal antibody prepared against human ovarian carcinoma on normal and pathological female genital tissues", Tumori, 1989, 75, 510-513.
Folate binding proteins are also present in normal adult oviduct epithelium and in kidney distal and proximal tubules, where they serve to prevent excessive loss of folate via the urine. Kidneys may, as a result, be a significant source of toxicity. Folic acid in high doses has been reported to be nephrotoxic and a kidney-specific tumor promoter, as it is rapidly concentrated in the kidney and precipitated in the tubules as urinary pH drops, causing obstructive nephropathy. This injury results in diffuse renal cell proliferation and hypertrophy. Rats given i.v. injections of folio acid (250 mg/kg) in 0.3 M sodium bicarbonate showed an increase in the ratio of kidney to body weight that reached 165% of control by 24 h after treatment. See for example:    Klinger E L J, Evan A P, Anderson R E, "Folic acid-induced renal injury and repair", Arch. Pathol. Lab. Med. 1980, 104, 87-93;    Hsueh W. Rostorfer H H, "Chemically induced renal hypertrophy in the rat", Lab. Invest. 1973, 29, 547-555; and    Dong L. Stevens J L, Fabbro D, Jaken S, "Regulation of Protein Kinase C isozymes in kidney regeneration", Cancer Res. 1993, 53, 4542-4549.
Overexpression of FBP by a number of different tumors has led a number of investigators to explore its potential as a delivery system for toxins or poorly permeable compounds coupled to folic acid and as a means to increase selective delivery of antifolate drugs such as methotrexate to tumors. The amount of FBP on the membrane of ovarian cancer cells is high (1×106 molecules/cell). IGROV cells in culture can bind 3H folic acid at a level of 10-12 pmol/106 cells; MA104 cells bind 1-2 pmol folic acid/106 cells. FBP has a very high affinity for folic acid and some of its reduced folate cofactors (Kd ˜1-10 nM); this presumably favors folate uptake at the usual folate concentrations that exist in vivo (5-50 nM). The recycling rate for the folate binding protein (in vitro) has been reported to range from ˜30 nm in MA104 cells to 5 hr in L1210 cells. Several antifolate drugs have been shown to bind to FBP; these compounds, of which methotrexate is characteristic, have been used to antagonize the growth of cancer cells. See, for example:    Orr R B, Kamen B A, "UMSCC38 cells amplified at 11q13 for the folate receptor synthesize a mutant nonfunctional folate receptor", Cancer Res. 1994, 54, 3905-3911;    Anthony A C, "The biological chemistry of folate receptors", Blood, 1992, 79, 2807-2820; and    Spinella M J, Brigle K E, Sierra E E, Goldman, I D, "Distinguishing between folate receptor-α-mediated transport and reduced folate carrier-mediated transport in L1210 leukemia cells", J. Biol. Chem., 1995, 270, 7842-7849.
These studies indicate an essential fact necessary to distinguish between normal cells and tumor cells when delivering pharmaceutical or diagnostic agents into a patient using folates to be internalized by FBP. FBP levels are low in many normal tissue types while, in comparison, FBP levels are high in many tumor cells. This difference between the folate receptor levels allows selective concentration of pharmaceutical or diagnostic agents in tumor cells relative to normal cells, thereby facilitating treatment or visualization of tumor cells.
In culture, cells were successfully targeted through FBP using folate-conjugated protein toxins that would not normally penetrate the cell membrane through diffusion, as well as with folate-derivatized drug/antisense oligonucleotide-carrying liposomes. See, for example:    Leamon C P, Low P S, "Cytotoxicity of momordin-folate conjugates in cultured human cells", J. Biol. Chem., 1992, 267, 24966-24967;    Leamon C P, Paston I, Low P S, "Cytotoxicity of folate-pseudomonas exotoxin conjugates towards tumor cells", J. Biol. Chem., 1993, 268, 3198-3204;    Lee R J, Low P S, "Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis", J. Biol. Chem., 1994, 269, 3198-3204;    Wang S, Lee R J, Cauchon G, Gorenstein D G, Low P S, "Delivery of antisense oligonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethyleneglycol", Proc. Natl. Acad. Sci U.S.A., 1995, 92, 3318-3322; and    Wang S, Lee R J, Mathias C J, Green M A, Low P S, "Synthesis, purification and tumor cell uptake of Ga-67-Deferoxamine-folate, a potential radiopharmaceutical for tumor imaging", Bioconj. Chem., 1996, 7, 56-63.
The prior art has spent considerable energy in studying folate binding protein as a potential target for delivery of exogenous molecules into cells that express folate binding protein, as further illustrated hereunder.
U.S. Pat. No. 5,416,016 and WO 96/36367 (Low et al.) are directed to a method for enhancing transmembrane transport of exogenous molecules and disclose such delivery wherein the method comprises: contacting a membrane of a living cell with a complex formed between an exogenous molecule and a ligand of folic acid and folate analogs to initiate receptor-mediated transmembrane transport of the ligand complex. The exogenous molecules include a large variety of compounds, peptides, proteins and nucleic acids, analgesics, antihypertensive agents, antiviral agents, antihistamines, cancer drugs, expectorants, vitamins, plasmids and diagnostic agents.
The synthetic methods described in these documents were not regioselective, and mixtures containing folic acid coupled to the exogenous molecule through either the α- or γ-carboxylate of folate are expected to form. In the process disclosed in U.S. Pat. No. 5,416,016 these mixtures were not separated.
WO 96/36367 distinguishes between the two isomers of DF-folates, i.e., those where deferoxamine is coupled to the folate moiety through the α- or through the γ-carboxyl group of folate, based on their competition with free folate for the cell surface FBP: it was found that the α-conjugate was unable to compete with free folate for the cell surface FBP. In a comparative test a 50% decrease in bound 3H folic acid was observed in the presence of an equimolar amount of the DF-folate (γ) conjugate, while the DF-folate (α) isomer displayed no ability to compete with the radiolabeled vitamin.
Wang et al., supra, studied the uptake of 67Ga-deferoxamine-folate into KB tumor cells (a human nasopharyngeal epidermal carcinoma cell line that greatly overexpresses the folate binding protein) as a potential radiopharmaceutical. When 0.15 μCi (100 pmol) of 67Ga-DF-folate (deferoxamine coupled to folic acid via the γ-carboxylate of folate) was incubated with monolayers of KB cells, the final % uptake of the compound by the KB cells was 32% of the applied radioactivity. The compound had very low non-specific binding as indicated by very low activity levels bound to a receptor-negative cell line control.
Wang et al. subsequently published another report* stating that folic acid derivatives that are modified at the alpha carboxylate have no affinity for cell surface folate receptors. They reported the preparation of FITC-EDA-folate derivatives containing a fluorescein moiety (FITC) linked to folate through either the α- or γ-carboxylate of folate (via an ethylenediamine [EDA] spacer). The two isomers were incubated with KB cells that overexpress FBP. The cells were ten washed to remove unbound compound and assayed for cell-associated fluorescence. The γ-isomer of FITC-EDA-folate showed half maximal binding to KB cells at a concentration of 1.6 nM (binding comparable to native folate), but the α-isomer of FITC-EDA-folate had "virtually no affinity for the cell surface receptors". *Wang, Susan; Luo, Jin; Lantrip, Douglas A.; Waters, David J.; Mathias, Carla J.; Green, Mark A.; Fuchs, Philip L.; Low, Philip S. Design and Synthesis of [111In]DTPA-Folate for Use as a Tumor-Targeted Radiopharmaceutical. Bioconjugate Chem. (1997), 8(5), 673-679.
The folate-based agents of the present application were designed for use in nuclear medicine, neutron capture therapy, or NMR applications. Based on the teachings in WO96/36367 that only folate adducts coupled to exogenous molecules through the gamma carboxylate of folate are recognized by FBP, we devised regiospecific syntheses for the preparation of these folate conjugates, rather than using the non-regiospecific methods used by others. The conjugates prepared by these regiospecific routes contained metal chelating ligands coupled to folate through its gamma carboxylate. The corresponding alpha isomers were prepared for use as negative controls. Surprisingly, when the ability of the alpha and gamma isomers to bind to FBP in tumor cells in vitro was compared, the alpha isomers (our "negative" controls) bound to FBP to the same extent as the gamma isomers in a variety of in vitro studies (vide infra). This result was surprising in light of the reports of Wang et al. Also surprising was our subsequent finding that folate compounds derivatized with metal chelates at both the alpha and gamma carboxylate of folate (bis derivatives) were also able to bind to FBP.
We also performed studies with the alpha and gamma isomers in tumor-bearing animals, where ability of the alpha isomers to localize in the tumors was surprisingly found to be equal to or greater than that observed with the corresponding gamma conjugates. In addition, the clearance behavior of the two isomers was compared, both in vivo and in vitro. As discussed in greater detail later, the urinary clearance of the alpha isomers from the body was significantly and unexpectedly higher than that observed with the corresponding γ-isomer or with 3H folate. This may be an advantage for some nuclear medicine and radiotherapy applications for these compounds, because retention in non-target organs causes higher radiation dose to the patient and lower target to background ratios. Compounds that are more rapidly excreted from the body provide an improved margin of safety.
We have also discovered that the alpha isomers of the folate conjugates of the present invention also show unexpectedly faster clearance from cells in vitro. Studies were performed to compare the clearance of metal complexes coupled to the γ- or α-carboxylate of folates or to both the α- and γ-carboxylates of folates (hereinafter sometimes termed bis derivatives) from KB and JAR cells. We obtained the surprising finding that the clearance rate of the α isomer and of the bis isomer from KB and JAR cells is significantly faster than that of the corresponding γ isomer or of 3H folate.
Based on this surprising discovery we have also found that the clearance rate of folate-based diagnostic agents designed for use in nuclear medicine or MRI applications can be varied or tailor-made by using various proportions of the α-isomer, the bis isomer and γ-isomer of such diagnostic agents. In addition to tailor-making the rate of clearance from certain organs, such as the kidney, liver, brain, liver, kidneys and from various tissues such as tumors that over-express folate binding protein, the use of chelating agents chosen for the compounds of the present invention provides a greater margin of safety against the toxicity of the metal used in the chelates.
Experiments from our laboratories on the cellular uptake of monomeric folate conjugates of Gd chelates designed for use in MR applications indicate that structural modifications that bring about an increase the intensity of the MR signal are advantageous, as the signal intensity obtainable with this technique is determined by the quantity of paramagnetic or superparamagnetic metal that can be localized in the target tissues. This is, in turn, limited by the quantity of folate binding protein present in those tissues. The desired increase in signal intensity could be achieved by attaching multimeric Gd chelates to a single folate residue and/or by the use of enhanced relaxivity Gd chelates, that are, as a result of their structure, expected to provide higher intrinsic signal intensity per Gd atom. Based on these observations the following concepts are presented for the design of new monomeric and multimeric folate conjugates of Gd chelates in order to enable MR imaging of tumors and other tissues that over-express the folate binding protein.

This patent is subject to a terminal disclaimer.

Metal complexes derivatized with folate for use in diagnostic and therapeutic applications


A peripheral device adapted for connecting to a mobile device is provided. The peripheral device includes a main body, at least one connecting arm, and at least one control module. The main body includes a clamping unit to clamp a mobile device in place. One end of the connecting arm is movably connected to one side of the main body, the connecting arm is movable and close to the one side of the main body to be in a storage position, or extends away from thereof to be in an expanded position. Each of the control modules includes at least one input unit, and the control module is detachably connected to another end of the connecting arm. When the connecting arm is in the expanded position, the control module is electrically connected to the mobile device, so as to provide control thereof.

With the emergence of smart phones and improvement of hardware performance thereof, various mobile games are rapidly being released on smart phones. The smart phones are, however, still limited to touch interfaces and can only provide virtual buttons for in-game controls, and virtual buttons have no realistic tactile feel like that provided by actual keyboards. Since a directivity of the virtual keyboard is not precise, a control experience is also greatly reduced. Conventional manners of touch control lack in authenticity; for example, a touch sensation reflecting an operating force of a user cannot be instantaneously fed back to the user.
In view of the abovementioned issues, the applicant of the present disclosure has proposed a "control handle" that can be combined with portable electronic devices via the Taiwan Patent Application Patent Publication Nos. TWM494350 and TWM494020. An external holding module is detachably assembled on the game handle device that can be used to clamp or carry the portable electronic device, so that the user can operate the portable electronic device through the game handle device.
However, an overall structure of the aforementioned control handle is still not convenient for storage and carrying. Therefore, how to improve the storability and portability of the peripheral device by improving a structural design of the control handle to overcome the above-mentioned shortcomings has become one of the issues to be solved in this technical field.


A dictionary management apparatus is disclosed, which can optimize a dictionary required for speech synthesis of character data. The apparatus checks if character data which is to undergo speech conversion includes character data which is not registered in the dictionary. When the unregistered character data is included, the apparatus generates new dictionary data of that character data using another dictionary and adds the generated new dictionary data to the dictionary.

A speech synthesis system that converts digital character data has been proposed. In order to convert English text or the like into synthetic speech, language analysis is required to extract information such as pronunciations and the like. The language analysis normally uses a dictionary for language analysis.
However, this dictionary normally includes several ten to thousands of lexical items required to analyze a language such as Japanese or the like, and has a large data size. Hence, when such dictionary is stored on a computer, a memory of several M bytes is required, thus disturbing efficient use of the memory.
On the other hand, the use frequencies of words (so-called trendy words), which reflect ever-changing social situation, become temporarily high, and such words must be registered in the dictionary with high necessity. However, the use frequencies of such words become very low after a given period. If such words are semi-permanently registered in the dictionary, the number of wasteful data increases, and such data cause analysis errors, resulting in analysis precision drop.

Dictionary management apparatus for speech conversion


Methods and systems disclosed herein can be used for testing an application's rendering of output to individual controls of a Graphical User Interface (GUI), displayed on a target device executing the application. A system according to the present invention includes a test tool running on a development computer that communicates with an agent executing on the target device. Testing is performed by using the test tool to execute test scripts, which cause test input to be injected via the agent into the application on the target device. The test tool can validate whether actual output on the target device matches expected output known to the test tool. The present invention includes a variety of key components, such as a flexible trap manager for handling unexpected screens that appear during an automated test, and a configuration manger for testing against multiple languages and platform configurations.

Handheld portable electronic devices have proliferated in recent years. These devices range broadly in terms of the functionality they offer. For example, computing devices such as personal digital assistants (PDAs), communication devices such as cellular or wireless telephone handsets, information acquisition devices such as barcode or radio-frequency identification (RFID) scanners, personal entertainment devices such as digital versatile disc (DVD) players, compact disc (CD) players, and gaming systems, hybridized devices incorporating functionality of more than one of the above devices, and numerous other kinds of handheld devices, are now available on the market for a variety of purposes desired by users.
Such handheld computerized devices incorporate embedded operating systems such as Windows CE and Palm OS which provide some of the functions of larger operating systems, but are much more compact in terms of the memory required for their storage and execution, the processing power required to execute them, and the speed with which they can be executed by a processor within the handheld device. With the proliferation of handheld devices, so too of course have the number of such devices incorporating a Windows CE operating system. This circumstance has driven greater demand for software development tools that operate with these and other types of Windows-based devices. Although there are a number of software test tools currently on the market, no one system provides a complete suite of capabilities for easily and effectively testing all facets of an application's rendering of output to a graphical user interface (GUI), which is displayed on a target device executing an application under test.
For example, when a test developer creates a test script to run an automated test, the test developer typically expects the device's state to sequence in a certain order so that he or she can effectively test particular aspects of the application under evaluation. However, it is not uncommon to have unexpected screens pop up on the target device during an automated test. The occurrence of these unexpected screens, referred to herein as "trap events," can adversely impact the results of the automated test, even causing it to fail. The ability to handle the instantiation of such unexpected screens, message boxes or other such "trap events" can be an important aspect of conducting the unattended execution of an automated test. While some prior art systems provide some basic functionality for dealing with these unwanted screens, such as having the test tool push a single "close" button, they do not provide a user with the flexibility to deal with such screens in any manner that the user deems appropriate for a given test situation.
Another important aspect of automated testing and validation of software applications is the need to have a robust system for testing against multiple languages and platform configurations. Testing software applications has become increasingly complex due in part to the fact that many applications now run on several different platforms with different configurations, and in different languages. The ability to test international releases of software applications is of vital importance to most test groups. Yet, many prior art systems do not provide a robust and easy-to-use system for conveniently testing against international releases of an application, within the same automated test.
Yet another aspect not adequately addressed in the prior art is the need to have a flexible system for accurately "identifying" and "verifying" controls and windows on the target device. Suppose a test developer wants to make a call to get the text from a specific text box that is believed to be present on the target device. Before the test tool can "grab" the specific control, the test tool needs to find that control. Some prior art systems include a window recording utility that includes a list of properties which can be selected to uniquely identify that window. After setting these properties once per recording session, such tools use this set of properties when identifying that window, and all controls within that window. However, there are many instances in which a user may require the flexibility to identify (or verify) a particular control based on a different set of properties than other such controls within that same window or within the same control class type.
A need therefore exists for an improved system and method of testing and validating an application's rendering of output to a graphical user interface (GUI) in a Windows-based environment, which overcomes at least the deficiencies in the prior art that are discussed above.

Automated test system for testing an application running in a windows-based environment and related methods


This invention provides a method for producing semiconductor nanoparticles having a monodispersed distribution of particle sizes and the semiconductor nanoparticles produced by the same, which were insufficient in conventional reversed micelle methods. This method for producing semiconductor nanoparticles comprises steps of: forming semiconductor nanoparticles in the reaction field in the micelle or in the reversed micelle; and regulating the particle size of the semiconductor nanoparticles by size-selective photoetching, wherein the reaction field in the micelle or in the reversed micelle serves also as the dissolution field for ions that are produced when the semiconductor nanoparticles are subjected to size-selective photoetching. In this method, particle sizes of the semiconductor nanoparticles are regulated by adjusting the size of the dissolution field for ions and regulating the reactivity of size-selective photoetching.

Semiconductor nanoparticles whose particle sizes are 10 nm or less are located in the transition region between bulk semiconductor crystals and molecules. Their physicochemical properties are therefore different from both bulk semiconductor crystals and molecules. In this region, due to the quantum-size effect, the energy gap of semiconductor nanoparticles increases as their particle sizes decrease. In addition, the degeneration of the energy band that is observed in bulk semiconductors is removed and the orbits are dispersed. As a result, the lower-end of the conduction band is shifted to the negative side and the upper-end of the valence band is shifted to the positive side.
Semiconductor nanoparticles exhibit spectra with peaks whose full widths at half maximum are relatively narrow. Accordingly, particle size regulation of semiconductor nanoparticles enables the development of various reagents which exhibit spectra whose full widths at half maximum are narrow. This enables the multi-color analyses in, for example, the detection and the imaging of biopolymers. Compared to common organic pigments, semiconductor nanoparticles are more durable and fade less.
Semiconductor nanoparticles can be easily prepared by dissolving equimolar amounts of precursors of Cd and X (X being S, Se or Te). This is also true for the manufacturing of, for example, CdSe, ZnS, ZnSe, HgS, HgSe, PbS, or PbSe.
Semiconductor nanoparticles have drawn attention since they emit strong fluorescences whose full widths at half maximum are narrow. Thus, various fluorescent colors can be created, and their future applications can be nearly infinite. However, the semiconductor nanoparticles obtained by the above method exhibit a wide distribution of particle sizes and therefore cannot provide the full advantage of the properties of semiconductor nanoparticles. Attempts have been made to attain a monodisperse distribution by using chemical techniques to precisely separate and extract only the semiconductor nanoparticles of a specific particle size from semiconductor nanoparticles having a wide distribution of particle sizes immediately after preparation. The attempts to attain a monodispersed distribution of particle sizes that have been reported so far include: separation by electrophoresis that utilizes variation in the surface charge of nanoparticles depending on their particle sizes; exclusion chromatography that utilizes differences in retention time due to different particle sizes; size-selective precipitation that utilizes differences in dispersibility in an organic solvent due to differences in particle sizes; and size-selective photoetching that utilizes the oxidative dissolution of a metal chalcogenide semiconductor in the presence of dissolved oxygen when irradiated with light.
The aforementioned production methods are carried out by preparing semiconductor nanoparticles having a wide distribution of particle sizes and then regulating and selecting the particles sizes. An example of a method for preparing previously monodispersed nanoparticles is the reversed micelle method that utilizes amphiphilic molecules. In this method, reversed micelles are formed in a non-polar solvent. The inside of the reversed micelle is regarded as a reaction field, and the size of the reaction field is regulated, thereby sorting nanoparticles into uniform particle sizes. This has been the most commonly employed method up to the present, and is the easiest method of particle size preparation. When monodispersion by the reversed micelle method is carried out, the distribution of particle sizes is approximately several dozen percentage points. Semiconductor nanoparticles emit fluorescence upon the application of excitation light, and the wavelength of this fluorescence is determined by the particle size. Specifically, a fluorescence spectrum whose full width at half maximum (FWHM) is narrow cannot be obtained where there is a wide distribution of particle sizes. Accordingly, the distribution of particle sizes should be further reduced in order to prepare semiconductor nanoparticles which emit relatively monochromatic fluorescences.
In contrast, size-selective photoetching for attaining monodispersion of particle sizes that utilizes the oxidative dissolution of a metal chalcogenide semiconductor in the presence of dissolved oxygen when irradiated with light has been heretofore used as a method for preparing monodispersed semiconductor nanoparticles having a wide distribution of particle sizes. In this method, particle size selection or the like is unnecessary, and particle sizes can be monodispersed in a bulk solution. When the semiconductor nanoparticles obtained by this method are irradiated with light having a wavelength of 476.5 nm, the average particle size is 3.2 nm and the standard deviation is 0.19 nm. These semiconductor nanoparticles exhibit a very narrow distribution of particle sizes, i.e., the standard deviation is approximately 6% of the average particle size. This indicates that the distribution of particle sizes is very close to the monodispersed state.
Previous methods of production of semiconductor nanoparticles required a stabilizer, and it was difficult to combine this production method with the latter monodispersion into a sequential method.
Therefore, an object of the present invention is to develop an effective sequential method for producing monodispersed semiconductor nanoparticles.

Method for producing semiconductor nanoparticles and semiconductor nanoparticles produced by the same


Systems and methods by which voice/data communications may occur are disclosed. In particular, systems and methods are provided with a computing system having a multi-bus structure, including, for example, a TDM bus and a packet bus. An integrated communication system is coupled to a digital telecommunications link, the communication system providing voice and data communications to a plurality of users. At least a first packet bus is coupled to one or more packet-based devices and adapted for transferring packetized data to and from the system. One or more time division multiplex (TDM) buses are coupled to one or more telephony devices. Data routing resources are provided internal to the integrated system. A network interface module couples data to and from a data router external to the integrated system. The data router external to the integrated system is coupled to the first packet bus. Data is routed via the external data router through the network interface module and coupled to data channels of the digital telecommunications link, while voice data is selectively coupled to voice channels of the digital telecommunications link.

This application contains subject matter that is related to the following applications, all owned by the assigned of the present application, which are hereby incorporated by reference: U.S. application Ser. No. 09/055,072, filed on Apr. 3, 1998, for Systems and Methods for Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses, now U.S. Pat. No. 6,181,694; U.S. application Ser. No. 09/055,036, filed on Apr. 3, 1998, for System and Method for Generating Voltages in Telephony Station Cards; U.S. application Ser. No. 09/161,550, filed on Sep. 25, 1998, for Systems and Methods for Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses and Methods for Performing Telephony and Data Functions Using the Same, now U.S. Pat. No. 6,208,658; U.S. application Ser. No. 09/163,596, filed on Sep. 29, 1998, for Systems and Methods for Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses and Methods for Performing Telephony and Data Functions Using the Same, now U.S. Pat. No. 6,343,074; U.S. application Ser. No. 09/167,408, filed on Oct. 6, 1998, for Systems and Methods for Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses and Methods for Performing Telephony and Data Functions Using the Same, now U.S. Pat. No. 6,154,465; U.S. application Ser. No. 09/283,101, filed on Mar. 31, 1999 for Systems and Methods For Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses and Methods For Performing Telephony And Data Functions Using the Same, now U.S. Pat. No. 6,266,340; and U.S. application Ser. No. 09/368,460, filed on Aug. 4, 1999 for Systems and Methods For Multiple Mode Voice and Data Communications Using Intelligently Bridged TDM and Packet Buses and Methods For Implementing Language Capabilities Using the Same, now U.S. Pat. No. 6,366,578 (all of the foregoing applications are hereby incorporated by reference and are referred to herein as the "Referenced Patent Documents").
Businesses, particularly small to medium size offices, typically have a need for a variety of voice and data communications. For example, a typical office might have a dedicated fax machine, using a dedicated or shared telephone line, one or more telephone lines for voice communications, perhaps coupled to a central or distributed voice mail system(s), and one or more computers or computer networks, often coupled to telephone lines via one or more modems. Many offices now use the Internet in some form for business communications or research or the like, often by way of a modem or modem pool coupled to individual computers.
Typically, such business communication needs have been fulfilled with piecemeal technical solutions, typically from separate equipment and service vendors, and with separate hardware, software and design considerations.
FIG. 1 illustrates a conventional small office communication configuration. Voice communication system 1 typically is implemented by way of multiple analog trunks 16 from wide area network ("WAN") 18. WAN 18 often consists of a telecommunication network by way of a local telephone company or other telecommunications service provider. Analog trunks 16 may be directed through switching system 10, which may be a conventional PBX or similar telephone switch. Telephones 12 and voice mail system 14 are coupled to switching system 10. Often, dedicated analog line 16A is coupled to facsimile 44 for facsimile communications.
Data system 2 typically is implemented with a plurality of computers (or workstations, etc.) 24 interconnected by way of packet network 26, which may be a standard Ethernet compliant network or other office network. Network 26 often is coupled to remote access server 32, which is connected to one or more analog trunks 40, and which may include one or more modems in a modem pool. Computers 24 may communicate with remote systems via the modem pool of remote access server 32 over analog lines 40 and WAN 42. Network 26 typically includes a connection to printer 22 and file server 20. In more sophisticated systems, network 26 may be coupled to switching hub 28 and router 30, which is coupled to WAN 42 over digital trunks 38. Data system 2 also may include a connection between one or more of computers 24 to modem 36, which in term is coupled to WAN 42 over dedicated analog trunk 40A.
Such a conventional system often is characterized by piecemeal equipment and network solutions, limited or non-existent coordination and management between voice system 1 and data system 2, non-optimized or non-integrated equipment, and inefficient use of costly network services (telephone lines, data lines, etc.), such as duplicate and often idle phone and data network lines, often provided from multiple equipment/service providers. In general, such conventional systems are neither constructed nor operated in a manner to provide efficient and integrated voice/data communications.
In addition, while systems described in the Referenced Patent Documents included data routing resources, it is desired to be able to utilize the capabilities of such a system also with external data routing or other equipment.

Systems and methods for voice and data communications including a network drop and insert interface for an external data routing resource