A counter release buckle is provided herein. More particularly, a counter release buckle disengages in a direction opposite the direction that the buckle member is tensioned in. The counter release buckle releases each of the buckle members in the opposite direction of tension that is or would be placed on the buckle member. The buckle also engages the opposing buckle portions by moving them in the direction that the tension is or would be pulling on the respective buckle member.

Traditional buckles are side release buckles such as the one shown in U.S. Pat. No. 5,794,316. In these buckles, two buckle portions engage one another by pulling the buckles toward one another to engage while the opposing portions of the article that the buckles are attached to are simultaneously pulled toward one another, frequently placing the opposing portions of the article in tension allowing the buckle to form a closure by maintaining this tension. In some instances, the article is not placed in tension during the buckling, but when or if the tension is applied it is in the same direction in which the opposing portions of the side release buckle would disengage from one another. Thus, side release buckles have a natural tendency to pull apart due to the tension in the article they hold together. Once clipped together, the two pieces can spontaneously pull apart if enough pressure is applied. Complicated locking solutions have been provided, such as in U.S. Pat. No. 5,794,316, but such solutions add cost and complexity to the device.
Additionally, many side release buckles require two-handed operation in order to easily align and clip together the male and female portions of the buckle. While some buckle designs enable one-handed operation and secure attachment, these solutions can be mechanically complex, such as U.S. Pat. No. 8,813,317, requiring more labor intensive manufacturing processes, costs, and unnecessary complexities.


In a catalyst for purifying exhaust gas which comprises zeolite carried on a refractory support and containing copper introduced thereinto by ion exchange, the zeolite has each site of ion exchange located on the surface of its supercage, and a square arrangement of four oxygen atoms around a copper ion. A method of producing the catalyst is also disclosed. Zeolite is dipped in a copper carboxylate solution to cause the ion exchange to take place. It is possible to obtain a catalyst having a high power of removing NO.sub.x from exhaust gas if the diameter of the supercage of zeolite is appropriately selected in accordance with the size of HC molecules which the exhaust gas contains.

1. Field of the Invention
This invention relates to a catalyst for purifying the exhaust gas of an automobile. More particularly, it is a catalyst which can remove NO.sub.x very effectively from even the combustion product of a lean fuel mixture containing an excess of oxygen. It also relates to a method of producing such a catalyst.
2. Description of the Prior Art
The catalysts which can oxidize carbon monoxide (CO) and hydrocarbons (HC) and reduce nitrogen oxides (NO.sub.x) simultaneously are widely used for purifying the exhaust gases of automobiles. These catalysts basically comprise a support formed from a refractory material, such as cordierite, and carrying a coated and baked layer of a slurry of .gamma.-alumina, and a metal such as Pd, Pt or Rh, or a mixture of such metals carried thereon. A great many proposals have hitherto been made to obtain catalysts of high activity. For example, Japanese Patent Application laid open under No. 11147/1986 discloses an improvement in the catalyst of the type which comprises a noble metal distributed on particles of .gamma.-alumina stabilized with an oxide of a rare earth element. The improved catalyst comprises rhodium distributed on particles which are substantially free from any oxide of a rare earth element.
The purifying characteristics of the catalysts which have hitherto been used or proposed, however, depend largely on the air-fuel ratio of the fuel mixture which is employed in an engine. If it is a lean mixture, the catalyst exhibits a high activity of oxidation but a low activity of reduction, as the combustion product contains a large amount of oxygen (O.sub.2) On the other hand, the catalyst exhibits a high activity of reduction but a low activity of oxidation, if a rich fuel mixture is employed. The catalyst works most effectively when the fuel mixture has a theoretical air-fuel ratio (A/F=14.6) at which its activities of oxidation and reduction are balanced. In an automobile equipped with an exhaust gas purifier employing a catalyst, therefore, it is usual to detect the amount of oxygen in the exhaust gas and feed back the results to control the air-fuel ratio of the fuel mixture to maintain it at or near the theoretical level which has hereinabove been stated.
The users of automobiles, however, also desire to reduce the consumption of fuel. It is known that their desire can be met if they employ a fuel mixture containing an excess of oxygen during their ordinary travel. If such a lean fuel mixture is employed, however, O.sub.2 adsorbed by the catalyst prevents NO.sub.x in the exhaust gas from contacting the active metal on the catalyst and make it difficult to reduce NO.sub.x, though HC and CO can be removed by oxidation. Therefore, a catalyst which comprises a transition metal, such as Cu, carried on zeolite by ion exchange has been proposed for use in the purification of exhaust gas from an engine in which a lean fuel mixture is employed.
Zeolites are crystalline aluminosilicates which are represented by the general formula: EQU xM.sub.2 /n.Al.sub.2 O.sub.3.ySiO.sub.2
as is well known in the art. There are commercially available many varieties of zeolites characterized by crystal structures having different channels or pore diameters which depend on M (a metal having a valency of n), x and y. They have a high cation exchange capacity, since they have the tendency to retain in the crystals cations, such as Na.sup.+ and K.sup.+, which make up for the insufficiency of a positive charge which is due to the substitution of Al.sup.3+ for a part of Si.sup.4+.
Japanese Patent Application laid open under No. 25250/1985 discloses a catalyst for the catalytic decomposition of nitrogen oxides which contains copper ions in a crystalline aluminosilicate having an appropriate spacing of lattice planes (d value) as determined by X-ray diffraction and having a molar ratio of SiO.sub.2 :Al.sub.2 O.sub.3 of 20 to 100:1, and a method of using it.
Japanese Patent Application No. 291258/1987, which was filed by the assignee of the inventors of this invention, proposes a catalyst for the purification of exhaust gas which comprises zeolite ionically exchanged with a transition metal and carried on a refractory support. The preferred transition metals are Cu, Co, Cr, Ni, Fe and Mn. Copper is the most preferable of all.
Zeolites have fine pores with a size of several .ANG.ngstrom units which is comparable with the size of a molecule, as they are called molecular sieves. Hydrocarbons are selectively caught in those pores. As the transition metal which has been introduced by ion exchange forms active sites in the pores, the hydrocarbons are adsorbed therein and react with nitrogen oxides. Therefore, it is possible to remove NO.sub.x effectively from even the combustion product of a lean fuel mixture.
However, zeolites are available in a wide variety of types differing in structure from one another and each type of zeolite has a variety of coordination arrangements. Therefore, the performance of a catalyst for purifying exhaust gas depends on the type of zeolite which is employed and its coordination arrangement, even if copper may be employed as the transition metal. No due consideration has hitherto been given to the nature of the active sites in a catalyst for purifying exhaust gas, but all of the known catalysts comprising zeolite and a transition metal have been unsatisfactory in performance.

Catalyst for purifying exhaust gas and a method of producing the same


The invention relates to a process of selecting germ line-transformed leguminous plants by introducing a DNA construct encoding a protein to confer imidazolinone or glyphosate resistance and selecting transformed shoots with a low concentration of herbicide.

The present invention refers to the use of biobalistic for introducing exogenous genes into a vegetable tissue and obtaining transgenic leguminous plants by regenerating the transformed tissue.
The use of genetic engineering techniques for introducing genes which are responsible for agronomic characteristics of interest may facilitate the development of new varieties of LEGUMINOSAE. The obtaintion of a transgenic plant requires methods of introducing the exogenous DNA into the vegetable tissue and regenerating the whole plant from such genetically transformed tissue. Depending upon the species to be transformed, various types of tissue have been used for the introduction of an exogenous DNA, the meristematic tissue been preferably employed in various transformation processes, primarily due to the ease regeneration of a plant from this type of tissue. Various processes have been proposed for introducing exogenous genes into apical meristematic cells of LEGUMINOSAE, among which the following can be pointed out: a) the Agrobacterium system; b) a system related to tissue electroporation and c) the biobalistic system. The introduction and integration of exogenous DNA into cells of LEGUMINOSAE have been demonstrated by various scientists and described in different publications such as (Aragxc3xa3o F. J. L., Grossi-de-Sxc3xa1 M. F., Almeida E. R, Gander E. S. Rech E. L. (1992); Particle bombardment mediated expression of a Brazil nut methionine-rich albumin in bean (Phaseolus vulgaris L.); Plant Molecular Biology 20:357-359. Lewis, M. F. and Bliss, F. A. (1994); Tumor formation and beta-glucuronidase expression in Phaseolus vulgaris L inoculated with Agrobacterium tumefactiens. Journal of the American Society for Horticultural Science; 119:361-366, Dillen W. Engler G. Van Montagu M. and Angenon G. (1995); Electroporation-mediated DNA delivery to seedling tissues of Phaseolus vulgaris L (common bean), Plant cell Reports, 15:119-124.
However, the low obtaintion frequency of the genetically transformed tissue, the low capacity of regenerating a fertile plant from said transformed tissue, together with the use of transformation methods the efficiency of which depends upon the genotype, have rendered it difficult to obtain transgenic leguminous plants (Brasileiro A. C. M.; Aragxc3xa3o F. J. L.; Rossi S. Dussi D. M. A.; Barros L. M. G.; and Rech E. L. (1996)xe2x80x94Susceptibility of common and tepary beans to Agrobacterium ssp. strains and improvement of Agrobacterium-mediated transformation using microprojectile bombardment J. Amer. Soc. Hort. Sci. 12:810-915 and Dillen W.; Van Montagu M. and Angenon G. (1995) Electroporation-mediated DNA delivery to seedling tissues of Phaseolus vulgaris L. (common bean). Plant Cell Reports 15:119-124).
With the development of the biobalistic process for the direct introduction of genes into vegetable cells at the end of the ""80 (Sanford J. C. Klein T. M., Wolf E. D. and Allen N. (1987) Delivery of substances into cell tissues using a particle bombardment process; Journal of Particle Science and Technology, 5:27-37), a great number of transgenic plants of several species have been obtained, including those species which proved to be recalcitrant to the transformation by the using other methods. This is due to the fact that it has become possible to introduce and express exogenous genes in any kind of vegetable tissue. Thus, any type of tissue having a potential ability to regenerate a whole fertile plant is suitable for transformation.
The biobalistic process was proposed by Sanford with a view to introduce genetic material into the nuclear genome of higher plants. Since then its universality of application has been appraised, and it has proved to be an effective and simple process for the introduction and expression of genes into bacteria, protozoa, fungi, algae, insects, vegetable and animal tissue, as well as isolated organcils as chloroplast and mitochondria, according to the results observed by Sanford J C, Smith F D and Russel J. A. (1993) Optimizing the biobalistic process for different biological application. Methods in Enzymology: 217:413-510. In the specialized literature there are several other examples of the use of biobalistic for the obtaintion of transgenic organisms such as, for instance, U.S. Pat. Nos. 5,565,346, 5,489,520 and WO 96/04392, among others.
In biobalistic microprojectiles accelerated at high speed are used for carrying and introducing nucleic acids and other substances into cells and tissues in vivo (Rech E. L. and Aragxc3xa3o F. J. L. (1997). The ballistics processxe2x80x94In: Brasileiro A. C. M. and Carneiro. V. T. C. (Ed)xe2x80x94Manual of genetic transformation of plants: EMBRAPA/Cenargen. This process has also been called as method of bombardment with microprojectiles, xe2x80x9cgene gunxe2x80x9d method, particle-acceleration method, among others. Different systems have been developed and constructed which are capable of accelerating microparticles (made of tungsten or gold), coated with nucleic acids sequences, at speeds higher than ink 1500 km/h-1. All these systems are based on the generation of a shock wave with enough energy for displacing a carrying membrane containing the microparticles coated with DNA. The shock wave can be generated by a chemical explosion (dry gunpowder), a discharge of helium gas under high pressure, by vaporization of a drop of water through a electric discharge at high voltage and low capacitance or at low voltage and high capacitance.
Those systems which use helium gas under high pressure and electric discharge have shown a wide spectrum of utilization. The accelerated particles penetrate the cellular wall and membrane in a non-lethal way, locating themselves randomly in the cellular organells. Then the DNA is dissociated from the microparticles by the action of the cellular liquid, and the process of integrating the exogenous DNA in the genome of the organism to be modified takes place (Yamashita T. lada, A. and Morikawa H. (1991)xe2x80x94Evidence that more than 90% of xcex2-glucuronidase-expressing cells after particle bombardment directly receive the foreign gene in their nucleus; Plant Physiol. 97:829-831).
In spite of the efficiency and universality of utilization of the biobalistic process, it depends upon the optimization of various physical and biological parameters, which is fundamental to the effective introduction of heterologous genes into a vegetable tissue.
For the obtaintion of transgenic plants from the apical region of embrionic axis, there are two essential requirements, namely: 1) introduction of exogenous genes with high frequencies into the cells of the apical regions, and integration of erogenous genes into the vegetable genome, and 2) regeneration and production of fertile transgenic plants from the resulting transformed cells.
With the development of the biobalistic process the in situ direct transformation of cells of the apical meristem is now possible. However, the development and further production of fertile transgenic plants require the regeneration and production of the plant from the transformed cells.
During the last few decades several attempts have been made to obtain the regeneration of fertile plants of commercially important LEGUMINOSAE. Although many advances have been achieved, no effectively positive results have been obtained yet. For instance, some methodologies of multiple shooting of apical and lateral meristems of embryos in different LEGUMINOSAE have been developed. However, these systems still present serious disadvantages.
Other regeneration systems developed for certain LEGUMINOSAE such as peanuts and soybeans involve the induction of somatic embryogenesis from mature and immature embryos cultivated at high doses of 2,4-D. However, the practical use of this system is limited since it is restricted to determined varieties, in addition to the fact that induction of unwanted genetic variations (somaclonal variation) also occurs with the consequent production of transgenic plants with their inherent agronomic characteristics changed.
Thus, the systems already known for the obtaintion of transgenic plants of LEGUMINOSAE based on the transformation of meristematic cells of the apical region, by using the biobalistic process present the disadvantages of impossibility of selecting the transformed cells, low production frequencies of transgenic plants and high frequency of chimeras (plants with an organ or groups of some transgenic cells and other non-transgenic cells).
It is therefore, the objective of the present invention to provide a process with high production frequency for the obtaintion of transgenic leguminous plants containing an exogenous DNA and which enables the selection of the transformed cells, the latter maintaining the agronomic characteristics of the plants from which they have originated.
The present invention refers to a process for producing transgenic leguminous plants containing exogenous DNA, which comprises the steps of:
a) introducing exogenous genes into cells of the apical meristem of the embryonic axis of leguminous plants by the biobalistic method:
b) inducing the multiple shooting of the cells in the apical meristematic region modified in step (a) by cultivating said embryonic axis in a medium containing a multiple shooting inducer; and
c) selecting the meristematic cells of the apical region as obtained in step (b) by further cultivation of said embryonic axis in a medium containing a molecule which concentrates in the apical meristematic region of said leguminous embryos.

Process for obtaining transgenic leguminous plants (leguminosae) containing exogenous DNA

EMBRAPA-Empress Brasileira de Pesquisa Agropecuxc3xa1ria


An object is to provide a resin composition having excellent performance as a binder such as adhesiveness and, at the same time, retaining solution properties favorably even after a solution is stored for a long period of time. A modified polyolefin resin composition includes a modified polyolefin resin (C), in which the modified polyolefin resin (C) is a resin made by modifying a polymer (A) that is a polymer (a) of a polyolefin resin or a chlorinated polyolefin resin and an α,β-unsaturated carboxylic acid derivative having a structure derived from at least one carboxy group or a chlorinated product (b) thereof with a modification component including an alcohol (B); and a residual ratio of the structure derived from at least one carboxy group in the modified polyolefin resin (C) is 50% or more and 80% or less.

Polyolefin resins are employed as substrates for various applications because the resins are inexpensive and have excellent formability. However, the polyolefin resins have low polarity and high crystallinity and thus painting, adhesion, and the like are difficult. In order to improve adhesion of paints to the polyolefin resins, use of modified chlorinated polyolefin resins obtained by modification treatment such as chlorination, acid modification with unsaturated carboxylic acids, and modification with (meth)acrylic acid ester as a binder to the polyolefin resins has been developed (Patent Literature 1).

Modified polyolefin resin composition and method for producing the same


A memory system includes a memory device, a switch device, and a built-in self-test circuit. The memory device is for storing data and toggling a notification signal whenever a read operation or a write operation is completed. The switch device has a first input terminal for receiving an external clock signal, a second input terminal coupled to the memory device for receiving the notification signal, a select terminal for receiving a selection signal, and an output terminal for outputting a memory clock signal to the memory device. The memory clock signal is one of the external clock signal and the notification signal. The built-in self-test circuit is for outputting a control signal required by the memory device to perform the read operation or the write operation and check whether the memory device functions normally.

1. Field of the Invention
This invention relates to a memory system, and more particularly, a memory system that is able to generate notification signals whenever an operation is completed.
2. Description of the Prior Art
To ensure reliability of memory devices, testing process is necessary before assembling memory devices to systems. However, before a memory device is assembled to the system, the testing process usually requires a test circuit for providing testing signals to the memory device and a clock generator for providing the clock signal required by the memory device. Since the size of a memory device can be rather small and the signal connections of the memory device can be very complicated, some of memory devices may include built-in test circuits, that is, the built-in self-test circuits, to simplify the manual efforts for signal connections.
However, an external clock generator such as a phase lock loop circuit for providing the clock signal may still be required. Since the phase lock loop circuit and the memory device are different types of devices, the extra phase lock loop circuit may require different manufacturing process from the manufacturing process of the memory macro of the memory device. Consequently, the manufacturing process can be complicated, the cost may be raised, and yield may be reduced.
Furthermore, when testing the highest frequency of the memory device, one has to adjust the clock generator gradually according to the condition of the memory device, and the memory speed limitation tested is bounded by the highest frequency of the clock generator. Therefore the testing process can be time consuming and inaccurate. How to test the memory device efficiently without adding complicated extra circuit has become an issue to be solved.

Memory system capable of generating notification signals


A self-locking fixing device and an antenna assembly are provided. The self-locking fixing device includes an inner mandrel arranged to include a nail head and a nail rod extending away from the nail head, and a bushing arranged to include a nail head bushing and a nail rod bushing extending away from the nail head bushing. A sidewall of the nail head bushing is provided with at least two elastic clamping units. If the inner mandrel is assembled with the bushing, the nail head is located in the nail head bushing, the nail rod is located in the nail rod bushing, and clamping portions of the elastic clamping units are engaged with an upper surface of the nail head to clamp the nail head in the nail head bushing.

When an antenna is assembled, a particular apparatus is often needed for fixing. Nylon rivets are widely used as a fixing means in antenna manufacturing.
The commonly used rivets usually have negative effects on antennas. For example, they have at least the following problems:
For a standard nylon rivet, an end of its inner mandrel will be higher than the bushing after assembling. If the end of the inner mandrel is collided during producing or utilizing of an antenna, the fixed connection formed by the rivet will become loose.
In addition, after an antenna is assembled, rivets will naturally become loose as usage time increases, which would influence RF performance of the antenna.
Therefore, there is a need for a fixing device with good fixing performance.

Self-locking fixing device and antenna assembly


A removable media tray for an image forming apparatus includes a housing, an exit port in the housing, a primary media stack, and a multi-purpose tray (MPT) input. Within the tray are first and second pick mechanisms operative to select a media sheet from the primary stack or MPT stack, respectively, and move the media sheet to the image forming apparatus through the exit port. A motor is disposed within the tray housing, and first and second drive assemblies operatively connect the motor to the first and second pick mechanisms, respectively. The motor drives the first pick mechanism forward by rotating in one direction, and drives the second pick mechanism forward by rotating in the opposite direction. A media sensor in the exit port senses media sheets from a variety of sources, including the primary media stack, the MPT stack, a duplex return path, or a large-capacity media sheet supply.

The present invention relates generally to the field of image forming apparatuses and in particular to an image forming apparatus with an integrated media input tray including electronics.
Many image forming apparatuses; copiers; multi-function machines, i.e., those that combine two or more functions such as fax, scan, copy, and print; and the like (all of which are encompassed herein by the term "image forming apparatus"), contain one or more primary media trays that an end user removes from the machine to load with a stack of media sheets, such as print paper. The uppermost sheet in the stack is selected, or "picked" from the stack by the image forming apparatus. In some image forming apparatuses, one tray is inserted into a single receptacle in the image forming apparatus, the tray selected from a plurality of removable trays, each configured to hold different size and/or type of media sheets. Other image forming apparatuses accept a plurality of removable media input trays simultaneously into different receptacles.
In addition, many image forming apparatuses include a Multi-Purpose Tray (MPT), a separate media sheet input that is used to feed specialty media such as transparencies, envelopes, and the like. In some image forming apparatuses these specialty media are input manually, one media sheet at a time. Other image forming apparatuses pick specialty media from a small stack at an MPT input. In some image forming apparatuses, the MPT input is also removable from the image forming apparatus.
Traditionally each of these media input trays mates with a media sheet pick mechanism, such as for example an autocompensator, located in the base image forming apparatus. The pick mechanism operates to select and separate one media sheet (usually the uppermost sheet) from a stack of media sheets in the tray, and feed the selected sheet into the print mechanism in the image forming apparatus. The pick mechanism is driven by a motor, which is connected to the pick mechanism by a drive train. Both the motor and the drive train are traditionally located in the image forming apparatus.
Prior art removable media input trays also may include a variety of media sensors (and/or configurable surfaces operative to trigger sensors located in the image forming apparatus) that sense, for example, media size, media near empty, transparency sensing, and media in the paper path. A large plurality of sensors, particularly if required on each of two or more removable media input trays, increases costs and reduces reliability by proliferating the number of potential failure points.
Conventional removable media input trays present several disadvantages. Because the pick mechanism, drive train, and motor are housed in the image forming apparatus, and media sheets are picked from a stack located in the tray, the drive force of the pick tire exerted on the media stack tend to push the tray out of the image forming apparatus. To combat this force, and avoid the media input tray being dislodged from the image forming apparatus, many removable media input trays include detents or other pliable surfaces that deform slightly upon insertion and removal of the tray from the image forming apparatus, thus "latching" the tray to the image forming apparatus when inserted. These securing mechanism add cost and complexity to the tray, make it more difficult to use by requiring greater force to insert or remove the tray, and decrease reliability as the pliable surfaces may break off from the tray in use.
In prior art image forming apparatuses including both a primary media input tray and an MPT input, the MPT input is typically located above the primary media input tray (to facilitate removal of the primary media tray). This necessarily increases the overall height of the image forming apparatus. In addition, if the same motor is used to drive pick mechanisms for both the primary media input tray and the MPT input, a complex drive train having a compliant member such as a swing arm clutch is required to break the drive train, such that the image forming apparatus can operate when one or the other of the primary media input tray and the MPT input are removed. Such a drive train adds cost and complexity to the image forming apparatus, and may further increase the undesirable dislodging force(s) exerted on the removable tray(s). Additionally, locating part of the paperfeed mechanism in the image forming apparatus and part in the removable tray increases the difficulty and cost of troubleshooting and servicing failed components.

Integrated media input tray including electronics


Even in a situation in which an image of the back side of an object cannot be captured, the shape of the object can be generated with high accuracy. For individual images captured from the circumference of an object, projection regions projected in an area from the surface of projection in a projective space to a projective plane that is distant from the surface of projection by a predetermined length in a depth direction in a case where the object reflected in the individual images is projected to the projective space from viewpoint positions of the individual images are detected. A portion common to the individual detected projection regions is extracted.

Biometrics authentication is a method for identifying a person by using an identification target of the living body of the person. Blood vessels of a finger are one identification target of a living body.
For example, an authentication apparatus that generates a three-dimensional image by combining images of different sides of a fingertip and uses the three-dimensional image as an identification target has been suggested (for example, see Patent Document 1).    Patent Document 1: Japanese Unexamined Patent Application Publication No. 2002-175529.
Incidentally, an object-shape generation method called a view-volume intersection method (Shape From Silhouette method) exists. The view-volume intersection method is a method for generating, in accordance with images of an object from a plurality of viewpoints, positional information of a camera, and the like, the shape of the target object by causing a region in which all the silhouettes in the individual images intersect with each other within a target space to remain as an object region.
When a three-dimensional blood vessel image is generated using the view-volume intersection method, compared with a two-dimensional blood vessel image (entire-circumference development image), the number of parameters serving as identification targets increases. Hence, it is considered that the authentication accuracy improves.
However, portions of a living body other than blood vessels are not hollow and are occupied by individual tissues such as fat. Therefore, for example, as shown in FIG. 1, an optical image pickup camera might not be able to project a blood vessel portion existing on the back side of an image pickup surface.
In this case, with the view-volume intersection method, a blood vessel portion on the back side of the image pickup surface that is not projected to the image pickup surface is not a region in which all the silhouettes in individual images intersect with each other within a target space. Thus, the region does not remain as an object region. As a result, there is a problem in that a shape different from that of the actual blood vessel may be generated.

Object-shape generation method, object-shape generation apparatus, and program


An AC Line Filter/Rectifier Module (ACLF/RM) has a metal housing and an outward appearance of a conventional AC line filter, but the ACLF/RM includes circuitry that performs both EMI filtering and line filtering as well as very efficient AC-to-DC rectification. Rectification circuitry within the ACLF/RM rectifies an AC voltage signal received onto AC input module terminals and outputs a rectified version of the AC voltage signal onto DC output module terminals. The rectification circuitry includes at least one low forward voltage rectifier, where the low forward voltage rectifier includes a bipolar transistor and a diode. Inductive components perform both EMI filtering and line filtering as well as current splitting required to drive the bipolar transistors of the low forward voltage rectifiers. Due to the use of the low forward voltage rectifiers, the AC-to-DC conversion is more efficient than would be case were a conventional diode bridge rectifier employed.

Many electronic appliances and devices include an AC line filter as well as a full-wave bridge rectifier. Although the AC line filter component goes by a few different names in the art such as, for example, "EMI filter", the term "AC Line Filter" will be used here. The electronic appliance or device receives AC power through its AC line filter. The AC line filter in some cases is a module assembly that includes a standard IEC 60320-1 C14 three-terminal power inlet socket through which 110 volt (RMS) AC wall power is received onto the AC line filter. The socket has three input terminals, one of which is a ground terminal GND. The other two input terminals may be referred to as the LINE terminal and the NEUTRAL terminal. A power cord, having a standard plug that engages the 110 volt AC socket, is coupled to the electronic device to provide AC wall power through the cord to the AC line filter. In addition to the three input terminals of the power input socket, the AC line filter module also has three output terminals. One of these output terminals is a ground terminal GND. The 110 volt (RMS) AC as output by the AC line filter across these other two output terminals is then rectified by the full-wave bridge rectifier into a rough DC voltage. This rough DC voltage is often times then smoothed or stored in a capacitor that is connected across the two output terminals of the full-wave bridge rectifier. If, for example, the input AC power to the electronic appliance is 110 volts (RMS), then the rough DC voltage as output by the full-wave bridge rectifier has an approximate DC voltage of 157 volts DC.

AC line filter and AC-to-DC rectifier module


An apparatus for the continuous production of hollow quartz-glass ingots, comprising a) a crucible or refractory tank for providing a softened quartz-glass mass having a dieorifice in the bottom of the crucible or refractory tank; b) a mandrel vertically drawing off the softened quartz-glass mass through a die toprovide a hollow quartz-glass ingot; and c) a cutting section for on-line cutting of the hollow quartz-glass ingot to a specificlength, characterized in that the apparatus comprises active means for cooling the internalsurface of the hollow quartz-glass ingot prior to the cutting station.

Methods and apparatus for the continuous production of hollow quartz-glass ingots are known from prior art. In these continuous processes, quartz is fused within a refractory crucible by supplying heat and the fused quartz is withdrawn through a die orifice in the centre of which is mounted a mandrel. Thereafter, the ingot is lowered gradually at a constant speed, and the fused silica is quenched thereby forming a hollow columnar ingot or tube. Respective processes are, for example, disclosed in U.S. Pat. No. 9,242,887 and CN 103 771 690. Usually the tubes (hollow ingots) provided by such methods have a relatively small diameter and a thin wall. In CN 103 771 690, for example, tubes (hollow ingots) are produced having a diameter of 300 to 320 mm and a wall thickness of 10 to 12 mm.
One problem which arises with the continuous production of hollow quartz-glass ingots having a large outside diameter, in particular having an outside diameter of more than 350 mm, and thicker walls, is the formation of cracks in the ingot as it is cut to length beneath the furnace. The problems of such cracks in the quartz-glass ingot are not solved with the teaching of the above-mentioned prior art references.
One further prior art which focusses in particular on the production of large hollow quartz-glass ingots is U.S. Pat. No. 7,305,852 and discloses a process in which a crucible is filled with fused quartz, and a limited amount of a rod, plate or hollow ingot is drawn after completing the fusion process. The furnace used in this process is not used continuously, but operates in batches, offering the possibility of filling the crucible with fused quartz, and then withdrawing the glass and emptying the furnace after fusion. Due to the thermal fluctuations this discontinuous operation causes, the ingots of the intended size could not be cut on-line without severe cracking. Moreover, respective batch processes have economical disadvantages.
US 2017/0349474 A describes the fusion of a conventional glass melt, and the manufacture of sections of ingots. The process disclosed is not intended to provide a continuous production of ingots which requires the process step of on-line cutting of the ingot after formation.
SU 740718 discloses an apparatus for the preparation of a hollow quartz-glass ingot. In detail. SU 740718 represents a modification of the conventional process for fusion of quartz to permit drawing of a tube from a melt of fused quartz, but with improved control of the flow of glass and internal diameter of the tube. This involves a mandrel, supported from above, but using the internal heat exchanger to control the viscosity of the glass as it flows through the die. There is no indication of the tube sizes under consideration. Moreover, the tube prepared by said prior art process are conventionally be allowed to cool naturally below the die, and there is no indication that any steps were taken to cool the glass progressively internally. Moreover, problems arising with the challenge of repeated crack-free cutting of large sized, thick-walled ingots of quartz-glass ingots are not described.
Starting from this prior art situation, it is the object to provide a method for the production of hollow quartz-glass ingots which can be prepared without the above-mentioned disadvantages.
In particular, it is the object to provide a method for the production of hollow quartz-glass ingots which can be prepared and cut continuously.
More particularly, it is the object to provide a method for the production of hollow quartz-glass ingots which can be prepared and cut continuously, and which have a large outside diameter, and a relatively thick wall.
More particularly, it is the object to provide a method for the production of hollow quartz-glass ingots which can be prepared and cut continuously without cracking and which have a large outside diameter and relatively thick wall.
Moreover, it is the object to provide an apparatus which can be used to produce and cut hollow quartz-glass ingots continuously without cracking, whereby the hollow quartz-glass ingots have a large outside diameter and a relatively thick wall. This apparatus should be suitable for carrying out the claimed method.


A method of extruding filament comprises the steps of cutting a bulk source material into pieces having size S1, performing a first extrusion pass comprising the steps of melting the pieces in an extruding device at a temperature T1 and extruding a first filament at an extrusion speed V1, and performing at least one additional extrusion pass k comprising the steps of cutting the first filament into pieces having size Sk, melting the pieces in an extruding device at temperature Tk, and extruding a final filament at an extrusion speed Vk. A system for extruding filament is also described.

Light weight composite materials such as polymer matrix syntactic foams have been used ubiquitously in the aerospace, marine and automotive industries for decades due to their high strength-to-density ratios. With the advent of additive manufacturing (AM) techniques or 3D printing, efforts are being made to manufacture parts from syntactic foams using 3D printing, which offers greatly increased flexibility in manufacturing. Compared to conventional subtractive manufacturing, AM offers quick prototyping, easy design changes, and fabrication of complex geometries that are otherwise impossible to make with previously-known techniques. Previously-used polymer-based syntactic foam is abundant, and so methods of recycling and reusing such materials for 3D printed parts offer economic and environmental benefits.
Current laboratory-scale filament extruders often produce poor quality filament with inconsistent cross-sectional area, prone to fracture during the 3D printing process and to getting jammed in the nozzle.
In addition, in manufacturing syntactic foam filament, breakage of hollow particles leads to higher than expected extruded filament density, and creates stress concentrations due to the presence of angular ceramic particle fragments. The fragments further cause poor material flow characteristics, leading to extrusion nozzle jamming, and poor quality printed parts. Thus, there is a need in the art for a system and method of extruding syntactic foam and other filaments for 3D printing, and for a method of recycling syntactic foam and other filaments. The present invention satisfies these needs.

System and method for extruding composite filament


Disclosed is a method of manufacturing a ceramic laminate which is adapted to manufacture a laminated ceramic capacitor, for example. This method includes the steps of stacking a plurality of ceramic green sheets containing ceramic powder and a first binder on a base and forming a metal paste film containing metal powder and a second binder for providing an internal electrode on an upper major surface of a prescribed one of the ceramic green sheets during the stacking step. In such a method, a junction member containing a solvent which can commonly dissolve the first and second binders is prepared in order to join the plurality of ceramic green sheets with no application of pressure, to be applied between adjacent pairs of plurality of ceramic green sheets, which are stacked with each other. The junction member joins the adjacent pairs of ceramic green sheets with each other through chemical action.

1. Field of the Invention
The present invention relates to a method of manufacturing a ceramic laminate which is adapted to provide a laminated ceramic capacitor, a laminated LC composite part, a ceramic multilayer substrate or the like, and more specifically, it relates to a method of manufacturing a laminate by stacking ceramic green sheets.
2. Description of the Background Art
A component such as a laminated ceramic capacitor or a ceramic multilayer substrate, for example, has a laminated structure comprising ceramic sheets provided with an internal electrode which is interposed at least one interface, between at least two of the sheets. Such components have been generally obtained by applying ceramic slurry on one surface of a carrier film through a doctor blade method or the like and drying the same, separating a resulting ceramic green sheet from the carrier film, printing metal paste on the ceramic green sheet by screen printing or the like and drying the same, stacking a desired number of such ceramic green sheets to obtain a laminate, and pressurizing the laminate along the direction of stacking under appropriate conditions. This laminate is then cut if necessary, and thereafter fired to obtain a sintered ceramic laminate.
FIG. 11 is a sectional view showing a ceramic multilayer substrate 1 which is obtained basically through the aforementioned steps. Referring to FIG. 11, the substrate 1 comprises a plurality of ceramic layers 2 to 9 and internal electrodes 10 to 14 which are provided in interfaces between specific ones of the ceramic layers 2 to 9. A plurality of conductor films 16 to 18 are formed on one major surface 15 of the substrate 1. The conductor film 16 is electrically connected with the internal electrode 10 through a conductive internal through hole 19 passing through the ceramic layer 2. Further, two through hole connecting portions 20 and 21, for example, are defined to pass through the substrate 1, so that the through hole connecting portion 20 electrically connects the conductor film 17 and the internal electrodes 10, 12 and 14 with each other while the other through hole connecting portion 21 electrically connects the conductor film 18 and the internal electrodes 11 and 13 with each other.
When the ceramic multilayer substrate 1 shown in FIG. 11 is obtained by the aforementioned method, however, the following problems are caused:
A laminate of ceramic green sheets prepared to obtain the laminated structure of the ceramic layers 2 to 9 is pressurized in a stage before firing, as hereinabove described. Relatively high pressure is applied for such pressurization, and this can easily cause distortion of the green ceramic laminate, including the metal paste films which provide the internal electrodes 10 to 14. In general, such distortion is so non-uniform that it is difficult to obtain a green ceramic laminate, including the metal paste films, having the designed dimensions. Thus, such a green ceramic laminate frequently deviates from the designed dimensions, which reduces the yield of the manufacturing process. Non-uniform distortion of the green ceramic laminate in the aforementioned pressurizing step causes a significant problem particularly in the ceramic multilayer substrate 1 shown in FIG. 11, for example, which requires high position accuracy for the internal electrodes 10 to 14, the conductive internal through hole 19 and the like.
Further, the dried ceramic green sheets which provide the ceramic layers 2 to 9 are basically different in their material composition from the dried metal paste films which provide the internal electrodes 10 to 14. Sufficient junction strength cannot be attained by compressing such members made of basically different materials under mechanical pressure, and hence the finished product obtained upon firing has reduced rupture strength and reduce resistance against thermal shock. Even delamination may result in an extreme case.
For example in order to obtain a large capacitance in a laminated ceramic capacitor, a ceramic layer located between each pair of internal electrodes is most typically reduced in thickness. Referring to FIG. 12, a ceramic green sheet 22 is so thinned that its physical thickness 23 is substantially equal to the physical thickness 25 of a metal paste film 24 upon drying. When such ceramic green sheets 22 are stacked with each other, the thickness 25 of the metal paste film 24 partially formed on one major surface of each ceramic green sheet 22 cannot be neglected. As shown in FIG. 13, relatively large stresses remain in portions 27 and 28 corresponding to the edges of the metal paste films 24 upon pressurization of a laminate 26 of the ceramic green sheets 22. Such stress causes delamination or insufficient resistance against thermal shock after firing. This problem restricts the amount the thickness of the ceramic layers can be reduced for obtaining a large capacitance.
Another problem that arises in manufacturing a laminated ceramic capacitor, occurs when metal paste films for providing internal electrodes are printed on ceramic green sheets and dried, and then the ceramic green sheets are stacked with each other in an aligned state. However, when such ceramic green sheets are reduced in thickness as hereinabove described, the mechanical strength thereof is also reduced. Thus, it has been extremely difficult to register the ceramic green sheets as required for the steps of printing the metal paste films, stacking the ceramic green sheets and the like. Even if carrier films are employed for holding thin ceramic green sheets in such registration in order to compensate for the lack of mechanical strength, complicated and high-priced equipment is required for a registration mechanism, in order to handle basically thin substances.
FIGS. 14 and 15 show the so-called print lamination method, which is adapted to solve the aforementioned problem. This method basically repeats the steps shown in FIGS. 14 and 15. Referring to FIG. 14, for example, a squeegee 31 is driven in the direction of the arrow to act on a quantity of metal paste 30 which is placed on a screen 29, thereby to form a metal paste film 33 for providing an internal electrode. Then, as shown in FIG. 15, another squeegee 36 is driven in the direction of the arrow to act on a quantity of ceramic slurry 35 which is placed on a screen 34, thereby to form a green ceramic layer 37 for covering the metal paste film 33. Respective ones of such quantities of ceramic slurry 35 and metal paste 30 are repeatedly printed and dried to obtain a desired laminate.
However, the aforementioned print lamination method has the following problems:
First, a green ceramic layer formed by printing has a higher number of defects than a sheet formed through casting by the doctor blade method or the like. Thus, it is necessary to reduce the number of defects by repeating the printing step a plurality of times particularly for forming a green ceramic layer to be held between internal electrodes. This leads to reduction in productivity.
Further, the only means available for adjusting the thickness of a ceramic layer located between internal electrodes is merely controlling the printing conditions. Such control is relatively difficult in practice. In addition, the thickness of the ceramic layer cannot be easily managed if printing must be repeated a plurality of times in order to obtain one ceramic layer as hereinabove described. Thus, the resulting capacitance often deviates from a designed value, to cause reduction in yield.
Another problem is that in order to attain sufficient mechanical required for a laminated ceramic capacitor, upper and lower portions of a laminate must be covered with ceramic outer layers having no internal electrodes. However, the maximum thickness of a ceramic layer which can be formed by screen printing is several to tens of micrometers at the most. Thus, if hundreds of micrometers are required for each of the upper and lower outer layers, the number of printing times is extremely increased to cause reduction in productivity.
In both of the aforementioned methods of forming ceramic green sheets, namely through casting by the doctor blade method or the like, and by the print lamination method, pores and pinholes may be defined in the ceramic layers when their thickness is reduced. Thus, a capacitor may be reduced in voltage resistance, for example, or a short may be caused across the internal electrodes, in an extreme case.

Method of manufacturing ceramic laminate


Black ink compositions are provided. First embodiment contains a water-soluble long-wavelength dye L and a water-soluble short-wavelength dye S, in which the water-soluble short-wavelength dye S has 3 or more azo groups per molecule and a naphthalene skeleton. Second embodiment contains a water-soluble short-wavelength dye S whose absorption spectrum in aqueous solvent has a maximum between 440 nm and 540 nm and a half-band width of 90 to 200 nm and a water-soluble long-wavelength dye L whose absorption spectrum in aqueous solvent has a maximum between 550 nm and 700 nm and a half-band width of 100 nm or more. Third embodiment contains water, a water-miscible organic solvent, and a coloring material, in which C. I. Direct Red 84 is contained as a water-soluble short-wavelength dye S.

An inkjet recording method has been spreading rapidly and is still being improved because of inexpensive material cost, high-speed recording, less noise during recording, and easy implementation of color recording.
The inkjet recording method includes: a continuous method which causes a droplet to continuously travel by air; and an on-demand method which causes a droplet to travel by air, depending on an image information signal. The droplet is ejected by using a pressure using a piezo element; by generation of bubbles in ink by heating; by using ultrasonic wave; or by suctioning with electrostatic force.
Examples of inkjet recording inks include water inks, oil inks, and solid (fusible) inks.
A coloring agent for use in the inkjet recording ink needs to have good solubility and dispersibility with respect to a solvent; excellent color developing ability which allows high-density recording; good hue; excellent fastness to light, heat, and active gas in the environment (NOx, acidic gas (ozone, etc.), SOx, etc.); excellent fastness to water and chemicals; good fixing ability and bleeding resistance with respect to an image receiving material; excellent preservability as ink; no toxicity; high purity; and inexpensive availability. However, it is considerably difficult to find a coloring agent meeting these criteria to a high extent. Particularly, there is a strong desire for a coloring agent for black ink which has good black tonality, allows high-density printing, and has fastness to light, humidity and heat.
Disazo dyes and trisazo dyes have been used as black dyes. When only these dyes are used, blue to green light are insufficiently absorbed, so that it is often that satisfactory black tonality is not obtained. Therefore, a color correcting dye which absorbs blue to green light is generally used in combination with the above-described dyes. Such a color correcting dye has been proposed in, for example, Japanese Unexamined Patent Publication No. H09-255906 and Japanese Patent No. 3178200 so as to make an attempt to improve black tonality adjusting ability, color developing ability, fastness, ink preservation stability, water resistance, and prevention of nozzle clogging.
However, the color correcting dye proposed in the related art has problems with the color tonality adjusting ability. Specifically, for example, it absorbs a very short wavelength, so that a large amount thereof needs to be added. Further, another color correcting dye is required.
Dyes capable of absorbing blue to green light are generally known, however, most of them have poor fastness, so that their hue may be significantly altered by exposure to light, heat, or active gas in the environment; and insufficient fixing ability, so that yellow bleeding appears at a contour portion under high temperature and high humidity conditions, for example. Therefore, a further improvement is required.
In consideration of these drawbacks, Japanese Unexamined Patent Publication No. 2002-332426 describes a black ink composition in which a triazine dye which has a maximum absorption of visible spectra in aqueous solvent at 435 nm (color correcting dye) is blended with a black dye.
However, a general black dye has a maximum absorption between 570 nm and 620 nm. Therefore, even when the color correcting dye is used, it is clear that a preferable black tonality is not obtained, taking into account a complementary color relationship which is important for adjustment of black tonality ("Shikisai Kagaku Handobukku (Handbook of Color Science) (Second Edition)", University of Tokyo Press, 1998, pp. 560-562).
Japanese Unexamined Patent Publication No. H08-302255 describes CI Direct Red 84. However, the publication does not disclose a black ink composition in which CI Direct Red 84 is used as a short-wavelength dye in combination with a long-wavelength dye.
Japanese Unexamined Patent Publication No. 2000-265099 describes CI Direct Red 84, which is used to obtain magenta (column 8). Similarly, however, the publication does not disclose a black ink composition in which CI Direct Red 84 is used as a short-wavelength dye in combination with a long-wavelength dye.

This patent is subject to a terminal disclaimer.

Black ink composition, ink set containing the same, and ink jet recording method


An ultrasound system comprises an ultrasound probe for transmitting transmit beams and receiving receive beams. A processor controls the ultrasound probe to direct the transmit beams in a first direction to acquire a first incidence frame of data and a second direction to acquire an second incidence frame of data, wherein the first and second directions are different with respect to each other. A tissue characterization module compares the normal and oblique incidence frames of data to determine at least one property parameter of a scanned medium based on amplitude differences between the receive beams.

This invention relates generally to ultrasound imaging, and more particularly to detecting and indicating differences in tissue within an ultrasound image.
With current ultrasound imaging it is difficult to detect tissue properties such as tissue elasticity, stiffness, morphology or type. Tissue elasticity varies, for example, between different types of tissue, such as hard and soft plaque within the carotid artery. Also, a tumor or other mass will have tissue elasticity that is different compared to surrounding tissues. Having the ability to detect the elasticity or stiffness differences would improve the ability to detect dangerous plaque as well as other pathologies.
Shear modulus is a parameter related to the hardness or elasticity of a material or tissue. The shear modulus of various soft tissues ranges over several orders of magnitude. Previous methods for imaging elastic properties with ultrasound, such as radiation force ultrasound, rely on high amplitude, low frequency acoustic radiation fields or external vibration sources to generate shear waves in the tissue. Examples of imaging techniques are tissue velocity imaging (TVI) and strain imaging. Other techniques use multiple ultrasound transducers, thereby increasing the cost and complexity of a procedure.
Therefore, a need exists for detecting elasticity properties of tissues and indicating elasticity differences using standard ultrasound imaging with a single ultrasound probe.

System and method for tissue characterization using ultrasound imaging


Disclosed are methods and devices that include a therapeutic fluid dispensing device (10) to deliver a therapeutic fluid into a body of a patient. The device includes a controller to control one or more of fluid delivery operations and notification operations, at least one auditory notifier (800) to produce one or more acoustic signals in response to application of one or more activation signals by the controller and a plurality of electrical contacts coupled to the at least one auditory notifier to enable the application of the one or more activation signals to the at least one auditory notifier. The device also includes at least one housing retaining the at least one auditory notifier therein, the at least one housing being structured to resonate at least one of the one or more acoustic signals produced by the at least one auditory notifier in response to application of at least one of the one or more activation signals.

Medical treatment of several illnesses requires continuous drug infusion into various body compartments, such as subcutaneous and intra-venous injections. Diabetes mellitus (DM) patients, for example, require the administration of varying amounts of insulin throughout the day to control their blood glucose levels. In recent years, ambulatory portable insulin infusion pumps have emerged as an alternative to multiple daily syringe injections of insulin, initially for Type 1 diabetes patients and subsequently for Type 2 diabetes patients. These pumps, which deliver insulin at a continuous (or periodic) basal rate, as well as in bolus volumes, were developed to liberate patients from repeated self-administered injections, and to allow them to maintain a normal or near-normal daily routine. Both basal and bolus volumes are generally delivered in precise doses, according to individual prescription, because an overdose or under-dose of insulin could be fatal.
The first generation of portable insulin pumps includes "pager like" devices with a reservoir contained within a housing. A long tube is provided for delivering insulin from the pump attached to a patient's belt to a remote insertion site. Examples of such devices are disclosed, for example, in U.S. Pat. Nos. 3,631,847, 3,771,694, 4,657,486 and 4,544,369, the contents of all of which are hereby incorporated by reference in their entireties. These devices represent an improvement over the requirement of multiple daily injections, but have drawbacks, among which are the large size and weight of the devices, the long tubing which limits the daily activities of the devices' users, and lack of discreetness.
To avoid the limitations associated with first generation infusion pumps, a new concept was proposed, which was implemented in second generation pumps. The new concept is predicated on the use of a remote contained skin-adherable device with a housing having a bottom surface adapted to be in contact with the patient's skin, a reservoir disposed within the housing, and an injection needle in fluid communication with the reservoir. These skin adherable devices are configured to generally be replaced every 2-3 days, similarly to currently available pump infusion sets. This paradigm is described, for example, in U.S. Pat. Nos. 4,498,843, 5,957,895, 6,589,229, 6,740,059, 6,723,072 and 6,485,461, the contents of all of which are hereby incorporated by reference in their entireties. These second generation skin securable devices also have several drawbacks. For example the entire device has to be typically disposed-of every 2-3 days, resulting in the devices' expensive components (such as electronics, driving mechanism, etc.) also being disposed of.
Third generation skin-adherable devices were developed to avoid the cost issues associated with second generation devices and to extend patient customization. An example of such a device was described in co-owned/co-pending. U.S. Patent publication no. 2007-0106218 and International Patent publication no. WO/2007/052277, the contents of all of which are hereby incorporated by reference in their entireties. Such a third generation device contains a remote control unit and a skin-adherable patch unit (also referred to as "dispensing patch unit" or "dispensing unit") that may include two parts: (1) a reusable part containing the electronics, at least a portion of the driving mechanism and other relatively expensive components, and (2) a disposable part containing the reservoir and, in some embodiments, at least one power source (e.g., a battery). A tube can also be provided which delivers the fluid from the reservoir to an outlet port that contains a connecting lumen.
This concept can provide a cost-effective skin-adherable infusion device and enables device versatility in terms of the various reservoir sizes that may be used, the various needle and cannula types that may be used, etc.
A skin-adherable fluid (e.g., insulin) delivery device was also disclosed in co-owned, co-pending U.S. patent application Ser. No. 11/989,681 and International Patent publication no. WO/2008/012817, both filed Jul. 24, 2007 and both claiming priority to U.S. Provisional Patent Applications Nos. 60/833,110, filed Jul. 24, 2006, and 60/837,877, filed Aug. 14, 2006, both entitled "Systems, Devices, and Methods for Fluid/Drug Delivery", the contents of all of which are hereby incorporated by reference in their entireties.
A fourth generation infusion device is disclosed in co-owned, co-pending U.S. Patent publication no. 2008-0215035 and International Patent publication no. WO/2008/078318, both filed Dec. 20, 2007, claiming priority to U.S. Provisional Patent Application No. 60/876,679, filed Dec. 22, 2006, entitled "Systems, Devices, and Methods for Sustained Delivery of a Therapeutic Fluid", the contents of all of which are hereby incorporated by reference in their entireties.
Fourth generation devices are configured as dispensing units that can be disconnected and reconnected to a skin-adherable cradle unit. Fourth generation skin-securable dispensing units can be remotely controlled and/or can be operated by a user interface (e.g., a buttons-based interface) that are located on the dispensing unit's housing (and/or, in some embodiments, on the reusable part) as disclosed, for example, in the co-owned, co-pending International Patent publication no. WO/2009/013736, filed Jul. 20, 2008, claiming priority to U.S. Provisional Patent Application No. 60/961,527, and entitled "Manually Operable Portable Infusion Pump", and International Patent publication no. WO/2009/016636, filed Jul. 31, 2008, claiming priority to U.S. Provisional Application Ser. Nos. 60/963,148 and 61/004,019, and entitled "Portable infusion device with means for monitoring and controlling fluid delivery", the contents of all of which are hereby incorporated by reference in their entireties.
Co-owned/co-pending U.S. Patent publication no. 2007-0191702, the content of which is hereby incorporated by reference in its entirety, discloses a device that includes a dispensing patch unit (e.g., an insulin dispensing patch) and an analyte sensor (e.g., a continuous glucose monitor). This type of dual function device has a similar configuration to that outlined above and can also be disconnected and reconnected from and to the skin at patient's discretion.
In some embodiments, fluid delivery devices include a notification component (also referred to as a notifier or indicator) for notification purposes, e.g., to notify the user that fluid delivery has started, and/or for alerting purposes, e.g., to alert the user in case of mechanical malfunction or of low battery status. Such a notification component can be located in a skin-securable dispensing unit and/or in a remote control. The notification component can provide auditory output (e.g., a buzzer), visual output (e.g., the notification component can include a display, flashing lights, etc.) or provide tactile output (e.g., a vibrator). An auditory notification component (also referred to as "Buzzer") can employ, for example, a piezoelectric element or a magnetic element, which is typically disposed within a resonance chamber (i.e., a cavity defined by interior surfaces that reflect acoustic/sound waves) in order to amplify the sound generated by the element.
A number of different forms of buzzers, employing piezoelectric elements or transducers to generate a relatively piercing and noticeable audible tone when energized with relatively little power, have come into use. Such systems are activated at or near the resonant frequency of the vibrating piezoelectric element to achieve the most efficient use of available electrical energy and greatest audible output.
In a device for delivering a therapeutic fluid (e.g., insulin) to the body of a patient, it is generally important to maximally amplify the sound generated by the buzzer, since the consequence of not hearing the generated sound can be hazardous, for example, in case of an alert generated upon occlusion detection. The generated sound can be maximally amplified by placing the buzzer inside a suitable resonance chamber and activating it at or near the resonant frequency of the piezoelectric element, i.e., the frequency at which the amplitude of the piezoelectric element's oscillation is the greatest.
However, individual piezoelectric elements often vary in precise resonant frequency, and thus, a manufacturer's data sheet typically specifies only a frequency range within which the actual resonant frequency of the piezoelectric element is guaranteed to lie (e.g. 4.0±0.5 KHz). In addition, placing the piezoelectric element inside a resonance chamber may further affect the resonant frequency of the individual piezoelectric element and contribute to the variation in precise resonant frequency, for example, due to different methods of supporting the element within the chamber (e.g., edge support, node support, etc.). Furthermore, the resonant frequency of a single piezoelectric element itself may vary due to such factors as aging, varying temperature and humidity conditions, etc.
In view of this, self-calibrating systems for determining the actual resonant frequency of an individual piezoelectric element/transducer and for driving/activating the element/transducer at its actual resonant frequency have been proposed. Such a system was described, for example, in U.S. Pat. No. 4,275,388, the content of which is hereby incorporated by reference in its entirety. The system described in that patent, as well as other known self-calibrating systems, is generally implemented using a feedback mechanism (e.g., a feedback electrode). In some embodiments, the feedback mechanism is connected to the piezoelectric element that generates a feedback signal representative of the amount of flexing of the element when driven at different frequencies. The optimum driving frequency is then determined based on the feedback signal.
Despite the hazardous consequences of inefficient buzzers, existing fluid delivery devices generally do not employ such self-calibrating systems. Furthermore, the existing self-calibration systems, which require the use of feedback mechanisms, are not suitable for skin-securable miniature fluid delivery devices due to some of the following reasons:                The need for additional components/modules (e.g., a feedback electrode, contacts) requires enlargement of the device and creates undesirable limitations regarding the spatial arrangement of the buzzer, and other components, within the delivery device.        The piezoelectric buzzer (also referred to as "piezoelectric diaphragm") typically includes a piezoelectric plate (e.g., a ceramic plate, a crystal plate) having electrodes on both sides (together referred to as "piezoelectric element"), and a metal plate (e.g., brass, stainless steel, etc.). Connecting a feedback mechanism to the piezoelectric element reduces the efficiency of the buzzer as it requires a size reduction of one of the element's electrodes.        Implementation of the described self-calibration systems increases the cost (and thus the price to the consumer) of the device as additional components are required.

Skin-patch type infusion pump comprising a resonant buzzer


The present invention relates to the field of biotechnology and provides antibodies that specifically binds to PD-L1. The invention also relates to DNA encoding said antibodies, to corresponding expression vectors and to methods of producing, and to methods of treatment using said antibodies.

Lymphocyte Development and Activation
The two major types of lymphocytes in humans are T (thymocytes) and B (bone marrow-derived). These cells are derived from hematopoietic stem cells in the bone marrow and fetal liver that are programmed to the lymphoid development pathway. The progeny of these stem cells follow divergent pathways to mature into either B or T lymphocytes. Human B-lymphocyte development takes place entirely within the bone marrow. T-cells, on the other hand, develop from immature precursors that leave the bone marrow and travel through the bloodstream to the thymus, where they proliferate and differentiate into mature T-lymphocytes.
Mature lymphocytes that emerge from the thymus or bone marrow are in a quiescent, or "resting" state, i.e., they are mitotically inactive. When dispersed into the bloodstream, these "virgin" or "naive" lymphocytes travel into various secondary or peripheral lymphoid organs, such as the spleen, lymph nodes or tonsils. Most virgin lymphocytes are characterized by an inherently short lifespan and die without a few days after leaving the bone marrow or thymus. However, if such a cell receives signals indicating the presence of an antigen, it may be activated and undergo successive rounds of cell division. Some cells of the resulting progeny then revert to the resting state and become memory lymphocytes—B- and T-cells that are essentially primed for the next encounter with the stimulating allergen. The other progeny of activated naive lymphocytes are effector cells that live for only a few days but perform specific defensive activities.
Lymphocyte activation is an ordered series of events through which a resting lymphocyte passes once it is stimulated to divide and produce progeny, some of which become effector cells. A full response includes both the induction of cell proliferation (mitogenesis) and the expression of immunologic functions. Lymphocytes become activated when specific ligands bind to receptors on their surfaces. The ligands are different from T-cells and B-cells, but the resulting intracellular physiological mechanisms are similar.
Some foreign antigens themselves can induce lymphocyte activation, particularly large polymeric antigens that cross-link surface immunoglobulins on B-cells, or other glycoproteins on T-cells. However, most antigens are not polymeric, and even direct binding to B-cells in large numbers fail to result in activation. These more common antigens activate B-cells when they are co-stimulated with nearby activated helper T-lymphocytes. Such stimulation may occur from lymphokines secreted by the T-cell but is transmitted most efficiently by direct contact of the B-cell with T-cell surface proteins that interact with certain B-cell surface receptors to generate a secondary signal.
T-Cells
T lymphocytes do not express immunoglobulins, but instead, detect the presence of foreign substances through surface proteins called T-cell receptors (TCR). These receptors recognize antigens by either direct contact or through influencing the activity of other immune cells. Together with macrophages, T-cells are the primary cell type involved in the cell-mediated immunity.
Unlike B-cells, T-cells can detect foreign substances only in specific conditions. In particular, T-lymphocytes recognize a foreign protein only if it is first cleaved into small peptides, which are then displayed on the surface of a second host cell, called an antigen-presenting cell (APC). Many types of host cells can present antigens under some conditions but certain types are more specifically adapted for this and are particularly important for regulation of the T-cell activity, including macrophages and other B-cells. Antigen presentation depends in part on specific proteins, called major histocompatibility complex (MHC) proteins, on the surface of the presenting cells. Thus, to stimulate cell-mediated immunity, foreign peptides must be presented to T-cells in combination with MHC peptides, and this combination must be recognized by a T-cell receptor.
There are two significant T-cell subsets: cytotoxic T-lymphocytes (Tc-cells or CTLs) and helper T (TH) cells, which can roughly be identified on the basis of cell surface expression of the marker CD8 and CD4. Tc-cells are important in viral defence and can kill viruses directly by recognizing certain cell surface expressed viral peptides. TH cells promote proliferation, maturation and immunologic function of other cell types, e.g. lymphokine secretion to control the activity of B-cells, macrophages and cytotoxic T-cells. Both naive and memory T-lymphocytes normally remain in the resting state, and in this state, they do not exhibit significant helper or cytotoxic activity. In the activated state, these cells undergo several rounds of mitotic division to produce daughter cells. Some of these daughter cells return to the resting state as memory cells, but others become effector cells that actively exhibit helper or cytotoxic activity. These daughter cells are similar to their parents: CD4+ cells can only product CD4+ progeny, and CD8+ cells yield only CD8+ progeny. Effector T-cells express cell surface markers that are not expressed on resting T-cells, such as CD25, CD28, CD29, CD40L, transferrin receptors and class II MHC proteins. Without the activating stimuli, cytotoxic or helper activity gradually subsides over several days as the effector cells either die or revert to the resting state.
Similar to B-cell activation, T-lymphocyte response to most antigens also requires two types of simultaneous stimuli. The first is the antigen, which is appropriately displayed by MHC proteins on an antigen-presenting cell, can be recognized and bound by T-cell receptors. While this antigen-MHC complex does not send a signal into the cell interior, it is usually insufficient to result in T-cell activation. Full activation, such as the one occurs with helper T-cells, requires co-stimulation with other specific ligands called co-stimulators that are expressed on the surface of the antigen-presenting cell. On the other hand, cytotoxic T-cell activation generally requires IL-2—a cytokine secreted by activated helper T-cells.
PD-1 Pathway
An important negative co-stimulatory signal regulating T-cell activation is provided by programmed death-1 receptor (PD-1, CD279), and its ligand binding partners PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273). The negative regulatory role of PD-1 was revealed by PD-1 knockouts (Pdcdl−/−), which are prone to autoimmunity. (Nishimura et al, Immunity JJ: 141-51 (1999); Nishimura et al, Science 291: 319-22 (2001)). PD-1 is related to CD28 and CTLA-4 but lacks the membrane proximal cysteine that allows homodimerization. The cytoplasmic domain of PD-1 contains an immunoreceptor tyrosine-binding inhibition motif (ITIM, V/IxYxxL/V). PD-1 only binds to PD-L1 and PD-L2 (Freeman et al, J. Exp. Med. 192: 1-9 (2000); Dong et al, Nature Med. 5: 1365-1369 (1999); Latchman et al, Nature Immunol 2: 261-268 (2001); Tseng et al, J. Exp. Med. 193: 839-846 (2001)).
PD-1 can be expressed on T-cells, B-cells, natural killer T-cells, activated monocytes and dendritic cells (DCs). PD-1 is expressed by activated, but not by unstimulated human CD4+ and CD8+ T-cells, B-cells and myeloid cells. This discriminates it from the more restricted expression of CD28 and CTLA-4 (Nishimura et al, Int. Immunol. 8: 773-80 (1996); Boettler et al, J. Virol. 80: 3532-40 (2006)). There are at least 4 variants of PD-1 that have been cloned from activated human T-cells, including transcripts lacking (i) exon 2, (ii) exon 3, (iii) exons 2 and 3 or (iv) exons 2 through 4 (Nielsen et al, Cell. Immunol. 235: 109-16 (2005)). With the exception of PD-1Δex3, all variants are expressed at similar levels as full-length PD-1 in resting peripheral blood mononuclear cells (PBMCs). Expression of all variants is significantly induced upon activation of human T-cells with anti-CD3 and anti-CD28 antibodies. The PD-1Δex3 variants lack a transmembrane domain and are similar to soluble CTLA-4, which plays an important role in autoimmunity (Ueda et al, Nature 423: 506-11 (2003)). This variant is enriched in the synovial fluid and serum of patients with rheumatoid arthritis (Wan et al, J. Immunol. 177: 8844-50 (2006)). The two PD-1 ligands differ in their expression patterns. PD-L1 is constitutively expressed on mouse T- and B-cells, CDs, macrophages, mesenchymal stem cells and bone marrow-derived mast cells (Yamazaki et al, J. Immunol. 169: 5538-45 (2002)). PD-L1 is expressed on multiple nonhematopoietic cells (e.g., cornea, lung, vascular epithelium, liver nonparenchymal cells, mesenchymal stem cells, pancreatic islets, placental syncytiotrophoblasts, keratinocytes, etc.) [Keir et al, Annu. Rev. Immunol. 26: 677-704 (2008)], and is upregulated on multiple cell types after activation. Both type I and type II interferons, IFNs, upregulate PD-L1 (Eppihimer et al, Microcirculation 9: 133-45 (2002)); Schreiner et al, J. Neuroimmunol 155: 172-82 (2004). PD-L1 expression in cell lines is decreased when MyD88, TRAF6 and MEK are inhibited (Liu et al, Blood HO: 296-304 (2007)). JAK2 has also been involved in PD-L1 induction (Lee et al, FEBS Lett, 580: 755-62 (2006); Liu et al, Blood HO: 296-304 (2007)). Loss or inhibition of phosphatase and tensin homolog (PTEN), a cellular phosphatase that modifies phosphatidylinositol 3-kinase (PI3K) and Akt signalling increased post-transcriptional PD-L1 expression in cancer (Parsa et al, Nat. Med. 13: 84-88 (2007)).
The PD-L2 expression is more restricted than PD-L1. PD-L2 is inducibly expressed on DCs, macrophages, and bone marrow-derived mast cells. PD-L2 is also expressed on about half to two-thirds of resting peritoneal B1-cells, but not on conventional B2 B-cells (thong et al, Eur. J. Immunol. 37: 2405-10 (2007)). PD-L2+B1 cells bind phosphatidylcholine and may be important for an innate immune response against bacterial antigens. Induction of PD-L2 by IFN-γ is partially dependent upon NF-KB (Liang et al, Eur. J. Immunol. 33_: 2706-16 (2003)). PD-L2 can also be induced on monocytes and macrophages by GM-CF, IL-4 and IFN-γ (Yamazaki et al., J. Immunol. 169: 5538-45 (2002); Loke et al, PNAS 100: 5336-41 (2003)).
PD-1 signalling typically has a greater effect on cytokine production than on cellular proliferation, with a significant effect on IFN-γ, TNF-α and IL-2 production. PD-1 mediated inhibitory signalling also depends on the strength of the TCR signalling, the greater inhibition being provided at low levels of TCR stimulation. This reduction can be overcome by co-stimulation through CD28 [Freeman et al, J. Exp. Med. 192: 1027-34 (2000)] or the presence of IL-2 [Carter et al, Eur. J. Immunol. 32: 634-43 (2002)].
There are a growing number of evidence that signalling through PD-L1 and PD-L2 may be bidirectional. That is, in addition to modifying TCR or BCR signalling, the signal may also be delivered back to the cells expressing PD-L1 and PD-L2. While treatment of dendritic cells with a naturally human anti-PD-L2 antibody isolated from a patient with Waldenstrom's macroglobulinemia was not found to upregulate MHC II or B7 costimulatory molecules, such cells produced greater amount of proinflammatory cytokines, particularly TNF-α and IL-6, and stimulated T-cell proliferation (Nguyen et al, J. Exp. Med. 196: 1393-98 (2002)). Mice treatment with this antibody also (1) enhanced resistance to transplated b16 melanoma and rapidly induced tumor-specific CTL (Radhakrishnan et al, J. Immunol. 170: 1830-38 (2003); Radhakrishnan et al, Cancer Res. 64: 4965-72 (2004); Heckman et al, Eur. J. Immunol. 37: 1827-35 (2007)); (2) blocked development of airway inflammatory disease in a mouse model of allergic asthma (Radhakrishnan et al, J. Immunol. 173: 1360-65 (2004); Radhakrishnan et al, J. Allergy Clin. Immunol. UJy. 668-74 (2005)).
One more evidence of reverse signaling into dendritic cells ("DCs") was obtained from the studies of bone marrow-derived DCs cultured with soluble PD-1 (PD-1 EC domain fused to Ig constant region—"s-PD-1") (Kuipers et al, Eur. J. Immunol. 36: 2472-82 (2006)). This sPD-1 inhibited DC activation and increased IL-10 production, in a reversible manner through the administration of anti-PD-1. Additionally, several studies identified a receptor for PD-L1 or PD-L2 that is independent of PD-1. B7.1 has already been identified as a binding partner for PD-L1 (Butte et al, Immunity 27: 111-22 (2007)). Chemical cross-linking studies show that PD-L1 and B7.1 may interact through their IgV-like domains. B7.1:PD-L1 interactions can induce an inhibitory signalling into T-cells. Ligation of PD-L1 on CD4+ T-cells by B7.1 or ligation of B7.1 on CD4+ T-cells by PD-L1 provides an inhibitory signal. T-cells lacking CD28 and CTLA-4 show decreased proliferation and cytokine production when stimulated by anti-CD3 plus B7.1 coated beads. In T-cells lacking all the receptors for B7.1 (i.e., CD28, CTLA-4 and PD-L1), T-cell proliferation and cytokine production were no longer inhibited by anti-CD3 plus B7.1 coated beads. This indicates that B7.1 acts specifically through PD-L1 on the T-cell in the absence of CD28 and CTLA-4. Similarly, T-cells lacking PD-1 showed decreased proliferation and cytokine production when stimulated in the presence of anti-CD3 plus PD-L1 coated beads, demonstrating the inhibitory effect of PD-L1 ligation on B7.1 on T-cells. When T-cells lacking all known receptors for PD-L1 (i.e., no PD-1 and B7.1), T-cell proliferation was no longer impaired by anti-CD3 plus PD-L1 coated beads. Thus, PD-L1 can exert an inhibitory effect on T-cells either through B7.1 or PD-1.
The direct interaction between B7.1 and PD-L1 indicates that the current understanding of costimulation is incomplete, and underscores the significance for the expression of these molecules on T-cells. Studies of PD-L1−/− T-cells show that PD-L1 on T-cells can downregulate cytokine production by T-cell. (Latchman et al, Proc. Natl. Acad. Sci. USA 101: 10691-96 (2004)). Because both PD-L1 and B7.1 are expressed on T-cells, B-cells, DCs and macrophages, there is the potential for directional interactions between B7.1 and PD-L1 on these cells types. Additionally, PD-L1 on nonhematopoietic cells may interact with B7.1 as well as PD-1 on T-cells, raising the question of whether PD-L1 is involved in their regulation. One possible explanation for the inhibitory effect of B7.1: PD-L1 interaction is that T-cell PD-L1 may trap or isolate APC B7.1 from interaction with CD28.
As a result, the antagonism of signalling through PD-L1, including blocking PD-L1 from interacting with either PD-1, B7.1 or both, thereby preventing PD-L1 from sending a negative co-stimulatory signal to T-cells and other antigen presenting cells is likely to enhance immunity in response to infection (e.g., acute and chronic) and tumour immunity. In addition, the anti-PD-L1 antibodies of the present invention may be combined with antagonists of other components of PD-1: PD-L1 signalling, for example, an antagonist of anti-PD-1 and anti-PD-L2 antibodies.
In particular, the inhibition of PD-L1 signalling has been proposed as a means to enhance T-cell immunity for the treatment of cancer (e.g., tumour immunity) and infections, including both acute and chronic (e.g., persistent) infections.
Inhibitors blocking the PD-L1: PD-1 interaction are known from, inter alia, WO2001014557, WO2002086083, WO2007005874, WO2010036959, WO2010077634, and WO2011066389.
Currently, in the early stage clinical trials, there are more than 10 mono- and bispecific drugs with an anti-PD-L1 component.
One monospecific anti-PD-L1 antibody, MPDL3280A (atezolizumab, Roche), has successfully passed clinical trials (CT) and is used in clinical practice. Athezolizumab has been approved by the FDA for use in patients with metastatic urothelial cancer; III phase CTs are continued in patients with non-small cell lung cancer (NSCLC), renal cell carcinoma, colorectal cancer (CRC), and breast cancer (BC). The preparation is an Ig1 antibody with a modified Fc-region (to eliminate the ADCC effect). Athezolizumab is described in WO2010077634.
Other anti-PD-L1 preparations in the final phase CT are avelumab (Pfizer) and durvalumab (AZ) preparations. Durvalumab (MEDI-4736) is described in WO2011066389. Avelumab is described in WO2013079174. The main difference of Avelumab preparation is the presence of the ADCC effect in the antibody, moreover, it can be enhanced with IFNg or IL12 (NCT01772004). In addition, the safety profile of the Avelumab preparation corresponds to that of other anti-PD-1/PD-L1 preparations (Cancer Immunol Res; 3(10) October 2015; Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti-PD-L1 Antibody Avelumab on Human Tumor Cells; Benjamin Boyerinas).
Thus, there is a need to provide an effective inhibitor of PD-L1 (programmed death ligand-1)
In reference to the above, of great importance is to provide new antibodies that effectively bind to PD-L1.
The BCD-135 antibody selectively binds to PD-L1 and is an effective inhibitor of the programmed death ligand-1.