A method and apparatus for implementing facsimile transmission over data networks is disclosed. In accordance with the preferred embodiment, the invention receives a modulated compressed facsimile message, which is then demodulated, decompressed and stored as a file. Thereafter, it is compressed for data transmission and sent to a server for transmission over a data network. At the receiving end, the file is decompressed and then re-compressed and modulated for transmission to a receiving facsimile machine.

Fax machines have long been used to transmit images from one location to another via a voice-grade telephone line. Such machines typically comprise a controller, a document scanner for converting the image of a document into a serial data message (and vice versa) and a modulator/demodulator, i.e. "modem", for converting the serial data into a series of tones (and vice versa) for communication on the telephone line. The telephone line may be a wire or optical cable, or may include a wireless connection such as a microwave, a satellite link or a cellular system. Generally, a sending fax machine will scan a sheet of paper and convert its image into a code for transmission over the telephone line. The receiving machine reconverts the codes and prints a facsimile of the original. Some fax modems can send and receive faxes, others can only send but not receive faxes.
In general, the various phases of a facsimile transmission are as follows:
Phase A is the call establishment phase in which the telephonic communication is established between a calling station, i.e. the station initiating the facsimile telephone call, and a called station, i.e. the station receiving the facsimile telephone call. Telephonic communication is established in the same way as in any telephone call: upon receiving a dial tone, the calling station provides the phone number of the called station to the telephone switching system, and, in response, the switching system establishes a circuit connecting the calling station to the called station and provides a ringing signal to the called station. The called station answers the ringing signal by going off-hook, i.e. the called station effectively lifts the receiver. For a facsimile transmission, as is well known, the calling station and the called station must have the capability of transmitting and receiving facsimile messages. Typically, this capability is provided by a transmitting fax machine and a receiving fax machine.
Phase B is a pre-message procedure phase or a negotiation phase between the calling station and the called station for identifying and selecting facsimile data encoding capabilities. Whichever station is to receive the facsimile message transmits a digital identification signal (DIS) to the transmitting fax machine. The DIS contains information indicating the data encoding capabilities of the receiving fax machine. The transmitting fax machine uses the information in the DIS to determine the appropriate data encoding format.
Phase C is the actual message transfer phase and comprises two simultaneous phases. Phase C1 is the "in-message" procedure phase, which controls the transfer of data between the transmitting fax machine and the receiving fax machine. This includes synchronization, error detection and correction, and line supervision. Phase C2 is the actual data transmission phase in which encoded data is transferred by the transmitting fax machine to the receiving fax machine under control of the signals generated in the C1 phase.
Phase D is the post-message procedure phase in which information is transferred regarding the end-of-message signaling, confirmation signaling, and end of facsimile signaling.
Phase E is the call-release phase in which the telephonic communication between the calling station and the called station is terminated.
The cost of sending a facsimile message long distance includes the transmission cost of the telephone call, which cost is directly related both to the size of the message being sent and to the transmission speed at which the message is sent. In some cases the cost of sending a facsimile message is also related to the time of day during which the facsimile telephone call is placed. To reduce costs, the user may send the facsimile message during low-cost periods, such as at night, when the demand for telephone lines is minimal. Thus, the telephone rate is decreased and the cost of sending the facsimile message is correspondingly decreased. The cost can also be reduced by minimizing the duration of the facsimile telephone call.
Although fax machines have gradually become faster and more efficient through the years, current standards and technology still limit the fax transmission speed. Fax machines in the 1960's (Group I) were analog units capable of transmitting a page within four to six minutes. These were replaced by fax machines introduced in the mid-1970's (Group II) which were capable of transmitting a page within two to three minutes. Group III fax machines are capable of transmitting at a rate of 9 to 20 seconds per page. Virtually all fax machines in the market today are Group III machines. Newer fax machines (Group IV) offer an even faster transmission speed of approximately 5 seconds per page. However, Group IV fax machines require access to digital telephone lines in order to achieve these high transmission speeds.
The cost of transmission can be reduced by minimizing the duration of the facsimile telephone call. One such method for minimizing the duration of the telephone call is to compress the data prior to transmission. Early facsimile machines used a basic data encoding technique, known as Modified Huffman (MH) encoding. This form of encoding permits compression of the facsimile message, with a corresponding decrease in the duration of the facsimile telephone call. Other data encoding techniques were developed for newer facsimile machines, although newer facsimile machines continue to retain MH encoding capabilities to enable facsimile communication of the older design. A Modified Read (MR) encoding permits two dimensional data encoding, which permits a higher degree of data compression than MH encoding permits. Both MH and MR encoding are described in standards established by the International Telegraph and Telephone Consultative Committee (CCITT) and published as Terminal Equipment and Protocols for Telematic Services (1989). The MH and MR data encoding are described in recommendation T.4 of the CCITT standard.
A third type of data compression is the Modified Modified Read (MMR) encoding, described in recommendation T.6 of the CCITT standard, which permits two dimensional encoding of low- or high-resolution facsimile messages.
Other types of data compression, such as Joint Bi-level Image Experts Group (JBIG), offer even greater compression capabilities than MMR but have not generally been integrated into fax machines. The JBIG data encoding is described in recommendations T.82 and T.85 of the CCITT standard. Generally, JBIG compresses binary (one bit/pixel) images. JBIG provides a compatible progressive/sequential coding, meaning that a progressively coded image can be decoded sequentially, and the other way around. All bits in the image, which is compressed using the JBIG format, before and after compression and decompression will be exactly the same. For further information concerning the use of data compression techniques in facsimile, see Gilbert Held, The Complete Modem Reference, (2d Ed.), pp. 237-256 (Wiley 1994) and Andrew Margolis, The Fax Modem Sourcebook, pp. 111-134 (Wiley 1995), both of which are incorporated herein by reference.
Another method for reducing the length of the telephone call is to increase the rate or transmission speed at which the message is sent. Most fax machines typically transmit data at a rate of 9.6 and/or 14.4 kilobits per second (kbps). Some modems can transmit fax at rates of 28.8 kbps or higher, but these are generally not used in the current installed base of fax machines.
Alternatives to the use of fax machines are well known. Many personal computers now have a modem and the capability of generating the serial data message of a facsimile internally without the need to scan a document. These computers also have the capability of executing the communication protocol required to transmit the message to a remote fax machine. These computers, however, transmit data using communications techniques employed by fax machines which are not as efficient as various other data communication methods. In addition, these computers transmit only computer files that are stored in digital format and are not useful for processing paper documents.
Many modern personal computers also have the capability of transmitting e-mail to a remote computer using various packet-switched digital communication networks such as the Internet. E-mail, however, is of no use if the message to be sent is initially in the form of document that has to be scanned.
From the foregoing it will be apparent that fax machines typically encode data somewhat inefficiently, transmit data at relatively slow rates (compared to computer generated facsimiles or e-mail), and use circuit-switched rather than packet-switched networks. While e-mail may be a more efficient communication medium, it does not provide any means for transmitting pre-existing documents other than re-creating them anew as e-mail documents. Moreover, there are currently millions upon millions of fax machines already in operation.
Thus, it is desirable to achieve efficiencies of packet-switched digital communication networks while continuing to use existing fax machines as well as to introduce fax machines which communicate over such networks. There is also a need for cost savings in fax transmission and, in particular, there is a need to reduce long distance telephone charges associated with faxes.

Method and apparatus for interfacing fax machines to digital communication networks


An insulated gate semiconductor device, includes an isolating structure shaped in a circulating section along the periphery of a semiconductor substrate to isolate that part from an inside device region, a peripheral diffusion region of the semiconductor substrate located outside the isolating structure, a plurality of cell structures defined in the inside device region and divided in segments by insulated trench-shaped gates to have a base region covered with an emitter region in its upper surface, a collector region, and an emitter electrode electrically connected to the emitter region and the base region, a dummy base region contiguous to the cell structures and configured as a base region that has its upper surface left without the emitter region connected to the emitter electrode, an inner region defined in and insulated from the dummy base region, and a connection part to electrically connect the inner region to the emitter electrode.

The present invention relates to an insulated gate semiconductor device, and more particularly, to an insulated gate bipolar transistor (IGBT) provided with a trench gate and a device structure of the same.
Typical insulated gate transistors include IGBTs broadly used in the art, and the improvement having a new feature of accumulating electrons below the gate has been developed in the name of injection enhanced gate transistor (IEGT), which can implement greater electric power and has become more common in the art.
In the prior art insulated gate semiconductor device, a ring-shaped diffusion region in the outer peripheral part and a diffusion layer underlying a gate interconnection are formed in connection with a base diffusion layer in a cell region.
In such an arrangement, however, a semiconductor device, such as the IEGT, of particularly enhanced withstand voltage has its cell region store an increased amount of cumulative carriers and reduce negative capacity, and therefore, it employs trench gates for gate electrodes to define a floating dummy base region without contact with an emitter electrode in a base region between the trench gates.
The negative capacity may be disadvantageous in that, unless a potential at a p-type dummy base layer in a dummy cell region is completely floating, there arises a problem of overshooting of gate-emitter voltage Vge. More specifically, even if the device design is deliberate in making the potential at the p-type dummy base layer floating, a parasitic structure (e.g., a partial connection with a cell edge and a terminating portion of the junction) permits parasitic resistance to fix the potential at approximately zero level during the OFF-time of the transistor, and succeedingly turning the transistor ON to cause the gate-emitter voltage Vge to reach threshold voltage Vth results in the potential at the p-type dummy base layer rapidly rising simultaneous with the injection of holes, which eventually brings about a phenomenon of overshooting of the gate-emitter voltage Vge.
The provision of the dummy base region isolated from the emitter layer urges carriers to be injected so as to reduce the ON-voltage, but there still arises a disadvantage that carriers remain in the dummy base region on switching the semiconductor device on, which adversely reduces the breakdown durability.
While the current is being cut off, the device must be drained by eliminating the carriers remaining therein, and thus, carriers in the cell region are removed through the emitter electrode while the carriers remaining in the peripheral regions of the device are eliminated through the ring-shaped diffusion region in the outer peripheral part and then through the base diffusion layer in the cell region. Completely isolating the ring-shaped diffusion region in the outer peripheral part and the diffusion layer underlying the gate interconnection from the base diffusion layer in the cell region, however, a device draining route disappears which urges the carriers to flow out of the outer peripheral part during the current cutoff, and this is prone to lead to the reduction of the cutoff durability.


A network node operates in accordance with a first radio access technology in a frequency band, wherein communication according to a second radio access technology may occupy one or more of the radio resources of the frequency band. A method comprises receiving a beacon signal associated with the second radio access technology and determining whether or not the beacon signal comprises information indicative of which of the radio resources of the frequency band are used as primary and secondary channels, respectively, in accordance with the second radio access technology. The method also comprises determining a communication activity rate of at least one of the radio resources of the frequency band and selecting one or more of the radio resources of the frequency band based on the determined communication activity rate, and allocating one or more of the selected radio resources to communication in accordance with the first radio access technology.

In a typical scenario (e.g. in a specific geographical area) the available radio communication spectrum is sub-divided into spectrum parts that are dedicated to communication and/or other activities subject to restrictions from a frequency allocation body (e.g. the International Telecommunication Union—ITU) and spectrum parts that are dedicated to communication and/or other activities not subject to such restrictions.
Example activities subject to these restrictions include cellular telecommunication (e.g. according to the Global System for Mobile communication (GSM) standard, the Universal Mobile Telecommunication Standard (UMTS), the UMTS Long Term Evolution (UMTS LTE) standard, or the UMTS LTE-Advanced (UMTS LTE-A) standard), radio astronomy, television, air traffic control, etc.
The spectrum parts that are not subject to these types of restrictions will be referred to herein as unlicensed frequency bands. The spectrum parts that are only partly subject to these types of restrictions will be referred to herein as non-exclusively licensed frequency bands. Example activities in unlicensed frequency bands include Wireless Local Area Network (WLAN) communication (e.g. based on the IEEE—Institute of Electrical and Electronics Engineers—802.11 standard), Bluetooth communication, cordless phone signaling, remote control signaling, etc. The Industrial, Scientific and Medical (ISM) radio bands are examples of unlicensed frequency bands.
Spectrum sharing for WLAN is typically achieved by dividing the total available bandwidth into a number of channels. The channels are typically partially overlapping and communication in adjacent channels will, thus, interfere with each other.
In the 2.4 GHz band, the channels are typically 20 MHz wide and up to 13 channels are defined. In a typical utilization, three non-overlapping channels are used in the 2.4 GHz band to avoid adjacent channel interference.
In the 5 GHz band, many more channels are available since the available bandwidth is much larger. However, with the development of IEEE 802.11n and IEEE 802.11ac, the potential bandwidth of each channel has been increased from 20 MHz to 40, 80, and even 160 MHz. Thus, the number of non-overlapping channels available may still be rather small, in particular when the wider channel bandwidths are used.
FIG. 1 schematically illustrates an available bandwidth 100 divided into eight channels 101-108 (e.g. of 20 MHz each). Depending on the particular choice of IEEE 802.11 application, channels of 20 MHz (e.g. 110, 115), 40 MHz (e.g. 120, 125), 80 MHz (130, 135) or 160 MHz (not shown) may be used.
In a typical WLAN deployment, the channel allocation to the access points may be such that the channels used by neighboring access points, as far as possible, are not overlapping. In practice, this is often achieved by aiming to maximize the distance between access points that use the same (and/or adjacent) channel(s).
Carrier Sense Multiple Access with Collision Avoidance (CSMA/CA) is typically used in WLAN systems to further lower the interference between WLAN devices. When CSMA/CA is employed, the channel to be used is first sensed (typically by performing suitable measurements), and a transmission is only initiated if the channel is declared free (i.e. un-used, also termed Idle). If the channel is declared occupied (i.e. already used, also termed Busy), the intended transmission is typically deferred until the channel is found to be Idle. The CSMA/CA approach may lead to time-sharing of a channel between two or more access points which are in range of one another and using the same or overlapping channels, which may lower the throughput of one or more of the access points.
Some WLAN systems (e.g. IEEE 802.11n and IEEE 802.11ac) define a structure where each channel is defined as a primary or secondary channel by the access point. The information regarding which channels are primary and secondary channels is broadcast by the access point in a beacon signal (which is typically sent periodically). In such a system, a WLAN station (STA) has to sense the primary channel of the access point and declare it to be Idle before it may access the channel, and the same applies to the secondary channel. However, if the secondary channel is Idle and the primary channel is Busy, the secondary channel still cannot be used. In the example of FIG. 1, channels 110, 125 and 130 may be primary channels, and channels 115, 120 and 135 may be respective secondary channels. Typically, the access point determines which channels are to be used as primary and secondary channels, respectively.
The unlicensed frequency bands are widely used by WLAN communication (e.g. 802.11n and 802.11ac). However, there are typically still a lot of available frequency resources in the unlicensed bands. It might be desirable to use such available frequency resources in the unlicensed frequency bands for cellular telecommunication (e.g. UMTS LTE). Introducing UMTS LTE-A operation in unlicensed bands would allow for more flexible use of the unlicensed bands, especially if WLAN access points (AP) cooperate with the network nodes of the cellular communication system.
Introduction of UMTS LTE-A communication in unlicensed bands may, for example, comprise using a licensed frequency band for a primary cell (PCell) of a carrier aggregation scheme and using the unlicensed frequency band for a secondary cell (SCell) of the carrier aggregation scheme. In this manner, a connection between the UMTS LTE-A network and a wireless communication device is still maintained via the PCell if the SCell is severely interfered (e.g. by WLAN or Bluetooth). Examples of carrier aggregation using unlicensed bands are disclosed in US 2013/0195073 A1 and US 2014/0044105 A1.
FIG. 2 illustrates an example scenario where a cellular communication 215 between a wireless communication device 210 and a network node 200 is taking place in the vicinity of two access points 220, 230 for WLAN communication. The WLAN communication uses unlicensed frequency resources, and may include the access points 220, 230 transmitting respective beacon signals 225, 235. The cellular communication 215 typically uses one or more licensed frequency bands, but may (alternatively or additionally) also use unlicensed frequency resources.
WLAN standards are primarily designed so that WLAN devices may smoothly coexist with other WLAN devices. Therefore, if UMTS LTE-A is employed in an unlicensed frequency band already used by WLAN, the performance for the WLAN system may be severely degraded. On the other hand, employing WLAN-type approaches (e.g. CSMA/CA) may be extraneous to, and inflict very strong restrictions on, UMTS LTE-A.
Therefore, there is a need for alternative approaches of deployment of UMTS LTE-A in an unlicensed or non-exclusively licensed band which may (potentially) be used by WLAN. Preferably, the approaches should enable high data rates in UMTS LTE-A while ensuring minimum (or at least acceptable) performance loss for WLAN.

Radio resource allocation of unlicensed frequency bands


A holder for grooving work includes a shank portion, and a head portion located on an end portion thereof. The head portion includes an insert attaching space, an upper and lower respectively located above and below the insert attaching space, a slit extending backward from the insert attaching space, an upper and a lower jaw connecting portions divided by the slit, an upper clamp surface on the upper jaw and a lower clamp surface on the lower jaw opposed to the insert attaching space. A column-shaped groove is connected to the deepest end of the slit. The column-shaped groove is formed to reduce the thickness of the upper jaw connecting portion, and extends from the lateral face on the side of the insert attaching space halfway along the deepest end of the slit toward the opposite lateral face. Upon attaching the insert to the holder the cutting tool is obtained.

To fasten a cutting insert in a throwaway cutting tool for performing grooving work and cut-off work, generally the insert is held between an upper jaw and a lower jaw, respectively provided at an upper and a lower position of a slit formed in the front end portion of a holder, and the slit is tightened with a screw so as to fasten the insert with the pressure. According to Patent Literature (PTL) 1 for example, a V-shaped or wave-shaped recessed groove is formed on each of the upper and lower faces of the insert, and a V-shaped or wave-shaped projection that fits in the recessed groove is formed on each of the upper jaw and the lower jaw of the holder, so that the insert is attached to the holder with the projection fitted in the recessed groove. Such a configuration increases the binding force.
With the mentioned binding method, the screw is located at a central portion of the upper jaw with which the screw is to be engaged, and the screw is tightened so as to warp the upper jaw, and therefore the end portions of the upper jaw are bent upward with respect to the bottom portion corresponding to the central portion where the screw is tightened. However, the insert is attached to either end portion of the holder in the width direction thereof, and hence the insert is downwardly pressed by the upper jaw and also subjected to a force exerted outward in the width direction of the holder, when the screw is tightened. Accordingly, the insert may tilt outward in the width direction of the holder, or may even fall off out of the holder.
To prevent the insert from tilting outward, PTL 2 proposes a holder in which the terminal length of the slit is set such that the side on which the insert is attached becomes longer than the other end, in other words the terminal end of the slit is formed to be oblique such that the side on which the insert is attached is located on the rear side and the other end is located on the front side.


An exemplary apparatus capable of picking and placing a workpiece into a container includes a suction device and a hollow body. The suction device is configured for providing a suction force for picking up the workpiece. The hollow body has a picking portion configured for picking and placing the workpiece into the container under the suction force, wherein a plurality of air slots are defined in an outer wall of the hollow body, the air slots are configured for providing an air passage between an interior of the container and an exterior thereof so as to facilitate movement of the hollow body into and out of the container, whereby the workpiece can be steadily placed in the container.

In the assembling of a product or a semi-finished product, apparatuses for picking and placing workpieces of such products are widely used. A typical such apparatus includes a suction device and at least one hollow body coupled to the suction device. The hollow body may pick a workpiece at an end thereof under a suction force provided by the suction device, and then place the workpiece into a container. Generally, an internal breadth of the hollow body is slightly smaller than an external breadth of the workpiece, thus allowing the workpiece to be picked precisely and steadily.
However, when the workpiece is, for example, a lens module, and the container is, for example, a barrel, the internal breadth (diameter) of the hollow body is closely approximate to the external breadth of the workpiece, and an external breadth of the hollow body is closely approximate to an internal breadth of the barrel. As a result, air inside the barrel may be compressed thereby increasing an atmospheric pressure inside the barrel during the workpiece being moved into the barrel, such that pressure imbalance is generated between the exterior of the barrel and the interior of the barrel. This makes it difficult to orient the workpiece precisely. In addition, when the hollow body moves out of the barrel after placing the workpiece, atmospheric pressure inside the barrel may immediately decrease, whereby pressure imbalance is generated between the interior of the barrel and the exterior of the barrel. As a result, it is difficult to move the hollow body out of the barrel.
What is needed, therefore, is a device capable of picking and placing a workpiece into a container, which overcomes the above-mentioned problems.

Apparatus for picking and placing workpiece


A vehicle dashboard has a fixed structure and a casing defining a pocket having a substantially rectangular perimeter, which is defined by an upper edge, a lower edge and two side edges so as to house a portable electronic device having a screen which remains visible through a window defined by a front frame of the casing; at one of the aforesaid edges, the casing has an opening which is used to insert/remove the portable electronic device along a sliding direction and is closed by a closing element.

Generally, portable electronic devices have a touchscreen and are coupled to a support which, in turn, is attached to the windscreen of the vehicle by means of a suction cap in such a position to be able to easily touch the screen and thus control the various functions. However, this type of suction cap coupling is subject to undesired releases and may compromise external visibility through the windscreen.
It is thus felt the need to integrate the portable electronic device directly in the dashboard of the vehicle, to make it comfortable and simple to use and to guarantee a stable coupling but without excessively compromising the appearance and the structural features of the dashboard.

Vehicle dashboard provided with a housing for supporting a portable electronic device


Heat transfer tubes have an exterior surface in contact with a refrigerant and an interior surface defining a path through which a liquid is conveyed in an axial direction of the tube. The exterior surface of the tube has a plurality of fins formed thereon; the interior surface of the tube has a plurality of ridges formed thereon. The fins have an average width v with respect to the axial direction of the tube and a pitch Q with respect to the axial direction of the tube. A channel is provided between adjacent fins, the channels having a channel bottom of length L with respect to the axial direction of the tube. The ridges have a ridge height (e) and a ridge base width (b). The tubes have a ratio of L/v in a range of from 1.22 to 3.40. L is greater than 45% of fin pitch Q, and is preferably between 45% and 75% of fin pitch Q. A ratio of (e.times.L)/b is in a range of from 0.0062 to 0.0165; a ratio of e/b is in a range of from 0.565 to 0.973.

1. Field of Invention
This invention pertains to mechanically formed heat transfer tubes including those employed in various refrigerant condensation and/or boiling applications.
2. Related Art and Other Considerations
Refrigeration apparatus is generally operated both with condenser tubes and boiling (evaporator) tubes. In submerged chiller refrigerating applications, the outside of a boiling tube is submerged in a refrigerant to be boiled, while the inside conveys liquid, usually water, which is chilled as it gives up its heat to the tube and refrigerant. In a condenser tube, on the other hand, refrigerant vapor on the outside of the tube is cooled by a liquid conveyed inside the condenser tube, so that liquid refrigerant condenses on the exterior of the tube and can drip away from the condenser tube.
An outer surface of heat transfer tubes (such as boiling tubes and condenser tubes) typically has fins formed thereon, the fins extending (at least in part) in a direction parallel to a radius of the tube. Heat transfer has also been enhanced by modifying the inner surface of the tube, e.g., by ridges on the tube inner surface, as taught (for example) in U.S. Pat. No. 3,847,212 to Withers, Jr. et al. (incorporated herein by reference). Withers specifically relates an improved heat transfer coefficient to a ridge-dependent severity factor .PHI.=e.sup.2 /pd.sub.i (where e is average height of a ridge, p is the average pitch of the ridges, and d.sub.i is the maximum projected internal diameter of the tube, all measured in inches). Various tubes produced in accordance with the Withers patent have been marketed by Wolverine Tube, Inc., under the trademark TURBO-CHIL.RTM..
FIG. 1 illustrates a portion of a prior art condensing tube 20 manufactured by Wolverine Tube, Inc., and known in the industry as Turbo-CII.TM.. On its tube wall 21, tube 20 of FIG. 1 has fins 22 formed in planes perpendicular to the tube's longitudinal axis 24. Between roots of adjacent fins 22 on the exterior surface 25 of tube 20 is a ravine-shaped channel 26. Channel 26 has a rounded bottom which forms a pocket wherein liquid refrigerant forms in pools 28 during condensation. Eventually the refrigerant which pools in channel 26 is drained away by gravity from an underside of the tube. However, as the depth of the pooled refrigerant 28 increases in channel 26, the distance between tube wall 21 and the refrigerant vapor 29 which is being condensed also increases and constitutes an increased resistance to condensation of more vapor.
Tube 20 also has helical ridges 30 formed on an inner surface 32. Ridges 30 have a predetermined ridge height and pitch and are positioned at a predetermined helix angle. The ridge height e of tube 20 shown in FIG. 1 is 0.015 inch; the inner diameter D.sub.i of tube 20 is 0.612 inch.
Other parameters of interest for tube 20 are the thickness of the tube wall x and the height g of the fins 22 from tube exterior surface 25. For tube 20, x is 0.028 inch and g is 0.040 inch.
The rounded shape of the bottoms of channels 26 results from the configuration of tooling applied to tube exterior surface 25 for forming fins 22. In particular, a series of rotating finning disks (not shown) are employed, in sequence, to apply a force to the tube exterior surface in a manner both to push metal on the exterior outwardly so as to form the fins 22 and to slightly elongate tube 20. Simultaneously, the internal ridges 30 are formed on a mandrel (not shown, which has grooves which are complementary to the ridges). Conventionally, the radially outermost forming portions of the finning disks, as viewed in axial cross section, are rounded (i.e., the finning disks have a profile corresponding to the shape of channels 26). Each of the finning disks in the series has essentially the same rounded profile, with each finning disk in the sequence digging progressively deeper into the tube metal.
It is an object of the present invention to increase heat transfer in boiling and condensing tubes, e.g., by widening and preferably substantially flattening the channels between roots of adjacent fins, thereby reducing the depth of refrigerant pooled in the channels.

Heat transfer tubes and methods of fabrication thereof


A RiG may simulate visual conditions of a real world environment, and generate the necessary amount of pixels in a visual simulation at rates up to 120 frames per second. RiG may also include a database generation system capable of producing visual databases suitable to drive the visual fidelity required by the RiG.

Air Force pilots entering the service generally have superior visual acuity, on the average 20/13. However, current research based simulators (or image generators) provide visual acuity on the average of 20/40 or 20/80. Furthermore, current research based simulators are often very expensive to build and fail to provide eye limiting resolution, i.e., acuity better than 20/13.
In order to study human vision in an operationally relevant environment, an image generator that matches conditions of the real world may be beneficial. For example, a research based image generator configured to provide eye limiting resolution, e.g., better than 20/13, may be particularly beneficial. A database that provides eye limiting resolution imagery based on a desired simulation context and hardware configured to produce the necessary amount of pixels at a minimum of 60 frames per second may also be beneficial. Existing legacy databases typically cannot provide sufficient resolution with high-fidelity.

The United States of America as Represented by the Administrator of the National Aeronautics and Space Administration


A molded seat that is formed from plastic and has improved strength and attachment mechanisms. The seat includes a seat back and a seat pan, both of which are constructed from a plastic material. The universal seat also includes an articulated recliner that is connected to both the seat back and the seat pan. The articulated recliner includes high-strength sheath portions into which plastic bayonets from the seat pan and the seat back are inserted. The use of the articulated recliner results in a seat having improved strength. In addition, the combination of the sheaths of the articulated recliner in conjunction with the bayonets of the seat back and seat pan help eliminate the need for additional attachment mechanisms, thereby making the universal seat easier to manufacture and install.

Blow-molded seats are presently used in a significant number of vehicles, especially for rear seats in many vehicles. These blow-molded seats include seat backs and seat pans that are formed from plastic materials using a blow molding process. Unfortunately, these blow-molded seats include relatively weak components that are not capable of withstanding loads generated when a seat belt is required, such as through rapid deceleration and/or an accident. As such, during these seat belt loads, the blow-molded seats may fail at the connections of the seat back and/or seat pan to the motor vehicle.
The prior art has attempted to rectify these issues through the use of reinforced blow-molded seats. In one embodiment, the reinforced blow-molded seats include a front, low back, bucket seat that utilizes a blow molded seat back frame reinforced with a vertical beam at one side to carry seat belt loads produced during rapid deceleration and/or an accident.
In another embodiment, blow molded seat frames having high strength, roll-formed metal tubes are used. These tubes permit the creation of belt carrying lower seat cushion frames, full bench frames, split bench frames, and high back captain's chairs. In this embodiment, the seat backs and/or seat pans may be attached to an articulated recliner using a hollow sheath in the seat back/seat pan into which the articulated recliner is inserted.
Nevertheless, these embodiments, while providing increased support during seat belt loads, still do not provide optimum strength. In addition, the seats constructed according to the prior art require additional mechanisms for connecting the seat to the vehicle, thereby making the seats more difficult to manufacture and/or install.


A pluggable optical transceiver with an enhance EMI tolerance is disclosed. The optical transceiver provides an electrically conductive receptacle, a ground member made of metal sheet, and a cover also made of metal sheet. The ground member is assembled so as to surround a periphery of the receptacle. The cover provides a first bridge in a front portion thereof, while, the ground member provides fingers and a second bridge connecting the fingers in the tip portion. Fully setting the optical transceiver in the cage, the finger comes in contact with the inside of the cage and the first bridge comes in securely contact with the second bridge so as to shield a gap between the transceiver and the cage.

1. Filed of the Invention
The present invention relates to an optical transceiver, in particular, the invention relates to an arrangement to reduce EMI radiation leaked from the optical transceiver.
2. Related Background Art
One type of an optical transceiver has been known as a pluggable optical transceiver, in which the pluggable optical transceiver is set within a cage provided on the host board from the front opening of the cage. Typical arrangements of the pluggable optical transceiver and the cage have been disclosed in, for instance, the U.S. Pat. No. 7,491,090, the U.S. Pat. No. 7,406,230 and the U.S. 2009/0176409A.
The pluggable optical transceiver typically comprises a body, a receptacle, a ground member and a cover. The body installs semiconductor optical devices, such as semiconductor laser diode (hereafter denoted as LD) and semiconductor photodiode (hereafter denoted as PD), a circuit board electrically connected with the optical devices. The receptacle, which is provided in a front portion of the body, may couple optical devices with external optical fibers secured in an optical connecter set in the receptacle. The cover installs the body therein and is assembled with the receptacle. The ground member, which covers the outer peripheral of the receptacle, provides a plurality of fingers. Setting the optical transceiver in the cage, the fingers may come in securely contact with an inside of the cage. Thus, the EMI tolerance of the optical transceiver may be enhanced. As the transmission speed of the optical communication system increases, the EMI tolerance of the optical transceiver applicable in the system has been requested in higher degree, because a signal with higher frequency components is easily radiated out from the optical transceiver.

Optical transceiver with enhanced EMI tolerance


A reverberation apparatus is designed for generating a reverberation sound from an input sound with use of an impulse response based on an instruction. In the reverberation apparatus, a first storage section stores first impulse response data representative of a first impulse response. A second storage section stores second impulse response data representative of a second impulse response which is different from the first impulse response represented by the first impulse response data. A new data creating section operates based on the first impulse response data and the second impulse response data for creating new impulse response data representative of a new impulse response in accordance with the instruction. A reverberation sound generating section generates reverberation sound data representative of the reverberation sound by filtering input sound data representative of the input sound with use of the new impulse response data, such that the generated reverberation sound is featured by the new impulse response.

1. Technical Field of the Invention
The present invention relates generally to a technology for generating reverberation sounds for a variety of music sounds such as performance sounds of musical instruments and singing voices.
2. Prior Art
Apparatuses are known in which a reverberation sound is artificially imparted to an input sound. In such apparatuses, it is a general practice that an impulse response is measured beforehand in an acoustic space such as a concert hall, and a convoluting computation based on this impulse response is applied to the input sound, thereby generating a reverberation sound. In addition, configurations have been proposed in which such various characteristics associated with the reverberation sound as reverberation time and frequency characteristic can be changed. For example, patent document 1 indicated below discloses a configuration in which a plurality of impulse responses having different characteristics are prepared and any one of these impulse responses is selectively used, thereby appropriately changing reverberation sound characteristics.
Patent document 1 is Japanese Patent publication No. Hei 5-47840. The related description is presented on page 4 of Patent document 1.
In the above-mentioned configuration, however, numerous impulse response data must be prepared, thereby causing a problem of increasing the scale of a storage unit for storing these data. To avoid this problem, the amount of the impulse response data may be decreased but at the cost of rough or coarse tuning of the reverberation sound characteristics, resulting in the inability to finely tune these characteristics.

Reverberation sound generating apparatus


A power injector is provided for injecting fluid from a replaceable syringe into the body of an animal. The syringe includes a syringe adapter interface for accepting side mountable syringes having pushrod extensions for actuating the syringe plungers from a point behind the syringe body. The injector is provided with an operator-removable and interchangeable interface in the form of a syringe mounting head. The interface includes a holder that has two halves, one fixed and one moveable, that open and close in a clam-shell fashion to respectively load or unload a syringe and to operate the syringe by driving the plunger thereof with a power driven ram that extends form the injector housing. The end of the injector ram, which is configured to normally couple to a button or key on the back of the plunger of a front or rear loadable syringe, is provided with an adapter that couples to the ram and to the large disk shaped end of a side loadable syringe pushrod. The adapter has opposed spring biased gripping fingers projecting forward of a coupling plate on the adapter in order to clip the pushrod end to the adapter. The fingers are configured and spaced relative to the coupling plate to engage the pushrod end either upon axial advancement against it or when the syringe is translated sideways into the holder.

Power injectors are devices used to inject fluids at controlled or programmed rates or pressures into patients. Important uses include computed tomography (CT) and angiography, where a radiopaque contrast medium is injected into a patient's vascular system to enhance diagnostic images. With power injectors, a motor-driven ram advances the plunger of a syringe under microprocessor control to provide control of injection parameters such as flow rate, volume and timing. Such injectors are often loaded with sterile empty syringes with their plungers forward and that are filled by drawing fluid from a supply into the syringe through the syringe nozzle by using the ram to draw the syringe plunger backward. In other situations, the injectors are loaded with prefilled syringes. In either case, the syringes used are typically disposed of after a single use.
A variety of syringes have been developed and are in use as both prefilled and fillable syringes. Some such syringes are provided with pushrods extending rearwardly from the plunger and beyond the rearward end of the syringe body. Reasons for this may include the need to operate the syringe plungers by hand, where the plunger pushrod serves as a handle for the manual advance or retraction of the plunger, or may include a desire to couple the plunger to a drive ram at a point outside of the syringe body, even where the syringe is empty and the plunger is at the forward end of the syringe. In such cases, the plungers may be permanently connected to the pushrods in manufacture or once assembled, and will project behind the rear rims of the syringe bodies.
Many of such syringes are further provided with an outwardly projecting flange which serves to hold or support the syringe against axial motion so that force can be applied between the flange and the remote end of the pushrod to operate the syringe plunger. The remote end of the pushrod is usually provided with a flat surface against which force can be applied to advance the plunger, as well as outwardly extending edge or rim structure that can be hooked and pulled to enable the plunger to be retracted. Such a pushrod may, for example, be provided with a disk shaped remote end that is larger in diameter than the pushrod shift. When inserted into holders of injectors or other syringe operating devices, such syringes are most conveniently configured to be loaded into the syringe holders of the devices from the side. Widely used syringes of this type include 100 ml. and 200 ml. syringes manufactured by Nemoto of Japan.
Certain of the inventors of the subject matter of the present application have provided front loading injectors that are adapted to receive front loadable syringes. A front loading injector is one in which a front loadable syringe is positioned in front of an opening in an injector holder and loaded into the holder by translating the syringe rearwardly, back end first, into the injector. Such a front loading injector is described and illustrated in U.S. Pat. No. 5,279,569, which is assigned to the assignee of the present application, and is expressly incorporated by reference herein.
In addition, breach loading or rear loading injector holders are still provided for many applications. Rear loading injectors are injectors in which a rear loadable syringe is positioned behind a holder of the injector and translated, so structure on the syringe, usually a flange or other outwardly extending element at the syringe rear, seats forwardly against the holder. Usually the holder opens for loading or unloading of a syringe by pivoting away from the injector housing, either in hinged or turret fashion. One such injector is described and illustrated in U.S. Pat. No. 4,695,271, which is assigned to the assignee of the present application, and is expressly incorporated by reference herein.
Both rear and front loading power injectors are provided with rams that extend into the rear of a body of a syringe supported in the holder of the injector. The rams have coupling elements on the front ends thereof that engage structure on the rear of the plunger, within the body of the injector, often in such a way that the plunger can be both advanced and retracted by the motion of the ram. Where empty syringes are used and filled after loading on the injector, the rams of many front and rear loading injectors are of a diameter somewhat smaller than the internal diameter of the syringe, which minimizes the risk that the ram will contact the inside of the syringe body and contaminate the cavity before the plunger is retracted to fill the syringe.
With syringes that have plunger pushrods or rearward plunger extensions, their use with either rear loading or front loading injectors is difficult to achieve. Such syringes are not compatible with the ram-plunger coupling structure with which front and rear loading injectors are provided and the extension of the pushrod rearwardly of the back end of the syringe body interferes with a support of the syringe in a suitable position on the syringe holder of the injector. Such coupling structure often includes a button or key at the center of the rear wall of the plunger with a mating socket or set of jaws centered on the tip of the ram. Furthermore, providing special purpose injectors configured to handle side loadable syringes has not been regarded as practical in the prior art.
Accordingly, there is a need for a power injector that can make use of pushrod type syringes, particularly prefilled syringes, and particularly for injectors that can also be used with syringes of the front and rear loadable types.

Power injector and side loadable syringe support therefor for plunger pushrod type syringes


A coin handling protection device is disclosed which prevents thieves from stuffing compressible material through the coin insert slot and into the coin return chute of coin-operated machines. The device prevents stuffing the coin return chute by incorporating a blocking plate across the top opening of the coin return chute such that compressible material stuffed into the coin insert slot is diverted into the open space within the payphone unit. The device is suitable for use in existing coin handling apparatus.

1. Field of the Invention
The present invention relates generally to a coin handling protection device and, more particularly, to a device which can be attached to a standard payphone coin handling apparatus to prevent tampering with the coin handling system.
2. Description of the Prior Art
The payphone coin handling apparatus in use today typically comprises a body having a downwardly-inclined coin chute through which coins are allowed to roll from an inlet end aligned with a coin insert slot. The body further includes a coin validator which provides a means of electronically detecting the authenticity and value of the coin as it rolls down the coin chute. The coin validator may comprise, for example, an "MS16" model coin validator manufactured by Mars Electronics. Alternatively, other types of coin validators may be used to determine the authenticity and value of coins inserted into the payphone, including those functioning mechanically or optically. Depending upon the type and value of the inserted coins and whether the telephone call is completed, the coin validator operates to selectively route the coins to a coin box or a coin return trough. A coin box chute is coupled to the outlet end of the coin chute and receives valid coins which are to be deposited in the coin box. A coin return chute is positioned adjacent to the coin validator and function to receive counterfeit coins or valid coins to be returned to the payphone customer. The coin return chute comprises a hollow body having front and back walls which are joined by opposing side walls. Each of the side walls converge at its bottom end to form a narrow throat at the exit end of the coin return chute. The coin return chute is coupled at its exit end to a coin return trough, from which a customer can retrieve coins returned from the payphone. The top of the coin return chute is open such that it may receive coins from the coin validator.
Theft of coins from payphone coin handling apparatus has been a continuing problem in payphones of the type described above. Initial forms of stuffing coin handling apparatus involved inserting compressible material, such as matchbook covers or slips of paper, through the coin insert slot and thereby lodging the compressible material in the coin chute. The compressible material caused the coin chute to fill up with coins as payphone customers unsuccessfully attempted to use the telephone. The thief retrieved these coins by pushing a coat hanger or other similar object into the coin chute and forcing the coins through an adjacent coin validator and into the coin return chute. These coins would cascade down the coin return chute and into the coin return trough where they would be retrieved by the thief.
Attempts at preventing this type of theft involved designing a coin chute that can be cleared of compressible materials. In particular, the coin chute body comprises two sidewalls pivotally connected along their top edges to a bracket through a pivot pin. Further, the coin chute sidewalls are biased together by a biasing spring positioned along their top edges. A coin release lever is pivotally connected to the exterior of the payphone unit and is coupled by a linkage to the coin chute. When the coin release lever is actuated, the coin chute sidewalls separate and release lodged coins or compressible material into the coin return chute.
While this mechanism has proved successful in preventing stuffing of the coin chute, it has given rise to yet another form of "stuffing." Rather than attempting to stuff the coin chute, thieves revert to stuffing the coin return chute. To "stuff" the coin return chute, the thief inserts compressible material through the coin insert slot and into the coin chute as described above. After the compressible material is lodged in the coin chute, the thief actuates the coin release lever, thereby depositing the compressible material into the coin return chute. Because the coin return chute converges at the exit end, the compressible material settles at the bottom of the coin return chute. The thief repeatedly deposits compressible material into the coin return chute in this manner until a sufficient amount of material collects and blocks the coin return chute exit end. After sufficient time, a sizable number of coins, which would otherwise be returned to the payphone customer, accumulates within the coin return chute behind the compressible material. The thief then pours a combustible fluid through the coin inlet slot and into the coin return chute and ignites the compressible material, thereby allowing the accumulated coins to cascade into the coin return trough for retrieval by thief. This not only means that money which should have been returned to the payphone customers is lost to the thief; but, often the coin handling apparatus is damaged by the ignited compressible material and must be repaired.
The payphone coin handling stuffing problem is an old one and until now no satisfactory solution has been found. This crime costs the phone companies enormous sums of money. Although the phone companies would not normally collect the returned money lost to the "stuffers," the phone companies incur high administrative costs in repairing the payphones and refunding the lost money to irate customers. More specifically, each phone company must employ personnel to investigate reports of payphones failing to return change, employ maintenance workers to examine and repair "stuffed" phones, and have accounting and payment systems in place to refund lost money to payphone customers. Consequently, there is a substantial need for an inexpensive device that reliably prevents stuffing which can be quickly and easily installed in an existing payphone.

Coin handling apparatus protection device


The invention provides antibodies that specifically bind human α-synuclein with a high affinity and reduces α-synuclein spreading in vivo, recombinant polypeptides comprising said antibodies or antigen-binding fragment thereof and methods for generating such polypeptides, as well as compositions and methods for generating α-synuclein antibodies, and methods of using α-synuclein antibodies for the treatment of diseases of the central nervous system, in particular alpha-synucleinopathies.

The present invention relates to α-synuclein antibodies and their use in the prevention or treatment of disease, in particular alpha-synucleinopathies, and more particularly Parkinson's disease (PD).
Alpha-synucleinopathies, also known as Lewy body diseases (LBDs), are a family of neurodegenerative diseases that all have at their core alpha-synuclein as the key pathological hallmark (Jellinger, Mov Disord (2003), 18 Suppl 6: S2-12; and Spillantini and Goedert, Ann N Y Acad Sci (2000), 920: 16-27; both of which are incorporated herein by reference). Alpha-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).
PD is a slowly progressive age-related movement disorder affecting greater than 1% of people over 65 years old. PD is the second most common neurodegenerative condition after Alzheimer's disease.
A defining hallmark pathology of alpha-synucleinopathies are Lewy bodies and Lewy neurites, which are insoluble inclusions of aggregated proteins found inside neurons of the brain revealed upon post-mortem histopathological examination.
The presence of Lewy pathology and neuronal loss in non-motor brain regions such as the basal forebrain, mesopontine system, amygdala, neocortex, dorsal motor nucleus of the vagus nerve, olfactory bulbs, locus coeruleus, and the brainstem, may cause cognitive deficits and dementia, hyposmia, sleep disturbances including rapid eye movement sleep behaviour disorder (RBD), mood disorders including depression and anxiety, autonomic dysfunction including cardiovascular and gastrointestinal problems such as constipation, and fatigue and somnolence. Some of these non-motor symptoms appear to characterise the premotor or prodromal phase of the disease (Kalia et al. Lancet (2015), 386(9996): 896-912; incorporated herein by reference).
The presence of Lewy pathology and neuronal loss in motor brain regions, including most notably the death of dopaminergic neurons in the substantia nigra, may cause resting tremor, rigidity, bradykinesia and postural instability (Spillantini and Goedert, Ann N Y Acad Sci (2000), 920: 16-27; incorporated herein by reference).
Alpha-synuclein (also called "α-synuclein" or "α-syn") protein is the major structural component of Lewy bodies and Lewy neurites. Alpha-synuclein is a small acidic protein made up of 140 amino acids (14 kDa). Human natural wild-type alpha-synuclein has the amino acid sequence SEQ ID NO: 1 as described under UniProtKB accession number P37840. Unless otherwise apparent from the context, reference to alpha-synuclein or its fragments includes the natural human wild-type amino acid sequence indicated above, and human allelic variants thereof, in particular those associated with Lewy body disease (e.g., E46K, A30P, H50Q, G51D and A53T, where the first letter indicates the amino acid in SEQ ID NO: 1, the number is the codon position in SEQ ID NO: 1, and the second letter is the amino acid in the allelic variant). Such variants can optionally be present individually or in any combination. The induced mutations E83Q, A90V, A76T, which enhance alpha-synuclein aggregation, can also be present individually or in combination with each other and/or with human allelic variants E46K, A30P, H50Q, G51D and A53T. At the structural level, alpha-synuclein contains three distinct regions: an amphipathic N-terminal alpha-helix domain that has lipid and membrane binding properties (residues 1-60), a central hydrophobic amyloid-binding domain that encodes the non-amyloid-beta component (NAC) of plaques (residues 61-95), and an acidic proline-rich C-terminal tail (residues 96-140). Residues 71-82 of the NAC domain are believed to be key to the aggregation/fibrillation properties of alpha-synuclein by enabling the protein to switch from a random coil structure to a beta-sheet structure (Bisaglia et al. FASEB J (2009), 23(2): 329-40; incorporated herein by reference). Although the C-terminal domain is free of significant secondary structure it contains a key phosphorylation site at residue Ser129 and a number of tyrosine residues that are nitrated in cytosolic alpha-synuclein inclusions. N-terminal and C-terminal truncated forms of alpha-synuclein also exist. Post-translational modifications to the protein can affect alpha-synuclein aggregation and toxicity (Oueslati et al. Prog Brain Res (2010), 183: 115-45; incorporated herein by reference).
Alpha-synuclein is abundant in the central nervous system (CNS)/brain where it is found both intracellularly in neurons and glia and also extracellularly in cerebrospinal fluid (CSF) (Mollenhauer et al. J Neural Transm (2012), 119(7): 739-46; incorporated herein by reference) and the interstitial fluid (ISF) that bathes and surrounds the cells of the brain (Emmanouilidou et al. PLoS One (2011), 6(7): e22225; incorporated herein by reference). Alpha-synuclein is a synaptic protein predominantly expressed in neurons of the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum (Iwai et al. Neuron (1995), 14: 467-475; incorporated herein by reference). Under physiological conditions, it is located in neuronal synaptic terminals and is specifically up-regulated at presynaptic terminals during acquisition-related synaptic rearrangement (Fortin et al. J Neurosci (2005), 25: 10913-10921; incorporated herein by reference).
In-vitro studies have shown that alpha-synuclein monomers may form the starting point for the aggregation process. The monomer can aggregate into a variety of small oligomeric species that are then stabilised by beta-sheet interactions, going on to form protofibrils which can polymerise into insoluble fibrillary structures reminiscent of those identified in Lewy bodies (Cremades et al. Cell (2012), 149(5): 1048-59; incorporated herein by reference).
Under pathological conditions, aberrant alpha-synuclein aggregation may be key to the pathological changes seen in alpha-synucleinopathies (Lashuel et al. Nature (2002), 418: 291; and Tsigelny et al. FEBS Journal (2007), 274: 1862-1877; both of which are incorporated herein by reference). In vitro and in vivo studies have shown that the neurotoxic effects of alpha-synuclein appear to be elicited by small soluble oligomeric conformers or protofibrils (Winner et al. Proc Natl Acad Sci USA (2011), 108(10): 4194-9; and Danzer et al. J Neurosci (2007), 27(34): 9220-32; both of which are incorporated herein by reference). While fibrillar aggregates of alpha-synuclein are characteristic of PD, oligomeric forms of alpha-synuclein are the toxic species (Danzer et al. J Neurosci (2007), 27(34): 9220-32; Lashuel et al. Nature (2002), 418: 291; and Winner et al. Proc Natl Acad Sci USA (2011), 108: 4194-4199; each of which are incorporated herein by reference).
Alpha-synuclein oligomers can be released to the extracellular environment and taken up by neighboring cells in a "propagation" mechanism (Angot and Brundin, Parkinsonism Relat Disord (2009), 15 Suppl 3: S143-147; Desplats et al. Proc Natl Acad Sci USA (2009), 106: 13010-13015; and Lee et al. J Biol Chem (2010), 285: 9262-9272; each of which are incorporated herein by reference). Aggregates of alpha-synuclein can propagate misfolding through a prion-like spreading mechanism (Lee et al. Nat Rev Neurol (2010), 6: 702-706; Luk et al. J Exp Med (2012), 209(5): 975-86; and Luk et al. Science (2012), 338(6109): 949-53; each of which are incorporated herein by reference). Alpha-synuclein can therefore induce neurodegeneration by either oligomer toxicity or propagation and prion-like spreading.
It is now well established and accepted that cells including neurons can secrete various forms of alpha-synuclein (monomers, oligomers, aggregates) under normal conditions and also under conditions of cellular stress, the secretion of monomeric and aggregated forms of alpha-synuclein is elevated under conditions of cellular stress, and through this release of alpha-synuclein into the extracellular milieu, pathological transmissible forms of alpha-synuclein may be propagated between neurons (Recasens and Dehay, Front Neuroanat (2014), 8: 159; incorporated herein by reference).
The effects of alpha-synuclein in PD may extend beyond the immediate damage to vulnerable neuronal cells. Like most neurodegenerative diseases there is also a pro-inflammatory cellular response observed (Lee et al. J Biol Chem (2010), 285: 9262-9272; incorporated herein by reference). Circulating alpha-synuclein and/or activated astrocytes can activate microglia, leading to increased generation of reactive oxygen species, nitric oxide and cytokine production, and further exacerbating neurodegeneration (Lee et al. J Biol Chem (2010), 285: 9262-9272; incorporated herein by reference).
A variety of different experimental models have demonstrated cell-to-cell transmission of alpha-synuclein in cultured cells, or in vivo spreading and propagation of alpha-synuclein pathologies. Lewy body pathology has been observed within embryonic mesencephalic neuronal grafts more than 10 years after the grafts were therapeutically transplanted into the striatum of PD patients. Specifically, grafted neurons contained a number of Lewy body-like inclusions that stained positively for alpha-synuclein, indicating that host-to-graft transmission of alpha-synuclein pathology had occurred (Li et al. Nat Med (2008), 14(5): 501-3; and Kordower et al. Nat Med (2008), 14(5): 504-6; both of which are incorporated herein by reference).
Further, preformed recombinant alpha-synuclein fibrils and alpha-synuclein oligomers can be internalised by cultured cells and neurons, and the direct transfer of alpha-synuclein from donor to recipient cells with the formation of alpha-synuclein inclusions similar to Lewy pathology has been demonstrated (Danzer et al. J Neurosci (2007), 27(34): 9220-32; Volpicelli-Daley et al. Neuron (2011), 72(1): 57-71; and Luk et al. Proc Natl Acad Sci USA (2009), 106(47): 20051-6; each of which are incorporated herein by reference). Injection of preformed synthetic alpha-synuclein fibrils or Lewy body-like alpha-synuclein containing material extracted from the brains of aged alpha-synuclein transgenic mice into the brains of asymptomatic recipient mice promotes the formation of Lewy body-like pathology in host neurons of the recipient animals along with neurodegeneration and neurological deficits (Luk et al. J Exp Med (2012), 209(5): 975-86; and Luk et al. Science (2012), 338(6109): 949-53; both of which are incorporated herein by reference). Alpha-synuclein containing Lewy body extracts isolated from PD brains inoculated into the substantia nigra or striatum of macaque monkeys and mice is rapidly taken up by host cells (within 24 hours) followed by a slower loss of striatal dopaminergic terminals, with cell loss evident after more than a year (Recasens et al. Ann Neurol (2014), 75(3): 351-62; incorporated herein by reference). Similarly, inoculation of mice with brain homogenates derived from patients with the synucleinopathies DLB or MSA triggers alpha-synuclein Lewy-like pathology in the host mice (Watts et al. Proc Natl Acad Sci USA (2013), 110(48): 19555-60; and Masuda-Suzukake et al. Brain (2013), 136 (Pt 4): 1128-38; both of which are incorporated herein by reference). Finally, transfer and transmission of both monomeric and oligomeric alpha-synuclein from the olfactory bulb to interconnected brain structures has been demonstrated in mice (Rey et al. Acta Neuropathol (2013), 126(4): 555-73; incorporated herein by reference).
Passive immunotherapy approaches with antibodies targeting alpha-synuclein have been tested in numerous preclinical alpha-synucleinopathy mouse models (Lawand et al. Expert Opin Ther Targets (2015): 1-10; incorporated herein by reference). Specifically, a study using a monoclonal antibody directed against alpha-synuclein (9E4) has shown in vivo clearance of alpha-synuclein aggregates and pathology, behavioural motor improvements, and neuroprotective effects (WO 2014/058924; which is incorporated herein by reference).
Further studies using passive immunisation of alpha-synuclein transgenic mice developed as experimental models of PD/DLB, with the 9E4 monoclonal antibody have shown the antibody to clear alpha-synuclein pathology, decrease synaptic and axonal deficits, abrogate loss of striatal tyrosine hydroxylase fibres, and significantly reduce memory deficits and motor function impairments (Games et al. J Neurosci (2014), 34(28): 9441-54; Bae et al. J Neurosci (2012), 32(39): 13454-69; and Masliah et al. PLoS One (2011), 6(4): e19338; each of which are incorporated herein by reference). Further it has been demonstrated that passive administration of anti-alpha-synuclein monoclonal antibodies in wild-type mice that were injected intrastriatally with synthetic alpha-synuclein preformed fibrils (pffs) led to robust reduction in Lewy pathology, prevention of dopamine neuron loss in the substantia nigra, and a significant improvement in motor impairments that are manifest in the mouse model after pffs treatment (Tran et al. Cell Rep (2014), 7(6): 2054-65; incorporated herein by reference).
Additionally, one of the major challenges associated with treating disorders of the CNS with large molecule therapeutics, such as antibodies, is getting these drugs into the affected tissue. The passage of large molecules into the brain and spinal cord is largely restricted by the blood-brain barrier (BBB). The BBB protects and regulates the homeostasis of the brain and prevents the free passage of molecules into most parts of the brain, thereby limiting the treatment of many brain diseases. Transport of essential molecules such as nutrients, growth factors, and hormones is achieved via a series of specific transporters and receptors that regulate passage across the brain endothelial cells. The delivery of biologics and other drugs to the brain therefore represents a significant challenge. Additionally, transport mechanisms appear to exist that rapidly remove antibodies from the brain, presumably to prevent inflammatory responses due to engagement of Fc with effector ligands that promote a pro-inflammatory response.
Over the last decade, reports of antibody transport across the BBB have emerged where binding to the extracellular domain of the transporter molecules facilitates transcytosis of the receptor antibody complex across the endothelial cell layer.
The BBB is mainly comprised of brain capillary endothelial cells, which have specialized characteristics, such as tight junctions, to limit transport of molecules into the brain (Reese et al. 1967, J. Cell Biol. 34: 207-217; Brightman et al. 1969, J. Cell Biol. 40: 648-677; Rubin et al. 1999, Ann. Rev. Neurosci. 22: 11-28), although other cell types, such as pericytes, astrocytes, and neuronal cells, also play an important role in the function of the BBB. Typically, less than 0.1% of a peripherally dosed antibody reaches the brain (Boado et al. 2010, Mol. Pharm. 7: 237-244; Pepinsky et al. 2011, Nat. Neurosci. 8: 745-751). The BBB functions as a physical, metabolic and immunological barrier (Gaillard et al. 2003, Microvasc. Res. 65: 24-31).
Antibody transport across the BBB can be enhanced by triggering receptor mediated transcytosis on brain endothelial cells. Through this process, engagement of antigens on the luminal side of the endothelial cell can induce the internalization and shuttling of the antibody across the cell, and then its subsequent release into the tissue.
Current drug therapies for PD are mainly focused on treating the motor-related symptoms of the disease. There are currently no marketed or available therapies that can treat or prevent alpha-synucleinopathy.
Accordingly, there is a need in the art for a therapy for treating alpha-synucleinopathies, particularly in humans.

Antibodies to alpha-synuclein and uses thereof


The present invention relates to a method and system that automatically finds, segments and measures lesions in medical images following the Response Evaluation Criteria In Solid Tumours (RECIST) protocol. More particularly, the present invention produces an augmented version of an input computed tomography (CT) scan with an added image mask for the segmentations, 3D volumetric masks and models, measurements in 2D and 3D and statistical change analyses across scans taken at different time points.

CT scans make use of x-ray imaging from a number of different angles to produce cross sectional slices of a scanned patient. Although CT scans provide radiologists a useful tool to identify, locate and classify lesions in patients, it is difficult to perform volumetric measurements of lesions from CT images in acceptable amount of time due to the sheer number of image slices contained in each CT scan.
CT scans are usually presented in grayscale and therefore consist of only one colour channel. This creates problems when radiologists want to view different elements of the image as the human eye is capable of distinguishing a limited number of grey levels that are not sufficient to visualise all the information in a CT slice. The different elements are presented in varying brightness-contrast settings on a number of different windows. For example, the view of skeletal element of the scan may be best viewed in one brightness-contrast setting (called 'window'), the view of the organs in another window, etc. Radiologists therefore have to look at different contrast windows in order to identify and locate lesions. It is an aim of the present invention to provide a solution to this problem.
Medical imaging devices usually encapsulate the scans into the Digital Imaging and Communications in Medicine (DICOM) format to enable more efficient handling, storing, printing and transmitting of medical imaging information.
The RECIST protocol is a set of rules that are used to assess the behaviour of a tumour in a patient. The RECIST protocol also provides a method that can be used to measure lesions, however, the current method requires a vast amount of input and uninformed decisions made before treatment from the radiologists which may result in inaccurate measurements, the inability to record measurements on suspect tumours and more importantly not identifying a lesion from an image.
When assessing tumour progression, radiologists need to assess tumour burden for scans performed at different time points and compare the results. It is critical that the same lesions are accurately identified at different time points and assessed for the purpose of comparison. The co-location and comparison process is a burdensome and inherently inaccurate.
When assessing tumour burden, radiologists perform 1D measurements of portions of lesions that fall into the 2D slices produced. This measurement is inherently limited in how accurately it represents tumour burden provided by a single lesion.

Abstract: According to a first aspect, there is provided a method for determining volumetric properties of one or more lesions in medical images comprising the following steps: receiving image data; determining one or more locations of one or more lesions in the image data; creating an image segmentation (i.e. mask or contour) comprising the determined one or more locations of the one or more lesions in the image data and using the image segmentation to determine a volumetric property of the lesion.


The present disclosure provides 2′-C-methyl-ribofuranosyl cytidine prodrugs, methods of making 2′-C-methyl-ribofuranosyl cytidine prodrugs, pharmaceutical compositions of 2′-C-methyl-ribofuranosyl cytidine prodrugs, and methods of using 2′-C-methyl-ribofuranosyl cytidine prodrugs and pharmaceutical compositions thereof to treat viral diseases such as hepatitis C.

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer et al., J. Hepatol. 2000, 32, 98-112). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie et al., Scientific American 1999, October, 80-85). An estimated 170 million persons are infected with HCV worldwide. Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplant.
HCV is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis. Preliminary evidence also implicates HCV in many cases of "idiopathic" chronic hepatitis, "cryptogenic" cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as Hepatitis B Virus (HBV). A small proportion of healthy persons appear to be chronic HCV carriers, varying with geography and other epidemiological factors. The numbers may substantially exceed those for HBV, though information is still preliminary; how many of these persons have subclinical chronic liver disease is unclear.
HCV has been classified as a member of the virus family Flaviviridae that includes the genera flaviviruses, pestiviruses, and hapaceiviruses, which includes hepatitis C viruses (Rice, C. M., Flaviviridae: The viruses and their replication. In: Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter 30, 931-959, 1996). HCV is an enveloped virus containing a positive-sense single-stranded RNA genome of approximately 9.4 kb. Currently, there are two primary antiviral compounds, Ribavirin and interferon-alpha, which are used for the treatment of chronic HCV infections in humans. The non-structural protein NS5B has been described as an RNA-dependent RNA polymerase that is required for viral replication. This polymerase is an essential component in the HCV replication complex and therefore is an excellent target for drug discovery.
Several 2′-modified nucleoside analogs with potent inhibitory activity against the HCV NS5B polymerase have been identified, including β-D-2′-C-methyl-ribofuranosyl cytidine (1) (e.g., see Sommadossi et al., U.S. Pat. No. 6,914,054 and references therein; and Clark et al., J. Med. Chem. 2005, 48, 5504-5508). Efforts to improve the oral bioavailability of (1) have resulted in the investigation of prodrug derivatives, including synthesis of compounds with acyl and/or α-aminoacyl moieties appended at one or more of the 5′-O, 3′-O, or N-4 positions of the ribonucleoside nucleus (e.g., see Pierra et al., Nucleosides, Nucleotides 2005, 24, 767-770; Pierra et al., J. Med. Chem. 2006, 49, 6614-6620; U.S. Application Publication No. 2004/0077587; International Publication No. WO 2004/002999; and International Application No. WO04/003000). One compound of particular interest is NM 283 (2), the 3′-O-L-valinyl ester of β-D-2′-C-methyl-ribofuranosyl cytidine, which shows good bioavailability in preclinical species and in humans (e.g., see Pierra et al., J. Med. Chem. 2006, 49, 6614-6620). NM 283 is currently undergoing clinical evaluation as a treatment for HCV, where significant antiviral activity has been demonstrated.

One significant problem with oral administration of NM 283 or β-D-2′-C-methyl-ribofuranosyl cytidine is the gastrointestinal (GI) toxicity of the parent nucleoside analog which results in unpleasant side-effects in some patients such as nausea, vomiting and diarrhea. This toxicity may arise as a result of accumulation of the phosphorylated nucleoside analog within intestinal cells, and its incomplete selectivity for inhibition of the viral RNA polymerase relative to mammalian polymerase enzymes. Thus, there is a need for improved prodrugs of (1) having a superior safety and tolerability profile than NM 283 (2). Preferred prodrugs are sufficiently stable in the intestinal lumen and during transit across the enterocyte barrier so that little or no compound (1) is liberated within the intestinal cells themselves. This limits direct exposure of sensitive GI cells to toxic levels of (1). However, once the prodrug has entered the portal circulation and is delivered to the liver, cleavage to compound (1) via enzymatic, chemical, or a combination of enzymatic and chemical means should occur in order that a therapeutically effective concentration of (1) is provided to virally infected cells (hepatocytes).

2′-C-methyl-ribofuranosyl cytidine prodrugs, pharmaceutical compositions and uses thereof


A power-off emergency braking system, or parking brake system is presented in which, at each power-up, energy is stored in the structure of the brake so as to ensure the power-off application of the brake and the holding of same in the event of an interruption to the power supply of the device.

European patent 1 957 228 of Nov. 3, 2006 is known and relates to an electric braking system. That device uses a variable mechanical gain system positioned between the motor shaft and the brake pad application system. Considering an automotive brake specification, in which the force on the brake pads varies from 0 to 15 kN, with an elastic deformation of 1 mm, the energy required to achieve this operation is 7.5 joules.
The maximum stroke of the moving parts of this brake is, by construction, 2.5 rad (less than ½ a turn). If, by using the variable mechanical gain system, a constant torque is applied to the motor during this operation, then, in order to deliver an energy of 7.5 joules, this torque will have a value of 3 Nm.
These are relatively low torque and stroke values and that means that it is possible to envision this solution whereby, on each start-up, the energy which, in the event of a break in the power supply, will allow the brake to be applied and maintained through lack of power can be stored.
The characteristics of these movements would in theory encourage the storage of this energy in mechanical form in springs placed within the very structure of the brake, although that being said, an electrical solution, notably involving capacitors, should not be excluded.
This power-off brake will operate as an emergency brake; it may also be used as a parking brake, holding the vehicle stationary for all the time it is not powered. It may replace the "handbrake".


Catalyst stripping in the fluid catalytic cracking process is improved by cooling the spent catalyst to quench catalytic condensation reactions, then stripping the cooled catalyst in a primary stripper, followed by heating and a stage of hot stripping. Quenched stripping reduces coke make by reducing conversion of light olefins, made during the FCC process, into coke.

The fluid catalytic cracking (FCC) process has become well-established in the petroleum refining industry for converting higher boiling petroleum fractions into lower boiling products, especially gasoline.
In the fluid catalytic process, a finely divided solid cracking catalyst promotes cracking reactions. The catalyst is in a finely divided form, typically with a particles of 20-100 microns, with an average of about 60-75 microns. The catalyst acts like a fluid (hence the designation FCC) and circulates in a closed cycle between a cracking zone and a separate regeneration zone.
In the cracking zone, hot catalyst contacts the feed so as to effect the desired cracking reactions and coke up the catalyst. The catalyst is then separated from cracked products which are removed from the cracking reactor for further processing. The coked catalyst is stripped and then regenerated.
A further description of the catalytic cracking process may be found in the monograph, "Fluid Catalytic Cracking With Zeolite Catalysts", Venuto and Habib, Marcel Dekker, N.Y., 1978, incorporated by reference.
Although the FCC process has been around more than 50 years, there are still many problem areas. A significant problem is poor stripping. The conventional stripping, in a single stage, by counter-current contact with steam, leaves a lot of cracked product adsorbed on or entrained with spent catalyst. From 10 to perhaps 40 to 50% of the material burned as coke in the regenerator is potentially recoverable hydrocarbon. Thus much work has been done to improve stripping, ranging from long residence time strippers to hot stripping designs.
U.S. Pat. No. 4,481,103, Krambeck et al taught conventional stripping followed by another 1-30 minutes of stripping at moderate temperature.
U.S. Pat. No. 4,789,458 Haddad et al taught an FCC process with a conventional stripper followed by a hot stripper. Hot stripping was achieved by adding some hot regenerated catalyst to the catalyst discharged from the conventional stripper.
Various other stripper arrangements have been proposed, including cyclonic strippers directly connected to an FCC riser reactor outlet.
We looked at these stripping approaches, and were concerned that none provided the optimum solution. Most of these approaches to stripping started with conventional steam stripping, wherein 1 to 5 wt % steam contacts spent catalyst discharged from a riser reactor. They usually then tried to improve stripping by heating the catalyst, or stripping it longer. We believed that it was important to quench and cool the catalyst, rather than heat it, as the first step. This would be considered a step backward by most FCC experts, in that the conventional wisdom is that hot stripping is better stripping. While this is true from a strict diffusion limited view of stripping, it ignores the complex and interconnected activities that go on in a conventional stripper.
Coke on FCC catalyst is associated to the CCR content of the feed stock and to the catalytic chemistries occurring in the FCC. The quenched stripper concept addresses minimizing catalytic coke formation in the stripper; whereas, the hot second zone of the stripper addresses removal of both CCR coke and catalytic coke.
Though no definitive reaction pathway for coke formation has been developed, numerous well accepted factors affect the rate of catalytic coke formation: reaction temperature and time, the nature of the catalyst, the partial pressure of the oil/coke precursors, and the type of oil/coke precursors. Higher reaction temperature will enhance the formation of coke if the coke precursors are present, and will continue to dehydrogenate soft coke to hard coke. Numerous catalyst functionalities affect the rate of coke formation, e.g. dehydrogenation activity via contaminate metals such as Ni, V, Fe; hydrogen transfer ability of the catalyst; and the concentration and strength of Lewis and Brondsted acid sites. The hydrocarbon type also affects coke formation. Hightower and Emmett [J. W. Hightower & P. H. Emmett, J.Am.Chem.Soc., 87; 939 (1965)] found olefins to have a much higher propensity for coke formation than paraffins or aromatics of nearly equivalent molecular weight. Light olefins and aromatics are the predominate FCC product hydrocarbons found in the stripper, thus minimizing their reaction rate to coke formation is of primary importance.
We seek to improve stripper performance by first removing the oil/coke precursors from the interstitial void volume of the stripper at a lower temperature than conventional FCC stripping. The lower temperature reduces the catalytic condensation reactions responsible for catalytic coke formation. This reduces the formation of coke in the stripper relative to conventional higher temperature stripping. We avoid reducing the temperature below 900.degree. F. at the top of the stripper, as this could condense heavy oil products on the catalyst.
We discovered that cool stripping of catalyst, followed by a hot stripping stage, produced significantly less coke than the conventional steam stripping, and much less than hot stripping.

Quenched multistage FCC catalyst stripping