A motion detector for detecting movement of a rail based vehicle and the direction of that movement is provided. The motion detector can be integral with or attachable to an end-of-train unit and can include a single axis accelerometer mounted at an angle from the rails for detecting acceleration in both the lateral and vertical directions. A systems controller, which can include an analyzer, can be provided to receive and analyze output from the accelerometer to determine a motion state and a direction. A power controller can be provided for supplying power to the accelerometer on an intermittent basis to conserve power. A calibration unit can be provided to both initially calibrate and to subsequently recalibrate the accelerometer after a stopped motion state is detected. Additionally, an input/output port and an output driver for conditioning the signal for output to the end-of-train unit can be provided.

1. Field of the Invention
The invention relates generally to motion detectors, and more particularly to a motion and direction detector of a railway vehicle and in some applications on an end-of-train (EOT) railroad telemetry system.
2. Description of the Prior Art
In railway systems such as those employing locomotive drawn trains, it can sometimes be difficult for the engineer or other operator to reliably be apprised of the state of motion of one or more vehicles that are located remotely from him. For example, when starting a train from a stop position it can in some operations be particularly difficult for the train driver to know when the driving force of the locomotive has propagated through the interconnected cars and accelerated the last vehicle into motion. Conversely, when coming to a stop, it is difficult for the driver to know when the last car has been decelerated to a standstill. Knowledge of these conditions of motion of the last vehicle can be extremely useful to the driver in controlling operation of the train.
EOT signaling and monitoring equipment is now widely used in place of cabooses, to meet operating and safety requirements of railroads. The information monitored by the EOT unit typically includes air pressure of the brake pipe, battery condition, marker, light operation, and train movement. This information can be transmitted to the crew in the locomotive by a battery powered telemetry transmitter. In addition, the EOT unit typically includes a marker light mounted at a specific height above the track and having a well defined beam pattern.
The early EOT telemetry systems were one-way systems; that is, data was periodically transmitted from the EOT unit to Head of Train (HOT) unit in the locomotive where the information was displayed. More recently, two-way systems have been introduced wherein radio transmissions are also made by the HOT unit to the EOT unit.
With the continuing development of EOT units for use in two-way railroad telemetry systems, one goal has been to improve the functionality of the existing motion sensor, especially when operated on a smooth rail. In addition, some older types of sensors do not report direction of motion.
Many contemporary motion and direction detectors for EOT units commonly employ a piezoelectric film as the sensing element. Examples of such contemporary motion and direction sensors are disclosed in U.S. Pat. No. 5,376,925 to Crisafulli et al., U.S. Pat. No. 5,003,824 to Fukada et al. and U.S. Pat. No. 4,752,053 to Boetzkes. Crisafulli, Boetzkes and Fukada each disclose devices which have two sensors utilizing piezoelectric film. One piezoelectric sensor for detecting motion, and a separate piezoelectric sensor for detecting direction.
Although piezoelectric film has been the medium of choice in many contemporary sensors, there can be disadvantages associated with the use of piezoelectric films especially environmental conditions such as shock, breakage, susceptibility to EMI, and temperature. Additionally, the piezoelectric sensors of contemporary motion detectors can also take hours to calibrate.
Furthermore, contemporary motion detectors typically may keep all motion and direction monitoring electronics powered and operating continuously. This may force the designer to use very high impedance sensors and processing electronics which can in some designs lead to the problems of sensitivity to temperature and humidity and susceptibility to EMI. Complex and time consuming algorithms can then be required to account for the errors introduced by these conditions.
Moreover, motion and direction detecting devices disclosed in each of the above patents employ separate piezoelectric sensors for determining motion and direction.

Detector for sensing motion and direction of a railway vehicle


Aspects of the subject disclosure may include, for example, embodiments and a method. The method includes iteratively providing messages to each Node Processor. Each Node Processor represents a node of a group of nodes. The iteratively providing of the messages comprises providing first messages. Each first message includes a cost associated with a path of nodes visited by each first message. A selected path is obtained from each node having a lowest cost of a group of common endpoint costs for paths having common endpoints. A next group of messages includes the selected path. The iteratively providing of the messages results in selected paths. Also, the method include determining a target path from a remaining path. Other embodiments are disclosed.

The traveling salesman problem is one in which a target path is found between a starting point and stopping point with several intermediate nodes. The target path can be a shortest path or most efficient path. Further, the target path includes each and every one of the intermediate nodes. In addition, the starting point and stopping point can be the same node. The calculating of the target path can require many computations and take significant time and processing resources.

This patent is subject to a terminal disclaimer.

Methods, devices and systems for determining a target path


There is provided a hydrocracking process using a catalyst comprising a hydrogenation/dehydrogenation component, such as a noble metal, and an acidic solid component comprising a Group IVB metal oxide modified with an oxyanion of a Group VIB metal. An example of this catalyst is zirconia, modified with tungstate and platinum. This catalyst is used to selectively hydrocrack naphtha range hydrocarbons to reduce the endpoint of reformulated gasolines.

One of the processing challenges for producing reformulated gasoline is endpoint reduction. Lowering gasoline endpointo,as been reported to reduce pollution. A specification of 90% of the gasoline boils below 300.degree. F. has been proposed for California.
Zeolite beta has been found particularly well-suited for use in a catalyst for hydrocracking naphtha under mild conditions. U.S. Pat. No. 3,923,641 to Morrison, discloses that C.sub.5 + naphtha can be readily upgraded to a product which contains increased amounts of isobutane relative to n-butane, by hydrocracking the naphtha over zeolite beta. There is no disclosure of endpoint reduction in gasolines.
It has now been found that a C.sub.5 + naphtha, e.g., C.sub.6 + or C.sub.7 + naphtha can be hydrocracked by a process which comprises contacting the naphtha with a catalyst composition comprising a hydrogenation/dehydrogenation component and an acidic solid component comprising a Group IVB metal oxide modified with an oxyanion of a Group VIB metal.
In the present invention a catalyst composition comprising a hydrogenation/dehydrogenation component and an acidic solid component comprising a Group IVB metal oxide modified with an oxyanion of a Group VIB metal is found to be selective for naphtha hydrocracking to reduce the endpoint of reformulated gasolines. The endpoint is lowered through selective hydrocracking of the C.sub.10 + fraction.


Processes for preparing silicon-containing polytrimethylene homo- or copolyethers, wherein at least a portion of the polymer end groups are silicon-containing end groups, are provided.

In UV curable cationic coatings, photoinitiators generate cationic species, which then function as catalysts for cationic polymerization. Epoxides, in particular cycloaliphatic epoxides, are the major reactive monomer/oligomers used for cationic UV cured coatings.
Typically, two types of crosslinkers are available for these coatings, low molecular weight alcohols and high molecular weight polyols. High molecular weight polyol crosslinkers, such as polyester, polyether, or caprolactone polyols, provide excellent flexibility; however, they are generally viscous, and as a consequence increase application related problems. Low molecular weight alcohols can reduce the viscosity of the coating formulations. However, they are volatile and lack the flexibility needed for most coating applications.
Homo- or copolyethers of 1,3-propanediol also can be used as crosslinkers for cationic UV curable coatings. However, they would have a greater effect if their functionality could be increased from the original 2 (i.e., 2 hydroxyls per molecule). Moreover, conversion of the hydroxyl end groups to a non-hydrogen bonding species would also serve to reduce viscosity.
U.S. Pat. No. 3,833,512 discloses organosilicon polymers containing monomeric units (A), (B) and (C) where (A) is an inorganic tetravalent silicon containing units, where all valencies of the Si atoms are saturated by oxygen linkages, (B) is polyvalent silicon containing units where 2-3 valencies of the silicon are linked to oxygen and at least 1 is linked to a carbon atom of an organic group containing a poly(oxyalkylene) chain, and (C) is monovalent silicon containing units where 1 valency is linked to oxygen and the other 3 are saturated by monovalent organic compounds, the mole ratio (A) to (B) to (C) being 0.4-2:1:0.2-2 respectively.
U.S. Pat. No. 6,737,482 discusses curable resin compositions comprising: (1) a reactive silicon group containing polyoxyalkylene polymer and epoxy resin, wherein the introduction rate of the reactive silicon into a molecular chain terminus is not less than 85% as analyzed by NMR spectroscopy, and (2) an epoxy resin.

Silicon-containing polytrimethylene homo- or copolyether composition


An up-down moving mechanism includes a support member; an up-down moving member that is formed separately from the support member and can be moved up and down with respect to the support member; a screw shaft for moving up and down the up-down moving member; a nut member that is screwed onto the screw shaft; a guide rail that guides the up-down moving member in a vertical direction; a guide block that slidably engages with the guide rail; and a gas spring that includes a cylinder and a piston rod biased in a direction projecting out from the cylinder, and that biases the up-down moving member toward an upper side with respect to the support member. To the support member, the screw shaft is rotatably attached, the guide rail is fixed, and the piston rod is attached.

An inkjet printer that performs printing on a print medium is conventionally known (see e.g., Japanese Unexamined Patent Publication No. 2009-248559). An inkjet printer described in Japanese Unexamined Patent Publication No. 2009-248559 includes a head unit with a plurality of inkjet heads arranged in the width direction of a transport line, a frame disposed above the head unit, and an actuator that moves up and down the head unit with respect to the frame. The actuator includes a servo motor and a screw that rotates by the power of the servo motor. The inkjet printer includes an air suspension that urges both end portions of the head unit toward the upper side. In this inkjet printer, the downward load of the head unit acting on the actuator is reduced by the air suspension.
Patent Literature 1: Japanese Unexamined Patent Publication No. 2009-248559

Up-down moving mechanism and inkjet printer


An electromagnetic actuating device. The device includes an electromagnetic coil including a central recess extending in an axial direction, a cylindrical pole tube inserted into the central recess and provided with a magnetic separation point, an armature situated displaceably in the pole tube, the armature being movable by an actuation of the electromagnetic coil, the armature being mounted in the pole tube in a sleeve-shaped bearing foil inserted into the pole tube, the bearing foil including an inner side facing toward the armature and used as a sliding surface and an outer side facing toward the cylindrical pole tube. It is provided that the bearing foil is coated at least on the inner side using a first layer made of perfluoroalkoxy polymer. A manufacturing method for such an electromagnetic actuating device is also described.

Electromagnetic actuating devices are used, for example, in electromagnetically actuated hydraulic valves for transmission clutches of a motor vehicle. In order that these shifting processes run preferably smoothly so they are not noticed by the driver, it is desirable to set the hydraulic pressure at the clutches in accordance with predetermined pressure ramps with ultrahigh pressure precision. The pressure required for this purpose may be provided with the aid of hydraulic slide valves. These slide valves may be actuated either via a pilot valve including an electromagnet (pilot control) or directly via an electromagnetic actuating device.
An electromagnetic actuating device is described, for example, in German Patent Application No. DE 10 2012 223 430 A1 and includes, among other things, an electromagnetic coil having a central recess extending in the axial direction, a cylindrical pole tube provided with a magnetic separation point, an armature situated displaceably in the pole tube, and a force transmission element displaceably mounted in the axial direction on the electromagnetic actuating device. The armature is movable by actuation of the electromagnetic coil in such a way that a force exerted by the armature is transmittable to the force transmission element.
In the electromagnetic actuating devices used in hydraulic valves, an electromagnetic force proportional to the coil current results, using which the hydraulic valve is actuated. To achieve the required high pressure precision, the electromagnet is to have a very precise force-current characteristic curve with little variation of the force level. A variation of the magnetic force level and a hysteresis of the force-current characteristic curve caused by friction are to be limited to a minimum.
To achieve this, the armature is mounted in the pole tube in a sleeve-shaped bearing foil inserted into the pole tube, the bearing foil including an inner side facing toward the armature and used as a sliding surface and an outer side facing toward the cylindrical pole tube and the bearing foil being manufactured at least partially from a friction-reducing material. For example, German Patent Application No. DE 10 2006 055 796 A1 describes an electromagnetic actuating device including a bearing foil which is made up of a glass fiber fabric, which may be saturated using PTFE in multiple steps in soaking baths and may be coated on both sides with a PTFE dispersion and subsequently sintered. The use of a bearing foil including PTFE coating results in minor friction forces and thus in a reproducible magnetic force for a specific armature position. Due to the minor friction, a magnetic force-distance characteristic curve including very slightly pronounced hysteresis and very minor variations of the hysteresis results upon movement of the armature.

Electromagnetic actuating device and method for manufacturing an electromagnetic actuating device


A network communication device measures an elapsed time from the transmission of facsimile data prepared by an e-mail message composing section to the reception of a delivery verification response by a clock section. In accordance with the measurement, a time managing section changes a waiting time by which an occurrence of a timeout error is determined to, for example, a mean value or a maximum value. This sets the waiting time to an optimal value suitable to a network environment, for example.

Recent development of networking has created new applications for network communication devices which transmit/receive e-mail messages over the Internet or like network.
Some newly developed network communication devices can not only capture an image with a built-in scanner function, but also forward the captured image information to a computer or like apparatus connected to the network in the form of an attachment file of an e-mail message. Network facsimile machines have been developed too which incorporate a built-in print function and telephone function in addition to the scanner function.
Such a network facsimile machine is disclosed in, for example, Japanese Published Unexamined Patent Application 2001-274944 (Tokukai 2001-274944, published on Oct. 5, 2001). FIG. 17 is a schematic showing an arrangement of the machine. In that network facsimile machine, an e-mail message sent from a transmitting-end terminal 1 to a transmitting-end mail server machine 2 is transferred to a receiving-end mail server machine 4 via a network 3 using an SMTP (Simple Mail Transfer Protocol) or another predetermined mail transfer protocol. The e-mail message is then stored in the receiving-end mail server machine 4. A receiving-end terminal 5 periodically accesses the receiving-end mail server machine 4 using POP3 (Post Office Protocol 3) or another mail receiving protocol to retrieve the stored e-mail message.
Further, the network facsimile machine is adapted to delete the e-mail message received by the mail server machine 4 so that the e-mail message is not repeatedly transferred after the e-mail message is received and its attached image information is printed out as a received document.
A problem occurs under these circumstances where information is transmitted using an e-mail message as in the foregoing: unlike, for example, those cases when information is transmitted by a normal facsimile machine, the transmitting end has no means to determine whether the information is received normally or processed properly by the receiving end. Specifically, unlike normal facsimile machines performing real time communication with each other over a PSTN (Public Switched Telephone Network), since the receiving-end terminal 5 of the network facsimile machine is not always connected to the mail server machine 4, and the transmitting-end terminal 1 can forward a message to the mail server machine 2 anytime no matter whether the receiving-end terminal 5 can receive it at that time, the receiving-end terminal 5 may take time to actually receive a message, and the transmitting end cannot judge at the time of transmission whether the message is receive normally or processed properly as mentioned in the foregoing.
Therefore, conventionally, when there is a need to confirm safe delivery of the information transmitted from the network facsimile machine, the operator must inconveniently confirm by a telephone call. It is also a problem that e-mail communication loses one of its advantages over telephone communication that the parties involved do not need to talk in real time.
Accordingly, a conventional method technique addressing these shortcomings is defined by the MDN (Message Disposition Notification) method in RFC 2298 which provides a means of confirming safe delivery of an e-mail message whereby upon reception of an e-mail message, the receiving-end terminal sends a confirmation message back to the transmitting-end terminal.
"RFCs" (Requests For Comments) are official documents issued by IETF (Internet Engineering Task Force), an Internet-related technology standards organization. The documents define, for example, specifications and requirements of Internet protocols, such as IP (Internet Protocol), TCP (Transmission Control Protocol), HTTP (HyperText Transfer Protocol), and FTP (File Transfer Protocol), and various Internet-related technologies. They are numbered throughout like "RFC 2298" and publicly available.
Japanese Published Unexamined Patent Application 2001-309109 (Tokukai 2001-309109, published on Nov. 2, 2001) discloses an arrangement of a machine equipped with the MDN function where if an MDN request is sent without receiving a return message by e-mail from the receiving end within a certain period of time after the completion of the transmission, a delivery failure notice is printed out to notify the operator that no return message is sent back. The operator can thereby confirm whether the message has been normally transmitted to the receiving-end terminal.
To realize the MDN function, it is determined, with a preset waiting time as a reference, if the delivery failure notice is to be output according to whether an e-mail message is sent back or not within the waiting time after the information is transmitted. Therefore, the suitable waiting time may differ depending on, for example, whether the receiving-end terminal 5 is always connected to the mail server machine 4 as mentioned in the foregoing, the network environment (connection state to the server) including the transfer rate between the mail server machine 4 and the receiving-end terminal 5, and the settings of the receiving-end terminal 5 (as to response timing and other conditions).
Therefore, if the waiting time is set to a value suitable to the transmission destination with the slowest response speed so as to be compatible with all the transmission destinations, a situation is possible where the operator may not be notified quickly of an error which has occurred at the transmission destination (receiving end) with a fast response speed and take an undesirably long time before retransmitting the information. In contrast, if the waiting time is set to a value suitable to the transmission destination with the fastest response speed, a situation is possible where the receiving end has normally received the message, but may be so slow in the operation of sending a return message that it triggers timeout errors requesting repeated transmissions.


When a intensity of a signal from a light detector 14 to measure a scattered light exceeds a predetermined value, a motion of a particle 20 is displayed as a locus of the scattered light, by means of extending an exposure time of the scattered light to the light detector, or by means of increasing a pulse oscillation frequency of a laser beam 13, or by means of extending a pulse width of the laser light. And then a straight line connecting start and terminal points of the locus is displayed to superimpose on the locus. An origin of the particle is estimated by extending the straight line beyond the start point, and a destination point of the particle is estimated by extending the straight line beyond the terminal point. A mass of the particle is estimated by dividing a projective length of the straight line in a vertical direction by the exposure time of the scattered light.

1. Field of the Invention
The present invention relates to a particle monitoring instrument which measures particles peeling off from a processing reactor and particles which are appeared and grow and fall down during processing steps, by means of a light scattering method in-situ and in real time.
2. Description of the Related Art
Particles appeared in a processing equipment during manufacturing steps of a large scale integrated circuit (hereinafter referred to as an LSI) are a major cause of reductions in a yield rate of the LSI and the amount of operational time of the processing equipment. In order to prevent the yield and the amount of operational time from being reduced, instruments to monitor the appearance of the particles have been developed.
These instruments are composed of a laser light source and a photodetector and there are two types of instruments, one of which is installed on an exhaust pipe of the processing equipment, and the other absorbs gas from the processing equipment. Both of these pass a sampled fluid through a space where a laser beam exists, and measure an intensity of scattered light whenever particles pass, and the number of the particles appeared. As conventional examples of these instruments, methods disclosed in Japanese Patent Applications Laid Open No. 4-297852/1992, 3-116944/1991, 63-11838/1988, 5-206235/1993, 5-206236/1993, 7-12707/1995, and 5-288669/1993 and Japanese Utility Model Publication No. 62-37160/1987 can be mentioned.
The methods to measure the particles in the sampled fluid involve a problem that the obvious relations between the number of the detected particles and the yield ratio of the LSI, and the relations between the number of detected particles and the amount of operational time of the processing equipment, were not observed. In order to solve this problem, a measurement of the floating particles appeared in the reactor therein in-situ and in real time has been attempted.
Measurement in this attempt is conducted in the following manner. Windows for introducing a laser light into the reactor and for measuring scattered light are fitted on the processing reactor, the laser light scattered by the particles is recorded on a video tape using a CCD camera, the video tape is reproduced to investigate the time for appearance the scattered light and the intensity change thereof, and finally the appearance of the particles can be estimated.
As examples of these conventional methods, there have been papers, here respectively cited, by Gary S. Selwyn, in Journal of Vacuum Science and Technology, Vol. B9, 1991. pp. 3487-3492 and in Vol. A14, 1996. pp. 649-654. Moreover, there have been papers, here respectively cited, by Watanabe et al., in Applied Physics Letters, Vol. 61, 1992. pp. 1510-1512 and by Shiratani et al., in Journal of Vacuum Science and Technology, Vol. A14, 1996. pp. 603-607.
The foregoing conventional technologies involve the following problems.
In the technologies disclosed in Japanese Patent Applications Laid Open No. 4-297852/1992, 3-116944/1991, 63-11838/1988, 5-206235/1993, 5-206236/1993, 7-12707/1995, and 5-288669/1993 and Japanese Utility Model Publication No. 62-37160/1987, which are mentioned as the conventional examples, the methods to measure the particles in the sampled fluid are described. Since these methods adopt measuring the scattered light in sampled fluid, it is difficult to specify the origin of the particles. Therefore, there is a problem that it is difficult to obtain a relation between the amount of operational time of the equipment and the amount of appeared particle and a relation between a yield ratio of the LSI and the amount of appeared particle.
In the papers that are respectively cited, by Gary S. Selwyn, in Journal of Vacuum Science and Technology, Vol. B9, 1991. pp. 3487-3492 and in Vol. A14, 1996. pp. 649-654, by Watanabe et al., in Applied Physics Letters, Vol. 61, 1992. pp. 1510-1512 and by Shiratani et al., in Journal of Vacuum Science and Technology, Vol. A14, 1996. pp. 603-607, the particles floating in the processing reactor are detected by the laser light scattering method, and measured spatial distribution of the particles and its change with time. However, it is difficult to know whether the observed particles cause the faults on wafers, to know the origin of the particles and to know which paths the particles travel to reach a wafer. For these reasons, the origin of the particles causing defective patterns on a wafer product can not be specified. Therefore portions and parts of the processing equipment to require the reform can not be recognized. And the measurement of particle appearance has been cleaning of the equipment. Specifically, there has been no policy to inhibit the appearance of the particles, so that the amount of operational time of the processing equipment cannot be improved owing to cleaning of the reactor and preparative operation.
When the measurement of the spatial distribution of the particles, the way of detecting particles adopts either the laser light scanned spatially or the laser light expanded spatially. In this case, distances from places where laser light scattering occur to the detector are different, and intensities of the scattered lights at the detector is inversely proportional to a square of the distance from the scattering point to the detector. Specifically, to estimate the particle size from the intensity of the scattered light, it is necessary to correct the intensity of the scattered light depending on the distance. However, such correction has not heretofore been performed.
Moreover, to estimate the particle size form the intensity of the scattered light, it is assumed that the shape of the particle is perfectly spherical. However, it has been known that many of the particles appeared on LSI manufacturing steps are in a flasky form and in a needlelike form. For the particles of such shapes, the intensity of the scattered light greatly depends on an arrangement of a direction of incident beam and particle. Therefore, by the estimation of the particle size assuming a perfect sphere particle, errors of a particle size, a distribution of particle size, and a numerical density of the particles become large.
Currently spatial distribution of the particles using the light scattering method is measured as follows. A specifically polarized light is introduced into the processing reactor and the changes of the polarization of the light scattered by the floating particles are measured. Only one wavelength of the light from the light source used is used. When a size of the observed particle is smaller than the wavelength of the irradiation light, the intensity of the scattered light is estimated with a Rayleigh scattering formula. When the size of the particle is larger than the wavelength of the irradiation light, a Mie scattering formula is employed. Although the Mie scattering formula gives a strict solution, its equation is complicated so that a long time is required for a numerical calculation. Therefore no positive information on the size and numerical density of particles, is available on real time, from the results of the scattered light intensity measurements.


A board mounted connector for a board to board connector system is disclosed which can be smaller, provide a more robust connection to a conductive circuit on a printed circuit board while allowing for a high degree of circuit design freedom on the board circuit due to the terminal insertion from the mating side of the housing where the terminals are generally above a bottom portion (33) of the non-conductive housing (31) adjacent the board. The housing (31) is provided with fitting holes (37) extending from an end surface (32d) on the side which mates with the male housing (21). The female terminals (35) have anchor portions (36) to be fitted into the fitting holes (37) of the female housing (31) and contact portions (35b) to engage terminals in a mating connector. Forward end portions (36a) of the anchor portions (36) are soldered to a circuit terminal of the board (3). Cut out portions (39) in the rectangular frame portion (32) allow for the solder joint between the end portion (36a) and the conductive circuit (38) to be inspected.

The present invention relates to a board mounted connector for connecting printed circuit boards to each other.
Existing board to board connecting systems include a male, or plug connector, to be soldered to one board and a female, or receptacle connector, to be soldered to another board. The male and female connectors are designed to engage and mate with one another. The plug connector and the receptacle connector are respectively provided with plug terminals and receptacle terminals that are to be soldered to conductive circuits on the boards. When the mating plug and receptacle are mated together, the plug and receptacle terminals are in electrical engagement with each other thereby electrically connecting the conductive circuits from one circuit board to the other circuit board.
Various types of board to board connectors have been used in the past. One such board connector has receptacle terminals with contact portions which electrically engage plug terminals in a mating plug connector, anchor portions for holding the receptacle terminals to a receptacle housing, and solder tail portions for soldering the receptacle terminals to a conductive circuit on a board.
In this board to board connector, the contact portions and the solder tail portions are spaced apart from one another since the solder tail portions extend from the anchor portions beyond the sides of the connector housing. The use of this connector requires a larger footprint on the printed circuit board. Also, because the solder tail portion extends from a flexible elongated arm located on the exterior of the connector, the strength of the solder joint is diminished. Furthermore, because of the long length of the solder tail arm, the signal has to travel a longer distance before it electrically communicates with the circuit on the circuit board. This extra length can be a factor in timing with high speed signals. Finally, such a connector has only one point of electrical and mechanical engagement with the printed circuit board which can result in a weak mechanical and electrical connection.
All of these characteristics are important for a connector with terminals which are inserted into a mating side of the connector housing opposite the side adjacent the printed circuit board. It is important that a bottom portion of the housing remains to prevent any short circuit between the terminals and the conductive circuits traveling under the housing after the terminals are inserted into the mating side of the connector. Providing this bottom housing portion will allow for more freedom of circuit designs on the printed circuit board.


The present invention relates to parstatin peptides, compositions comprising parstatin peptides and their use in the treatment of various disorders, including angiogenesis-related diseases, ocular neovascularization and related disease states, ischemia-reperfusion injury and myocardial-related disease states, and renal disorders.

A. Angiogenesis and Neovascular Ocular Diseases
A1. Angiogenesis and Angiogenesis-Related Diseases
Angiogenesis is the generation of new blood vessels in a tissue or organ (Carmeliet, 2005, Nature, 438: 932-936). Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific and restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development, and formation of the corpus luteum, endometrium and placenta.
Angiogenesis is controlled through a highly regulated system of angiogenic stimulators and inhibitors (Yancopoulos et al., 2000, Nature, 407: 242-248). Angiogenesis is turned on by specific angiogenic molecules such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), angiogenin, transforming growth factor, tumor necrosis factor-alpha (TNF-alpha) and platelet derived growth factor (PDGF). On the other hand, angiogenesis can be suppressed by inhibitory molecules such as interferon-α, thrombospondin-1, angiostatin, and endostatin. It is the balance of these naturally occurring stimulators and inhibitors that controls the normally quiescent capillary vasculature. When this balance is upset, as in certain disease states, capillary endothelial cells are induced to proliferate, migrate and ultimately differentiate.
The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the underlying pathology associated with the diseases is related to uncontrolled angiogenesis. Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the local dissolution of the basement membrane by enzymes released by endothelial cells and leukocytes. Endothelial cells, lining the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimuli promote endothelial cell migration through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating a new blood vessel.
Persistent, upregulated angiogenesis occurs in many disease states, including tumor growth metastases. The diverse pathological diseases states in which upregulated angiogenesis is present have been grouped together as angiogenic-diseases, angiogenesis-associated or angiogenesis-related diseases.
One example of diseases dependent on angiogenesis is ocular neovascular diseases (Gariano and Gardner, 2005, Nature, 438: 960-966). These diseases are characterized by invasion of new blood vessels into the structure of the eye, such as the retina or cornea. They are the most common cause of blindness and comprise approximately twenty eye diseases. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of choroidal capillaries through defects in Bruch's membrane, with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, and retrolental fibroplasias. Other diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca.
Another example of angiogenesis-related disease is rheumatoid arthritis (Bainbridge et al., 2006, Curr Pharm Des, 12: 2631-2644). The blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. Angiogenesis may also play a role in osteoarthritis. The activation of the chondrocytes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors promote new bone growth. Therapeutic intervention that prevents the cartilage destruction could halt the progress of the diseases and provide relief for persons suffering from arthritis.
Chronic inflammation may also involve pathological angiogenesis. Such disease as ulcerative colitis and Crohn's disease show histological changes with the ingrowth of new blood vessels into inflamed tissue. Bartonellosis, a bacterial infection found in South America, in a chronic stage is characterized by proliferation of vascular endothelial cells.
Several lines of direct evidence now suggest that angiogenesis is essential for the growth and persistence of solid tumors and their metastases. To stimulate angiogenesis, tumors upregulate the production of a variety of angiogenic factors, including the bFGF and VEGF (Yancopoulos et al., 2000, Nature, 407: 242-248). However, many malignant tumors also generate inhibitors of angiogenesis, including angiostatin, endostastin, and thrombospondin (Nyberg et al., 2005, Cancer Res, 65: 3967-3979). It is postulated that the angiogenic phenotype is the result of a net balance between these positive and negative regulators of neovascularization. Several other endogenous inhibitors of angiogenesis have been identified, although not all are associated with the presence of a tumor. These include, platelet factor 4, interferon-alpha, interferon-inducible protein 10, which is induced by interleukin-12 and/or interferon-gamma, the 16 kDa N-terminal fragment of prolactin, tumstatin, arresten, canesten, anastellin, vasostatin, and vasohibin.
A2. Ocular Neovascularization and Related Disease States
Pathologic or aberrant angiogenesis/neovascularization, aberrant remodeling, fibrosis and scarring and inflammation occur in association with retinal and ocular ischemic diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR) and in retinopathy of prematurity (ROP) and other developmental disorders (Eichler et al., 2006, Curr Pharm Des, 12: 2645-60) as well as being a result of infections and mechanical or chemical injury to the cornea and the eye in general (Ciulla et al., 2001, Curr Opin Opthalmol, 12: 442-9; Dart et al., 2003, Eye, 17: 886-92).
Diabetic retinopathy is a leading cause of blindness in adults of working age. The leading cause of vision loss for Americans under the age of 65 is diabetes; 16 million individuals in the United States are diabetic and 40,000 per year suffer from ocular complications of the disease, often a result of retinal neovascularization. DR, therefore, is a retinal microvascular disease that is manifested as a cascade of stages with increasing levels of severity and a worsening prognosis for vision. DR is broadly classified into 2 major clinical stages: nonproliferative diabetic retinopathy and proliferative diabetic retinopathy (PDR), where the term "proliferative" refers to the presence of preretinal neovascularization (PNV) emanating from the retina into the vitreous. Ocular neovascularization occurs in areas where capillary occlusions have developed, creating areas of ischemic retina and acting as a stimulus for neovascular proliferation that originate from pre-existing retinal venules at the optic disk and/or elsewhere in the retina posterior to the equator of the eye. Vitreous haemorrhage and tractional retinal detachment from PDR can cause severe vision loss (Boulton et al., 1997, Br J Ophthalmol, 81: 228-223). Diabetic macular edema (DME) is a further common cause of blindness (Levin, 2001, J Glaucoma 10:19-21; Stefansson et al., 1992, Am J. Ophthalmol. 113:36-38). A clinical hallmark of PDR includes the increased vascular permeability, leading to DME, and endothelial cell proliferation.
Age-related macular degeneration is a leading cause of vision loss in people over 65 years old. For example, AMD affects 12-15 million American over the age of 65 and causes vision loss in 10-15% of them. In contrast to ROP and PDR, in which neovascularization emanates from the retinal vasculature and extends into the vitreous cavity, AMD is associated with neovascularization originating from the choroidal vasculature and extending into the subretinal space. Choroidal neovascularization (CNV) causes severe vision loss in AMD patients because it occurs in the macula, the area of retina responsible for central vision (Kitaoka et al., 1997, Curr Eye Res, 16:396-399).
Multiple theories exist but, the exact etiology and pathogenesis of AMD are still not well understood. Aging is associated with cumulative oxidative injury, thickening of Bruch's membrane and drusen formation. Oxidative stress results in injury to retinal pigment epithelial cells (RPE) and, in some cases, the choriocapillaris (Zarbin, 2004, Arch Opthalmol, 122: 598-614; Gorin et al., 1999, Mol V is, 5: 29). Injury to RPE likely elicits a chronic inflammatory response within Bruchs membrane and the choroid (Johnson et al., 2000, Exp Eye Res, 70: 441-9). This injury and inflammation fosters and potentiates retinal damage by stimulating CNV and atrophy (Zarbin, 2004, Arch Opthalmol, 122: 598-614; Witmer et al., 2003, Prog Retin Eye Res, 22: 1-29). CNV results in defective and leaky blood vessels (BV) that are likely to be recognized as a wound (Kent and Sheridan, 2003, Mol V is, 9: 747-55).
Retinopathy of prematurity (ROP) occurs most prominently in premature neonates. In various cases, the retina becomes completely vascularized at full term/near birth. In the premature baby, the retina remains incompletely vascularized at the time of birth. Rather than continuing in a normal fashion, vasculogenesis in the premature neonatal retina becomes disrupted. Abnormal new proliferating vessels develop at the juncture of vascularized and avascular retina. These abnormal new vessels grow from the retina into the vitreous, resulting in haemorrhage and tractional detachment of the retina (Neely et al., 1998, Am. J. Pathol, 153:665-670). It is estimated that visual impairment from this disease affects 3400 infants and causes blindness in 650 infants annually in the United States. Angiogenesis is the hallmark of this debilitating condition.
Others retinal diseases associated with retinal neovascularization include sickle cell retinopathy, retinal vein occlusion, certain inflammatory diseases of the eye, ocular tumorigenesis, Eale's disease, myopic choriodal neovascularization, and polypoidal choriodal vasculopathy. These, however, account for a much smaller proportion of visual loss caused by ocular neovascularization (Neely et al., 1998, American J. of Path. 153:665-670).
Corneal neovascularization, the abnormal formation of blood vessels in the cornea, is a common and serious complication of many corneal diseases and is a major cause of blindness that affects millions of people (Adamis, 2005, Retina, 25: 111-118). The condition is associated with severe visual impairment and is a high risk factor for graft rejection after allograft corneal transplantation. In addition, corneal neovascularization and subsequent opacification remain the most frequent causes of blindness after severe alkali burn trauma. To date, there are no pharmacological or surgical treatment options for the inhibition of corneal neovascularization that have been proven to be both safe and effective. Despite the routine use of topical steroids, the inflammatory response can lead to oedema, lipid deposition and corneal scarring that may not only significantly alter visual acuity, but also worsen the prognosis of subsequent penetrating keratoplasty. In addition, longer-term use of these drugs can lead to various adverse side effects such as cataracts, glaucoma, infection, and delay corneal epithelial healing.
VEGF plays a dominant role in iris neovascularization and neovascular retinopathies. While reports clearly show a correlation between intraocular VEGF levels and ischemic retinopathic ocular neovascularization, FGF likely plays an essential role. Basic FGF is known to be present in the normal adult retina, even though detectable levels are not consistently correlated with neovascularization. This may be largely due to the fact that FGF binds very tightly to charged components of the extracellular matrix and may not be readily available in a freely diffusible form that would be detected by standard assays of intraocular fluids. Furthermore, overexpression of bFGF in the eye does not stimulate neovascularization because it is sequestered (Osaki et al., 1998, Am J Pathol, 153: 757-765), but bFGF does contribute to choriodal neovascularization when there is tissue disruption from the disease process itself or attempts at treatment (Yamada et al., 2000, J Cell Physiol, 185:135-142).
Viable and approved current treatments for diseases related to ocular neovascularization are limited. The approved treatments for AMD are photodynamic therapy with VISUDYNE® (QLT/Novartis) and intravitreal injection of Macugen® (pegaptanib) (Eyetech/Pfizer) or Lucentis® (ranibizumab) (Genentech). Laser photocoagulation alone or photodynamic therapy with VISUDYNE® are therapies that involve laser-induced occlusion of the affected vasculature, which can result in localized damage to the retina. Macugen® (Eyetech/Pfizer) is an anti-VEGF aptamer that binds to VEGF165 preventing ligand-receptor interaction and is labeled for intravitreal injections every 4 weeks. Lucentis® (Genentech) is a humanized anti-VEGF antibody fragment that also binds directly to all isoforms of human VEGF and is labeled for intravitreal injections every 6 weeks. A variety of other pharmacologic therapies are undergoing clinical evaluation for AMD, such as RETAANE® 15 mg (anecortave acetate suspension, Alcon Research, Ltd.), Envision (squalamine, Genera), the VEGF R1R2 Trap, (Regeneron), Cand5 (anti-VEGF siRNA, Acuity), Sirna-027 (anti-VEGFR1 siRNA, SIRNA/Allergan), a topical receptor tyrosine kinase antagonist (TargeGen), sirolimus (rapamycin, MacuSight), etc.
Grid and pan retinal laser photocoagulation are the only proven options currently available for patients with diabetic macular edema or PDR, respectively. Multifocal laser photocoagulation may reduce retinal ischemia and inhibit angiogenesis by destroying healthy tissue and thus decreasing the total metabolic demand of the retina. Laser photocoagulation may also modulate the expression and production of various cytokines and trophic factors. Unfortunately, laser photocoagulation is a cytodestructive procedure and the visual field of the treated eye is irreversibly compromised. Surgical interventions, such as vitrectomy and removal of preretinal membranes, are widely used with or without laser treatment. Similar to the AMD trials, various pharmacologic agents are in clinical trials for DME, such as ARXXANT™ (ruboxystaurin mesylate, Lilly), RETISERT™ (fluocinolone acetonide, Bausch & Lomb), Posurdex (fluocinolone acetonide erodible implant, Occulex/Allergan), I-vation (nonerodible Dexamethasone implant, Occulex), Medidur (fluocinolone acetonide erodible implant, Alimera), etc. Intravitreal or periocular injection of triamcinolone acetonide, a corticosteroid (Kenalog®, Schering-Plough), and intravitreal Avastin® (anti-VEGF Mab (bevacizumab), Genentech) are also being used "off-label" for the treatment of both macular edema and wet AMD.
Anti-VEGF therapies represent a recent, significant advance in the treatment of exudative AMD. However, the phase III VISION Trial with PEGAPTANIB, a high affinity aptamer which selectively inhibits the 165 isoform of VEGF-A, demonstrated that the average patient continues to lose vision and only a small percent gained vision (Gragoudas et al., 2004, N Engl J Med, 351: 2805-16). Inhibition of all isoforms of VEGF-A (pan-VEGF inhibition) with the antibody fragment RANIBIZUMAB yielded much more impressive results (Brown et al., 2006, N Eng J Med, 355:1432-44; Rosenfeld et al., 2006, N Eng J Med 355:1419-31). The 2 year MARINA trial and the 1 year ANCHOR trial demonstrated that approximately 40% of patients achieve some visual gain. Although these results represent a major advance in our ability to treat exudative AMD, they also demonstrate that 60% of patients do not have visual improvement. Furthermore, these patients had to meet strictly defined inclusion and exclusion criteria. The results in a larger patient population may be less robust. In addition, adverse effects on neurons and vessels have been observed in primates after a single administration of the humanized anti-VEGF antibody (Bevacizumab) (Peters et al., 2007, Am J Ophthalmol, 91: 827-831) and sporadic case reports of complications of anti-VEGF therapy related to regression of blood vessels, increased risk for stroke and myocardial infarction, and local side effects due to the intravitreal application mode have appeared (Fraunfelder et al., 2005, Drugs Today, 41: 703-709; Tobin et al., 2006, Insight, 31: 11-14; Rosenfeld et al., 2006, Ophthalmol Clin NA, 19: 361-372; Baffert et al., 2006, Am J Physiol Heart Circ Physiol, 290: H547-H559; Hurwitz et al., 2004, Clin Colorectal Cancer, 4(suppl): 2: S62-S68). The limited efficacy and potential adverse effects of currently implemented therapies emphasize the need for alternative therapeutic strategies.
B. Ischemia-Reperfusion Injury and Myocardial-Related Disease States
Ischemia-reperfusion injury (I/R injury) refers to an event in which the blood supply to a tissue is obstructed, such as myocardial infarction. Whenever there is a transient decrease or interruption of blood flow the net injury is the sum of two components: the "direct" injury occurring during the ischemic interval and the "indirect" or reperfusion injury which follows. Reperfusion injury can be defined as the damage that occurs to an organ that is caused by the resumption of blood flow after an episode of ischemia. This damage is distinct from the injury resulting from the ischemia per se. One hallmark of reperfusion injury is that it may be attenuated by interventions initiated before or during the reperfusion. Reperfusion injury results from several complex and interdependent mechanisms that involve the production of reactive oxygen species, endothelial cell dysfunction, microvascular injury, alterations in intracellular Ca2+ handling, changes in tissue metabolism, and activation of neutrophils, platelets, cytokines and the complement system. All of the deleterious consequences associated with reperfusion constitute a spectrum of reperfusion-associated pathologies that are collectively called reperfusion injury. Reperfusion injury can extend not only acutely, but also over several days following the tissue attack.
During blood vessel obstruction, the endothelial tissue lining the affected blood vessels becomes "sticky" and begins to attract circulating white blood cells (Tohoku, 2008, J Exp Med, 215: 257-266). The white cells bound to the endothelium eventually migrate into the cardiac tissue causing significant tissue destruction. Although acute myocardial infarction is not directly caused by inflammation, much of the underlying pathology and the damage that occurs after an acute ischemia-reperfusion injury is caused by acute inflammatory responses during reperfusion, the restoration of blood flow to the affected myocardium. White blood cells present to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA and the plasma membranes. Damage of the cell membrane may in turn causes release of more free radicals signaling apoptosis. Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia.
Cardiovascular disease is the leading cause of death in the western world. Coronary artery disease can lead to prolonged or irreversible episodes of cardiac ischemia that result in myocardial infarction (MI) which is associated with a high rate of mortality. The reduced blood flow in heart diseases is typically caused by blockage of a vessel by an embolus (blood clot); the blockage of a vessel due to atherosclerosis; the breakage of a blood vessel (a bleeding stroke); the blockage of a blood vessel due to vasoconstriction such as occurs during vasospasms and possibly, during transient ischemic attacks (TIA) and following subarachnoid haemorrhage. Conditions in which ischemia occurs further include myocardial infarction; trauma; and during cardiac and thoracic surgery and neurosurgery (blood flow needs to be reduced or stopped to achieve the aims of surgery). Procedures that can cause myocardial ischemia include coronary thrombolysis, coronary angioplasty (with or without stent placement), and coronary artery bypass grafts. During myocardial infarct, stoppage of the heart or damage occurs which reduces the flow of blood to myocardium, and ischemia results. Cardiac tissue itself is also subjected to ischemic damage. During various surgeries, reduction of blood flow, clots or air bubbles generated can lead to significant ischemic damage of the myocardium.
During an ischemic event, there is a gradation of injury that arises from the ischemic site. Cells at the site of blood flow restriction, undergo necrosis and form the core of a lesion. A penumbra is formed around the core where the injury is not immediately fatal but progresses slowly toward cell death. This progression to cell death may be reversed upon reestablishment of blood flow within a short time of the ischemic event. Timely reperfusion to reduce the duration of ischemia is the definitive treatment to prevent cellular injury and necrosis in an ischemic myocardium. Typically reperfusion, after a short episode of myocardial ischemia (up to 15 min), is followed by the rapid restoration of cellular metabolism and function. Even with the successful treatment of occluded vessels, a significant risk of additional tissue injury after reperfusion may still occur. If the ischemic episode has been of sufficient severity and/or duration to cause significant changes in the metabolism and the structural integrity of heart muscle, reperfusion may paradoxically result in a worsening of heart function, out of proportion to the amount of dysfunction expected simply as a result of the duration of blocked flow. Although the beneficial effects of early reperfusion of ischemic myocardium with thrombolytic therapy, PTCA, or CABG are now well established, an increasing body of evidence indicates that reperfusion also induces an additional injury to ischemic heart muscle, such as the extension of myocardial necrosis, i.e., extended infarct size and impaired contractile function and metabolism. Hearts undergoing reperfusion after transplantation also undergo similar reperfusion injury events.
Despite efforts towards the development of new therapies for the treatment of diseases and conditions such as heart failure and cardiac ischemia/reperfusion injury, this remains an unmet need for additional or alternative agents to treat or prevent the onset or severity of this condition (Ferdinandy et al., 2007, Pharmacol Rev, 59: 418-458). Current therapies include the use of vasodilators, anti-thrombotics/thrombolytics, beta-blockers and coronary artery bypass graft are used pre and post myocardial ischemia to maintain/restore coronary blood flow and limit oxygen demand.
C. Acute Renal Failure and Related Disease States
Acute renal failure (ARF), also known as acute renal injury (ARI) or acute kidney injury (AKI), is a clinical syndrome characterized by rapid deterioration of renal function that occurs within days. ARF is estimated to occur in at least 5% of all hospitalized patients, and in 30-50% of those admitted to the intensive care unit. ARF secondary to a renal tubular cell injury, including an ischemic injury or a nephrotoxic injury remains a common and potentially devastating problem in clinical medicine and nephrology, with a persistently high rate of mortality and morbidity despite significant advances in supportive care (Chatterjee and Thiemermann, 2003, Expert Opin Emerg Drugs, 8: 389-435).
Pioneering studies over several decades have illuminated the roles of persistent vasoconstriction, tubular obstruction, cellular structural and metabolic alterations, and the inflammatory response in the pathogenesis of ARF. While these studies have suggested possible therapeutic approaches in animal models, translational research efforts in humans have yielded disappointing results. The reasons for this may include the multifaceted response of the kidney to ischemic injury and nephrotoxins, and a paucity of early biomarkers for ARF with a resultant delay in initiating therapy.
The most common cause of ARF—acute tubular necrosis—is most frequently observed in the setting of renal ischemia reperfusion injury, post-renal transplant, sepsis, post-myocardial infarct, in the elderly with diminished fluid intake, and as a consequence of exposure to radiocontrast agents and a wide range of toxins, including cis-platinum, aminoglycosides, amphotericin B, and acyclovir. The notion that only severe renal failure impacts on long-term morbidity is dispelled by the fact that even modest degrees of renal insufficiency significantly increase the risk of death for critically ill patients
Renal ischemia-reperfusion injury refers to an event in which the blood supply to kidneys is obstructed, such as renal occlusion (Chatterjee, 2007, Naunyn-Schmiedeberg's Arch Pharmaco J, 376: 1-43). Reperfusion injury can be defined as the damage that occurs to kidney that is caused by the resumption of blood flow after an episode of ischemia. This damage is distinct from the injury resulting from the ischemia per se. Renal ischemia-reperfusion injury results from several complex and interdependent mechanisms that involve the production of reactive oxygen species, endothelial cell dysfunction, microvascular injury, alterations in intracellular Ca2+ handling, changes in tissue metabolism, and activation of neutrophils, platelets, cytokines and the complement system. All of the deleterious consequences associated with reperfusion constitute a spectrum of reperfusion-associated pathologies that are collectively called reperfusion injury. Reperfusion injury can extend not only acutely, but also over several days following the tissue attack.
Due to obstruction, the endothelial tissue lining the affected blood vessels becomes "sticky" and begins to attract circulating white blood cells (Tohoku, 2008, J Exp Med, 215: 257-266). The white cells bind to the endothelium and eventually migrate into the kidneys causing significant tissue destruction. Although acute renal occlusion is not directly caused by inflammation, much of the underlying pathology and the damage that occurs after an acute ischemia-reperfusion injury is caused by acute inflammatory responses during reperfusion, the restoration of blood flow to the kidney. White blood cells present to the area by the newly returning blood release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membranes. Damage of the cell membrane may in turn promotes release of more free radicals signaling apoptosis. Leukocytes may also built up in small capillaries obstructing them and leading to more ischemia.
During an ischemic event, there is a gradation of injury that arises from the ischemic site. Cells at the site of blood flow restriction, undergo necrosis and form the core of a lesion. A penumbra is formed around the core where the injury is not immediately fatal but progresses slowly toward cell death. This progression to cell death may be reversed upon reestablishment of blood flow within a short time of the ischemic event. Timely reperfusion to reduce the duration of ischemia is the definitive treatment to prevent cellular injury and necrosis in an ischemic kidney. Typically reperfusion, after a short episode of renal ischemia (up to 30 min), is followed by the rapid restoration of cellular metabolism and function. Even with the successful treatment of occluded vessels, a significant risk of additional tissue injury after reperfusion may still occur. If the ischemic episode has been of sufficient severity and/or duration to cause significant changes in the metabolism and the structural integrity of renal tissue, reperfusion may paradoxically result in a worsening of renal function, out of proportion to the amount of dysfunction expected-simply as a result of the duration of blocked flow.
Without being bound by theory acute kidney injury may be the result of renal ischemia-reperfusion injury (ischemia-reperfusion) that occurs, for example, in patients undergoing major surgery such as major cardiac surgery (Padanilam, 2003, Am J Physiol, 284: F608-F627). Renal ischemia, whether caused by shock or during surgery or transplantation, is a major cause of acute kidney injury. Although reperfusion is essential for the survival of ischemic tissue, there is strong evidence that reperfusion itself caused additional cellular injury and together ischemia-reperfusion of the kidney leads to ischemic ARF. Renal ischemia-reperfusion injury is caused by multiple insults involving tubular cell apoptosis, oxygen free radical formation, mitochondrial dysfunction, inflammatory cytokine generation and neutrophils sequestration.
Contrast-induced nephropathy (CIN) is generally recognized as acute renal failure occurring within 48 hours of exposure to intravascular contrast material, and where other causes of renal failure are not attributable. Its presence is generally determined when an increase in serum creatinine levels is exhibited in a subject who has been exposed to intravascular contrast material. CIN is an important problem in clinical practice and contrast-induced morbidity has become a significant cause of hospital morbidity and mortality with the increasing use of iodinated contrast media in diagnostic imaging and interventional procedures such as angiography. In 2003, over 80 million doses of iodinated intravascular contrast media were administrated, corresponding to approximately 8 million liters according to Katzberg et al. (2006, Kidney International, 69: S3-S7). With the increasing use of contrast media in diagnostic and interventional procedures, CIN has become the third leading cause of hospital-acquired acute renal failure, accounting for 10 to 25% of all acute renal failure cases, despite the introduction of newer and safer contrast media, the improvement of hydration protocols, and the introduction of additional preventive strategies.                There are different classes of contrast agents in use such as:        High osmolar agents, such as Iothalamate and Diatrizoate. The osmolality of these agents is about 5 times greater than the osmolality of blood.        Low osmolar agents, such as Iohexyl, Ioversol, Iopamidol, Iopromide, Iomeprol and Ioxaglate. The osmolality of these agents is about 2-3 times greater than the osmolality of blood.        Iso-osmolar agents, such as Iotrolan and Iodixanol. The osmolality of these agents is the same as the osmolality of blood.
The pathophysiological mechanisms that underlie the development of CIN are not fully understood (ref). Nevertheless, there are recognized risk factors that pre-dispose individuals for the development of contrast agent-induced acute renal failure and these include subject-related factors and procedure-related factors (Kagan and Sheikh-Hamad, 2010, Clinical Cardiology, 33: 62-66). It has been the subject of numerous studies addressing characteristics of the populations at risk and prophylactic strategies. Evidence-based reviews, summarizing recent literature, provides a nephrologists' perspective on contrast-induced nephropathy, focusing on: the pathophysiology of contrast-induced nephropathy; identification of populations at risk; correlation between contrast-induced nephropathy and the type of contrast agent used; and finally, measures to prevent contrast-induced nephropathy, including intravenous fluids, sodium bicarbonate, N-acetylcysteine, and hemofiltration/hemodialysis.
In addition, sepsis and septic shock remain the most important cause of ARF in critically ill patients and account for more than 50% of cases of ARF in the intensive care unit. Despite increasing ability to support vital organs and resuscitate patients, the incidence and mortality of septic ARF remain high. Its mortality varies with the severity of acute kidney injury from 21% to 57%.
Therefore, there is a great need for new, effective strategies for prevention of ARF and in particular therapies for the treatment of diseases and conditions such as I/R injury-, pharmacotherapy-, contrast- and sepsis-induced ARF. This unmet medical need for novel agents to treat, prevent or protect from the onset or severity of these conditions presents opportunities for developing blockbuster drugs.
D. Parstatin: a Protease-Activated Receptor 1-Derived Peptide
Thrombin is a serine protease, which plays a pivotal role in haemostasis. It acts as procoagulant converting fibrinogen into fibrin that anchors platelets at the site of lesion and stabilizes the clot by activating factor XIII and enhances its own generation from prothrombin by activation of factors V, VIII and XI. On the other hand, thrombin acts as an anti-coagulant by activating protein C (Di Cera, 2003).
Apart from its role in blood clotting and fibrin generation, thrombin has important roles in the initiation of angiogenesis (Tsopanoglou and Maragoudakis, 2004, Sem Thromb Hemost, 30: 63-69). Thrombin's angiogenic activity is mostly independent of its coagulant activity and is more dependent on signaling via the protease-activated receptors 1 (PAR1). This supported by the observations obtained in mouse models, wherein a lack of thrombin generation (TF−/−, FX−/−, FV−/−, FII−/−) results in severe vascular defects in embryonic development (Moser and Patterson, 2003, Arterioscler Thromb Vasc Biol, 23: 922-930). Similar phenotypes occur in models of impaired thrombin binding to its PAR receptor (PAR1−/−).
Protease-activated receptors (PARs) consists a family of G protein-coupled receptors which can be activated by proteolytic cleavage of their N-terminal extracellular domain (Ossovskaya and Bunnett, 2004, Physiol Rev, 84: 579-621). PAR1 is the first member of this family to be cloned in which the extracellular amino terminus is cleaved to expose a new amino terminus that is involved in receptor activation (Vu et al., 1991, Cell, 64: 1057-1068). Subsequently, three other members of this receptor family have been identified, designated as PAR2, PAR3 and PAR4. Proteolytic cleavage at the R41/S42 bond of human PAR1 by thrombin releases a 41 amino acid peptide and unveils a tethered peptide ligand with the recognition sequence SFLLRN (SEQ ID NO: 15). This sequence binds to conserved regions in the second extracellular loop of the cleaved receptor, resulting in the initiation of signal transduction. There is evidence that not only thrombin but also other molecules, such as plasmin, factor Xa, activated protein C, as well as matrix metalloprotease-1, might be able to activate this receptor under certain conditions and induce down-stream signals (Leger et al., 2006, Circulation, 114: 1070-1077).
Thrombin, through PAR1 signaling, interacts and stimulates a variety of vascular cells including, but is not limited to, platelets, endothelial cells, smooth muscle cells and regulates the release, expression and activation of the majority of angiogenesis mediators. For example, thrombin-induced angiogenesis in a chick chorioallontoic membrane system is associated with up-regulation of VEGF as well as angiopoietin-2 (Ang-2) (Caunt et al, 2003, J Thromb Haemost, 1: 2097-2102). Also, in endothelial cells thrombin up-regulates VEGF (Huang et al, 2001, Thromb Haemost, 86: 1094-1098), Ang-2 (Huang et al., 2002, Blood, 99: 1646-1650) and the major VEGF receptor KDR (Tsopanoglou and Maragoudakis, 1999, J Biol Chem, 274: 23969-23976), and activates metalloproteinase-2 (Zucher et al., 1995, J Biol Chem, 270: 23730-23738). It was recently shown that thrombin markedly up-regulates growth-regulated oncogene-α and this chemokine in turn mediates the thrombin-induced increase of vascular regulatory proteins (MMP-1, MMP-2), growth factors (VEGF, Ang-2), and receptors (KDR) (Gaunt et al, 2006, Cancer Res, 66: 4125-4132). In addition thrombin induces the secretion of VEGF (Mohle et al., 1997, Proc Natl Acad Sci USA, 94: 663-668) and Ang-1 (Li et al., 2001, Thromb Haemost, 85: 204-206) from platelets. Furthermore, it was demonstrated that thrombin regulates in an opposing fashion the release of VEGF and endostatin (the potent endogenous inhibitor of angiogenesis) in platelets (Ma et al., 2005, Proc Natl Acad Sci USA, 102: 216-220). Thrombin has also been shown to activate the proliferation of endothelial cells by acting directly as mitogenic factor (Olivot et al., 2001, Circ Res, 88: 681-687).
The fact that thrombin plays an important role in angiogenesis, suggests a crucial role for thrombin and its receptor, PAR1 in tumor progression and metastasis (Nierodzik and Karpatkin, 2006, Cancer Cell, 10: 355-362). Thrombin, through PAR1 signaling, contributes to a more malignant phenotype by activating platelet-tumor aggregation, tumor adhesion to subendothelial matrix, tumor growth and metastasis.
In addition, PAR1 expressed on platelets and the vascular endothelium, has been shown to play important roles in normal blood vessel biology (Coughlin, 2005, J Thromb Hemost, 3: 1800-1814) and to contribute to the pathogenesis of several cardiovascular diseases including atherosclerosis, restenosis and thrombosis (Leger et al., 2006, Circulation, 114: 1070-1077). In particular, aberrant over-expression of PAR1 has been documented in the endothelium and vascular smooth muscle cells of human atheroscrerotic arteries, including regions of intimal thickening (Nelken et al., 1992, J Clin Invest, 90: 1614-1621). Activation of PAR1 triggers mitogenic responses in smooth muscle cells and fibroblast and angiogenesis. Targeting PAR1 with a blocking antibody reduced intimal hyperplasia by approximately 50% in a catheter-induced injury model of restenosis (Takada et al., 1998, Circ Res, 82: 980-987). PAR1 deficiency also reduced restenosis in arterial injury models (Cheung et al., 1999, Arterioscler Thromb Vasc Biol, 19: 3014-3024). Recently, it has been shown that thrombin contributes to ischemia/reperfusion injury independently of its effects on platelets and fibrinogen. In addition, PAR1 inhibition has been demonstrated to protect against myocardial ischemia/reperfusion injury by recruiting cardioprotective pathways (Strande et al, 2007, Basic Res Cardiol, 102: 350-358).
Despite the wealth of information relating to the role of thrombin and PAR1 in physiology and diseases states, the information regarding the biological role of cleaved peptides upon activation of PAR1 is very limited. There are only three reports which associate the 41 amino acid cleaved peptide of the PAR1 with potential biological functions (Furman et al., 1998, Proc Natl-Acad Sci USA, 95: 3082-3087; Furman et al., 2000, Thromb Haemost, 84: 897-903; Furman et al., 2003, J Vasc Surg, 37: 440-445). The name of "parstatin" has been coined for this peptide.
The present invention seeks to provide novel peptides derived from parstatin, together with new therapeutic applications for full length parstatin peptide and various peptide fragments thereof.


A method for controlling rotation of an image displayed in a display screen includes establishing a coordinate system with an origin being set at a center of the display screen. The coordinate system includes a coordinate plane in parallel to an average plane associated with the display screen. The method further includes dividing the coordinate plane to four azimuth intervals corresponding respectively to four display modes with four boundary lines being all intersected at the origin of the coordinate system. Additionally, the method includes defining a respective buffer region in a respective angular range around a respective boundary line. Furthermore, the method includes determining whether an azimuth angle of a gravity acceleration vector component in the coordinate plane is kept in a respective azimuth interval corresponding to a current display mode of the image including two buffer regions respectively associated with two boundary lines of the respective azimuth interval.

In an electronic apparatus having a display screen, such as a smart phone, the image displayed in the display screen can be switched from a landscape display mode to a portrait display mode as the gravity acceleration vector changes relative to the display screen. However, display mode switching sometime becomes unnecessary, or improper switching due to incorrect response, or failure to obtain rotated image due to fast rotation of the electronic apparatus in space. Therefore, an improved method and apparatus for controlling rotation of displayed image are desired.

Method and apparatus for controlling rotation of displayed image, display apparatus, and computer-program product


A method, apparatus, system, and computer-readable storage device is configured to perform three-dimensional (3D) modeling. A modeling tool is activated in a 3D modeling application executing on a multi-touch device. An input touch event and input gesture for creating a new 3D geometric form is received. Dynamically, in real-time as the input gesture is received, the new 3D geometric form is created and displayed. The shape of the new 3D geometric form corresponds to the input gesture.

1. Field of the Invention
The present invention relates generally to three-dimensional (3D) modeling, and in particular, to a method, apparatus, and article of manufacture for dynamically creating and modeling/editing a solid model (e.g., on a multi-touch device).
2. Description of the Related Art
(Note: This application references a number of different publications as indicated throughout the specification by reference numbers enclosed in brackets, e.g., [x]. A list of these different publications ordered according to these reference numbers can be found below in the section entitled "References." Each of these publications is incorporated by reference herein.)
Many 3D modeling and drawing applications are used in both desktop and multi-touch devices. However, none of the existing multi-touch 3D modeling or drawing applications provide a comprehensive 3D modeling system that take advantage of the multi-touch capabilities available across multiple mobile devices, without interfering with basic 3D navigation or requiring proficiency in the "art" of 3D modeling. Further, none of the prior art modeling systems provide the ability to dynamically create and dynamically modify/edit a 3D solid model (e.g., via user gestures). To better understand the problems and deficiencies of the prior art, a description of prior art modeling applications and activities may be useful.
Some prior art modeling applications (e.g., the Spaceclaim Engineering™ application), have explored multi-touch interactions in the context of 3D modeling tasks. However, such prior art applications mimic the interaction available via a mouse pointer. These interactions are not tailored for laymen to use without 3D modeling experience. Many of the operations also require two hand interactions that may not be adequate for smaller devices and require more muscle memory. Further, prior art applications involve multiple steps in which 3D solid models are not created dynamically in real-time consistent with the user's gestures.
In some cases, specific creation tools (e.g., extrude, revolve, offset, etc.) may have been implemented for multi-touch use. However, such creation tools are all static modality tools or commands that require proper selection. The tools are detached from the 3D navigation experience and do not fully take advantage of the multi touch input devices.
In view of the above, it may be understood that 3D modeling activities and tasks generally imply and require an understanding/mastering of concepts such as coordinate systems, tool operations, tool selection sequence, and validity of selections. Accordingly, what is needed is the capability to easily perform a variety of modeling operations (including creation, modification, and navigation) on a multi-touch input device in a dynamic manner without multiple steps or selection requirements.

Dynamic creation and modeling of solid models


A system and method of indirectly modifying an environmental condition at a test site in one embodiment includes providing a test site on a substrate, providing a first activatable stimulant at the test site, providing an actuator configured to activate the first activatable stimulant at the test site, controlling the actuator to activate the first activatable stimulant, and modifying the local chemical environment at the test site with the first activated stimulant.

Diagnostic tests that can be performed at the point of care of an individual, such as at the bedside of a patient, at a care provider location, or at the home of the patient, are becoming increasingly popular. The promise of such diagnostic tests is described, for example, by Leroy Hood et al., "Systems Biology and New Technologies Enable Predictive and Preventative Medicine," Science 306, no. 5696 (Oct. 22, 2004): 640-643. Depending upon the particular diagnostic test, the substance tested may be human body fluids such as blood, serum, saliva, biological cells, urine, or other biomolecules. Diagnostic tests are not, however, limited to biomolecules since testing may be further desired on consumables such as milk, baby food, or water.
Many diagnostic testing devices incorporate affinity based sensors which are considered to be the state-of-the-art in detection of biomarkers. Affinity based sensors function according to a "key-lock" principal in which a molecule with very high association factor to the marker of interest is used for detection. For example, a pregnancy test kit may incorporate a monoclonal antibody specific to a β-subunit of hCG (βhCG). The antibody is conjugated with a tag, e.g., gold, latex, or fluorophore, which is used for detection. If the targeted molecule binds with the conjugated antibody, the tagged key-lock pair will be detectable such as by a visible test line.
ELISA plates and microarrays (e.g., Nucleic Acid, peptide, and protein) incorporate a similar principal. FIG. 1 depicts an ELISA assay 10 wherein antibodies 12 are immobilized on a substrate 14. The substrate 14 may be positioned within a well (not shown). A blocker 16 is provided to cover the surface of the substrate around the antibody 12. In a typical ELISA assay, a sample including molecules of interest 18 is then added to the well in which the primary antibody 12 is immobilized. Next, the sample is incubated for some time. During incubation, the blocker 16 prevents the molecules of interest in the sample from binding to the surface of the substrate 14 in order to avoid false binding. During incubation, some of the molecules of interest 18 become bound with some of the antibodies 12 as depicted in FIG. 2. After incubation, the remaining sample is washed to remove the unbound molecules of interest 18.
Subsequently, a secondary antibody 20 with a bound label 22 is added to the well, incubated, and washed resulting in the configuration of FIG. 3. As depicted in FIG. 3, the labeled secondary antibodies 20 are bound to the molecules of interest 18 that are in turn bound to the antibodies 12. Accordingly, the number of labels 22 bound by the antibodies 20 to the molecules of interest 18 is proportional to the concentration of the target antigen. Depending on the label used, the number of labels can be finally detected using colorimetry, amperometry, magnetometry, voltammetry, luminescence, or fluorescence detection. Other label-free antibody processes such as surface plasmon resonance may alternatively be used.
The two main figures-of-merit in a detection assay include sensitivity and cross-reactivity; both of which affect the minimum detectable concentration and the diagnosis error rate. The sensitivity in such tests is generally limited by label detection accuracy, association factor of the antibody-antigen pair, and the effective density of the probe antibody on the surface.
One issue that arises with affinity based sensors is the cross-reactivity of the sensor to other biomarkers. In other words, rather than sensing a single biomarker or molecule of interest, a sensor tends to also sense biomarkers other than the biomarker of interest. The cross-reactivity issue is depicted in FIG. 4 wherein an ELISA assay 30 includes antibodies 32 immobilized on a substrate 34 with a blocker 36 covering most of the substrate surface 34. Additionally, a labeled secondary antibody 38 is bound to a molecule of interest 40 which is in turn bound by the primary antibody 32. The labeled secondary antibody 38 has also bound to a molecule 42 which exhibited an affinity for the primary antibody 32 and was labeled by a secondary antibody 38. The sensitivity to a broad range of biomarkers thus increases the false negative/positive rate of diagnostic tests at clinical level as reported, for example, by P. A Benn et al., "Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross identification and double positive results," Prenatal Diagnosis, Vol. 21, No. 1, pp 46-51, 2001. The presence of other molecules (secondary molecules or antigens) in the sample thus affects the minimum detectable concentration by binding to the primary antibody.
The accuracy of the assay may further be affected by physiosorption. As further depicted in FIG. 4, some features 44 present in the ELISA assay 30, either contaminants or simply an incongruity, may also be bound to a labeled secondary antibody 38. The physiosorbed labeled secondary antibody 38 thus causes an increased background signal.
Provision of diagnostic tests with a high fidelity is further complicated by the relative scarcity of the molecules of interest in a particular sample. As reported by Robert F. Service, "PROTEOMICS: Proteomics Ponders Prime Time," Science 321, no. 5897 (Sep. 26, 2008): 1758-1761, the concentrations of different proteins in blood varies by more than 10 orders of magnitude. Thus, to ensure a desired level of fidelity, the affinity of the capture molecule to the biomarker of interest must be orders of magnitude higher than the affinity of the capture molecule to any other molecule in the sample.
Overcoming the cross-reactivity and background problems can significantly delay development of a new assay test and can increase the cost and complexity of the overall test. For example, in an effort to mitigate the various sensitivity and interference issues involved with affinity based testing, a particular assay is typically optimized by finding a combination of reagents and environmental conditions that maximizes the binding of the molecule of interest to the antibody. Thus, optimization can entail incorporating highly selective antibodies. Accordingly, a typical development of an ELISA assay requires several scientists working for more than a year to identify an acceptable antibody. Cross-reactivity of proteins is a common source of the failure of such development efforts.
Another approach for optimizing the diagnostic test for a particular molecule of interest entails controlling the test conditions locally at different sites of the platform to increase the specificity of the tests. One such approach is described in U.S. patent application Ser. No. 12/580,113, filed on Oct. 15, 2009, the entire contents of which are herein incorporated by reference. Control of the test conditions locally at different sites of the platform can also be used to increase the dynamic range of the assay as described in U.S. patent application Ser. No. 12/688,193, filed on Jan. 15, 2010, the entire contents of which are herein incorporated by reference.
Control of the test conditions locally at different sites of the platform has generally been attempted by electrically influencing biochemical reactions. Various attempts at such electrical control have been reported by R. G. Sosnowski et al., "Rapid determination of single base mismatch mutations in DNA hybrids by direct electric field control," Proceedings of the National Academy of Sciences of the United States of America 94, no. 4 (Feb. 18, 1997), Ian Y. Wong and Nicholas A. Melosh, "Directed Hybridization and Melting of DNA Linkers using Counterion-Screened Electric Fields," Nano Letters 0, no. 0 (January), Ian Y. Wong, et al., "Electronically Activated Actin Protein Polymerization and Alignment," Journal of the American Chemical Society 130, no. 25 (Jun. 1, 2008): 7908-7915, and Ulrich Rant et al., "Switchable DNA interfaces for the highly sensitive detection of label-free DNA targets," Proceedings of the National Academy of Sciences 104, no. 44 (Oct. 30, 2007): 17364-17369, among others.
Controlling test conditions by electrically influencing biochemical reactions, while promising, is problematic. For example, most of the electrical potential is dissipated at the electric double layer formed over the electrode surface. Accordingly, the electrical influence has a limited range of effectiveness.
A need exists for a device and method of performing an assay incorporating low cost antibodies. A further need exists for tests such as multiplexed assays, e.g., protein arrays, competitive assays, or bead based arrays, as well as low cost devices, e.g., lateral flow devices, or other biochips. They all provide accurate results and a method of using such arrays. Methods and devices which provide more accurate results than so-called optimized assays would be a further benefit.

Device and method for indirect modulation of detection environment


A variable speed transmission of the continuously variable type. The transmission includes an input pulley having primary and secondary sheaves and an output pulley having primary and secondary sheaves. The primary and secondary sheaves of the input pulley are mounted on a first axle shaft carried by an actuator plate and the primary and secondary sheaves of the output pulley are carried on a second axle shaft carried by the actuator plate. The input shaft of the transmission carries pin mounted roller bearings which are received in skewed slots in an actuator sleeve so that the actuator sleeve is moved axially along the input shaft in response to variations in torque loading. The actuator plate is annular and includes a central circumferential groove receiving pin mounted roller bearings carried by the actuator sleeve so that the actuator plate, and the axle shafts carried thereby, undergoes the same axial movement as the actuator sleeve in response to variations in torque loading. One sheave of each pulley is fixedly mounted on the respective axle shaft and the other sheave is slidably and rotatably mounted on the shaft. The mounting of the pulleys on the respective axle shafts is such that axial movement of the actuator plate has the effect of moving the sheaves of one pulley apart and simultaneously moving the sheaves of the other pulley together whereby to cause the entrained drive belt to move radially outwardly relative to the sheaves of one pulley while moving radially inwardly with respect to the sheaves of the other pulley whereby to change the drive ratio of the transmission.

This invention relates to variable speed transmissions and more particularly to transmissions of the continuously variable type.
A myriad of continuously variable transmissions have been proposed and/or utilized to deliver torque in a continuously variable manner between an input drive and an output drive. Whereas these prior art continuously variable transmissions have been generally satisfactory, the mechanisms for varying the drive ratio in response to variations in the input torque are sometimes relatively insensitive to relatively small changes in input torque and/or the changes in drive ratio in response to variations in input torque are sometimes not accomplished in a smooth, positive manner.


A lean detector for a vehicle is capable of reducing the cost of the parts of a lean sensor and enhancing the waterproof property thereof. The lean detector also detects when the leaning of the vehicle body has reached a prescribed angle in the right, left, front or rear direction. The lean sensor is installed at a position above a bottom end of a baseplate of the seat of a saddle-ride type four-wheeled vehicle.

1. Field of the Invention
The present invention relates to a lean detector for a vehicle. In particular, the present invention relates to a lean sensor that can detect leaning of a vehicle body.
2. Description of Background Art
It is known to detect a banking angle (inclination angle in the right or left direction) of a motorcycle body by installing a lean sensor at a lower part of the vehicle body (see, for example, Japanese Patent Application Laid-Open No. Hei. 8-133155).
It sometimes happens that a vehicle that is used for traveling on rough terrain, such as an All Terrain Vehicle (ATV), also uses a lean sensor to detect that the leaning of the vehicle body in the right or left direction has reached a prescribed angle and carry out a prescribed engine control (stop of ignition, stop of fuel injection and the like) in response thereto.
In such a vehicle, when traveling with a lower part of the vehicle body dipped in water, in the case of the above configuration according to the background art, the waterproof property of the lean sensor must be enhanced. This enhancement can increase the cost of the lean sensor.
Furthermore, in the above vehicle, it is desirable to detect the leaning of the vehicle body that has reached a prescribed angle in the right and left directions and in the front and rear directions. However, it is not preferable to add another lean sensor for that purpose because that increases the costs of the vehicle.