A semiconductor memory device includes a column enable signal generator, a row enable signal generator and a final column enable signal generator. The column signal enable generator may generate a latency control signal and generating a buffered clock signal as a column enable signal in response to the latency control signal. The row enable signal generator may generate a row enable signal. The final column enable signal generator may generate a first signal in response to the column enable signal, a second signal in response to the row enable signal, and may output the first and/or the second signal as a final column enable signal.

1. Field of the Invention
Example embodiments of the present invention relate to semiconductor memory devices. For example, at least some example embodiments of the present invention provide semiconductor memory devices operating with a latency dependent on a frequency of an external clock signal and methods for generating a column enable signal thereof.
2. Description of The Conventional Art
A conventional semiconductor memory device may operate with a latency dependent on an external clock signal frequency. However, even though the latency may vary, a row enable signal may be activated constantly and may maintain the activation state during a time period before deactivation. On the other hand, a column enable signal may be delayed for a clock cycle corresponding to the latency prior to activation. For example, even though the latency may vary, an activation time of the row enable signal may be the same or substantially the same, while an activation time of the column enable signal may vary.
FIG. 1 is a block diagram illustrating a conventional semiconductor memory device. The conventional semiconductor memory device of FIG. 1 may include a memory cell array 100, a command decoder 10, a mode setting circuit 12, a clock buffer 14, a column enable signal generator 16, a row enable signal generator 18, a column decoder 20 and a row decoder 22. In FIG. 1, "MC" denotes a representative memory cell, "BL" denotes a representative bit line and "WL" denotes a representative word line.
The command decoder 10 may decode a command signal COM applied from an external source to generate a read command RD and a mode setting command MRS. The mode setting circuit 12 may receive a code CODE applied from an external source to generate a burst length signal BLS and a latency signal LA in response to the mode setting command MRS. The clock buffer 14 may buffer an external clock signal CLK to generate a buffered clock signal PCLK. The column enable signal generator 16 may receive the read command RD, the burst length signal BLS, the latency signal LA, and the buffered clock signal PCLK, and may generate a latency control signal (not shown). The latency control signal may be activated after being delayed for a clock cycle corresponding to the latency signal LA after the read command RD is applied. The column enable signal generator 16 may deactivate the latency control signal after being activated for a clock cycle corresponding to the burst length signal BLS and may generate the buffered clock signal PCLK as a column enable signal PCSLE in response to the latency control signal.
The row enable signal generator 18 may generate a row enable signal PWL, which may be activated after a time period, and may be deactivated after being activated for a time period. The row enable signal generator 18 may generate the row enable signal PWL in response to the read command RD. The column decoder 20 may decode a column address CA to activate one of n column selecting signals CSL1 to CSLn in response to the column enable signal PCSLE. The row decoder 22 may decode a row address RA to activate one of m word line selecting signals WL1 to WLm in response to the row enable signal PWL.
FIG. 2 is a block diagram illustrating the column enable signal generator of the conventional semiconductor memory device of FIG. 1. The column enable signal generator of FIG. 2 may include a latency control signal generator 30 and an enable signal generator 32.
The latency control signal generator 30 may activate a latency control signal lat after being delayed in response to the buffered clock signal PCLK and after the read command RD is generated. The delay may comprise a clock cycle corresponding to the latency signal LA. The latency control signal generator 30 may deactivate the latency control signal lat using the buffered clock signal PCLK after maintaining the activation state for a clock cycle corresponding to the burst length signal BLS. The enable signal generator 32 may generate the buffered clock signal PCLK as the column enable signal PCSLE in response to the latency control signal lat.
FIG. 3a is a timing diagram illustrating an example operation of the semiconductor memory device of FIG. 1. In the example shown in FIG. 3A, the latency signal LA is set to 2, and the burst length signal BLS is set to 4. A latency signal LA set to 2 indicates that data may be read 2 clock cycles after the read command RD is generated. The burst length signal BLS set to 4 indicates that 4 data may be output sequentially through one data output pin.
Referring to FIG. 3a, when the read command RD is applied, the row enable signal PWL may be activated a time T1 after (and in response to) the read command RD and may be deactivated after a time T2. The row decoder 22 may decode the row address RA to activate one word line selecting signal WL in response to the row enable signal PWL. The latency control signal generator 30 may generate the latency control signal lat after the read command RD is applied, and the latency control signal lat may be active being delayed for 2 clock cycles corresponding to the latency signal 1a. The latency control signal lat may be deactivated after maintaining the activation state for 4 clock cycles corresponding to the burst length signal BLS. The enable signal generator 32 may generate the buffered clock signal PCLK as the column enable signal PCSLE in response to the latency control signal lat. Thus, 4 column enable signals PCSLE may be generated sequentially. The column decoder 20 may decode the column address CA to activate a first column selecting signal CSL1 in response to the column enable signal PCSLE. Second to fourth column selecting signals CSL2 to CSL4 may be activated sequentially. Although not shown, the row address RA and/or a first column address CA may be applied concurrently with the command signal CMD. The row address RA may be applied to the row decoder 22, the first column address CA may be applied to an internal address generator (not shown), and the internal address generator (not shown) may sequentially generate 4 column addresses corresponding to the burst length signal BLS.
FIG. 3B is a timing diagram illustrating an example operation of the semiconductor memory device of FIG. 1 in which a frequency of the clock signal CLK is higher than the frequency of the clock signal CLK of FIG. 3A, the latency signal LA is set to 3 and the burst length signal BLS is set to 4.
In FIG. 3B, the row enable signal PWL may be generated in the same or substantially the same manner as in FIG. 3A. The clock buffer 14 may buffer the clock signal CLK to generate the buffered clock signal PCLK. The row decoder 22 may decode the row address RA to activate one word line selecting signal WL in response to the row enable signal PWL. The latency control signal generator 30 may generate the latency control signal lat after the read command RD is applied. The latency control signal lat may be activated after being delayed for 3 clock cycles corresponding to the latency signal LA. The latency control signal lat may be deactivated after being maintained in an activation state for 4 clock cycles corresponding to the burst length signal BLS. The enable signal generator 32 may generate the buffered clock signal PCLK as the column enable signal PCSLE in response to the latency control signal lat. Thus, 4 column enable signals PCSLE may be generated sequentially. The column decoder 20 may decode the column address CA to sequentially activate first to fourth column selecting signals CSL1 to CSL4 in response to the column enable signal PCSLE. Four column addresses CA may be generated by the internal address generator (not shown).
As shown in FIGS. 3A and 3B, the latency changes as the frequency of the clock signal varies, while the row enable signal PWL may be generated at the same time point. However, as the latency varies, a time at which the latency control signal lat is generated may vary. Thus, a time period spanning from the generation of the word line enable signal WL to the generation of the first column selecting signal CSL1 may be t1 in FIG. 3A and t2 in FIG. 3B. Time periods t1 and t2 may be different.
The time period from generation of the word line enable signal WL to generation of the first column selecting signal CSL1 may vary as the latency varies, depend on variations in process, voltage and/or temperature. As a result, if data of the bit line pair is not sufficiently amplified, the first column selecting signal CSL1 may be generated, and the data of the bit line may be read, which may result in data read errors.

Semiconductor memory devices and methods for generating column enable signals thereof


A computer system for remote interactive graphical display and data management includes a data storage device storing data records, a remote data acquisition computer configured to selectively trigger display actions for the data records based on at least a time-based rule and a time-independent rule; a classification engine configured to classify a response received from a remote display interface having user-selectable options arranged to define a scale of values, in one of two categories, a first category and a second category, being below a first threshold value being classified as being in the first category, and responses on the scale above a second threshold value being in the second category, and a display interface generator configured to selectively generate a supplemental interface or a conclusion message dependent on the category.

Marketing experts are coming to recognize that engendering customer loyalty is a crucial ingredient in generating increased profitability. Typical tools for measuring customer loyalty include surveying customers after completion of interaction between customers and company employees. Results of such surveys can be employed to improve employee training and designs of customer service practices. Similarly, survey results may be used to inform an appropriate allocation of resources, such as funding and information technology resources, to better serve customers. Such improvements may lead to future increases in customer loyalty. In some cases, an insurance company or agent may wish to use comments and other information about a customer to better improve service and/or to offer additional services that might be of interest to that customer. In some cases, an insurance company or agent may wish to use comments and other information about a customer in testimonial marketing messages (e.g., web-based advertising, etc.). For example, an insurance company may utilize one or more "third party administrators" to help facilitate claims processing in connection with insurance policies. In this case, survey results may be used to assess the performance of the third party administrators and/or to improve the service being provided. By way of further example, an insurance company may utilize one or more sales or distribution partners to help facilitate the marketing of other insurance policies. It can be difficult, however, to determine which customers and/or customer responses would be suitable for such purposes by manually reviewing the feedback information.


A multilayered polymeric structure for use as a packaging container comprising a first layer of oxygen barrier material and a second protective layer bonded to the first layer where the oxygen barrier layer material is selected from the group consisting of saponified ethylene-vinyl acetate copolymer, polyamide, polyvinyl alcohol, modification products thereof, and mixtures thereof, and the second protective layer comprises a polymer and an inorganic filler in an amount sufficient to further enhance the moisture barrier property of the outer protective layer over what it would be in the absence of the filler.

Oxygen barrier resins such as saponified ethylene-vinyl acetate copolymer (hereinafter referred to as "EVOH") have low oxygen permeability and yet can be adversely affected by high humidity and are liable to undergo an increase of oxygen permeability under a highly humid atmosphere. Generally, packaging structures are adapted to retain their oxygen barrier property by including a protective layer, such as of a polyolefin or some other barrier polymer having a low water absorption or low moisture absorption on a layer of an oxygen barrier resin of high humidity dependency thereby precluding direct exposure of the oxygen barrier layer to water or moisture.
The dependence of the performance of a packaging structure on humidity is an important property because packages are used to store mammal foodstuffs, generally for humans or pets. Often packages are subjected to a "retort process" in which the molded package/container is subjected to excessive moisture as steam and at elevated temperatures typically around 250° F. (around 130° C.) and the ingress of moisture through the outer protective layers exponentially increases with temperature. This effect leads to lowering of the efficiency of EVOH as the barrier, an effect called "retort shock." Although this lowering is almost a reversible process and the barrier efficiency generally returns almost to its pre shock value, in order to meet the expectations of the shelf life for the food contained in the retorted container the thickness of the EVOH barrier layer must be increased, or lower ethylene mole percent EVOH must be used. These are both expensive alternatives and the most economical way to ensure shelf life is still to protect the EVOH layer from the moisture/steam.
The present inventors have made the unexpected discovery that addition of certain fillers in an effective level to a protective layer results in improved protection of the oxygen barrier component of a packaging structure from moisture.


A humidifier is superior in terms of hygiene, simple in terms of maintenance, humidity is easily adjusted, and energy consumption is low. The humidifier uses, as a moisture permeable membrane, a moisture-permeable polyurethane obtained by using, as raw materials, at least an isocyanate component, a diol as a chain extender, and polyethylene glycol as a polyol component, and reacting these raw materials.

1. Field of the Invention
The present invention relates to a humidifier for supplying moisture to any desired space such as the interior of a room and the like, thus raising the humidity, and relates in particular to a humidifier employing moisture-permeable polyurethane as a moisture-permeable membrane.
This application is based on Japanese Patent Applications, Nos. 2001-389560, 2002-208170, and 2002-370808, the contents of which are incorporated herein by reference.
2. Description of Related Art
GORE-TEX (registered trademark), a product comprised of polytetrafluoroethylene (PTFE) resin incorporating innumerable micropores, and polyurethane resin, are known as moisture-permeable resins used in conventional humidifiers. When polytetrafluoroethylene resin is employed, particularly as a fabric, it provides the opposing functions of being waterproof while at the same time being moisture-permeable in that it is impermeable to liquid water while being permeable to water vapor, and is therefore employed in a variety of clothing.
In recent years, the applications of materials having the functions of being waterproof while at the same time being moisture-permeable have expanded, and humidifiers wherein the aforementioned materials are employed to release only a preset amount of clean moisture (water vapor) are under investigation, and have been implemented in some cases.
The related art is disclosed in the documents hereunder.
Japanese Unexamined Patent Application, First Publication No. Hei 08-100935
Japanese Unexamined Patent Application, First Publication No. Sho 60-171337
Japanese Unexamined Patent Application, First Publication No. Sho 61-250429
In humidifiers employing the moisture-permeable resin formed from polytetrafluoroethylene resin, a hollow structure in the shape of a bag formed from layers of the moisture-permeable resin is filled with water, and water vapor is passed through the micropores formed in the moisture-permeable resin. However, it has been pointed out that various bacteria which reproduce both inside and outside the humidifier pass through the micropores with the water vapor and are dispersed in the air, resulting in problems of hygiene.
Furthermore, foreign matter such as calcium deposits and microscopic metal constituents (generally referred to as 'scale') and the like included in the water remain in the interior of the hollow structure, and tend to be gradually concentrated due to the structure of humidifiers wherein only water is evaporated and released. Therefore, the concentrated calcium deposits and foreign matter and the like tend to block the micropores with operation of the humidifier over a long period of time, and once the micropores are blocked, passage of the water vapor deteriorates and the performance of the humidifier deteriorates dramatically. In such cases, since the functions of the humidifier cannot be recovered unless the components employing the moisture-permeable resin are replaced, there is also a problem of the costs of maintenance. These costs increase due to the complex structure of the hollow structure, and are therefore comparatively high.
Moreover, conventional humidifiers require a heater to produce humidified air for the adjustment of humidity. However since considerable energy is consumed in driving a large-capacity heater to generate heat, it is not possible to satisfy consumer requirements in terms of energy-efficiency as desired by the market.


Systems, methods, and program products for subjective and locatable color theme extraction for images. Determining a color density for each of a plurality of colors in an image where each of the plurality of colors belongs to a color space, extracting one or more distinct theme colors from the plurality of colors based on qualitative parameters and the determined color densities, and mapping each extracted theme color to a color occurring in the image where the mapping is based on a color distance between the theme color and colors occurring in the image.

A color theme can be automatically derived from a digital image. For example, a color theme might consist of the five most frequently occurring colors in an image. Yet the extraction of a set of colors from a digital image is not a well defined problem—it is a subjective process which is shaped by the user's intent. One person may differ from another in the choice of colors. One person may choose to extract bright and cheery colors; another may choose a more natural set; yet another may choose a more drab or dreary set. Moreover, typical techniques for extracting colors produce them from an approximate color distribution (e.g., a histogram) and do not ensure that these colors actually correspond to exact colors or locations in the image.

Subjective and locatable color theme extraction for images


A probe for use in situ analysis of light absorbing fluids wherein light emitted from a source is collimated by a lens and transmitted through a fluid onto and substantially perpendicular to a reflector. Light is reflected by the reflector back through the fluid and focused by the lens onto a reflected light collector for transmission to analyzing apparatus. The length of the path traversed by the emitted and reflected light is adjustable.

It is common practice in the analysis of light absorbing fluids to immerse in the fluid one end of a probe having an opening therein through which the fluid may flow, transmit light from a source across the opening onto a reflector which reflects the light back across the opening, collect the reflected light, and conduct it to one or more devices for analysis.
There are many occasions in which it would be desirable to adjust the length of the path across the opening. For example, the translucency of one fluid may be sufficient to enable light to traverse a relatively short path, but insufficient to enable the light to traverse a longer path. By adjusting the length of the light path variations in translucency can be accommodated.
Heretofore, adjustment of the length of the light path has been accomplished by removing one mirror support and substituting therefor another mirror support which, when installed in the probe, provides a different path length to be traversed by the illuminating light and the reflected light. This kind of adjustment is troublesome and time consuming inasmuch as it necessitates physical replacement of one mirror support with another.
Light transmitted by conventional probes often is introduced into the fluid medium in such manner that the light is refracted in its passages through the fluid, thereby making it difficult, if not impossible, to analyze simultaneously light of different wave lengths.
Conventional probes of the general class to which the invention relates utilize reflectors exposed to the fluid with which they are used, thereby subjecting the reflective surfaces thereof to damage, either as a result of handling or from contact with the fluid in which the probe is immersed.
Apparatus constructed in accordance with the invention overcomes the objectionable characteristics referred to above of known probes for the in situ analysis of light absorbing fluids.

Variable path length light transmission probe


A loudspeaker assembly for a vehicle includes a loudspeaker having a first side and an opposed second side, wherein the loudspeaker is configured to generate an acoustical signal having a front wave directed into an interior of the vehicle and a rear wave directed toward an exterior of the vehicle. The loudspeaker assembly further includes a coupler disposed on the second side of the loudspeaker, the coupler including an inlet portion for receiving the loudspeaker and an outlet portion. A flexible port is removably connectable to the coupler, the flexible port including an inlet end arranged to be connected to the outlet portion of the coupler, an outlet end arranged to be connected to an opening in an exterior body panel, and an elongated body extending between the inlet end and the outlet end, the flexible port configured to transmit the rear wave to the exterior of the vehicle.

Automotive audio systems typically include several loudspeakers positioned in various locations within the interior of a vehicle, such as the passenger compartment or the trunk. Typical loudspeaker positions may include door panels or interior trim panels. Low-frequency loudspeakers, also known as woofers or subwoofers, are often located in the trunk, the rear panel shelf, under the rear seats, the chassis or in other frame elements of a vehicle.
In an externally coupled subwoofer (ECS), the loudspeaker housing may be omitted because the front and the back side of the loudspeaker are isolated from each other by a vehicle panel or frame element. In acoustical terms, an ECS configuration is referred to as an "infinite baffle", allowing optimized low frequency extension and maximized bandwidth, while simultaneously eliminating the requirement for a large sealed or vented-box subwoofer enclosure. This approach provides a very compact and weight efficient arrangement for audio inside the vehicle without sacrificing acoustical performance.
Typical ECS configurations include a metal or plastic frame which supports the loudspeaker, and a rear enclosure or acoustic coupler which connects to the frame and vents audio waves from the rear of the loudspeaker to the outside of the vehicle. Current implementations involve rigid plastic conduits for interfacing with an exterior vehicle body panel, where the rigid conduits are either molded as part of the acoustic coupler or assembled to the coupler by methods such as welding.

Externally coupled loudspeaker assembly with flexible port

Harman International Industries, Incorporated


A cellular X-ray grid comprises a main grid portion having a plurality of cells separated from one another by a plurality of partitions, the main portion has on a plan view a side which extends parallel to a direction of movement of the grid during exposure, the cells having sides arranged so that the sides of the cells are not parallel to the side of the main portion which is parallel to the direction of movement of the grid and extend relative to the side of the main portion at such an angle as to erase an image of the cells on an X-ray picture during exposing with the movement of the grid, the cells contain gas or vacuum.

The present invention relates to cellular X-ray grids which are used in medical X-ray technique.
More particularly, it relates to a cellular X-ray grid which can be utilized during investigations conducted with X-rays in medicine as well as in other areas.
X-ray grids are known in which a lattice is composed of light sensitive glass which has slots or cells isolated from one another by specially oriented partitions which abosrb the X-ray radiation covered through the whole depth with an X-ray transmitting substance. Such a cellular X-ray grid is disclosed for example in the Soviet Inventor's Certificate No. 441109. The known grids possess several disadvantages. In the case of the cellular structure of the grid, with the size of the cell extending parallel to the direction of its movement during the exposure during exposure the complete erasing of the structure of the cells on the X-ray picture is not provided. This can lead to reduction of the informative capacity of the X-ray gram. A completely throughgoing perforated structure of the monolithic grid which is not reinforced mechanically at its ends and over its upper and lower surfaces does not provide a sufficient strength of the grid during bending and impact. The partitions which are covered with the X-ray non-transmitting layer over their full depth and which however do not have this coating at the end, can transmit a certain part of dispersed radiation through the non-protected ends. This also can somewhat reduce the informative property of the X-ray image. When the structural material is in the spaces in the cells or slots, the material absorbs a part of the information within long wave part of the exposing radiation which passes through the grid, since a great percentage of the long wave radiation is absorbed. It also reduces the informative property of the grid about the pathologies which are faintly distinguishable as to their density and sizes. This is very important for early or preventive diagnosis.


There is disclosed a process for efficiently producing a carboxylic acid ester and formamide by reacting a carboxylic acid amide with a formic acid ester or with an alcohol and carbon monoxide in the presence of a strongly basic anion-exchange resin. By the use of the strongly basic anion-exchange resin as the catalyst, the process of the present invention enables the efficient production of the carboxylic acid ester as well as formamide from the Carboxylic acid amide and Formic acid ester, etc. with a high selectivity under mild reaction conditions and facilitates the separation of the catalyst from the reaction product, thereby greatly enhancing the industrial significance of itself.

1. Field of the Invention
The present invention relates to a process for production of a carboxylic acid ester and formamide. More particularly it pertains to a process for efficiently producing a carboxylic acid ester and formamide from a carboxylic acid amide and formic acid ester or from a carboxylic acid amide, an alcohol and carbon monoxide (hereinafter referred to as "Carboxylic acid amide and Formic acid ester, etc." including the above two combinations).
2. Description of Related Art
Carboxylic acid esters are industrially important compounds. As the processes for producing a carboxylic acid ester from a carboxylic acid amide, there are available, for example, the process for production of methyl acetate from acetic acid amide, that of methyl methacrylate from methacrylic acid amide, that of methyl acrylate from acrylic acid amide, that of methyl .alpha.-hydroxyisobutyrate from .alpha.-hydroxyisobutyric acid amide.
Formamide is used as a solvent, a treating agent, an electrolyte, an antifreezing agent, a starting material for producing hydrogen cyanide or as an intermediate for production of a medicine, a dye, a pigment or for organic synthesis.
As the process for producing a carboxylic acid ester from a carboxylic acid amide, there has heretofore been known a process wherein a carboxylic acid amide is reacted with an alcohol in the presence of sulfuric acid, which process has been widely put into practice for the industrial production of methyl methacrylate. However, the aforesaid process is confronted with such problems as the production of a large amount of acidic ammonium sulfate, a high cost required for the disposal thereof and the necessity of expensive corrosion-resisting equipment.
As the process without the use of sulfuric acid, there is proposed, for example, in Japanese Patent Application Laid-Open Nos. 14452/1978, 141216/1978, etc. a process wherein a carboxylic acid ester is produced by the catalytic reaction of a carboxylic acid amide with an alcohol. The aforementioned process, however, involves various problems in industrial application such as the low yield and low selectivity of the objective carboxylic acid ester, the formation of a large amount of ammonia necessitating the separation and recovery thereof and the formation of an ammonium salt by the reaction with a by-produced carboxylic acid.
As the process without the formation of ammonia, there is disclosed in Japanese Patent Application Laid-Open Nos. 55444/1983 and 78937/1985 a process wherein a carboxylic acid amide is reacted with a formic acid ester instead of alcohol to produce the objective carboxylic acid ester and formamide. In the above process, however, it is necessary to separate or deactivate the catalyst immediately after the reaction as the reaction proceeds as an equilibrium reaction. In addition, the above process suffers the disadvantages that the catalyst system is expensive and requires complicated steps for the regeneration and recycling of the catalyst, since the catalyst is composed of a metal salt of an organic or inorganic acid or a metal chelate compound in combination with an organic compound containing nitrogen or phosphorus or of an amidine or tertiary amine combined with a metal carbonyl.
There is also proposed in Japanese Patent Application Laid-Open Nos. 255640/1990, 268137/1990 and 48637/1991 a process wherein a carboxylic acid amide is reacted with a formic acid ester to produce the object carboxylic acid ester and formamide by the use of a catalyst composed of a dehydration condensation product of an alkali metal alcoholate, an alkaline earth metal oxide or a carboxylic acid amide with an alkali metal hydroxide or an alkaline earth metal hydroxide. The above-mentioned catalyst is relatively inexpensive and does not necessarily require recycling of itself, but still involves the problem that the salt formed in the deactivation step of the used catalyst complicates the separation of itself.
As described hereinbefore, in spite of the various processes for production of a carboxylic acid ester which have been disclosed so far, none of them meets the industrial requirement at the present time. Nevertheless, the process for producing a carboxylic acid ester and formamide from a Carboxylic acid amide and Formic acid ester, etc. is industrially advantageous in many respects, and gives rise to the need for the development of a catalyst applicable to the process with excellent characteristics in many industrial aspects.
Under such circumstances intensive research and investigation were concentrated by the present inventors on the solution of the above various problems in the production of a carboxylic acid ester and formamide from a Carboxylic acid amide and Formic acid ester, etc.
As the result, it has been discovered by the present inventors that the use of a strongly basic anion-exchange resin as the catalyst in the aforesaid process enables the proceeding of the reaction under mild conditions and the production of the objective carboxylic acid ester with formamide with a high yield and high selectivity and further, greatly facilitates the separation, recovery and recycling of the catalyst. The present invention has been accomplished on the basis of the above-mentioned finding and information.

Process for production of carboxylic acid ester and formamide


An intravascular catheter having controllable stiffness or flexibility, and adapted for use with various contrast media. The stiffness of the catheter may be increased during the use of the catheter by applying a fluid under pressure at the proximal end of the catheter to thereby fill a cavity within the body of the catheter to thereby cause the region of the catheter defined by the cavity to become less flexible. When the fluid pressure is decreased, this region of the catheter becomes more flexible. The fluids to be applied inside the cavities may be a variety of types of contrast media, used with imaging techniques such as either MRI or X-ray fluoroscopy.

The present invention relates to a catheter for use within the vasculature of the human body, and, more particularly, concerns a catheter in which the stiffness, or flexibility, may be controlled during the use thereof.
Medical devices such as intravascular catheters, and the like, are placed into various body orifices for many purposes, including the infusion of fluids, withdrawal of fluid samples from the body, and for the insertion of angiography balloons. Very often, such a device has to be placed in a remote part of the body, or perhaps threaded for a considerable distance through the vascular system. Most catheters of the type designed for placement into a deep body position are made of pliable, very flexible, plastic material. Such material facilitates any bending or curving that may be necessary during placement and also serves to eliminate or decrease the traumatic effect of the insertion of the medical device. However, the relatively low flexural modulus of most catheters which provides the pliable nature of the catheter often produces difficulties in controlling the catheter as it is passed through the vascular system.
One problem which arises using most of the very flexible catheters during insertion into the vessels is the tendency of the catheter to bend and flex during the insertion stage. This action produces awkward and erratic threading of the catheter by the operator. This problem can become acute when the catheter is long and is intended to be positioned deep within the vasculature of the patient.
Catheters have employed fluid pressurization to accomplish various functions. For example, U.S. Pat. No. 3,525,329 discloses an evertable, extensible probe which when pressurized extends the probe into the body cavity to be examined. U.S. Pat. No. 3,502,069 employs a rigid tubular casing and a flexible evertable tubing inside. When fluid pressure is applied to the casing the tubing is everted out of an open end of the casing. U.S. Pat. No. 3,168,092 describes a probing instrument with a tubing which becomes extraverted under pressure, whereby the tubing exerts pressure on the walls of the cavity to separate the walls thereof.
Accordingly, it is most desirable to employ a catheter, or like instrument, which has a certain level of stiffness in order to facilitate placement of the catheter with relative ease within the vascular system of a patient. However, as pointed out above, after placement of the catheter well into the vasculature, the initial level of stiffness is undesirable since more pliability and flexibility may be required. It can be seen, then, that it is desirable to be able to vary the degree of stiffness of the catheter so as to have a relatively high degree of stiffness during placement of the catheter into the patient and then a relatively low degree of stiffness for final positioning.
A catheter having a variable flexibility, or flexural modulus, for insertion into a body comprises a length of flexible tubing having a normally relatively low flexural modulus. A lumen inside the tubing provides a free flow path therethrough. A fluid control system is associated with the tubing for controllably increasing the flexural modulus of the tubing to stiffen the same during insertion of the tubing into the body. After being positioned in the body, the fluid control system is adjusted to allow the tubing to return to its normally relatively low flexural modulus.
In the preferred embodiment of this aspect of the invention, the means for increasing the flexural modulus of the tubing includes a lumen associated with the catheter tubing. This lumen is coupled to one or more fluid cavities within the catheter tubing and to a pressure source. An increase in pressure in the lumen serves to increase the flexural modulus of the catheter tubing at one or more regions defined by the cavities with the pressure being controllable so that the flexural modulus of the catheter is also controllable. This lumen may be a second tube located within the catheter tubing.
In accordance with the principles of the present invention, the catheter advantageously offers the desirable stiffness characteristic during the placement or insertion stage into the body, while also providing the ability to reduce the stiffness after final positioning so that the catheter may be pliant and flexible for final positioning. Accordingly, the catheter, or like instrument, of the present invention allows the operator to manipulate the catheter into the patient with relative ease and substantially eliminates, or reduces, the awkwardness which accompanies the insertion of catheters which do not have the variable stiffness feature.
There is provided a catheter according to the invention for use within the vasculature of the human body comprising a flexible outer cylindrical tubing having an inner lumen and proximal and distal ends, a first cylindrical sealing plug positioned within the lumen of the cylindrical tubing at the distal end of the tubing, a second cylindrical sealing plug positioned within the lumen of the cylindrical tubing and spaced apart at a predetermined distance proximally from the first sealing plug so as to define a cavity between the first and second sealing plugs, a fluid passageway extending through the second sealing plug, and connector means connected to the proximal end of the catheter and having a lumen which is in fluid communication with the passageway of the second sealing plug so that fluid under pressure may be applied to the connector means to fill the cavity between the first and second sealing plugs to thereby stiffen the catheter in a region between the first and second sealing plugs.
Also, the catheter preferably includes a cylindrical spacer disposed between the first and second sealing plugs to maintain the predetermined distance between the sealing plugs.
Still further, the cylindrical spacer has a central axis which is coaxial with the central axis of the first and second sealing plugs and the outside diameter of the cylindrical spacer is less than the diameter of the inner lumen of the cylindrical tubing of the catheter.
In addition, preferably the passageway which extends through the second sealing plug is defined by the wall of a longitudinal slot which extends through the second sealing tube and an adjacent portion of the wall of the inner lumen of the cylindrical tubing of the catheter.
Still further, the catheter includes a guidewire lumen which extends through and is coaxial to the central axis of the first cylindrical sealing plug, the cylindrical spacer and the second cylindrical sealing plug to thereby provide a guidewire lumen which is coaxial with the flexible outer tubing of the catheter.
In addition, the catheter includes a flexible guidewire slidably received by the guidewire lumen.
Further, the catheter includes a third cylindrical sealing plug positioned within the lumen of the cylindrical tubing and spaced apart at a predetermined distance from the second cylindrical sealing plug so as to define a second cavity between the second and third sealing plugs, and a fluid passageway extending through the third sealing plug and being in communication with the lumen of the connector means so that fluid pressure may be applied to the connector means to fill the cavities between the first and second sealing plugs and between the second and third sealing plugs to thereby stiffen the regions between the respective sealing plugs.
There is provided a catheter according to the invention is such that the cavity is ring-shaped. In this case the cavity has been arranged so as to surround the guidewire lumen.
There is also provided a catheter according to this invention in which the guidewire lumen may be used for other purposes, such as conveying a fluid through the catheter or for receiving a glass fibre cable.
Still further there is provided a catheter according to this invention which the passageway may be used to fill the cavity with a fluid such as a contrast medium, air or another liquid which may later be removed from the cavity.
The fluids to be applied inside the cavities may for instance be a contrast medium, used with imaging techniques such as MRI or when using X-radiation, air or a resin curing under the influence of visible or UV-light.

Catheter having a controllable stiffness and adapted for use with various contrast media


The invention relates to a method and system for authenticating a user of a data transfer device (such as a terminal in a wireless local area network, i.e. WLAN). The method comprises: setting up a data transfer connection from the data transfer device to a service access point. Next, identification data of the mobile subscriber (for example an MSISDN) are inputted to the service access point. This is followed by checking from the mobile communications system whether the mobile subscriber identification data contains an access right to the service access point. If a valid access right exists, a password is generated, then transmitted to a subscriber terminal (for example a GSM mobile phone) corresponding to the mobile subscriber identification data, and login from the data transfer device to the service access point takes place with the password transmitted to the subscriber terminal.

Prior art knows different methods for authenticating users of data transfer devices. One authentication method is based on the use of a SIM card (Subscriber Identity Module) placed in the data transfer device, the method requiring, however, a smart card reader in the data transfer device. Moreover, the solution is not easy to apply in situations where a data transfer service is to be used temporarily, maybe only once, on the data transfer service, because for that purpose a SIM card would have to be delivered to the data transfer device of the user.
U.S. Pat. No. 6,112,078, which is incorporated herein as a reference, discloses a solution which does not include a SIM card and in which at least some of the authentication data are transmitted to a mobile station or a paging device which the user of the data transfer device has at his/her disposal. For reasons of data security, all the authentication data, for example the user ID and the password, are not sent over the same the transmission path.

Method and system for authenticating user of data transfer device


The present invention provides a chimeric adenovirus coat protein, which differs from the wild-type coat protein by the introduction of a nonnative amino acid sequence. Such a chimeric adenovirus coat protein according to the invention is able to direct entry into cells of a vector comprising the coat protein that is more efficient than entry into cells of a vector that is identical except for comprising a wild-type adenovirus coat protein rather than the chimeric adenovirus coat protein. The chimeric coat protein preferably is a fiber, hexon, or penton protein. The present invention also provides an adenoviral vector that comprises the chimeric adenovirus coat protein, as well as methods of constructing and using such a vector.

Adenoviruses belong to the family Adenoviridae, which is divided into two genera, namely Mastadenovirus and Aviadenovirus. Adenoviruses are nonenveloped, regular icosahedrons of about 65 to 80 nanometers in diameter (Horne et al., J. Mol. Biol., 1, 84-86 (1959)). The adenoviral capsid is composed of 252 capsomeres of which 240 are hexons and 12 are pentons (Ginsberg et al., Virology, 28, 782-783 (1966)). The hexons and pentons are derived from three different viral polypeptides (Maizel et al., Virology, 36, 115-125 (1968); Weber et al., Virology, 76, 709-724 (1977)). The hexon comprises three identical polypeptides of 967 amino acids each, namely polypeptide II (Roberts et al., Science, 232, 1148-1151 (1986)). The penton contains a penton base, which is bound to the capsid, and a fiber, which is noncovalently bound to and projects from the penton base. The fiber protein comprises three identical polypeptides of 582 amino acids each, namely polypeptide IV. The adenovirus serotype 2 (Ad2) penton base protein is a ring-shaped complex composed of five identical protein subunits of 571 amino acids each, namely polypeptide III (Boudin et al., Virology, 92, 125-138 (1979)). Proteins IX, VI, and IIIa are also present in the adenoviral coat and are thought to stabilize the viral capsid (Stewart et al., Cell, 67, 145-154 (1991); Stewart et al., EMBO J., 12(7), 2589-2599 (1993)).
Once an adenovirus attaches to a cell, it undergoes receptor-mediated internalization into clathrin-coated endocytic vesicles of the cell (Svensson et al., J. Virol., 51, 687-694 (1984); Chardonnet et al., Virology, 40, 462-477 (1970)). Virions entering the cell undergo a stepwise disassembly in which many of the viral structural proteins are shed (Greber et al., Cell, 75, 477-486 (1993)). During the uncoating process, the viral particles cause disruption of the cell endosome by a pH-dependent mechanism (Fitzgerald et al., Cell, 32, 607-617 (1983)), which is still poorly understood. The viral particles are then transported to the nuclear pore complex of the cell (Dales et al., Virology, 56, 465-483 (1973)), where the viral genome enters the nucleus, thus initiating infection.
An adenovirus uses two separate cellular receptors, both of which must be present, to efficiently attach to and infect a cell (Wickham et al., Cell, 73, 309-319 (1993)). First, the Ad2 fiber protein attaches the virus to a cell by binding to an as yet unidentified receptor. Then, the penton base binds to .alpha..sub.v integrins, which are a family of a heterodimeric cell-surface receptors that mediate cellular adhesion to the extracellular matrix molecules, as well as other molecules (Hynes, Cell, 69, 11-25 (1992)).
The fiber protein is a trimer (Devaux et al., J. Molec. Biol., 215, 567-588 (1990)) consisting of a tail, a shaft, and a knob. The fiber shaft region is composed of repeating 15 amino acid motifs, which are believed to form two alternating .beta.-strands and .beta.-bends (Green et al., EMBO J., 2, 1357-1365 (1983)). The overall length of the fiber shaft region and the number of 15 amino-acid repeats differ between adenoviral serotypes. For example, the Ad2 fiber shaft is 37 nanometers long and contains 22 repeats, whereas the Ad3 fiber is 11 nanometers long and contains 6 repeats. The receptor binding domain of the fiber protein is localized in the knob region encoded by the last 200 amino acids of the protein (Henry et al., J. Virol., 68(8), 5239-5246 (1994)). The regions necessary for trimerization are also located in the knob region of the protein (Henry et al. (1994), supra). A deletion mutant lacking the last 40 amino acids does not trimerize and also does not bind to penton base (Novelli et al., Virology, 185, 365-376 (1991)). Thus, trimerization of the fiber protein is necessary for penton base binding. Nuclear localization signals that direct the protein to the nucleus to form viral particles following its synthesis in the cytoplasm are located in the N-terminal region of the protein (Novelli et al. (1991), supra). The fiber, together with the hexon, are the main antigenic determinants of the virus and also determine the serotype specificity of the virus (Watson et al., J. Gen. Virol., 69, 525-535 (1988)).
Recombinant adenoviral vectors have been used for the cell-targeted transfer of one or more recombinant genes to diseased cells or tissue in need of treatment. Such vectors are characterized by the advantage of not requiring host cell proliferation for expression of adenoviral proteins (Horwitz et al., In Virology, Raven Press, New York, vol. 2, pp. 1679-1721 (1990); and Berkner, BioTechniques, 6, 616 (1988)). Moreover, if the targeted tissue for somatic gene therapy is the lung, these vectors have the added advantage of being normally trophic for the respiratory epithelium (Straus, In Adenoviruses, Plenan Press, New York, pp. 451-496 (1984)).
Other advantages of adenoviruses as potential vectors for human gene therapy are: (i) recombination is rarely observed with use of such vectors; (ii) there are no known associations of human malignancies with adenoviral infections despite common human infection with adenoviruses; (iii) the adenoviral genome (which is a linear, double-stranded DNA) can be manipulated to accommodate foreign genes that range in size; (iv) an adenoviral vector does not insert its DNA into the chromosome of a cell, so its effect is impermanent and unlikely to interfere with the cell's normal function; (v) the adenovirus can infect non-dividing or terminally differentiated cells, such as cells in the brain and lungs; and (vi) live adenovirus, having as an essential characteristic the ability to replicate, has been safely used as a human vaccine (Horwitz et al. (1990), supra; Berkner et al. (1988), supra; Straus et al. (1984), supra; Chanock et al., JAMA, 195, 151 (1966); Haj-Ahmad et al., J. Virol., 57, 267 (1986); and Ballay et al., EMBO, 4, 3861 (1985); PCT patent application WO 94/17832).
A drawback to adenovirus-mediated gene therapy is that significant decreases in gene expression are observed after two weeks following administration of the vector. In many therapeutic applications, the loss of expression requires re-administration of the viral vector. However, following re-administration, neutralizing antibodies are raised against both the fiber and hexon proteins of the viral vector (Wohlfart, J. Virology, 62, 2321-2328 (1988); Wohlfart et al., J. Virology, 56, 896-903 (1985)). This antibody response against the virus can prevent effective re-administration of the viral vector.
Another drawback of using recombinant adenovirus in gene therapy is that certain cells are not readily amenable to adenovirus-mediated gene delivery. For instance, lymphocytes, which lack the .alpha..sub.V integrin adenoviral receptors, are impaired in the uptake of adenoviruses (Silver et al., Virology 165, 377-387 (1988); Horvath et al., J. Virol., 62(1), 341-345 (1988)). This lack of ability to infect all cells has lead researchers to seek out ways to introduce adenovirus into cells that cannot be infected by adenovirus, e.g. due to lack of adenoviral receptors. In particular, the virus can be coupled to a DNA-polylysine complex containing a ligand (e.g., transferring for mammalian cells (e.g., Wagner et al., Proc. Natl. Acad. Sci., 89, 6099-6103 (1992); PCT patent application WO 95/26412). Similarly, adenoviral fiber protein can be sterically blocked with antibodies, and tissue-specific antibodies can be chemically linked to the viral particle (Cotten et al., Proc. Natl. Acad. Sci. USA, 89, 6094-6098 (1992)).
However, these approaches are disadvantageous in that they require additional steps that covalently link large molecules, such as polylysine, receptor ligands, and antibodies, to the virus (Cotten (1992), supra; Wagner et al., Proc. Natl. Acad. Sci., 89, 6099-6103 (1992)). This adds to the size of the resultant vector as well as its cost of production. Moreover, the targeted particle complexes are not homogeneous in structure, and their efficiency is sensitive to the relative ratios of viral particles, linking molecules, and targeting molecules used. Thus, this approach for expanding the repertoire of cells amenable to adenoviral-mediated gene therapy is less than optimal.
Recently, the efficiency of adenovirus-mediated gene transfer in vivo to even those cells which adenovirus has been reputed to enter with high efficiency has been called into question (Grubb et al., Nature, 371, 802-806 (1994); Dupuit et al., Human Gene Therapy, 6, 1185-1193 (1995)). The fiber receptor by means of which adenovirus initially contacts cells has not been identified, and its representation in different tissues has not been examined. It is generally assumed that epithelial cells in the lung and gut produce sufficient levels of the fiber receptor to allow their optimal transduction. However, no studies have confirmed this point to date. In fact, studies have suggested that adenovirus gene delivery to differentiated lung epithelium is less efficient than delivery to proliferating or to undifferentiated cells (Grubb et al., supra; Dupuit et al., supra).
Similarly, adenovirus has been shown to transduce a large number of tissues including lung epithelial cells (Rosenfeld et al., Cell, 68, 143-155 (1992)), muscle cells (Quantin et al., Proc. Natl. Acad. Sci., 89, 2581-2584 (1992)), endothelial cells (Lemarchand et al, Proc. Natl. Acad. Sci., 89, 6482-6486 (1992), fibroblasts (Anton et al., J. Virol., 69, 4600-4606 (1995), and neuronal cells (LaSalle et al., Science, 259, 988-990 (1993)). However, in many of these studies, very high levels of virus particles have been used to achieve transduction, often exceeding 100 plaque forming units (pfu)/cell, and corresponding to a multiplicity of infection (MOI) of 100. The requirement for a high MOI to achieve transduction is disadvantageous inasmuch as any immune response associated with adenoviral infection necessarily would be exacerbated with use of high doses.
Accordingly, there remains a need for vectors, such as adenoviral vectors, that are capable of infecting cells with a high efficiency, especially at lower MOIs, and that demonstrate an increased host cell range of infectivity. The present invention seeks to overcome at least some of the aforesaid problems of recombinant adenoviral gene therapy. In particular, it is an object of the present invention to provide a vector (such as an adenoviral vector) having a broad host range, and an ability to enter cells with a high efficiency, even at a reduced MOI, thereby reducing the amount of recombinant adenoviral vector administered and any side-effects/complications resulting from such administration. A further object of the present invention is to provide a method of gene therapy involving the use of a homogeneous adenovirus, wherein the viral particle is modified at the level of the adenoviral genome, without the need for additional chemical modifications of viral particles. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the following detailed description.

Vectors and methods for gene transfer to cells


A silicon film is formed on a first region and a second region, respectively of a semiconductor substrate; P-type impurities are selectively ion-implanted into the silicon film in the first region; a first annealing is carried out, thereby the P-type impurities implanted in the silicon film are activated; N-type impurities are selectively ion-implanted into the silicon film in the second region, after the first annealing; a silicide film is formed on the silicon film according to a CVD method, after the ion-implantation of the N-type impurities; a second annealing is carried out, thereby gas contained in the silicide film is discharged and the N-type impurities are activated; a barrier metal film and a metal film are formed in this order on the silicide film; and the metal film, the barrier metal film, the silicide film and the silicon film are patterned, thereby a P-type polymetal gate electrode formed in the first region and an N-type polymetal gate electrode formed in the second region.

In recent years, there is a high demand for a high speed and low power consumption of a semiconductor device, particularly for a dynamic random access memory (DRAM). In order to meet this demand, a polymetal gate structure and a dual-gate structure are employed.
The polymetal gate structure has metal films laminated on a polycrystalline silicon film. The polymetal gate structure can have lower resistance than that of a polycide gate structure that has been conventionally used. In general, the polymetal gate structure has a barrier metal (such as a tungsten nitride (WN) film), and a metal film (such as a tungsten (W) film), laminated together on the polycrystalline silicon film. However, this polymetal gate structure has a problem in that interface resistance, that is, contact resistance between the barrier metal film and the polycrystalline silicon film, becomes nonlinearly high. Therefore, the polymetal gate structure having the silicide film present between the polycrystalline silicon film and the barrier metal film has come to be employed.
On the other hand, according to the dual-gate structure, a gate electrode that contains N-type polycrystalline silicon having N-type impurities (such as phosphorus) implanted in the polycrystalline silicon, is used for the gate electrode of an NMOS transistor, and a gate electrode that contains P-type polycrystalline silicon having P-type impurities (such as boron) implanted in the polycrystalline silicon, is used for the gate electrode of a PMOS transistor. Because the PMOS transistor has a surface-channel type in the dual-gate structure, a short-channel effect can be suppressed when the gate length is short. This is advantageous in increasing the performance of the transistor. Furthermore, because a threshold level can be decreased from that of the conventional embedded channel-type MOS transistor, the driving voltage can be lowered.
A conventional method of manufacturing the gate electrodes having the polymetal gate structure and the dual-gate structure will be explained with reference to FIGS. 12 to 20. In FIGS. 12 to 20, a "region N" represents a region where the gate electrode containing N-type polycrystalline silicon is formed, and a "region P" represents a region where the gate electrode containing P-type polycrystalline silicon is formed.
First, as shown in FIG. 12, a silicon oxide film 202a is formed on the surface of a silicon substrate 201 by thermal oxidation. Next, as shown in FIG. 13, the silicon oxide film 202a is nitrided by plasma nitrization, thereby forming a gate oxynitride film 202.
Next, as shown in FIG. 14, an amorphous silicon film 203a is formed on the gate oxynitride film 202.
Next, as shown in FIG. 15, the region P is covered with a resist film 204, and phosphorus is ion-implanted as N-type impurities into the region N. Thereafter, the resist film 204 is removed.
Next, as shown in FIG. 16, the region N is then covered with a resist film 205, and boron is ion-implanted as P-type impurities into the region P.
As shown in FIG. 17, after the resist film 205 is removed, a tungsten silicide (WSi) film 206 is formed on the whole surface of the amorphous silicon film 203a, according to a CVD method using a mixed gas of WF6 and SiH2Cl2. The WSi film 206 can be also formed by a physical vapor deposition (PVD) method such as sputtering. However, when the PVD method is used, oxygen is mixed into the film, and the oxygen increases sheet resistance of the WSi film. The CVD method is therefore used.
As shown in FIG. 18, a rapid thermal annealing (RTA) is carried out in the atmosphere of 700 to 950° C. for 10 to 60 seconds, as what is called degasification, to discharge gases of chlorine, fluorine and so on that remain in the WSi film 206 formed in the CVD method, to the outside. By this RTA, the N-type impurities and the P-type impurities that are implanted into the amorphous silicon 203a are simultaneously activated, and the amorphous silicon film 203a is converted into a polycrystalline silicon film. Consequently, an N-type polycrystalline silicon film 203n and a P-type polycrystalline silicon film 203p are formed on the gate oxynitride film 202, respectively.
Next, as shown in FIG. 19, a tungsten nitride (WN) film 207 and a tungsten (W) film 208 are sequentially formed on the WSi film 206 by sputtering. Furthermore, a silicon nitride film 209 of a gate electrode pattern is formed on the tungsten (W) film 208. Thereafter, as shown in FIG. 20, the W film 208, the WN film 207, tungsten silicide (WSi) film 206 and the polycrystalline silicon films 203n and 203p are patterned, using the silicon nitride film 209 as a mask, thereby completing an N-type polymetal gate electrode 210n and a P-type polymetal gate electrode 210p.
Methods of manufacturing the semiconductor device having the gate electrodes of the polymetal gate structure and the dual-gate structure are described in, for example, Japanese Patent Application Laid-open Nos. 2000-77540, H8-306802, H9-51040, H9-190983, and H9-246206.
FIG. 21 is a graph showing a relationship between the RTA temperature when degassing the WSi film 206, the interface resistance of the N-type polymetal gate electrode 210n (the contact resistance between the N-type polycrystalline silicon 203n and the WSi film 206), and the interface resistance of the P-type polymetal gate electrode 210p (the contact resistance between the P-type polycrystalline silicon 203p and the WSi film 206). "N-gate" represents the interface resistance of the N-type polymetal gate electrode 210n, and "P-gate" represents the interface resistance of the P-type polymetal gate electrode 210p. A value 1.0 in the vertical axis represents a standard value of the interface resistance.
As shown in FIG. 21, according to the above conventional manufacturing method, there is no temperature range of RTA in which both the interface resistance of the N-type polymetal gate electrode 210n and the interface resistance of the P-type polymetal gate electrode 210p satisfy the standard value of the interface resistance. In the temperature range where the interface resistance of the N-type polymetal gate electrode 210n satisfies the standard value, the interface resistance of the P-type polymetal gate electrode 210p becomes very high as compared with the interface resistance of the N-type polymetal gate electrode 210n.
As explained above, when there is a large difference between the interface resistance of the N-type polymetal gate electrode and the interface resistance of the P-type polymetal gate electrode, the following problems arise.
FIGS. 22A and 22B show a ring oscillator circuit. FIG. 22A shows a circuit symbol, and FIG. 22B shows a circuit diagram. As shown in FIG. 22A, an output OUT of an inverter 300 returns to an input IN. As shown in FIG. 22B, the inverter 300 includes a PMOS transistor 301 and an NMOS transistor 302. These gate electrodes employ a polymetal gate structure and a dual-gate structure.
In the ring oscillator circuit as shown in FIGS. 22A and 22B, when the interface resistance of the polymetal gate electrode of the PMOS transistor 301 is much higher than the interface resistance of the polymetal gate electrode of the NMOS transistor 302 (corresponding to a region A shown in FIG. 21), as shown in FIG. 23A, the waveform of the rise of the output signal OUT is slowed down to a large extent as compared with the waveform of the input signal IN. On the other hand, when the interface resistance of the polymetal gate electrode of the NMOS transistor 302 is much higher than the interface resistance of the polymetal gate electrode of the PMOS transistor 301 (corresponding to a region B shown in FIG. 21), as shown in FIG. 23B, the waveform of the fall of the output signal OUT is slowed down to a large extent as compared with the waveform of the input signal IN.

Method of manufacturing semiconductor device having gate electrodes of polymetal gate and dual-gate structure


A method for improving the crosstalk and time-of-flight performance for signals in an integrated circuit with respect to the package-related wiring. I/O pads in the package-related wiring of a logic design meeting specified crosstalk and time-of-flight constraints are identified using a software tool. The tool produces a graphical display in which the identified I/O pads are highlighted. The tool enables a user to graphically manipulate the display to assign, i.e., establish an electrical connection, between I/O circuits corresponding to the signals and the highlighted I/O pads.

The present invention relates to a method for improving integrated circuit (IC) performance in view of crosstalk and time-of-flight characteristics associated with package-related wiring for the IC.
Advances in IC design and manufacturing technologies have resulted in progressively smaller IC feature sizes, having commensurately lower operating voltages and packed more densely. Also, performance of ICs at increasingly higher frequencies is demanded. As such trends continue, the importance of handling performance-degrading factors such as crosstalk (coupling noise), and of reducing signal propagation times, also referred to as time-of-flight (TOF), becomes greater.
Higher device density on an IC chip, or die, requires correspondingly denser package-related wiring for carrying signals on and off the die, while the higher clock rates associated with higher frequencies require faster signal transition and reduced TOF for signals on and off the die. Thus. the crosstalk and TOF behavior of the package-related wiring for a die affect overall crosstalk and TOF performance.
Package-related wiring on an IC die can be implemented in a number of different forms, but typically includes at least I/O circuits coupled to xe2x80x9cnetsxe2x80x9d or signals that are input or output to a logic design on the die. The I/O circuits receive input signals and drive output signals off the die, via connections to off-die package pads in a package containing the die. The package pads are in turn typically connected, via a card pad in a card including multiple die packages, to other package pads connected via I/O circuits to other logic designs.
As signals that may be input/output to a logic design approach the several hundreds or more and die interface speeds scale upward, the crosstalk and TOF characteristics of the package-related wiring become factors that significantly impact performance. Accordingly, a method for improving chip performance with respect to the crosstalk and TOF characteristics of the package-related wiring is needed.
A method according to the present invention provides for establishing an assignment of signals to package-related wiring such that the assignment meets desired crosstalk and TOF constraints.
In an embodiment, I/O circuits corresponding to signals that are input/output to a die in a package are selected for assignment to package wiring meeting defined crosstalk and TOF criteria.
In the foregoing embodiment, a software tool according to the invention uses a database including crosstalk and TOF characteristics for the package wiring to identify package wiring meeting crosstalk and TOF constraints specified by a user. The software tool produces a graphic display highlighting components of the package wiring in terms of their crosstalk and TOF characteristics, and allows a user to graphically assign the selected I/O circuits to wiring meeting the required constraints. The assignment of the I/O circuits constitutes part of a definition of a floorplan for the die which will result, when the die is physically fabricated, in package-related wiring corresponding to the assignment of I/O circuits and consequently having the desired crosstalk and TOF characteristics.

Method of assigning integrated circuit I/O signals in an integrated circuit package

International Business Machines Corporation


The present invention provides a process for the preparation of a bicyclic aminoalcohol which comprises reacting a starting compound, nopinone (I), with XCH2COOR1 wherein X is halogen, and R1 is alkyl, in the presence of an additive and a base to produce a compound (II), converting it to oxime derivative (III), and reducing it with an aluminum hydride

The following scheme is disclosed in Chem. Pharm. Bull., 37(6), 1524–1533 (1989) as processes for the preparation of a bicyclic aminoalcohol (IV).

A starting material, myrtenol, is reacted with ethyl orthoformate to give an exomethylene derivative. The exomethylene derivative is oxidized by ozone to give a ketone derivative, compound (II-1), which is further reacted with O-methylhydroxyamine to give an O-methyloxime derivative, compound (III-1). The obtained O-methyloxime derivative is reduced in n-propanol with metallic sodium to give a bicyclic aminoalcohol, compound (IV).
It is disclosed in the above document that alkylation of nopinone, compound (I), gives a mixture of the starting material, a di-substituted product and a mono-substituted product as shown below. Moreover, the mono-substituted product is disclosed as a mixture of two stereo isomers.

Processes for the preparation of bicyclic aminoalcohols


There is provided a semiconductor testing apparatus comprising a current measuring portion which converts a load current quantity at the time of application of a relatively high test voltage to a DUT to fall within a low-voltage range, and then subjects the low-voltage range to quantization conversion with a predetermined measurement resolution even when the relatively high test voltage is applied to the DUT. This is a differential voltage measuring apparatus comprising: an applied voltage source which applies a predetermined constant voltage to a load device; current/voltage converting means for directly inserting a predetermined resistance between an output end of the applied voltage source and the load device, and converts a quantity of a current flowing through the load device into a voltage; and current measuring means which switches and receives a common mode voltage and a detection voltage in time series, shifts the received voltages to predetermined low voltages, and outputs low-voltage measurement data obtained by receiving each of the shifted voltages and subjecting this voltage to quantization conversion.

In case of highly accurately measuring a direct-current voltage or a direct current of a device under test (DUT) by a semiconductor testing apparatus, each accurate component is required in an operational amplifier, a peripheral resistance, an AD converter and others.
When mounting these circuits on a silicon substrate, there is a problem that a manufacturing process of the silicon substrate becomes complicated, laser trimming is required or a chip size is increased in order to realize highly accurate measurement.
FIG. 1 is a circuit configuration view of a primary part of one channel, showing a voltage source and current measurement (VSIM) which applies a desired voltage to a DUT and measures a current flowing at this moment. This measures a quantity of a current which breaks in an IC pin of the DUT through pin electronics of a test head and flows through the IC pin.
As well known, in a VSIM for a high voltage, a voltage up to, e.g., approximately ±40 V is applied to a DUT, and a current measurement range is switched in order to measure a current quantity in a wide dynamic range of pico-ampere/micro-ampere/mill-ampere. In a VSIM for a low voltage, a voltage up to, e.g., approximately ±10 V is applied to a DUT, and a current measurement range is switched in order to measure a current quantity of micro-ampere/milli-ampere. It is to be noted that a semiconductor testing apparatus include a predetermined number of these VSIMs. Here, since the semiconductor testing apparatus and the voltage source and current measurement (VSIM) are publicly and technically known, any other signals or constituent elements and their detailed explanation will be eliminated except the primary part according to the present invention.
As shown in FIG. 1(a), as simple primary constituent elements of a VSIM, there are included a DA converter 10, an operational amplifier A1, a current detection resisting means RM and a current measuring portion 100.
The DA converter 10 generates a positive/negative set voltage 10s which should be applied to an IC pin of a DUT. For example, it generates an arbitrary voltage which is not less than ±40 V.
The operational amplifier A1 is an operational amplifier for error reduction and power increase which receives the set voltage 10s and supplies it as a test voltage VS to the IC pin of the DUT through the current detection resisting means RM.
The current detection resisting means RM is inserted in series into a line connected with the IC pin of the DUT, and a resistance value with which a quantity of a current flowing through this line is converted into a potential difference Vx of approximately several-hundred milli-volt is used. A common mode voltage Va and a detection voltage Vb which are generated at each of both ends of the current detection resisting means RM are supplied to the current measuring portion 100. In this example, as to the current detection resisting means RM, there are a case in which the current detection resisting means RM is constituted by using a single resistance alone and a case in which a current measurement range function formed of a plurality of resistances and a switching relay is included as shown in FIG. 1(c) because of a measurement range or any other reason.
The current measuring portion 100 receives the common mode voltage. Va and the detection voltage Vb at the both ends of the current detection resisting means RM, performs quantization conversion, obtains a result as measurement data of a potential difference Vx between these voltages, and specifies a quantity of the current flowing through the IC pin of the DUT based on this data.
FIG. 1(b) is a first internal fundamental circuit diagram of the current measuring portion. This is an example in which operational amplifiers A2 and A3, resistances R1, R2, R3 and R4, a changeover switch SW1 and an AD converter 20 are provided as constituent elements.
A structure of the operational amplifier A3 and the resistances R1, R2, R3 and R4 is a general differential amplification structure which receives two signals, converts them into a differential signal Vc corresponding to a potential difference Vx between these signals, and outputs the obtained signal. The operational amplifier A2 is just a voltage buffer. In this example, when performing accurate measurement, a voltage division ratio of the resistances R1 and R2 and a voltage division ratio of the resistances R3 and R4 must precisely match with each other.
The changeover switch SW1 is a switching relay which is used when a connection is switched to a circuit earth side and 0 V as a reference is measured in order to specify an offset voltage or the like of the operational amplifiers A2 and A3.
The AD converter 20 receives a differential signal Vc from the operational amplifier A3, and outputs measurement data obtained by quantization conversion of the received signal.
Error factors involved by the common mode voltage and the voltage division resistances will now be evaluated by using numerical expressions. Here, α is an error rate with respect to a target resistance value, and n is a gain (an amplification degree).
Error factors of the respective resistances can be regarded as R1=R(1+α), R2=n*R(1−α), R3=R(1−α), and R4=n*R(1+α).
An offset=Ao is assumed as an error factor of the operational amplifier A2, and an offset=Bo is assumed as an error factor of the operational amplifier A3.
The differential signal Vc to be outputted can be represented by an expression Vc=Va*(R4/(R3+R4))*((R1+R2)/R1)−Vb*(R2/R1)−Ao*(R2/R1)+Bo*((R1+R2)/R1).
In this example, when Vb=Va+Vx is substituted, there can be obtained an expression Vc=Va*[(R4/(R3+R4))*((R1+R2)/R1)−(R2/R1)]−Vx*(R2/R1)−Ao*(R2/R1)+Bo*(R2/R1+1).
A common mode voltage error n1 can be represented by an expression n1=[(R4/(R3+R4))*(R1+R2)/R1]−(R2/R1)].
A gain error n2 can be represented by an expression n2=(R2/R1).
An offset error n3 can be represented by an expression n3=Ao*(R2/R1)+Bo*((R1+R2)/R1).
When the common voltage error n1 is calculated based on the above-described expressions, there can be obtained an expression n1={n(1+α)/[(1−α)+n((1+α))]*{[(1+α)+n((1−α))/(1+α)]−[n(1−α)/(1+α].
Here, when 1−α=A and 1+α=B are substituted, there can be obtained an expression n1=(B+nA)/(A+nB)−A/B=(A*A−B*B)/(AB−nB*B)=[1−2α+α*α−(1+2α+α*α)]/[1−α*α+n(1+2α+α*α)].
Here, since α<<1 is achieved and α*α and 2αn are sufficiently smaller than 1 so that they can be approximated by 0,
there can be generated a common mode voltage error represented as n1′=−4α/(1+n+2αn)≈4α/(1+n). For example, when numerical values of a common mode voltage Va=10 V, a resistance error α=0.1% and a gain n=1 are substituted, the common mode voltage error takes a value of 10 V*(4*0.1%)/2=20 mV. There is a problem that this error value results in a serious measurement error factor.
On the other hand, the resistance has peculiar non-linear characteristics of a resistance element called a voltage coefficient. In the peculiar non-linear characteristics, a resistance value varies depending on a voltage which is applied to the resistance as shown in an explanatory view of FIG. 10 in which a non-linear deviation is generated with respect to an ideal resistance due to an applied voltage.
For example, although a highly accurate resistance using a nickel-chrome-based thin film or the like has a small voltage coefficient, a polysilicon-based resistance formed in an monolithic IC may have a voltage coefficient which varies 0.1 to 0.5% with 1 V in some cases.
Therefore, since the resistances R1 to R4 for voltage division complicatedly vary due to the common mode voltage Va as well as the potential difference Vx of Va−Vb in the above-described circuit, there is a problem that resistances with good characteristics which are formed of nickel chrome or the like are required. On the contrary, when a voltage to be applied to the resistances is in proportion to the differential signal Vc as a measurement value, the peculiar non-linear characteristics of the resistance elements can be corrected by calibration or the like.
FIG. 2(b) is a second internal fundamental circuit diagram of the current measuring portion 102, which is a primary fundamental structure of the current measuring portion which measures a current of the IC pin of the DUT in each of a plurality of channels disclosed in Japanese Patent Application Laid-open No. 174113-1999 (a voltage source and current measuring circuit of an IC tester). Here, FIG. 2(a) shows a primary fundamental structural example when a current flowing through the IC pin of one channel is measured. This is a technique which directly AD-converts each of the common mode voltage Va and the detection voltage Vb at both ends, stores them in a data memory, and then calculates a potential difference Vx by software processing. According to this technique, since the resistances R1 to R4 for voltage division are not used, the problem of the common mode voltage error is solved.
However, there is adversely a problem that an AD converter having a high-input voltage range and a high resolution is required for-the AD converter 45. For example, in cases where measurement is carried out with a resolution of ±0.1% (±1000) when the potential difference Vx is 1 Vmax, a 11-bit resolution (±1000) can suffice if a test voltage VS is 1 V. However, there is a problem that an AD converter having a high-input voltage range with a 15-bit resolution (±10000) is required if the test voltage VS is 10 V and an AD converter having a high-input voltage range with an 18-bit resolution (±100000) is required if the test voltage VS is 100 V. There is a drawback that an AD converter which can cope with a high-input voltage range and a high resolution is expensive.
As described above, in the current measuring portion according to the prior art, as shown in FIG. 2, the common mode voltage Va and the detection voltage Vb at the both ends of the current detection resisting means RM are directly subjected to quantization conversion by the AD converter, and hence there is a problem that an AD converter having a high-input voltage range and a high resolution is required. An AD converter which can cope with a high-input voltage range is expensive. The semiconductor testing apparatus must include such AD converters for several-ten channels, which results in a problem that the testing apparatus becomes expensive.
It is, therefore, an object of the present invention to provide a semiconductor testing apparatus comprising a current measuring portion which converts a load current quantity at the time of application of a relatively-high test voltage to fall within a low-voltage range and then subjects the low-voltage range to quantization conversion with a predetermined measurement resolution even when the relatively high test voltage is applied to a DUT.
Further, it is another object of the present invention to provide a semiconductor testing apparatus comprising a voltage source and current measurement (VSIM) having a current measuring portion which can convert a load current quantity at the time of application of a relatively high test voltage to fall within a relatively low voltage range and then subject the relatively low voltage range to quantization conversion with a predetermined measurement resolution even when the relatively high test voltage is applied to a DUT.
Furthermore, it is still another object of the present invention is to provide a semiconductor testing apparatus comprising a current measuring portion having a circuit configuration which can minimize an impact on a measurement accuracy even if there are irregularities in resistances formed on an IC when forming the current measuring portion as a monolithic IC.
Moreover, it is yet another object of the present invention to provide a semiconductor testing apparatus comprising a current measuring portion having a circuit configuration which can minimize an impact on a measurement accuracy by performing linear correction processing even if peculiar non-linear characteristics of resistance elements formed on an IC exist when forming the current measuring portion as a monolithic IC.

Differential voltage measuring apparatus and semiconductor testing apparatus


An embodiment of the invention may include a first electrode, a second electrode, and a multi-level nonvolatile electrochemical cell located between the first electrode and second electrode. The multi-level nonvolatile electrochemical cell may have a read path and a write path through the cell, where the read path and the write path are different.

The present invention relates to memory devices, and more specifically, to resistive analog memory devices.
Technical problems such as character recognition and image recognition by a computer are known to be well handled by machine-learning techniques. "Machine learning" is used to broadly describe a primary function of electronic systems that learn from data. In machine learning and cognitive science, artificial neural networks (ANNs) are a family of statistical learning models inspired by the biological neural networks of animals, and in particular the brain. ANNs can be used to estimate or approximate systems and functions that depend on a large number of inputs and are generally unknown. ANNs can include deep neural networks (DNNs), convolutional neural networks (CNNs), and other types of neural networks. Crossbar arrays are high density, low cost circuit architectures used to form a variety of electronic circuits and devices, including ANN architectures, neuromorphic microchips and ultra-high density nonvolatile memory. A basic crossbar array configuration includes a set of conductive row wires and a set of conductive column wires formed to intersect the set of conductive row wires. The intersections between the two sets of wires are separated by so-called cross-point devices. Such cross-point devices may be analog memory devices capable of storing a weighted value (e.g., 0-1 instead of the binary 0 or 1), and may be capable of use in analog computing devices.
Cross-point devices can be implemented as so-called resistive memory (colloquially, memristive) devices. Characteristics of a memristive device may include non-volatility, the ability to store a variable analog resistance value, the ability to determine the analog resistance value without disturbing the state of the memristive device, and the ability to tune up or tune down a resistance using current or voltage pulses. These memristive devices can be used in hardware to simulate the artificial synapses of an ANN.

Three-dimensional confined memory cell with decoupled read-write

International Business Machines Corporation


Methods and systems for managing resources in a storage system are provided. The methods include tracking performance of a plurality of resources used for reading and writing information at storage devices in a networked storage system, each resource represented by a logical object in a hierarchical structure and performance data associated with each logical object is maintained by a processor executing a management application out of a memory device; identifying a root object associated with a resource having a performance issue as indicated by a threshold violation for the resource; selecting a related object associated with a resource similar to the resource of the root object by the management application for comparing performance data of the root object with the related object; and using the comparison to verify that the root object is a root cause of the performance issue.

Various forms of storage systems are used today. These forms include direct attached storage (DAS) network attached storage (NAS) systems, storage area networks (SANs), and others. Network storage systems are commonly used for a variety of purposes, such as providing multiple clients with access to shared data, backing up data and others.
A storage system typically includes at least a computing system executing a storage operating system for storing and retrieving data on behalf of one or more client computing systems (may just be referred to as "client" or "clients"). The storage operating system stores and manages shared data containers in a set of mass storage devices.
Quality of Service (QOS) is a metric used in a storage environment to provide certain throughput for processing input/output (I/O) requests, a response time goal within, which I/O requests are processed and a number of I/O requests processed within a given time (for example, in a second (IOPS). Throughput means an amount of data transferred within a given time in response to the I/O requests, for example, in megabytes per second (Mb/s).
To process an I/O request to read and/or write data, various resources are used within a storage system, for example, network resources, processors, storage devices and others. The different resources perform various functions in processing the I/O requests.
As storage systems continue to expand in size, complexity and operating speeds, it is desirable to efficiently monitor resource usage, identify performance issues, determine the root cause of the performance issues and provide appropriate remediation options. Continuous efforts are being made to better manage networked storage environments.

Methods and systems for trouble shooting performance issues in networked storage systems


A bracket and frame assembly permits attaching and removing a bucket or other tool to and from an arm of an excavator, backhoe, or the like. The bracket and frame assembly comprises two portions, a bracket and a detachable frame. The bracket mounts onto the arm of the implement. The bracket carries a latch member. The bracket can be moved onto a frame on a bucket or other tool, and is latched in place without dismounting from the backhoe, excavator or the like. The latch member can be released, either manually or under power, and then by manipulating the arm, the tool and frame can be removed from the bracket and a new tool mounted. The engaging portions of the frame and bracket are such that as wear occurs, the parts will compensate and remain secured without play or slop.

The present invention relates to interchangeable tool attachments powered such as a bucket, a grapple, hydraulic hammer, tampers, augers and the like used with a power operated arm of an implement such as an excavator or backhoe. The tools use a common frame mounting for coupling to a quick attachment bracket as shown in the present invention. The tools also are made to receive a separate mounting plate for regular pin connection to the arm.
Efforts have been made to provide couplings that can automatically connect tools to an articulated arm of an excavator, backhoe or the like, but most of these require operator action, as well as lacking reliability. Many of the present quick attachment brackets are complicated and time consuming in operation, requiring mechanically removing pins for connection as well as disconnection. One of the prior art couplings is illustrated in U.S. Pat. No. 5,110,254. Problems can persist with wear as the unit is used, in that there is no adequate compensation to take care of wear that occurs.

Attachment construction for earthworking implement


A surface movement guidance system for airport traffic of a continuous elongated row of one or more indicia extending lengthwise along a route on the airport surface to be traversed by the traffic, which indicia convey information about position on the airport surface.

The present invention relates to surface movement guidance systems for traffic on airfield pathways adapted to convey to the vehicle operators information regarding the position of a vehicle, particularly when visibility is poor.
Ground safety remains a problem at busy airports across the United States. The movement of aircraft in and around busy airports along taxiways between terminal gates and runways presents numerous opportunities for runway incursions, particularly when visibility is poor. A runway incursion is the entry of an aircraft without clearance onto an active runway from an adjacent ramp or taxiway, for which there is a great deal of risk of collision with a landing or departing aircraft. Incursions are often the inadvertent result of pilot disorientation caused by poor visibility.
As recently as Dec. 3, 1990, in an accident attributed to fog-reduced visibility, a Northwest Airlines jet at Detroit Metropolitan Airport took two wrong turns and taxied in front of another Northwest Airlines jet that was taking off, resulting in a collision that killed eight people. A runway incursion by a fog-disoriented pilot who mistook an active runway for a taxiway resulted in the worst disaster in aviation history when the ground collision of two Boeing 747 jetliners at Tenerife Airport in the Canary Islands in March 1977 resulted in the deaths of 583 people.
In 1990 in the United States alone, over 250 runway incursion incidents were reported. This does not include incidents such as taxiway collisions or near-misses resulting from vehicle operators mistaking one taxiway for another. Runway incursions and other taxiway incidents can still represent inconvenience and expense even when a ground collision does not result. To return an aircraft to a path from which it has strayed requires a considerable expenditure of time and fuel, and a compromise to the safety of all involved.
Guidance systems are known that assist taxiing aircraft in finding the centerline of taxiways and runways during poor visibility conditions, such as disclosed by U.S. Pat. No. 3,662,977 to Shannon. Airport pathways such as runways and taxiways are routinely marked at either or both ends by signs adjacent to the pavement or pavement markings. However, these signs and pavement markings are not visible from most locations on the runway or taxiway during conditions of poor visibility.
Lighted runway guidance systems are also known that illuminate the paths to be followed by an aircraft on a taxiway or runway when taking off and landing at night and when visibility is poor. Airport Surface Detection Systems are currently under procurement for major U.S. airports that utilize advanced ground-mapping radar to control aircraft and ground vehicles during inclement weather. However, such systems will not be procured for every airport, and, regardless, there remains a need for a simple, easily-installed system that identifies the path and the location and identity of intersecting pathways for pilots, especially during periods of poor visibility.

Airport pavement marking system for surface movement guidance


A footer square apparatus may be used to measuring a building foundation and may include a footer square body, a first guide line, a second guide line, a third guide line, a corner marking, and at least one angle marking. The first guide line and second guide line may be perpendicular, and the third guide line may form a 45° angle with the first guide line and second guide line. The at least one angle marking may identify an angle as measured between a line from the corner marking to the angle marking and at least one of the first guide line, the second guide line, and the third guide line.

Measuring the foundation of a structure, wherein a construction surface is marked at the perimeter of the foundation of a structure, is a necessary step in many construction projects. For example, a construction project may require the corners of a rectangular foundation of a structure be visually marked, such as with posts. However, measuring foundations of structures can be a difficult and time consuming process.
Special tools may be required to precisely mark the position where a structure is to be built. However, some of these tools may not give users any concrete and discernable indication of being completely square or rectangular with 90° angles on all sides, or other needed angles, requiring users to determine the proper position simply by their visual perception. This method may cause inaccuracies and thus, flaws in the resulting structure.
Accordingly, a need exists for a device and process to efficiently mark a foundation of a structure.

This patent is subject to a terminal disclaimer.


A microfluidic device for separating target components from a source fluid includes one or more source channels connected to one or more collection channels by one or more transfer channels. The target components of the source fluid can be magnetic or bound to magnetic particles using a know binding agent. A source fluid containing magnetically bound target components can be pumped through the source channel of the microfluidic device. A magnetic field gradient can be applied to the source fluid in the source channel causing the magnetically bound target components to migrate through the transfer channel into the collection channel. The collection channel can include a collection fluid that is stagnant until a predefined volume of source fluid is processed or a predefined volume of target components accumulate in the collection channel, at which point collection fluid can be pumped into the collection channel to flush the target components out of the collection channel. The target components can be subsequently analyzed for detection and diagnosis.

1. Technical Field of the Invention
The present invention is directed to fluidic devices that can be used to separate target components from flowing fluids. More specifically, the invention is directed to methods for and systems using fluidic and microfluidic devices to separate particulate, molecular and cellular material from a flowing fluid.
2. Description of the Prior Art
Chemical and biological separation and concentration has historically included methods such as solid-phase extraction, filtration chromatography, flow cytometry and others. Known methods of magnetic separation in biological fields include aggregation in batches, capture on magnetized surfaces, and particle deflection (or "steering") in single-channel devices. Typically, the particle of interest is chemically bound to magnetic microparticles or nanoparticles.
Existing methods are typically batch processes rather than continuous free-flow processes. This limits their usefulness in in-line systems. Moreover, existing methods typically operate at the macroscale, where diffusion distances require slower flow speeds, resulting in limited throughput. This problem is compounded in single-channel devices. The present invention improves on known methods and apparatuses for magnetic separation of particles from a fluid by providing a continuous, free-flow, higher throughput separation.
Published US Patent Application No. 2009-0220932 to Ingber, et al. and published US Patent Application No. 2009-0078614 to Varghese et al, both of which are hereby incorporated by reference in their entirety, disclose fluid separation devices and methods for separating particles from a flowing fluid. These devices and methods involve directing an input fluid, containing target particles, and a collection fluid into a common microfluidic channel. The input fluid and the collection fluid flow side-by-side through the microfluidic channel and a magnetic field is used to pull magnet target particles or target particles bound to target particles from the input fluid to the collection fluid before the input fluid and the collection fluid are separated and directed through separate outlets.

The Charles Stark Draper Laboratory, Inc.