To overcome obstacles faced by current remediation technologies for contaminated sediments, the present invention provides a new strategy based on in situ control of hydrophobic organic contaminants (HOC) bioavailability. The strategy employs the addition of activated carbon sorbents to sediments. These activated carbon materials sorb HOC contaminants strongly, reduce release of HOCs into water, and reduce HOC uptake by benthic biota, thereby reducing environmental exposure and human health risk to such contaminants. By in situ sorbing the contaminants, the inventive approach reduces environmental exposure and avoids massive material removal while controlling food web transfer of HOCs including polychlorinated biphenyls (PCBs).

In 1997, the U.S. Environmental Protection Agency (EPA) estimated that 10 percent of the nation's lakes, rivers, and bays have sediment contaminated with toxic chemicals that can kill fish living in those waters or impair the health of people and wildlife who consume contaminated fish or water. The magnitude of the sediment contamination problem in the United States is evidenced by the more than 2,100 state advisories that have been issued against consuming fish. An important class of such contaminants are hydrophobic organic compounds (HOCs), which includes polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), pesticides (such as DDT), and some organometallic compounds (such as dimethyl mercury). HOCs are important contaminants of concern in sediments because of their association with fine-grained, organic-rich sediment material. HOCs persist in sediments for many years and exhibit the potential for bioaccumulation and toxicity. Thus, HOCs in sediments pose risks to human health and the environment.
The importance of the HOC contamination of sediments is exemplified by PCBs, which are long-lived in sediments and leach into overlying water, accumulate in benthic invertebrates, and transfer through the food chain to animals and humans. This has resulted in 697 fish consumption advisories for PCBs in the U.S. in 1998.
The cost of remediating contaminated sediments often runs into billions of dollars. The most commonly considered technologies for contaminated sediment management are (1) dredging and placement in confined disposal facilities (CDFs) or hazardous waste landfills and (2) capping, an option for containment in engineered subaqueous sites. However, either option is expensive and requires large-scale material handling and long-term management. Further, since most PCB-contaminated sediment sites are large, the application of any remediation option is a difficult task.
Traditional sediment treatments based on dredging are costly and problem-prone and will leave residual PCBs, and thus do not completely eliminate environmental and human health risks. In addition, dredging operations can cause temporary high levels of contaminants in the water column due to resuspension of buried sediments and release of pore water. Dredging also destroys aquatic habitats. Further, all known sediment treatment technologies will leave residual contaminants. In situ treatment is thus needed even if dredging is employed.
Therefore, active, in situ stabilization methods that do not involve sediment relocation are attractive.
Prior in situ sediment stabilization efforts include capping with clean sand and geofabric. Some major unresolved issues regarding the long-term efficiency of caps include maintenance of cap integrity during high flow or storm events, physical alteration of the indigenous habitat, and organisms that can burrow into the caps and impair their efficacy.
U.S. Pat. No. 5,391,300, "METHOD FOR THE REMOVAL OF HALOGENATED ORGANIC COMPOUNDS FROM AN ENVIRONMENT", issued to Webb et al. and assigned to General Electric Company of N.Y., U.S.A., Feb. 21, 1995, discloses sorbing halogenated organic compounds such as PCBs and PAHs from aqueous solutions and mixtures by a variety of organic polymeric materials. Recently, the use of Ambersorb polymeric resin has been explored for in situ remediation and containment of contaminants, as reported by West, W. W.; Kosian, P. A.; Mount, D. R.; Makynen, E. A.; Pasha, M. S.; Sibley, P. K.; Ankley, G. T. "Amendment of Sediments with a Carbonaceous Resin Reduces Bioavailability of Polycyclic Aromatic Hydrocarbons", Environmental Toxicology and Chemistry, 20, 1104–1111. The major uncertainties regarding the feasibility of these approaches are: the high cost of the sorbent material, the permanence of the treatment effectiveness, and the lack of knowledge of sequestration processes controlling phase transfer and stabilization of the contaminants.
There exists a continuing need, therefore, for an inexpensive, nonremoval, in situ remediation technology for submerged sediments contaminated with persistent hydrophobic organic compounds.

The Board of Trustees of the Leland Stanford Junior University


An IC socket for receiving an IC package having a plurality of electrical contacts on a bottom face thereof is disclosed. The IC socket has an insulating housing that receives the IC package and a plurality of elastic contacts, one end each being secured to the insulating housing, and a remaining end of each contacting at least one of the electrical contacts on the bottom face of the IC package. The IC socket also has a spring member carried by the insulating housing that determines an accepting position for the IC package being accepted into the insulating housing, and that restrains an amount of horizontal movement of the IC package caused by bending of the elastic contacts as the IC package is pressed down.

There are various kinds of IC packages that package a semiconductor device. For example, one type called LGA (Land Grid Array) in which a flattened pad is arranged, one type called BGA (Ball Grid Array) in which a spherical pad is arranged, and one type called PGA (Pin Grid Array) in which a lead pin is arranged. When the various kinds of IC packages are electrically connected with a wiring pattern on a circuit board, an IC socket which has a contact which makes electrical contact to a wiring pattern on a circuit board (for example, see Patent Documents: Japanese Patent Application Publication No. Hei 7-282931, Japanese Patent Application Publication No. Hei 10-302925, and Japanese Patent Application Publication No. 2005-19284) has been used. It is desirable to increase the density of electrical contacts of pads or the like in IC packages and the corresponding electrical contacts of IC sockets.
Prior Art FIGS. 1A-1C show a part of an existing IC socket which accepts an IC package type called LGA.
Prior Art FIGS. 1A-1C show an insulating housing 91 and a contact 92 both of which are included in an IC socket 9, an IC package 8 which is mounted in the IC socket 9, and a pad 81 of the IC package 8. In the insulating housing 91 is a recess 911 in which the IC package 8 is accepted from an upper side. A cantilever spring is applied to the contact 92, and a side of a contact point 921 shown left in Prior Art FIGS. 1A-1C is a free end. In the socket 9 which employs the contact 92 in a cantilever spring form, when the IC package 8 is pressed down (a vertical load is applied), the IC package 8 goes down with the contact 92 being bent, and a contact position slides horizontally in a plan view.
Prior Art FIG. 1A shows a state in which the IC package 8 is set from above in the recess 911 so that the IC package 8 is settled at a side in a direction in which the IC package 8 is going to slide (left side, see an arrow in Prior Art FIG. 1C). Prior Art FIG. 1B shows a state where the IC package 8 is set in the recess from above so that the IC package 8 is settled at a side opposite to the direction in which the IC package is going to slide (right side).
In the states shown in Prior Art FIGS. 1A and 1B, the contact 92 of the IC socket 9 contacts with the pad 81 of the IC package 8 set in the recess 911 of the IC socket 9. The IC package 8 set in the recess 911 of the IC socket 9 receives a vertical load by a pressing cover (not shown). Accordingly, the IC package 8 is pressed in until a bottom face 80 of the IC package abuts on a support section 912 of the insulating housing 91.
Prior Art FIG. 1C shows a state in which the IC package 8 shown in Prior Art FIG. 1B is pressed in until the bottom face 80 abuts on the support section 912 of the insulating housing 91.
When a vertical load is applied to the IC package 8 which is set at the side opposite to the direction in which the IC package is going to slide (see the arrow in Prior Art FIG. 1C), the contact 92 in a cantilever spring form of the IC socket 9 falls downward (see the contact shown by dotted line in the drawing), and the contact point 921 moves left in the drawing. At this point, an amount of the movement is described as R in the drawing. When the contact point 921 of the contact 92 is moved left in the drawing, the pad 81 of the IC package 8 slides as well by friction. Accordingly, by this friction of the sliding, the IC package also slides left in the drawing (see the arrow in Prior Art FIG. 1C). As a result, the IC package 8 abuts on the edge 911a of the recess 911, and the bottom face 80 abuts on the support section 912 of the insulating housing 91. Thus, the IC package 8 is positioned in a final predetermined mount position. In the IC socket 9 shown in Prior Art FIG. 1B, when a vertical load is applied to the IC package 8, the IC package 8 is moved left. At this point, an amount of movement is described as S in the drawing. Therefore, an amount of relative movement of the contact 921 to the pad 81 of the IC package becomes |R-S|.
In addition, by the sliding of the contact 92 and the pad 81, oxide film formed on the pad and contact is removed.
As shown in Prior Art FIG. 1A, when a vertical load is applied through the pressing cover (not shown) to the IC package set in the recess 911 in the state in which the IC package is settled at the side in the direction in which the IC package 8 is going to slide (see the arrow in of Prior Art FIG. 1C), the IC package 8 goes downward. However, because the IC package 8 is already in contact with the edge 911a of the recess 911 before the vertical load is applied, the IC package 8 may not slide left further more in the drawing. Therefore, in this case an amount of relative movement of the contact point 921 to the pad 81 of the IC package 8 is R, which is larger than the amount of relative movement of the IC socket 9 shown in Prior Art FIG. 1B whose amount of relative movement is |R-S|. Or, a contacting point of the contact 92 with the pad 91 is shifted left by R while the state is changed from where the IC package is set in the recess to where the IC package is positioned in the final predetermined mount position. Regarding the IC package 8 shown in Prior Art FIG. 1C, in consideration of the sliding distance by R in which the contacting point of the contact 92 with the pad 81 is shifted left when the IC package is set in the recess 911 in the state in which the IC package 8 is settled at the side in the direction (see the arrow in Prior Art FIG. 1C) in which the IC package 8 is going to slide as shown in Prior Art FIG. 1A, the pad 81 is made larger than an enough size required to make electrical contact with the contact point 921 of the contact 92. Therefore, density increase of an electrical contact (or pad) in an IC package is restrained. In addition, because the contact 92 of the IC socket 9 corresponds to the pad of the IC package 8, a pitch between each adjacent contact 81 becomes bigger as the pad 81 gets larger. Accordingly, density increase of an electrical contact in an IC socket is also restrained.
Referring to FIG. 1B again, the IC package 8 shown in slides to the final mount position. If a distal end 801 in a direction in which the IC package 8 slides abuts on the edge 911a of the recess 911 before the bottom face 80 of the IC package 8 abuts on the support section 912 of the insulating housing 91, friction increases because both the distal end 801 of the IC package 8 and the edge 911a of the insulating housing 91 are made of resin. Accordingly, the IC package 8 does not move further down, which is problematic. Even if the IC package 8 moves down, when the IC package 8 moves down, the bottom face 80 abuts on the support section 912 while the IC package 8 and the insulating housing 91 scrape each other.


The invention relates to the field of sonar antennas, in particular those intended to be installed on an underwater vehicle in order to constitute a mounted head of the vehicle. Specifically, the invention relates to a sonar antenna having at least two identical transducers that exhibit sensitivity peaks at at least two frequencies .nu., and .nu..sub.2, wherein the head mass dimension of the transducers is between 0.35 and 0.65 times the wavelength .lambda..sub.2 corresponding to the higher of the frequencies .nu..sub.1 and .nu..sub.2.

The present invention relates to the field of sonar antennas, in particular those intended to be installed on an underwater vehicle in order to constitute a mounted head of said vehicle. It relates in particular to a sonar antenna capable of operating in different frequency bands.
A sonar antenna generally consists of a large number of transducers Each transducer, for example a receiving transducer, consists of an element for converting the pressure energy that propagates in the liquid medium into electrical energy that can be processed by electronic means. In an underwater antenna such as that used in sonars for torpedoes, the transducers are arranged alongside one another on an acoustically transparent material which ensures energy transfer; they are moreover fastened mechanically, in a more or less complex manner, onto a support capable of withstanding compression forces.
One example that may be cited is French Patent No. 2603761, which describes a sonar antenna constituting the mounted head of an underwater vehicle, said antenna having a core which is a block of rigid syntactic foam that is resistant to immersion-related hydrostatic pressure, said block having receptacles in each of which is placed an electro-acoustic transducer, the outer surface of which is flush with the outer surface of said block. This antenna has a sealed casing made of an acoustically transparent material, which is overmolded around the block and the transducers and which has a hydrodynamic tapered profile which extends that of the vehicle hull, and means for fastening onto the outer surface of the front end of the vehicle hull. Underwater antennas can operate exclusively passively or actively, or can have the capability for simultaneous active and passive operation.
In all cases, the antenna possesses an optimum operating frequency which is characterized by the fact that sampling of the sensitive area, in other words the number of transducers per unit area, is suitable; and, for active antennas, that each transducer can convert electrical energy into mechanical energy with the best possible efficiency. In an effort to meet the needs of designers of torpedo seeker heads, who are demanding more and more frequency agility for the sonar, experiments with "wide-band" active antennas have led to the design, by more or less complex means, of transducers whose efficiency remains at a level sufficient for a frequency excursion on the order of 30% of the optimum frequency. Factors which, however, still cannot be varied as a function of frequency are on the one hand the dimension of the transducer head mass which constitutes the coupling element between the medium and the energy conversion material, said dimension establishing the area sampling; and on the other hand the dimensions of the constituent parts of the transducers, which establish the optimum operating frequency.
The "dimension" of a transducer head mass is understood to mean the diameter of the head mass if it is in the shape of a flattened cylinder, or the length of one side if it is in the shape of a rectangular parallelepiped with a square base.
For physical reasons relating to energy transmission and reduced interaction among the transducers, the designer arranges the elements at distances that remain close to half the wavelength that is propagating in the medium.
British Patent No. 2,077,552 describes a sonar antenna which can be used to search for shoals of fish or sandbanks, and which has transducers that emit at two frequencies .nu..sub.1, and .nu..sub.2, respectively 55 kHz and 130 kHz, the dimension of the head mass of each transducer being substantially equal to half the wavelength .lambda..sub.1 corresponding to frequency .nu..sub.1. With an antenna of this kind, however, efficiency drops considerably when the transducers are operating at frequency .nu..sub.2. Moreover an antenna of this kind cannot be used in a torpedo seeker head because of its very low directivity.

Etat Francais represente par le Delegue General pour l'Armement


A novel greeting card is disclosed having metallic leaves secured with one or more mechanical hinges. Various forms of engravings, hinges, leaves and overlays may be provided. Interior leaves may be inserted as well. The greeting card constitutes a permanent or semi-permanent commemoration of a special occasion or event.

Most people have, at some time in their life, purchased or received a greeting card. Such cards are often given to celebrate milestones in a person's life, such as birthdays and anniversaries, or to commemorate important events such as graduations, religious holidays, or the death of a loved one. Cards are, in short, a common and well-liked means of expressing an appropriate sentiment to a friend, relative or colleague on an important occasion.
Recently, many new forms of greeting cards have been proposed and introduced into the art. For example, U.S. Pat. No. 5,435,085, discloses a greeting card device comprised of a pair of foldable panels with an inner foldable receptacle capable of holding water for a living plant. The card combines the common practice of bestowing flowers on special occasions with the practice of sending a card. The greeting card is intended to be discarded within a few days of receipt.
U.S. Pat. No. 5,338,241 discloses a packaged balloon and greeting card combination. An uninflated balloon with an image printed thereon is provided with a greeting card having a face displaying an image corresponding to the image on the balloon. A separate envelope may also bear an imprint of the same image. The greeting card and the envelope serve as a protective cover for the balloon during shipment, storage and display. The balloon and greeting card are packaged together as a unit.
U.S. Pat. No. 5,375,351 discloses a greeting card having a magnetic picture frame temporarily attached to the card's surface with a releasable adhesive. The frame can hold a picture on the front of the card that can be removed from the card and magnetically attached to a ferrous metal surface such as a refrigerator.
Notwithstanding the numerous new and unusual embodiments that have been developed, the traditional greeting card has remained relatively unchanged over the years. Although they may vary in size, greeting cards uniformly consist of one or more folded sheets of paperboard or paper stock material. An appropriate sentiment or illustration is printed on either the inside or outside of the card, or both.
Despite the importance that many persons attach to giving and receiving greeting cards, and the fact that they are often sent to commemorate important occasions, such cards generally do not last very long, and are, in fact, made of disposable materials. Thus, after prolonged display, use or storage, greeting cards tend to warp, sag, tear, or yellow and deteriorate with age. This is particularly unfortunate since some cards may be important enough to the recipient that he or she wishes to save them for many years to come.
Accordingly, there is a need in the art for a durable, long lasting greeting card which can be saved and displayed after receipt for an extended period, beyond the lifespan of the traditional paper greeting card. Moreover, consumers are always interested in new and interesting ways of sending gifts or holiday sentiments.
There is also a need and interest in the industry for a new, improved form of greeting card, having novel features which enhance or improve their impact on a recipient.


Embodiments relate to a method of manufacturing a transistor having a metal silicide layer. In embodiments, the method may include sequentially forming a gate insulating layer pattern and a gate conductive layer pattern on a semiconductor substrate, forming a first metal silicide layer on the gate conductive layer pattern and a second metal silicide layer on the semiconductor substrate, forming a spacer layer on side-walls of the gate insulating layer pattern and the gate conductive layer pattern, and forming a source/drain region in the semiconductor substrate below the second metal silicide layer by performing ion implantation.

As semiconductor devices become more highly integrated, a width of a gate pattern within the semiconductor device may be gradually narrowed. However, such a reduction in a width of the gate pattern may increase a resistance of the gate pattern. This may degrade high-speed operation of a transistor. To ameliorate such problems, a method of forming a metal silicide layer having superior conductivity on a gate pattern or a doped region such as a source/drain region has been used.
FIGS. 1 through 3 are example cross-sectional diagrams illustrating a related art method of manufacturing a transistor having a metal silicide layer. FIGS. 4 and 5 are example cross-sectional diagrams illustrating problems that may be caused in the related art method of manufacturing a transistor having a metal silicide layer.
Referring to FIG. 1, gate insulating layer pattern 110 and gate conductive layer pattern 120 may be sequentially stacked on semiconductor substrate 100. Gate conductive layer pattern 120 may include a polysilicon layer. A first ion implantation process may then be performed to form source/drain extension region 131. After that, spacer layer 140 may be formed on the side-walls of gate insulating layer pattern 110 and gate conductive layer pattern 120. A second ion implantation process may be performed to form deep source/drain region 132. Source/drain extension region 131 and deep source/drain region 132 constitute source/drain region 130 of an LDD (Lightly Doped Drain) structure.
Referring to FIG. 2, metal layer 150 may be deposited on a surface (for example, the entire surface) of semiconductor substrate 100. Metal layer 150 may be a titanium (Ti) layer or a cobalt (Co) layer, and may be formed on the surface of semiconductor substrate 100 by a sputtering method.
Referring to FIG. 3, metal layer 150 adjacent to source/drain region 130 of the LDD structure and gate conductive layer pattern 120 may be heat treated. Metal layer 150 may thereby become silicide. As a result, first metal silicide layer 151 and second silicide layer 152 may be formed on gate conductive layer pattern 120 and source/drain region 130 of the LDD structure, respectively. After that, metal layer 150 that is not subject to the reaction may be removed.
Referring to FIG. 4, a spacer insulating layer, e.g., a nitride layer, may not be completely removed, but may remain on source/drain region 130 when forming the metal layer 140. In this case, as indicated by "A" in FIG. 4, the remaining insulating layer may interrupt the formation of second metal silicide layer 152 on source/drain region 130 during the process of forming the metal silicide layer.
Referring to FIG. 5, since non-reacted metal layer 150 may not be completely removed, metal layer residue 150′ may remain on a side surface of spacer layer 140. In this case, as indicated by "B" in FIG. 5, a bridge may be generated between first metal silicide layer 151 and second metal silicide layer 152, which may cause a malfunction of the transistor.


Carbon--carbon composite parts are joined with minimum surface preparation. A reactive-bonding joint interlayer having thickness greater than 1 mil is formed of fine particles of carbide-forming metallic ingredients and carbon. The joint interlayer is sandwiched between the two carbon--carbon parts to be joined and the assembly is heated under a compressive pressure to a temperature sufficient to complete the bonding reaction. No special surface preparation is required for the carbon--carbon parts due to the nature of the reactive-bonding. The mechanical properties of the joint are assured by selecting the metal-carbon ingredients so that thermal expansion mismatch is minimized. Shear strength exhibited by the resulting joints is greater than the interlaminar shear strength of the carbon--carbon composite material.

1. Field of the Invention
The present invention relates to carbon--carbon composites, and more particularly to a method for joining carbon--carbon composites parts with minimum surface preparation.
2. Description of the Prior Art
Joining of carbon--carbon composites becomes increasingly important as new technology developments demand larger and more complex geometries. Available joining methods are limited to bonding with adhesive materials, alloy brazing, diffusion bonding, and welding. Joints produced by bonding with adhesive materials or alloy brazing are only suitable for low to intermediate temperature applications, well below the temperature capability of the carbon--carbon composites. Diffusion bonding using refractory metals or compounds usually requires quite careful joining surface preparations of essentially porosity free carbons as well as long heating times at very high temperatures (often >2000.degree. C.) under high pressures. Welding requires even higher joining temperatures, and the joints produced are poor and exhibit low strength. U.S. Pat. No. 5,021,107 describes a process for joining finely finished carbon--carbon composites requiring a joint interlayer thickness of 25-100 micrometers. That process requires rather careful surface preparation and high joining temperatures close to the melting point (TMP, Tungsten is approximately 344.degree. C.) of the joint interlayer material. Furthermore, the strength of the joints, which is low, was not specified in the patent. There is a strong technical need for a process for joining common carbon--carbon composites which requires minimal surface preparation and produces joints having high strength and high temperature application capability. Further needed is a process that produces reliable joints at low temperatures under low pressures.

Joining of rough carbon-carbon composites with high joint strength


A workflow for a work item may be executed using an on-device persistent state machine-based architecture. The on-device state machine-based architecture may include a state machine manager that executes the workflow in accordance with a state machine that includes multiple states corresponding to stages of execution in the workflow. Each state in the state machine is associated with one or more tasks to be executed in connection with that state. The state machine further specifies one or more state transitions for each state of the state machine. A state transition associated with a particular state indicates a next state to transition to from the particular state upon completion of the one or more tasks associated with the particular state.

Web browsers or applications designed for execution on mobile devices may encounter a failure (e.g., may crash) during a multi-device transaction (e.g., after selecting an item for purchase but before completing the purchase). When this happens, the user may need to initiate the transaction from an initial starting point after re-launching the web browser or dedicated application because transaction data generated prior to the crash may not have been persisted. The inventions described below are improvements in technology that enable, among other things, a better user experience.


Homogeneous competitive immunoassay methods for simultaneously detecting analytes using capillary electrophoresis and fluorescent detection systems are described. The methods are useful for detecting and/or quantitating the concentration of a plurality of drugs of abuse in a single urine sample using a single assay method.

The ability to detect and/or quantitate the concentration of a pharmacological agent, metabolite, or toxin is a central aspect of modern diagnosis, management of disease. In some cases, such analytes can be detected directly by assaying their biological activities. In most cases, however, it is more efficient to detect such molecules by virtue of their capacity to specifically bind to antibodies, or by their physical characteristics such as electrophoretic mobility.
Immunoassays are assay systems that exploit the ability of an antibody to specifically recognize and bind to a particular target analyte. The concept of immunoassays is based on a specific chemical reaction between an antibody and its corresponding antigen. Quantitation involves the separation of antibody bound antigen from the free antigen followed by detection of antibody bound antigen or free antigen in solution depending upon the specific analytical scheme. Such assays are used extensively in modern diagnostics (e.g., Fackrell, J. Clin. Immunoassay 8:213-219 (1985); Yolken, R. H., Rev. Infect. Dis. 4:35 (1982); Collins, W. P., In: Alternative Immunoassays, John Wiley & Sons, NY (1985); Ngo, T. T. et al., In: Enzyme Mediated Immunoassay, Plenum Press, NY (1985)).
There are many variations of immunoassays and the critical steps are either physical separation or discrimination and detection. Immunoassays that require physical separation are termed heterogeneous immunoassays. In contrast, homogeneous immunoassays are designed such that the removal of bound from unbound species is unnecessary. Because homogeneous assays lack a separation step and are more easily automated, they are more desirable than heterogeneous assays in applications that entail the screening of large numbers of patients.
Analytes present at concentration levels below 10.sup.-9 M are generally assayed using a solid-phase based "sandwich" or competitive method. Typically, in such assays, the antigen of interest competes with a labeled antigen for a judicious amount of antibody. A direct immunoassay is typically a sandwich assay involving two antibodies binding to different antigenic sites of an antigen. One antibody is bound to a solid phase material and is employed to harvest the antigen. The other antibody is labeled and used to generate quantitative information from the bound antigen (Cone, E. J. et al., J. Forens. Sci. 35:786-781 (1990); Baugh, L. D. et al., J. Forens. Sci. 36:79-85 (1991); Standefer, J. C. et al., Clin. Chem. 37:733-738 (1991)).
In order to facilitate the detection of antibody binding, one or more reaction analytes is typically labeled (as with a radioisotope, an enzyme, a fluorescent moiety, a chemiluminescent moiety, or a macroscopic label, such as a bead, etc.) (see, Chard, T. et al., In: Laboratory Techniques and Biochemistry in Molecular Biology (Work, T. S., Ed.), North Holland Publishing Company, NY (1978); Kemeny, D. M. et al. (Eds.), ELISA and Other Solid Phase Immunoassays, John Wiley & Sons, NY (1988)). Radioisotopes have long been used in immunoassays. O'Leary, T. D. et al., for example, describe a radioimmunoassay for digoxin serum concentrations (O'Leary, T. D. et al., Clin. Chem. 25:332-334 (1979)). The difficulty of handling such hazardous materials and the problem of radioactive decay have led to the development of immunoassays that use other labels.
Enzymes, in particular, are now widely used as labels in immunoassay formats. The enzyme-multiplied immunoassay technique (EMIT.RTM., Syva Co.) has been used to assay acetaminophen, cocaine and other analytes (Helper, B. et al., Amer. J. Clin. Pathol. 81:602-610 (1984); Campbell, R. S. et al., J. Clin. Chem. Clin. Biochem. 24:155-159 (1986); Khanna, P., U.S. Pat. No. 5,103,021; Cone, E. J. et al., J. Forens. Sci. 35:786-781 (1990); Baugh, L. D. et al., J. Forens. Sci. 36:79-85 (1991); Standefer, J. C. et al., Clin. Chem. 37:733-738 (1991); Roberts, D. W. et al., J. Pharmacol. Exper. Therap. 241:527-533 (1987); Bartolone, J. B. et al., Biochem. Pharamcol. 37:4763-4774 (1988)).
In addition to enzymes, fluorescent moieties are frequently used as labels (see, Ichinose, N. et al., In: Fluorometric Analysis in Biomedical Chemistry, Vol 10 110, Chemical Analysis (Winefordner, J. D. et al., Eds.) John Wiley & Sons, NY (1991)). For example, a fluorescence polarization immunoassay format for cocaine has been described (TDx.RTM., Abbott Laboratories, Inc.), and has been found to be approximately equivalent to the EMIT.RTM. formats (Schwartz, J. G. et al., Amer. J. Emerg. Med. 9:166-170 (1991)). The TDx.RTM. format has also been used to assay acetaminophen serum levels (Koizumi, F. et al., Tohoku J. Exper. Med. 155:159-(1988); Edinboro, L. E. et al., Clin. Toxicol. 29:241-(1991); Okurodudu, A. O. et al., Clin. Chem. 38:1040 (1992)), and serum digoxin levels (Okarodudu, A. O. et al., Clin. Chem. 38:1040 (1992)). Wong, S. H. Y. et al., have described the use of an automated (OPUS) analyzer to measure digoxin concentration in a monoclonal antibody mediated, fluorescence-based assay protocol (Wong, S. H. Y. et al., Clin. Chem. 38:996 (1992)). Lee, D. H. et al. also disclose the use of a fluorescence polarization assay and a chemiluminescent assay format to assay digoxin levels (Lee, D. H. et al., Clin. Chem. 36:1121 (1990)).
As indicated, electrophoretic methods have also been used to facilitate the detection of target analytes. Such methods exploit the fact that molecules in solution have an intrinsic electrical charge. Thus, in the presence of an electric field, each molecular species migrates with a characteristic "electrophoretic" mobility which is dependent upon the mass to charge ratio of the molecular species. When this ratio is different from among the various species present, they separate from one another. Under the influence of such a field, all of the variants will move toward a designated charge opposite to the charge of the variants; those having a lower electrophoretic mobility will move slower than, and hence be separated from, those having a (relative) higher electrophoretic mobility.
Immunological electrophoretic methods, such as Immunofixation electrophoresis ("IFE"), Immunoelectrophoresis ("IEP"), and immunosubtraction electrophoresis ("ISE") have been described which combine the capacity of slab gel electrophoretic methods to separate molecular species with the detection capacity of immunoassays. Such assays have been used to detect and quantitate serum proteins.
IEP and IFE are related procedures (Beckman Bulletin EP-2. "Immunoelectrophoresis Applications Guide." (1991)). IFE is a two stage procedure using agarose gel protein electrophoresis in the first stage and immunoprecipitation in the second. In a clinical setting for the analysis of immunoglobulins, a clinical sample (e.g., whole blood, serum, plasma, urine, cerebrospinal fluid) is placed in multiple positions ("lanes") on an agarose gel. When an electric field is applied to the gel-containing sample, the immunoglobulins will traverse the gel from anionic to cationic electrode. Thereafter, antisera comprising antibodies to specific immunoglobulin classes (typically IgG, IgA, IgM, kappa and lambda) are applied to specific lanes. The gel and antisera are incubated, during which time immune complexes form between the specific immunoglobulins and the antibodies. The location of such immune complexes are visualized by staining. By using a reference pattern on the gel, one can then determine the type of immunoglobulin present on the gel. The presence of a particular band is thus indicative of the presence of an M-protein corresponding to a particular immunoglobulin type. Methods of conducting IFE are disclosed by Chen, F-.T. A, U.S. Pat. No. 5,202,006; Chen, F-T. A., U.S. Pat. No. 5,120,413; Hsieh, Y-Z et al., U.S. Pat. No. 5,145,567; all herein incorporated by reference).
The PARAGON.RTM. electrophoresis system (Beckman Instruments, Inc., Fullerton, Calif., U.S.A.) is a commercially available system for conducting both IFE and IEP (See also, Gebott et al., U.S. Pat. No. 4,669,363; Pentoney, S. L., U.S. Pat. No. 5,208,466, herein incorporated by reference; Beckman Bulletin EP-3 "Paragon.RTM. Serum Protein Electrophoresis II (SPE-II) Applications Guide" (1990); Beckman Bulletin EP-2. "Immunoelectrophoresis Applications Guide" (1991); Beckman Bulletin EP-4 "Immunofixation Electrophoresis Applications Guide" (1991); Beckman Instructions 015-246513-H "Paragon.RTM. Electrophoresis System-IFE" (1990); Beckman Bulletin EP-6 "High Resolution Electrophoresis in the Detection of Monoclonal Gammopathies and Other Serum Protein Disorders." (1990); Chen, F-.T. A. et al. Clin. Chem. 37:14-19 (1991)).
Immunosubtraction electrophoresis (ISE) is a variation of IFE (Aguzzi, F. et al., Estratto dal. Boll. 1st Sieroter, Milanese 56:212-216 (1977); White, W. A. et al., Biochem. Clin. 10:571-574 (1986); Merlini, G. et al., J. Clin. Chem. Biochem. 21:841-844 (1983); Lui, C-M. et al., U.S. Pat. No. 5,228,960, herein incorporated by reference). In ISE, however, the sample is pretreated with an insolubilized antibody directed to a particular "target" protein. If the target protein is present, it will bind to the antibody and thus be removed from the sample. The sample is then applied to a gel and subjected to electrophoresis. If the target protein had been present in the initial sample, visualization of the proteins in the gel would reveal a "negative band" (i.e. an absence of staining) at the position in the gel where the removed band would have migrated to, had it not been removed by the antibody. Thus, the absence of a particular band is indicative of the presence of the corresponding target protein in the sample.
IEP, IFE and ISE each require multiple steps, and the preparation and use of a separation gel and a signal-generating stain. Thus highly labor intensive nature of these procedures is an obvious impediment in a clinical setting. Additionally, the amount of disposable end-products associated with these procedures can further increase the allied costs associated with these procedures.
In view of the deficiencies of these methods in clinical settings, less labor-intensive methods that permit greater throughput with lower cost have been sought. One such method is "Capillary Electrophoresis" ("CE") (Chen, F-T. A. et al., Clin. Chem. 77:14-19 (1991); Nielsen et al., J. Chromatogr. 539:177 (1991); U.S. Pat. No. 5,120,413, all herein incorporated by reference). Capillary electrophoresis (CE) is one of the most powerful tools yet developed for the separation of ionic species such as proteins, peptides and other water soluble molecules.
In general, CE involves introducing a sample into a capillary tube, i.e., a tube having an internal diameter of from about 2 .mu.m to about 2000 .mu.m (preferably, less than about 50 .mu.m, most preferably, about 25 .mu.m or less) and applying an electric field to the tube (Chen, F-T. A., J. Chromatogr. 516:69-78 (1991); Chen, F-T. A. et al., J. Chromatogr. 15:1143-1161 (1992)). Since each of the sample constituents has its own individual electrophoretic mobility, those having greater mobility travel through the capillary tube faster than those with slower mobility. Hence, the constituents of the sample are resolved into discrete zones in the capillary tube during their migration through the tube. (Heegard, N. H. H. et al., Anal. Chem. 64:2479-2482 (1992); Gordon, M. J. et al., Anal. Chem. 63:69-72 (1991); F-T. A., U.S. Pat. No. 5,202,006; Chen, F-T. A., U.S. Pat. No. 5,120,413; Hsieh, Y-Z. et al., U.S. Pat. No. 5,145,567). The method is well-suited to automation, since it provides convenient on-line injection, detection and real-time data analysis.
In particular, capillary electrophoresis methods have been shown to permit rapid and efficient separations of proteins. Advantageously, this technique has been extended to include the rapid separation of the constituents of clinical samples which can be accomplished typically in less than 20 minutes. For example, separation of proteins in plasma and serum sample have been attempted by Jorgenson, J. W. et al. (Science 222:266-272 (1983)) and Hjerten, S. (Electrophoresis 11:665-690 (1990)). The feasibility of routine analysis of serum proteins by CE in an untreated fused-silica capillary has been demonstrated (Chen, F-T. A. et al., Clin. Chem. 37:14-19 (1991); Gordon, M. G. et al., Anal. Chem. 63:69-72 (1991)). Detection of protein in CE is usually based on the intrinsic ultraviolet (UV) absorbance of the peptide bond at or near 200 nm, which provides a detection limit of about 10.sup.-5 M. Fluorescence-based detection assays have, however, also been described (Lee, T. T. et al., J. Chromatogr. 595:319-325 (1992)).
One problem associated with current immunochemical analyses is that these procedures are capable of quantifying and analyzing only one analyte at a time. For example, immunochemical analyses such as traditional radioimmunoassay, enzyme immunoassays (EMIT and ELlSA) and fluorescence polarization immunoassays (TDX) are limited in their sample throughput and usefulness because they can accommodate only one analyte at a time. There are numerous conditions in which it would be desirable to have the ability to analyze very low concentrations of multiple analytes in a single sample at the same time. For example, screening urine samples for a variety of different drugs, drug metabolites, or the presence of proteins indicative of a variety of diseases is particularly desirable.
The ability to analyze components of urine provides an important source of information to aid in the definition of states of health, disease, and personal health practices. More specifically, urine is a complex mixture containing proteins, lipids, carbohydrates and many smaller-molecule metabolic products. Each component of urine can be considered to provide an image of the serum, reflecting the body's metabolic state. The kidney regulates the body water, excretes metabolic products and toxic substances and maintains the body's electrolytes and pH by means of urine formation. Thus, studies of urine provide important diagnostic information in diseases, not only of the kidney, but also of many other tissues, including the liver, pancreas, blood, bone, muscle, and the urinary tract, gastrointestinal and cardiovascular systems.
Methods for separating and quantitating urine components traditionally involve HPLC techniques which are tedious and typically result in the analysis of only one sample per day. Using CE methods, many more samples can be analyzed per day. However, these analytical approaches involve UV/visible spectrometry based detection and are limited in sensitivity by the intrinsic molecular absorptivities of the species in urine to concentrations of 10.sup.-5 and above.
In view of the importance of accurately detecting and quantitating analytes in samples, it would be desirable to provide processes which combine the advantages of immunoassays, capillary electrophoresis, and fluorescent detection techniques to simultaneously separate and detect very small quantities of analytes. In particular, it would be desirable to provide processes for analyzing urine samples for metabolites using immunoassay procedures and capillary electrophoresis detection techniques. A capillary electrophoresis technique that could additionally be employed to resolve organic analytes (such as pollutants, toxins, etc.) and which could provide a facile means of detection would also be highly desirable. The present invention provides such methods.

Simultaneous analysis of analytes by immunoassay using capillary electophoresis with laser induced fluorescence


The present invention relates to epilepsy. More particularly, the present invention relates to idiopathic generalized epilepsy (IGE) and to the identification of three genes mapping to chromosome 2, which show mutations in patients with epilepsy. The invention further relates to nucleic acid sequences, and protein sequences of these loci (SCNA) and to the use thereof to assess, diagnose, prognose or treat epilepsy, to predict an epileptic individual's response to medication and to identify agents which modulate the function of the SCNA. The invention also provides screening assays using SCN1A, SCN2A and/or SCN3A which can identify compounds which have therapeutic benefit for epilepsy and related neurological disorders.

Epilepsy is one of the most common neurological conditions, occurring in about 1.0% of the general population. The disease is characterised by paroxysmal abnormal electrical discharges in the brain, which lead to transient cerebral dysfunction in the form of a seizure. A seizure is considered partial when the epileptic discharge is limited to part of one brain hemisphere, or generalised when it involves both cerebral hemispheres at the onset. The current classification of the epileptic syndromes rests on two criteria: 1) seizure type which may be generalised or partial at the onset, according to clinical and EEG features; and 2) etiology, which may be idiopathic, cryptogenic and symptomatic. Symptomatic epilepsies have multiple and heterogeneous causes including brain injury, CNS infection, migrational and metabolic disorders. In the majority (65%) of the patients with either generalised or partial epilepsy, there is no underlying cause (idiopathic) or the cause is though to be hidden or occult (cryptogenic). Also, in the idiopathic epileptic syndromes, there is no evidence of cerebral dysfunction other than the seizure, and the neurological examination is normal. There is now increasing evidence that in this latter group, genetic factors are important, especially for the idiopathic generalised epilepsy (IGE). In a recent study, Berkovic et al (1998) showed a 62% concordance rate in monozygotic twins overall for epilepsy. In this study, a higher concordance rate has been found in the generalised compared to the partial epilepsies, with 76% concordance rate for IGE. Recent studies using molecular genetic approaches have shown that many susceptibility genes for the epilepsies in human involve membrane ion channel and related proteins. These studies include the syndrome of benign familial neonatal convulsions where two loci have been identified [EBN1 on chromosome 20, the KCNQ2 gene (a potassium channel); and EBN2 on chromosome 8, the KCNQ3 gene (also a potassium channel)] (Bievert et al, 1998; Charlier et al, 1998; Singh et al, 1998), as well as autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE—chromosome 20, and the CHRNA4 gene (the neuronal nicotinic acetylcholine receptor alpha 4 subunit)] (Steinlein et al, 1995). More recently, there was a clinical description of a new syndrome (GEFS), which consisted of generalised epilepsy with febrile seizures. According to the current classification of epileptic syndrome, this syndrome would fall in the category of IGE, based on the seizure and electroencaphalographic features. However, febrile seizures were present in all probants with GEFS, and the pattern of inheritance was clearly autosomal dominant, which are not part of the usual IGE phenotype. This unique GEFS syndrome has been shown to be associated with a mutation on the beta-1 subunit of brain voltage-gated sodium channel (SCN1B) gene (Wallace et al, 1998). In addition, three different groups, including the group of the present inventors, have identified another locus on chromosome 2 in large kindred with this specific syndrome (GEFS). This region contains many candidate genes, including a cluster of alpha subunits of sodium channels (SCNA). Voltage-gated sodium channels play an important role in the generation of action potential in nerve cells and muscle. The alpha subunit (SCNA) is the main component of the channel, and would be sufficient to generate an efficient channel when expressed in cells in vitro. In turn, the beta-1 and 2 subunits need an alpha subunit to give an effective channel. The role of these subunits would be to modify the kinetic properties of the channel, mainly by fast inactivation of the sodium currents. The mutation found in the GEFS syndrome on the SCN1B gene was shown to reduce the fast inactivation of the sodium channels as compared to a normal SCNB1, when co-expressed with an alpha subunit. It is probable that this could be the mechanism by which the mutation induce an hyperexcitability state in the brain, leading to seizure in humans. Interestingly, the mechanism of action of most of the anticonvulsant drugs is through a reduction of the repetitive firing of neurons, which is also known to be dependent on fast inactivation. These finding make it likely that additional epilepsy genes will be identified by mutations in ion channels.
There thus remains a need to identify whether IGE is caused by a mutation in a sodium channel (SCNA). There also remains a need to assess whether a mutation(s) in SCNA is associated with GEFs. There also remains a need to determine whether a mutation that affects the fast inactivation of a sodium channel, given the particular phenotype of GEFS or IGE, could be linked to a region which includes SCNA genes.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.

Nucleic acids encoding sodium channel SCN1A alpha subunit proteins with mutations associated with epilepsy


Methods for generating highly enriched Th1/Tc1 and Th2/Tc2 functions are described. In particular, the generation of these functions are attained by the addition of an immune suppression drug, rapamycin or a rapamycin derivative compound. In addition to enhanced purity of T cell function, the T cells generated in rapamycin also express molecules that improve immune T cell function such as CD28 and CD62L. Such rapamycin generated functional T cell subsets may have application in the prevention or treatment of GVHD after allogeneic hematopoietic stem cell transplantation, the treatment of autoimmunity, or the therapy of infection or cancer.

Ongoing advances in solid organ and hematopoietic stem cell transplantation (HSCT), including new immunosuppressive agents and improvements in histocompatibility matching, organ procurement, and surgical techniques, are gradually improving the outcome of clinical transplantation (Hariharan et al, 2000. N. Engl. J. Med. 342:605-12). However, chronic allograft rejection remains the prime determinant of long-term graft survival (Paul. L. C., 1999, Kidney International 56:783-793). Furthermore, stem cell graft rejection typically limits the application of allogeneic HSCT to those patients having an HLA-matched sibling donor, which represents a minority of all patients that might benefit from allogeneic HSCT therapy.
Tissue transplantation between genetically non-identical individuals results in immunological rejection of the tissue through T cell-dependent mechanisms. To prevent allograft rejection, immunosuppressive agents such as calcineurin phosphatase inhibitors and glucocorticosteroids which directly or indirectly interfere with IL-2 signaling are administered to transplant recipients (see, e.g., Morris, P. J., 1991, Curr. Opin. Immunol. 3:748-751; Sigal et al., 1992, Ann. Rev. Immunol. 10:519-560; and L'Azou et al., 1999, Arch. Toxicol. 73:337-345). The most commonly used immunosuppressive agents today are the calcineurin inhibitors cyclosporin A and FK506, which act relatively indiscriminately by impairing T cell receptor ("TCR") signal transduction. A third primary immune suppression drug, rapamycin, which has recently received FDA approval for prevention of organ transplant rejection, acts through a distinct mechanism of inhibition of the protein mammalian target of rapamycin (mTOR). The biological effect of these three immunosuppressive agents is short-lasting, and as such, transplant recipients normally require life-long treatment of immunosuppressive agents to prevent transplant rejection. As a result of the long-term nonspecific immunosuppression, these immunosuppressive agents have many serious adverse effects. For example, the administration of cyclosporin A or FK506 to a transplant recipient results in degenerative changes in renal tubules. Transplant recipients receiving long-term immunosuppressive treatment have a high risk of developing infections and tumors. For example, patients receiving immunotherapy are at higher risk of developing lymphomas, skin tumors and brain tumors (see, e.g., Fellstrom et al., 1993, Immunol. Rev. 134:83-98).
In addition to graft rejection, immune T cells also mediate the primary cause of lethality after allogeneic HSCT, graft-versus-host disease (GVHD). GVHD, which is primarily initiated by donor CD4+ T cells expressing a Th1 cytokine phenotype characterized by IL-2 and IFN-γ secretion, manifests clinically as damage to the skin, intestine, liver, and immune system. To reduce the incidence and severity of GVHD, immune suppression therapy involving either cyclosporin A or FK506 is typically administered, often in combination with other immune suppression agents such as methotrexate. This immune suppression approach to the prevention of GVHD is problematic, as significant morbidity and mortality from GVHD still occurs, and the immune suppression therapy reduces the potency of the allogeneic T cell-mediated graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect, and predisposes to multiple viral, bacterial, and fungal infections.
An alternative to immunosuppressive agents for the prevention of allograft rejection is the blockage of specific receptors involved in T cell costimulation. T cell activation requires both TCR-mediated signal transduction and simultaneously delivered costimulatory signals. These costimulatory signals are contributed, in part, by the activation of the costimulatory molecule CD28, which is expressed on resting T cells, by CD80 (B7-1) or CD86 (B7-2) expressed on antigen presenting cells ("APCs"). The activation of the costimulatory molecule CD40, which is expressed on APCs (i.e., B cells, dendritic cells, and macrophages), by CD40 ligand ("CD40L"), which is expressed on activated T cells, contributes to the upregulation of T cell activation by inducing the expression of B7-1 and B7-2 on APCs and the production of certain chemokines and cytokines such as IL-8, MIP-1-α, TNF-α, and IL-12 (Cella et al., 1996, J. Exp. Med. 184:747-752: and Caux et al., 1994, J. Exp. Med. 180:1263-1272). The CD40/CD40L interaction also results in the differentiation of T cells to T helper ("Th") type 1 cells in part due to the expression of cytokines such as IL-12 by dendritic cells and macrophages.
CTLA-4 is normally expressed as a membrane-bound receptor on T cells and, similar to CD28, binds to B7-1 and B7-2 molecules on APCs; however, signaling of T cells via CTLA-4 downregulates T cells. The administration of soluble CTLA-4Ig is believed to prevent allograft rejection by competing with CD28 for B7-1 and B7-2. Soluble CTLA-4Ig has been administered to transplant recipients to disrupt the CD28/B7 interaction so that T cell costimulation is blocked and allograft rejection does not occur (Zheng et al., 1999, J. Immunol. 162:4983-4990; Lenschow et al., 1996, Ann. Rev. Immunol. 14:233-258). Unfortunately, CTLA-4Ig has variable efficacy, and typically does not prevent development of chronic rejection.
Anti-CD40L (anti-CD154) monoclonal antibodies have also been administered to transplant recipients to prevent allogaft rejection. These antibodies function by blocking the interaction of CD40 on antigen presenting cells (APC) and CD40L on activated T cells. It has recently been shown that graft survival achieved through the use of anti-CD40L monoclonal antibodies results in a significant inhibition of Th1 type cytokines (i.e., IL-2, IL-12; TNF-α, and IFN-α), and an increase in the levels of the Th2 type cytokines (i.e., IL-4, and IL-10) in the graft sections (Hancock et al., 1996, Proc. Natl. Acad. Sci. USA 93:13967-13972). Although the administration of anti-CD40L monoclonal antibodies has been shown to result in permanent graft survival when given to mice in combination with donor-specific spleen cells, adverse side effects such as coagulation have also been shown to be associated with the administration of anti-CD40L monoclonal antibodies. Initial clinical trials in adult renal transplant recipients receiving anti-CD40L monoclonal antibody plus glucocorticoids were halted because of thromboembolic complications though the extent to which thromboembolism was attributable to monoclonal antibodies versus non-specific factors in the antibody formulation is unclear (Kawai et al., 2000, Nature Med. 6:114; and Kirk et al., 2000, Nature Med. 6:114). Further, in the primate renal allograft study, concomitant use of mainstream immunosuppressive agents such as FK-506, methylprednisolone and mycophenolate mofetil diminished the efficacy of CD40L (CD154) mAb, though the exact contribution of each of the individual drugs to this reduction in efficacy was not determined (Kirk, A. D., 1999, Nature Medicine 5:686-693.).
Immunocompromised patients lack a fully active and effective immune system, and are vulnerable to infection by a host of opportunistic organisms that are effectively controlled in a healthy individual. Cancer patients and transplant recipients are especially vulnerable to these infections since their therapeutic regimen often includes radiation and chemotherapeutic agents, which compromise the immune system. Immunodeficient patients, such as AIDS and SCID patients, are also at high risk from these opportunistic pathogens. In particular, patients undergoing bone marrow transplantation (BMT) are severely immunocompromised until their immune systems reconstitute. During the period prior to reconstitution, these patients are susceptible to serious, and sometimes fatal, virus infections caused by normally benign viruses such as adenovirus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
In a normal individual, recognition and destruction of virally infected cells is performed principally by CD8+ cytotoxic T lymphocytes (CTLs). The mounting of a CTL immune response requires that the viral proteins undergo intracellular processing to peptide fragments. Selected peptides of defined length are subsequently presented at the cell surface in conjunction with MHC class I molecules. This complex provides the first stimulatory signal recognized by the specific cytotoxic T lymphocyte.
Processing of antigens for presentation by class I MHC involves a complex cellular process (Berzofsky and Berkower, Fundamental Immunology, Third Edition, Paul (ed.), Raven Press, Ltd.: New York, pp. 258-259 (1993). Unlike processing of exogenous antigen via endosomal pathways for presentation by class II MHC, antigen presented by class I MHC generally must be synthesized endogenously and processed by a nonendosomal pathway into peptides. However, exogenous antigens can enter the cytoplasm for processing by the nonendosomal pathway and presentation by class I MHC.
No satisfactory methods presently exist for monitoring whether a transplant graft is being accepted or rejected by a recipient. In general, signs of cellular damage within the transplant tissue can be assayed. Alternatively, for tissues such as kidney or liver, physiological function of the transplant tissue can be assayed. Often, however, by the time overt signs of either cellular damage or a decrease in physiological function are detected, the tissue graft is already beyond rescue. This is particularly true in the case of such organ transplants as heart transplants, with which the first overt signs of rejection are often complete failure of the heart's function. Similarly, in the setting of allogeneic HSCT, there exist no reliable method to detect GVHD prior to the onset of significant end-organ impairment; oftentimes, when GVHD does develop, the donor immune reaction is relatively mature, and can thereby be refractory to even the most potent immune suppression therapies available.
Accordingly, there is a need for improved, safer immunomodulatory treatments that have long-lasting effects for the prevention of transplant rejection or GVHD. In particular, there is a need for treatments that are more specific and less toxic than the currently available therapeutic agents.
In addition to graft rejection and GVHD, immune T cells of autologous or allogeneic source may play a beneficial role in mediating anti-tumor effects and anti-infectious disease effects, including against viral, bacterial, and fungal processes. This T cell biology offers the possibility that adoptive transfer of ex vivo generated T cell populations might be utilized in the therapy of cancer or infection. However, full realization of this possibility is limited by a general inability to amplify a potent autologous immune response against cancer or infectious disease antigens in vivo. Furthermore, immune T cell therapy in the allogeneic setting is limited by allogeneic T cell attack against normal host tissues, which is manifested as GVHD. In the allogeneic anti-tumor immune therapy setting, the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect is reduced by the immune suppression drugs cyclosporine A, FK506, corticosteroids, and methotrexate that are utilized to prevent or treat GVHD. Avoidance of standard GVHD prevention or treatment agents through rapamycin administration post-transplant will predictably facilitate improved GVL and GVT effects, resulting in improved rates of cancer cure.

Rapamycin-resistant T cells and therapeutic uses thereof

The United States of America, as represented by the Department of Health and Human Services

The Trustees of the University of Pennsylvania


The invention relates to a measurement device 1 comprising a rotatable magnetic object 4 which can oscillate with a resonant frequency if excited by an external magnetic torque. The measurement device 1 is adapted such that the resonant frequency depends on the temperature or on another physical or chemical quantity like pressure, in order to allow for a wireless temperature measurement or measurement of the other physical or chemical quantity via an external magnetic field providing the external magnetic torque. This measurement device can be relatively small, can be read-out over a relatively larger distance and allows for a very accurate measurement.

Especially during interventional procedures it is often desired to accurately determine the temperature of, for instance, a certain tissue part of a subject like the temperature of a tumor, or to accurately consider the influence of temperature changes on a measurement of another physical or chemical quantity like pressure. However, in many cases the desired and often also required accuracy cannot be provided.

Magnetic measurement device for measuring temperature or other property


A method of fabricating a coil-embedded inductor provides steps for obtaining uniform density of coil-embedded inductor. The cavity of a first die is filled with dust before being flipped, and then filled with dust a second time. The dust in the cavity is pressed only once for improving the density.

The present invention relates to a method of fabricating an inductor, and particularly to a method of fabricating a coil-embedded inductor.
Generally, an inductor comprises an iron core wound by a coil. Coil-embedded inductors are utilized to provide an inductor with reduced volume.
Refer to FIGS. 1A to 1D and 2A to 2D together. FIGS. 1A, 1B, 1C, and 1D show a coil of a conventional coil-embedded inductor. FIGS. 2A, 2B, 2C, and 2D show a conventional coil-embedded inductor. In fabrication of the coil-embedded inductor, a wrapped coil 1 with two terminals 10 is enclosed by a core housing 20, exposing the terminals 10, as shown in FIG. 2A and FIG. 2B.
Ferrite powder and ferromagnetic metal powder are widely used to form the iron core by powder die-casting. With ferrite powder, powder sintering is further required to increase inductance and strength of the iron core. As a result, ferromagnetic metal powder is utilized more frequently due to enhanced magnetic flux density and DC-bias characteristics.
U.S. Publication No. 2001/0016977 discloses a method of fabricating a coil-embedded inductor, in which an iron core base 2 illustrated in FIG. 2 of this art thereof is formed previously, and a coil is inserted therein later. Press forming completes fabrication of the coil-embedded inductor. Detailed process of the method is illustrated in FIG. 5A to FIG. 5I of the related art thereof. This method, however, requires iron core base 2 to be fabricated prior to press forming, such that a gap may occur between the iron core base 2 and the coil due to non-uniform density distribution. The area near the gap shows increased magnetic flux density, achieving magnetic saturation easily, affecting the electrical characteristics of the coil-embedded inductor.
U.S. Publication No. 2003/0141952 discloses another method of fabricating a coil-embedded inductor, described with reference to FIG. 3 and FIG. 11A to FIG. 11D of this art thereof. The terminals of the coil are bent to a single plane. The coil is then placed in a die for formation of the coil-embedded inductor. Due to this reason, resistance of the coil-embedded inductor will increase from the bent terminals of the coil results in heat production at high electric current levels, affecting the electrical characteristics of the coil-embedded inductor.
As a result, there is a need for a coil-embedded inductor with a core housing having uniform density distribution.

Method of fabricating coil-embedded inductor


A portable storage unit for a fuel additive such as DEF comprising: a housing including a tray support and a cover; a container disposed in the lower area for containing a fluid; a first heating element disposed between an inner wall of the housing and the outer wall of the container; a fluid pump removable attached to the tray for pumping fluid from the container to a nozzle and for being removed from the tray to pump fluid from an external fluid source into the container; an intake hose connected to a coupler providing fluid communications between the container and the fluid pump.

In the United States, the Clean Air Act established emission standards to regulate several pollutants that include nitrogen oxide (NOx), particulate matter (PM), carbon monoxide (CO), and hydrocarbons. One challenge for engine operators, under the Clean Air Act, is to limit the NOx emissions to comply with the ammonium g/bhp-hr standards. For operators of diesel engines, this standard proved to be problematic. One solution is known as the Selective Catalytic Reaction (SCE) technology.
SCR is an "after treatment" technology to reduce the NOx in the exhaust emissions of a diesel engine. The SCR relies upon an operating fluid called Diesel Exhaust Fluid or DEF. DEF is injected into the exhaust pipe in front of a SCR catalyst and downstream of the engine. The heat of the engine exhaust causes the DEF to decompose into ammonia. The NOx reacts with the ammonia in the catalyst and the Nox molecules are converted into N2 and H2O.
DEF is a solution that is about 32% of a high-priority area in deionized water THE DEF is stored as a separate DEF tank, which is connected to the DEF injector. The average consumption of DEF is about 3% per gallon of diesel fuel so that the DEF tank is significantly smaller than the fuel tank.
Historically, operators would purchase DEF in small portable containers that would only hold a few gallons and use these portable containers to fill the DEF tanks associated with the diesel engine. Since about 3 gallons of DEF would be needed for about 100 gallons of fuel plastic containers from 35 to 15,000 gallons, over time, bulk containers began to appear and were located on-site of the operator so that the DEF tank was filled from a bulk dispenser.
However, storage of DEF began to exhibit problems due to the nature of DEF. For example, DEF freezes around 12° F. and will expand about 7%. As a result, the container expands and there is damage to the hose and pump. Additives should not be added to DEF to reduce the freezing point, as such additives can harm the SRC catalyst.
Another difficulty created by the Clean Air Act is to have diesel engines that are used in remote areas to have DEF sources that are portable. For example, farm equipment, construction equipment, diesel engines, and the like. Many of these diesel engines operate in location that are remote from fuel sources and therefore have high capacity fuel tanks. It would be advantageous to have a portable DEF source so that the diesel equipment would not have to leave it operational area to refill on DEF.
Another hurdle to portable DEF supplies is DEF's freezing point. Since DEF in a container above is not useful, a pump, power source for the pump, hose, and nozzle are also a consideration. If DEF fluid is "trapped" in the hose, pump, or nozzle and then freezes and expands, the hose, pump, and nozzle can be cracked or otherwise damaged.
Additionally, portable DEF supplies also need to be refilled and it would be advantageous to be able to use the same hose, pump, and nozzle to fill the portable DEF source from a bulk container that is used to fill the DEF tank of a diesel engine from the DEF portable supply.
Another challenge that exists for portable DEF source is the dust, dirt, and water (rain, snow, ice) that the portable DEF can damage the pump. Furthermore, water can enter the nozzle, freeze, and damage the nozzle. It would be advantageous to have a portable DEF source that is protected from the environment.
Therefore, it is also an object of this invention to provide a portable DEF source that is shielded from environmental hazards.
It is also an object of the present invention to provide for a dispensing assembly that can be used to fill the portable DEF source from a bulk storage container and to fill a DEF tank on a diesel engine from the portable DEF source.

Portable transportable storage unit for dispensing a fuel additive


Low temperature, co-fired ceramic (LTCC) modules (10, 80, 82, 110, 102, 140, 160) are interconnected to one another, stacked and automatically connected to other modules by rigid LTCC interconnecting modules (104), or provided with covers or hermetically sealed covers (130, 166) that automatically register and make electrical or mechanical connections between the cover and the protected module. The various types of connections are achieved by forming in the LTCC modules, during the lamination process, patterns of frictionally interfitting bumps (60, 62, 66, 84a, 84b, 84c) on one side and depressions (70, 72, 76, 81a, 81b, 81c) on the other, whereby a pattern of bumps on one side of one module will connect both mechanically and electrically to a mating pattern of depressions on the other module to stack and automatically lock vertical packages of LTCC modules. The concept is applicable to an LTCC test board (120) at which a module (124) to be tested may be registered and connected to a test board and then tested and readily removed without time consuming registration and connection, and allowing reuse of the test board.

1. Field of the Invention
The present invention relates to laminated multi-layer circuit modules or packages and more particularly concerns electrical or mechanical interconnection of such modules.
2. Description of Related Art
Multi-layer electronic circuitry is often fabricated in the form of individual modules bearing various types of internal circuitry and having components mounted on or connected thereto. At times it is necessary to connect one or more of such modules to other circuitry or to each other, or to provide a protective cover for such of those modules that have components such as IC chips and the like surface mounted thereon. Frequently it is desirable to cover the surface mounted components and hermetically seal the multi-layer module.
Modules have been interconnected by soldering two or more together, or by the use of separate connection components, such as flexible cables or other cable connectors which must be separately fabricated and individually connected to the individual modules. Such types of connections are effective, but relatively expensive, time consuming to fabricate and connect, and in some forms may not provide rigid mechanical connection of the modules.
Prior techniques for interconnection of such modules do not readily lend themselves to efficient and economic interconnections for test probe connections and disconnections, nor for stacking of a group of modules to afford compact packaging.
Accordingly, it is an object of the present invention to provide for electric circuit module interconnection by techniques and means that avoid or minimize above mentioned problems.


A customized gynecological brachytherapy applicator is formed by placing a molded balloon, which is secured to a handle, into a vaginal cavity and then filling the mold balloon with a settable liquid material. The material may be an expanding foam or any other form of curable material that becomes solid, rigid or pliable, when set by chemical action, temperature change, oxidation, a curing means such as a light, or other curing regime. The mold balloon can be elastic or inelastic, depending on the degree to which the applicator is to conform its external surfaces to the vaginal contours. One or more lumina are provided in the set filler material to receive a radiation source, with additional lumina optionally provided for purposes such as drainage or administration of therapeutic agents. The applicator may be withdrawn and reinserted into the vagina during treatment, and selected tissues adjacent to the applicator are irradiated in accordance with a radiation prescription.

This invention concerns radiation therapy, especially brachytherapy, for treating tissues which may have diffuse proliferative disease. In brachytherapy, the radiation source is generally placed within a surgically created or naturally occurring cavity in the body. In particular, this invention relates to an applicator for delivering radiation therapy to a vaginal cavity and/or to adjacent tissue, often following surgical treatment of cancer. Radiation therapy of this sort is generally administered over a period of time in partial doses, or fractions, the sum of which comprises a total prescribed dose. This fractional application takes advantage of cell recovery differences between normal and cancerous tissue whereby normal tissue tends to recover between fractions, while cancerous tissue tends not to recover.
In brachytherapy, a prescribed dose is selected by the therapist to be administered to a volume of tissue (the target tissue) lying outside the treatment cavity into which the radiation source will be placed. Generally the prescribed dose will include a minimum dose to be delivered at a preferred depth outside the treatment cavity (the prescription depth). Since, in accordance with the laws of physics, radiation intensity falls off with increasing distance from the radiation source, it is desirable to create and maintain a space between the source of radiation and the first tissue surface to be treated (generally the cavity wall since the source is placed within the cavity) in order to moderate the absorbed dose at the cavity surface. Although not always the case, generally the absorbed dose at the prescription depth outside the cavity is to be uniform. In this isotropic case, it is therefore important that the incident radiation on the interior surface of the cavity be the same at all points being treated. To accomplish this objective, it may be necessary to sequentially position a single radiation source through a series of positions (or utilize multiple sources strategically placed) which, in the aggregate, produce a uniform absorbed dose incident on the cavity surface being treated. When this is achieved, the absorbed dose reaching into tissue will be the same at all points being treated, and the minimum prescribed dose can be delivered at the prescription depth as nearly as the treatment plan will allow. Furthermore, by selecting the radiation source intensity (radioisotope emissions or X ray tube output) and controlling treatment time and the distance from the source(s) to the cavity interior surface, the incident radiation can be sufficiently moderated to avoid substantial damage to normal tissue.
Rigid applicator cylinders designed to receive radioisotopes have traditionally been used to treat vaginal cancer or malignancies in adjacent tissues. A principal function of an applicator is to establish and maintain distance relationships between the radiation source and the tissues being treated such that the prescribed dose is delivered to a desired prescribed depth of tissue, and yet normal tissues nearest the radiation source are not subjected to absorbed doses sufficient to risk significant necrosis. Applicators of this general type are available, for example, from Varian Medical Systems, Inc., Charlottesville, Va. Such prior art applicator cylinders are sized to the vaginal cavity or adjacent anatomy, but because the tissues should be positioned closely against the exterior surface of the applicator, large applicators must be chosen that are often painful on insertion, and once inserted still fail to provide a good fit. Additionally, prior art cylinders are generally straight, with a central lumen into which radioactive seeds are delivered and later removed after completion of prescribed therapy. As a result, anisotropic treatment plans are difficult to achieve with such symmetrical applicators. Thus conventional applicators are less than ideal in many cases.

Customized gynecological brachytherapy applicator and method


A printer (100) includes a casing (200), an operation section (6), a light emitting section (61), a cover (60), and a pressing member (62). The operation section (6) includes a reference surface (201B), an LCD panel (204) disposed along the reference surface (201B) and displaying predetermined information, and operation keys (202) disposed to protrude though the reference surface (201B). The light emitting section (61) is disposed adjacent to the operation section (6) and emits light based on predetermined notification information. The cover (60) covers the LCD panel (204) and the operation keys (202). The pressing member (62) presses the cover (60) and supports the light emitting section (61).

An image forming apparatus disclosed in Patent Literature 1 is one of commonly known image forming apparatuses for forming images on sheets. The image forming apparatus has an apparatus body in which an image forming section is provided. The apparatus body is provided with an operation section that includes operation keys for user operation and a display panel. The operation section includes an operation sheet that is detachably attached thereto. The operation sheet has openings through which the display panel and the operation keys are exposed and also has printed information pertaining to the various keys. Another known image forming apparatus includes a light emitting section disposed near an operation section to indicate an operation state of the image forming apparatus.


A method of fabricating an abrupt hetero interface by organometallic vapor growth comprises supplying a first Group III source gas at a predetermined flow rate and a first Group V source gas at a predetermined flow rate to a growth chamber during a first growth process to form a first Group III-Group V compound layer. During a growth interruption process, the inflow of the first Group III source gas to the growth chamber is stopped, while the supply of the first Group V source gas to the growth chamber is continued, to thereby interrupt the growth of the first Group III-Group V compound layer. Finally, during a second growth process, the first Group V source gas flowing into the growth chamber is switched to a second Group V source gas, and a second Group III source gas is simultaneously supplied at a predetermined flow rate to the growth chamber, thereby forming a second Group III-Group V compound layer on the first Group III-Group V compound layer.

The present invention relates to a method of fabricating an abrupt hetero interface in the crystal growth of a chemical compound semiconductor multiple quantum well structure.
In the prior art, an example of this kind of technology is mentioned in the Journal of Crystal Growth Vol.107, pp. 567-572, "OMVPE growth of GaInAs/InP and GaInAs/GaInAsP quantum wells". In this reference (p.567, left column, line 21-p.569, left column, line 3, and FIG. 1), a method is indicated for growing an abrupt hetero interface comprising InP and InGaAs using an organometallic vapor growth technique.
When a InP/InGaAs interface having, for example, a multiple quantum well structure is formed by organometallic vapor growth, growth is interrupted for a short interval during the growth of the InGaAs layer and the growth of InP layer, or between growth of the InP layer and the growth of InGaAs layer, to allow valve switching and purge of residual gases in the growth chamber. At that time, P and As may separate from the growth layer surface or substitution from As to P may occur so that the quality of the hetero interface deteriorates. This is due to the fact that the vapor pressures of P and As, which are Group V elements, are high. It is thus important to prevent the separation of Group V elements and substitution so as to improve the quality of the hetero interface.
The method for fabricating a InGaAs/InP hetero interface by growing a InGaAs layer on a InP layer given in the aforesaid reference, is described below. FIG. 1 is a diagram showing a timing at which a source gas is switched over in the conventional process for fabricating a hetero interface disclosed in the above reference.
Firstly, trimethylindium (TMIn) and phosphine (PH.sub.3) are supplied to a growth chamber, and a InP layer is grown. Immediately after growth of the InP layer, supply of TMIn is stopped, and passage of PH.sub.3 is continued for t1 seconds to purge TMIn from the growth chamber. The source gas is then switched from PH.sub.3 gas to arsine (AsH.sub.3) gas, and AsH.sub.3 gas is supplied to the growth chamber for t2 seconds. After T2 seconds, TMIn and triethylgallium (TEGa) are supplied to the growth chamber, and a InGaAs layer is grown. t1 and T2 are growth interruption intervals. The optimum intervals are calculated to be t1=T2=0.5 seconds. When fabricating a InP/InGaAs hetero interface, the times for which arsine and phosphine are supplied are reversed, but the same method and times are used.
However, if a InGaAsP layer was grown on a InGaAs layer or a InGaAs layer was grown on a InGaAsP layer when the growth interruption condition shown above was t1=t2=0.5 seconds, for example, a substitution from As to P occurred on the InGaAs surface for t1 seconds causing a deterioration of the hetero interface.

Method of fabricating an abrupt hetero interface by organometallic vapor phase growth


If a WiMAX base station cannot receive a ranging signal from a WiMAX-embedded wireless terminal or if adjustment is not completed even after the WiMAX-embedded wireless terminal adjusts a parameter depending on adjusted value information for a pre-determined number of times, negotiation is performed via a heterogeneous network to establish a communication connection for upstream communication from the WiMAX-embedded wireless terminal to the WiMAX base station, and only downstream communication from the WiMAX base station to the WiMAX-embedded wireless terminal is performed via a WiMAX network.

1. Field of the Invention
The present invention relates to a wireless communication system, and more particularly, to a WiMAX (Worldwide Interoperability for Microwave Access) [IEEE 802.16a] system, and a wireless terminal and a wireless base station used for the system. WiMAX® is one of standards of radio communication technology, and is a generic term for technology that is standardized by the IEEE 802.16 working group and the WiMAX Forum® which is an industry organization.
2. Description of the Related Art
In a current WiMAX system, a communication area is smaller in Up Link communication than in Down Link communication. This is caused by problems of asymmetry of transmission powers or transmission and reception timing between a WiMAX base station and a WiMAX-embedded wireless terminal.
As shown in FIG. 1, a WiMAX base station (BS) receives a CDMA Ranging Request from a WiMAX-embedded wireless terminal (MS), and notifies WiMAX-embedded wireless terminal 4 of respective adjusted values of power, timing and frequency in a Ranging Response. When the respective parameters of power, timing and frequency are values within permissible ranges, the WiMAX base station notifies the WiMAX-embedded wireless terminal of Ranging completion in a Ranging Response.
Until the WiMAX-embedded wireless terminal is notified of the Ranging completion by the WiMAX base station, the terminal repeats transmission of a CDMA Ranging Request to the WiMAX base station for a prescribed number of times by referring to adjusted values notified in the Ranging Response by the WiMAX base station. In this manner, the terminal adjusts the respective parameters of power, timing and frequency. However, the WiMAX base station cannot notify the WiMAX-embedded wireless terminal of the Ranging completion, that is, it cannot adjust a value of any of the parameters even by adjusting prescribed number of times. If the parameters cannot be adjusted, Network Entry fails, so that the WiMAX-embedded wireless terminal cannot get service in Down Link or Up Link.
One cause why respective parameters cannot be adjusted to be within permissible ranges in a CDMA Ranging Request by a prescribed number of times includes, for example, that the transmission power of the WiMAX-embedded wireless terminal is lower than the transmission power of the WiMAX base station.
A WiMAX-embedded wireless terminal is often used with information equipment such as a PC, or used independently as a mobile phone terminal. In either case, the WiMAX-embedded wireless terminal needs to be operated in a power-saving mode. As such, power consumption of the WiMAX-embedded wireless terminal even when operating at maximum power is lower than that of a WiMAX base station. The WiMAX-embedded wireless terminal cannot often gain a sufficient receiving electric field in Up Link, in which the WiMAX-embedded wireless terminal is a transmitter, even in an area where in Down Link, in which the WiMAX base station is a transmitter, the WiMAX-embedded wireless terminal can receive a signal in a preferable state in which it can gain a sufficient receiving electric field.
Another cause includes the following.
In a CDMA Ranging Request, timing is adjusted in addition to the power. Accordingly, in Up Link, when a WiMAX base station receives the signals transmitted from WiMAX-embedded wireless terminals, if the respective signals are received at different times, interference is caused among Subchannels, thereby causing a great influence on demodulation.
In Down Link, a WiMAX-embedded wireless terminal identifies the head of a Down Link Subframe in Preamble, so that a delay due to propagation causes no problem. On the other hand, in Up Link, a WiMAX base station defines the head of an Up Link Subframe by a TTG (Transmit/Receive Transition Gap) from the end of a Down Link Subframe. As such, if a delay due to propagation is too long, a WiMAX base station can not receive a CDMA Ranging Request.
To address the case in which Up Link communication is difficult or the communication quality is low, a technique is provided such as handover to a heterogeneous network such as a mobile network as disclosed in Japanese Patent Laid-Open No. 2005-184820, or amplification of a signal source by a relay as disclosed in Japanese Patent Laid-Open No. 2006-196985. However, communication by a WiMAX system for only a Down Link service has not been realized.
According to the invention disclosed in Japanese Patent Laid-Open No. 2005-184820, handover is performed to a heterogeneous network if a WiMAX Up Link service is unnecessary and only a Down Link service is necessary. Thus, if the fee for communication via the heterogeneous network is high, the user must pay a high communication fee.
The invention disclosed in Japanese Patent Laid-Open No. 2006-196985  has the problem in which there is a need to invest in equipment for installing a relay.
A technique for Down Link communication includes "Communication System" disclosed in Japanese Patent Laid-Open No. 2003-153238, or "Radio Communication System and Retransmission Control Method Thereof" disclosed in Japanese Patent Laid-Open No. 8-274758.
However, according to the inventions disclosed in Japanese Patent Laid-Open No. 2003-153238 and Japanese Patent Laid-Open No. 8-274758, a communication system for a Down Link service is not specified. Moreover, they do not assume a WiMAX system. Furthermore, the patent documents do not disclose anything about a connection method.
Further, a Down Link service is limited to a broadcast channel according to the invention disclosed in Japanese Patent Laid-Open No. 2003-153238, so that it is difficult to apply the invention to Down Link services other than the broadcast channel.
As in the above, according to the inventions disclosed in Japanese Patent Laid-Open No. 2003-153238 and Japanese Patent Laid-Open No. 8-274758, it is impossible to provide only a Down Link service by a WiMAX system.

Wireless communication system, wireless terminal and wireless base station


An apparatus and method are disclosed for enhancing the operation of an ESD protective circuit in a VLSI chip with a combination of elements for an SCR that lower the turn-on voltage of the SCR below the oxide breakdown voltage of the CMOS devices in the VLSI circuits. A low voltage trigger source is provided for the SCR by forming an N+-P-LDD junction between the SCR and a CMOS device incorporated therein. The prior art N-channel device used in triggering the known LVTSCR is modified by removing the rate electrode and thin oxide and implanting, adjacent the N+ drain region, a P-type lightly doped drain (P-LDD) region in the substrate to form the N+-P-L.DD junction. The turn-on voltage of this N+-P-LDD junction can be made lower than the oxide breakdown voltage of the CMOS devices by adjusting the P-LDD dosage. Junction breakdown causes a forward bias resulting in turn ON of the PNP bipolar device followed by turn ON of the interconnected NPN bipolar device to produce the high current flow through the SCR. Concern about damage to the gate oxide of the prior art NMOS is obviated as there is no longer a gate oxide.

With recent advances in the development of high density very large scale integration (VLSI) circuits, the dimensions of the devices continue to shrink resulting in a corresponding decrease in the gate oxide thicknesses in the CMOS devices. This decrease, relative to breakdown voltage, has resulted in the greater susceptibility of these devices to damage from the application of excessive voltages such as caused by an electrostatic discharge (ESD) event. During an ESD event, charge is transferred between one or more pins of the integrated circuits and another conducting object in a short period of time, typically less than one microsecond. The charge transfer generates voltages that are large enough to break down insulating films, e.g., gate oxides on MOSFET devices, or that can dissipate sufficient energy to cause electrothermal failures in the devices. Such failures include contact spiking, silicon melting, or metal interconnect melting. Consequently, in order to deal with transient ESD pulses, an integrated circuit must incorporate protection circuits at every input and I/O pin. Various circuit structures for ESD protection can be found, e.g., in U.S. Pat. Nos. 5,019,888 to Scott et al; 5,182,220 to Ker et al, 5,218,222 to Roberts; and 5,329,143 to Chan; and in the literature in "Internal Chip ESD Phenomena Beyond the Protection Circuit", C. Duvvury, IEEE Transactions on Electron Devices, Vol .35, No. 12, December 1988; "A Low-Voltage Triggering SCR for On-Chip ESD Protection at Output and Input Pads", A. Chatterjee, IEEE Electron Device Letters, Vol. 12, No. 1, January 1991; and "ESD Protection in a Mixed Voltage Interface and Multi-Rail Disconnected Power Grid Environment in 0.50- and 0.25-.mu.m Channel Length CMOS Technologies", S. Voldman, EOS/ESD Symposium Proceedings, pp. 125-134, 1994.
An example of one form of ESD protection device of the type discussed in the above-cited "A Low-Voltage Triggering SCR for On-Chip ESD Protection at Output and Input Pads", A. Chatterjee, IEEE Electron Device Letters, Vol. 12, No. 1, January 1991 paper is shown in FIG. 1, which is a cross-sectional view of a known low-voltage threshold silicon controlled rectifier (LTVSCR) integrated circuit (IC) device 10 fabricated from a semiconductor substrate 12 of a first conductivity type, such as P-type conductivity, with various diffusions and circuit components formed thereon to provide protection against ESD damage due to excessive stresses. The SCR is known in the art as an ideal device for on-chip protection against ESD since in its ON state it protects sensitive devices by virtue of its comparatively low resistance. Also, the failure threshold of the SCR is high because the heat generation is distributed over a large volume. However, there are sensitive devices that are damaged at voltages less than the SCR trigger voltage, which typically is comparatively high, so that the SCR alone is insufficient for protecting devices such as NMOS transistors which have the lowest breakdown voltage in CMOS technology. For example, the trigger voltage of a lateral SCR is approximately 50 V, as compared to an NMOS transistor drain breakdown voltage of less than 15 V. To achieve a reduction of the SCR trigger voltage to a level less than the NMOS breakdown voltage, an NMOS-like structure is incorporated in the SCR device as a trigger. Accordingly, a thin-oxide NMOS field-effect transistor (MOSFET) 26, is shown in the FIG. 1 device in the form of an N-channel device, composed of N+ regions, 18 and 20, having a gate electrode 22 with a thin oxide 24 therebetween. The inner N+ region 20 of MOSFET 26 is connected to internal circuits 30 and its outer N+ region 18 is coupled to an adjacent outer P+ conductivity region 14 by a contact or bus 16 which is connected to a negative voltage source VSS or ground. The Vss source is also coupled to the gate electrode 22 to keep the LVTSCR OFF during normal operation. In the absence of the SCR, the NMOS thick-field device 26 would deal with either positive or negative ESD stresses developed between the Vss voltage on contact 16 and the voltage communicated from the internal circuits 30. The N+ diffusion regions, 18 and 20, and underlying P-type substrate 12 act as a bipolar device when there is an excessive positive stress on the internal circuit 30 with respect to Vss, i.e., a parasitic lateral NPN transistor results, with its base at the substrate 12, its emitter at N+ region 18, and its collector or drain at N+ region 20. The NP junction (20,12) at the drain breaks down, typically at about 13 volts, to offer protection to the other circuit devices, and the generated electrons are swept into the collector region 20. The generated holes injected into the base region 12 cause the substrate voltage to increase, forward biasing the emitter junction, and causing the NPN transistor to turn ON. As a consequence, injection of electrons from the emitter 18 into the base 12 is increased and those electrons reaching the collector-base junction (20,12) generate new electron hole pairs and current growth continues. This "positive feedback" would cause the emitter-to-collector current to increase indefinitely, resulting in damage to the device if the current is not somehow limited. Also, in the absence of the SCR, when a negative stress on the internal circuit with respect to Vss occurs, a forward biased diode would result between P+ region 14 and N+ region 20, through the substrate 12, that would turn ON to protect the other internal integrated devices.
To complete the LVTSCR, an N-well 28 is provided in substrate 12 that substantially overlaps N+ region 20 and extends laterally beyond a second N+ region 32 which is coupled to an adjacent inner P+ conductivity region 34 by a contact or bus 36 connected to an I/O Pad. N-well 28 increases the junction breakdown voltage between N+ region 20 and the substrate 12, and alleviates the chances of contact spiking produced by the N+ junction and thus avoids short circuiting of the N+ junction to the P-substrate. Moreover, even were a breakdown to occur in the N+ junction, the increased cross-sectional area of the N-well 28 available for current flow decreases the current density and thus improves the ESD immunity. In this arrangement the NMOS-like device acts as a trigger for the SCR. The internal circuits connection acts as a "drain tap"and the N+ region 18 source as a cathode, and the charge generated during avalanche breakdown near the drain tap triggers the LVTSCR. Prior to triggering, the LVTSCR characteristics resemble that of an NMOS with the same gate length, and since for short channel MOSFETs the drain breakdown voltage decreases with reduction of the gate length, if the gate length of the LVTSCR is kept less than that of an NMOS of the output buffer in parallel with it and at the same potential, then the LVTSCR will fire first and protect the NMOS.
There exists a danger, since the N-well is lightly doped, that the SCR turn-on voltage may still be so high that the gate oxide of NMOS devices may become damaged. Thus, the LVTSCR device turn-on voltage is dependent on the NMOS beakdown voltage. It is therefore desirable to be able to reduce the trigger voltage required to turn ON a protective SCR as much as possible.
It is therefore an object of the present invention to provide an enhanced ESD protection performance apparatus and method for protecting VLSI circuits and particularly CMOS devices by reducing the trigger voltage required to turn ON a protective SCR.
It is another object of the present invention to provide an enhanced ESD protection performance apparatus and method utilizing an improved SCR structure with a low turn-on voltage.
It is a further object of the present invention to provide an improved SCR for enhanced ESD protection performance using a P-LDD dosage in the SCR trigger structure to create an N+-P-LDD junction with a reduced breakdown voltage.

Low voltage turn-on SCR for ESD protection

Taiwan Semiconductor Manufacturing Co. Ltd.