A brushless generator with permanent-magnet multi-pole rotor disks and coreless stator winding disks includes integral electronics to efficiently generate regulated DC current and voltage from shaft input power over a broad speed range. Its power rating is scalable, and it incurs no cogging torque, or friction from gearing. Integral power control electronics includes high-frequency pulse-width-modulated boost regulation, which provides regulated current at requisite voltage over its broad speed range. A main embodiment to produce DC power at widely variable speeds includes signal processing so output power varies according to the third power of speed. A version for use with vertical-axis wind turbines has a relatively large diameter to facilitate a large number of poles. Combined boost-regulation, zero cogging torque, and no gearing, enable a wide speed range, for better power quality and higher wind energy yields. An alternate embodiment is intended to produce DC power from a variety of shaft drive sources, with selectable shaft torque.

1. Field of the Invention
This invention pertains generally to rotary dynamoelectric machines, and more particularly to dynamoelectric machines having novel rotor and stator structures, to generators having permanent-magnet axial-field rotor and stator disks, and further to cooperative integrated electronics for wide range power control and efficient electric power interface with loads.
Applicant sets forth a brushless self-synchronous generator with permanent-magnet rotor disks and stator winding disks, including integral electronics, to efficiently generate DC (direct-current) electric power, at current and voltage regulated by the electronics, from broadly variable speed rotary mechanical drive. Its various embodiments are intended to generate useful electric power efficiently, especially at low speed and torque, from a wide variety of variable speed and torque drive sources. Moreover, it is intended to substantially improve and expand sustainable environmentally responsible energy options, such as wind power, hydrodynamic power, and human-power-assisted electric vehicles. A main embodiment is intended to generate better quality electric power from wind turbines, and higher energy yields, compared to prior art wind turbine generators.
2. Description of the Related Art
Poly-phase (usually 3-phase) alternating-current (AC) salient-pole induction machines, having wound stators and rotors, are presently directly connected to power grids in "wind farms" to augment grid power from windy locations. They do not incur major grid synchronization problems, as do directly connected synchronous generators, which are mostly used in generating plants where their shaft speed is regulated and output carefully synchronized prior to parallel connection with on-line generators. However, induction machines generate power only when shaft speed exceeds that needed at zero slip speed. They cannot self-start from turbine drive, and consume grid power (not augment it) whenever their speed falls below a critical zero slip speed level. Moreover, their power is unregulated, and they must be disconnected from the grid at very high wind speeds, because their power fluctuations and internal generator heating are excessive. For a comprehensive analysis and Thevenin equivalent circuits of induction machines, see, for example, the textbook "Electric Machinery" (an integrated treatment of AC and DC machines) McGraw-Hill Book Co. 1952, by Fitzgerald & Kingsley, Massachusetts Institute of Technology, Chapter 3 (especially page 131 and Chapter 9). For further analysis and performance prediction of broader speed range but less efficient 2-phase induction machines, see "Effects of Phase-Shift and Distortion on Servomotor Performance," 1960, by Richard B. Fradella, MSEE research and thesis, California Institute of Technology.
Peripheral equipment needed for augmenting grid power from wind turbines, which drive induction generators, may include gears to increase generator shaft speed, switchgear to connect and disconnect said generators from the grid as wind speed varies, gear lubricant, pumps and heat exchangers to cool the lubricant, a generator cooling system, and external heat-dumps.
Over the past two decades, power electronics has been developed to provide a power control interface between induction machines and DC voltage supplies such as chemical batteries. This electronics converts the DC voltage to substantially variable-frequency poly-phase voltage (albeit with high distortion) at the induction machine poly-phase terminals, enabling these machines to perform as bi-directional motors or generators. For example, an induction machine with applied fundamental frequency component appropriately higher than its electrical frequency at a given shaft speed can be driven as a variable-speed induction motor, from zero to a desired speed. With its shaft driven by rotary power, the same induction machine with applied poly-phase voltage having a frequency appropriately lower than its electrical frequency at a given shaft speed can instead generate power as a variable-speed induction generator. By reversing the poly-phase sequence, the induction machine can likewise drive in the opposite direction, or can generate power from a shaft driven in the opposite direction. Silicon Controlled Rectifier (SCR) power switching semiconductors are useful as the DC to poly-phase power switching interface for induction machines, because they are rugged and can control considerably higher power than comparable cost high-frequency switching semiconductors. Moreover, the iron cores of said induction machines have high inductance, so it is not feasible to use a series low-loss ferrite core inductor as described for the present invention. Induction machine core loss would be very high, with attendant heating problems, if subjected to high-frequency switching pulse-duration-modulation (PWM) to provide poly-phase sinusoidal voltages having low harmonic distortion across the induction machine stator winding terminals.
Prior art inventions that provide examples of power interface electronics for variable-speed induction machines that are driven by chemical batteries and regenerate power thereto include: U.S. Pat. No. 5,099,186 by Rippel et al; and U.S. Pat. No. 5,355,070 by Cocconi.
Synchronous AC generators include salient-pole alternators having wound stators and permanent-magnet rotors. Their output voltage and frequency are substantially proportional to their shaft speed. Brushless salient-pole reluctance machines having wound stator poles with magnetic bias from permanent magnets, is one type. Those generators may include field windings, to afford limited voltage regulation. Homopolar machines are also a synchronous brushless type, with their power output frequency proportional to speed; they afford wider range voltage adjustment. If their field is derived only from a field winding, they will need electric startup power for that winding. Cogging torque (wherein the rotor angle aligns its iron cores with and holds minimum magnetic reluctance positions), like stiction and friction in gears, may cause wind turbines to stall at low wind speeds. These shortcomings and too low output voltage at low shaft speeds prevent usable power generation at low wind speeds from this prior art machine. Adding a boost regulator in series with the rectified and filtered alternator type generator output can facilitate higher voltages at low shaft speeds, needed for loads such as chemical batteries, but the boost regulator incurs tandem losses and machine cogging may stall the wind turbine driving it so no electric power output is produced from this prior art machine at low wind speeds.
By comparison, the present invention is intended to generate power at requisite voltage over its entire wide speed range, will not need electric startup power from its load or any other external source, and will efficiently generate power even from very low shaft torque rotation from low wind speeds, not stalled by cogging torque, stiction, or friction.
Besides their use for AC power generation in power plants, applications for synchronous generators range widely, usually with their AC outputs rectified, to charge batteries and the like. However, their varying voltage and frequency can be a major disadvantage. Generated and rectified voltage must be sufficient, and usually regulated, to meet needs of given applications. Moreover, very low frequency ripple at low shaft speed requires large filter capacitors, which cost more and have shorter lifetimes than ceramic or film capacitors. These properties usually limit synchronous generator applications to high shaft speeds. Their cogging torque is another drawback. Peripheral equipment needed for augmenting grid power, from alternators used as generators driven by wind turbines, usually include gears to increase generator shaft speed, rectifiers to convert their AC outputs to DC, and power inverters to convert the DC to regulated AC in phase with the grid. Moreover, their varying output voltage and current must be regulated, for chemical battery charging applications; which requires a battery charger.
Brush-commutated DC generators may have permanent-magnet field excitation. They may also have field excitation windings, for limited output voltage adjustment. Besides shorter lifetimes due to their commutator brush and armature wear, commutator sparking can be troublesome; and, similar to most prior art generators, their DC output voltage is proportional to speed, thus precluding many low shaft speed applications, unless their output is connected to loads via boost regulator circuits. Alternatively, their varying output voltage and current may require a buck regulator, between the generator output and its load. Such external and series electronics reduces overall power efficiency, particularly at low turbine shaft speeds.
Regardless of said drawbacks, these machines are widely used as generators for some applications. Peripheral equipment, for use as generators driven by wind turbines, may include speed-up gearing and output rectifiers. Said rectifiers may be needed, to prevent power from a DC power-bus load, which it feeds, such as chemical batteries it is meant to charge, from driving said DC generator as a motor, and discharging connected batteries whenever the generator output voltage is less than the battery voltage. Power regulator circuits, such as battery chargers, are usually needed. Besides these limitations, brush-commutated generators also need periodic commutator maintenance; as their commutators are damaged with use, by wear and sparking.
Gearing needed to increase prior art generator shaft speed, so prevalent in wind power systems, also needs bearings for the gears, is subject to wear, needs periodic maintenance, and incurs power losses. The gearing stiction further inhibits and usually prevents power generation at low wind speeds. Conversely, the present invention, having no cogging torque and no speed-up gearing, is intended to generate power over a very wide speed range.
Most electric motors can be used as generators. There is fundamentally no difference, between most prior art motors and generators, of a specific type, except for how they are used to meet needs of specific applications. For example, an induction machine can serve as an induction motor or as a generator. Motors used in ubiquitous machinery, tools, and appliances can be configured mechanically and electrically as generators.
Insofar as drive speed and torque is regulated at steam driven and large hydroelectric power plants, the prior art generators described above have provided acceptable options, to generate most of the electric power that is distributed by power grids, for over a century.
Smaller and portable versions of said generators, driven by fuel-burning engines, also serve viable small markets. However, need for wider speed range has been long recognized.
Some prior art inventions have intended to accommodate variable-speed drives, by means substantially different from my present invention:
U.S. Pat. No. 4,694,187 "Electromechanical Constant Speed Drive Generating System" by Baker, includes a mechanical differential gear, to obtain constant speed drive for a generator. It is mainly intended to accommodate variable-speed aircraft engine drive, by including controlled variable compensatory drive. It does not teach a generator assembly similar to the present invention, nor does it include electronics similar to the present invention.
U.S. Pat. No. 6,969,922 "Transformerless Load Adaptive Speed Controller" by Welches, includes electromechanical means, to obtain constant speed generator drive, from a variable-speed drive source. Its generator assembly is substantially different from the present invention, and it does not teach electronics similar to the present invention.
U.S. Pat. No. 5,982,074 "Axial Field Motor/Generator" by Smith et al and my U.S. Pat. No. 4,530,200 teach, with some differences, a motor/generator assembly having multi-pole axial magnetic field rotor disks and stator disks between them, but they do not set forth electronics similar to the present invention, intended to efficiently generate regulated electric power over a broad speed range.
U.S. Pat. No. 5,245,238 "Axial Gap Dual Permanent Magnet Generator" by Lynch et al, describes means for generating constant output voltage that do not include electronics similar to the present invention. Its generator assembly and rotor disks are also distinctly different from those herein described in all embodiments of the present invention.
U.S. Pat. No. 7,190,101 "Stator Coil Arrangement for an Axial Airgap Electric Device Including Low-Loss Materials" by Hirzel, teaches a substantially different generator assembly and materials, and does not set forth electronics similar to the present invention.
U.S. Pat. No. 5,021,698 "Axial Field Electrical Generator" by Pullen et al, describes a high-speed generator assembly substantially different from the present invention, and does not describe electronics.
U.S. Pat. No. 6,217,398 "Human-Powered Or Human-Assisted Energy Generation And Transmission System With Energy Storage Means And Improved Efficiency" by Davis; and U.S. Pat. No. 7,021,978 "Human-Powered Generator System With Active Inertia And Simulated Vehicle" by Jansen; describe means to use variable effort pedal power. They teach using electric generators with operator adjustable control means, and their advantages over mechanical drives, for augmenting vehicle power, in applications including electric vehicles, watercraft, and the like. However, they do not teach generator assembly configurations nor an electronics power interface as set forth in the present invention.
Other exemplary patents for rotary dynamoelectric machines and for other apparatus which may or may not be related but which provide illustration from which the teachings are incorporated herein by reference, include: U.S. Pat. No. 295,534 by Frick; U.S. Pat. No. 459,610 by Desroziers; U.S. Pat. No. 1,566,693 by Pletscher; U.S. Pat. No. 2,743,375 by Parker; U.S. Pat. No. 2,864,964 by William Kober; U.S. Pat. No. 3,050,650 by Jacques; U.S. Pat. No. 3,069,577 by Royal; U.S. Pat. No. 3,090,880 by Henri; U.S. Pat. No. 3,091,711 by Jacques; U.S. Pat. No. 3,124,396 by Barager; U.S. Pat. No. 3,219,861 by Burr; U.S. Pat. No. 3,230,406 by Jacques; U.S. Pat. No. 3,231,807 by Willis; U.S. Pat. No. 3,239,702 by Van De Graaff; U.S. Pat. No. 3,304,598 by Jacques; U.S. Pat. No. 3,337,122 by Johann; U.S. Pat. No. 3,375,386 by Hayner et al; U.S. Pat. No. 3,401,284 by Park; U.S. Pat. No. 3,407,320 by Mclean; U.S. Pat. No. 3,441,761 by Painton et al; U.S. Pat. No. 3,569,753 by Babikyan; U.S. Pat. No. 3,584,276 by Ringland et al; U.S. Pat. No. 3,696,277 by Liska et al; U.S. Pat. No. 3,731,984 by Habermann; U.S. Pat. No. 3,796,039 by Lucien; U.S. Pat. No. 3,845,339 by Heinzmann et al; U.S. Pat. No. 3,899,731 by Smith; U.S. Pat. No. 3,982,170 by Gritter et al; U.S. Pat. No. 4,127,799 by Nakamura et al; U.S. Pat. No. 4,207,510 by Woodbury; U.S. Pat. No. 4,228,391 by Owen; U.S. Pat. No. 4,264,856 by Frierdich et al; U.S. Pat. No. 4,295,083 by Leenhouts; U.S. Pat. No. 4,358,723 by Scholl et al; U.S. Pat. No. 4,371,801 by Richter; U.S. Pat. No. 4,384,321 by Rippel; U.S. Pat. No. 4,390,865 by Lauro; U.S. Pat. No. 4,394,597 by Mas; U.S. Pat. No. 4,415,963 by Rippel et al; U.S. Pat. No. 4,417,194 by Curtiss et al; U.S. Pat. No. 4,426,613 by Mizuno et al; U.S. Pat. No. 4,483,570 by Inoue; U.S. Pat. No. 4,513,214 by Dieringer; U.S. Pat. No. 4,618,806 by Grouse; U.S. Pat. No. 4,645,961 by Malsky; U.S. Pat. No. 4,656,413 by Bourbeau; U.S. Pat. No. 4,694,187 by Baker; U.S. Pat. No. 4,734,839 by Barthold; U.S. Pat. No. 5,021,698 by Pullen et al; U.S. Pat. No. 5,117,141 by Hawsey et al; U.S. Pat. No. 5,204,569 by Hino et al; U.S. Pat. No. 5,258,697 by Ford et al; U.S. Pat. No. 5,289,361 by Vinciarelli; U.S. Pat. No. 5,341,075 by Cocconi; U.S. Pat. No. 5,392,176 by Anderson; U.S. Pat. No. 5,419,212 by Smith; U.S. Pat. No. 5,441,222 by Rosen; U.S. Pat. No. 5,495,221 by Post; U.S. Pat. No. 5,514,923 by Gossler et al; U.S. Pat. No. 5,525,894 by Heller; U.S. Pat. No. 5,614,777 by Bitterly et al; U.S. Pat. No. 5,681,012 by Rosmann et al; U.S. Pat. No. 5,705,902 by Merritt et al; U.S. Pat. No. 5,712,549 by Engel; U.S. Pat. No. 5,717,303 by Engel; U.S. Pat. No. 5,729,118 by Yanagisawa et al; U.S. Pat. No. 5,754,425 by Murakami; U.S. Pat. No. 5,783,885 by Post; U.S. Pat. No. 5,798,591 by Lillington et al; U.S. Pat. No. 5,847,480 by Post; U.S. Pat. No. 5,861,690 by Post; U.S. Pat. No. 5,880,544 by Ikeda et al; U.S. Pat. No. 5,883,499 by Post; U.S. Pat. No. 5,969,446 by Eisenhaure et al; U.S. Pat. No. 5,977,677 by Henry et al; U.S. Pat. No. 5,977,684 by Lin; U.S. Pat. No. 6,011,337 and U.S. Pat. No. 6,049,149 by Lin et al; U.S. Pat. No. 6,121,704 by Fukuyama et al; U.S. Pat. No. 6,130,831 by Matsunaga; U.S. Pat. No. 6,137,187 by Mikhail et al; U.S. Pat. No. 6,166,472 by Pinkerton et al; U.S. Pat. No. 6,246,146 by Schiller; U.S. Pat. No. 6,259,233 by Caamano; U.S. Pat. No. 6,262,505 by Hockney et al; U.S. Pat. No. 6,288,670 by Villani et al; U.S. Pat. No. 6,388,347 by Blake et al; U.S. Pat. No. 6,407,466 by Caamano; U.S. Pat. No. 6,750,588 by Gabrys; U.S. Pat. No. 6,815,934 by Colley; U.S. Pat. No. 6,858,962 by Post; U.S. published patent application 2006/0208606 by Hirzel.
Additional patents by the present inventor, the teachings which are additionally incorporated herein by reference, include: U.S. Pat. Nos. 4,085,355 and 4,520,300 by Fradella; U.S. Pat. Nos. 6,566,775 and 6,794,777 by Fradella.


This new wheel compressor has a spring loaded, shaft with a foot operated torque brace, that when stepped on moves the shaft down. The shaft has an ACME threaded collar welded to the inside that has an ACME bolt threaded T-bar that has a compressor wing that when inserted through the center axel of the wheel threaded to the shaft compresses the wheel.

The present invention related generally to aircraft and more specifically to an improved aircraft wheel and tire compressor system. Air Force military aircraft have their tires serviced in accordance with USAF Technical Orders 4T-1-3 the disclosure of which is incorporated by reference.
Previously our aircraft wheel and tire assemblies were compressed by stepping on the wheel assembly, while placed on boards, or on top of workbench. Another method that was used was placing the wheel and tire assembly between two large pieces of wood in the bead breaker compressing the assembly by drawing the rings together and inserting the nuts and bolts.
Before the compressor was implemented, O-rings were pinched causing air leaks resulting in having to take the assembly apart to repair. The tie bolts would not always come completely through the tie bolt holes and the individual standing on the wheel assembly would have to shift weight forward to the person installing the nut and bolt, or bounce up and down to insert a nut on the bolt. Quite often, trying to insert the nut to the bolt would result in having to aim the nut to the bold before the bolt receded back into the hole. Placing the wheel and tire assembly into the bead breaker on small wheels would require balancing the tire assembly on your knee between two boards and than compressing, often the bolts would catch on the other half and push back out (gravity angle), you would than have to push bolts back in and then install nuts. You're finger manipulation area was smaller and the assemblies very limited.

The United States of America as represented by the Secretary of the Air Force


The present invention relates to antibodies or fragments thereof that specifically bind FcγRIIB, particularly human FcγRIIB, with greater affinity than said antibodies or fragments thereof bind FcγRIIA, particularly human FcγRIIA. The invention provides methods of enhancing the therapeutic effect of therapeutic antibodies by administering the antibodies of the invention to enhance the effector function of the therapeutic antibodies. The invention also provides methods of enhancing efficacy of a vaccine composition by administering the antibodies of the invention.

I. Fc Receptors and their Roles in the Immune System
The interaction of antibody-antigen complexes with cells of the immune system results in a wide array of responses, ranging from effector functions such as antibody-dependent cytotoxicity, mast cell degranulation, and phagocytosis to immunomodulatory signals such as regulating lymphocyte proliferation and antibody secretion. All these interactions are initiated through the binding of the Fc domain of antibodies or immune complexes to specialized cell surface receptors on hematopoietic cells. The diversity of cellular responses triggered by antibodies and immune complexes results from the structural heterogeneity of Fc receptors. Fc receptors share structurally related ligand binding domains which presumably mediate intracellular signaling.
The Fc receptors, members of the immunoglobulin gene super family of proteins, are surface glycoproteins that can bind the Fc portion of immunoglobulin molecules. Each member of the family recognizes immunoglobulins of one or more isotypes through a recognition domain on the A chain of the Fc receptor. Fc receptors are defined by their specificity for immunoglobulin subtypes. Fc receptors for IgG are referred to as FcγR, for IgE as FcεR, and for IgA as FcαR. Different accessory cells bear Fc receptors for antibodies of different isotype, and the isotype of the antibody determines which accessory cells will be engaged in a given response (reviewed by Ravetch J. V. et al (1991) "Fc Receptors," Annu. Rev. Immunol. 9: 457-92; Gerber J. S. et al (2001) "Stimulatory And Inhibitory Signals Originating From The Macrophage Fcgamma Receptors," Microbes and Infection, 3: 131-139; Billadeau et al (2002), "ITAMs Versus ITIMs: Striking A Balance During Cell Regulation," The Journal of Clinical Investigation, 2(109): 161-1681; Ravetch J. V. et al (2000) "Immune Inhibitory Receptors," Science, 290: 84-89; Ravetch J. V. et al, (2001) "IgG Fc Receptors," Annu. Rev. Immunol. 19:275-90; Ravetch J. V. (1994) "Fc Receptors: Rubor Redux," Cell, 78(4): 553-60). The different Fc receptors, the cells that express them, and their isotype specificity is summarized in Table 1 (adapted from IMMUNOBIOLOGY: THE IMMUNE SYSTEM IN HEALTH AND DISEASE, 4th ed. 1999, Elsevier Science Ltd/Garland Publishing, New York).
A. Fcγ Receptors
Each member of this family is an integral membrane glycoprotein, possessing extracellular domains related to a C2-set of immunoglobulin-related domains, a single membrane-spanning domain and an intracytoplasmic domain of variable length. There are three known FcγRs, designated FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). The three receptors are encoded by distinct genes; however, the extensive homology among the three family members suggest they arose from a common progenitor perhaps by gene duplication. This invention specifically focuses on FcγRII (CD32).
B. FcγRII (CD32)
FcγRII proteins are 40 KDa integral membrane glycoproteins which bind only the complexed IgG due to a low affinity for monomeric Ig (106 M−1). This receptor is the most widely expressed FcγR, present on all hematopoietic cells, including monocytes, macrophages, B cells, NK cells, neutrophils, mast cells, and platelets. FcγRII has only two immunoglobulin-like regions in its immunoglobulin binding chain and hence a much lower affinity for IgG than FcγRI. There are three human FcγRII genes (FcγRII-A, FcγRII-B, FcγRII-C), all of which bind IgG in aggregates or immune complexes.
Distinct differences within the cytoplasmic domains of FcγRIIA and FcγRIIB create two functionally heterogenous responses to receptor ligation. The fundamental difference is that the A isoform initiates intracellular signaling leading to cell activation such as phagocytosis and respiratory burst, whereas the β isoform initiates inhibitory signals, e.g., inhibiting B-cell activation.
C. Signaling Through FcγRs
Both activating and inhibitory signals are transduced through the FcγRs following ligation. These diametrically opposing functions result from structural differences among the different receptor isoforms. Two distinct domains within the cytoplasmic signaling domains of the receptor called Immunoreceptor Tyrosine based Activation Motifs (ITAMs) or Immunoreceptor Tyrosine based Inhibitory Motifs (ITIMS) account for the different responses. The recruitment of different cytoplasmic enzymes to these structures dictates the outcome of the FcγR-mediated cellular responses. ITAM-containing FcγR complexes include FcγRI, FcγRIIA, FcγRIIIA, whereas ITIM-containing complexes only include FcγRIIB.
Human neutrophils express the FcγRIIA gene. FcγRIIA clustering via immune complexes or specific antibody cross-linking serves to aggregate ITAMs along with receptor-associated kinases that facilitate ITAM phosphorylation. ITAM phosphorylation serves as a docking site for Syk kinase, activation of which results in activation of downstream substrates (e.g., PI3K). Cellular activation leads to release of proinflammatory mediators.
The FcγRIIB gene is expressed on B lymphocytes; its extracellular domain is 96% identical to FcγRIIA and binds IgG complexes in an indistinguishable manner. The presence of an ITIM in the cytoplasmic domain of FcγRIIB defines this inhibitory subclass of FcγR. Recently the molecular basis of this inhibition was established. When colligated along with an activating FcγR, the ITIM in FcγRIIB becomes phosphorylated and attracts the SH2 domain of the inositol polyphosphate 5′-phosphatase (SHIP), which hydrolyzes phosphoinositol messengers that are released as a consequence of ITAM-containing FcγR-mediated tyrosine kinase activation. This prevents the influx of intracellular Ca++. Thus, crosslinking of FcγRIIB dampens the activating response to FcγR ligation and inhibits cellular responsiveness. B cell activation, B cell proliferation and antibody secretion is thus aborted.
TABLE 1Receptors for the Fc Regions of Immunoglobulin IsotypesReceptorBindingCell TypeEffect of LigationFcγRIIgG1Macrophages, Neutrophils,Uptake(CD64108 M−1Eosinophils, Dendritic cellsStimulationActivation ofrespiratory burstInduction ofkillingFcγRII-AIgG1Macrophages, Neutrophils,Uptake(CD32)2 × 106 M−1Eosinophils, DendriticGranulecells, Platelets, LangerhanreleasecellsFcγRII-B2IgG1Macrophages, Neutrophils,Uptake Inhibition(CD32)2 × 106 M−1Eosinophilsof StimulationFcγRII-BIIgG1B cells, Mast cellsNo uptake(CD32)2 × 106 M−1Inhibition ofStimulationFcγRIIIIgG1NK cells, EosinophilInduction of(CD16)5 × 105 M−1macrophages, Neutrophils,KillingMast CellsFcεRIIgG1Mast cells, EosinophilSecretion of1010 M−1BasophilsgranulesFcαRIIgG1, IgA2Macrophages, NeutropilsUptake Induction(CD89)107 M−1Eosinophilsof killing
II. Diseases of Relevance
A. Cancer
A neoplasm, or tumor, is a neoplastic mass resulting from abnormal uncontrolled cell growth which can be benign or malignant. Benign tumors generally remain localized. Malignant tumors are collectively termed cancers. The term "malignant" generally means that the tumor can invade and destroy neighboring body structures and spread to distant sites to cause death (for review, see Robbins and Angell, 1976, BASIC PATHOLOGY, 2d Ed., W. B. Saunders Co., Philadelphia, pp. 68-122). Cancer can arise in many sites of the body and behave differently depending upon its origin. Cancerous cells destroy the part of the body in which they originate and then spread to other part(s) of the body where they start new growth and cause more destruction.
More than 1.2 million Americans develop cancer each year. Cancer is the second leading case of death in the United States and if current trends continue, cancer is expected to be the leading cause of the death by the year 2010. Lung and prostate cancer are the top cancer killers for men in the United States. Lung and breast cancer are the top cancer killers for women in the United States. One in two men in the United States will be diagnosed with cancer at some time during his lifetime. One in three women in the United States will be diagnosed with cancer at some time during her lifetime.
A cure for cancer has yet to be found. Current treatment options, such as surgery, chemotherapy and radiation treatment, are oftentimes either ineffective or present serious side effects. Currently, cancer therapy may involve surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (See, for example, Stockdale, 1998, "Principles of Cancer Patient Management", in Scientific American Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of the patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent and although can be effective, is often used to prevent or delay recurrence of cancer after other treatments have removed the majority of the cancer cells. Biological therapies/immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A significant majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of the deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division (See, for example, Gilman et al, GOODMAN AND GILMAN'S: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Eighth Ed. (Pergamom Press, New York, 1990)). These agents, which include alkylating agents, such as nitrosourea, anti-metabolites, such as methotrexate and hydroxyurea, and other agents, such as etoposides, campathecins, bleomycin, doxorubicin, daunorubicin, etc., although not necessarily cell cycle specific, kill cells during S phase because of their effect on DNA replication. Other agents, specifically colchicine and the vinca alkaloids, such as vinblastine and vincristine, interfere with microtubule assembly resulting in mitotic arrest. Chemotherapy protocols generally involve administration of a combination of chemotherapeutic agents to increase the efficacy of treatment.
Despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks (See, for example, Stockdale, 1998, "Principles Of Cancer Patient Management" in SCIENTIFIC AMERICAN MEDICINE, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10). Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, including severe nausea, bone marrow depression, immunosuppression, etc. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even those agents that act by mechanisms different from the mechanisms of action of the drugs used in the specific treatment; this phenomenon is termed pleiotropic drug or multidrug resistance. Thus, because of drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.
There is a significant need for alternative cancer treatments, particularly for treatment of cancer that has proved refractory to standard cancer treatments, such as surgery, radiation therapy, chemotherapy, and hormonal therapy. A promising alternative is immunotherapy, in which cancer cells are specifically targeted by cancer antigen-specific antibodies. Major efforts have been directed at harnessing the specificity of the immune response, for example, hybridoma technology has enabled the development of tumor selective monoclonal antibodies (See Green et al. (2000) "Monoclonal Antibody Therapy For Solid Tumors," Cancer Treat Rev., 26: 269-286; Weiner LM (1999) "Monoclonal Antibody Therapy Of Cancer," Semin Oncol. 26(suppl. 14):43-51), and in the past few years, the Food and Drug Administration has approved the first MAbs for cancer therapy: Rituxin™(anti-CD20) for non-Hodgkin's Lymphoma and Herceptin™[anti-(c-erb-2/HER-2)] for metastatic breast cancer (S. A. Eccles (2001) "Monoclonal Antibodies Targeting Cancer: 'Magic Bullets' Or Just The Trigger?," Breast Cancer Res., 3: 86-90). However, the potency of antibody effector function, e.g., to mediate antibody dependent cellular cytotoxicity ("ADCC") is an obstacle to such treatment. Methods to improve the efficacy of such immunotherapy are thus needed.
B. Inflammatory Diseases and Autoimmune Diseases
"Inflammation" is a process by which the body's white blood cells and chemicals protect the body from infections by foreign substances, such as bacteria and viruses. It is usually characterized by pain, swelling, warmth and redness of the affected area. Chemicals known as cytokines and prostaglandins control this process, and are released in an ordered and self-limiting cascade into the blood or affected tissues. This release of chemicals increases the blood flow to the area of injury or infection, and may result in the redness and warmth. Some of the chemicals cause a leak of fluid into the tissues, resulting in swelling. This protective process may stimulate nerves and cause pain. These changes, when occurring for a limited period in the relevant area, work to the benefit of the body.
In autoimmune and/or inflammatory disorders, the immune system triggers an inflammatory response when there are no foreign substances to fight and the body's normally protective immune system causes damage to its own tissues by mistakenly attacking self. There are many different autoimmune disorders which affect the body in different ways. For example, the brain is affected in individuals with multiple sclerosis, the gut is affected in individuals with Crohn's disease, and the synovium, bone and cartilage of various joints are affected in individuals with rheumatoid arthritis. As autoimmune disorders progress destruction of one or more types of body tissues, abnormal growth of an organ, or changes in organ function may result. The autoimmune disorder may affect only one organ or tissue type or may affect multiple organs and tissues. Organs and tissues commonly affected by autoimmune disorders include red blood cells, blood vessels, connective tissues, endocrine glands (e.g., the thyroid or pancreas), muscles, joints, and skin. Examples of autoimmune disorders include, but are not limited to, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, dermatomyositis, lupus erythematosus, multiple sclerosis, autoimmune inner ear disease myasthenia gravis, Reiter's syndrome, Graves disease, autoimmune hepatitis, familial adenomatous polyposis and ulcerative colitis.
Rheumatoid arthritis ("RA") and juvenile rheumatoid arthritis are types of inflammatory arthritis. "Arthritis" is a general term that describes inflammation in joints. Some, but not all, types of arthritis are the result of misdirected inflammation. Besides rheumatoid arthritis, other types of arthritis associated with inflammation include the following: psoriatic arthritis, Reiter's syndrome, ankylosing spondylitis arthritis, and gouty arthritis. Rheumatoid arthritis is a type of chronic arthritis that occurs in joints on both sides of the body (such as both hands, wrists or knees). This symmetry helps distinguish rheumatoid arthritis from other types of arthritis. In addition to affecting the joints, rheumatoid arthritis may occasionally affect the skin, eyes, lungs, heart, blood or nerves.
Rheumatoid arthritis affects about 1% of the world's population and is potentially disabling. There are approximately 2.9 million incidences of rheumatoid arthritis in the United States. Two to three times more women are affected than men. The typical age that rheumatoid arthritis occurs is between 25 and 50. Juvenile rheumatoid arthritis affects 71,000 young Americans (aged eighteen and under), affecting six times as many girls as boys.
Rheumatoid arthritis is an autoimmune disorder where the body's immune system improperly identifies the synovial membranes that secrete the lubricating fluid in the joints as foreign. Inflammation results, and the cartilage and tissues in and around the joints are damaged or destroyed. In severe cases, this inflammation extends to other joint tissues and surrounding cartilage, where it may erode or destroy bone and cartilage and lead to joint deformities. The body replaces damaged tissue with scar tissue, causing the normal spaces within the joints to become narrow and the bones to fuse together. Rheumatoid arthritis creates stiffness, swelling, fatigue, anemia, weight loss, fever, and often, crippling pain. Some common symptoms of rheumatoid arthritis include joint stiffness upon awakening that lasts an hour or longer; swelling in a specific finger or wrist joints; swelling in the soft tissue around the joints; and swelling on both sides of the joint. Swelling can occur with or without pain, and can worsen progressively or remain the same for years before progressing.
The diagnosis of rheumatoid arthritis is based on a combination of factors, including the specific location and symmetry of painful joints, the presence of joint stiffness in the morning, the presence of bumps and nodules under the skin (rheumatoid nodules), results of X-ray tests that suggest rheumatoid arthritis, and/or positive results of a blood test called the rheumatoid factor. Many, but not all, people with rheumatoid arthritis have the rheumatoid-factor antibody in their blood. The rheumatoid factor may be present in people who do not have rheumatoid arthritis. Other diseases can also cause the rheumatoid factor to be produced in the blood. That is why the diagnosis of rheumatoid arthritis is based on a combination of several factors and not just on the presence of the rheumatoid factor in the blood.
The typical course of the disease is one of persistent but fluctuating joint symptoms, and after about 10 years, 90% of sufferers will show structural damage to bone and cartilage. A small percentage will have a short illness that clears up completely, and another small percentage will have very severe disease with many joint deformities, and occasionally other manifestations of the disease. The inflammatory process causes erosion or destruction of bone and cartilage in the joints. In rheumatoid arthritis, there is an autoimmune cycle of persistent antigen presentation, T-cell stimulation, cytokine secretion, synovial cell activation, and joint destruction. The disease has a major impact on both the individual and society, causing significant pain, impaired function and disability, as well as costing millions of dollars in healthcare expenses and lost wages.
Currently available therapy for arthritis focuses on reducing inflammation of the joints with anti-inflammatory or immunosuppressive medications. The first line of treatment of any arthritis is usually anti-inflammatories, such as aspirin, ibuprofen and Cox-2 inhibitors such as celecoxib and rofecoxib. "Second line drugs" include gold, methotrexate and steroids. Although these are well-established treatments for arthritis, very few patients remit on these lines of treatment alone. Recent advances in the understanding of the pathogenesis of rheumatoid arthritis have led to the use of methotrexate in combination with antibodies to cytokines or recombinant soluble receptors. For example, recombinant soluble receptors for tumor necrosis factor (TNF)-α have been used in combination with methotrexate in the treatment of arthritis. However, only about 50% of the patients treated with a combination of methotrexate and anti-TNF-α agents such as recombinant soluble receptors for TNF-α show clinically significant improvement. Many patients remain refractory despite treatment. Difficult treatment issues still remain for patients with rheumatoid arthritis. Many current treatments have a high incidence of side effects or cannot completely prevent disease progression. So far, no treatment is ideal, and there is no cure. Novel therapeutics are needed that more effectively treat rheumatoid arthritis and other autoimmune disorders.
C. Allergy
Immune-mediated allergic (hypersensitivity) reactions are classified into four types (I-IV) according to the underlying mechanisms leading to the expression of the allergic symptoms. Type I allergic reactions are characterized by IgE-mediated release of vasoactive substances such as histamine from mast cells and basophils. The release of these substances and the subsequent manifestation of allergic symptoms are initiated by the cross-linking of allergen-bound IgE to its receptor on the surface of mast cells and basophils. In individuals suffering from type I allergic reactions, exposure to an allergen for a second time leads to the production of high levels of IgE antibodies specific for the allergen as a result of the involvement of memory B and T cells in the 3-cell interaction required for IgE production. The high levels of IgE antibodies produced cause an increase in the cross-linking of IgE receptors on mast cells and basophils by allergen-bound IgE, which in turn leads to the activation of these cells and the release of the pharmacological mediators that are responsible for the clinical manifestations of type I allergic diseases.
Two receptors with differing affinities for IgE have been identified and characterized. The high affinity receptor (FcεRI) is expressed on the surface of mast cells and basophils. The low affinity receptor (FcεRπ/CD23) is expressed on many cell types including B cells, T cells, macrophages, eosinophils and Langerhan cells. The high affinity IgE receptor consists of three subunits (alpha, beta and gamma chains). Several studies demonstrate that only the alpha chain is involved in the binding of IgE, whereas the beta and gamma chains (which are either transmembrane or cytoplasmic proteins) are required for signal transduction events. The identification of IgE structures required for IgE to bind to the FcεRI on mast cells and basophils is of utmost importance in devising strategies for treatment or prevention of IgE-mediated allergies. For example, the elucidation of the IgE receptor-binding site could lead to the identification of peptides or small molecules that block the binding of IgE to receptor-bearing cells in vivo.
Currently, IgE-mediated allergic reactions are treated with drugs such as antihistamines and corticosteroids which attempt to alleviate the symptoms associated with allergic reactions by counteracting the effects of the vasoactive substances released from mast cells and basophils. High doses of antihistamines and corticosteroids have deleterious side effects (e.g., central nervous system disturbance, constipation, etc). Thus, other methods for treating type I allergic reactions are needed.
One approach to the treatment of type I allergic disorders has been the production of monoclonal antibodies that react with soluble (free) IgE in serum, block IgE from binding to its receptor on mast cells and basophils, and do not bind to receptor-bound IgE (i.e., they are non-anaphylactogenic). Two such monoclonal antibodies are in advanced stages of clinical development for treatment of IgE-mediated allergic reactions (see, e.g., see, e.g., Chang, T. W. (2000) "The Pharmacological Basis Of Anti-IgE Therapy," Nature Biotechnology 18:157-6262).
One of the most promising treatments for IgE-mediated allergic reactions is the active immunization against appropriate non-anaphylactogenic epitopes on endogenous IgE. Stanworth et al (U.S. Pat. No. 5,601,821) described a strategy involving the use of a peptide derived from the CεH4 domain of the human IgE coupled to a heterologous carrier protein as an allergy vaccine. However, this peptide has been shown not to induce the production of antibodies that react with native soluble IgE. Further, Hellman (U.S. Pat. No. 5,653,980) proposed anti-IgE vaccine compositions based on fusion of full-length CεH2—CεH3 domains (approximately 220 amino acids long) to a foreign carrier protein. However, the antibodies induced by the anti-IgE vaccine compositions proposed in Hellman will most likely it result in anaphylaxis since antibodies against some portions of the CεH2 and CεH3 domains of the IgE molecule have been shown to cross-link the IgE receptor on the surface of mast cell and basophils and lead to production of mediators of anaphylaxis (See, e.g., Stadler et al. (1993) "Biological Activities Of Anti-IgE Antibodies," Int. Arch. Allergy and Immunology 102:121-126). Therefore, a need remains for treatment of IgE-mediated allergic reactions which do not induce anaphylactic antibodies.
The significant concern over induction of anaphylaxis has resulted in the development of another approach to the treatment of type I allergic disorders consisting of mimotopes that could induce the production of anti-IgE polyclonal antibodies when administered to animals (See, e.g., Rudolf, et al (1998) "Epitope-Specific Antibody Response To IgE By Mimotope Immunization," Journal of Immunology 160:3315-3321). Kricek et al. (International Publication No. WO 97/31948) screened phage-displayed peptide libraries with the monoclonal antibody BSWI7 to identify peptide mimotopes that could mimic the conformation of the IgE receptor binding. These mimotopes could presumably be used to induce polyclonal antibodies that react with free native IgE, but not with receptor-bound IgE as well as block IgE from binding to its receptor. Kriek et al. disclosed peptide mimotopes that are not homologous to any part of the IgE molecule and are thus different from peptides disclosed in the present invention.
As evidenced by a survey of the art, there remains a need for enhancing the therapeutic efficacy of current methods of treating or preventing disorders such as cancer, autoimmune disease, inflammatory disorder, or allergy. In particular, there is a need for enhancing the effector function, particularly, the cytotoxic effect of therapeutic antibodies used in treatment of cancer. The current state of the art is also lacking in treating or preventing allergy disorders (e.g., either by antibody therapy or vaccine therapy).

This patent is subject to a terminal disclaimer.

FcγRIIB specific antibodies and methods of use thereof


A method employing fuzzy logic for identifying a detected object in LADAR data is disclosed. The method includes extracting a feature of the object; determining a confidence level in the extracted feature; comparing the extracted feature to a corresponding feature of a potential identification using a fuzzy logic process, and identifying the object. The comparison includes weighting at least one rule according to the confidence level in the extracted feature employed by the rule; shifting a membership function for the extracted feature responsive to the confidence level for the extracted feature; and executing the fuzzy logic process to obtain an indication of whether the segmented object corresponds to the potential identification.

1. Field of the Invention
The present invention pertains to identifying objects in three-dimensional data and, more particularly, an automatic target recognition system employing a fuzzy logic process to identify targets in LADAR data.
2. Description of the Prior Art
Automatic target recognition ("ATR") systems identify objects represented in two-dimensional or three-dimensional data to determine whether they are potential targets. Three-dimensional data may be acquired in numerous ways and laser detection and ranging ("LADAR") systems are commonly employed for this purpose. In such systems, a laser signal is transmitted from a platform and, upon encountering an object, is reflected back to the platform. The platform can then process the reflected signal to obtain three-dimensional data regarding the object causing the reflection. Typically, this data includes a number of the object's features such as its height, length, and width. However, the platform typically transmits many laser signals across a general area that will contain a number of objects reflecting the signals. Thus, it is necessary for the ATR system to examine the data to see which reflecting objects might be of interest.
ATR systems are often divided into four subsystems: detection, segmentation, feature extraction, and identification. Identification can be described as the final process which takes inputs such as the features discussed above and establishes an identity for the object based on previously determined features of known objects. The accuracy of the identification depends on several factors including the correctness of the object features used in the comparison and the number of known objects constituting potential identifications.
The ATR system would ideally be able to compare completely accurate feature measurements against those of all known objects to establish the unknown object's identity. However, identification is frequently hampered by poor measurements such that, even if one of the potential identifications is correct, a complete match cannot be recognized. For instance, a length measurement might be compromised if part of the unknown object is obscured by a wall or fence and a width measurement might be affected by the orientation of the object relative to the platform. ATR system design constraints for size and speed may also affect performance.
An ATR system must therefore, as a practical matter, quickly establish the best possible identity with minimal computing resources. However, conventional computing techniques are poorly suited to meet these design constraints. For instance, conventional computing resources classically analyze information in two states such as "yes" and "no", or "true" and "false." An incomplete match in the comparison phase of a suitable operational ATR system cannot easily be represented in two states and consequently requires extensive analysis to produce a useable answer. The extensive analysis, in turn, consumes time and computing resources. This consumption becomes more acute as the list of potential identifications becomes more comprehensive since there typically will be no or, at most, only a few complete matches. Conventional computational techniques are consequently poorly adapted to meet the various design constraints in practically implementing an ATR system and, as demand for improved system performance rises, become still less suited. Thus, there is a need for a new method for identifying objects in three-dimensional data.

Dynamic fuzzy logic process for identifying objects in three-dimensional data


The present invention provides polynucleotide molecules comprising nucleotide sequences encoding plasminogen activating (PauA) proteins from Streptococcus uberis, and substantially homologous polypeptides, peptide fragments, and fusion proteins thereof. The present invention further provides compositions and methods for recombinantly expressing the PauA proteins, substantially homologous polypeptides, peptide fragments and fusion proteins encoded by the polynucleotide molecules of the present invention. The present invention further provides a vaccine for protecting a member of a mammalian species against mastitis, comprising a PauA protein, substantially homologous polypeptide, peptide fragment, fusion protein, or polynucleotide molecule of the present invention.

The present invention is in the field of animal health, and is directed to vaccine compositions and diagnostics for disease. More particularly, the present invention relates to vaccines against mastitis in mammals, and polynucleotide molecules having nucleotide sequences encoding plasminogen activating proteins useful in the production of said vaccines.
Bovine mastitis causes significant loss of milk production in dairy cattle, resulting in severe economic impact on the dairy industry. Mastitis may be caused by one or more types of bacterial pathogens. Infection by Streptococcus is estimated to account for approximately 30% of all clinical cases of bovine mastitis. Infection by S. uberis, specifically, is estimated to account for approximately 20% of all clinical cases of bovine mastitis.
Conventional methods for the prevention and treatment of mastitis in animals include the use of sanitary milking techniques and the administration of chemical antibiotics. The use of antibiotics, however, is limited by the fact that milk containing antibiotic residues is often not considered safe for human consumption and must be discarded. Specific approaches to the treatment or prevention of mastitis in animals include that of U.S. Pat. No. 5,198,214 to Stolle et al., which describes the use of polyvalent anti-mastitis vaccines comprising inactivated mastitis-causing pathogens cultivated from the milk of infected animals. In addition, U.S. Pat. No. 5,234,684 to Sordillo et al. describes a method of treating or preventing mastitis in cows, comprising administering bovine interferon gamma to the animals.
The ability of Streptococcus spp. to infect the lactating mammary gland is dependent on the bacteria""s ability to grow in the secretion and avoid phagocytosis by bovine neutrophils (Leigh et al., 1990, Res. Vet. Sci. 49: 85-87). The majority of nitrogen in bovine milk is present in the form of protein (Aston, 1975, Austral. J. Dairy Tech. 30: 55-59) and, in the absence of proteolysis, growth of Streptococci in milk is limited by the lack of free amino acids. This is highlighted by the dependence of the lactic streptococci on extracellular, caseinolytic proteinases for growth in milk (Mills and Thomas, 1981, N. Zeal. J. Dairy Sci. Tech. 15: 43-55). In addition, the ability of bacteria to grow in milk is enhanced by the presence of the caseinolytic enzyme, plasmin (Marshall and Bramley, 1984, J. Dairy Res. 51:17-22), which breaks down milk proteins into free amino acids.
Bovine milk contains plasminogen that is normally proteolytically inactive, but which can be converted to proteolytically active plasmin by the action of a plasminogen activator. It has been demonstrated that mastitis-causing strains of Streptococcus, such as, e.g., S. uberis, produce a plasminogen activator capable of converting bovine plasminogen to plasmin. The activity of this plasminogen activator results in the break-down of milk protein to release free amino acids that, in turn, support the growth of the bacteria in the mammary gland. From this observation, it has been proposed that induction of an immune-based response, e.g., the production of neutralizing antibodies, against the plasminogen activator of Streptococcus, might serve to protect animals against mastitis. International Patent Publication WO 93/14209, which is incorporated herein by reference, demonstrates the purification of a plasminogen activator (designated therein as a xe2x80x9cstreptokinasexe2x80x9d) from culture filtrates of S. uberis, and further teaches anti-mastitis vaccine compositions based on such plasminogen activators from Streptococcus spp.
The isolation of a polynucleotide molecule having a nucleotide sequence encoding a plasminogen activator such as that, e.g., from Streptococcus, would greatly facilitate the preparation of anti-mastitis vaccines.
The present invention provides an isolated polynucleotide molecule comprising a nucleotide sequence encoding a biologically active plasminogen activator protein (designated herein as a xe2x80x9cPauA protein,xe2x80x9d previously designated as xe2x80x9cPAxe2x80x9d or xe2x80x9cstreptokinasexe2x80x9d). In a preferred embodiment, the PauA protein is from a bacterium, such as, e.g., Streptococcus, that causes or contributes to mastitis in a member of a mammalian species. In a more preferred embodiment, the species of Streptococcus is S. uberis or S. dysgalactiae.
In a preferred embodiment, the isolated polynucleotide molecule of the present invention comprises a nucleotide sequence encoding an amino acid sequence that is the same as the amino acid sequence from about amino acid position 26 (IIe) to about amino acid position 286 (Pro) of SEQ ID NO:2 or SEQ ID NO:4. In a non-limiting embodiment, such polynucleotide molecule comprises the nucleotide sequence from about nucleotide position 195 to about nucleotide position 977 of SEQ ID NO:1, or from about nucleotide position 196 to about nucleotide position 978 of SEQ ID NO:3, respectively.
In a further preferred embodiment, the isolated polynucleotide molecule of the present invention comprises a nucleotide sequence encoding an amino acid sequence comprising the amino acid sequence from about amino acid position 1 (Met) to about amino acid position 286 (Pro) of SEQ ID NO:2 or SEQ ID NO:4. In a non-limiting embodiment, such polynucleotide molecule comprises the nucleotide sequence from about nucleotide position 120 to about nucleotide position 980 of SEQ ID NO:1, or from about nucleotide position 121 to about nucleotide position 981 of SEQ ID NO:3, respectively. In a further non-limiting embodiment, the polynucleotide molecule of the present invention comprises the nucleotide sequence of SEQ ID NO:1, or the nucleotide sequence of SEQ ID NO:3, respectively.
The present invention further provides a polynucleotide molecule that is substantially homologous to the polynucleotide molecule of the present invention encoding a PauA protein.
The present invention further provides a polynucleotide molecule comprising a nucleotide sequence that encodes a polypeptide that is substantially homologous to a PauA protein encoded by a polynucleotide molecule of the present invention.
The present invention further provides a polynucleotide molecule consisting of a nucleotide sequence encoding a peptide fragment of a PauA protein or substantially homologous polypeptide of the present invention. In a specific though non-limiting embodiment, the present invention provides a polynucleotide molecule consisting of a nucleotide sequence encoding a peptide fragment consisting of a sub-sequence of amino acids from SEQ ID NO:2 or SEQ ID NO:4 selected from the group consisting of amino acids at positions of about 28 to about 286, about 104 to about 286, about 172 to about 286, about 28 to about 170, about 104 to about 170, about 104 to about 208, about 172 to about 208, about 28 to about 103, about 28 to about 208, and about 149 to about 286.
The present invention further provides a polynucleotide molecule comprising a nucleotide sequence that encodes a fusion protein comprising a PauA protein, substantially homologous polypeptide, or peptide fragment of the present invention joined to a carrier or fusion partner.
The present invention further provides oligonucleotide molecules that are useful as primers in amplification techniques, and as diagnostic probes in differential disease diagnosis. In a non-limiting embodiment, an oligonucleotide molecule of the present invention consists of a nucleotide sequence selected from the group consisting of SEQ ID NOS:13-27 and the complements of said sequences. In a further non-limiting embodiment, an oligonucleotide molecule of the present invention comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS:13-27 and the complements of said sequences.
The present invention further provides compositions and methods for the recombinant expression of a polynucleotide molecule of the present invention, including recombinant cloning vectors and recombinant expression vectors comprising the polynucleotide molecule, and host cell lines transformed with any of said vectors.
The present invention further provides a recombinantly-expressed PauA protein, substantially homologous polypeptide, peptide fragment, or fusion protein encoded by a polynucleotide molecule of the present invention.
The present invention further provides analogs and derivatives of a PauA protein, substantially homologous polypeptide, peptide fragment or fusion protein of the present invention.
The present invention further provides a vaccine for protecting a member of a mammalian species against mastitis, comprising an immunologically effective amount of a PauA protein, substantially homologous polypeptide, peptide fragment, fusion protein, analog, derivative, or polynucleotide molecule of the present invention that is capable of inducing a protective response against mastitis in the mammal, and a veterinarily acceptable carrier. The vaccine can optionally comprise an adjuvant or other immunomodulatory component.
In a non-limiting embodiment, the vaccine of the present invention is a combination vaccine for protecting a member of a mammalian species against mastitis and, optionally, one or more other diseases or pathological conditions that can afflict the mammal, which combination vaccine comprises an immunologically effective amount of a first component comprising a PauA protein, substantially homologous polypeptide, peptide fragment, fusion protein, analog, derivative, or polynucleotide molecule of the present invention that is capable of inducing a protective response against mastitis in the mammal; an immunologically effective amount of a second component comprising an antigen capable of inducing a protective response against a disease or pathological condition that can afflict the mammal; and a veterinarily acceptable carrier.
The present invention further provides a method of preparing a vaccine for protecting a member of a mammalian species against mastitis, comprising combining an immunologically effective amount of a PauA protein, substantially homologous polypeptide, peptide fragment, fusion protein, analog, derivative, or polynucleotide molecule of the present invention that is capable of inducing a protective response against mastitis in the mammal, with a veterinarily acceptable carrier.
The present invention further provides a method of vaccinating a member of a mammalian species against mastitis, comprising administering the vaccine of the present invention to the mammal.
The present invention further provides antibodies that specifically bind to a PauA protein, substantially homologous polypeptide, peptide fragment, fusion protein, analog, or derivative of the present invention.
The present invention further provides vaccine kits and diagnostic kits.

DNA encoding a plasminogen activating protein


Apparatus and method for sensing and measuring optically active material in a sample, comprising:                a) a light source emitting light of a wavelength that can pass through the sample;        b) a light transparent sample container for holding the sample;        c) a linear polarizer interposed between the light source and the sample for producing a polarized light beam;        d) a symmetrical linear split-field polarizer fixedly positioned to intercept the polarized light that passed through the sample;        e) detectors to detect the split light beams passing through each polarizer of the split-field polarizer;        f) means to amplify the current or voltage passing through each of the detectors;        g) a differential amplifier;        h) a data processor;        i) a display; and        j) electronic circuitry to operate the apparatus and provide an output on the display.

Certain solutions, e.g. containing sugar, possess the property of being able to rotate the plane of linear polarized light. The degree of rotation of the plane of vibration per unit of the solution traversed by the polarized light varies in accordance with the concentration of the solution. It is well known in the art to use a device having a light polarizer and an analyzer to measure the rotation of the plane of vibration of light passing through a solution, and to thereby determine the percent sugar content of the solution. One example of such an apparatus is shown in U.S. Pat. No. 3,411,342. In this patent, the polarimeter consists of a mercury vapor lamp light source, a collimating lens, a primary polarizer to establish a reference point for measurement of optical rotation, a sample cell through which a continuous stream of crude syrup is circulated, and a measuring circuit that determines the extent of optical rotation caused by the sample and provides an appropriate output signal.
Such conventional polarimeters of the prior art generally use visible light sources in the 400-700 nanometer wavelength emission range.
U.S. Pat. No. 4,467,204 describes a polarimeter system and method using an infrared light source to gauge and measure the optical rotation of dark sugar solutions.
German Patent No. 2724543 and U.S. Pat. Nos. 3,724,957; 4,699,514 and 4,671,660 disclose multi-beam measurement of polarimetry.
U.S. Pat. No. 5,009,230 describes a device for polarimetrically measuring the concentration of blood glucose by producing two alternating linearly polarized states of infrared light, passing these through a sample, detecting the intensities of these two states after passing through the sample and detector and calculation means for measuring the ratio of the sum and differences of the transmitted intensities.
U.S. Pat. Nos. 4,167,676; 4,350,163; 4,427,889; 4,586,513 and 4,655,225 describe polarimetric devices using absorption and/or backscattering of incident radiation to determine glucose levels.
None of these known devices have the sensitivity achievable by more rigorous available analytical techniques. The degree of rotation caused by glucose levels of the body, for example, is very small and is normally difficult to measure with any sensitivity without using large and bulky equipment and invasive procedures.

Apparatus and method for measuring optically active materials


The present invention pertains to footwear where the tongue may be reversed in order to open and close vents in the upper of a shoe. Secondarily, the reversible tongue changes the aesthetics, coloration, indicia, or other appearance of the footwear. A shoe has an upper upon a sole. On the sides of the upper, generally vertical stripes have vent between them. The reversible tongue has a symmetric shape and it rotates upon a longitudinal axis. Placed within the upper upon a swivel, the tongue rotates to extend across the vents to close them and to retreat from the vents to open them. In rotating, the tongue changes the coloration, indicia, design, or other appearance aspects of the shoe. Rotation of the tongue occurs with shoe laces loosened or with removal of a foot from the shoe.

This invention relates generally to footwear, and more specifically pertains to shoes and the like where the tongue may be reversed, in order to ventilate a shoe and to change the aesthetics, coloration, indicia, or other appearance of the overall footwear.
Numerous styles of footwear, constructed of various components and for achieving multiple purposes, have long existed in the prior art. Most of these types of innovations have been in the area of running or athletic shoes which have enjoyed resurgence in recent years. Various styles or modifications to the shoes, as in their tongue configurations, to make them more comfortable, more resilient, add to the efficiency of the runner or suitable to fashion have been considered in the prior art. Shoes as a class borrow various accessories and modifications from other footwear, such as tongue flaps.
Recent trends have even considered reversing various components of footwear, such as tongues, to alter the aesthetics of, to change the style of, and to improve the appearance of footwear when worn. Modifications to the structure of the shoe itself, such as adding pockets to the side or within the tongue or gusset of the shoe, have been considered in the prior art. For example, the patent to Adamik, U.S. Pat. No. 4,372,060, relates to this type of technology, and its modifications. Then the patent to Benjamin, U.S. Pat. No. 2,049,347, shows a shoe wherein a strap, held by one or more D-Rings, can be turned to reverse the positioning of the strap within the shoe structure. In addition, the patent to Tonkel, U.S. Pat. No. 4,805,321, shows the use of a separable tongue held by Velcro to its vamp, but which must be removed to provide for its turning and to vary the appearance of the shoe. However, shoes have retained their basic form of an upper upon a sole including a tongue over the instep of a foot.
The current invention modifies the tongue and upper of footwear or shoes, particularly athletic shoes. The modifications add further variations in the use of the shoe, enhance its styling, and further enhance the comfort of a foot within the shoe, by providing ventilation to its components particularly the tongue, when structured into the shoe itself.

Ventilated footwear with a reversible tongue


An improved vision tester apparatus and method are disclosed for use in conducting optometric examinations of patients who use video display terminals (VDTs). Specifically, the tester simulates images that are displayed to the patient by a typical VDT, so as to facilitate prescribing corrective lenses that will perform well for the patient when used with an actual VDT. The tester (10) includes a flat-panel electroluminescent light source (32) for illuminating a screen (14) without hot spots. The screen includes a colored ink layer (78,80,82) and an opaque ink mask (70) for forming pixel-like light elements (24). Lensing structures (52,56,58,60) degrade the image such that each light element exhibits a generally Gaussian light amplitude curve (FIG. 5B) characteristic of a pixel of an actual VDT. A rechargeable battery (34) coupled to a inverter circuit (30) provide portable power for the EL panel to complete a compact, portable tester.

The present invention relates to vision testing equipment and more specifically to instruments and methods for use in conducting optometric examinations.
As use of the video display terminal ("VDT") has become more widespread, for example in connection with computers, so too have certain ophthalmological problems associated with its use become more common. A recent survey of optometrists, reported in the J. Am. Optom. Assoc. 1992 (vol. 63, pp 687-92), shows that more than 14% of optometric patients present with symptoms primarily associated with use of the VDT, or almost 10 million examinations annually when projected to the U.S. population. Responding optometrists were unable to confidently arrive at a diagnosis and treatment more frequently for VDT patients (20.87%) compared to non-VDT patients (14.05%).
Alphanumeric characters displayed on video display screens are made up of dots or pixels which do not have well defined borders and therefore are difficult for the eye to focus upon. Further, since video screens are maintained at a constant distance of about 50 cm from the user's eyes, the same eye muscles are in constant use in focusing on the screens. These factors cause significant amounts of stress and fatigue on the eyes of video display terminal users which are often aggravated by the fact that many such users utilize their computers for extended periods on a daily basis. The stress associated with video display use frequently results in peculiar types of eye problems requiring special corrective prescriptions in the spectacles selected for the users suffering from these problems.
In order to accurately diagnose these problems, appropriate test equipment and test procedures must be provided. In accordance with the process currently used by medical practitioners to determine the spectacle requirements of typical patients, an apparatus (phoropter) is placed in front of the eyes of the patient which enables the doctor to rapidly change a wide selection of lenses while the patient views a set of test images through the lens changing apparatus. As the patient focuses on the test images, the doctor assesses the status of the muscles inside the patient's eyes and judges their degree of relaxation through the use of a retinoscope. The doctor determines the combination of lenses and the prescription best suited to the patient by changing the lenses until he detects the combination which provides the most relaxed state in the eye muscles of the patient.
As may be understood from the above, the fitting of corrective lenses is basically a trial and error process in which the doctor observes the reaction of the patient's eye muscles to an appropriate test image for various combinations of lenses. However, without a test image which accurately simulates the conditions under which the patient may experience eye problems, a prescription for suitable corrective lenses may not be reliably determined. When presented with an image which does not have sharply defined edges or which is slightly out of focus, the eye will respond by reverting to a level of tonic muscle activity known as the resting point of accommodation, having a focal length with a sharply defined image placed at the same distance from the eye. Accordingly, the prescription required for eyeglasses used with a video display terminal can differ from a prescription for use in viewing printed material.
Commercially available equipment and clinical protocols do not provide a satisfactory system for generating test images which simulate the characteristics of video display terminals such as computer screens. Consequently, most practitioners have no recourse but to make educated guesses as to the lens corrections which may work best for their patients. After the patients go back to work and try the new prescriptions, many return because their glasses are not suitable. Testing is repeated, and a new prescription may be tried. This is, however, a time consuming, expensive, inaccurate and generally unsatisfactory method of proceeding to provide spectacle prescriptions for computer users.
It is therefore an object of the present invention to provide an improved system for testing the vision of video display terminal users which allows for accurate determination of the best corrective lens prescriptions for such patients.
It is another object of the present invention to provide an improved system for testing the vision of video display terminal users which allows for accurate determination of the best corrective lens prescription for such patients.
It is another object of the present invention to provide an improved apparatus which accurately simulates alphanumeric characters as presented on a video display screen and which can be conveniently used in accordance with current optometric test procedures.
It is a further object of the present invention to provide an improved optometric instrument for use in determining prescriptions for corrective lenses which is economical, reliable, compact and simple to use.

Computer display screen simulation for optometric examination


A light (10) comprising: a cup-shaped, substantially rigid base (12) having a circumferential ridge (14) on the outer wall (16) of the base (12); a battery (18) having first and second poles (20, 22) within the base (12); a PCB (24) overlying the battery (18) within the base (12), the PCB (24) having a plurality of apertures (26) therein, at least one of the apertures (26) containing a LED (28) having first and second lead-ins (20a, 22a), a first of the lead-ins (20a) being electrically connected to the first pole (20) via a connector (30); switch means (32) associated with the PCB (24) electrically connecting the second lead-in (22a) to the second pole (22); and a cup-shaped, flexible, translucent cover (34) on the base, the wall (36) of the cover (34) engaging the outer wall (16) and the circumferential ridge (14).

Light emitting diodes have very long lives and are very small. Accordingly, it would be an advantage to utilize these features in a portable light that was easily attachable to objects where incidental illumination was difficult to achieve. It would further be desirable if the light was inexpensive, convenient to use and able to provide at least two signaling functions.


An efficient request-reply protocol for a client-server communication and data processing model. Under the novel protocol, a client sends a Request to a server and awaits a Reply. If the Reply is not sent before expiration of a timeout period in the client, the client sends a second Request. The server provides a conditional Acknowledge if a second Request is received from the client. Thereafter, the client waits for the server to transmit a Reply without the client sending additional Requests. Under normal conditions, the inventive protocol performs as well as the best prior art protocol (the optimistic model), while under abnormal conditions, the inventive protocol performs better than the optimistic protocol and only slightly worse than the prior art pessimistic protocol. Since normal conditions should prevail for a substantially longer amount of time than abnormal conditions, the present invention provides better average performance than either prior art client-server protocol.

1. Field of the Invention
This invention relates to communication and data processing technology, and more particularly to an efficient request-reply protocol for a client-server communication and data processing model.
2. Description of Related Art
In recent architectures for data communication and data processing technologies, many user workstations are typically interconnected by a computer network. The network may be of the direct connection type (e.g., LAN or WAN) or a wireless type, or a combination of both.
Among current designs for such architectures, the "client-server" model has become a typical model in which computers on the network communicate with each other. A typical client-server interaction involves a client computer requesting a server computer to perform a certain operation, whereupon the server performs the operation and conveys the result back to the client.
Currently, there are two basic types of protocols used by the client and server to communicate with each other based on the two pacing parameters of this architecture--network performance and server performance. Network performance varies with, among other things, network reliability and load. Server performance varies with, among other things, load and operation complexity.
FIG. 1 is a ladder diagram showing the flow and timing of communications between a client-server system according to a first prior art protocol. This protocol takes a "pessimistic" view of network characteristics. As shown, a Request is initially transmitted by a client 10 to a server 12 over a communication network. The server 12 responds with an Acknowledge. The Acknowledge must be received by the client 10 within a first elapsed time period TIMEOUT.sub.REQUEST or an error occurs. Such an error may represent, for example, a disruption or failure by the server 12 or in the network. If the client 10 does not receive the Acknowledge before the TIMEOUT.sub.REQUEST time elapses, the client 10 retransmits the Request until the client 10 receives an Acknowledge. The timer value, TIMEOUT.sub.REQUEST, is a function principally of the network characteristics. That is, the timer value is based upon some estimate as to how long an Acknowledge should take to be sent to the client 10 by the server 12.
After completing the requested operation, the server 12 responds back to the client with a Reply containing the result of the operation. If the client 10 does not receive the Reply within a second elapsed time period TIMEOUT.sub.REPLY, measured from the receipt of the Acknowledge, the client 10 conveys an error to higher layers of the application software executing within the client 10. The timer value TIMEOUT.sub.REPLY is a function of a time estimate as to how long the server 12 should take to perform the desired operation.
The biggest advantage of this protocol is the separation of the network and the server 12 performance variables, so even if the server 12 takes a longer time to reply than expected, only 3 protocol data units (PDUs) are exchanged between the client 10 and the server 12 in the normal case. The problem with this protocol is that even for the best case scenario, where the Request is not lost by the underlying network, there is an extra Acknowledge. This extra PDU results in unnecessary wastage of network bandwidth, which usually is a very precious resource. This becomes more apparent in a wireless network, with many nodes competing for limited radio bandwidth.
FIGS. 2a and 2b are ladder diagrams showing the flow and timing of communications between a client-server system according to a second prior art protocol. This protocol takes an "optimistic" view of network characteristics. Again, a Request is initially transmitted by a client 10 to a server 12 over a communication network. A Reply is used to convey the result to the client 10. Since the Reply indirectly indicates receipt of the Request by the server 12, a separate Acknowledge signal directly indicating such is unnecessary. Thus, no separate Acknowledge is sent by the server 12. If the server 12 sends the Reply before a time period TIMEOUT elapses (i.e., the anticipated "normal" condition), only 2 PDUs are exchanged between the client 10 and the server 12, as shown in FIG. 2a. However, if the client 10 does not receive the Reply within the Timeout period, the client 10 retransmits the Request under the assumption that the prior Request was "lost" in the network.
Although this protocol is the most efficient for the best case scenario (only 2 PDUs exchanged), it behaves rather poorly when the operation performed on the server 12 takes a longer time than expected, as shown in FIG. 2b. When completion of the operation by the server 12 is delayed, the client 10 has no way to determine whether the Request was lost or whether the server 12 was delayed in completing the operation. The client 10 can only assume that the server 12 did not get the prior Request, and so retransmits the Request again. If the operation takes long enough, this can cause multiple retransmissions of the Request, resulting not only in wastage of the network bandwidth but possibly overloading the server 12 with more processing, which in turn could cause more delay in the operation being performed on the server 12.
Accordingly, it would be desirable to have a more efficient protocol for the client-server model in a data communication and processing system.
The present invention provides such an improved protocol.

Efficient request-reply protocol for a client-server model


The present invention relates to methods of treating or reducing the risk of necrotizing enterocolitis (NEC) in an infant comprising orally administering an effective amount of a CpG-ODN. It is based, at least in part, on the results of experiments in which orally administered CpG-ODNs were observed to reduce the histopathology and markers of inflammation in a murine model for NEC. The present invention further provides for oral formulations of CpG-ODN for administration to infants.

The leading cause of death from gastrointestinal disease in neonates is necrotizing enterocolitis ("NEC"; as reviewed in reference 51). 90 percent of the cases of NEC occur in premature infants (51). Over forty years of research have unfortunately made relatively little progress towards improving the prognosis of patients with NEC (3), which, after surgical treatment, bears a survival rate of only approximately 50% (4).
One area of recent development is the discovery that a class of bacterial receptors named Toll like receptors ("TLR's") play an essential role in the pathogenesis of NEC. Of particular importance is TLR4, the receptor for lipopolysaccharide (LPS), which is the outer membrane component of gram negative bacteria (12). It has been found that (i) mice with mutations in TLR4 are protected from the development of NEC (22); (ii) TLR4 signaling regulates the balance between injury and repair in the newborn intestine (21); and (iii) TLR4 is increased in the intestinal mucosa of mice, rats and humans with NEC compared to controls (21, 23). TLR4 activation appears to not only promote intestinal injury, but also reduces the ability of the mucosa to heal. It has been postulated that that prematurity, hypoxia and endotoxemia, each of which are linked to NEC, result in persistent upregulation of intestinal TLR4 and consequent disease (21). Therapeutic approaches to NEC have been developed that involve inhibiting activity of TLR4. For example, see U.S. Pat. No. 8,188,058 by Hackam.
Modulation of other TLRs may also be used therapeutically. Activation of TLR9, the enterocyte receptor for bacterial DNA (which, unlike mammalian DNA, is rich in CpG groups and significantly hypomethylated) with CpG-DNA led to reduced TLR4 signaling both in vitro and in newborn's intestine (U.S. Pat. No. 8,188,058 by Hackam and 40). The potential use of oral CpG-ODNs in asthma has been explored (53).

Oral therapy of necrotizing enterocolitis

University of Pittsburgh-Of the Commonwealth System of Higher Education


A CD-ROM testing system includes a personal computer, a programmable logic control (PLC), a testing apparatus with sensors and an industrial man-machine interface. The personal computer is in communication with the PLC for performing tests on the CD-ROM. The PLC is connected to both the personal computer and the man-machine interface to control the operation of the testing apparatus. The testing apparatus is to carry out tests on the CD-ROM and collects the test results. The man-machine interface is to indirectly control the testing apparatus and display test signal. The CD-ROM testing system is capable to replace human labor in continuously testing a plurality of CD-ROMs to provide an efficient and precise test results of the functions of the CD-ROMs and the test results are stored in the personal computer for further use and analysis.

CD-ROMs that have been completed in a manufacturing line are subject to tests on all functions thereof, such as disk carrier tray opening/closing, disk driving, data reading and the lighting of all the LED (light emitting diode) indicators, in order to ensure the quality of the CD-ROMs before they are packed and shipped. Conventionally, the CD-ROMs are tested manually, and in order to avoid the reduction of the quality caused by errors and mistakes, the CD-ROMs are only tested by trained and experienced operators. However, the testing operation which includes opening/closing the tray, loading/unloading test disk, repeatedly checking the indicators is a very boring and monotonous job so that even the most experienced operators may accidentally make mistake in the test of the CD-ROMs. This causes serious problem in the quality control.
Another disadvantage associated with manual test operation of the CD-ROM products is that it requires a lot of labor. This increases the overall cost of the CD-ROMs. Training operators is also a significant cost. This all makes the manual test operation very inefficient and costly.
Thus, in order to improve the conventional manual test operation of CD-ROM products, it is desired to have a CD-ROM test system which allows a plurality of CD-ROM products to be tested automatically and sequentially so as to overcome the drawbacks in the prior art.


A method for forming an oxide film includes a first in-situ steam generation (ISSG) process using a 1%-H2 concentration in the ambient gas and a subsequent second ISSG process using a 5%-H2 concentration in the ambient gas, wherein the second ISSG process compensates an in-plane thickness distribution of the film formed by the first ISSG process. The time length for the first and second ISSG steps is determined based on a desired film thickness, a time length dependency of a film formed by the second ISSG process, and the oxidation rate of the first and second ISSG processes.

(a) Field of the Invention
The present invention relates to a method for controlling the thickness distribution of a thin film and, more particularly, to a method suitable for controlling the thickness distribution of an oxide film formed in an in-situ steam generation (ISSG) technique.
(b) Description of the Related Art
The process for manufacturing semiconductor devices generally uses the step of forming a silicon oxide film on a wafer. An ISSG technique is known to form the silicon oxide film, as described in Patent Publications JP-2003-086716A and JP-2002-373984A. The ISSG technique has an advantage over the conventional dry-oxidation technique etc. in that the resultant silicon oxide film has a uniform thickness.
It is known that the silicon oxide film (referred to as merely oxide film hereinafter) formed by the ISSG technique has an in-plane thickness distribution depending on the combinational process condition (process condition) used therein. For example, the in-plane thickness distribution varies depending on the H2 concentration and ambient pressure in the ISSG process. More specifically, a higher H2 concentration provides an oxide film having a larger thickness in the peripheral area than in the central area of the wafer, whereas a lower H2 concentration provides an oxide film having a smaller thickness in the peripheral area than in the central area. A higher ambient pressure provides an oxide film having a larger thickness in the central area than in the peripheral area of the wafer, whereas a lower ambient pressure provides an oxide film having a smaller thickness in the central area than in the peripheral area.
FIG. 9 shows an example of the ambient pressure dependency of the thickness of the oxide film formed by the ISSG process. In this example, the ambient pressure in the ISSG process is varied, with the process temperature being fixed at a specific temperature and the H2 concentration in the ambient gas being fixed at 1%. As understood from FIG. 9, the thickness distribution of the oxide film has a significant dependency on the ambient pressure in the ISSG process.
It may be expected that since the film thickness has the ambient pressure dependency and the H2 concentration dependency of the thickness distribution, an optimum combination of the H2 concentration and the ambient pressure provides a smaller range of variation in the in-plane film thickness. However, it is known that control of the H2 concentration varies the thickness of the oxide film in a larger amount to render the film thickness being out of control.
Thus, in the conventional ISSG technique, the ambient pressure is varied stepwise from 7 Torr to 10 Torr, for example, to form oxide films, with the H2 concentration being fixed for a specific film thickness, and the thickness distribution of the resultant oxide film is measured for each of the ambient pressures, as shown in FIG. 9. Thereafter, a process condition or ambient pressure, which provided an oxide film having an optimum thickness distribution is selected. By employing the selected process condition or ambient pressure, the ISSG process is conducted for forming oxide films in the product semiconductor devices.
In the conventional technique as described above, since the ambient pressure dependency of the in-plane thickness distribution of the oxide film must be investigated for a variety of combinational process conditions each including a processing temperature, a H2 concentration etc., a large amount of fundamental data must be obtained for this investigation. In particular, if maintenance of the oxidation system, such as replacement of the lamp or cleaning of the chamber which affects the thickness distribution, is performed, the fundamental data must be again obtained. Thus, the technique for improving the in-plane thickness distribution to obtain an excellent in-plane thickness uniformity of the oxide film has been required in the ISSG process, and it is an essential issue in the ISSG process to meet this requirement.

Method for controlling thickness distribution of a film


The invention relates to the generation of digital signatures by the use of which the legally binding nature of a digital signature is enhanced. For this, an expanded digital signature is created which, in addition to the hash, contains other information, in particular information identifying the hardware and software environment used in generating the signature.

Digital signatures can be seen as the counterpart to handwritten signatures. The digital signature appended by a sender to an electronic document can be used to establish the sender's identity and the authenticity of the transmitted document. The legally binding nature of the digital signature is a key topic for public administration, for companies and, increasingly, for private individuals.
The principle of the digital signature is known. It is based on an asymmetric method in which each user is assigned two different keys: a private key and a public key. The public key is generally accessible. The prerequisite is that each pair of keys is unique. With the private key, which is usually on a chipcard, the digital signature is generated by the sender. The recipient of a document signed with a digital signature can separate the signature from the document using an appropriate software program and can decode the hash with the aid of the sender's public key, thereby verifying the authenticity of the document and the identity of the sender. This method can be used between natural persons and between hardware devices.
Methods of generating digital signatures are known. For example, signature devices are used which apply cryptographic methods such as the familiar RSA (Rivest-Shamia-Adleman cryptographic algorithm) public key method. In this, a document extract value (hash) generated by a hashing method such as MD5 (Message Digest #5) or SHA-1 (Secure Hashing Algorithm) is signed with the private key of the sender (encrypted) and appended to the document as a digital signature prior to dispatch.
In cryptographic methods it is necessary that the length of the digital signature matches the length of the key used, e.g. 512, 758 or 1024 bits. Since the size of the hash is only around 20 bytes, the unused area of the signature is filled out with filler characters (pads). Consequently, in a digital signature for example 108 bytes of these pads are stored and transported uselessly when a 1024-bit RSA key and the SHA-1 hashing algorithm are used.
In the known methods there is no unique allocation of the digital signature to a specific signature device. Thus it would be possible, for example, with the aid of a fake or stolen key and a signature device, to append a fake signature to a document. The legitimate owner of the key used has little or no chance of proving that such an unauthorized signature was indeed made without his or her knowledge.
It would also be possible that a manipulated or stolen signature device of the key holder may be used, together with a third-party program (virus), to sign documents without the knowledge of the key holder. This may also occur with no intervention from outside, for example as a result of faulty software or interfaces. Here, too, the key holder has little chance of proving the illegitimacy of the signatures generated.
It is therefore the object of the present invention to deliver a digital signature by the use of which the legally binding nature of a digital signature is enhanced.

International Business Machines Corporation