An airfield hazard automated detection device having a radar for scanning the airfield for obstacles and an automated target recognition system, operably connected to the radar, for comparing the images of the scans of the obstacles to images of known potential hazards and for instructing a directed imaging system to verify the potential hazard by scanning the potential hazard and indicating the result.

Each year the Federal Aviation Administration records many accidents that result in millions of dollars in damage to aircraft and uncounted costs to airfield operations. These accidents are often caused by wildlife that wandered onto the flight line, manmade objects forgotten on the flight line, or other objects blown onto the flight line.
Traditional methods of detecting these hazards have been time consuming and prone to large margins of error as both false positives and complete misses resulting in airfield hazards. Historically, even in sophisticated operations, an air traffic controller (ATC) would monitor a low resolution radar system. Based on the output from the system, the ATC would make a judgment whether the radar had detected a hazard. Often the hazards would be misinterpreted or altogether missed. The ATC would frequently also stop time sensitive flight line operations to manually verify that the flight line was clear of all airfield hazards.
There are at least two problems with this system. First, the radar is not a very precise instrument for detecting hazards. The radar typically has a very low resolution. Secondly, even if the radar does identify an airfield hazard, because of human error and interpretation it may not be verified and corrected.
As such, a need currently exists for an improved method and device for detecting hazards to airfield operations.

Airfield hazard automated detection system

The United States of America as represented by the Secretary of the Army


The technology relates generally to the field of immunology and relates in part to compositions and methods for controlling the proliferation of T cells, for example, therapeutic T cells. The methods further relate to compositions and methods for inducing an immune response in a subject.

T cell activation is an important step in the protective immunity against pathogenic microorganisms (e.g., viruses, bacteria, and parasites), foreign proteins, and harmful chemicals in the environment. T cells express receptors on their surfaces (i.e., T cell receptors) that recognize antigens presented on the surface of antigen-presenting cells. During a normal immune response, binding of these antigens to the T cell receptor initiates intracellular changes leading to T cell activation.
Chimeric antigen receptors (CARs) are artificial receptors designed to convey antigen specificity to T cells. They include an antigen-specific component, a transmembrane component, and an intracellular component selected to activate the T cell and provide specific immunity. Chimeric antigen receptor-expressing T cells may be used in various therapies, including cancer therapies. While effective against tumors, in some cases these therapies have led to side effects due, in part to non-specific attacks on healthy tissue. A method for controllable T cell therapy is needed that provides a strong immunotherapeutic response and avoids toxic side effects.

Methods for controlling T cell proliferation


A clock recovery apparatus includes a mask generator configured to generate a plurality of time masks using a multi-phase clock signal and a clock recovery unit configured to select one of the time masks to recover a clock from a data stream.

1. Field of the Invention
The present invention relates to a serial interfacing technique, and more particularly, to a clock recovery apparatus in which a clock embedded in data is recovered by using multiple time masks (windows).
2. Discussion of the Related Art
In the field of flat panel displays (FPD), panel size, the number of pixels, and operating speed have been sharply increased. As a result, the amount of data has also been increased. Therefore, it is necessary to improve the performance at a data receiving end to process the data substantially simultaneously.
A conventional interface, such as multipoint-low voltage differential signaling (m-LVDS) or LVDS, separately transmits the clock and the data. In the serial interface that separately transmits the clock and the data, as the data rate increases, timing skew between the clock and the data may adversely affect correct data transmission.
In recent years, a clock-embedded serial interface that transmits a clock embedded in data has been proposed.
FIG. 1 is a view illustrating a clock recovery structure of a conventional clock-embedded serial interface.
In the clock embedded serial interface of FIG. 1, a transmitting end transmits data having a clock embedded therein, and a receiving end extracts and recovers the clock from the data.
A phase locked loop/delay locked loop (PLL/DLL) 10 generates multi-phase clocks. A mask generator 20 generates a time mask using the multi-phase clocks at a time when a clock is extracted from data. As a result, the clock is accurately recovered by positioning the time mask at the corresponding timing or phase.
Specifically, the mask generator 20 generates the time mask using the multi-phase clocks generated by the PLL/DLL 10, and an AND gate 30 receives the original input data and the time mask generated by the mask generator 20 and recovers the clock.
At this time, the generated time mask is positioned to be synchronized with the clock or the cover a rising edge and a falling edge of the clock, so that the clock is recovered irrespective of a value of the data region.
However, process, voltage, and temperature (PVT) conditions act as considerable variables in clock recovery and can cause severe variations in clock recovery conditions. Therefore, stable clock recovery may not be performed efficiently or correctly.
Specifically, even if the time masks are ideally generated using the multi-phase clocks of the PLL/DLL 10 (which are not independent of PVT conditions), a time delay generated during generation of the time mask can vary depending on the PVT conditions, so that the time mask is not accurately positioned.
When the time delay depending on the PVT conditions is greater than a predetermined setting amount, the recovered clock is output later than the original timing, which increases the amount of jitter of the PLL/DLL 10. Consequently, an error in clock recovery may gradually increase, and therefore, an error rate in data recovery may also gradually increase.
On the other hand, when the time delay is smaller than the predetermined setting amount, the recovered clock may be output earlier than the original timing, which can also increase the amount of jitter of the PLL/DLL 10. Consequently, the clock and the data may not be properly recovered.
For this reason, the position of the time mask should be gradually and/or manually corrected in view of the respective PVT conditions. Therefore, a new apparatus for performing such operations is proposed.


A graphical user interface is provided for displaying network analysis including a window including a plurality of gauges selected from the group consisting of a first gauge for indicating a number of packets specified by the network analysis, a second gauge for indicating a network utilization specified by the network analysis, and a third gauge for indicating a number of errors specified by the network analysis.

The present invention relates to the field of computer networks. In particular, the present invention relates to a system, computer program product and method for analyzing handshake protocols for the physical link layer of a computer network.
Network protocol analyzers are widely used to monitor computer network performance and assist users in analyzing the causes of network slowdowns or outages. Protocol analyzers assist in explaining possible causes for network problems, collect expert analysis data automatically, learn network configurations continuously, show breakdown of network protocol activity automatically, display network errors, frame size, and station statistics, enable creation and generation of management reports, consolidate information from remote sites at a central location, point out problems proactively by communicating alarms to a central location, and display multiple windows concurrently allowing a service person to view prioritized alarms, global statistics, traffic statistics, and expert analysis information from one or several servers simultaneously. An exemplary protocol analyzer is the Sniffer Pro 3.0 currently available from Network Associates, Inc, described in the user""s manuals for the Sniffer Pro 3.0(copyright) and Sniff master(copyright) for Windows, the contents of which are hereby incorporated by reference. Protocol analyzers are described in various white papers, available at Network Associate""s website, http://www.nai.com, and specifically at the webpage http://www.nai.com/asp_set/buy_try/try/whitepapers.asp, hereby incorporated by reference as of the filing date of this application.
FIG. 1 is a diagram of an exemplary enterprise network 100, comprising a plurality of local area networks 104,106, 108 and 110. Local area networks 104, 106 and 110 are connected via routers 132 and 134. Local area network 108 is a remote network coupled to the remaining network through the Internet 112 and gateway devices 114 and 116. The network 100 includes a protocol analysis server 140, and protocol analysis agent computers 148, 150 and 152, to provide monitoring and troubleshooting information for the entire network 100. Protocol analysis software, such as the Sniffer Pro 3.0, loads onto protocol analysis server 140 and may also comprise remote agents that are loaded onto the protocol analysis agent computers 148, 150, and 152. The protocol analysis software compiles and displays information on network activity from the data-collecting protocol analysis agent computers 148, 150, and 152.
For many network topologies, including Gigabit Ethernet, communication requires establishing a point-to-point linkxe2x80x94that is, the link at the physical layer. To establish this link, the two devices attempting to communicate go through a training and negotiation process until an agreement is reached on parameters for communication. If no agreement is reached within some reasonable period (on the order of several seconds), or an error condition occurs, the attempt to establish a link has failed.
An example of this process for Gigabit Ethernet is shown in FIG. 2. At time t0, node 1 initiates the training and negotiation process by sending information in the form of an xe2x80x9cauto-negotiation ordered setxe2x80x9d to node 2. The auto-negotiation ordered set is the physical link layer handshake protocol control packet used for Gigabit Ethernet. An auto-negotiation ordered set includes of several copies of an auto-negotiation configuration register value, reg_value, transmitted with alternating headers. The two alternating headers are /C1/and /C2/, consist of two ten-bit codes, and signify that what follows is an auto-negotiation configuration register value. The register value is conveyed by two 10-bit codes, which are converted to two eight-bit words corresponding to hexadecimal characters. The register value consists thus consists of one sixteen bit word. The individual bits in the sixteen-bit word have meanings defined by the protocol standard, indicating the various capabilities of the sending node. The receiving node responds at time t1 with its own auto-negotiation configuration register value, indicating its own capabilities, along with an acknowledgment.
The two nodes continue to modify their requirements, as reflected in the auto-negotiation configuration register value, until an agreement is reached. When a node receives an acceptable auto-negotiation configuration register value from the other node, the node transmits an xe2x80x9cIDLExe2x80x9d signal. When both nodes transmit xe2x80x9cIDLExe2x80x9d signals an agreement has been reached and frames may be sent. Details of the auto-negotiation process, the ten-bit to eight-bit conversion, and the register values for Gigabit Ethernet are described in the IEEE 802.3z standard, the contents of which are hereby incorporated by reference into the present application.
Prior art protocol analyzers are directed primarily to gathering and analyzing information relating to data transmissionxe2x80x94that is, the frames of data exchanged by the various devices attached to the network. Efforts to establish the physical layer link are not traditionally visible to users. As shown in FIG. 3, the protocol analyzer does not begin capture 303 or analysis 304 until after a link is established 302. Until the link is established 302, no frames of data can be exchanged. For relatively low-speed communication protocols, establishing a link is usually not problematic, because the technology for low-speed links is mature.
However, for some high-speed topologies such as Gigabit Ethernet, many network failures occur during attempts to establish a link. For example, one device may have communication requirements that are incompatible with another device, or a device may not modify its requirements appropriately in order to reach an agreement. Most prior art protocol analyzers fail to capture any information on the training and negotiation process, requiring the use of one or more logic analyzers to capture the information as digital waveforms, and extensive effort to decode the information. That is, the physical link layer handshake protocol control packets are not captured by these prior art protocol analyzers. Furthermore, those prior art protocol analyzers that do capture the physical link layer handshake protocol control, packet provide no merged information and no decoding or analysis, requiring a time-consuming process to troubleshoot the link failure. For example, as shown in FIG. 4, Version 2.5 of Network Associate""s Sniffer Pro(copyright) protocol analyzer captures the auto-negotiation ordered sets 401 for each of the two channels between the two devicesxe2x80x94one channel transmitting in each directionxe2x80x94and displays the raw binary and converted hexadecimal auto-negotiation ordered sets for each channel on a separate page 405, without merging the information for the two channels onto a single, time-ordered display. The auto-negotiation ordered sets for each channel are kept in the order in which they were sent 402 on separate displays for each channel. No decoding or analysis is provided for the auto-negotiation ordered setsxe2x80x94only for the frame data.
FIGS. 5a-5i are screen displays for Sniffer Pro v.2.5 corresponding to the process sown in FIG. 4. FIG. 5a is a screen display of the main menu, before the training and negotiation process is initiated. Neither channel is up, and the capture buffers are both empty. FIG. 5b is the help menu describing the various display capabilities. FIGS. 5c-5e show the sequentially-ordered auto-negotiation ordered sets 405 for channel 1, corresponding to node 1. The auto-negotiation register values and frame information are provided in hexadecimal in the first two columns, and decoding for the frame information and the idle signals is provided in the third column. The time stamps appear in the far right column.
The first auto-negotiation ordered set appears on FIG. 5c at timestamp 01:998:509:424, in units of seconds: milliseconds: microseconds: nanoseconds. The training and negotiation is complete and the link established 404 by timestamp 08:856:536:079, when channel 1 has transmitted several idles, and the start_of_frame is transmitted. FIGS. 5f-5h show the auto-negotiation ordered sets 403 in raw binary form. The raw binary information is provided in the first column, along with the corresponding 8 bit register values in hexadecimal in the second columnxe2x80x94that is, the 8 bits is the hexadecimal value corresponding to a ten-bit code. The third column is the header information, which provides the name of the corresponding ten-bit code; the code may be either a control code or a data code. Corresponding hexadecimal and raw data for channel 2 is shown in FIGS. 5i-5l.
Once both channels are carrying the idle signal, the link is established 404 and frame data is captured 405. FIG. 5m shows frame data for channel one in hexadecimal form, and FIG. 5n shows decoded frame data 406. FIGS. 5o and 5p show hexadecimal and decoded frame data 406 for channel 2. Finally, FIG. 5q shows a merged view of the decoded frame data for both channels 406.
As shown in FIGS. 5a through 5q, decoding is provided only for the frame data and the idle state. The raw auto-negotiation ordered set data is converted from 10-bit to hexadecimal form, but no decodingxe2x80x94no bitwise explanation of the register valuexe2x80x94is provided. Furthermore, although the frame data from both channels is merged, the auto-negotiation ordered sets for the two channels are not merged to facilitate analysis of a link failure. Instead, the auto-negotiation ordered sets for each channel are shown in a separate display. Thus, a user attempting to determine why the devices failed to establish a link, using the information provided in FIGS. 5c through 5l, must go through a tedious and time-consuming process. First, the user must combine the information from channel 1 and channel 2, locating the timestamps for each auto-negotiation ordered set, and putting the merged auto-negotiation ordered sets for both channels in sequential order. Then, for each auto-negotiation ordered set, the user must look up and decode the register value in a reference such as the IEEE 802.3z standard. This decoding must be distinguished from simply identifying the hexadecimal value corresponding to a ten-bit code: here, xe2x80x9cdecodingxe2x80x9d means that the user must look up the meaning of each individual bit to determine the configuration represented by the register value. Finally, the user must analyze the sequence of events to determine the cause of the failure and identify a possible solution.
Accordingly, it would be desirable to provide a protocol analyzer which captures, merges, decodes, analyzes and displays information on the training and negotiation process used to establish a linkxe2x80x94that is, the physical link layer handshake protocol control packets.
It would be further desirable to provide an function to determine the cause of a failure to establish a link, based on an analysis of the failure of the training and negotiation process.
A graphical user interface is provided for displaying network analysis including a window including a plurality of gauges selected from the group consisting of a first gauge for indicating a number of packets specified by the network analysis, a second gauge for indicating a network utilization specified by the network analysis, and a third gauge for indicating a number of errors specified by the network analysis.

Graphical user interface system and method for visually gauging network performance


A solenoid valve for a fuel system has an electric coil and an armature disposed in a housing. A preassembled valve unit with valve seat, valve member, valve spring, and armature plate connected captively to each other is provided. In the valve unit, the valve seat is loosely secured between valve member and armature plate. The valve unit is inserted and secured in an open housing end and the valve spring contacts an inner shoulder of the housing. Armature plate and armature form a magnetic circuit. The valve member is supported on the armature plate and switched to open and close an outlet of the valve seat. By suppling current, a magnetic field is generated in the armature and attracts the armature plate into an operative valve position. The valve spring returns the armature plate into a rest position when the coil is currentless.

The invention relates to a solenoid valve for a fuel system comprising a housing in which an electric coil and an armature are arranged. The armature and an armature plate together form parts of a magnetic circuit wherein the armature plate supports a valve member which forms, together with an outlet provided at a valve seat, the switchable valve. When current is flowing through the coil, a magnetic field is generated in the armature and the armature plate is attracted by the armature into an operative valve position. A valve spring is provided which returns the armature plate into a rest position when the coil is currentless (no current is flowing through the coil). The valve seat, the valve member, the valve spring, and the armature plate are secured in the housing.
Such a solenoid valve comprises a housing in which an electric coil and an armature are arranged, wherein the armature and an armature plate form parts of a magnetic circuit. The armature plate supports a valve member which controls a valve seat with an outlet. When current is flowing through the coil, a magnetic field is produced and the armature plate is attracted by the armature into a first valve position, which is the operative valve position. When the coil is currentless, the armature plate is returned by means of a valve spring into a second valve position, which is the rest position. The valve seat, the valve member, the valve spring, and the armature plate are secured in the housing.
Assembly of the solenoid valve from its individual parts is complex and in particular the positional adjustment of the valve seat, the valve member, the valve spring, and the armature plate is complex.
The invention has the object to further develop a solenoid valve of the aforementioned kind in such a way that a positionally correct assembly of valve seat, valve member, valve spring, and armature plate is facilitated.


An intake air amount control system for an internal combustion engine, which controls respective amounts of intake air drawn into four cylinders #1 to #4, independently of each other, by variable inter-intake cam phase mechanisms 80, identifies intake air amount variation coefficients Φ#i, based on a model [equation (43)] defining a relationship between an estimated value Gth_est of a TH passing intake air amount and a plurality of simulation values Gcyl_OS#i, such that the estimated value Gth_est becomes equal to the TH passing intake air amount, calculates a target inter-intake cam phase θssi#i_cmd, on a cylinder-by-cylinder basis, according to the identified intake air amount variation coefficients Φ#i (step 81), and calculates control input DUTY_ssi#2 to #4 to the variable inter-intake cam phase mechanisms 80 according to the target inter-intake cam phases θssi#i_cmd (step 75).

Conventionally, as an intake air amount control system for an internal combustion engine, there is known one described in Patent Literature 1, for example. The engine is of a four-cylinder type, and is comprised of an electromagnetic valve mechanism provided for each cylinder, for changing the valve-closing timing relative to the valve-opening timing of each cylinder, and a throttle valve mechanism. As described hereinafter, in this intake air amount control system, to control idling speed, the valve-closing timing of each intake valve is controlled via the electromagnetic valve mechanism, whereby the intake air amount is controlled. More specifically, a target intake air amount for feedforward control is calculated according to target engine speed, and further, the maximum value of absolute values of the differences between an average value of valve-closing times of the intake valves of all the cylinders and the valve-closing times of the cylinders is calculated. Further, according to the maximum value of the absolute values of the differences, a gain for feedback control is calculated. A target intake air amount for feedback control is
calculated according to the gain, and the valve-closing timing of each intake valve is calculated based on the two target intake air amounts for feedback control and feedforward control and so forth, and the valve-closing timing of the intake valve is controlled by the calculated valve-closing timing. The valve-closing timing of each intake valve is controlled as described above, thereby suppressing variation in the idling speed caused by the difference in the intake air amount between the cylinders resulting from the different valve-closing times of the respective intake valves.
According to the conventional intake air amount control system, the target intake air amount for feedback control is calculated based the maximum value of the respective absolute values of differences between the average value of the valve-closing times of the intake valves of all the cylinders and the valve-closing times of the cylinders, and finally only one value is calculated as the valve-closing timing for the intake valves. Then, the intake valves of all the cylinders are only controlled using the one value. Therefore, there is a problem of incapability of correcting variation in the intake air amount between the cylinders. Therefore, in the control of the engine speed in a very low load region, such as an idling speed region, it is possible to suppress the rotational variation, but in a normal operation load region, torque variation or rotational variation occurs due to variation in the intake air amount between the cylinders, and the combustion state is degraded. As a consequence, drivability and exhaust emission characteristics are degraded. This problem becomes conspicuous particularly in a high load region or during lean operation (during execution of EGR).
The present invention has been made so as to solve the above problems, and an object thereof is to provide an intake air amount control system for an internal combustion engine, which is capable of correcting variation in intake air amount between cylinders, to thereby improve both drivability and exhaust emission characteristics even in a normal operation load region including a high load region.
[Patent Literature 1]
Japanese Laid-Open Patent Publication (Kokai) No. 2001-140661 (pages 5 and 6, FIGS. 6 to 18)

Intake air volume controller of internal combustion engine


The invention provides a holster for a longbarrelled gun which allows the gun to be worn by the outdoorsman without impeding his activities such that the gun is always quickly and easily accessible to the wearer. The holster comprises a holster for carrying a gun having a long barrel on the body of the wearer without impeding the activity of the wearer which comprises in combination an elongated sheath adapted to accommodate the barrel of the gun and a harness adapted to fit over the body of the wearer such that the sheath extends down the back of the body of the wearer such that said gun in said holster is readily accessible to the wearer on reaching back over his shoulder whereby to quickly and easily withdraw the gun from the holster.

The present invention relates to gunholsters. In particular, the present invention relates to holsters for long barrelled guns which may be worn on the body without impeding the activities of the wearer and where the gun is always quickly and easily accessible to the wearer.
Outdoorsmen who have activities in the wilderness, such as the forests and bush of British Columbia, Canada such as fishermen, hikers, surveyors and oil field exploration people when indulging in their recreational or professional activity find it necessary to carry a gun so as to defend themselves if attacked by wild animals, in particular by bears, such as brown bears. However, handguns are not effective against large wild animals and the fisherman, for example, usually has to have a more powerful gun which is effective in killing large wild animals, such as bears. Such a gun is longbarrelled gun and by the term longbarrelled gun as used herein and in the claims of this application is meant a gun which has a longer barrel than a hand gun, such as a rifle or a shotgun which may, for convenience, have a shortened barrel or a pistol grip or a collapsible stock. Thus, for example, such guns include riot shotguns and assault rifles. Some typical examples include the Winchester Defender Shotgun, the Remington 870 Riot Shotgun and the Ruger Min 14 Rifle which has a collapsible stock.
Such longer barrelled gun, if carried by the fisherman, impedes his fishing activity and thus heretofore the fisherman has laid the gun on the ground nearby where he is fishing, such as with his fishing tackle. However attacks by bears come very quickly and unexpectedly, the bears travelling at about 45 miles an hour and it is necessary for the fisherman to quickly retrieve his gun ready for firing if the attack turns out to be serious. It is quite probable that in such circumstances the gun is at a distance from the fisherman and not readily accessible to him and under stress of the charging bear the fisherman simply finds it impossible to retrieve his gun.
The present invention provides a holster for a longbarrelled gun of sufficient power to kill large wild animals such as bears which allows the wearer to carry the gun on his body without impeding his activity in the absence of danger from such animals and at the same time allows him to readily and quickly pull the gun from the holster so as to be in a position to fire the gun and thus defend himself against the charging wild animal.


The present invention is directed to the provision of pharmaceutical compositions. The compositions include a therapeutic agent and a relatively low amount of surfactant for providing higher bioavailability of the therapeutic agent. The compositions are particularly desirable as ophthalmic compositions in which the therapeutic agent is a prostaglandin such as travoprost and the surfactant is a vegetable oil such as castor oil.

The present invention is directed to pharmaceutical compositions formulated to exhibit enhanced bioavailability of a therapeutic agent of the composition. The composition may also exhibit other additional or alternative desired characteristics. For example, the composition may also be sterile, may exhibit desired antimicrobial or preservation efficacy, may exhibit a desired degree of stability, combinations thereof or the like.
Therapeutic agents (e.g., ophthalmic drugs) of many pharmaceutical compositions are often required to be stable within those compositions. It is typically undesirable for the therapeutic agents or overall compositions to decompose or chemically or physically change to a significant degree prior to application of the agents to an individual or otherwise. For maintaining stability, pharmaceutical compositions are typically formulated with ingredients that can enhance such stability or ingredients that can minimize destabilizing effects of other entities (e.g., chemicals, ambient conditions or the like).
Surfactants are one preferred family of ingredients that have exhibited significant efficacy in stabilizing pharmaceutical compositions and/or therapeutic agents thereof (particularly aqueous ophthalmic solutions including relatively lipophilic and/or relatively insoluble components). Moreover, it has generally been believed that stability of an agent or composition can often be achieved by using larger concentrations of surfactant within that pharmaceutical composition.
In addition to stability of the agents or compositions, it is also typically desirable for the therapeutic agents of the pharmaceutical compositions to exhibit relatively high degrees of bioavailability. Such bioavailability often becomes particularly important where the method or manner of application or dosing of a particular pharmaceutical composition provides only a limited amount of time for the therapeutic agent of that composition to be absorbed or otherwise taken in by a biological target such as an eye, ear, throat or nose of an individual. As an example, topically applied ophthalmic pharmaceutical compositions may only dwell in or on an individual's eye for a limited period of time (e.g., before tears transport the composition elsewhere). Thus, it is often desirable to limit the concentration of any ingredient in a pharmaceutical composition where that ingredient tends to inhibit bioavailability of a therapeutic agent of that composition.
Recently, it has been discovered that surfactants, when used at certain higher concentrations, may act as an ingredient that can limit the bioavailability of a therapeutic agent, particularly an ophthalmic therapeutic agent. As a consequence, the addition of surfactant to pharmaceutical compositions and particularly ophthalmic compositions can limit the bioavailability and, in turn, the efficacy of the therapeutic agent in the composition. However, as suggested above, surfactants can also be quite desirable in a pharmaceutical composition since they can significantly enhance the stability of a pharmaceutical composition or therapeutic agent.
In view of the above, it would be desirable to provide a pharmaceutical composition with a lower surfactant concentration and/or a higher bioavailability of a therapeutic agent. Moreover, it would also be desirable, although not required unless otherwise specifically stated, for such composition to exhibit a desirable level of stability.

This patent is subject to a terminal disclaimer.

Pharmaceutical compositions having desirable bioavailability


Techniques are provided for overdrive pacing the ventricles using a pacemaker wherein an increase in an overdrive pacing rate is performed primarily to achieve a high degree of rate smoothing. The ventricles are paced at an overdrive pacing rate selected to permit the detection of the least some intrinsic ventricular pulses and then the overdrive pacing rate is dynamically adjusted based on the detected intrinsic ventricular pulses. In one example, an increase in the ventricular overdrive rate is performed only in response to detection of at least two intrinsic ventricular beats within a predetermined search period. If at least two intrinsic ventricular beats are not detected within the search period, the overdrive pacing rate is decreased. Various techniques are also provided for determining when to activate ventricular overdrive pacing depending, in part, on the capabilities of the particular pacemaker, the current mode of operation, the density of premature ventricular contractions, the degree of heart rate stability, and the presence of atrial fibrillation. Adaptive techniques for automatically adjusting ventricular overdrive pacing control parameters are also described.

A dysrhythmia is an abnormal heart beat pattern. One example of dysrhythmia is bradycardia wherein the heart beats at an abnormally slow rate or wherein significant pauses occur between consecutive beats. Other examples of dysrhythmias include tachyarrhythmias wherein the heart beats at an abnormally fast rate. With atrial tachycardia, such as atrial fibrillation (AF), the atria of the heart beat abnormally fast. With ventricular tachycardia, the ventricles of the heart beat abnormally fast. Though often unpleasant for the patient, a tachycardia is typically not fatal. However, some tachycardias, particularly ventricular tachycardia, can trigger ventricular fibrillation wherein the heart beats chaotically such that there is little or no net flow of blood from the heart to the brain and other organs. Ventricular tachycardia, if not terminated, is fatal. Hence, it is highly desirable to prevent or terminate dysrhythmias, particularly ventricular tachycardias.
One technique for preventing or terminating dysrhythmias is to overdrive pace the heart wherein a implantable cardiac stimulation device, such as a pacemaker or implantable cardioverter defibrillator (ICD), applies electrical pacing pulses to the heart at a rate somewhat faster than the intrinsic heart rate of the patient. For bradycardia, the cardiac stimulation device may be programmed to artificially pace the heart at a rate of 60 to 80 pulses per minute (ppm) to thereby prevent the heart from beating too slow and to eliminate any long pauses between heart beats. To prevent tachyarrhythmias from occurring, the cardiac stimulation device artificially paces the heart at a rate of at least five to ten beats per minute faster than the intrinsic tachyarrhythmia heart rate of the patient. In other words, a slight artificial tachycardia is induced and maintained in an effort to prevent an actual tachycardia from arising. If an actual tachycardia occurs, such as a supraventricular tachycardia (SVT) wherein the heart may begin beating suddenly at 150 beats per minute (bpm) or more, the cardiac stimulation device senses tachycardia and immediately begins pacing at a rate of at least five to ten ppm faster than the tachycardia, then slowly decreases the pacing rate in an effort to slowly reduce the heart rate back to a normal resting rate thereby terminating the tachycardia.
It is believed that overdrive pacing is effective for at least some patients for preventing or terminating the onset of an actual tachycardia for the following reasons. A normal, healthy heart beats only in response to electrical pulses generated from a portion of the heart referred to as the sinus node. The sinus node pulses are conducted to the various atria and ventricles of the heart via certain, normal conduction pathways. In some patients, however, additional portions of the heart also generate electrical pulses referred to as "ectopic" pulses. Each pulse, whether a sinus node pulse or an ectopic pulse has a refractory period subsequent thereto during which time the heart tissue is not responsive to any electrical pulses. A combination of sinus pulses and ectopic pulses can result in a dispersion of the refractory periods which, in turn, can trigger a tachycardia. By overdrive pacing the heart at a uniform rate, the likelihood of the occurrence of ectopic pulses is reduced and the refractory periods within the heart tissue are rendered uniform and periodic. Thus, the dispersion of refractory periods is reduced and tachycardias triggered thereby are substantially avoided. If a tachycardia nevertheless occurs, overdrive pacing at a rate faster than a tachycardia helps to eliminate ectopic pulses and reduce refractory period dispersion, and thereby helps to terminate the tachycardia.
Thus, it is desirable within patients prone to tachyarrhythmias to ensure that most beats of the heart are paced beats, as any unpaced beats may be ectopic beats. A high percentage of paced beats can be achieved simply by establishing a high overdrive pacing rate. However, a high overdrive pacing rate has disadvantages as well. For example, a high overdrive pacing rate may be unpleasant to the patient, particularly if the artificially-induced heart rate is relatively high in comparison with the heart rate that would otherwise normally occur. A high heart rate may also cause possible damage to the heart or may possibly trigger more serious dysrhythmias, such as a ventricular fibrillation.
A high overdrive rate may be especially problematic in patients suffering from heart failure, particularly if the heart failure is due to an impaired diastolic function. A high overdrive rate may actually exacerbate heart failure in these patients. Also, a high overdrive rate may be a problem in patients with coronary artery disease because increasing the heart rate decreases diastolic time and decreases perfusion, thus intensifying ischemia. Also, the need to apply overdrive pacing pulses operates to deplete a power supply of the implantable cardiac stimulation device, perhaps requiring frequent surgical replacement of the power supply.
Problems associated with overdrive pacing are particular severe for certain aggressive overdrive techniques which trigger an increase in the pacing rate based upon detection of a single intrinsic heart beat. With such techniques, a significant increase in the pacing rate is triggered by detection of a single intrinsic heart beat so as to respond promptly to the occurrence of a high rate tachycardia, such as an SVT. As a result, even in circumstances where a high rate tachycardia has not occurred, the detection of a single intrinsic heart beat can cause a significant increase in the overdrive rate, which may be reduced only gradually. If a second intrinsic heart beat is detected before the overdrive rate has been gradually lowered to a standard overdrive pacing rate, a still further increase in the pacing rate occurs. As can be appreciated, the foregoing can cause the overdrive pacing rate to increase significantly, perhaps to 150 ppm or more, even though no high rate tachycardia has occurred.
Hence, it would be desirable to provide techniques for overdrive pacing which reduce the average overdrive pacing rate, yet still attain a sufficiently high rate to significantly reduce the likelihood of a dysrhythmia within the patient or to terminate a dysrhythmia if one nevertheless occurs. In particular, it would be highly desirable to provide overdrive pacing techniques which permit a certain percentage of paced beats (such as 90% or 95%) to be sustained by the cardiac stimulation device so as to enable the overdrive rate to be minimized while still ensuring that most beats of the heart are paced beats. It was to these ends that aspects of the invention of the parent application were primarily directed.
The parent patent application referenced above was primarily directed to a technique for overdrive pacing the atria wherein an increase in the overdrive pacing rate is performed only in response to detection of at least two intrinsic atrial beats within a predetermined search period. In one specific technique, an increase in the atrial pacing rate occurs only if two P-waves are detected within X cardiac cycles of one another. In another specific technique, the overdrive rate is increased only if at least two P-waves are detected within a block of N consecutive cardiac cycles. In both techniques, the overdrive rate is decreased if no increase has occurred in the last Z cardiac cycles. By increasing the overdrive pacing rate only in response to detection of at least two P-waves within a predetermined number of cardiac cycles, an excessively high overdrive pacing rate is avoided which might otherwise occur if a rate increase were triggered based upon detection only of a single P-wave.
Insofar as the ventricles are concerned, overdrive pacing is also beneficial. However, unlike the atria, where it is generally desirable to achieve a high percentage of overdrive paced beats, with the ventricles it is generally best to provide rate smoothing, i.e. to provide a generally uniform ventricular rate as a function of time. Significant variations in the ventricular rate as a function of time presents a considerable annoyance to the patient who feels his or her heart rate increasing or decreasing frequently. Moreover, significant variations in ventricular rate can sometimes trigger atrial and ventricular tachyarrhythmias.
Various techniques have been developed in an attempt to provide rate smoothing of the ventricular rate. However, heretofore, ventricular rate smoothing techniques have often attempted to achieve rate smoothing primarily through fixed, non-overdrive ventricular pacing. In this regard, it has been found that there is a correlation between the degree of variation in the actual ventricular rate and the fixed rate at which the ventricles are paced. If the ventricles are paced at, for example, a fixed rate of 80 ppm, the resulting ventricular rate varies between the fixed rate of 80 ppm and much higher rates, such as 140 ppm. However, by pacing the ventricles at a higher fixed rate, for example, 100 ppm, the actual ventricular rate may only vary between the fixed rate of 100 ppm and a reduced upper rate of, perhaps, only 130 ppm. By pacing the ventricles at a still higher fixed rate, for example, 120 ppm, the actual ventricular rate may vary only within a much narrower range, such as from 120 to 125 ppm. In other words, the higher the fixed ventricular paced rate, the smoother the resulting ventricular rate.
Thus, rate smoothing of the ventricles can be achieved by pacing the ventricles at a high fixed rate. However, fixed rate pacing of the ventricles can result in "pacemaker syndrome", which is typically characterized by hypotension, shortness of breath, and fatigue. Also, in many cases, fixed rate pacing of the ventricles at a high rate can cause "concealed retrograde conduction", wherein a retrograde impulse travels from the ventricular pacing site back to the AV junction. Although this may not cause the atria to fire, the result is a lengthening of the AV junctional repolarization time, possibly adversely affecting the proper function of the atria and triggering atrial tachycardias.
Certain other ventricular rate smoothing techniques seek to achieve smoothing using adjustable ventricular pacing rates. However, these techniques appear to suffer from problems similar to those described above in connection with conventional atrial overdrive techniques, namely such techniques may be too sensitive to changes in the intrinsic ventricular rate. As an example of a technique which seeks to achieve ventricular rate smoothing using adjustable ventricular pacing rates see U.S. Pat. No. 5,792,193 to Stoop, entitled "Pacemaker System And A Method With Ventricular Rate Smoothing During High Rate Atrial Arrhythmia." In the technique described by Stoop, during a pathologically high atrial rate episode, the pacemaker determines a ventricular pacing escape interval, corresponding to a flywheel rate, with the flywheel rate set at the beginning of the episode to be substantially equal to the atrial rate just before the high rate episode. As long as the episode continues, the flywheel rate is incremented upward whenever a ventricular sense occurs, thereby attempting to follow the average ventricular rate. Whenever a flywheel escape interval times out and a ventricular pacing pulse is delivered, flywheel rate is decremented. Ventricular sensing and pacing occurs only after timeout of the flywheel escape interval. Thus, detection of a single ventricular intrinsic sensed event causes an increase in the flywheel rate; whereas failure to detect an intrinsic ventricular event during the flywheel escape interval triggers an immediate decrease in the flywheel rate. As such, the pacemaker may be too sensitive to individual ventricular intrinsic sensed beats to provide for optimal ventricular rate smoothing. Moreover, the technique of Stoop only appears to provide for rate smoothing during episodes of pathologically high atrial rates and does not provide rate smoothing at other times.
In any case, it does not appear that, heretofore, any techniques have been developed for performing ventricular overdrive pacing, either for the purpose of achieving ventricular rate smoothing or for other reasons, which effectively controls and limits changes in the ventricular overdrive rate. Hence, it would be desirable to provide techniques for providing dynamic overdrive pacing of the ventricles either for ventricular rate smoothing or for other reasons, and aspects of the present CIP application are primarily directed to that end. Whereas atrial overdrive pacing is typically performed more or less continuously once activated by a physician, with ventricular overdrive pacing, care should be taken to ensure that the overdrive pacing of the ventricles is performed only when needed so as not to unduly increase the risk of ventricular dysrhythmias. Accordingly, techniques are also provided herein for activating and deactivating ventricular overdrive pacing based on various factors such as the capabilities of the particular pacing device (i.e. DDD vs. VVI pacers), the mode of operation (i.e. tracking vs. non-tracking mode) and the general medical condition of the patient (i.e. chronic AF vs. non-chronic AF.) In particular, techniques are provided for evaluating of the density of premature ventricular contractions (PVCs) and for disabling ventricular overdrive pacing in circumstances where overdrive pacing inadvertently triggers an increase in PVC density, which can in turn trigger ventricular tachyarrhythmia.

System and method for dynamic ventricular overdrive pacing


A pressure type flow rate control apparatus is provided wherein flow rate of fluid passing through an orifice is computed as Qc=KP1 (where K is a proportionality constant) or as Qc=KP2m (P1-P2)n (where K is a proportionality constant, m and n constants) by using orifice upstream side pressure P1 and/or orifice downstream side pressure P2. A fluid passage between the downstream side of a control valve and a fluid supply pipe of the pressure type flow rate control apparatus comprises at least 2 fluid passages in parallel, and orifices having different flow rate characteristics are provided for each of these fluid passages, wherein fluid in a small flow quantity area flows to one orifice for flow control of fluid in the small flow quantity area, while fluid in a large flow quantity area flows to the other orifice for flow control of fluid in the large flow quantity area.

Not only is high flow rate control accuracy required for a flow rate control apparatus used with semiconductor manufacturing facilities, and the like, but also a considerably wide control range is required with regard to the flow rate control range. As the required flow rate control range becomes greater, it is inevitable that control accuracy is lowered in low flow rate situations. Thus, it is difficult to make up for the degradation of control accuracy in a low flow rate state using only a flow rate control apparatus provided with a feature with which to correct a measured value. To overcome this problem in a general way, a flow rate control range may be divided into a plurality of flow rate areas, e.g. the area for a large flow quantity, the area for a medium flow quantity and the area for a small flow quantity, in order to meet a required flow rate control range. This solution, however, involves providing 3 sets of flow rate control apparatuses, each one responsible for the flow rate control of one of each one of the flow rate areas in parallel so that high flow rate control accuracy can be maintained over a wide flow rate control range.
However, in a system, in which a plurality of devices responsible for different flow rate control ranges, respectively, are provided in parallel, installation costs unavoidably go up, which makes it difficult to reduce the installation costs. At the same time, switching operations of flow rate control apparatuses become time-consuming and troublesome. Also, with respect to semiconductor manufacturing facilities, it has become more popular these days to replace the conventional thermal type mass flow rate control apparatus with a pressure type flow rate control apparatus. The reason for this replacement is that a pressure type flow rate control apparatus is not only simple in structure, but also has excellent properties with respect to responsiveness, control accuracy, control stabilities, manufacturing costs, maintainability, and the like. Furthermore, a flow rate control apparatus can be easily replaced with a thermal type mass flow rate control apparatus.
FIG. 7(a) and FIG. 7(b) illustrate one example of the basic structure of the afore-mentioned conventional pressure type flow rate control apparatus FCS. A major portion of the pressure type flow rate control apparatus FCS comprises a control valve 2, pressure detectors 6, 27, an orifice 8, flow rate computation circuits 13, 31, a flow rate setting circuit 14, a computation control circuit 16, a flow rate output circuit 12, and the like.
In FIG. 7(a) and FIG. 7(b), 3 designates an orifice upstream side pipe; 4 designates a valve driving part; 5 designates an orifice downstream side pipe; 9 designates a valve; 15 designates a flow rate conversion circuit; 10, 11, 22, 28 designate amplifiers; 7 designates a temperature detector; 17, 18, 29 designate A/D converters; 19 designates a temperature correction circuit; 20, 30 designate computation circuits; 21 designates a comparison circuit; Qc designates a computation flow rate signal; Qf designates a switching computation flow rate signal; Qe designates a flow rate setting signal; Qo designates a flow rate output signal; Qy designates a flow rate control signal; P1 designates orifice upstream side gas pressure; P2 designates orifice downstream side gas pressure; and k designates a flow rate conversion rate. The afore-mentioned pressure type flow rate control apparatus FCS shown in FIG. 7(a) is mainly used either in the case where the ratio P2/P1 of the orifice upstream side gas pressure P1 and the orifice downstream side gas pressure P2 is equal to the critical value of a fluid, or in the case where the ratio P2/P1 is lower than the critical value (that is, when a gas flow is constantly under the critical state). The gas flow rate Qc passing through the orifice 8 is given by Qc=KP1 (where K is a proportionality constant).
The afore-mentioned pressure type flow rate control apparatus FCS shown in FIG. 7(b) is mainly used for the flow rate control of gases that will be in the flow condition in both the critical and non-critical states. The flow rate of a gas passing through an orifice is given, in this case, by Qc=KP2m (P1-P2)n (where K is a proportionality constant, m and n are constants).
With the afore-mentioned pressure type flow rate control apparatus in FIG. 7(a) and FIG. 7(b), the setting value of the flow rate is given by a voltage value as Qe, the flow rate setting signal. For example, suppose that the pressure control range 0˜3 (kgf/cm2 abs) of the upstream side pressure P1 is expressed by the voltage range 0˜5V, then Qe=5V (full scale value) becomes equivalent to the flow rate Qc=KP1 at the pressure P1 of 3 (kgf/cm2 abs). For instance, when the conversion rate k of the flow rate conversion circuit 15 is set at 1, a switching computation flow rate signal Qf (Qf=kQC) becomes 5V if the flow rate setting signal Qe=5V is inputted; thus, a control valve 2 is operated for opening and closing until the upstream side pressure P1 becomes 3 (kgf/cm2 abs) in order to allow the gas of flow rate Qc=KP1, corresponding to P1=3 (kgf/cm2 abs), to flow through the orifice 8.
In the case where the pressure range to control is switched to 0˜2 (kgf/cm2 abs), and the pressure range is expressed by a flow rate setting signal Qe of 0˜5(V) (that is, when a full scale value 5V gives 2 (kgf/cm2 abs)), the afore-mentioned flow rate conversion rate k is set at ⅔. As a result, if a flow rate setting signal Qe=5(V) is inputted, the switching computation flow rate signal Qf becomes Qf=5×⅔(V) because of the relationship Qf=kQC. And thus, the control valve 2 is operated for opening and closing until the upstream side pressure P1 becomes 3×⅔=2 (kgf/cm2 abs).
In other words, the full scale flow rate is converted so that Qe=5V expresses a flow rate Qc=KP1 equivalent to P1=2 (kgf/cm2 abs). Under a critical condition, the flow rate Qc of a gas passing through the orifice 8 is given by the afore-mentioned equation Qc=KP1. However, when the type of gas whose flow rate is to be controlled changes, then the afore-mentioned proportionality constant K also changes if the same orifice 8 is in use.
It is also same, in principle, with the afore-mentioned pressure type flow rate control apparatus in FIG. 7(b). The flow rate Qc of a gas passing through the orifice 8 is given by Qc=KP2m (P1-P2)n (where K is a proportionality constant, and m and n are constants). When the type of gas changes, the afore-mentioned proportionality constant K also changes.
[Patent Document 1] TOKU-KAI-HEI No. 8-338546 Public Bulletin
[Patent Document 2] TOKU-KAI No. 2000-66732 Public Bulletin
[Patent Document 3] TOKU-KAI No. 2000-322130 Public Bulletin
[Patent Document 4] TOKU-KAI No. 2003-195948 Public Bulletin
[Patent Document 5] TOKU-KAI No. 2004-199109 Public Bulletin

Flow rate range variable type flow rate control apparatus

National University Corporation Tohuku University


A fabric printable medium includes a fabric base substrate including yarn strands and voids among the yarn strands; a finishing coating attached to the yarn strands of the fabric base substrate to form coated yarn strands; and pore spaces among the coated yarn strands and coinciding with at least some of the voids of the fabric base substrate. The finishing coating includes a crosslinked polymeric network. The fabric printable medium further includes a fire retardant coating applied to aback-side of the coated yarn strands.

The application of inkjet printing technology has been expanded to large format, high-speed, commercial and industrial printing, in addition to home and office usage, because of its ability to produce economical, high quality, multi-colored prints. This technology is a non-impact printing method in which an electronic signal controls and directs droplets or a stream of ink that can be deposited on a wide variety of medium substrates. Inkjet printing technology has been used on different substrates including, for examples, cellulose paper, metal, plastic, fabric/textile, and the like. The substrate plays a key role in the overall image quality and permanence of the printed images. Textile printing has various applications including the creation of signs, banners, artwork, apparel, wall coverings, window coverings, upholstery, pillows, blankets, flags, tote bags, etc.

Hewlett-Packard Development Company, L.P.


This invention relates to novel protein transduction domains (PTDs) derived from secretory leukocyte protease inhibitor (SLPI). SLPI-derived PTDs are able to deliver cargo moieties in vivo and in vitro into the cytoplasm and nucleus of a host cell. The invention also relates to a transduction complex comprising one or more SLPI-derived PTDs linked or fused to one or more cargo moieties, which may comprise, for example, proteins, nucleic acids, lipids, carbohydrates, small molecules and other chemical compounds. The invention also relates to the manufacture of SLPI-derived PTDs, complexes comprising them; compositions comprising SLPI-derived PTDs or complexes; and utilization of SLPI-derived PTDs or complexes comprising them for therapeutic, diagnostic and research methods involving delivery of heterologous molecules across cellular membranes, and especially, across nuclear membranes.

Cells are generally impermeable to macromolecules such as proteins, nucleic acids, lipids, carbohydrates and other chemical compounds. Methods for efficient translocation of these agents across biological membranes are thus useful for both therapeutic and research applications. However, existing methods of intracellular delivery, such as electroporation, liposome fusion, gene gun particle bombardment, DEAE-dextran transfection, recombinant viral infection, and direct microinjection are often inefficient and/or toxic to cells. Accordingly, there is a continuing need for improved intracellular delivery methods, including methods that can be used for in vivo delivery of agents such as proteins, nucleic acids, lipids, carbohydrates, small molecules and other chemical compounds.
Studies have identified polypeptide sequences known as protein transduction domains (PTDs) that may serve this need. PTDs, also known as "cell penetrating peptides" (CPPs), possess the ability to translocate across biological membranes. PTDs are relatively short amino acid sequences that can be linked to a cargo moiety, allowing transport of the cargo moiety across a biological membrane, such as a cell membrane, an organelle membrane, and/or a nuclear membrane. Cargo moieties can include, for example, small molecules, macromolecules, lipids, liposomes, carbohydrates, proteins, or nucleic acids. While the mechanism of translocation remains unclear, some studies suggest that the mechanism is energy-independent and non-receptor-mediated (Derossi et al., J. Biol. Chem. 269:10444-50 (1994); Derossi et al., J. Biol. Chem. 271:18188-93 (1996); Vives et al., J. Biol. Chem. 272:16010-7 (1997); Nagahara et al., Nat. Med. 4:1449-52 (1998); Schwarze et al., Trends Cell Biol. 10:290-5 (2000)). Other studies suggest that PTDs operate through pinocytotic mechanisms (Leifert et al., Gene Ther. 9:1422-8 (2002); Fittipaldi et al., J. Biol. Chem. 278:34141-9 (2003); Whitton and Whitton, Mol. Ther. 8:13-20 (2003); Lundberg et al., Mol. Ther. 8:143-50 (2003); Richard et al., J. Biol. Chem. 278:585-90 (2003); Vives et al., Curr. Protein Pept. Sci. 4:125-32 (2003)).
PTDs are typically cationic in nature, often comprising, for example, multiple arginines or lysines. Naturally occurring PTDs have been derived from proteins which can efficiently pass through biological membranes. The best characterized of these PTDs are derived from the Drosophila homeoprotein antennapedia transcription protein (AntHD) (Joliot et al., New Biol. 3:1121-34 (1991); Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-8 (1991); Le Roux et al., Proc. Natl. Acad. Sci. USA, 90:9120-4 (1993); Derossi et al., Trends Cell Biol. 8:84-87 (1998)), the herpes simplex virus structural protein VP22 (Elliott and O'Hare, Cell 88:223-33 (1997); Elliot et al., Cell 88:223-233 (1997)) and the HIV-1 transcriptional activator TAT protein (Green and Loewenstein, Cell 55:1179-1188 (1988); Frankel and Pabo, Cell 55:1189-1193 (1988); U.S. Pat. Nos. 5,804,604; 5,747,641; 5,674,980; 5,670,617; and 5,652,122). Recent studies have also identified other PTDs, such as Mph-1 (U.S. Patent Application No. 20060148060); Sim-2 (Chrast et al., Genome Res. 7, 615-624 (1997)); and Pep-1 and Pep-2 (Morris et al., Nat. Biotech. 19:1173-1175 (2001)), among others. In addition, studies have isolated artificial PTDs and PTDs selected from random libraries (see, e.g., Joliot and Prochiantz, Nat. Cell Biol. 6(3):189-96 (2004); Zhao and Weissleder, Med. Res. Rev. 24(1):1-12 (2003); Saalik et al., Bioconj. Chem. 15:1246-1253 (2004)).
PTD-mediated translocation appears to circumvent many of the problems and limitations associated with other techniques of intracellular delivery. This method of transduction appears to work on all cell types, and has been shown to efficiently transduce up to 100% of cells in culture with no apparent toxicity (Nagahara et al., Nat. Med. 4:1449-52 (1998)). PTDs have been used successfully to induce the intracellular uptake of full-length proteins (Nagahara et al., Nat. Med. 4:1449-52 (1998)), DNA, antisense oligonucleotides (Astriab-Fisher et al., Pharm. Res., 19:744-54 (2002)), small molecules (Polyakov et al., Bioconjug. Chem. 11:762-71 (2000)) and even inorganic iron particles (Dodd et al., J. Immunol. Methods 256:89-105 (2001); Wunderbaldinger et al., Bioconjug. Chem. 13:264-8 (2002); Lewin et al., Nat. Biotechnol. 18:410-4 (2000); Josephson et al., Bioconjug. Chem. 10:186-91 (1999)) suggesting that there is no apparent limit to the size of molecules that can be translocated.
Due to the many advantages of PTD-mediated intracellular delivery, there is a continuing need in the art to identify and characterize new PTDs. It would be useful to have new PTDs capable of efficiently and effectively translocating a variety of different types of cargo moieties across cellular membranes and thus useful for a multitude of therapeutic, diagnostic and research methods which require targeted delivery of cargo moieties into a cell or into one or more specific locations within a cell. Further, it would be especially useful to identify PTDs that can cross not only the outer cell membrane, but also the nuclear membrane. Such PTDs would be useful, for example, for gene therapy applications, or for in vitro or in vivo transfection of cells.
SLPI is a serine protease inhibitor that plays an important role in protection of the mucosal epidermis and skin (Thompson et al., Proc. Natl. Acad. Sci. USA 83:6692-6696 (1986); Franken et al., J. Histochem. Cytochem. 37:493-498 (1989); Masuda et al., British J. Pharmacol. 115:883-888 (1995)). SLPI is a potent inhibitor of leukocyte serine proteases such as elastase and cathepsin G from neutrophils, and chymase and tryptase from mast cells, as well as trypsin and chymotrypsin from pancreatic acinar cells (Jin et al., Cell 88:417-26 (1997) and references cited therein; Grüter et al., EMBO 7:345-51 (1988)). Studies suggest that SLPI also functions in wound healing (Zhu et al., Cell 111:867-878 (2002)) and epithelial proliferation (Zhang et al., J. Biol. Chem. 277:29999-30009 (2002)), and has antibacterial, antiviral and anti-inflammatory properties (McNeely et al., J. Clin. Invest. 96:456-464 (1995); Song et al., J. Exp. Med. 190:535-542 (1999); Hiemstra et al., Curr. Pharm. Des. 10:2891-2905 (2004)).
Human SLPI is a nonglycosylated, 11.7 kD protein consisting of a single 107 amino acid polypeptide chain. SLPI comprises two cysteine-rich domains with a protease inhibitory site situated at leucine 72 in the carboxy-terminal domain. SLPI is found in parotid saliva, and in seminal plasma, cervical, nasal, and bronchial mucus. In human epithelial cells, SLPI is constitutively expressed and its expression is increased by phorbol ester, TNF-α, and LPS at supraphysiologic concentrations, as well as by synergistic combinations of elastase and corticosteroids (Jin et al., supra).
In the immune system, studies show SLPI to be a lipopolysaccharide (LPS)-induced, IFNγ-suppressible phagocyte product that inhibits LPS responses. SLPI binds to the membrane of human macrophages through annexin II (Jin et al., supra; Ma et al., J. Exp. Med. 200:1337-46 (2004)). SLPI binds to NF-κB binding sites in the promoter regions of the IL-8 and TNF-α genes in monocytes and inhibits the expression of those genes (Taggart et al., J. Exp. Med. 202:1659-68 (2005) and references cited therein). It has been suggested that the anti-inflammatory function of SLPI arises from such gene inhibition.
Recent studies suggest that SLPI may play a neuroprotective role in focal stroke because of rapid inhibition of activated proteases and its suppression in inflammatory response mediated by leukocytes (e.g., neutrophils and macrophages), which contributes to ischemic brain injury (Taggart et al., supra; Ilzecka et al., Cerebrovascular Diseases 13:38-42 (2002)). Elevated levels of serum SLPI are also observed in human stroke patients (Ilzecka et al., supra).
We previously discovered that secretory leukocyte protease inhibitor ("SLPI") overcomes the inhibitory effect of myelin inhibitors on nerve fiber growth and promotes neuronal (e.g., axonal) regeneration. Before that discovery, it was not known that SLPI possesses neurostimulatory function. See PCT/US2007/008270, filed Mar. 30, 2007, which is incorporated by reference herein in its entirety.
Upon incubation with peripheral blood monocytes and the U937 monocytic cell line, SLPI has been shown to enter cells, becoming rapidly localized to the cytoplasm and nucleus (Taggart et al., supra). But the portions of SLPI necessary and sufficient for cellular localization of SLPI were not known. Nor was it known whether part or all of the amino acid sequences of SLPI could be linked to a cargo moiety and co-transport that moiety across one or more biological membranes.

Protein transduction domains derived from secretory leukocyte protease inhibitor

Research Foundation of City University of New York


A fluid treatment method reduces a concentration of a first component included in a fluid-to-be-treated. A fluid treatment apparatus reduces a concentration of a first component included in a fluid-to-be-treated. A concentration of a second component differing from the first component is reduced in the fluid-to-be-treated in order to obtain a first fluid. The first fluid passes through at least part of an adsorption unit in order to obtain a second fluid. The adsorption unit is capable of adsorbing both the first component and the second component and has at least an ability to adsorb the first component that is temperature dependent. A third fluid pass through a portion of the adsorption unit through which the first fluid has passed. The third fluid has a concentration of the second component that is lower than in the fluid-to-be-treated and a temperature that is higher than the fluid-to-be-treated.

For example, as described in Japanese Patent Publication No. 2001-205045, a method of recovering carbon dioxide from exhaust gas with a high recovery efficiency has been proposed. In this method, carbon dioxide is recovered by leading exhaust gas that has been dried beforehand to an adsorbent that adsorbs carbon dioxide. Then, by supplying air that has been heated to this adsorbent, carbon dioxide is desorbed from the adsorbent and the adsorption capacity of the adsorbent is regenerated.

Fluid treatment method, fluid treatment apparatus, and fluid


The present invention provides a technique for enabling permanent magnets constituting the field magnet system of an IPM electric rotating machine to be embedded in a rotor core in a shallower depth. The IPM electric rotating machine is composed of a stator and a rotor. The rotor includes a rotor core and permanent magnets constituting the field magnet system. The rotor core has a side face opposed to the stator, and the permanent magnets are shallowly embedded so that the distance between the pole face thereof and the rotor side face is reduced. Furthermore, two adjacent permanent magnets are intensively spaced so that the following formula holds:0.3<(Lq−Ld)/Ld,where Lq is the q-axis inductance of the rotor, and Ld is the d-axis inductance thereof.

The IPM motor is a brushless motor having permanent magnets embedded in a rotor core. The IPM motor is advantageous in large output torque per volume, and reduced input voltage. These advantages make it preferable to apply the IPM motor to drive motors of electric vehicles.
An IPM motor also functions as a generator, when externally fed with motive energy. The fact that an IPM motor also functions as a generator is especially important for application to electric vehicles. Hereinafter, IPM motors and IPM generators are collectively referred to as IPM electric rotating machines, when it is unnecessary to distinguish IPM motors and IPM generators.
The IPM electric rotating machine is desired to generate a large output torque. An IPM motor structure for generating a large output torque is disclosed in Japanese Laid Open Patent Application No. Jp 2002-153033A. In the disclosed IPM motor, permanent magnets of the field magnet system are shallowly embedded in a rotor core. Such structure enables generating an increased magnet torque and an auxiliary reluctance torque, and thereby effectively increases the output torque of the IPM motor. The above-mentioned document discloses that the increase in the flux density of the flux applied to armature coils is preferable for increasing the magnet torque. Additionally, the above-mentioned document discloses that it is preferable that the permanent magnets are shallowly embedded in the rotor core, and thereby the q-axis inductance and the d-axis inductance satisfy the following relation:0≦(Lq−Ld)/Ld<0.3.


Disclosed is an outboard motor including an exhaust manifold having a first passage that is provided with a plurality of first openings connected to a plurality of exhaust ports and extends vertically, and a second passage that is arranged under the first passage and has a second opening provided in a lower end portion and connected to a third passage formed in the engine holder. The first and second passages of the exhaust manifold are formed integrally, and the exhaust manifold is formed separately from the cylinder head and the cylinder block and is detachably installed.

Field of the Invention
The present invention relates to an outboard motor, and more particularly, to an outboard motor preferably employed in a ship model having an engine provided with a catalytic converter.
Description of the Related Art
An outboard motor mounted on a small boat and the like is configured such that an upper unit and a guide exhaust are connected to an upper portion of a lower unit provided with a propeller, an engine is supported and fixed on the guide exhaust, the engine is covered by an engine cover, and the propeller is rotated and driven by the engine. An exhaust gas from the engine is discharged to the seawater through an exhaust passage vertically provided on the side surface of the engine across upper and lower units. In such an engine of the outboard motor, a catalytic converter may be provided in the exhaust passage in order to purify the exhaust gas and comply with an exhaust gas control requirement in some cases.
For example, in Patent Document 1, there is discussed an outboard motor engine having a crankshaft arranged vertically, in which an exhaust passage communicating with an exhaust port is formed in the side surface of the engine, and a catalyst is arranged in parallel with a flow of the exhaust gas.
In such a type of outboard motors, output power may be differently set under the same basic engine configuration in some cases. In addition, a specific level of the exhaust gas control requirement may be differently established depending on nations or regions. Therefore, it is necessary to change a configuration of the catalytic converter depending on nations or regions under the same engine configuration. Furthermore, in some cases, there is a demand for sharing of the engine between a catalyst-mounted model and a non-catalyst-mounted model. Conventional outboard motors are not easy to satisfy such a demand.


An electromagnetic actuator includes an electromagnet having a coil, which coil surrounds a pole core, and a magnet armature, which can be moved toward the pole core by the electromagnet, wherein the magnet armature has a bearing surface facing the pole core and the pole core has a correspondingly opposite counter surface. The bearing surface and/or the counter bearing surface has a layer that prevents direct contact of the bearing surface with the counter bearing surface and that causes damping of the approaching movement.

An electromagnetic actuator and a valve within a fuel injection pump are known in particular from the international laid-open specification WO 2013098249 A1.
In the case of generic electromagnetic actuators and valves, those faces of magnet armature and pole core of the electromagnetic actuator which face one another impact against one another during the actuation of the valve. This not only generates loud operating noises but can, in particular in the case of valves with fast closing speeds, have the effect that the surfaces impacting against one another are damaged. As a consequence, under some circumstances, the service life or the usage life of the valves is limited, and the valves must be checked or exchanged at relatively short intervals. In the case of magnetic valves, it is sought in the prior art to counteract this problem through optimization of the actuation of the magnet.

Electromagnetic actuator, valve, and injection pump


An array substrate and a manufacturing method thereof are disclosed. The manufacturing method includes forming, on a substrate, a first metal pattern layer, a first insulating layer, a second metal pattern layer, and a second insulating layer, successively; coating a photoresist on the second insulating layer; forming a photoresist pattern and an etching protection layer, in a first region of the array substrate, the photoresist pattern exposing a part of the top surface of the second insulating layer, and being coupled to the second insulating layer through the etching protection layer; and performing etching in the first region by using the photoresist pattern as a mask to remove the etching protection layer and at least part of the second insulating layer, without etching the first insulating layer, so as to expose a part of the second metal pattern layer and form a liquid crystal diversion groove.

With the development of the thin film field effect transistor liquid crystal display (TFT-LCD) technology and the progress in the industrial technologies, the production cost of liquid crystal displays is continuously reduced and the manufacturing process thereof is increasingly improved, thus they have become a mainstream technology in the flat panel display field in place of cathode ray tube displays. TFT-LCD displays have become ideal display devices due to their advantages such as small size, low power consumption, no radiation, and so on. The basic structure of a TFT-LCD comprises an array substrate, a color filter substrate, and a liquid crystal layer (LC) sandwiched between the two substrates. A polyimide film layer (alignment film layer) having an orientation effect on the liquid crystals is arranged on the surfaces of the array substrate and the color filter substrate. Taking the existing twisted nematic (TN) type TFT-LCD as an example, the TFT structure is formed by depositing a gate electrode, a common electrode, a first insulating layer, an active layer, a source/drain electrode, a second insulating layer, and a pixel electrode on a glass substrate successively, the gate electrode and the common electrode are arranged in the same layer.

Array substrate and manufacturing method thereof, liquid crystal display device and manufacturing method thereof


A system may include a federated shipping node. The federated shipping node may receive shipping information for a parcel and determine a new shipping state for the parcel based on the shipping information. The federated shipping node may append the new shipping state to a blockchain. In addition, the federated shipping node may store the new shipping state in an off-chain database. A previous shipping state for the parcel may be replaced with the new shipping state in the off-chain database. To display the real-time information related to the parcel, the federated shipping node may receive the new shipping state from the off-chain database, and send the new shipping state to a device for display. To display the historical information related to the parcel, the federated shipping node may receive previous shipping states from the blockchain, and send the previous shipping states to the device for display.

Shipping organizations, such as postal services, may transfer parcels between geographic locations. In some circumstances, parcels are shipped between two separate shipping organizations located at distant geographic locations. For example, during inter-postal transfers, parcels may be shipped between the postal services of two different countries. Shipping organizations, such as postal services, may store shipping information for the parcels according to organization specific data structures, formats, and/or protocols. As shipping errors and data inconsistencies arise between shipping organizations, the incompatible infrastructure of the shipping organizations may inhibit accurate and efficient parcel tracking and dispute resolution, particularly in inter-postal settings where monthly transfer volumes exceed several million parcels. Lack of trust amongst the shipping organizations adds to the complexities of settlement dues. Once a parcel is delivered, a destination party may initiate a settlement activity with an origin party, which, in its present form, is error prone and involves largely manual settlement activities that lack reliability and/or uniform repeatability. Management of duplicate packages is also a major challenge in settling disputes between parties.

High performance blockchain architecture for logistics services


The invention relates to immobilized metal alkylidene catalysts. The catalysts are useful in olefin metathesis.

Due to the growing importance of olefin metathesis, a great need exists for providing suitable catalysts, which beneficially perform at industrial scale. A considerable number of organometallic alkylidene catalysts is already known to homogeneously catalyze olefin metathesis. Although it is further known that in general heterogeneous catalysts may be easier separated off from reaction mixtures than homogeneous catalysts, e.g. by filtration, which is an advantage particular at industrial scale, comparatively few heterogeneous catalysts have been accessible for olefin metathesis. Exemplarily, in the following, known heterogeneous tungsten catalysts are briefly discussed:
WO3 on SiO2 may be used for metathesis reactions; however, such catalysts typically operate at rather elevated temperatures. E.g., http://handle.net/10413/896 describes the performance of a WO3/SiO2 catalyst for the metathesis of 1-hexene in an isothermal, gas-phase fixed bed tubular reactor between 420 and 500° C.
Mazoyer, E. et al. report the synthesis of an alkyl oxo tungsten derivative supported on silica as olefin metathesis catalyst (Chem. Commun. 2010, 46, 8944-8946). Herein, (tBuCH2)3XWO (X=alkyl, halogen, alkoxide, . . . ) was reported to react with silica, pretreated at 700° C., to give (≡SiO)(tBuCH2)2Cl(W═O) and/or (≡SiO)(tBuCH2)3(W═O), although a targeted alkylidene structure was (≡SiO)(tBuCH2)X(W═O)(═CHt-Bu) (X═Cl or CH2tBu). However, said supported catalyst works at relatively high temperature, i.e. >100° C., and the actual nature of the active site is unknown.
Rhers et al., Organometallics, 2006, vol. 25, 3554, disclose the formation of ethene and butenes, including 1-butene, from propene in a self-metathesis reaction catalyzed by a silica supported tungsten catalyst. The catalyst has been characterized as syn-[(—SiO)(W(═NAr)(═CHtBu)(CH2tBu)] (Ar=2,6-iPrC6H3) of following formula:

F. Blanc et al., Proc. Natl. Acad. Sci. USA, Aug. 26, 2008, vol. 105, no 34, 12123-12127, later disclose the selective formation of ethene and 2-butene from propene in a self-metathesis reaction by a silica supported tungsten catalyst. This reaction is a heterogeneously catalyzed. The catalyst is of the following structure:
and is prepared by grafting [W(═N(2,6-diisopropylphenyl)(═CHtBu)(2,5-Me2C4H2)2] on SiO2-(700).
WO 2015/049047 relates to supported tungsten catalysts of the general formula(≡SiO)xW(═O)(═CR1R2)(R3 or R4)2-x,wherein each of R1 and R2 is independently R, —OR, —SR, —N(R)2, —OC(O)R, —SOR, —SO2R, —SO2N(R)2, —C(O)N(R)2, —NRC(O)R, or —NRSO2R; each R is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, ferrocene, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen atom are taken together with the nitrogen to form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl ring having 0-5 additional heteroatoms not including the same nitrogen atom independently selected from nitrogen, oxygen, or sulfur; or: two R groups on the same oxygen atom are taken together with the oxygen to form an optionally substituted 3-12 membered saturated, partially unsaturated, or aryl ring having 0-5 additional heteroatoms not including the same oxygen atom independently selected from nitrogen, oxygen, or sulfur; R3 and R4 have independently the same meaning as R1 and R2; or tris(C1-20 alkyl)silyl, tris(C1-20 alkyl)silyloxy, tris(C1-20 alkoxy)silyl, tris(C1-20 alkoxy)silyloxy, tris(aryl)silyl, tris(aryl)silyloxy, tris(aryloxy)silyl, or tris(aryloxy)silyloxy; and wherein x=1 or 2.
WO 2015/162245 A2 relates to metal alkylidene N-heterocyclic carbene complexes of general Formulas (A) to (D)
wherein A1 stands for NR2 or PR2, A2 stands for CR2R2′, NR2, PR2, O or S, A3 stands for N or P, and C stands for a carbene carbon atom, ring B is an unsubstituted or a mono or poly-substituted 5 to 7-membered ring, substituents R2 and R2′ stand, inter alia, for a linear or branched C1-C10-alkyl group and, if A1 and A2 each stand for NR2 or PR2, are the same or different, M in Formulas (A), (B), (C) or (D) stands for Cr, Mo or W, X1 or X2 in Formulas (A) to (D) are the same or different and represent, inter alia, C1-C18 carboxylates and C1-C18-alkoxides, Y is inter alia oxygen or sulfur, Z is inter alia a linear or branched C1-C10-alkylenoxy group, and R1 and R1′ in Formulas (A) to (D) are, inter alia, an aliphatic or aromatic group. Ring B may be coupled via a spacer to a solid support such as glass, zirconia, titania, silica or polymer organic support materials, e.g. based on poly(methacrylates) or polystryrene/polydivinylbenzene. The compounds are suitable for use as catalysts for olefin metathesis reactions and are reported to have the advantage, compared to known Schrock carbene complexes, of displaying clearly increased tolerance to functional groups such as, in particular, aldehydes, secondary amines, nitriles, carboxylic acids and alcohols.
WO 2015/003815 discloses metathesis tungsten catalysts of the following formula
wherein M is W; R1 is H, aryl, heteroaryl, alkyl, or heteroalkyl, optionally substituted, respectively; R2 and R3 can be the same or different and are alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, or heteroaryl, optionally substituted, respectively, or hydrogen; R5 is a residue R6—X—, wherein R6 is alkyl, aryl, heteroalkyl, heteroaryl, optionally substituted, respectively; (R7, R8, R9)Si; wherein R7, R8, R9 are independently alkyl, alkoxy, phenyl or phenoxy, optionally substituted, respectively; (R10, R11, R12)C, wherein R10, R11, R12 are independently phenyl, alkyl, optionally substituted, respectively; X═O, S, or NR13, wherein R13 is H; or alkyl or aryl, optionally substituted, respectively; or R5 is R6—CO—NR13, wherein R6 and NR13 have the meaning as defined above, or wherein R6 and R13 taken together form a carbon chain having from 2 to 6 carbon atoms; R5 is a 4 to 8 membered N-containing carbon ring, wherein N is linked to M; and R4 is a residue O—Si(O—)3, and represents silica to which M is linked forming a M—O—Si(O—)3 moiety, preferably wherein silica is comprised in a solid support; under the proviso that a compound in which R1=2,6-diisopropylphenyl, R5 dimethylpyrrol-1-yl, R2=tBu, and R3=H is excluded.

Immobilized metal alkylidene catalysts and use thereof in olefin metathesis


A skirt for a lay-down type hunting blind of the type having a shell for enclosing an occupant in a recumbent position. The skirt comprises at least one panel having a proximate edge and a distal edge. The proximate edge of the skirt attaches to the top perimeter edge of the shell. The skirt's distal edge is securable to a ground surface such that the skirt may be extended outwardly from the top perimeter edge of the shell to a ground surface at a slope sufficiently gradual to minimize shadows and blend more naturally into outdoor environments.

Lay-down type hunting blinds are widely used by waterfowl hunters. This type of hunting blind is readily portable, easy to set up in a relatively flat location, and permits the occupant to assume a recumbent position in the blind. As deployed in the field, a lay-down blind has an elongated configuration forming an enclosure. A pair of cooperating longitudinal doors on the top side of the blind affords access to the enclosure's interior. While in the blind with its doors closed, an occupant is effectively concealed from view. When an object of interest approaches, the occupant can throw open the blind doors using his or her hands and arms, abruptly sit up, and take appropriate action such as firing a weapon.
One disadvantage with existing lay-down type hunting blinds is that shadows are created when light strikes them at lower angles. The substantially vertical portions of the sides of these blinds cast shadows which can deter approaching prey. Another problem encountered with these type of blinds is that they appear as abrupt angular changes appear out of place in the terrain which tend to ward off prey.
Thus, there is a need for a lay-down type hunting blind having a profile that minimizes shadows cast and maximizes the appearance of safety to waterfowl flying in the vicinity of the blind.

Hunting blind having a camouflaging sloped profile


A method and apparatus for stabilizing the scale factor and the loop gain of the control loop of a fiberoptic Saganc interferometer with phase resetting. A digital evaluation circuit includes two auxiliary control loops, one for nominal gain of the scale factor control and the other for stabilization of loop gain of the primary control loop, in addition to the control loop for the readjustment of the phase modulator. The evaluation circuit can be realized as an integrated circuit. In addition to the optimization of control bandwidth, the circuit avoids substantial complexity of the circuit subassemblies for generating modulation and demodulation signals and control signals for the scale factor control loop.

1. Field of the Invention
The present invention relates to apparatus and methods for measuring rotational speed with a fiber optic Sagnac interferometer. More particularly, this invention pertains to apparatus and methods for stabilizing the scale factor and loop gain of the control loop of a fiber optic Sagnac interferometer with phase resetting.
2. Description of the Prior Art
European patent publication EP-A1-0,441,998 discloses a fiber optic Sagnac interferometer suitable for inertial rotational speed measurement and also known for short as a fiber-optic gyro. In that device, bias errors and deadbands caused by electromagnetic overcoupling based thereupon are removed through a modulation method controlled by a random number generator. The method guarantees the correlation freedom of a demodulator reference signal. Unfortunately, the solution described in the above-mention publication entails highly complex circuitry for the subassemblies that generate the modulation and demodulation signals and obtain a control signal for the scale factor control loop.

Method and apparatus for stabilizing control loop scale factor and gain in a fiber optic Sagnac interferometer