A constrained-layer damping material including a bitumen material, a binder material, and a tackifier, wherein the bitumen is a soft grade with a penetration of at least 150 dmm and a ring and ball softening point of greater than about 35° C.

Vibration damping materials are widely used in automotive applications to dampen the vibration and sounds of road noise and the engine. Viscoelastic materials are commonly preferred as damping materials. A damping effect, linked to the energy dissipated in the viscoelastic material, increases with an increase of the Young modulus and of the loss factor of the viscoelastic material. Additionally, the damping effect also increases in relation to the subjected deformation of the damping material. Traditional materials with a very high loss factor but a low Young modulus provide limited damping to a metal plate, and are not effective dampers. Other materials with a high Young modulus but a relatively low loss factor (like rubber), are also not very good as dampers. Good damping materials incorporate a compromise between Young modulus and loss factor.
In viscoelastic materials, the Young modulus decreases with temperature and the loss factor has a peak in function of temperature. Therefore, there is a temperature window where the damping effect on a metal plate (called the composite damping) has a peak. Dampers are designed to have this peak fitted to the application temperature.
There are two main principles of damping: the free layer damping (FLD) and the constrained layer damping (CLD).
In FLD, the main deformation in the viscoelastic material is from strain caused by bending of the metal sheet, normally the structural part that is prone to vibration due to sound waves. The amount of energy dissipated increases with the thickness of the damping material. Therefore, traditional damping materials tend to be rather thick. Additionally, traditional damping materials have a rather high Young modulus. In CLD, the main deformation in the viscoelastic material is from shear, since the damping material is sandwiched between two stiffer plates (a structural base layer and an aluminum constraining layer) that are displaced along their planes during vibration. A thin layer of viscoelastic material can be used for CLD, since the shear deformation is much larger than the tensile deformation of the FLD. The damping material is also typically softer than in FLD to ensure that there is a big difference between the stiffness of the metal sheets and the damping effect, thus ensuring a high shear force. The fact that the deformation is very large compensates for the low Young modulus. If the material is too stiff, then the strain deformation is too low. Of course the damping effect increases with increase of the damping factor of the viscoelastic material.
Stiffer structures, like car body panels, require constrained-layer damping. Constrained-layer damping consists of a constrained damping material (3) between a structural base layer (4) and a constraining layer (2) (FIG. 1). Both the structural base layer (4) and the constraining layer (2) are effectively working as constraining layers. For constrained layer damping, the method of attaching the layers does not matter as long as adequate surface contact and coupling occurs. However adhesives (5) if needed should have high shear stiffness, as softer adhesives will not adequately transfer shear strain to the middle-damping layer.
The constrained layer damping material (3) and a metal sheet as the constraining layer (2) are applied to selected parts or areas of the vehicle, which form the base structural layer (4) of the constrained damping system. These layers prevent vibrations and noise from being transmitted inside the vehicle to the passenger compartment. However, many of the surfaces to be treated with this type of damping system are not horizontal, but instead are in the vertical direction, sloping or even up-side down. Therefore, the adhesive (5) must work against gravity and should have little or no slow creep or flow characteristics with age.
Typically, materials for the constrained layer dampening material (3) comprise of thermoplastic or rubber materials, which are capable of suppressing vibrations and sounds. Bitumen based damping material is cheaper than rubber based material but has the disadvantage that it is not auto adhesive.
Bitumen materials are normally characterized by a combination of penetration, softening point and viscosity, and can be divided in the following classes of material: penetration grade bitumen, oxidized bitumen, and hard grade bitumen.
Penetration grade bitumen is obtained from fractional distillation of crude oil. The lightest fraction are vapours i.e. butane and propane, while the heavier fractions are taken off the column for gasoline production. The heavier fractions include kerosene, then gas oil, and high molecular weight hydrocarbons as the heaviest fraction. These heavy hydrocarbons, which are called long residue, are further distilled in a vacuum distillation column to produce gas oil, distillates, and short residue. The short residue is the feed stock for producing over 20 grades of bitumen. These are classified by their penetration index, typically PEN values of 10 to 330 dmm, which is the distance in tenth millimeters that a needle penetrates the bitumen under a standard test method. Penetration grade bitumen are characterized by penetration and softening point.
Oxidized bitumen are characterized by softening point and penetration, eg 85/40 is oxidized bitumen with a softening point of 85 and a penetration of 40. Oxidized bitumen is obtained by further processing the short residues. They are semi blown or fully blown with air to increase their molecular weight.
Hard grade bitumen are characterized by their softening point and penetration, but are only designated by the softening point range, e.g. H80/90.
Experience has shown that, in sound deadening panels in vehicles, penetration or PEN grades typically provide better damping characteristics than oxidized grades. However it is common belief that 15-pen is to brittle, whereas 50-pen and higher pen grades are too soft, producing panels that flow during storage. The bitumen is positioned on the vehicle body panels to be dampened and subjected to heat (around 140° C.), whereupon they conform to the shape of the body panel under their own weight and adhere strongly. Typical composition is (% of mass):                Bitumen (25 pen) 25-30%        Polymer (e.g. APP, EVA etc) 0-5%        Fibre 3-5%        Filler (e.g. Jimestone, clay, mica etc) 60-70%. Morgan et al., Shell Bitumen Industrial Handbook, Thomas Telford, 1995.
A common method of applying vibration damping material (3) is to provide it in the form of a sheet or tape, which includes an adhesive layer (5). The adhesive layer (5) adheres the damping material (3) to the desired substrate, such as an automobile body panel or interior panel. However this requires the vibration damping material (3) be laminated to at least one pressure sensitive adhesive layer, or heat activated adhesive layers.
It is well known that the optimal time for installing these damping sheets is prior to curing the exterior surface paint of the vehicle, which typically occurs in a bake oven that can reach temperatures in excess of 190° C. As such, the ability of the adhering material of the sheet must be able to withstand such intense temporary temperatures. It has been found that thermoplastic resin based adhesives do not provide adequate adhesive strength after the heat bake process due to loss of mechanical properties as temperatures increase.
As such it is well known that heat activated adhesives, such as thermosetting adhesives, are preferred wherein the adhesive's activation point can be appropriately modified, for example, based upon the temperature of the heat bake process. Such adhesives thus have the ability of withstanding the temperatures typically found in the heat bake process, while maintaining the requisite adhesive strength. However, the damping material laminate must be temporarily attached to the metallic medium, such as the automobile body panel or interior panel, in the interim until the adhesive is properly activated.
U.S. Pat. No. 3,243,374 discloses the use of a ferrite powder within a bitumen-based noise and vibration-damping sheet to allow preliminary positioning of the sheet during assembly together with a heat activated adhesive. At application and before the adhesive is heat activated, the sheet is held on in place magnetically.
An alternative to thermosetting adhesives is the use of an auto adhesive damping material. Currently, there are two main materials on the market, one material composite based on bitumen and one based on rubber.
Constrained layer damping material can be made of a combination of bitumen and a tackifier, for example hydrocarbon resin to obtain an auto adhesive damping material. Normally two grades of bitumen, a 20/30 pen grade bitumen, which has a penetration between 20-30 dmm and a ring & ball softening around 55° C., and a blown bitumen, with a penetration between 35-40 dmm and a ring & ball softening around 100° C., produce the damping material. During manufacturing, the two different bitumen materials are stored in separate tanks and mixed together during the preparation of the damping material, in order to increase the melting temperature of the final material. However, the blown bitumen is a niche product for big oil companies, and therefore it is increasingly difficult to obtain the blown bitumen material to make the dampers. Bitumen with hydrocarbon resin, can be used without the need for curing as the resin is already mixed in the bitumen. However, hydrocarbon resin is no longer allowed inside the passenger area of the car due to its high level of VOC (Volatile organic compounds).
U.S. Pat. No. 6,828,020 discloses an example of a butyl rubber type of damping material. Butyl rubber constrained layer material was developed for the building industry and is now commonly used in the damping of automotive body panels. However, the production and raw materials for butyl rubber are expensive. In particular, the mixing of the ingredients requires a high shear stress mixer and is therefore an energy consuming process. Currently, butyl rubber material developed for the building industry is also used for vehicle applications, but not all auto adhesive butyl rubber material is able to withstand the required curing temperatures. For example, the aluminum foil of the constraining layer (2) tends to delaminate or start sliding from the damping material (3) during the curing process. The butyl damping material currently on the market for automotive applications have partly been modified in order to support a curing temperature of 190° C.
These self-adhesive or auto-adhesive damping materials are produced in sheet form with an aluminum foil as a constraining layer on one side and a release paper on the opposite side of the sheet. After removing the release paper, the adhesive material of the damping material is directly applied to the panel to be dampened, without the need of additional adhesive layers.


An apparatus measures a voltage of a cell while scanning a group of cells in a cell stack, in which a plurality of cells is electrically connected in series. The apparatus has a first switching device and a voltage detecting device. The first switching device is connected in series with a signal line carrying a voltage of a cell. The voltage detecting device detects the voltage of the cell, which is electrically connected with signal lines carrying voltages of cells belonging to a group. When the first switching device is electrically connected with a connecting point between two successive groups of cells, the first switching device is shared by the two groups.

The present invention relates to an apparatus for measuring voltage, and more particularly to an apparatus for measuring voltage of a cell while scanning a group of cells in a cell stack such as a fuel cell stack in which a plurality of cells is electrically connected in series.
A fuel cell is a type of battery which generates electromotive force by electrochemical reaction between hydrogen contained in a fuel gas as a main substance and oxygen. As a cell voltage of the fuel cell only reaches as high as 1 volt, some hundreds of cells are in general electrically connected in series to form a fuel cell stack, which provides a high voltage, 260 volts, for example. If power generation is continued while one cell generates an extremely low voltage, 0.5 volts for example, it may result in damage of the fuel cell stack due to a drop in its aggregate output voltage, which is caused by corrosion occurring in the failed cell. It is typical that measurement and monitoring of a voltage of cell is carried out during operation of a fuel cell stack by scanning cells one by one or a group of cells group by group. In this way, continuous measurement and monitoring of a cell voltage provides prompt notification of occurrence of an abnormal cell, because when a cell or a plurality of cells suffers damage, there is a remarkable drop in voltage. Accordingly, it is possible to immediately stop operation of the fuel cell stack so as to prevent development of damage which results from delay in sensing an occurrence of abnormal operation.
An example of measurement of voltage for an individual cell is disclosed in patent document 1, which uses a terminal shaped like a projection provided for a separator between successive cells. Because a hole is no more required of an end surface of the separator by introduction of the terminal, a socket of a lead wire can be connected with the terminal even if the separator gets thinner. Accordingly, it is possible to measure a voltage for the individual cell even if a fuel cell decreases in dimension.
Various techniques associated with measurement of cell voltage for a fuel cell have been reported. FIG. 5 is a diagram showing a conventional apparatus for measuring voltage. As shown in FIG. 5, a voltage of an individual cell is measured and monitored in the following manner. Cells contained in a fuel cell are divided into a plurality of groups. For example, when switches S31, S32, S33 and S34 belonging to a first group are simultaneously turned on, individual voltages of cells C31, C32 and C33 belonging to the first group are detected by differential amplifiers D31, D32 and D33 of a detecting circuit 30. The voltages are sent to an A/D converter of a central processing unit (CPU) (not shown), where measurement and monitoring are carried out. Subsequently, when the switches S31, S32, S33 and S34 of the first group are simultaneously turned off and switches S35, S36, S37 and S38 belonging to a second group are simultaneously turned on, individual voltages of cells C34, C35 and C36 belonging to the second group are detected by the differential amplifiers D31, D32 and D33, and measured and monitored by the CPU. In this way, it is possible to measure a voltage of each cell in the fuel cell by scanning groups one by one while switches of the groups are turned on and off one after another.
FIG. 6 is a diagram illustrating a polarity of measured voltage for each cell in the detecting circuit shown in FIG. 5. When groups of cells are scanned group by group as described above, voltages imposed on the differential amplifiers D31, D32 and D33 have a constant polarity irrespective of groups. This will allow use of a single power supply, which for example is a one-way power supply having a ground and a positive power source, for each of the differential amplifiers D31, D32 and D33. In this way, the differential amplifiers D31, D32 and D33 can be simply configured. In this connection, filters F31, F32 and F33 disposed in the detecting circuit 30 are elements for removing noise. Buffers B31, B32 and B33 are elements for shaping a wave form of detected voltage.
A technique related to an apparatus for measuring voltage using a flying capacitor is disclosed in patent document 2. The technique is applied to a fuel cell stack in which many cells are electrically connected in series. A capacitor is connected in parallel with each of the cells, and a group is arranged so as to include five cells, for example. Measurement of voltage is carried out by detecting a voltage imposed on a capacitor corresponding to a cell while a switch corresponding to this cell is turned on. By repeating this measurement with switching, it is possible to measure voltages for all the cells of the group. The measurement is carried out for groups one after another so as to complete measurement for all the cells in the fuel cell stack. This technique results in a simplified configuration of circuit. In addition, a technique is disclosed in patent document 3, which measures voltages of individual cells one by one using a plurality of switches in a fuel cell stack, in which a plurality of cells is electrically connected to each other in series. This technique brings about measurement of a voltage of an individual cell with high precision, which does not require a complicated setup.    Patent document 1: Japanese Published Patent Application 11-339828    Patent document 2: Japanese Published Patent Application 2002-156392 (paragraphs 0051-0058, and FIG. 1)    Patent document 3: Japanese Published Patent Application 11-237455 (paragraphs 0018- 0024, FIG. 1 and FIG. 2)
Because a large number of cells are electrically connected to each other in series, the detecting circuit shown in FIG. 5 requires more pieces of switches than number of cells so as to measure a voltage for an individual cell. Specifically speaking, a cell lying in an interface between two successive groups requires two pieces of switches so as to turn off one signal line of a previous group and to turn on the other line of a next group. For example, the cell C34 lying in one interface between a first group and a second group requires the switches S34 and S35. Similarly, the cell C36 lying in the other interface of the second group and a third group requires the switches S38 and S39. It is deduced that switches more than 181 pieces, namely 181+180÷3−1=240 pieces, are necessary in case of a fuel cell stack having 180 cells electrically connected to each other in series, when a group is arranged so as to include three cells. Because PhotoMOS relays having high withstand voltage are in general selected for these switches, the more the number of switches increases, the more expensive material cost will be. In this connection, it may be possible to anticipate some decrease in total number of switches if number of cells belonging to a group is increased. The reason for this is that number of switches decreases, which lie in an interface between successive groups. However, an increase in the number of cells belonging to a group induces an increase in number of filters, buffers and differential amplifiers in a detecting circuit 30, resulting in an increase in material cost of an apparatus for measuring voltage as a whole.
Although the apparatus for detecting voltage disclosed in patent document 2 simplifies a setup of a circuit made of switches, it additionally requires a capacitor on which a voltage of a cell is imposed, resulting in a cost increase. In addition, the circuit for detecting voltage for a cell stack disclosed in patent document 3 has a drawback that a setup of circuit for switching devices turns complex.


A new contiguous genome sequencing method is described which allows the contiguous sequencing of a very long DNA without need to be subcloned. It uses the basic PCR technique but circumvents the usual need of this technique for the knowledge two primers for contiguous sequencing, enabling the knowledge of only one primer sufficient. The present invention makes it possible to PCR amplify a DNA adjacent to a known sequence with which one primer can be made without the knowledge of the second primer binding site present in the unknown sequence. The present invention could thus be used to contiguously sequence a very long DNA such as that contained in a YAC clone or a cosmid clone, without the need for subcloning smaller fragments, using the standard PCR technique. It can also be used to sequence a whole chromosome or genome without any need to subclone it.

The present invention provides a method for contiguous sequencing of very long DNA using a modification of the standard PCR technique without the need for breaking down and subcloning the long DNA.
The PCR technique enables the amplification of DNA which lies between two regions of known sequence (K. B. Mullis et al., U.S. Pat. Nos. 4,683,202; 7/1987; 435/91; and 4,683,195, 7/1987; 435/6). Oligonucleotides complementary to these known sequences at both ends serve as "primers" in the PCR procedure. Double stranded target DNA is first melted to separate the DNA strands, and then oligonucleotide (oligo) primers complementary to the ends of the segment which is desired to be amplified are annealed to the template DNA. The oligos serve as primers for the synthesis of new complementary DNA strands, using a DNA polymerase enzyme and a process known as primer extension. The orientation of the primers with respect to one another is such that the 5' to 3' extension product from each primer contains, when extended far enough, the sequence which is complementary to the other oligo. Thus, each newly synthesized DNA strand becomes a template for synthesis of another DNA strand beginning with the other oligo as primer. Repeated cycles of melting, annealing of oligo primers, and primer extension lead to a (near) doubling, with each cycle, of DNA strands containing the sequence of the template beginning with the sequence of one oligo and ending with the sequence of the other oligo.
The key requirement for this exponential increase of template DNA is the two oligo primers complementary to the ends of the sequence desired to be amplified, and oriented such that their 3' extension products proceed toward each other. If the sequence at both ends of the segment to be amplified is not known, complementary oligos cannot be made and standard PCR cannot be performed. The object of the present invention is to overcome the need for sequence information at both ends of the segment to be amplified, i.e. to provide a method which allows PCR to be performed when sequence is known for only a single region, and to provide a method for the contiguous sequencing of a very long DNA without the need for subcloning of the DNA.
DNA sequencing is a technique by which the four DNA nucleotides (characters) in a linear DNA sequence is ordered by chemical and biochemical means. There are two techniques: 1) the chemical method of Maxam and Gilbert (A. M. Maxam, and W. Gilbert, "A new method of sequencing DNA." Proceedings of the National Academy of Sciences, USA, 74:560-564 (1977)), and the enzymatic method of Sanger and colleagues (F. Sanger, S. Nicklen, and A. R. Coulson, "DNA sequencing with chain-terminating inhibitors." 74:5463-5467 (1977)). In the chemical method, the DNA strand is isotropically labeled on one end, broken down into smaller fragments at sequence locations ending with a particular nucleotide (A, T, C, or G) by chemical means, and the fragments ordered based on this information. The four nucleotide-specific reaction products are resolved on a polyacrylamide gel, and the auto radiographic image of the gel is examined to infer the DNA sequence.
In the enzymatic method, the following basic steps are involved:
(i) annealing an oligonucleotide primer to a suitable single or denatured double stranded DNA template; (ii) extending the primer with DNA polymerase in four separate reactions, each containing one .alpha.-labeled dNTP or ddNTP (alternatively a labeled primer can be used), a mixture of unlabeled dNTPs, and one chain-terminating dideoxynucleoside-5'-triphosphate (ddNTP); (iii) resolving the four sets of reaction products on a high resolution polyacrylamide-urea gel; and (iv) producing an auto radiographic image of the gel that can be examined to infer the DNA sequence. Alternatively, fluorescently labeled primers or nucleotides can be used to identify the reaction products. Known dideoxy sequencing methods utilize a DNA polymerase such as the Klenow fragment of E. coli DNA polymerase, reverse transcriptase, a modified T7 DNA polymerase, or the Taq polymerase.
The PCR amplification procedure has been used to sequence the DNA being amplified (e.g. "Introduction to the AmpliTaq Cycle Sequencing Kit Protocol", a booklet from Perkin Elmer Cetus Corporation). The DNA could be first amplified and then it could be sequenced using the two conventional DNA sequencing techniques. Modified methods for sequencing PCR-amplified DNA have also been developed (e.g. Bevan et al., "Sequencing of PCR-Amplified DNA" PCR Meth. App. 4:222 (1992)). However, amplifying and sequencing using the PCR procedure requires that the sequences at the ends of the DNA (the two primer sequences) be known in advance. Thus, this procedure is limited in utility, and cannot be extended to contiguously sequence a long DNA strand. If the knowledge of only one primer is sufficient without anything known about the other primer, it would be greatly advantageous for sequencing very long DNA molecules using the PCR procedure. It would then be possible to use such a method for contiguously sequencing a long genomic DNA without the need for subcloning it into smaller fragments, and knowing only the very first, beginning primer in the whole long DNA.
In the currently existing methods for sequencing very long DNA of millions of nucleotides, the DNA is fragmented into smaller, overlapping fragments, and sub-cloned to produce numerous clones containing overlapping DNA sequences. These clones are sequenced randomly and the sequences assembled by "overlap sequence-matching" to produce the contiguous sequence. In this shot-gun sequencing method, approx. ten times more sequencing than the length of the DNA being sequenced is required to assemble the contiguous sequence. In the "directed" sequencing method, the linear order of the DNA clones has to be first determined by "physical mapping" of the clones.
There exists a contiguous DNA sequencing method called the "primer-walking" method using the Sanger's DNA polymerase enzymatic sequencing procedure. In this method, however, the DNA copying has to occur always from the template DNA during DNA sequencing. In contrast, in the PCR procedure, the target DNA amplified in the first rounds from the original input template DNA will function as the template DNA in subsequent cycles of amplification. After a certain cycles of amplification, the DNA sequencing reaction will be started by adding the sequencing "cocktail". Thus in the PCR reaction, only one copy of template DNA is theoretically sufficient to amplify into millions of copies, and therefore a very little genomic (or template) DNA is sufficient for sequencing. The advantage of DNA amplification that exists in PCR is lacking in the conventional Sanger procedure. Thus, this primer-walking method will require a larger amount of template DNA compared to the PCR sequencing method. Also, because the long DNA has a tendency to re-anneal back to duplex DNA, the sequencing gel pattern may not be as clean as in a PCR procedure, when a very long DNA is being sequenced. This may limit the length of the DNA, that could be contiguously sequenced without breaking the DNA, using the primer-walking procedure. The PCR method also enables the reduction of non-specific binding of the primers to the template DNA because the enzymes used in these protocols function at high-temperatures, and thus allow "stringent" reaction conditions to be used to improve sequencing.
The present method of contiguous DNA sequencing using the basic PCR technique has thus many advantages over the primer walking method. Also, so far no method exists for contiguously sequencing a very long DNA using PCR technique. The present invention thus offers a unique and very advantageous procedure for contiguous DNA sequencing.


An apparatus is provided for directing toner from a hopper containing a supply of toner to evenly fill a non-symmetric container without excessive dusting and spills. The apparatus includes (a) a conduit member operably connected to the hopper and having a discharging end for permitting a toner to be moved therethrough; (b) a conveyor device located at least partially within the conduit member for moving the toner from the hopper in a toner moving direction towards the non-symmetric container; and (c) a nozzle member for directing the toner from the conveyor to evenly fill the non-symmetric container. The nozzle member is operably connected to the discharge end of the conduit member and has a first end connected to the conduit member, a second and opposite end for dispensing moving toner into the non-symmetric container, and a central portion between the first end and the second and opposite end. The second and opposite end includes an enclosed toner redirecting structure for changing the toner moving direction so as to enable even-filling of the non-symmetric container without excessive dusting and spills.

This invention relates generally to apparatus for filling a container with dry particulate material, and more particularly concerns a filling apparatus having an even-filling shaped nozzle for achieving even filling of a container with particulate materials such as toner.
Currently when filling particulate materials, for example toners into toner containers, toner is transported from the toner supply hopper into the container by a rotating auger. The auger is a spiral shaped mechanical part which pushes particles of toner inside a fill tube by direct mechanical contact. The nature of this mechanical contact process creates substantial limitations on accuracy and productivity of the toner filling operation. The speed of the toner movement in the fill tube is proportional to the speed of rotation of the auger and is limited by heat release due to auger/toner/funnel friction.
Toner containers for small low cost printers and copiers typically have a small opening into which the toner is to be added. Furthermore, the toner containers often have irregular shapes to conform to the allotted space within the copying machine. Therefore it becomes difficult to fill the toner container because of the small tube required to fit into the small toner container opening and secondly for all the toner within the container to completely and evenly fill the remote portions of the container before the container overflows.
Some of the problems associated with controlling the filling of such toner containers are due primarily to the properties of the toner. Toner is the image-forming material in a developer which when deposited by the field of an electrostatic charge becomes the visible record. There are two different types of developing systems known as one-component and two-component systems.
In one-component developing systems, the developer material is toner made of particles of magnetic material, usually iron, embedded in a black plastic resin. The iron enables the toner to be magnetically charged. In two-component systems, the developer material is comprised of toner which consists of small polymer or resin particles and a color agent, and carrier which consists of roughly spherical particles or beads usually made of steel. An electrostatic charge between the toner and the carrier bead causes the toner to cling to the carrier in the development process. Control of the flow of these small, abrasive and easily charged particles is very difficult.
The one-component and two-component systems utilize toner that is very difficult to flow. This is particularly true of the toner used in two component systems, but also for toner for single component systems. The toner tends to cake and bridge within the hopper. This limits the flow of toner through the small tubes which are required for addition of the toner through the opening of the toner container. Also, this tendency to cake and bridge may cause air gaps to form in the container resulting in partial filling of the container.
Attempts to improve the flow of toner have also included the use of an external vibrating device to loosen the toner within the hopper. These vibrators are energy intensive, costly and not entirely effective and consistent. Furthermore, they tend to cause the toner to causing dirt to accumulate around the filling operation.
Other attempts made to effectively fill such toner containers have included use of adapters positioned on the end of the toner filling auger which has an inlet corresponding to the size of the auger and an outlet corresponding to the opening in the toner container. Clogging of the toner, particularly when attempting to increase toner flow rates and when utilizing toners with smaller particle size, for example, color toners having a particle size of 7 microns or less, has been found to be a perplexing problem. The adapters that are fitted to the augers, thus, tend to clog with toner. The flow rates through such adapters is unacceptably low.
In accordance with the present invention, there is provided an apparatus for directing toner from a hopper containing a supply of toner to evenly fill a non-symmetric container without excessive dusting and spills. The apparatus includes (a) a conduit member operably connected to the hopper and having a discharging end for permitting a toner to be moved therethrough; (b) a conveyor device located at least partially within the conduit member for moving the toner from the hopper in a toner moving direction towards the non-symmetric container; and (c) a nozzle member for directing the toner from the conveyor to evenly fill the non-symmetric container. The nozzle member is operably connected to the discharge end of the conduit member and has a first end connected to the conduit member, a second and opposite end for dispensing moving toner into the non-symmetric container, and a central portion between the first end and the second and opposite end. The second and opposite end includes an enclosed toner redirecting structure for changing the toner moving direction so as to enable even-filling of the non-symmetric container without excessive dusting and spills.

Filling apparatus having an even-filling nozzle


An ink ejection device includes: a head section ejecting a plurality of kinds of inks; and an ink supply section supplying the plurality of kinds of inks to the head section. The ink supply section includes: two outlet ports which are separated from each other in a first direction intersecting with a vertical direction and through which a first kind of ink among the plurality of kinds of inks is supplied toward the head section; and an air-trap chamber in communication with the two outlet ports. The air-trap chamber protrudes to one side of a second direction intersecting with the vertical direction and the first direction relative to the two outlet ports. A portion connecting the two outlet ports of the air-trap chamber has an arc shape in a plane containing the first direction and the second direction or a bent portion of the portion connecting the two outlet ports of the air-trap chamber has an obtuse angle in the plane.

As an example of a liquid ejection device, an ink jet printer is known. The ink jet printer includes: an ink jet head (a liquid ejection section) ejecting an ink; and a buffer tank (a liquid supply section) arranged above the ink jet head and supplying the ink to the ink jet head.
The buffer tank is connected to four ink tanks through tubes and then receives inks of four colors supplied from the four ink tanks. The buffer tank includes four air-trap chambers corresponding to the inks of four colors. The air-trap chamber for yellow ink is formed in a U-shape having two right-angled corner portions. Further, the air-trap chamber for cyan ink is formed in a U-shape having two right-angled corner portions, along the air-trap chamber for yellow ink.
The ink in the buffer tank is supplied to the ink jet head after the air is separated and removed in the air-trap chamber. The air collected in the upper portion of the air-trap chamber is discharged to the outside through an air discharge section connected to the air-trap chamber.


A first editor memory is supplied with picture data that a user has selected, a second editor memory is supplied with a template that the user has selected, and a key memory is supplied with a key information that the user has selected. A switch inserts the picture data into the template in accordance with key information to deliver it to a video memory. A picture synthesis section inserts the picture data stored in the first editor memory into the picture insertion area designated by the key information within the template stored in the second editor memory in accordance with instruction from the user.

Hitherto, in the case of inserting a picture recorded on a film, etc. into, e.g., an insertion pattern, there is carried out a so called multiple exposure to allow the insertion pattern to be exposed to light in the state where the picture insertion area into which picture of printing (photographic) paper is inserted is light-shielded thereafter to carry out exposure by picture recorded on film, etc. in the state where the area except for the picture insertion area is light-shielded.
In addition to the above, in order to prepare a synthetic picture, a method using a general purpose computer, for example, is known. In accordance with such a method, a film is first read by, e.g., a film scanner, etc. to convert picture (pictorial image) recorded on the film into picture data to input it to the general purpose computer, etc. Then, picture editor which carries out editing of picture data, is used to insert picture data into the area designated by a user on an insertion pattern prepared in advance.
However, in the case of preparing a synthetic picture by the multiple exposure as described above, it is necessary to carry out a plural number of exposure operations and development operations of the printing paper. As a result, complicated operation is required. In addition, it takes a lot of time to prepare a synthetic picture. For this reason, it is difficult to change the position where the picture is synthesized and/or trimmed, for example, while confirming the prepared synthetic picture to carry out the picture synthesis, and the operability is thus poor. As a result, the working efficiency is low.
Moreover, as described above, in the preparation of synthetic picture using the general purpose computer, the cost of the entirety of the apparatus is increased, but a wide variety of processing can be made. To the contrary, in order to prepare a synthetic picture, complicated operations such as selection of the synthetic picture, designation of trimming and setting of picture synthesis position, and so on are required. In addition, with such general purpose computer, there are problems such as low picture processing speed of synthesis of picture data, and poor operability.
This invention has been made in view of the above-described problems, and its object is to provide a picture editing apparatus which can improve working efficiency, and which can improve operability.


The present invention relates to a machine intended for the machining of profiled elements (10), of the type comprising a longitudinal frame (1) provided with holding dollies (11, 13) for holding the profiled element to be machined (10). This machine is characterized in that it comprises at least two holding dollies (11, 13) capable, in the machining, of securing the slide-holding of the profiled element (10), and at least one drive dolly (15, 17), in which the profiled element (10) is slide-mounted, this drive dolly (15, 17) being provided with a device for securing its temporary fixed connection to the profiled element (10) such that the relative displacement of the latter relative to the machining head (9) in the longitudinal direction (yy′) is secured, at least in part, by the displacement of this drive dolly (15, 17).

Machines intended for the machining of such profiled elements, which are constituted by two assemblies, namely a milling assembly comprising a machining head movable along three axes, vertical, longitudinal and transverse, and an assembly of two dolly carriages, which are each capable of admitting the profiled elements in sliding and clamping arrangement and of positioning them angularly relative to the machining head. During the machining operation, the dollies secure the holding of the profiled element and, in order to do so, are fixedly connected thereto. These dollies are disposed at a certain distance apart which is a function of the rigidity dictated by the type of machining to be performed. This spacing thus defines a work window representing the maximum machining length which the machine will be able to perform in one step, so that, in order to machine the whole of the rod, an approach based on successive steps is adopted.
In order to simplify the restart procedures necessary between each step, it has been proposed to combine with these dollies one or more additional dollies. These dollies, while realizing a holding with reference to the profiled element, secure the displacement of the latter between the different machining phases corresponding to the different successive steps.
Such devices only permit a step-by-step machining of the profiled element, wherein the step length may not exceed the width of the window defined by the spacing of the two dollies, this spacing itself being a function of the precision of the desired machining.

Milling machine for longitudinal profiled elements


Oligonucleotides in which one or more purine residues are substituted by pyrazolo[3,4-d]pyrimidines exhibit improved hybridization properties. Oligonucleotides containing pyrazolo[3,4-d]pyrimidine base analogues have higher melting temperatures than unsubstituted oligonucleotides of identical sequence. Thus, in assays involving hybridization of an oligonucleotide probe to a target polynucleotide sequence, higher signals are obtained. In addition, mismatch discrimination is enhanced when pyrazolo[3,4-d]pyrimidine-containing oligonucleotides are used as hybridization probes, making them useful as probes and primers for hybridization, amplification and sequencing procedures, particularly those in which single- or multiple-nucleotide mismatch discrimination is required.

This application is in the field of molecular biology relating to the use of oligonucleotides as probes and primers. It relates further to the use of modified nucleic acid bases to improve the hybridization properties and discriminatory abilities of oligonucleotides that are used as probes and primers.
Many techniques currently in use in molecular biology utilize oligonucleotides as probes and/or primers. It is often advantageous, in the practice of these techniques, to be able to distinguish between two or more sequences which are related but which differ by one or more nucleotides. For example, many mutations of clinical significance differ by only a single nucleotide from the wild-type sequence. Polymorphisms in mammalian genomes are also often characterized by sequence differences of one or a few nucleotides. The ability to make such a distinction is known as mismatch discrimination. In practical terms, mismatch discrimination describes the property by which a defined sequence oligonucleotide, at a given stringency, hybridizes strongly (one manifestation of which is that the hybrids have a high melting temperature) to a target sequence with which it is complementary along its entire length (a perfect hybrid or perfect match), but hybridizes detectably more weakly to a target sequence that is non-complementary to the sequence of the oligonucleotide at one or a few nucleotides (a mismatch). The differences in hybridization strength are such that a particular stringency can be selected at which a perfect match is detectable as a hybrid and a mismatch fails to form a hybrid.
In a nucleic acid duplex, each base pair contributes to stability. Hence, the shorter the duplex, the greater the relative contribution of each individual base pair to the stability of the duplex. As a result, the difference in stability between a perfect match and a mismatch will be greater for shorter oligonucleotides. However, short oligonucleotides hybridize weakly, even to a perfectly complementary sequence, and thus must be hybridized under conditions of reduced stringency. Thus, the potential discriminatory power of short oligonucleotides cannot be easily realized except under conditions of low stringency, which counteract their discriminatory ability. It would constitute a substantial advance in the art if it were possible to achieve mismatch discrimination, particularly for single-nucleotide mismatches, under conditions of high stringency; for example, at the elevated temperatures characteristic of most amplification reactions.
Stabilization of duplexes by pyrazolopyrimidine base analogues has been reported. Seela et al. (1988) Helv. Chim. Acta. 71:1191-1198; Seela et al. (1988) Helv. Chim. Acta. 71:1813-1823; and Seela et al. (1989) Nucleic Acids Res. 17:901-910. Pyrazolo[3,4-d]pyrimidine residues in oligonucleotides are also useful as sites for attachment of various pendant groups to oligonucleotides. See co-owned PCT Publication WO 90/14353, Nov. 29, 1990. In addition, oligonucleotides in which one or more purine residues have been substituted by pyrazolo[3,4-d]pyrimidines display enhanced triplex-forming ability, as disclosed, for example, in Belousov et al. (1998) Nucleic Acids Res. 26:1324-1328. Pyrazolopyrimidines, when incorporated into an oligonucleotide, may provide improved duplex and triplex formation. U.S. Pat. No. 5,594,121.
It is an object of the present invention to provide new oligonucleotide compositions with improved properties related to hybridization and mismatch discrimination. It is a further object of the present invention to provide improved methods for hybridization, primer extension, hydrolyzable probe assays, PCR, single-nucleotide mismatch discrimination, nucleotide sequence analysis, array analysis and related techniques involving the use of oligonucleotides as probes and/or primers.
Accordingly, in one aspect, the present invention provides modified oligonucleotide compositions comprising one or more pyrazolo[3,4-d]pyrimidine base analogues substituted for at least one purine. In preferred embodiments, the guanine analogue 6-amino-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (ppG) is substituted for guanine, and/or the adenine analogue 4-amino-1H-pyrazolo[3,4-d]pyrimidine (ppA) is substituted for adenine. In other embodiments, the guanine analogue 1H-pyrazolo[3,4-d]pyrimidin-4(5H) one (ppI) is substituted for guanine. The pyrazolo[3,4-d]pyrimidine-substituted oligonucleotides can comprise, in addition, other moieties such as detectable labels and/or minor groove binders and/or other types of modified bases or base analogues.
Another aspect of the invention is a method for hybridization of nucleic acids, wherein at least one of the nucleic acids is a modified nucleic acid wherein one or more purine residues are substituted with a pyrazolo[3,4-d]pyrimidine base analogue. This method provides higher melting temperatures and enhanced mismatch detection. The improved hybridization methods provided by the present invention can be used in techniques which include, but are not limited to, hybridization, primer extension, single-nucleotide polymorphism detection, hydrolyzable probe assays, cDNA synthesis, nucleotide sequence determination, amplification reactions, and other techniques such as are known to those of skill in the art.
When the guanine bases in an oligonucleotide are replaced by the guanine analogue ppG, the Tm values of probes containing the analogues are slightly higher than those of oligonucleotide probes containing guanine. Hence, G-containing and ppG-containing oligonucleotides perform similarly in hybridization assays. However, when ppG-substituted oligonucleotides are used as hydrolyzable probes (described infra and see U.S. Pat. No. 5,210,015), two properties are significantly enhanced. First, ppG-substituted probes are more effective at mismatch discrimination, as measured by higher signal-to-noise values comparing the fluorescent signal obtained from a perfectly-matched hybrid with that from a hybrid containing a single-nucleotide mismatch. In addition, ppG-substituted probes provide higher absolute signal from a perfectly-matched target.

Oligonucleotides containing pyrazolo[3,4-d]pyrimidines for hybridization and mismatch discrimination


An imaging apparatus comprising a plurality of pixels each of which includes a photoelectric conversion portion, and a light-condensing portion arranged on the plurality of pixels, wherein the light-condensing portion has an area smaller than an area of the photoelectric conversion portion.

1. Field of the Invention
The present invention relates to an imaging apparatus and imaging system.
2. Description of the Related Art
An imaging apparatus can include microlenses as means for condensing incoming light. However, for example, like a full-HD sensor of a 35-mm full size, an imaging apparatus having a unit pixel larger than a diameter of each microlens used in the related art is known.


The DLL circuit includes a control circuit which controls bias currents of the unit delay circuits according to an externally input column address strobe writing latency (CWL) signal, and/or a DCC control circuit which adjusts steps of a DCC current of the DCC according to the externally input column address strobe writing latency (CWL) signal. The CWL signal may be input by a semiconductor memory device and may be indicative of a column address strobe writing latency of the semiconductor memory device. The semiconductor memory device may be a double data rate (DDR) synchronous DRAM (SDRAM) device.

The inventive concepts described herein generally relate to semiconductor devices, and more particularly, to delay-locked loop (DLL) circuits which may be used, for example, in synchronous memory devices.
In certain types of semiconductor memory devices, such as Rambus DRAM (RDRAM) devices and synchronous DRAM (SDRAM) devices, a DLL circuit may operate in synchronization with reference clock signals, that is, external clock signals. The DLL circuit receives the external clock signals and generates internal clock signals which are delayed for a predetermined time period, where the internal clock signals are used as clock signals by components of a semiconductor memory device.
A DLL circuit is generally worst-case designed so that it is operational at the highest possible operating frequency of the semiconductor memory device. This can result in current consumption inefficiencies at lower operating speeds, as well as deterioration of duty cycle correction characteristics at lower operation speeds.

Delay-locked loop circuit controlled by column strobe write latency


A method for processing a 3D image signal and an image display device for implementing the method are provided. The 3D image signal processing method is implemented by the 3D image display device. Although an image signal transmission side transmits information to be included in a plurality of image signals, while omitting a portion of the information, a receiver can synthesize the transmitted information to reproduce an image. The device restores at least one image from a broadcast signal, and additionally generates an image at a virtual camera view from the restored image and displays it three-dimensionally. To this end, the image display device receives a broadcast signal and obtains at least one set of camera parameters from signaling information. Then, the image display device generates a virtual view image according to the camera parameters, and formats the virtual view image and the broadcast image included in the broadcast signal three-dimensionally.

The advancement of television techniques has reached a level of implementing a device for displaying stereoscopic images. Various stereoscopic image display schemes have been proposed, and at the time when the present application, full-fledged commercialization of a stereoscopic type 3D television is at hand. In a stereoscopic 3D system, two images are captured by using two image sensors, which are separated from each other by about 65 millimeters, similar to human eyes, and the captured images are transmitted as a broadcast signal to a receiver. Then, the receiver processes the two images to be input to left and right eyes of a viewer (i.e., a user), thereby simulating binocular disparity to allow for depth perception and stereoscopic vision.
In addition, active research is being conducted with respect to multi-view video, in which a plurality of images is captured through several cameras and the captured images are provided to a receiver such that 3D images of various views can be displayed on the receiver. Multi-view video is anticipated to give the advantages of providing three-dimensional (3D) image effects via a wide screen and viewpoint freedom.
However, in commercially implementing the multi-view video, the amount of instantly processed data is increased at the transmission side and the reception side, and high-priced equipment is required. In particular, in order to transmit images having different viewpoints, considerable bandwidth is required for a transmission process no matter how heavily signals are compressed by removing temporal redundancy and spatial redundancy. Although cable networks or satellite broadcast networks have been extended, a considerable number of receivers at the time of filing the present application will still receive television signals via the air interface, and coding a plurality of images and transmitting the coded images through a bandwidth allocated to respective broadcast channels for radio signals are not considered to be easy.
Such a problem may arise with a system transmitting two image signals for a stereoscopic 3D display besides the multi-view video.
Thus, a method for significantly reducing the amount of image signal information in transferring information regarding a plurality of image signals to a receiver to implement a stereoscopic 3D display or a multi-view video is urgently required.

Method for 3D image signal processing and image display for implementing the same


Provided are a device and method for using bilirubin photoisomerization to reduce bilirubin interference with laboratory blood tests for other chemical analytes.

Field of the Invention
The present invention relates to a device and method for bilirubin photo-isomerization to reduce laboratory test interference in mammalian fluids.
Background of the Invention
Bilirubin has spectral and chemical properties that lead to interference with the measurement of common clinical laboratory analytes in patient samples. For example, bilirubin is known to interfere with fluid tests for the measurement of creatinine, cholesterol, and triglycerides. Spectral interference is caused when absorption of a certain wavelength of light is similar between bilirubin and the analyte of interest, thereby artificially increasing the apparent absorption profile of the analyte. Alternatively, bilirubin may absorb or "quench" the signal emanating from an analyte, artificially suppressing the signal. Chemical interference is caused when bilirubin reacts with chemical intermediaries designed to detect an analyte, resulting in compromised measurement of the analyte. These forms of interference may artificially suppress or inflate the values of important diagnostic analytes in a patient sample, reducing the accuracy of clinical chemistry testing. This loss of accuracy may lead serious diagnostic errors and even the administration of inappropriate medical treatments or interventions, which may have unwanted and/or harmful effects on the patient.
Bilirubin is primarily a breakdown byproduct of hemoglobin which is released upon death and decomposition of red blood cells. Jaundice is a clinical condition experienced by many newborn babies as well as children and adults stricken with certain diseases where abnormally high levels of bilirubin have accumulated in their bodies. Its most pronounced symptom is yellow coloring of the skin and eyes.
Normally, bilirubin is conjugated with glucuronic acid in the liver so that it can be solubilized and eliminated from the body through the bile. However, several of the proteins and enzymes that perform this function are not present at the necessary levels in newborns and in certain pediatric and adult diseases. This leads to a rise in bilirubin levels in the blood. Since the bilirubin is not water-soluble it tends to accumulate in body tissues, thereby causing the yellow coloration.
Bilirubin has the chemical structure shown in FIG. 1A. The carboxyl groups form hydrogen bonds with nearby nitrogen atoms, which hides the hydrophilic moieties and increases the molecule's overall hydrophobicity. Bilirubin's hydrophobicity makes it dangerous because it will readily absorb into tissue and cross the blood/brain barrier.
The danger of high levels of bilirubin is that it can be neurotoxic, a condition known as kernicterus. If levels remain elevated there can be irreversible nerve damage, or even death.
Light-mediated isomerization (referred to as phototherapy in therapeutic settings) initiates a structural isomerization of bilirubin to lumirubin, an isomer with substantially different chemical and light absorption properties than bilirubin. Among other differences, the isomerization of bilirubin yields a free carboxyl group that makes lumirubin much more hydrophilic than bilirubin. The magnitude of phototherapy-mediated conversion of bilirubin to lumirubin increases with the intensity of the light, so a device designed to generate light of the proper wavelength and focus that light directly on subject fluid samples will yield substantial benefits in the speed and efficiency of the preparation of fluids for "clean" chemical analyte testing. Since testing labs, in hospitals and outside hospitals, tend to handle scores or hundreds of samples a day, a device maximizing efficiency by reducing time to process bilirubin cleansing will yield a substantial economic benefit to the testing company.
Light-mediated photoisomerization, including phototherapy, is considered to be extremely safe. The only potential risk is damage to the eyes by the intense light. Therefore, it is highly recommended that the eyes of any photoisomerization operators and/or recipients be protected appropriately. Otherwise, no significant side effects of phototherapy have been documented.
The most efficient wavelength for the isomerization of bilirubin is approximately 450 nm, whether applied to the cleansing of fluid samples for testing or the treatment of jaundice. Wavelengths that fall within the range of 400 nm-500 nm, and more specifically 445 nm-475 nm are known to effect isomerization. In addition, a light intensity of at least 6 microWatts per square centimeter per nanometer of light wavelength is needed for phototherapy. This intensity is equivalent to 2.7 milliwatts per square centimeter of 450 nm wavelength light.
Hyperbilirubinemia, an elevation in bilirubin circulating in the blood, can arise from both acute and congenital circumstances. Bilirubin is a natural byproduct of the metabolism of hemoglobin derived from aged or injured red blood cells. Infant hyperbilirubinemia (neonatal jaundice) is common but easily treated by placing the infant under blue lights, known as phototherapy. Unmanaged hyperbilirubinemia, however, leads to kernicterus (brain damage, ataxia) and early mortality.
Solitary bilirubin is insoluble in the blood and cannot be efficiently excreted in this form. It is therefore conjugated and solubilized by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), allowing excretion through the feces and urine. Unconjugated hyperbilirubinemia is a hallmark of Crigler-Najjar Syndrome (CNS) Type 1, a genetic deficiency of UGT1A1. The current standard treatment for CNS is phototherapy, which is conducted within a bed or chamber fitted with blue lights (wavelength of approximately 450 to 530 nm). Light of this wavelength initiates a photo-isomerization reaction which converts unconjugated bilirubin into an isomer known as lumirubin, which is water soluble and readily excreted. However, the onset of puberty is characterized by thickening and pigmentation of the skin, accompanied by a decrease in the body's surface area:volume ratio. These changes represent barriers to light penetration into circulating blood (which contains the majority of bilirubin). Therefore, the efficacy of phototherapy decreases substantially following puberty. Consequently, older CNS patients are particularly susceptible to elevated bilirubin in the blood, which may interfere with clinical chemistry measurements taken on patient samples.
As mentioned above, bilirubin is a byproduct of the natural turnover and destruction of red blood cells, which releases hemoglobin into the blood. Breakdown of hemoglobin releases a heme group which is further catabolized into bilirubin. At physiological blood pH (around pH 7.4), bilirubin's hydrophilic domain is masked by hydrogen bonding, reducing its solubility. However, bilirubin is conjugated to glucuronic acid in the endoplasmic reticulum of hepatocytes by the enzyme uridine diphosphate glycosyltransferase 1-A1 (UGT1A1), disrupting the hydrogen bonds. The resulting configurational and structural changes facilitate bilirubin solubilization and excretion through the liver, kidneys, and intestines. Crigler-Najjar Syndrome (CNS) Type 1 patients lack UGT1A1 activity due to a genetic abnormality and suffer from chronic unconjugated hyperbilirubinemia. While the normal level of unconjugated bilirubin in the blood is 0.2-0.9 mg/dL, CNS patients have ≧20 mg/dL of bilirubin in their blood.
It should be noted that disorders similar to CNS also present in the veterinary context, and that the device and methods described herein apply to all blood samples from mammals, whether human or animal. The same benefits regarding fluid testing protocols for human patients described herein will also apply in the veterinary context.
What is needed is a device and method for processing high-bilirubin fluid samples being tested for other chemical analytes for diagnostic purposes in order to reduce or remove the bilirubin from such samples and thereby minimize the bilirubin's interference with the measurement of such other chemical analytes.

Device and method for bilirubin photoisomerization to reduce laboratory test interference


An apparatus and method for clearing of a surgical site during the performance of a medical procedure where a single phase wash fluid, which has been conditioned, is directed at the surgical site to inhibit or prevent harm to the body tissue as unwanted debris is blown away from the surgical site thereby permitting a surgeon to safely perform a medical procedure without the presence of unwanted liquids or unwanted debris at the surgical site.

The use of various types of devices for cleaning body tissue are known in the art. Some devices remove debris by suction while other devices remove debris by blowing debris away from the body tissue. An example of a surgical device that removes debris from a body tissue through suction is shown in U.S. Pat. No. 5,827,218. Other devices for cleaning body tissue include a combination of methods. An example of a device that employs multiple methods is shown in U.S. Pat. No. 5,902,264, which discloses an endoscopic surgical instruments for aspirating, irrigation and blowing gas adjacent to body tissue. These type of devices are well suited to cases where the body tissue is not adversely impacted by the cleaning action of the device. However, in some cases the body tissue is fragile and could be injured by a harsh cleaning action. In addition in some cases the body dynamics need to be considered, for example during the performance of an anastomosis, a more gentle or delicate removal of the debris proximate to a dynamic surgical site is necessary in order to preserve the integrity of the body tissue at the surgical site as blood exudes or flows from the anastomosis site.
One of such devices that have been developed for cleaning a surgical site during the performance of an anastomosis is a blower/mister, which relies on the atomization of liquid droplets. The blower/mister devices deliver a stream of pressurized gas that is intermixed with a stream of a sterile liquid to produce an intermixed stream of gas and liquid droplets, which can be used to wash debris away from the surgical site. In the blower/mister device a gas stream is directed past a liquid stream to entrain particles or droplets of the liquid in the gas stream, which results in an intermixed fluid stream of both gas and liquid droplets.
An example of a fluid entrainment device or atomization device is shown in U.S. Pat. No. 6,168,577. The fluid entrainment device contains coaxial lumens with liquid saline directed through a central lumen and a gas directed through an outer annular lumen. The gas flowing past the central stream of liquid saline entrains droplets of the saline with the gas stream. The intermixed liquid and gas stream is then directed at a surgical site to blow away debris from the surgical site.
U.S. Pat. No. 5,336,170 shows an example of another blower/mister having a fan shaped wand for blowing an intermixed gas and liquid stream onto a surgical site to blow debris away from the surgical site. One of the touted advantages of the blower/misters is that they have the ability to blow away debris from a surgical site without desiccating the tissue at the surgical site since they simultaneously deliver both a liquid and a gas to the surgical site.
Another type of blower mister, which moisturizes the fluid stream through entrainment or atomization of liquid droplets is shown in U.S. Pat. No. 6,156,003. The patent contends that the use of multiple smaller lumens each containing a liquid stream within a larger lumen containing a gas stream provides for greater efficiency in the atomization or entrainment of the liquid since the patent states smaller drops can be injected into the gas stream, which prevents liquid from dripping from his wand.
One of the more challenging tasks for a surgeon is forming an anastomosis on coronary arteries while the heart continues to beat. As the blood is pumped through the arteries it can disrupt the surgeons view of the surgical site, which further complicates the task of suturing the arteries under dynamic conditions. The suturing of an anastomosis is not only a dynamic task but also a delicate and difficult task since the ends of the arteries need to be viewed clearly in order to suture the ends of the arteries to each other. It is important that the surgeon not only have a clear view of the surgical site but he or she should have an assurance that the process of cleaning the surgical site does not harm the body tissue at the surgical site. Because of the difficult task in cleaning a dynamic surgical site without harming the tissue a tissue clearing device such as the blower/misters, which mix a gas stream and a liquid stream have been preferred. The blower/misters intermix a liquid stream and gas stream to produce a fluid stream, which is directed at the surgical site. The intermixing of the moving fluid streams occurs through a process of fluid entrainment whereby a gas stream and a liquid stream are directed along side each other. The friction between boundary layers of the two streams results in intermixing of the liquid droplets and the gas. Because of the need to enhance visualization at an anastomosis site where blood may be exuding or flowing from vessels the aforementioned devices for intermixing streams of both gas and liquid droplets, which are described in U.S. Pat. Nos. 6,168,577 and 5,336,170 have been used to blow away debris from delicate and dynamic surgical sites.
Although the aforedescribed blower/misters have been widely used to blow debris away from delicate and dynamic surgical sites they have the disadvantage that they may also introduce additional debris to the surgical site since the liquid droplets in the intermixed stream may remain at the surgical site, which has the potential to interfere with the surgeons view of the surgical site as well as affect the condition of the tissue at the surgical site. In addition, the liquid droplets, which have been entrained by the gas stream of the blower/misters, create multiple micro impacts on the tissue at the surgical site as one blows the intermixed gas and liquid stream at the surgical site. Consequently, the micro impacts of the liquid droplets have the potential to result in tissue damage at the surgical site. That is, even though the velocity of the gas stream and the velocity of the atomized liquid droplets may be the same the larger mass or momentum of the liquid droplets can generate a greater impact on the delicate tissue than the impingement of the molecules of the gas stream. Thus, while it may appear the velocity of the gas is sufficiently low so as not to harm the tissue the velocity of the liquid droplets may not be.
Another drawback with blower/misters is that oftentimes it is difficult to control the entrainment process as it often results in too much liquid saline solution or too little liquid saline solution being delivered to the surgical site.
A further disadvantage with the blower/misters is that the intermixed stream of liquid and gas leaves a residue of droplets of liquid debris at the surgical site. In addition, the liquid droplets may accumulate and coalesce at the end of the wand since the liquid droplets are always present when a two-phase stream is used to blow debris away from the surgical site.
While the use of blower/misters that intermix streams of liquid and gas are known in the art sometimes those who use the blower/misters mistakenly believe that devices that intermix the streams of liquid and gas humidify the gas, however, the coaction of fast moving streams of gas and liquid with each other actually produces entrainment or atomization of the liquid particles in the gas as opposed to humidification of the gas.
The invention described herein eliminates the problems of introducing extraneous foreign materials to the surgical site or the need for atomization of a liquid while at the same time inhibiting and preventing desiccation or injury to the tissue during the cleaning of a surgical site. The invention is well suited for cleaning and preserving tissue at delicate and dynamic surgical sites for example, an anastomosis site where blood may be exuding from a vessel during the surgical procedure. In addition the invention can eliminate the need for use of multiple fluid streams in cleaning a surgical site.

Medical devices for clearing a surgical site


A “Stochastic Clustering-Based Network Generator” enables rapid formation of an interconnected hierarchical network structure from an arbitrary number of agents via an iterative turn-based coalescence process. Given N agents wishing to coalesce into one hierarchical network, a turn-based process allows each agent (or the head of each hierarchical cluster of agents), to randomly decide whether to issue or listen for merge requests in each round. Issuing a request amounts to contacting a randomly chosen agent with a merge request. Given multiple received requests, a cluster head will randomly accept one request for a merge received by any agent in that cluster. The requesting cluster then merges as a hierarchical child of the accepting cluster. In a related embodiment, given multiple merge requests, the request from the smallest cluster is accepted. In further embodiments, ties of the smallest cluster size are broken based on various options.

Technical Field
A "Stochastic Clustering-Based Network Generator" provides various automated techniques that enable rapid formation of an interconnected hierarchical network structure from an arbitrary number of agents via an iterative turn-based coalescence process.
Background
Conventional stochastic coalescence techniques typically involve processes that act via a continuous-time process where the coalescence rate of two clusters with given masses x,y (which can be either discrete or continuous) is dictated up to re-scaling by a rate kernel K. One well-known example of such techniques, referred to as "Kingman's coalescent," corresponds to the kernel K(x,y)=1 and has been intensively studied in mathematical population genetics. In general, Kingman's coalescent can be obtained as the continuous/infinite limit of a process where at each time t there is a population of N individuals, and each individual picks a parent at random from the previous generation of individuals, located in time t+1/N. Other examples of highly studied rate kernels include "Aldous's continuum random tree" which provides the additive coalescent K(x,y)=x+y, and "Erdos-Renyi random graphs" which provide the multiplicative coalescent K(x,y)=xy. These types of classical stochastic coalescence processes are generally understood to function as an asynchronous series of individual merges whose occurrences are governed by independent exponentials.

Distributed stochastic clustering for automated formation of connected networks of agents


The present invention provides a multi-drug-loading site and high drug-loading capacity ligand-drug conjugate. The ligand-drug conjugate has a structure of general formula (I). The ligand-drug conjugate has the characteristics of high loading capacity, high drug efficacy, low toxicity, and low risks. The ligand-drug conjugate can be used particularly to connect to a low toxicity chemical molecule, thereby extending a therapeutic window. Furthermore, the present invention provides an antibody-drug conjugate molecule. The antibody-drug conjugate molecule has the characteristics of multiple drug-loading ability and high drug-loading capacity, such that the antibody-drug conjugate can carry a large amount of a low toxicity chemical molecule and achieve a therapeutic effect without depending on antibody targeting or high toxicity chemicals.TM-{R2-PEG1-[R1-PEG2-(R3-A′-D)n]m}l  (I

Antibody-Drug Conjugates (ADC) is a conjugating product formed by coupling a monoclonal antibody (Monoclonal Antibody, mAb) to a biologically active small molecule drug through a linker. It can "accurately" deliver the small molecule drug to the tumor cells by use of the characteristics through which the antibody specifically recognizes the tumor cell, increasing the drug concentration at the tumor site while reducing the drug concentration at normal tissues and organs, thereby achieving an anti-tumor effect with high efficiency and low toxicity. The first antibody-drug conjugate, gemtuzumab ozogamicin (Mylotarg®), was approved by US FDA in 2000. Although the drug was withdrawn after 10 years due to safety concerns, brentuximab vedotin (SGN-35, Adcetris®) was approved for the treatment of Hodgkin's lymphoma, and anaplastic large cell lymphoma by US FDA and the European Medicines Agency in 2011, and trastuzumab emtansine (T-DMI, Kadcyla®) was approved for the treatment of HER-2 positive breast cancer in 2013. Both the ADCs have achieved exciting therapeutic effects. At present, there are more than 50 kinds of ADCs in the clinical research stage, and ADCs have become an important new anti-tumor drugs.
Although the development of new ADC drugs has achieved unprecedented success, the technology still needs further optimization. Most of the coupling agents in the ADC are short-chain rigid hydrophobic molecules, which also have a certain effect on the water solubility and immunogenicity of the drug itself. In addition, most of the drugs in the ADC are hydrophobic, which may cause problems due to aggregation after the hydrophobic drug is attached to the antibody. The aggregates do not dissolve, which in turn affects the drug loading. Studies have shown that ADC aggregates accumulate in the liver, causing hepatotoxicity (Jarvis L M, Jarvis L M. Rethinking Antibody-Drug Conjugates [J]. Chem. eng. news, 2013, 90(25)). Finally, protein aggregation of biological formulation generally causes immunogenicity (Joubert M K, Hokom M, Eakin C, et al. Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses [J]. Journal of Biological Chemistry, 2012, 287(30): 25266-25279).
Patent document CN201510160703.5 discloses an antibody-drug conjugate obtained by covalently coupling a drug molecule and a Fab′ fragment to a heterobifunctional polyethylene glycol. Although the above antibody conjugate has a determined drug-loaded point and an exact drug loading ratio, the drug loading point is only a few, which is not favorable to increasing the drug loading of the whole conjugate.

Multi-drug-loading-site, high drug-loading capacity ligand-drug conjugate