An EP controller, which is located on the leading locomotive, is connected by a cable to the leading end trainline connector of the lead locomotive. This powers the EP controller and provides communication by the EP controller over the trainline. A second cable connects the EP line of the first car in the train to the trailing end trainline connector of the last locomotive for providing communication between the EP controller and the electro-pneumatic brakes on each car over the trainline and the EP line.

The present invention relates generally to electro-pneumatic brakes on trains and more specifically to a method of connecting and interconnecting the controller of the locomotive to the electro-pneumatic brakes on the cars.
The installation of electro-pneumatic (EP) operated brake equipment on railcars and the train is a relatively straight forward procedure. The control equipment and electronic trainline cables are permanently installed on the individual cars. As long as these cars are operated as a unit train with a locomotive that has also been modified to interface with the EP train, the brake system can perform in its electro-pneumatic mode. Keeping the modified locomotive and cars together as a unit train, in most cases, it is not a problem for railroads. However, modifying and then dedicating these modified locomotives to a single unit train, does present problems for the railroads. This increases the cost of operation in relation to other load factors. Also, the industry has decided to provide electro-pneumatic brakes on all cars, including freight cars. Unless all of the locomotives are modified or some are modified and dedicated EP service, the train cannot be operated in its electro-pneumatic mode.
Thus, as an object of the present invention to provide a simplified modification of locomotives for electro-pneumatic brake service.
Another object of the present invention is to provide a modification of locomotives for electro-pneumatic brake systems without the need for permanent rewiring.
These and other objects are achieved by using the existing electric trainline connectors on each end of the locomotives as a connection point for the electro-pneumatic controllers on the locomotive and the connection of the electro-pneumatic line of the cars to the locomotive consist.
Each train includes one or more locomotives and a plurality of cars. Each locomotive includes a leading and trailing end electrical trainline connector for interconnecting power and control lines to an adjacent locomotive. Each car on the electro-pneumatic train is serial connected electrically to an adjacent car forming an EP line. Each car includes an electro-pneumatic brake controlled by an EP controller in a locomotive over the EP line. The EP controller, which preferably is located on the leading locomotive, is connected by a cable to the leading end trainline connector of the lead locomotive. This powers the EP controller and provides communication by the EP controller over the trainline. A second cable connects the EP line of the first car in the train to the trailing end trainline connector of the last locomotive for providing communication between the EP controller and the electro-pneumatic brakes on each car over the trainline and the EP line. The trainline is a standard 27 pin multiple unit trainline. Alternatively, the EP controller is connected to a cable to an end trainline connector to receive power and is connected by a cable directly to the EP line of the first car.
The first cable connects a pair of power lines in the trainline to the controller. The first cable also connects a pair of control lines, at least one of which is not used by a locomotive control, to the EP controller for communication. The second cable connects the pair of control lines to the EP line. Preferably, a pair of unused control lines are used by the EP controller and the EP line. If used control trainline lines have to be used, they generally carry locomotive DC signals. The EP controller would then transmit AC control signals on the trainlines. Thus, the locomotive circuits connected to the used control trainlines are responsive only to the DC signals and the electro-pneumatic brakes on each of the cars are only responsive to the AC signals. The EP controller can also transmit power to the EP lines over the trainlines.

Locomotive M. U. trainline/jumper for EP brake application


Methods for detecting defective pixels in imaging arrays involve establishing probabilities that individual pixels are defective and updating those probabilities by analysing images acquired by the imaging arrays. Probabilities may be evaluated for each of two or more defect conditions. The methods may be used to detect defects such as stuck-low, stuck-high, high-sensitivity, low sensitivity, hot, and defect-free conditions. Other more complicated defect conditions can also be detected. Apparatus for detecting defective pixels may be integrated with a camera or other imaging device or provided separately.

Digital cameras and other imaging devices are becoming widely used in both consumer and industrial applications. Such devices acquire images by way of an imaging array. An imaging array typically comprises an array of radiation-sensing elements or "pixels". The pixels are typically arranged in rows and columns. Arrays of Charge-Coupled Devices (CCDs) and Active Pixel Sensor ("APS") arrays are two examples of imaging arrays.
The resolution of images acquired by an imaging array depends upon the density of pixels in a sensing area of the imaging array. Providing more pixels within the same sensing area provides higher-resolution images. An imaging array in a digital camera may have several million pixels, for example.
The probable number of defective pixels in an imaging array tends to increase with the number of pixels in the imaging array. Pixel failure may occur when the imaging array is fabricated, later when the imaging array is exposed to a stressful environment or as a result of components degrading over time. Like all microelectronics, as imaging arrays age their components can start to fail. General electronic devices tend to produce failures either during their first six months (called infant mortality) or after a few years (typically three years or more). In many devices (computers, cell phones) these failures render the device unusable. However, in camera systems, failures of some pixels are not necessarily catastrophic because such failures can often be corrected for.
In an imaging array having a large number of pixels, it is likely that at least a few of the pixels will be defective. For this reason, many digital cameras employ software correction. The software correction may replace the outputs from pixels determined at fabrication time to be defective with corrected outputs. The corrected outputs are often weighted averages of outputs from adjacent non-defective pixels.
In the fields of amateur and professional photography, pixel failures have become more noticeable as digital camera use has become more widespread. Such failures tend to appear as defective pixels or areas of the picture which are not correct. These can be quite noticeable and will tend to accumulate over time. Higher-end cameras, such as digital single lens reflex ("SLR") cameras, are quite expensive. It is undesirable to have to replace such equipment because a few pixels have become defective. However, unless the defective pixels are identified and corrected for the presence of the defective pixels degrades images obtained with the camera.
Defective pixels in imaging arrays can cause particularly acute problems in imagers operating at wavelengths outside of the visible spectrum. For example, fabrication processes for infrared imagers are often more complex than those for visible light imagers. Thus infrared imagers often have defect rates significantly higher than visible imagers. Similarly, digital medical X-ray imagers require large areas and are fabricated using processes that can make them more prone to faults. Further, obtaining accurate images can be important in the medical and scientific areas in which such imagers are applied.
Faults in imaging systems are becoming more prevalent as the areas and pixel counts of imaging arrays increase while pixel size shrinks. Consequently, identifying and correcting for pixel faults is crucial to improve the yield (during fabrication) and reliability (during operation) of imaging arrays.
To correct defective pixels with either software or hardware techniques, the location of defective pixels must be determined. The simplest defect models assume a pixel can be "good" (non-defective), "stuck high" (always bright or white), or "stuck low" (always dark). More advanced fault models include low- and high-sensitivity pixels and hot pixels.
It is known to detect defective pixels in an imaging array at fabrication time by taking two exposures with the array. A dark-field (no illumination) exposure detects pixels that are stuck high. A light-field (illumination level near saturation) exposure detects pixels that are stuck low or have low sensitivity. Dark-frame exposures can typically be obtained in the field. Uniform light-field illumination (or any uniform illumination) is difficult to obtain without additional hardware.
It is more difficult to detect pixels which respond to exposure but have defects which cause the pixels to have sensitivities that are significantly different from the nominal pixel sensitivity. More advanced techniques can detect faults such as high-sensitivity pixels. A high-sensitivity pixel provides a low output value when it is not illuminated but rapidly saturates at modest illumination levels. High-sensitivity pixels are thus not detectable with two simple illumination fields.
Most cameras employ colour imaging arrays. Colour imaging arrays present further complications. A colour imaging array typically comprises red-, green- and blue-filtered pixels. The pixels may be arranged in a pattern called the "Bayer Matrix pattern" as disclosed in Bayer, U.S. Pat. No. 3,971,065. Defects will typically be distributed among pixels at each colour site on the matrix, and hence defect detection must take into account the colour filter pattern of the imaging array.
Frame et al., U.S. Pat. No. 4,590,520 discloses detecting pixel faults by performing a post-production calibration to obtain "correction coefficients" for each pixel. A pixel is identified as being bad if its correction coefficient is not close to the values of the correction coefficients of neighbouring pixels.
Kagle et al., U.S. Pat. No. 6,819,358 discloses identifying defective pixels by means of light-, dark- and intermediate-range exposures. This technique can identify some pixels that have abnormal sensitivities (high or low).
St. Clair, U.S. Pat. No. 4,193,093 discloses that stuck-high pixels can be identified in a video imager by comparing the pixel values to the saturated video signal. However, in any complex image, this would falsely detect as being stuck-high many pixels that are in saturation due to the exposure of the image.
Peairs et al., U.S. Pat. No. 5,694,228 discloses methods for identifying defects in an imager based upon digital images of scanned documents. The methods involve incrementing a counter for potential defects when a pixel location has the same colour in more than a threshold number of the digital images. Otherwise the counter is reset or decremented.
Jin et al. Modeling and Analysis of Soft-Test/Repair for CCD-Based Digital X-ray Systems IEEE Trans. Instrumentation and Measurement vol. 52, pp. 1712-1721, December 2003 compare the difference between a pixel value and the average of pixel values for eight nearest-neighbour pixels to high or low threshold values to identify faulty pixels.
Tan et al., U.S. Pat. No. 6,381,357 discloses identifying pixel faults using the difference between a pixel value and the average of pixel values for the four or eight nearest-neighbour pixels combined with sequential probability ratio testing on multiple images to identify defects.
These methods can be susceptible to incorrectly identifying good pixels as being defective (i.e. creating significant numbers of false positives). In some reported cases these methods can give as many, or more, false positives as correctly-identified faults. In some cases these methods have been found to yield two or more times as many false positives as the actual number of defective pixels.
False positives can be as detrimental to image quality as defective pixels. If the outputs of pixels falsely identified as faulty are replaced by interpolating the output from neighbouring pixels, as understood by practitioners of the art, the image quality can be reduced. This is particularly true if the pixel lies in an area where the image changes rapidly, such as at the edge of an object.
There remains a need for robust methods and apparatus for detecting defective pixels in imaging arrays. There is a particular need for such methods and apparatus that can be performed on-line (i.e. while a device is operating) to detect faults that occur after fabrication.

Methods and apparatus for detecting defects in imaging arrays by image analysis


The present invention provides a glycoprotein derived from human cell membrane, which has a molecular weight of 20 to 25 Kd as estimated by SDS polyacrylamide gel electrophoresis, and contains N-glycoside type carbohydrate chain and phosphatidylinositol, and possesses an inhibitory activity to complement-mediated cell membrane damage. The present invention further provides a gene coding for the glycoprotein, and a method for the production of the glycoprotein and the gene therefor.

1. Field of the Invention
The present invention relates to a novel glycoprotein possessing activity of inhibiting complement-mediated cell membrane damage, and to a gene coding for the glycoprotein.
2. Description of the Prior Art
Complement is a reaction system which includes a group of proteases being present in blood and body fluids. In response to invasion of exogeneous (non-self) substances into the body, activation of the complement system will take place and part of complement components that have been deposited on the exogeneous substances will then actively eliminate them by, for example, facilitating phagocytosis by phagocyte as well as inducing immune cytolysis. Furthermore, various peptide fragments which have been produced in the pathways of the complement activation may act upon a variety of cells. That is, they will activate lymphocytes and promote migration of neutrophils and degranulation of mast cells, thereby taking part in diverse immune and inflammatory reactions.
Although, complement may promptly react with foreign substances, its activation does not proceed on autologous normal cells. In inflammatory parts of such diseases as rheumatoid arthritis, systemic lupus erythematosus and glomerulo nephritis, however, it is generally thought that complement recognizes a self tissue as a foreign one and reacts with cell membranes of the self tissue. Consequently, complement may induce inflammatory reaction, and at the same time it may facilitate phagocytosis by phagocytes or cause cytolysis, thereby leading to cytotoxicity and aggravation of the inflammatory condition.
In recent years, it has been shown that proteins which are capable of inhibiting self-complement activation are present on cell membrane (Mol. Immunol., 20, 1233-1236 (1983)), several of which have been identified as a protein having with this function. For example, Decay Accelerating Factor (DAF) with a molecular weight of 68 Kd (J. Exp. Med., 160, 1558-1578 (1984)) and Homologous Restriction Factor (HRF) with a molecular weight of 65 Kd (PNAS, 83, 6975-6979 (1986)) have been obtained as complement inhibiting factors present on the human cell membrane. Precise function of DAF and HRF in vivo, nevertheless, has been not yet clarified in detail.
The present inventors have studied to find a membrane protein capable of inhibiting the complement activation on the self-cell membrane, besides the above factors.
Previously, the present inventors prepared a number of antibody-producing hybridomas by hybridizing spleen cells from mice immunized with human erythrocytes with mouse myeloma cells (P3U1) in the presence of polyethyleneglycol. These hybridomas were repeatedly screened to select those producing an antibody (in a supernatant of culture medium) which causes hemolysis of neuraminidase-pretreated human erythrocytes in the presence of human complement, succeeding in cloning a hybridoma producing such monoclonal antibody, which was designated as 1F5 (Proc. Gen. Conf. Jpn. Soc. Immunol., 17, 498 (1987), and Abstracts, Symposium on Complement, 24, 180 (1987)).


In a computer system having a user interface, a memory, a repository and a database, a repository program operating in the computer system for accessing the database, the repository program executing a method for supporting modeling, the method comprising the steps of examining a collection of types forming a model; sorting object types into data and persistent type objects; creating all data type objects and adding to a collection of all objects owned by the model; creating all persistent type objects and adding to a collection of all objects owned by the model; initializing all persistent type objects in the collection of objects.

The storage and manipulation of data records or objects within a database application is well known in the prior art. A database allows one to store information in it; and it does not necessarily have any special meaning associated with the things that are stored in the database. A repository not only uses the database as a data store, but it is a layer above a database. A repository has information about the things stored in the database. Stated otherwise, a repository is like a card catalog that is found in the library, with the library being analogous to a database.
With the advent of repositories, improvements in the accessibility of data within databases has improved. However, as these repositories have become larger and more complex a method is required to support object modeling in a repository.

Method for supporting object modeling in a repository


A transmitting apparatus for transmitting digital data includes storage unit for storing a digital data delay due to digital processing inside the transmitting apparatus; and delay information transmitting unit for transmitting delay information indicating the delay stored in the storage unit.

1. Field of the Invention
The present invention relates to a transmitting apparatus, a receiving apparatus, and a transmitting/receiving system for digital data, such as a digital audio signal.
2. Description of the Related Art
Recently, a large number of digital appliances, such as digital wireless microphones, digital audio mixers, and digital camcorders are used to produce audio-visual productions. In such digital appliances, digital processing is carried out to record and edit audio and images.
In addition to real-time processing in the same way as analog processing carried out inside an existing analog appliance, such digital processing includes processing that incurs a delay, such as digital filtering and digital compression.
For example, when, during ENG (Electronic News Gathering) or studio recording, a plurality of audio signals(in the case of music, vocal, guitar, and bass tracks for example) are inputted into a digital audio mixer or a digital camcorder using individual digital wireless microphones, the delay before input into the digital audio mixer or digital camcorder will differ between the audio signals, due to differences in the internal circuit specifications and/or firmware of the digital wireless microphones that transfer the audio signals.
Accordingly, before the different audio signals (or alternatively the different audio signals and images picked up by a digital camcorder) are merged into a single production, it may be necessary to adjust the delays of the different audio signals inputted into the digital audio mixer or digital camcorder.
However, since the delay times of individual digital wireless microphones are not known in an existing system, the recording engineer or editor has had to measure the delays of the different audio signals and appropriately adjust the respective delays of the audio signals. This means that adjusting the delays takes a lot of time and effort.
Japanese Unexamined Patent Application Publication No. 2004-312281 discloses a technology for transmitting digital image data that is appended with attribute information (such as image pickup time/date and scene number) and information on image pickup conditions (such as the camera in use and shutter speed) as metadata and displaying the received metadata superimposed on images. However, a technology that can transmit and receive information that is useful in adjusting the delays of digital data is yet to be disclosed.

Transmitting apparatus, receiving apparatus and transmitting/receiving system for digital data


A smart phone or tablet includes laser diodes configured to be pulsed and generate near-infrared light between 700-2500 nanometers. Lenses direct the light to a sample. A detection system includes a photodiode array with pixels coupled to CMOS transistors, and is configured to receive light reflected from the sample, to be synchronized to the light from the laser diodes, and to perform a time-of-flight measurement of a time difference between light from the laser diodes and light reflected from the sample. The detection system is configured to convert light received while the laser diodes are off into a first signal, and light received while at least one laser diodes is on, which includes light reflected from the sample, into a second signal. The smart phone or tablet is configured to difference the first signal and the second signal and to generate a two-dimensional or three-dimensional image using the time-of-flight measurement.

Remote sensing or hyper-spectral imaging often uses the sun for illumination, and the short-wave infrared (SWIR) windows of about 1.5-1.8 microns and about 2-2.5 microns may be attractive because the atmosphere transmits in these wavelength ranges. Although the sun can be a bright and stable light source, its illumination may be affected by the time-of-day variations in the sun angle as well as weather conditions. For example, the sun may be advantageously used for applications such as hyper-spectral imaging only between about 9 am to 3 pm, and it may be difficult to use the sun during cloudy days or during inclement weather. In one embodiment, the hyper-spectral sensors measure the reflected solar signal at hundreds (e.g., 100 to 200+) contiguous and narrow wavelength bands (e.g., bandwidth between 5 nm and 10 nm). Hyper-spectral images may provide spectral information to identify and distinguish between spectrally similar materials, providing the ability to make proper distinctions among materials with only subtle signature differences. In the SWIR wavelength range, numerous gases, liquids and solids have unique chemical signatures, particularly materials comprising hydro-carbon bonds, O—H bonds, N—H bonds, etc. Therefore, spectroscopy in the SWIR may be attractive for stand-off or remote sensing of materials based on their chemical signature, which may complement other imaging information.
A SWIR super-continuum (SC) source may be able to replace at least in part the sun as an illumination source for active remote sensing, spectroscopy, or hyper-spectral imaging. In one embodiment, reflected light spectroscopy may be implemented using the SWIR light source, where the spectral reflectance can be the ratio of reflected energy to incident energy as a function of wavelength. Reflectance varies with wavelength for most materials because energy at certain wavelengths may be scattered or absorbed to different degrees. Using a SWIR light source may permit 24/7 detection of solids, liquids, or gases based on their chemical signatures. As an example, natural gas leak detection and exploration may require the detection of methane and ethane, whose primary constituents include hydro-carbons. In the SWIR, for instance, methane and ethane exhibit various overtone and combination bands for vibrational and rotational resonances of hydro-carbons. In one embodiment, diffuse reflection spectroscopy or absorption spectroscopy may be used to detect the presence of natural gas. The detection system may include a gas filter correlation radiometer, in a particular embodiment. Also, one embodiment of the SWIR light source may be an all-fiber integrated SWIR SC source, which leverages the mature technologies from the telecommunications and fiber optics industry. Beyond natural gas, active remote sensing in the SWIR may also be used to identify other materials such as vegetation, greenhouse gases or environmental pollutants, soils and rocks, plastics, illicit drugs, counterfeit drugs, firearms and explosives, paints, and various building materials.
In one or more embodiments, a smart phone or tablet comprises an array of laser diodes configured to generate light having one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers, and wherein at least a portion of the array of laser diodes is configured to be pulsed. One or more lenses is configured to receive a portion of the light from the array of laser diodes and to direct the portion of the light from the array of laser diodes to a sample. A detection system comprises a photodiode array with a plurality of pixels coupled to CMOS transistors, wherein the detection system is configured to receive at least a portion of light reflected from the sample, and wherein the detection system is configured to be synchronized to the light from the at least a portion of the array of laser diodes. The detection system is configured to perform a time-of-flight measurement by measuring a time difference between the generated light from the at least a portion of the array of laser diodes and the at least a portion of light reflected from the sample. The detection system is further configured to: receive light while the array of laser diodes is off and convert the received light into a first signal; and receive light while at least a part of the array of laser diodes is on and convert the received light into a second signal, the received light including at least some of the at least a portion of the light reflected from the sample. The smart phone or tablet is configured to difference the first signal and the second signal and to generate a two-dimensional or three-dimensional image using at least a portion of the time-of-flight measurement, wherein the smart phone or tablet further comprises a wireless receiver, a wireless transmitter, a display, a voice input module, and a speaker.
In one or more embodiments, a smart phone or tablet comprises an array of laser diodes configured to generate light having one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers, and wherein at least a portion of the array of laser diodes is configured to be pulsed. One or more lenses configured to receive a portion of the light from the array of laser diodes is configured to direct the portion of the light from the array of laser diodes to a sample. A detection system comprises a photodiode array with a plurality of pixels coupled to CMOS transistors, wherein the detection system is configured to receive at least a portion of light reflected from the sample, and wherein the detection system is configured to be synchronized to the at least a portion of the array of laser diodes. The detection system is further configured to perform a time-of-flight measurement by measuring a time difference between the generated light from the at least a portion of the array of laser diodes and the at least a portion of light reflected from the sample. The smart phone or tablet is configured to generate a two-dimensional or three-dimensional image using at least a portion of the time-of-flight measurement. The smart phone or tablet further comprises a wireless receiver, a wireless transmitter, a display, a voice input module, and a speaker.
Embodiments include a smart phone or tablet comprising an array of laser diodes configured to generate light having one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers, and wherein at least a portion of the array of laser diodes is configured to be pulsed at a modulation frequency. One or more lenses configured to receive a portion of the light from the array of laser diodes is configured to direct the portion of the light from the array of laser diodes to a sample. A detection system comprises a photodiode array with a plurality of pixels coupled to CMOS transistors, wherein the detection system is configured to receive at least a portion of light reflected from the sample, is configured to be synchronized to the at least a portion of the array of laser diodes, and is configured to use a lock-in technique that detects the modulation frequency. The detection system is further configured to perform a time-of-flight measurement by measuring a time difference between the generated light from the at least a portion of the array of laser diodes and the at least a portion of light reflected from the sample. The smart phone or tablet is configured to generate a two-dimensional or three-dimensional image using at least a portion of the time-of-flight measurement, wherein the smart phone or tablet further comprises a wireless receiver, a wireless transmitter, a display, a voice input module, and a speaker.
In one or more embodiments, a measurement system includes a light source configured to generate an output optical beam, comprising a plurality of semiconductor sources configured to generate an input optical beam, a multiplexer configured to receive at least a portion of the input optical beam and to form an intermediate optical beam, and one or more fibers configured to receive at least a portion of the intermediate optical beam and to form the output optical beam. At least a portion of the one or more fibers comprises a fused silica fiber. The output optical beam comprises one or more optical wavelengths, at least a portion of which are between 700 nanometers and 2500 nanometers and has a bandwidth of at least 10 nanometers. The system also includes a measurement apparatus configured to receive a received portion of the output optical beam and to deliver a delivered portion of the output optical beam to a sample, wherein the delivered portion of the output optical beam is configured to generate a spectroscopy output beam from the sample. A receiver is configured to receive at least a portion of the spectroscopy output beam having a bandwidth of at least 10 nanometers and to process the at least a portion of the spectroscopy output beam to generate an output signal, wherein the receiver processing includes at least in part using chemometrics or multivariate analysis methods to permit identification of materials within the sample. The light source and the receiver are remote from the sample, and the sample comprises plastics or food industry goods.
In various embodiments, a measurement system includes a light source configured to generate an output optical beam, the light source comprising a plurality of semiconductor sources configured to generate an input optical beam, a multiplexer configured to receive at least a portion of the input optical beam and to form an intermediate optical beam, and one or more fibers configured to receive at least a portion of the intermediate optical beam and to form the output optical beam. At least a portion of the one or more fibers comprises a fused silica fiber. The output optical beam comprises one or more optical wavelengths, at least a portion of which are between 700 nanometers and 2500 nanometers, and has a bandwidth of at least 10 nanometers. The system also includes a measurement apparatus configured to receive a received portion of the output optical beam and to deliver a delivered portion of the output optical beam to a sample, wherein the delivered portion of the output optical beam is configured to generate a spectroscopy output beam from the sample; and a receiver configured to receive at least a portion of the spectroscopy output beam having a bandwidth of at least 10 nanometers and to process the at least a portion of the spectroscopy output beam to generate an output signal, wherein the receiver processing includes at least in part using chemometrics or multivariate analysis methods to permit identification of materials within the sample. The output signal is based at least in part on a chemical composition of the sample. The spectroscopy output beam comprises at least in part spectral features of hydrocarbons or organic compounds.
In at least one embodiment, a measurement system includes a light source configured to generate an output optical beam, comprising a plurality of semiconductor sources configured to generate an input optical beam, a multiplexer configured to receive at least a portion of the input optical beam and to form an intermediate optical beam, and one or more fibers configured to receive at least a portion of the intermediate optical beam and to form the output optical beam. At least a portion of the one or more fibers comprises a fused silica fiber. The output optical beam comprises one or more optical wavelengths, at least a portion of which are between 700 nanometers and 2500 nanometers, and has a bandwidth of at least 10 nanometers. The system includes a measurement apparatus configured to receive a received portion of the output optical beam and to deliver a delivered portion of the output optical beam to a sample, wherein the delivered portion of the output optical beam is configured to generate a spectroscopy output beam from the sample, and a receiver configured to receive at least a portion of the spectroscopy output beam having a bandwidth of at least 10 nanometers and to process the at least a portion of the spectroscopy output beam to generate an output signal. The receiver processing includes at least in part using chemometrics or multivariate analysis methods to permit identification of materials within the sample. The output signal is based on a chemical composition of the sample, which comprises tissue including collagen and lipids.
In one embodiment a remote sensing system is provided with an array of laser diodes, one or more scanners, and a detection system. The array of laser diodes is adapted to generate light having an initial light intensity and one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers, and wherein at least a portion of the array of laser diodes comprises one or more Bragg reflectors. The one or more scanners comprises moving mirrors that configured to receive a portion of the light from the array of laser diodes and to direct the portion of the light from the array of laser diodes to an object. The moving mirrors are configured to scan the received portion of the light across at least a part of the object. The detection system comprises a photodiode array with a plurality of pixels coupled to CMOS transistors, wherein at least a portion of the photodiode array comprises an indium gallium arsenide semiconductor. The detection system is configured to receive at least a portion of light reflected from the object, wherein the detection system is configured to be synchronized to the at least a portion of the array of laser diodes comprising Bragg reflectors. The detection system is further configured to perform a time-of-flight measurement, and wherein the detection system further comprises one or more filters to select at least some of the one or more optical wavelengths. The remote sensing system is configured to generate a two-dimensional or three-dimensional mapping using at least a portion of the time-of-flight measurement. The remote sensing system is configured to improve signal-to-noise ratio of at least a portion of the two-dimensional or three-dimensional mapping by increasing light intensity of the array of laser diodes relative to the initial light intensity. The at least a portion of the one or more optical wavelengths falls within an eye safe window corresponding to an optical wavelength longer than 1400 nanometers. The remote sensing system is adapted to be mounted on a vehicle, wherein the at least a portion of the two-dimensional or three-dimensional mapping is combined with global positioning system information, and wherein the remote sensing system is configured to communicate with a cloud.
In another embodiment, a remote sensing system is provided with one or more laser diodes, one or more scanners, and a detection system. The one or more laser diodes are configured to generate light having an initial light intensity and one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The one or more scanners are configured to receive a portion of the light from the one or more laser diodes and to direct the portion of the light from the one or more laser diodes to an object, wherein the one or more scanners are configured to scan the received portion of the light across at least a part of the object. The detection system comprises a photodiode array comprising semiconductor material. The detection system is configured to receive at least a portion of light reflected from the object, wherein the detection system is configured to be synchronized to at least a portion of the one or more laser diodes. The detection system is further configured to perform a time-of-flight measurement, and wherein the detection system further comprises one or more filters to select at least some of the one or more optical wavelengths. The remote sensing system is configured to generate a two-dimensional or three-dimensional mapping using at least a portion of the time-of-flight measurement. The remote sensing system is configured to improve signal-to-noise ratio of at least a portion of the two-dimensional or three-dimensional mapping by increasing light intensity of the one or more laser diodes relative to the initial light intensity. The remote sensing system is configured to use artificial intelligence to process the at least a portion of the time-of-flight measurement, wherein the artificial intelligence comprises pattern identification or classification. The remote sensing system is configured to apply regression signal processing methodologies to the at least a portion of the time-of-flight measurement.
In yet another embodiment a remote sensing system is provided with one or more laser diodes, one or more scanners, and a detection system. The one or more laser diodes are configured to generate light having an initial light intensity and one or more optical wavelengths, wherein at least a portion of the one or more optical wavelengths is a near-infrared wavelength between 700 nanometers and 2500 nanometers. The one or more scanners are configured to receive a portion of the light from the one or more laser diodes and to direct the portion of the light from the one or more laser diodes to an object, wherein the one or more scanners are configured to scan the received portion of the light across at least a part of the object. The detection system comprises a photodiode array comprising semiconductor material, wherein at least a portion of the photodiode array is coupled to an amplifier having a gain configured to improve detection sensitivity. The detection system is configured to receive at least a portion of light reflected from the object, wherein the detection system is configured to be synchronized to at least a portion of the one or more laser diodes. The detection system is further configured to perform a time-of-flight measurement, and wherein the detection system further comprises one or more filters to select at least some of the one or more optical wavelengths. The remote sensing system is configured to generate a two-dimensional or three-dimensional mapping using at least a portion of the time-of-flight measurement. The remote sensing system is configured to improve signal-to-noise ratio of at least a portion of the two-dimensional or three-dimensional mapping by increasing light intensity of the one or more laser diodes relative to the initial light intensity. The remote sensing system is configured to use artificial intelligence to process the at least a portion of the time-of-flight measurement. The remote sensing system is at least in part configured to identify the object, and a property of the at least a portion of the time-of-flight measurement is compared by the remote sensing system to a threshold.

This patent is subject to a terminal disclaimer.

Near-infrared time-of-flight cameras and imaging


A system, a method, and a non-transitory computer readable for generating a profile of one or more data objects comprising determining a format of the at least one data object and selecting a data transformation policy based on the format of the at least one data object and generating a model descriptive of the non-structured data contained in the at least one data object based on the data transformation policy and selecting at least a portion of the model indicative of a portion of the non-structured data and generating a profile of the portion of the non-structured data contained in all of the one or more data objects.

Data profiling is an important tool in, for example, systems which may require a user to inspect or interact with extremely large data sets that must be analyzed computationally to reveal, among other things, patterns, trends and associations. It is often the case that these extremely large data sets are contained in a number of computer readable files that may be collocated, or may be located in numerous locations.
One way to simplify human interaction with such extremely large data sets is to generate a profile of the data contained within all the objects of a data set. In some cases, the data to be profiled may be contained in an extremely large number of small files containing small amounts of data represented as one or more data objects, or the data may be contained in a smaller number of extremely large files containing an extremely large number of data objects. The individual computer readable files themselves may be in any format, such as text files, stored in a file system within a computer operating system, or they may be stored in a distributed file system (DFS) such as the Apache Hadoop Distributed File System (HDFS) or the Google File System (GSF).
Extremely large data sets such as these are often referred to under the generalized term, "big data." Big data describes data sets that are so large or complex that traditional data processing applications are inadequate for handling, accessing and manipulating the data. Big data sets suffer from challenges relating to the analysis, capture, curation, searching, sharing, storage, transfer, visualization, querying, and updating of the data contained therein. Compounding these issues is that big data sets are typically growing rapidly, often because they are generated and gathered by cheap and numerous information collection devices, for example mobile devices, aerial remote sensing devices, software logs, cameras, microphones, radio frequency identification (RFID) readers, wireless sensors, and consumer devices that contain or more of the above. Other sources of "big data" are social media exchanges and web-based transaction facilities. The emerging concept of Internet of Things (IOT) will only add to the number of devices that collect data and the distributed nature of data storage. To derive meaning from such a "big data" system one typically needs considerable processing power, as well as appropriate analytical tools.
Beyond the size of modern big data sets, challenges are compounded by the fact that very little real world data is conveniently available as structured data represented in a canonical relational format or model. First, while a computer can more readily handle structured data in an efficient manner; humans typically deal with non-structured data, for example text strings, web pages, email, or ad-hoc spreadsheets, because humans rarely interact with information in a strict relational model in day-to-day life. Second, much of the data created today is stored in disparate files or locations by various systems designed to operate in an efficient manner when executing a particular task, without concern for conforming to canonical or accepted standard data formats (which may require additional programming or cause inefficiencies in the relevant system, for example in SCADA systems). Also, data describing similar things may be sensed by two separate systems which then store that data in two entirely different formats in two entirely different file systems.
Generally, data may fall into the categories of structured data, semi-structured data, and unstructured data. Structured data is data with a high level of organization, and such information can be seamlessly included in a relational database or other forms of tables. The canonical structured data is data stored in one or more relational tables, which are defined according to a well-defined schema. Structured data is also readily searchable by simple search engine algorithms or other search operations. Semi-structured data, and unstructured data, on the other hand is not easily collected or searched.
Known systems for profiling large data sets require first that semi-structured and unstructured data first be collected and stored in a relational database before it can then be analyzed or profiled. There are a number of known methods for mapping semi-structured data stored in a particular configuration into relational databases. Typically these fall into one of two categories: using a fixed mapping method to store semi-structured data in relational databases, or requiring a user to supply a mapping schema. Therefore, the lack of structure in such data makes compilation of the data into a time and energy-consuming tasks of storing all the data in a persistent table format which can then be subjected to analysis, or the generation of a mapping schema or a combination of these two tasks.
First, a schema must be created and supplied to a computer system, which relies on the schema to map the unstructured data to a structured format, and secondly all of the data must first be converted to a structured format irrespective of what data a user desires to profile. Also, these mapping schemas do not adapt to changes in the data, which may occur over time as the software and hardware generating the data changes or is upgraded; or if there is simply an error in the data giving rise to outlier data elements. Each of these hurdles becomes increasingly time-consuming as the data sets to be analyzed get larger and larger. While what is considered "big data" differs from user to user based on the computational abilities available or a user's needs, it will be appreciated that relational database management systems and available data statistics and visualization packages are insufficient for handling modern big data sets which may have extremely large numbers of data objects.

Method, apparatus, and computer-readable medium for non-structured data profiling


A mechanism is disclosed which produces linear motion from a rotating input while preventing the transmission of back forces in either direction. The mechanism includes a housing with an output shaft mounted for rotation within the housing. A rotatable input drive means is mounted coaxial with the shaft. The drive means includes a radially extending impelling portion. The output shaft extends axially on both sides of the impelling portion. A tubular hub is fixedly mounted on the housing and extends around the output shaft on each side of the impelling portion of the drive means. A pair of coil springs are wrapped around the output shaft with one spring on each side of the impelling portion of the drive means. Each spring has a release toe at one end which extends axially to the impelling portion and which is capable of being engaged by the impelling portion upon rotation of the drive means. The other end of each spring engages the shaft, so that the spring rotates with the shaft. A portion of each spring has a relaxed outer diameter larger than the inner diameter of the hub, so that the springs engage the hub when relaxed. Means are provided for producing linear motion from the rotation of the output shaft.

1. Field of the Invention
This invention relates to mechanisms for producing linear motion from a rotatable input drive means, and particularly those mechanisms which include means for preventing forces on the driven element from being transmitted back to the input drive means.
2. Description of the Prior Art
Known mechanisms are available for operating a linearly driven element, such as a control element from a rotatable input drive means. For example, such control elements may include a flap used in the flight control of airplanes. External forces on the control element may tend to move the control device undesirably. If the control element is permitted to be moved by these external forces, a loss in control may result. In addition, these external forces may backdrive the input drive means, and such back forces may be detrimental to the input drive means.
Mechanisms are available for locking out backdriven forces and preventing these forces from being transmitted to the input drive means while being capable of deactuation upon activation of the input drive means to allow the input drive means to operate the control element. Known locking means of this type have often been characterized by significant friction losses which significantly adversely affect the efficiency of such mechanisms.

Linear motion mechanism with means for preventing back forces


The present invention provides methods for detecting disease by analysis of a patient sample to determine the integrity of nucleic acids in the sample.

Many diseases are associated with genomic instability. That is, a disruption in genomic stability, such as a mutation, has been linked to the onset or progression of certain diseases. Accordingly, various aspects of genomic instability have been proposed as reliable markers for disease. For example, mutations in the BRCA genes have been proposed as markers for breast cancer, and mutations in the p53 cell cycle regulator gene have been associated with numerous cancers, especially colorectal cancer. It has been suggested that specific mutations might be a basis for molecular screening assays for the early stages of certain types of cancer. See, e.g., Sidransky, et al., Science, 256: 102-105 (1992).
The search for genomic disease markers has been especially intense in the area of cancer detection. Cancer is characterized by uncontrolled cell growth which can be associated with one or more genetic mutations. Such mutations can cause the affected cells to avoid cell death. For example, a mutation in a tumor suppressor gene can cause cells to avoid apoptosisxe2x80x94a type of cell death thought to be under direct genetic control. During apoptosis, cells lose their membranes, the cytoplasm condenses, and nuclear chromatin is split into oligonucleotide fragments of characteristically short length. In fact, those characteristic DNA cleavage patterns have been proposed as an assay for apoptosis.
Attempts have been made to identify and use nucleic acid markers that are indicative of cancer. However, even when such markers are found, using them to screen patient samples, especially heterogeneous samples, has proven unsuccessful either due to an inability to obtain sufficient sample material, or due to the low sensitivity that results from measuring only a single marker. Simply obtaining an adequate amount of human DNA from one type of heterogeneous sample, stool, has proven difficult. See Villa, et al., Gastroenterol., 110: 1346-1353 (1996) (reporting that only 44.7% of all stool specimens, and only 32.6% of stools from healthy individuals produced sufficient DNA for mutation analysis). Other reports in which adequate DNA has been obtained have reported low sensitivity in identifying a patient""s disease status based upon a single cancer-associated mutation. See Eguchi, et al., Cancer, 77: 1707-1710 (1996) (using a p53 mutation as a marker for cancer).
Investigators have attempted to analyze mutations in DNA of tumor cells shed into luminal areas, such as the colon, bile ducts, blood vessels and the like. Such attempts have only been successful when there is a known mutation and a relatively high concentration of cellular material has been found. See e.g., Mulcahy, et al., Ann. Oncol. 10 Suppl 4:114-117 (1999). No attempts have been made to correlate disease status with DNA integrity in shed cellular material.
The present invention provides that the integrity of nucleic acids in biological samples comprising shed cellular material is an indicator of the disease status of the patient from whom the sample was obtained. According to the invention, certain tissue or body fluid samples, especially those described below, contain debris from cells that have been shed from surrounding organs or tissue. In healthy patients, such debris is the result of apoptosis as part of the normal cell cycle. Apoptosis reduces nucleic acid integrity, so that only small-fragment nucleic acids exist in exfoliated cellular debris in healthy individuals. To the contrary, in diseases such as cancer in which cell cycle mechanisms are destroyed or impaired, cellular debris comprises high-integrity nucleic acids (i.e., nucleic acids that have not been degraded by apoptosis ). Thus, methods of the invention comprise using nucleic acid integrity as a measure of patient disease status. Integrity can be measured by any convenient means. Preferred means include the amount of nucleic acid in a sample, the length of nucleic acids in a sample, or the molecular weight of nucleic acids in a sample.
The invention provides methods for detecting disease in a patient based upon the integrity of patient nucleic acids present in a specimen or sample obtained from the patient. According to methods of the invention, a tissue or body fluid specimen containing sloughed cellular debris obtained from a patient having a disease contains an amount of intact nucleic acid that is greater than would be expected in such a specimen obtained from a healthy patient. Thus, a measure of intact nucleic acid in a patient sample is indicative of the overall disease status of the patient. As used herein, xe2x80x9cintactxe2x80x9d refers to nucleic acids that are longer than those expected to be present as a result of apoptosis. The invention is equally applicable to human and to veterinary uses. Accordingly, xe2x80x9cpatientxe2x80x9d as defined herein means humans or other animals.
A healthy patient generally produces cellular debris through normal apoptotic degradation, resulting in relatively short nucleic acid fragments in samples derived from luminal tissue and fluids. Patients having a disease generally produce cells and cellular debris, a proportion of which has avoided normal cell cycle regulation, resulting in relatively long, intact nucleic acid fragments. Without being held to theory, the present invention takes advantage of this and other insights concerning the ways in which cells respond to diseases, especially diseases associated with genetic abnormalities (either induced or inherited). As a result, it has been discovered that the disease status of a patient is determined by analysis of patient nucleic acids produced in specimens obtained from the patient. Most preferably, such specimens are those most likely to contain sloughed cellular debris. Such specimens include, but are not limited to, stool, blood serum or plasma, sputum, pus, colostrum, and others. In diseases, such as cancer, in which genomic instabilities or abnormalities have interfered with normal cell cycle regulation, specimens such as those identified above contain relatively intact nucleic acid fragments. The presence of such fragments is a general diagnostic screen for disease.
Accordingly, methods of the invention comprise screening a patient for disease by analysis of the integrity of nucleic acids in a tissue or body fluid specimen obtained from the patient. Preferred specimens include those comprising shed cells or cellular debris. Thus, highly-preferred specimens are those not containing an abundance of intact (non-exfoliated) cells. Such preferred specimens comprise stool, sputum, urine, bile, pancreatic juice, and blood serum or plasma, all of which contain shed cells or cellular debris. Methods of the invention are especially useful as screens for cancer. Cancer is a disease thought to be associated with genomic instabilities, and specifically with the loss of control over the normal cell cycle. Thus, tumor cells are typically intact and routinely are shed into, for example, stool, sputum, urine, bile, pancreatic juice, and blood. Such shed cells and cellular debris contain higher integrity nucleic acids compared to those found in specimens obtained from a healthy patient. There are numerous ways in which the integrity of nucleic acids in a patient specimen are measured as a screen for disease.
In a preferred embodiment, nucleic acid integrity is measured by the ability to amplify nucleic acids in a sample. Thus, a preferred method comprises conducting in a tissue or body fluid sample an amplification reaction using as a template a nucleic acid locus suspected to be in the sample. If the amount of amplification product (amplicon) is greater than the amount of amplicon expected to be present in a normal sample (e.g., one not having the disease being screened), the sample is determined to be positive. In some cases, the presence of any amplification product is sufficient to justify a positive screen for disease. It is preferable that, in the case of DNA, the amplification reaction is a polymerase chain reaction (PCR) or, in the case of RNA, that the amplification reaction is reverse transcriptase PCR. Primers are designed to amplify the locus or loci chosen for analysis. For purposes of the invention a xe2x80x9cgenomic locusxe2x80x9d is any genetic element, including but not limited to a coding region of a gene, a non-coding nucleic acid region, a regulatory element of a gene, an intron or RNA. It is not required that the target genomic loci be associated with any specific disease, as an increase in amplifiable nucleic acid is itself diagnostic.
In one preferred embodiment, the presence of a single high molecular weight amplicon is a positive screen. Preferably, a fragment of about 1.3 Kb or greater is measured as an indicator of high integrity nucleic acids in the patient sample.
In a highly-preferred embodiment, a profile of amplification products across a range of nucleic acid fragments of different lengths is produced. In a preferred embodiment, a series of amplification reactions is conducted at a single genomic locus, each reaction being designed to amplify a fragment of unique length. If detectable amplicon is produced in each reaction, or in a number of reactions greater than expected in a sample obtained from a healthy patient, the sample is determined to be positive. For example, attempts are made to amplify fragments of 200 bp, 400 bp, 800 bp, 1.3 Kb, 1.8 Kb, and 2.4 Kb at the same genomic locus. In a sample obtained from a healthy individual (a xe2x80x9cnormalxe2x80x9d sample), it would be expected that little or no amplification product is observed, especially when the longer portions of the locus are used as the template. To the contrary, at least some proportion of cells and cellular debris in a sample obtained from a diseased patient will contain intact fragments.
In another embodiment, a profile of amplification products across a range of nucleic acid fragments of different lengths is produced by a series of amplification reactions conducted on a series of different genomic loci, each reaction being designed to amplify a fragment of unique length. If detectable amplicon is produced in each reaction, or in a number of reactions greater than expected in a sample obtained from a patient not having the disease being screened, the sample is determined to be positive.
According to methods of the invention, normal samples do not produce significant amounts of detectable amplicon at any length significantly greater than the typical apoptotic fragment (about 175 bp). Accordingly, whether primers are spaced to amplify fragments of only one length at a given genomic locus, or whether a series of amplifications at the locus are conducted, differences are readily observable between normal and diseased samples.
As detailed below, methods of the invention are useful to detect disease, preferably cancer or precancer, in biological samples comprising shed cells or cellular debris. For example, the presence in a patient stool sample of amounts of nucleic acid, preferably DNA, above a predetermined threshold for healthy patients is indicative that the patient has cancer. Follow-up analysis is used to determine where the disease resides. However, the general disease screen is effective independent of the locus of the disease and the specimen taken for analysis. Thus, while the analysis of nucleic acids in stool is predictive of disease generally, it does not necessarily indicate that the disease is of gastrointestinal origin. However, follow-up screening based, for example, on mutational analysis, is adequate to identify the locus of disease. Numerous mutational analyses are known in the art and include, for example, U.S. Pat. No. 5,670,325, incorporated by reference herein.
In an alternative embodiment, screening of patient samples by detecting amounts of nucleic acid in the sample is combined with an assay for apoptotic cell activity. Such assays may be combined with detecting amounts of nucleic acid in a patient sample as a screen for disease status. A positive screen is one that produces both: (1) an amount of nucleic acid that is greater than the amount expected to be present in a normal sample (e.g., one not having the disease being screened), and (2) an amount of apoptotic cell activity that is less than that expected to be present in a normal sample. In a highly preferred embodiment, methods of the invention comprise analyzing a plurality of genomic loci to determine an amount of amplifiable nucleic acid present at each locus. Analysis across multiple loci using methods of the invention may increase the sensitivity of the screening assay.
As will be exemplified in detail below, methods of the invention comprise screening a biological sample for an abnormality in a nucleic acid by conducting an amplification reaction using as a template a nucleic acid suspected or expected to be in the sample; determining an amount of amplification product obtained; comparing the amount of amplicon obtained to a standard amount of amplification product; and identifying a sample as having an abnormality in a nucleic acid if the amount of amplification product differs from the standard amount. In a preferred embodiment, a standard amount of amplification product is determined by amplification of a locus, or portion thereof, being screened (e.g., an intact, wild-type nucleic acid) in a known normal sample (one obtained from an individual known not to have the disease being screened). Also in preferred embodiments, a standard amount is determined by reference to the art. In certain embodiments of the invention, the standard amount is essentially no detectable amplicon due to the lack of high-integrity nucleic acids in the sample. Accordingly, any detectable amplicon in a patient sample is indicative of a positive screen. That is the case especially when a large (e.g., 1.8 Kb or 2.4 Kb) fragment is being screened. Finally, the standard amount can be a molecular weight marker on, for example, an electrophoretic gel.
In a preferred embodiment of the invention, the sample is prepared from a specimen selected from the group consisting of stool, sputum, blood, urine, cerebrospinal fluid, seminal fluid, saliva, breast nipple aspirate, and biopsy tissue. However, any tissue or body fluid specimen may be used according to methods of the invention. Especially preferred are samples of luminal fluid because such samples are generally free of intact, healthy cells. Such samples include blood, urine, bile, pancreatic juice, stool, sputum, pus, and the like.
Also in a preferred embodiment, the nucleic acid or nucleic acids being interrogated is (are) DNA. In a more particular embodiment, the nucleic acid being analyzed is selected from a coding region of a gene, or portion thereof, a noncoding nucleic acid region, or portion thereof, a regulatory element of a gene or a portion thereof, and an unidentified fragment of genomic DNA. Also in a preferred embodiment, the nucleic acid being interrogated is RNA. As is appreciated by the skilled artisan, any genomic locus is amenable to screening according to the invention. The particular locus or loci chosen for analysis depends, in part, on the disease being screened, and the convenience of the investigator. It is not necessary that the locus or loci chosen for analysis be correlated with any specific disease because methods of the invention contemplate measuring either the total nucleic acid in a sample or amplifiable nucleic acid in a sample as an indicator of overall disease status or the presence and/or extent of apoptosis in the sample. However, disease-associated loci (those in which a mutation is indicative, causative, or otherwise evidence of a disease) can be used. Preferred disease-associated loci include p53, apc, MSH-2, dcc, scr, c-myc, B-catnenin, mlh-1, pms-1, pms-2, pol-delta, and bax.
The amount of amplification product may be determined by any suitable or convenient means. Preferably, the amount of amplification product is determined by gel electrophoresis. Labels, such as fluorescent or radioactive labels, may be used.
The amounts of amplification product produced may be compared to standard amounts by any suitable or convenient means, including, but not limited to visual comparison, machine-driven optical comparison, densitometry, mass spectroscopy, hybrid capture, and other known means. The amplification reaction itself can be any means for amplifying nucleic acid, including, but not limited to PCR, RT-PCR, OLA, rolling circle, single base extension, and others known in the art. The amplification product can also be measured by signal amplification techniques, such as branch chain amplification (Chiron). Methods of the invention are useful with any platform for the identification, amplification, sequencing, or other manipulation of nucleic acids. For example, methods of the invention can be applied to ligase chain reaction, strand displacement (Becton-Dickinson), and others.
Also in a preferred embodiment of the invention, a series of amplification reactions is conducted on a single genomic locus. Each amplification reaction in the series is designed to amplify a fragment of a different length. In a preferred embodiment, the target fragment lengths are 200 bp, 400 bp, 800 bp, 1.3 Kb, 1.8 Kb, and 2.4 Kb. Primers for amplification are designed according to knowledge in the art in order to amplify template, if present, of the desired length at the desired locus. A positive screen is one that produces amplicon in at least one, and preferably at least two of the series of amplification reactions. As noted above, a normal sample which has undergone or which is undergoing apoptosis typically contains little or no fragments of significant length. Thus, a series of amplification reactions targeting fragments from about 200 bp to about 2.4 Kb and longer reveals samples that contain nucleic acids that have avoided apoptosis as evidenced by the amplification of large fragments.
Preferred methods of the invention also comprise conducting amplification reactions on a series of different genomic loci. Preferably, from about 2 to about 7 loci are used. However, the precise number of interrogated loci is determined by the individual investigator based upon the disease to be detected or based upon convenience. According to methods of the invention, primers are designed to amplify nucleic acid (preferably DNA) at each of the chosen loci. A sample in which at least one locus, preferably at least two loci, and most preferably at least three loci produce detectable amplification product is considered a positive sample. The lengths of fragments to be amplified in this assay may be varied, but are preferably at least about 180 bp each in length. It is not necessary that the same length fragments be amplified at each of the chosen loci.
Methods of the invention also comprise conducting a series of amplification reactions at a series of different genomic loci. Each amplification reaction in the series is designed to amplify a fragment of a different length. Preferably, from about 2 to about 7 amplification reactions on about 2 to about 7 loci are used. However, the precise number of interrogated loci is determined by the individual investigator based upon the disease to be detected or based upon convenience. In a preferred embodiment, the target fragment lengths are 200 bp, 400 bp, 800 bp, 1.3 Kb, 1.8 Kb, and 2.4 Kb. Primers for amplification are designed according to knowledge in the art in order to amplify template if present. It is preferred, but not necessary, that the same length fragments be amplified at each of the chosen loci. A positive screen is one that produces amplicon in at least one, and preferably at least two of the series of amplification reactions and in which at least one locus, preferably at least two loci, and most preferably at least three loci produce detectable amplification product. As noted above, a normal sample which has undergone or which is undergoing apoptosis typically contains little or no fragments of significant length. Thus, a series of amplification reactions targeting fragments from about 200 bp to about 2.4 Kb and longer reveals samples that contain nucleic acids that have avoided apoptosis as evidenced by the amplification of large fragments.
Methods of the invention may also be used to assess the integrity of DNA in a biological sample. Such methods comprise conducting an amplification reaction using at least two loci suspected to be in the sample as templates; determining which loci produce detectable amplicon; and assessing the integrity of DNA in the sample as a function of the number of loci producing amplicon. The integrity of DNA in the sample is high when amplicon is produced in one or more of the amplification reactions. This method is especially useful for determining whether a heterogeneous sample has sufficient nucleic acid for measurement. Accordingly, such methods are used to screen or to xe2x80x9cqualifyxe2x80x9d samples for further analysis (e.g., genetic, biochemical, cytological, or other analyses).
Methods of the invention may also be used to assess fetal abnormalities by conducting amplification reactions on nucleic acids in maternal blood. Just as described above, the ability to amplify significant amounts of nucleic acid is an indicator of a genomic instability. A baseline for comparison of the extent of nucleic acid amplification can be amounts of nucleic acids from known normal samples. The amount of amplification obtained from fetal samples is placed on a continuum, and the investigator must analyze any given sample in terms of the amount of fetal nucleic acid produced in various disease states and in normal samples.
Methods of the invention are useful as diagnostic screening methods. Often it is desirable to perform follow-up testing on a patient in order to confirm a suspected disease state. Such follow-up procedures are determined based upon the disease state being interrogated. For example, a colonoscopy may be suggested in a case in which a stool sample is positively screened according to methods of the invention. Such follow-up procedures are contemplated herein as part of the invention.
Methods of the invention are useful as screens for a wide range of disease states. In addition to colon cancers and adenomas, methods of the invention are useful to screen for other diseases, for example, as screens for lymphomas, or stomach, lung, liver, pancreas, prostate, kidney, testicular, bladder, uterus, or ovarian cancers or adenomas. In addition to cancer, methods of the invention are useful, for example, as screens for diseases such as inflammatory bowel syndrome, inflammatory bowel disease, Crohn""s disease, and others in which a genomic instability is thought to play a role. Methods of the invention are especially useful as screens for any disease that impairs the proper function of the gastrointestinal system; most especially diseases of the colon. Methods of the invention are also useful to screen for apoptosis in a cellular sample. The profile of amplifiable DNA in a sample is correlated with proteins that have been associated with disease. For example up regulation of the apoptosis protein, survivin, is correlated with increased amounts of amplifiable DNA, as is the Ras oncogene, as well as other oncogenes and their gene products.
Methods of the invention are also useful as assays for apoptosis. The presence of high-integrity fragments or large quantities of nucleic acids in a sample indicates that the sample was derived from cells that did not proceed through apoptosis. The absence of such fragments or quantities indicates that cells that contributed to the sample did undergo apoptosis. Accordingly, an apoptotic activity assay of the invention, either alone or in combination with other assays for genomic instability, are useful as screens for disease.
Finally, methods of the invention can be carried out by hybrid capture. For example, hybrid capture and subsequent analysis of the captured fragments can be used to determine the nucleic acid integrity of a sample.
The invention also provides a profile of nucleic acid fragments indicative of disease. A preferred profile is obtained through methods described above. Preferred profiles comprise nucleic acids having between about 200 bp and about 2.4 Kb obtained in a patient sample comprising cellular debris according to methods described herein. A highly preferred profile contains at least one nucleic acid of at least 1.3 Kb.
Other objects and advantages of the invention are apparent upon consideration of the following drawings and detailed description thereof.


A ship propulsion device (1) is adapted to rotate a propeller (20) to propel a ship (2). In a case where the rotating speed of the propeller (20) is less than a predetermined rotating speed, a low-output sub-motor (M2) is controlled and rotationally driven by a small-capacity general-purpose inverter (24), and the rotational driving is transmitted to the propeller (20) so as to rotate the propeller. In that case, in a drive system of a main motor (M1), rotation is not transmitted to a slip clutch (23) or an input shaft (7) by cutting off an on-off clutch (8). In a case where the rotating speed of the propeller (20) becomes equal to or more than the predetermined rotating speed, a driving source is switched from the sub-motor (M2) to the main motor (M1) so as to couple the on-off clutch (8), and the rotating speed of the main motor (M1) is controlled by the slip clutch (23) and transmitted to the propeller (20) so as to rotate the propeller (20).

In the related art, as ship propulsion devices used for work barges for towing or the like, for example those described in Patent Documents 1 to 4 are suggested.
Patent Document 1 discloses a hybrid drive device for a ship having a first drive motor and a second drive motor disposed inside a ship. The first drive motor is embodied in the form of an internal combustion engine, and the second drive motor is of an electric type.
Additionally, a ship propulsion device described in Patent Document 2 is an electric propulsion device for a ship that uses neither an inverter nor a variable-pitch propeller, and includes a diesel engine, an engine control panel that controls the rotating speed of the engine, a power generator, a motor, a speed reducer, a fixed-pitch propeller fixed to a output shaft of the speed reducer. The speed reducer allows the rotating speed to be switched to the rotating speed of either a first reduction gear or a second reduction gear.
Ship propulsion devices described in Patent Document 3 and Patent Document 4 are ship propulsion devices, such as an azimuth thruster. These Patent Documents 3 and 4 suggest ship propulsion devices in which propulsion using a single motor generator, propulsion using a single main engine, and hybrid propulsion in which assist using a motor generator is added to the output of a main engine are allowed by coupling a motor generator other than an internal combustion engine that is a main engine.

Ship propulsion method and ship propulsion device


An antenna system for a navigation satellite receiver tuned to dual-frequency transmissions from orbiting navigation satellites. Respective L1 and L2 microwave patch antennas are mounted flat and adjacent to one another on a common ceramic substrate and have their centers grounded to a groundplane on the opposite side of the substrate with vias. Each patch antenna is connected to a respective near-by low-noise amplifier. The low-noise amplifiers are both connected to a signal combiner and a final radio frequency amplifier for down feed to a navigation satellite receiver. A direct current signal from the navigation satellite receiver is used on the down-feed to selectively control which one of the two low-noise amplifiers is to operate. Thus one coaxial down-feed supplies power to the low-noise amplifiers and provides for the selection between the L1 and L2 carrier frequencies on the down-feed.

1. Field of the Invention
The invention relates generally to radio communication and more specifically to dual-frequency microwave antenna systems that operate with signals received from orbiting navigation satellites.
2. Description of the Prior Art
The global positioning system (GPS) supported by the United States government enables satellite navigation for military and civilian users alike. Two codes, a coarse-grained acquisition code (C/A-code) and a fine-grained precision code (P-code) are transmitted on two L-band microwave frequencies, e.g., L1 on 1575.42 MHz and L2 on 1227.6 MHz, and each provide ranging and GPS-system time information. The C/A-code is available to civilian users and the P-code is available primarily to authorized users. During certain periods, the P-code is encrypted and such encrypted P-code is referred to as Y-code. The C/A-code is a digital sequence that repeats each millisecond and is unique to one of two dozen satellites. The P-code is a digital sequence that has a period of 269 days, with one week long segments of it transmitted intact. Which segment is being sent in any one week is classified. A single week-long segment is 10.23.times.10.sup.6 .times.604800 bits long, which comes from the P-code transmission rate of 10.23 MHz times the exact number of seconds in seven whole days. So a code phase uncertainty of even .+-.1 second can call for a search through 20,460,000 chips.
The L1 and L2 carrier frequencies are sufficiently separated in the radio spectrum as to require separate antennas for their reception. Microwave patch antennas to receive L-band radio transmissions are conventional and comprise a rectangular conductive foil on a flat ceramic substrate. With a center feed, such antennas behave as two dipole antennas set at right angles. With a square conductive foil, the two dipole antennas will have the same frequency response. With a rectangular conductive foil, the two dipole antennas will have different frequency responses, depending on the respective lengths of the sides of the rectangle formed.
Prior art dual-frequency GPS antennas include a stacked array, where two microwave patch antennas, one for L1 and one for L2, are stacked one in front of the another, with their respective planes in parallel. A single down-feed is connected to a conventional navigation satellite receiver.
Authorized GPS users need to be able to switch between receiving the L1 and L2 carrier frequencies. Acquisition of the P-code on the L2 carrier often requires first bootstrapping through the C/A-code on the L1 carrier frequency. Sometimes jamming or spoofing will be present on one of the carrier frequencies but not the other. Some receivers need to peak at the other carrier frequency briefly to measure the automatic gain control (AGC) voltage of the intermediate amplifier.

Dual-frequency microwave radio antenna system


A game system comprises an instant win first game based on the purchase of a game ticket which is a win ticket or a lose ticket, and at least one game console which is initialized by a win ticket to participate in at least one second game, for example a video game, displayed on the game console and executed under the control of a remote computer at a central site.

A distinction can be drawn between "on line" games and "off line" games.
An "on line" game relies on computer processing of data collected from players via game terminals which dispense game receipts.
These terminals are connected by a transmission network to a computer at a central site where independent apparatus, such as a sphere containing numbered balls, performs a draw whose result is transmitted by the computer to the various terminals for checking the win game receipts before issuing the winnings in application of a prepublished table of winnings.
An "off line" game involves selling lottery tickets with the draw taking place later in the case of the traditional national lottery or on the spot in the case of an instant win computer lottery. In this type of game there are no game terminals and no transmission network connected to a central computer.

Game system including an instant win game and a second game initialized by a winning instant win game ticket


An automatic toothpaste dispenser employs a roller-type squeeze device that is driven along the toothpaste tube simultaneously with the opening of a gate that permits the toothpaste to flow. After the desired amount of toothpaste has been dispensed, the roller is automatically retracted and the gate is simultaneously closed. However, the retraction of the gate only continues until the gate is closed, which results in a ratchet-like effect, the roller being retracted a smaller distance than that by which it is advanced.

The present invention relates to toothpaste dispensers. Although the teachings of the present invention are particularly advantageous for elctrically operated dispensers, manual toothpaste dispensers can also be made based upon its teachings.
The ordinary toothpaste tube is a device that is simple and easy to use, and it has gained wide acceptance. In the hands of most adults, it provides neat as well as simple operation. However, children have proven themselves capable of employing the toothpaste tube in such a manner so as to cause a considerable mess. It is not uncommon for children to neglect to replace the cap on a toothpaste, thus sometimes allowing the toothpaste to leak out and more often allowing the toothpaste to dry out in the tube neck. Furthermore, children have a tendency not to squeeze the tube from the end opposite the mouth, and the result is wasted toothpaste. Leakage can also result from this type of squeezing because creases tend to turn up in parts of the tube that still contain toothpaste. For families with young children, then, a toothpaste dispenser can be an advantage if it makes dispensing the toothpaste simpler, and particularly if it reduces the occurrence of messes.
If a toothpaste dispenser is to gain acceptance, then, attention must be paid to reducing the possibility of leakage and waste of toothpaste. If a dispenser merely makes dispensing easier but is still likely to cause a mess, it is less likely to be accepted. The result of this requirement is that the toothpaste dispenser must provide an effective gate means at the tube outlet so as to prevent leakage, and it is desirable that the device be so designed that opening of the gate and dispensing of the toothpaste can be accomplished in a single operation.
Numerous devices have been proposed for achieving this result. For instance, there is illustrated in U.S. Letters Patent No. 2,830,733 to Garibaldi a toothpaste tube that opens automatically when the paste is squeezed out but is closed again when the squeezing operation is finished. However, this device requires that the toothpaste tube be quite a bit more elaborate than those that currently have found acceptance, and the Garibaldi device has not enjoyed widespread use.
An arrangement that provides opening of the gate means and squeezing of a conventional tube in a single operation is illustrated in U.S. Letters Patent No. 2,537,008 to Abbott. The Abbott device is quite simple, but it is thought that the pivotal cover that serves as a squeeze means does not provide sufficient control over the amount of toothpaste dispensed. This is a drawback in a manual arrangement, and it could be a serious problem in an electric dispenser.
An arrangement that affords more control over the amount of toothpaste dispensed is illustrated in U.S. Letters Patent No. 2,936,006 to Henley, in which a roll is rotated as it progresses down the dispenser to squeeze a conventional toothpaste tube from the end opposite the tube mouth. However, the Henley device requires a separate operation for opening of the gate means, and it will be seen by comparison to the device of the present invention that adaptation for automatic opening of the gate means upon squeezing would present some problems unless the teachings of the present invention were employed.
It is the object of the present invention to provide operation that is an improvement over that afforded by prior art devices. It is another object to permit relatively fine control over the amount of toothpaste dispensed while automatically opening the gate means in the same operation that provides the dispensing. It is still another object to avoid the application of pressure to the tube between operations and thus avoid leakage.


The present invention relates to the identification of a novel biomarker for cardiac ischemia: nitrated cardiac troponin I. The present invention also provides methods for the identification and use of a nitrated cardiac troponin as a biomarker for the diagnosis, prognosis and treatment management of myocardial ischemia, with and without necrosis of heart muscle.

Acute coronary syndromes are among the major causes of mortality and morbidity in the world. Millions of patients are treated annually with chest pain of acute onset. In this situation it is extremely important to quickly identify when this pain is due to myocardial ischemia so that adequate care may be started. Myocardial ischemia is a clinical condition characterized by reduced blood supply to the heart. Currently, there are no effective diagnostic methods for this disease. Presently, the diagnosis is based on common non-invasive tests such as exercise testing, myocardial perfusion scintigraphy, however, these tests are expensive and have limited sensitivity and specificity (Parikh; Lemos, 2006). Also, a large part myocardial ischemia patients go undiagnosed due to the absence of accurate diagnostic tests for myocardial ischemia without necrosis of the heart muscle (Pope at al, 2000; McCaig; Burt, 2002; Lloyd-Jones et al, 2009).
In the United States, the FDA has approved the use of ischemia modified albumin (IMA) as a marker for ischemia. This marker consists of the loss of affinity of albumin for cobalt after myocardial ischemia. However, this marker is not sufficiently specific, as it has been shown to be elevated in several clinical situations such as in renal failure, stroke and heavy-load aerobic exercise (Debashis I, et al, 2004; Lippi, et al, 2005; Morrow, et al, 2007; Singh et al, 2010).
Recently, the use of the levels of cytoplasmic cardiac troponins in serum as markers for myocardial injury has been suggested, Cardiac troponins are specific to cardiac myocytes, however, due to the high sensitivity of the assay, these proteins are also detectable in the serum of healthy patients and in other heart diseases as well as acute coronary syndromes or clinical situations where myocardial ischemia occurs (Eggers, et al, 2009; Reichlin et al, 2009; Masson et al, 2010; Hochholzer et al, 2011).
Thus, the currently available cardiac ischemia markers are either nonspecific because they are present in other organs and tissues other than the myocardium, and/or they are elevatedin other clinical situations other than myocardial ischemia.
Due to the prominent lack of markers of cardiac ischemia, the diagnosis and early treatment may occur at a very late stage in patients with unstable angina. On the other hand, in patients with non-ischemic chest pain, the uncertainty about the diagnosis may require hospital admission for investigation which results in undesirable excessive health care costs.
In addition to emergency testing, an accurate marker of myocardial ischemia is also useful in ambulatory management of patients in the diagnosis of stable angina, especially in association with exercise testing or stress myocardial scintigraphy.
Interestingly, cardiovascular diseases, especially acute coronary syndromes, are strongly associated with an oxidative imbalance, leading to increased free radicals and increased reactive oxygen and nitrogen species. Thus, in such diseases, there is an increase in the production of nitric oxide, superoxide and a change in the antioxidant pathways, leading to nitroxidative and oxidative stress (Levrand et al, 2006; Peluffo, Radi, 2007; Aslan, Dogan, 2011).
As a result of the increase of these reactive species, intermediate species such as peroxynitrite and formed. Peroxynitrite, among other actions, leads to the formation of nitrated proteins by the addition of a NO2 group to the phenolic ring of the tyrosine residues (Ischiropoulos, 2009).
This nitration may alter the protein in several ways: the protein may become resistant to degradation, it may activate the immune system, it may become inactivated or it may acquire a new function. These changes in protein activity can impact the pathophysiology of the cardiovascular system (Abello et al, 2009).
Several proteins have been identified as being nitrated in different compartments of the cardiovascular system, such as fibrinogen, plasmin and Apo-1 in the plasma; Apo-B, cyclooxygenase, prostaglandin synthase and Mn-SOD in the vessel walls; myofibrillar creatine kinase and α-actinin in the myocardium. These nitrated proteins were associated to cardiovascular disease (Aslan, Dogan, 2011).
In view of this, nitrated proteins are emerging as new markers for cardiovascular disease. However, protein nitration also occurs in other pathophysiological situations involving increased reactive oxygen and nitrogen species, such as in diabetes, stroke, neurodegenerative diseases, kidney disease and other diseases associated with ischemia/reperfusion and inflammation (Gole et al, 2000; Castegna et al, 2003; Turko et al, 2003, Ahmed et al, 2005; Heffron et al, 2009; Isobe et al, 2009; Choi et al, 2010; Tyther et al, 2011; Piroddi et al, 2011). Thus, in the search for a nitrated biomarker that is specific to cardiovascular disease it is important that the modified protein target is expressed only or mainly in cardiac tissue.
Troponins are cytoplasmic proteins that have specific cardiac muscle isoforms and are found in the circulation in very low concentrations in healthy subjects and that have its concentration increased in situations of stress to the heart muscle, such as necrosis of the cardiomyocytes. Cardiac troponin I is a cytoplasmic protein unique to cardiac myocytes and is one of three subunits that form the troponin protein complex. This subunit is responsible for sensitivity to calcium and regulates muscle contraction. Troponin I binds to actin and inhibits the ATPase activity of actomiosin in the absence of calcium (Bhaysar et al, 1996).

Nitrated cardiac troponin I as a biomarker of cardiac ischemia

Abstract: Diagnosis and prognosis is conducted by determining the amount of nitrated cardiac troponin I in serum samples of subjects and the ratio of nitrated cardiac troponin I to non-nitrated cardiac troponin I in serum samples of subjects. This biomarker can be detected by immunoassay techniques and tandem mass spectrometry. The present invention further relates to peptides, antibodies, compositions, methods, techniques, tests and kits for the identification and quantification of nitrated cardiac troponin I in samples of subjects.