A method of covalently immobilizing a charged chemical species on or near a sensor surface of a mass-sensitive chemical sensor, the sensor surface bearing functional groups capable of forming covalent bonds with the chemical species, the method involving the application of an electric field between the charged chemical species and the sensor surface such that the electrostatic attraction therebetween is increased.

Mass sensitive chemical sensing with a molecular recognition interface typically involves localisation or attachment of a first molecular species near or onto a sensor surface, which converts a subsequent localisation or binding interaction with a second molecular species into a readable signal. A mass sensitive chemical sensor can be defined as any device that allows for measurement of a property that scales proportionally to mass associated with or bound to a sensitive surface of that device. Several such sensor techniques can be utilised, such as evanescent wave-based sensors, e.g. surface plasmon resonance (SPR, which is capable of registering mass changes by the associated change in refractive index at the surface), optical waveguides (also dependent on refractive index changes associated with mass binding events), ellipsometry and acoustic wave devices (for example quartz crystal micro balances (QCMs)). These sensor approaches are well established in the art (see, for example, Biomolecular Sensors, Gizeli and Lowe. Taylor and Francis, London; 2002) and these types of instruments can be used for studies of chemical reactions in situ and for detection of certain molecules in a sample. Attachment of the first molecular species to the sensor surface can be performed by covalent coupling, adsorption or physical entrapment (e.g. in a polymer layer or by the use of a membrane). The covalent coupling can be done directly to the otherwise unmodified sensor transducer surface, to a polymer layer on the sensor surface or with the use of a chemical/biochemical "capture system". The best approach for a particular application depends on several factors including the nature of the sample, the sensor transducer type, the manner in which the sensor will be used and the surface chemistry.
For some applications, electrostatic repulsion between the first molecular species and the sensor surface may decrease the ability of a molecule to approach and become bound to the sensor surface. This effect can reduce the sensitivity and the number of possible immobilisation strategies. In the field of biosensing, covalent coupling of biomolecules via their superficial primary amino groups to a carboxylated sensor surface has been found to be a useful and versatile immobilisation strategy. This technology can be used for the determination of specificity, concentration, affinity constants, kinetic parameters, and monitoring of multimolecular interactions in various biomolecular systems. The immobilisation of proteins to a carboxymethyldextran-modified gold surface has been previously described (Johnsson et al. Analytical biochemistry 198, 266-277 (1991)). In the first step of the immobilisation procedure a mixture of NHS(N-hydroxy succinimide) and EDC(N-ethyl-N′-(dimethylaminopropyl) carbodiimide) is passed over a carboxymethyldextran gold sensor surface. The EDC/NHS injection activates the surface due to the transformation of a proportion of the carboxyl groups into reactive esters (N-hydroxysuccinimide esters). In general, not all of the carboxyl groups are activated, thus leaving a degree of negative charge in the sensor surface matrix. In the next step, a protein (as first molecular species) dissolved in a low-ionic strength buffer at a pH below the isoelectric point (pI) of the protein is passed over the activated surface. The protein is concentrated in the matrix by electrostatic attraction between the positively charged protein and the negatively charged carboxyl groups in the matrix. During this process the NHS-esters react with the primary amino groups of the protein. The electrostatic adsorption uptake and thus also the covalent immobilisation will decrease with the buffer ionic strength. This is due to competition between the positive proteins and other positive ions in the solution. Therefore a low-ionic strength buffer is preferably used. In the last step, the remaining NHS-esters are transformed into amides by injection of ethanolamine hydrochloride. This step also removes electrostatically (i.e. non-covalently) bound material, although a subsequent optional injection of buffer or dilute acid can be employed to enhance this process. A key parameter in the covalent immobilisation is the pH of the protein solution. The covalent binding of the proteins to the active esters is favoured by a high pH (when the primary amino groups of the protein are uncharged). On the other hand, pH must be lower than the isoelectric point of the protein to achieve the electrostatic attraction of the protein to the negative carboxyl groups in the sensor surface matrix. It has generally been found that a successful immobilisation can only be performed at a pH lower than the isoelectric point of the protein, i.e. when the protein is positively charged. At the low pH value needed for relatively acidic proteins, however, both the protein binding capacity of the matrix and the reactivity of the protein is low. This immobilisation procedure has, until now, therefore been limited to proteins with pI higher than 4.
Brett et al. (Electrochem. Comm. 5, 178-183 (2003)) have described the adsorption of DNA onto pyrolytic graphite in the preparation of an electrochemical biosensor. Application of an electric potential during adsorption led to a stronger DNA-electrode surface interaction and improved DNA films were obtained in a lower pH buffer, i.e. when the charge on the DNA can be expected to be reduced. Badia et al. (Sensors and Actuators B54, 145-165 (1999)) disclose a surface plasmon spectroscopy/atomic force microscopy study of alkanethiol deposition and desorption on gold surfaces under electric potential control. Similarly, Brusatori and van Tessel (Biosensors and Bioelectronics 18, 1269-1277 (203)) employed optical waveguide light mode spectroscopy to monitor electric potential-controlled adsorption of proteins on an indium tin oxide film. Potential dependent protein adsorption has also been monitored using SPR by Schlereth (J. Electroanal. Chem. 464, 198-207 (1991)).
Heaton et al. (PNAS USA 98, 3701-3704 (2001)) have examined the hybridisation and denaturation of DNA duplexes under an applied electrostatic field using SPR. Similar experiments are reported in U.S. Pat. No. 6,203,981. In DE10049901, adjacent and independently chargeable 'mobilisation' electrodes and detection electrodes are used to concentrate charged analytes for detection. The applied electric field accelerates and facilitates detection (e.g. by impedance changes). The electric field-augmented binding event concerned, however, is non-covalent (e.g. DNA hybridisation), with no consideration given to the additional problems involved in achieving covalent attachment of chemical species. Ge et al. (Biosensors and Bioelectronics 18, 53-58 (2003)) have described the effect of applied potential on the covalent immobilisation of DNA on a gold surface modified with a layer of aminoethanethiol (AET) for the purpose of constructing molecular logic circuits. Such an approach is not, however, appropriate for the preparation of a sensor surface for a mass-sensitive chemical sensor—the AET layer, with its short alkyl claims, would not provide a sufficiently ordered surface for mass-sensitive chemical sensing, and non-specific binding would consequently be high. In addition, the amino-groups on the surface will make the surface highly positive, which will further increase non-specific binding effects in many applications since most proteins have a net negative charge at physiological pH. Furthermore, the effects reported using this chemical coupling scheme are likely to be at least partially due to non-covalent attachment to the surface.
In EP0395222, an SPR study is conducted on the non-covalent capture and release of polarisable species under the influence of an alternating electric potential. U.S. Pat. No. 5,858,799 describes an electrochemical study during which an applied potential is used to oxidise and/or reduce analytes at the surface of an SPR metal film.
Thus, the prior art primarily deals with the effect of applied electric field on the adsorption or other non-covalent immobilisation of chemical species at a surface. No consideration is given to the particular difficulties which are presented when covalent immobilisation is required in an ordered and controllable manner at or near a sensor surface of a mass-sensitive chemical sensor. Those methods which are concerned with covalent immobilisation are either limited to molecular species having particular charge characteristics or do not allow the control of immobilisation and surface characteristics required for chemical sensing applications.


The invention relates to a method and apparatus for transmitting control information over an audio data stream, such as PCM coded speech information. The device comprises a control unit having two inputs receiving the PCM speech samples and control information signal. Each PCM sample is made up of a plurality of bits arranged according to different significance positions, such as position 0, 1, 2, 3, _N, where N+1 is the number of bits in the sample. The control unit receives a selected sample and shifts a bit at a selected significance position to a lower significance position. The empty slot at the predetermined significance position is used to receive a bit from the control information signal. The compound signal thus obtained is then released over a transport path, such as a T1 link, for transmission to a remote location. At the receiver, the control information bit is extracted from the selected sample at the predetermined significance position, and the PCM speech sample is recovered by shifting upwardly at least one bit at a significance position lower than the selected significance position.

This invention relates to signal processing and more particularly to a method and apparatus for transmitting control information over an audio data stream. This invention finds applications in digital communication systems, such as a digital cellular system or a Voice-over-IP (VoIP) network, in particular codec bypass capable systems that can selectively de-activate encoding/decoding functions in the connection to provide improved speech quality.
In a digital communication system such as a wireless network or a VoIP network, an audio signal may be processed by a series of speech encoders and decoders as it is transmitted from one endpoint to another. In the example of a cellular mobile-to-mobile connection, the audio signal is first encoded by a speech encoder at the first mobile telephone and transmitted in an encoded format to a base transceiver station of a cell site where it is transferred to the base station controller servicing that cell site. At the base station controller, the encoded speech information is processed by a compatible speech decoder that converts the compressed speech stream into PCM samples. The PCM samples are then transported over the landline network, such as the PSTN, toward the base station controller servicing the cell site communicating with the other mobile telephone. At the second base station controller, the PCM speech samples are again processed by a speech encoder. The encoded information is sent from the base transceiver station of the cell site to the second mobile telephone where the compressed speech stream is converted one more time by a speech decoder into PCM samples that can be used to generate an audio signal.
In this example, codecs on both sides of the mobile-to-mobile call are connected in tandem, which is known to degrade the speech quality as a result of the successive encoding/decoding of the audio signal.
The xe2x80x9ccodec bypassxe2x80x9d technique alleviates this problem. During a connection, when the codecs at the base station controllers are made aware of their mutual existence, they are switched off such that the encoded speech information arriving at the first base station controller flows into encoded format through the PSTN and arrives as such at the second base station controller. This procedure eliminates one decoding operation of the speech signal at the first base station controller and one re-encoding operation of the signal at the second base station controller. As a result, the audio quality is significantly improved.
For additional information on the xe2x80x9ccodec bypassxe2x80x9d technique, the reader is invited to refer to the U.S. Pat. No. 5,768,308 granted to the same assignee that describes the process in great detail. The contents of this document are hereby incorporated by reference.
The codec in one base station controller can switch to the bypass mode as a result of an in-band hand-shaking operation with the companion codec in the other base station controller. Transmitting control information from one codec to the other over the audio data stream allows this hand-shaking operation to take place. The control information is transmitted by bit stealing. This is effected by inserting in selected PCM samples bits from the control information signal. The control information bit is inserted at a position of pre-determined significance in the sample. Since this insertion mechanism destroys the audio information bit at the position of predetermined significance, it is desirable to carry out the insertion at the lowest possible bit significance position. In a specific example, a T1 connection between the two codecs may require signalling information to be embedded in some speech samples at the least significant bit position, where this signalling information is necessary for the transmission facility linking the two codecs. Accordingly, the control information is sent over the next available bit position, specifically bit significance position 1. This effectively destroys the audio information at bit significance position 1 in every sample carrying control information.
Although the above described technique allows obtaining an overall good speech quality, it would be desirable to effect the transmission of the control signal while avoiding as much as possible the loss of the audio information in the bit position in which the control information bit is carried.
The present invention provides a device and a method for transmitting control information over an audio data stream. This device can be used in a digital communication system implementing the xe2x80x9ccodec bypassxe2x80x9d feature, for example a Time Division Multiple Access (TDMA) system or a Code Division Multiple Access (CDMA) system. The device comprises a first input for receiving the audio data stream, the audio data stream being characterised by a plurality of data blocks, each block including a plurality of bits arranged in different significance positions. The device also includes a second input for receiving a control information signal including a plurality of bits. A control unit is coupled to the first and to the second inputs to insert in selected data blocks of the audio data stream bits from the control information signal. More particularly, the control unit is operative to shift a bit at a selected significance position in a data block to a lower significance position and insert a bit from the control signal at the vacated selected significance position of the data block. More than one bit can be shifted to lower significance positions if more positions in the data block are to be vacated so that more than one control information bit can be inserted in the data block.
The resulting signal is then released from the device for transmission to a remote location. In a specific example, the data block is a PCM sample.
Preferably, at the receiving end of the transmission, the multiplexed audio data stream and the control information signal are separated. The operation involves, for selected ones of the data blocks, extracting a bit at a first pre-determined significance position and shifting the bit(s) at significance position(s) below the first pre-determined significance position towards the first pre-determined significance position. The extracted bits from the selected data blocks can then be used to assemble the control information signal, while the selected data blocks with the shifted bits can be used in the formation of the audio stream suitable for further processing.
The bit shifting allows preserving an audio information bit in the data block, that would be lost under prior art bit stealing transmission techniques. Objectively, a bit loss will also occur in some samples that receive, in addition to a control information bit a signalling information bit. This event does not occur very often as most of the data blocks selected for carrying information other than audio information carry either control information or signalling information but not both. Note that, in a specific example, the transmission facility linking the two codecs may be a single T1 link formed of a series of T1 connections having unsynchronised symmetry. In such a situation, the multiple T1 signalling has a higher chance of coinciding with the control bits, such that a particular data block may be selected to carry both control and signalling information.
The invention also provides a device and a method for demultiplexing a compound digital signal into audio data and a control information signal.
Yet, the invention also provides a data structure containing audio and control information implemented over a machine readable data transmission medium, said data structure having a bit pattern XYZ, where X is a bit set including at least one audio information bit, Y is a bit set including at least one control information bit and Z is a bit set including at least one audio information bit, when bit set Z is shifted up by the number of bits forming the bit set Y a bit word XZ being formed that is characterised by bits arranged in predetermined significance positions, the bits in the word XZ communicating in conjunction with one another audio information. In a specific example, the bit sets Y and Z contain each a single bit.
Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

Method and apparatus for transmitting control information over an audio data stream


A folding table includes a frame with a folding top mounted to the frame. A linkage mounts to the frame and to the top and facilitates movement of the top between a horizontal use position and a folded position wherein the top is substantially vertical. The linkage includes a link mounted to the frame at a first end and to the table top at a second end. A first element mounts to the underside of the top and has a slot with a straight portion and an end portion extending upward at an oblique angle to the straight portion. A follower mounts at the top of the frame and slides in the slot and resting in the end portion when the top is in the use position. The slot, follower and linkage are configured so that the table top does not require latching, but cannot be accidentally folding when force is applied to the top.

1. Field of the Invention
The present invention relates to a table with a folding top and in particular to a table with a folding top that automatically moves into a use position wherein the tabletop cannot be accidentally folded and automatically releases by lifting the top.
2. Description of the Prior Art
In large, multi-purpose rooms that are utilized at various times as dining rooms, meeting halls, dance areas, training rooms, classrooms and for other varied activities, it is often desirable that multi-purpose furniture be used. Such furniture includes tables, chairs, benches and/or stools or table and seat combinations. Such furniture provides added utility if it folds so that it takes up less space when stored. Examples of folding tables are shown in U.S. Pat. Nos. 2,771,937 to Wilson; 3,075,809 to Wilson; 3,099,480 to Wilson; and 6,254,178 to Bue, all assigned to Sico, Inc., the Assignee of the present invention.
Folding tables that are used for quick setup and takedown have added utility if they are easily transported. Therefore, it is desirable to have folding tables mounted on casters or rollers. Moreover, the tables should nest close to one another when folded so that much less floor space is needed when the tables are not in use.
In addition to easy transport and less space required for storage, such tables should be easy and safe to operate. Such tables should have a safe, simple and reliable folding mechanism that cannot accidentally allow the table to fold from the use configuration. An issue often encountered with folding furniture is accidental folding. In particular, some folding tables may be subject to accidental folding if a heavy load is placed on an edge of the table. The folding and unfolding should provide sufficient resistance so the tabletop does not fold too quickly, yet does not offer too much resistance leading to accidentally tipping the table over when the top is urged toward a folded position.
It can be seen that a new and improved folding table is needed. Such a table should provide for safe and reliable operation with the tabletop folding between a use position and a storage position. The table should nest closely when configured for storage. Moreover, the table should have a linkage that prevents accidental folding from weight being placed on the tabletop surface in the use position. Such a table should not require a separate latch to actuate or separate latching and unlatching steps. Such a table should also provide for safe and reliable actuation when designer tops over a wide range of weights are supported. The present invention addresses these problems, as well as others associated with folding tables and their operation.


A method of communicating a presence state for a group of users having user terminals relating to their presence in a virtual communication space provided by a communication server on a communication network. The virtual space provides a plurality of distinct communication modes referred to as “activities” that can be shared by all of the users of said group. The method includes associating each activity of the virtual space with a graphics icon representing the activity, the icon being for displaying via a graphics interface implemented by any activity sharing client application that is installed in each user terminal. A presence state is determined for each user of the group. For each of the activities, a graphical representation for the associated icon is determined as a function of the presence state for the users relative to the activity, enabling visual identification of user(s) participating in the activity.

With the development over recent years of communication terminals such as smart phones, and of communications networks, in particular with the appearance of so-called social networks based on the Internet, the users of fixed or mobile terminals can make use of applications installed on their terminals and/or accessible over the Internet for the purpose of sharing activities such as sharing photos or videos, playing games, or exchanging messages. By way of example, mention may be made of the Facebook™ social network service that serves in particular to enable friends to share photos and/or videos, the WhatsApp™ mobile application incorporating an instant messaging system, and the Draw Something™ drawing game mobile application.
Applications of the types mentioned above generally implement user interfaces enabling a user who is connected to the service in question to know whether another user is connected to the service, e.g. by displaying an icon of color that represents the connected state (e.g. green).
Nevertheless, the above-mentioned user interfaces generally do not make it possible to indicate that a user is connected to only one of the activities made available by the service, and they are therefore not suitable for giving a user effective information about the simultaneous presence of several users with one activity taken from a set of activities that can be shared by a group or community of users.

Method for communicating a status of presence of a group of users in a virtual communication space provided by a communication server on a communication network


A refrigerated appliance with a hinged access panel is disclosed. The refrigerated appliance comprises a frame, the panel, and one or more hinges coupling the panel to the frame. Each hinge has a linkage that guides the movement of the panel between a closed position and an open position. The movement of the linkage has a linear component and a rotational component. The refrigerated appliance may include a latch configured to retain the panel in the open position. The refrigerated appliance may include one or more biasing elements configured to bias the panel toward the open position.

The present invention relates to an access door or panel for a refrigerated appliance. More specifically, the present invention relates to an access panel hingedly coupled to a refrigerated appliance.
Refrigerated appliances having one or more refrigerator compartments and/or freezer compartments are generally known. It is generally known to provide such refrigerated appliances with a removable panel to provide access to mechanical or electrical components that control or operate the refrigerator (e.g., for maintenance, repair, installation, cleaning, etc.). However, access panels are typically mounted with fasteners (e.g., bolts, snaps, etc.) that may be (undesirably) visible or difficult to access or remove/operate. Also, when used on larger refrigeration systems (particularly those that also have a decorative panel), the access panel is typically heavy, which makes its support or attachment susceptible to fatigue and unwieldy when being removed and reattached. Further, in instances were a hinge is provided to combination or integrated refrigerated appliances, the hinge only provides for pivoting or rotation of the panel about a single axis, which requires an undesirable amount of clearance between the panel and its environment in some installations.
Accordingly, it would be advantageous to provide a hinged access panel for a refrigerated appliance that allows multiple axis/plane/direction movement of the access panel. It would also be advantageous to provide a hinged access panel that is retained in the open position when desired and/or biased to the open position to assist opening. It would further be advantageous to provide an access panel with a hinge linkage that allows both pivoting and translational movement to allow clearance with its adjacent environment. It would be desirable to provide for an access panel hinge for refrigerator having one or more of these or other advantageous features. To provide an inexpensive, reliable, and widely adaptable access panel that avoids the above-referenced and other problems would represent a significant advance in the art.

Hinged access panel for refrigerated appliance


A manufacturing method of a thin film transistor of a liquid crystal display device using 3-mask includes forming a gate electrode over a substrate, consecutively forming a gate insulating layer and an active layer, forming a first photoresist pattern, removing an active layer formed at a source/drain region, ashing the first photoresist pattern to expose a part of an active region, forming a source/drain electrode, forming a passivation layer, forming a second photoresist pattern that exposes a pixel region over the passivation layer; forming a pixel region by using the second photoresist pattern as a mask, side-etching a part of the passivation layer to expose a part of the drain electrode, forming a pixel electrode material over the second photoresist pattern and the pixel region, and simultaneously removing the second photoresist pattern and the pixel electrode material formed thereon to form a pixel electrode.

1. Field of the Invention
The invention relates to manufacturing a thin film transistor used as a switching device of a liquid crystal display device, and more particularly, to a method for reducing the number of masks used when manufacturing a thin film transistor.
2. Description of the Conventional Art
Generally, a liquid crystal display (LCD) device displays desired information on a screen by controlling the alignment direction of a liquid crystal aligned by an electric field applied between a pixel electrode formed on a TFT (thin film transistor) array substrate and a common electrode on a color filter. Here, the thin film transistor is mainly used as a switching device for applying a voltage to the pixel electrode existing on the TFT array substrate.
The number of masks used for manufacturing the LCD device directly affects the number of process steps. Decreasing the number of process steps increases productivity and yield. Accordingly, one tries to reduce the number of masks used in manufacturing the thin film transistor.
The related art methods for manufacturing TFTs utilize a 5-mask or 4-mask process.
A manufacturing process of a TFT of an LCD device using a related art 5-mask will be explained with reference to FIGS. 1A to 1E.
FIG. 1A shows a gate electrode material being formed on a substrate 1. The gate electrode material is a metal material, and is formed by sputtering.
The metal layer for forming the gate line also serves as a storage line for maintaining the voltage at a TFT for a predetermined time, and it also serves as a gate pattern of a gate pad portion.
After forming the gate metal layer, photoresist (not shown) is deposited on the metal layer, and a photolithography process is performed using a first mask (not shown), thereby selectively forming a gate line, a storage region line, and a gate pattern 2 in the gate pad region on the substrate 1.
FIG. 1B shows a gate insulating layer 3, an active layer of semiconductor, and a high-concentration impurity layer that are sequentially formed on the resulting material. Then, photolithography is performed using a second mask (not shown) to thus selectively etch so that an active region 4 forms in the channel region. Here, the active region 4 is formed by stacking an amorphous silicon (a-Si) and an ohmic contact layer, and a high-concentration of impurity is doped into the semiconductor layer.
The gate insulating layer and the active layer are generally deposited using a plasma enhanced chemical vapor deposition (PECVD) method.
FIG. 1C shows source/drain electrode material that are formed on the resulting material. Then, photolithography is performed using a third mask (not shown) to thus selectively etch so that the source/drain material can be separated from each other at both sides of the active region 4 at the channel region. Also, the source/drain material can be applied as one electrode 7 of a capacitor on the gate insulating layer 3 at the storage region, and the source/drain material can also be applied as a data electrode 8 on the gate insulating layer 3 of a data pad portion.
FIG. 1D shows a passivation layer 9 being formed on the resulting material. Then, a contact hole is formed using a fourth mask (not shown) so that the drain region 6 of the channel region, the electrode 7 of the storage region, the gate pattern 2 of the gate pad portion, and the data electrode 8 of the data pad portion can be exposed.
FIG. 1E shows an electrode material being formed on the resulting material. Then, photolithography performed by a fifth mask (not shown) forms a pixel electrode 10 connecting the drain region 6 of the channel region and the electrode 7 of the storage region. At this time, a gate line and a data line are simultaneously formed on the gate pad portion and the data pad portion.
The aforementioned method for manufacturing an LCD device by using a 5-mask process limits the possibilities to reduce manufacturing cost and to simplify processes due to the performance of multiple photolithographic steps.
In order to solve this problem, a related art LCD device manufacturing method using a 4-mask process was proposed.
A manufacturing process for an LCD device using a 4-mask process will be explained with reference to FIGS. 2A to 2G.
FIG. 2A shows a gate electrode material that is formed on a glass substrate 21. Then, a photolithography process using a first mask (not shown) is performed to thereby selectively form a gate line, a line of the storage region, and an electrode pattern 22 on the substrate 21.
FIG. 2B shows a gate insulating layer 23, an active layer 24, and a conductive layer 25 of a metal that are sequentially formed on the resulting material. Here, the active layer 24 is a stacked layer of a semiconductor layer and a high-concentration impurity layer.
In FIG. 2C, a photoresist layer (not shown) is formed on the conductive layer 25. Then, a photolithographic step using a second mask (not shown) patterns the photoresist layer 40 remaining on the channel region, the storage region, and a data pad portion. A stepped photoresist pattern forms on the conductive layer 25 at the channel region by applying a diffraction exposure to the photoresist layer 40. A source/drain electrode and a channel are formed by using the stepped photoresist pattern as a mask.
FIG. 2D shows that the conductive layer and the active layer of regions where the photoresist pattern is not present are etched and removed by using the photoresist layer 40 pattern as a mask.
FIG. 2E shows the diffraction-exposed photoresist pattern being partially removed by an ashing process, and the conductive layer above the channel region is exposed.
Thereafter, the photoresist layer 40 pattern is selectively removed to thus etch the exposed electrode layer 25 above the channel region. Next, the active layer 24 is etched to a predetermined thickness to form source/drain electrodes 26 and 27 separated from each other at both sides on the active layer 24. Then, as shown in FIG. 2F, the remaining photoresist layer 40 pattern is removed.
FIG. 2G shows a passivation layer 28 that is formed on the entire resulting material. Then, a photolithography step is performed using a third mask (not shown) to selectively etch so that the drain electrode 27 of the channel region, the electrode layer 25 of the storage region, the gate pattern 22 of the gate pad portion, and the electrode layer 25 of the data pad portion can be exposed.
FIG. 2H shows an electrode material that is formed on the resulting material. Then, a photolithography process is performed using a fourth mask (not shown) to selectively etch so that a pixel electrode 29 connecting the drain region 27 of the channel region and the electrode layer 25 of the storage region can be formed. Also, a line 30 connected to the gate pattern 22 of the gate pad portion and a line 31 connected to the electrode layer 25 of the data pad portion can be simultaneously formed during this step.
In this related art manufacturing method of an LCD device using the 4-mask step photolithographic process, the manufacturing cost can be reduced and processes can be simplified compared to the manufacturing method of an LCD device using a 5-mask step photolithographic process.
That is, minimizing the number of masks contributes to reducing the manufacturing cost and to simplifying the overall process.
However, efforts to reduce the number of masks used in manufacturing LCD devices are being continued. The invention is therefore directed at developing an LCD manufacturing method in which the number of masks is minimized when compared to the related art.

Manufacturing method of liquid crystal display device


A technique for position based dynamics constrains deformation of triangles within a simulation mesh configured to model a cloth object. The constraints comprise at least a weft, warp, and shear constraint per triangle within the simulation mesh. A non-rigid shear constraint yields realistic cloth dynamics while avoiding locking within the simulation mesh. The technique may be implemented in real-time or batch simulation environments.

1. Field of the Invention
The present invention relates to the field of computer graphics and, in particular, to techniques for a continuum based model for position based dynamics.
2. Description of the Related Art
Improving realism is a key factor driving development of new generations of computer graphics systems. Tremendous strides have been made improving realism with respect to lighting, surface features and texture, and dynamics for rigid objects. Progress has also been made in simulating dynamics of soft objects, such as thin cloth objects in a range of different environments. Highly realistic cloth simulation can produce visually appealing animation, and contribute a high degree of overall realism to a graphics scene. However, simulating the dynamics of cloth objects has conventionally been challenged by locking and convergence problems.
One class of conventional simulator for object dynamics implements techniques based on integration of force and mass over time to indirectly compute updated position information. For example, a mesh of vertices defines a surface for a soft object. Each vertex within the mesh comprises a particle with attributes of mass and position. Velocity for a given vertex may be computed by integrating the effective acceleration for the vertex due to an applied force. A distance constraint may be established between vertices to maintain an appropriate physical structure for the mesh. During simulation, a new position for each vertex within the mesh is computed via time integration, while adhering to physical constraints, such as one or more distance constraints. If a physical constraint is violated, then additional iterations for each vertex may be executed to attempt to converge on a valid solution. A given mesh may not easily converge or it may converge into a physically meaningless configuration and become "locked" in the configuration. Both scenarios degrade the quality of simulator results and oftentimes require intervention from a user.
Another class of conventional simulator for object dynamics implements position based dynamics (PBD) rather than force-based time integration simulation. The central theme of PBD is to use constraints to directly update vertex position, instead of calculating forces that indirectly influence position via time integration. In cloth simulation, the most important constraints are distance constraints, because they prevent a simulation mesh from falling apart. One distance constraint is conventionally established per edge within the mesh. A PBD solver performs a sequence of time steps to solve for evolving position state information of vertices within the mesh. A typical PBD time step involves a set of simulation steps that iteratively project all of distance constraints within the mesh. Typically, one simulation step involves several constraint projection steps that each solves an approximation of a distance constraint. The mesh is commonly represented as a collection of triangles. Unfortunately, a triangle with three distance constraints along its edges does not allow for any internal deformation, leading to a high propensity of meshes locking during simulation. One solution to locking in PBD simulators is to implement non-rigid distance constraints. Greater slack in the non-rigid distance constraints for a mesh leads to a greater likelihood that the PBD solver will converge without locking. Unfortunately, increasing slack in the distance constraints makes the mesh appear to be stretchy. Unless a cloth being modeled by the mesh is supposed to be stretchy, this is a highly undesirable outcome.
As the foregoing illustrates, what is needed in the art is an efficient technique for simulating object dynamics that avoids locking.

Continuum based model for position based dynamics


A battery-operated hand vacuum cleaner includes a drive part which has a housing, wherein a handle is integrally formed onto the housing and the housing contains an electric motor for a blower, and an intake part with an air inlet, wherein the intake part is separable from the drive part. The drive part contains a tank for containing a liquid, the intake part is provided with a spray nozzle for the liquid, and separable means connecting the tank and the spray nozzle are provided for discharging the liquid.

1. Field of the Invention
The present invention relates to a battery-operated hand vacuum cleaner with a drive part which has a housing, wherein a handle is integrally formed onto the housing and the housing contains an electric motor for a blower, and with an intake part with an air inlet, wherein the intake part is separable from the drive part.
2. Description of the Related Art
Hand vacuum cleaners of the above-described type are used for quickly and efficiently cleaning surfaces of all types. EP 0 008 117 B2 discloses a self-contained dry vacuum cleaner which includes a drive part and an intake part which can be separated from each other. A handle is formed onto the housing of the drive part. An electric motor operated by batteries for a blower and air outlet openings are provided in the housing.
The intake part has a hollow housing which has an air inlet and an open end which can be releasably connected to the housing by means of snap-type closures, and a dust bag unit arranged between the air inlet and the blower. Such a hand vacuum cleaner merely serves for vacuuming granular and dust-like materials from tables and floors.
EP 0 357 189 discloses a self-contained wet/dry vacuum cleaner in which the intake part has a baffle plate for separating liquids. However, cleaning agents must be applied separately.
EP 0 586 762 discloses a line-powered steam vacuum cleaner in which the steam generator with its steam nozzles are arranged in the drive part. The steam vacuum cleaner merely serves for vacuuming a liquid.
U.S. Pat. No. 5,507,068 relates to a washing vacuum cleaner which merely has a single-piece housing to which a fresh water tank and a waste water tank can be coupled. This washing vacuum cleaner is also only capable of collecting water or dirty water because it merely has very narrow slot openings. Solid and dry materials cannot be removed with this apparatus.

Battery-operated hand vacuum cleaner with liquid spray


A terminal device, a sensing method, and a sensing apparatus are provided. The terminal device include a plurality of optical sensors, wherein the plurality of optical sensors are arranged in a plurality of sub-regions, and each of the plurality of sub-regions has a respective optical parameter; and a processor, configured to: control the optical sensor in each sub-region to, upon detecting a target object, sense the target object with a first optical parameter value, and obtain a first sensing signal in each sub-region; determine a target signal range according to the first sensing signal in each sub-region; determine a second optical parameter value with respect to each sub-region according to the first sensing signal in the sub-region and the target signal range; and set the optical parameter of each sub-region to the second optical parameter value.

With rapid development of science and technology, terminal devices (for example, mobile phones) become increasingly popular. Benefiting from various sensing technologies, convenience in the use of the terminal devices is also continuously improving. For example, a fingerprint identification apparatus of the terminal device is capable of sensing fingerprint information of a user, such that various convenient functions such as unlocking and mobile payment may be achieved. Thus, sensing performance of the terminal device needs to be further improved.

Terminal device, sensing method and apparatus with sensor for fingerprint identification

Beijing Xiaomi Mobile Software Co., Ltd.


Methods for passivating crystalline grains in an active layer for an optoelectronic device and optoelectronic devices having active layers with passivated crystalline grains are disclosed. Crystalline grains of an active layer material and/or window layer material are formed within the nanotubes of an insulating nanotube template. The dimensions of the nanotubes correspond to the dimensions of a crystalline grain formed by the deposition technique used to form the grains. A majority of the surface area of these grains is in contact with the wall of the nanotube template rather than with other grains.

Optoelectronic devices such as photovoltaic devices are often made in the form of one or more cells. Each cell typically includes an active layer (sometimes including a window layer) between two electrodes, at least one of which is usually transparent. The active layer of the cells absorbs light to produce a current and voltage. Thin-film inorganic cells for optoelectronic devices are often contain polycrystalline inorganic materials in the active layer. Polycrystalline materials have distinct grains of crystal structures separated by grain boundaries. Unfortunately devices made from such cells can suffer from losses in efficiency, stability, and reproducibility due to effects at the grain boundaries arising from the polycrystallinity of the active layer of the cell.
The active layer of inorganic cells can be comprised of a range of light-absorbing and charge-transmitting materials. For example, an active layer can be created by forming an alloy of copper, indium, gallium, and selenide or sulfur (CIGS). Alternatively, an active layer can be created by synthesizing C admium Telluride (CdTe) or C admium Selenide (CdSe). Copper Sulfide can also be used an inorganic absorber material in the active layer. Additional inorganic active layers include blends, alloys, and mixtures of metals from groups IB, IIIA and VIA in the periodic table of elements. For each of these inorganic materials, the absorber layer typically forms in crystalline domains.
While the ideal target of an inorganic solar cell (CIGS, CdTe, etc.) may be one that is (or closely approximates) a single-crystalline cell, it is generally most economical and commercially viable to apply techniques and processes that produce cells with a poly-crystalline active absorber layer. FIG. 1 illustrates a solar cell device 100 according to the prior art. The device 100 can be built up from a substrate 102 and includes bottom electrode 104, a window layer 106, e.g., cadmium sulfide (CdS), an active layer 108 e.g., Copper Indium Gallium Selenium (CIGS), and a top electrode 110. The window layer 106 and active layer 108 often tend to form distinct grains separated by grain boundaries 107, 109 respectively. The grain boundaries 107, 109 inhibit carrier transport, provide sites for carrier non-productive recombination, and facilitate unwanted diffusion of materials (e.g. the diffusion of S from CdS in inorganic solar cells—a known cause of poor long-term stability). The grain boundaries 107, 109 also tend to be irregular and varied in size, which can give rise to issues of variability and/or reproducibility arising from the uniform/non-uniform application of inorganic materials, and correspondingly varied active layer performance in different areas of the cell. All of these effects tend to degrade to performance of the solar cell 100.
Further, certain active layer materials such as grains comprised of combinations of copper with indium and/or gallium and selenium or sulfur tend to have poor adhesion to common substrate materials. In the prior art, the substrate 102 has been coated with about 500 nm of (relatively expensive) molybdenum (which may double as the electrode 104) to promote adhesion between the CIGS layer and that underlying substrate 102.
Thus, there is a need in the art, for an optoelectronic cell architecture that addresses the detrimental effects of grain boundaries and a corresponding method for making such a cell.

Polycrystalline optoelectronic devices based on templating technique


An LGA socket includes a socket body (10), a number of contacts planted in the socket body, a hollowed floating frame (50) floating on a number of push fingers (11) formed on the socket body, a stiffener (20) disposed right round the socket body and the floating frame, and a socket plate (40) and a load lever (30) respectively mounted to opposite ends of the stiffener. The floating frame is provided with a number of receiving sections (54) to hold an LGA package (60). The floating frame with the LGA package held thereon is vertically movable between a free state in which the conductive pads of the LGA package do not engage with the contacts, and a compressed state in which the conductive pads of the LGA package resiliently register with corresponding contacts. Thus, damage to the contacts during installation is avoided and reliable electrical connection is ensured.

1. Field of the Invention
The present invention relates generally to electrical connectors, and more particularly to a land grid array (LGA) socket having contact-protecting mechanism for electrically connecting an LGA package with a circuit substrate, such as a printed circuit board (PCB).
2. Description of the Prior Art
An integrated circuit package having conductive pads arranged on a bottom surface thereof in an LGA fashion is known as an LGA package. LGA packages have been widely used due to relatively low height and reliable electrical characteristics.
Connectors for removably connecting an LGA package with a PCB are known as LGA sockets. Normally, an LGA socket comprises a socket body, a plurality of contacts received in the socket body, a stiffener attached to the socket body, and a socket plate and a load lever pivotally attached to opposite ends of the stiffener respectively. The socket plate and the load lever can rotate relative to the stiffener to jointly hold the LGA package on the LGA socket or release the LGA package from the LGA socket.
Turning to FIGS. 9 and 10, there is shown a conventional LGA socket 8 comprising a socket body 82, a plurality of contacts 81 received in the socket body 82, a stiffener 83 attached to the socket body 82, and a load lever 86 and a socket plate 84 pivotally assembled to opposite ends of the stiffener 83, respectively. When the contact 81 is correspondingly accommodated in the socket body 82, spring arm 88 of the contact 81 protrudes from an upper surface of the socket body 82, to resiliently and electrically register with a corresponding conductive pad (not shown) arranged on a bottom surface of an LGA package 100.
In operation, prior to rotating the socket plate 84 onto a top surface of the LGA package 100, the LGA package 100 is appropriately set on the socket body 82 with the conductive pads thereof mating with corresponding spring arms 88 of the contacts 81. A driving arm 85 of the load lever 86 is urged to drive the LGA package 100 to move downwardly. In a close position, the conductive pads arranged on the LGA package 100 substantially engage with corresponding spring arms of the contacts 81, and electrical connection between the LGA package 100 and a PCB is achieved.
During installation of the LGA package 100, the LGA package 100 need to be vertically set on the socket body 82 so that the conductive pads of the LGA package 100 can appropriately contact with the corresponding spring arms 88 of the contacts 81. Generally, the installation of the LGA package 100 is manually operated and the LGA package 100 is susceptible to be inclined with respect to the socket body 82. As a consequence, the LGA package 100 is liable to contact with some of the spring arms 88 foremost. This tends to cause inadvertent damage to the contacts 81 and impact reliability of the electrical connection between the LGA socket 8 and the PCB. This problem arises particularly in high density and miniaturized LGA socket wherein the contacts are very closely spaced in a compact array.
Hence, it is strongly desired to provide a new LGA socket which overcomes the disadvantages of the prior art described immediately above.

Land grid array socket having contact-protecting mechanism


Low-k dielectric materials are incorporated as an insulator material between bit lines and an inter-level dielectric material. The device is first processed in a known manner, up to and including the deposition and anneal of the bit line metal, using a higher dielectric constant material that can withstand the higher temperature process steps as the insulator between the bit lines. Then, the higher dielectric constant material is removed using an etch that is selective to the bit line metal, and the low-k dielectric material is deposited. The low-k material may then be planarized to the top of the bit lines, and further low-k material deposited as an inter-level dielectric. Alternatively, sufficient low-k material is deposited in a single step to both fill the gaps between the bit lines as well as serve as an inter-level dielectric, and then the low-k dielectric material is planarized. Standard processing may then be carried out.

The present invention is directed to memory devices and, more particularly, to dynamic random access memory (DRAM) structures formed in a substrate.
Dynamic random access memory devices (DRAMs) typically include a semiconductor memory cell array formed of a plurality of memory cells arranged in rows and columns and include a plurality of bit lines as well as a plurality of word lines that intersect the bit lines. Each memory cell of the array is located at the intersection of a respective word line and a respective bit line and includes a capacitor for storing data and a transistor for switching, such as a planar or vertical MOS transistor. The word line is connected to the gate of the switching transistor, and the bit line is connected to the source or drain of the switching transistor. When the transistor of the memory cell is switched on by a signal on the word line, a data signal is transferred from the capacitor of the memory cell to the bit line connected to the memory cell or from the bit line connected to the memory cell to the capacitor of the memory cell.
When data stored in one of the memory cells is read onto one of the bit lines, for example, a potential difference is generated between the bit line of the respective memory cell and the bit line of another memory cell which form a bit line pair. A bit line sense amplifier connected to the bit line pair senses and amplifies the potential difference and transfers the data from the selected memory cells to a data line pair.
An advantage of DRAMs over other types of memory technology is their low cost because of the simplicity and scaling characteristics of the memory cell. Though the DRAM memory cell is based on simple concepts, the actual design and implementation of such cells typically requires a highly complex DRAM design and process technology.
An example of current DRAM technology is a buried capacitor DRAM memory in which memory bits are constructed in pairs to allow sharing of a bit line contact. The sharing of the bit line contact significantly reduces the overall cell size. Typically, the memory bit pair includes an active area (AA), a pair of active word lines and a pair of passing/field word lines, a bit line contact, a metal or polysilicon bit line, and a pair of cell capacitors.
The bit line pitch, i.e., the width of the bit line plus the distance between adjacent bit lines, typically determines the active area pitch and the capacitor pitch. The active area width is typically adjusted to maximize the transistor drive and minimize the transistor-to-transistor leakage.
The word line pitch typically determines the space available for the bit line contact, the transistor length, the active area space, and the capacitor length. Each of these dimensions must be optimized to maximize device capacitance, minimize device leakage and maximize process yield.
As semiconductor devices become increasingly smaller, the distance between adjacent bit lines decreases, thereby increasing the capacitance between adjacent bit lines, known as the bit line-to-bit line capacitance. The increased capacitance induces delays which are more critical for such smaller devices because the devices operate at higher speeds so that the time between the read and/or sense signals on the bit line decreases. It is therefore desirable to reduce the bit line-to-bit line capacitance.
The use of low dielectric-constant insulator materials, known as low-k materials, as the insulator between the bit lines in place of TEOS or other insulators has been proposed. However, such low-k materials are typically unable to withstand temperatures above 400° C. and thus cannot withstand the subsequent annealing steps that are carried out at much higher temperatures. Therefore, such low-k materials are presently unsuitable to serve as insulators between the bit lines.
It is therefore desirable to provide a DRAM structure and fabrication process that avoids these problems.

Inclusion of low-k dielectric material between bit lines


To improve work efficiency and reduce work costs, automatic transmission/reception and conversion of a print job can be performed (without requiring manual work) among plural printing systems having different functions. An information processing apparatus, connected to plural printing systems, can create a job ticket for a second system based on a job ticket and content data for a first system and device function information for the second system.

1. Field of the Invention
The present invention relates to a print job conversion control for an information processing apparatus configured to perform conversion of a print job among plural printing systems having different functions.
2. Description of the Related Art
The commercial printing industries are based on a print-ordering system capable of receiving, from clients, print requests for various products (e.g., magazines, newspapers, catalogs, advertisements, and gravures), creating printed products requested by the clients, and delivering the printed products to respective clients.
This kind of commercial printing industries generally uses large-scale printing apparatuses, such as offset printing machines, to perform various processes including document entry, design and/or layout, comprehensive layout (print output for presentation), correction (layout correction and color correction), proof print, camera-ready block copy creation process, printing process, post-processing process, and delivery.
On the other hand, highly-advanced technologies of recent electrophotographic printing apparatuses and inkjet printing apparatuses can realize a print on demand (hereinafter, referred to as POD) market comparable to the printing service provided by the conventional printing industries.
The POD system is useful in processing a relatively small lot of job in a short period of time without using large-scale apparatuses and systems. The POD system can utilize best performances of digital image forming apparatuses, such as digital copying machines and digital multifunction peripherals, to obtain a digital print of electronic data, which cannot be realized by the above-described conventional printing system using large-scale printing machines or printing methods.
According to the POD system, management and control of printing processes can be greatly digitized and computerized compared to the conventional printing system.
Furthermore, the POD system can use a workflow including plural processing processes (e.g., pre-print process, print process, and post-print process) required for outputting a print result. The printing system can execute the print processing according to the workflow and can efficiently obtain a print result requested by a client (orderer).
A technique for automatically creating a workflow including plural processing process is, for example, discussed in Japanese Patent Application Laid-open No. 2004-164570. According to a method for automatically creating a workflow discussed in Japanese Patent Application Laid-open No. 2004-164570, a workflow creation apparatus holds environment information (e.g., output conditions including attribute values of a final output product, workflow creation rules stored beforehand, presence of processing modules, and designation of computers that can execute respective processing modules). Then, based on the environment information, the workflow creation apparatus automatically creates a workflow for obtaining a final output product.
However, according to the above-mentioned Japanese Patent Application Laid-open No. 2004-164570, no consideration is given to print data created for a different printing system although the workflow required to obtain a final output product can be automatically created. As an example of print data, the print data may include portable document format data (PDF) (content data) and print instruction data (job ticket).
For example, creation of PDF for a system A is generally optimized by performing down-sampling suitable for the resolution of a printing device in the system A. Therefore, if a digital print section in a system B is different in resolution from a digital print section in the system A, the digital print section of the system B cannot execute optimum print processing for PDF transferred from the system A. Accordingly, if the PDF transferred from the system A is processed by the digital print section in the system B, the print quality will be deteriorated.
Furthermore, a printing device in the system A and a printing device in the system B may have different printable regions even if they can print the same regular size (A4/A3) documents. For example, a printing device in the system B may require a larger printing margin compared to that of a printing device in the system A. In such a case, if PDF created by a prepress section in the system A is processed by the printing device in the system B, the peripheral region of an image may not be printed properly due to the difference of printing margin.
As described above, various problems arise when print data created for a particular printing system is processed by another printing system. An output result requested by a client may not be obtained. It is, however, difficult and time consuming for a worker to carefully check function information of devices and print data processed in both systems and rearrange the print data to smoothly execute the print processing.

Information processing apparatus for converting print jobs among a plurality of printing systems, print job conversion method, and program


A noise adaptive automatic gain control circuit (100) includes an automatic gain control amplifier (105) for automatically adjusting the gain of the circuit (100) in response to an input signal applied to the input. A detector (135) is provided for detecting the presence of any background noise that may be present. Further, a voltage generator (126), a comparator (124), and a microcomputer (150) is provided for dynamically adjusting the gain of the AGC amplifier (105) to substantially prevent the amplification of the background noise. In other aspects of the present invention, a voice lull detector (140) detects voice lulls (402) in the input signal applied to the input. Further, a programmable amplifier (120) substantially maintains the gain of the AGC amplifier (105) to a constant level during voice lulls (402) to prevent excessive amplification.

Conventional automatic gain control (AGC) systems are generally designed to provide a constant output signal with an input signal that varies in amplitude over a given range. These systems are used in a variety of applications including radio communication devices. Present AGC circuits employ feedback systems to allow the gain of the circuit to vary in relationship to the input signal. As the input signal is increased or decreased, a constant level is maintained at the output. Several problems are in general encountered in typical AGC circuits. The first problems is associated with voice lulls that are present in conversational speech. Voice lulls are pauses that are present in the utterance of words. During a voice lull, the signal at the input of an AGC circuit is reduced to a very low level causing a surge in the gain of the AGC in order to maintain a constant level at the output. This surge in the gain causes annoying noise pumping which is a sudden surge in noise level. A second problem with conventional AGC systems, has to do with background noise. In applications, where background noise is high, the signal level becomes unintelligible. This is due to the fact that the gain of the amplifier does not increase according to the level of input signal because of the overriding noise power. Another problem associated with conventional AGC circuits is their dynamic range fixity. This problem is encountered when an AGC circuit is expected to operate in whisper mode (very low level signal, hence very high gain) or high noise mode (high level signals, hence low gain). The deficiencies of the prior art have limited the use of AGC circuits, particularly in portable and mobile communication devices. It can therefore be appreciated that a need exists for an AGC circuit that overcomes the deficiency of the prior art.

Noise adaptive automatic gain control circuit


A system for configuring solid-state storage devices comprises a solid-state storage device and an error correction code (ECC) selection system. The ECC selection system is configured to automatically select a set of error correction code based on an error rate of the storage device. The ECC selection system is further configured to install the selected set of error correction code in the solid-state storage device.

A typical solid-state storage device comprises one or more arrays of storage cells for storing data. Existing semiconductor technologies provide volatile solid-state storage devices suitable for relatively short term storage of data, such as dynamic random access memory (DRAM), or devices for relatively longer term storage of data such as static random access memory (SRAM) or non-volatile flash and electrically erasable programmable read-only memory (EEPROM) devices.
A magnetoresistive storage device has been developed as a new type of non-volatile solid-state storage device. The magnetoresistive solid-state storage device is also known as magnetic random access memory (MRAM device. MRAM devices have relatively low power consumption and relatively fast access times, particularly for data write operations, which render MRAM devices ideally suited for both short term and long term storage applications.
A problem arises in that MRAM devices are subject to physical failure, which can result in an unacceptable loss of stored data. Physical failures within a MRAM device can result from many causes including manufacturing imperfections, internal effects such as noise in a read process, environmental effects such as temperature and surrounding electromagnetic noise, or ageing of the device in use. Failures can generally be classified as either systematic failures or random failures. Systematic failures consistently affect a particular storage cell or a particular group of storage cells. Random failures occur transiently and are not consistently repeatable. Systematic failures can arise as a result of manufacturing imperfections and ageing. Random failures occur in response to internal effects and to external environmental effects.
Currently available manufacturing techniques for MRAM devices are subject to limitations, and as a result, manufacturing yields of acceptable MRAM devices are relatively low. Although better manufacturing techniques are being developed, these tend to increase manufacturing complexity and cost. It is also desirable to increase cell density formed on a substrate such as silicon, but as the density increases, manufacturing tolerances become increasingly difficult to control, leading to higher error rates and lower device yields.
Currently, error correction coding implemented with memory to remedy manufacturing defects affecting memory accuracy is of one pre-determined size regardless of the level of accuracy of the memory or the intended application of the memory. Typically, the one pre-determined size is the most powerful level of ECC available. However, where the actual defect level of the MRAM device is not taken into account, error correction coding with a higher level of correction capability ("power level") may be installed for use with an MRAM device than is needed to provide an acceptably accurate device. Similarly, where the intended application of the MRAM device is not taken into account prior to installing the error correction coding, error correction coding capable of a higher accuracy level than is necessary for the intended application may be implemented. Use of over-corrective (higher "power level" than necessary) ECC can unnecessarily slow the speed of operations performed by the device with which the ECC is used and requires greater power to run the machine in which the device is installed.

System and method for configuring a solid-state storage device with error correction coding

Hewlett-Packard Development Company, L.P.


A drilling fluid is diluted and a cementitious component added thereto. In a more specific embodiment the dilution is carried out by introducing liquid such as water to a flowing stream of the drilling fluid and thereafter a cementitious component is mixed therewith. Thus, the drilling fluid can be used in a conventional manner to drill a well and thereafter diluted and a cementitious component added to produce a cement for cementing operations such as setting a casing in the well and/or can be used for remedial cementing.. In another embodiment of the invention, the drilling fluid itself contains a small amount of cementitious component and additional cementitious component is added after the dilution.

This invention relates to forming cementitious slurries from drilling fluids and to using such slurries in drilling and cementing.
Cementing of the annulus between an oil well casing and the surrounding borehole has been practiced for over 90 years. Long ago, it was recognized that it would be advantageous to solidify drilling fluid in the annulus so as to reduce the cost of the cementing of the casings. Over the decades, various attempts have been made along this line as evidenced by the disclosures in Williams et al., U.S. Pat. No. 2,649,160 (Aug. 18, 1953), Tragesser, U.S. Pat. No. 3,557,876 (Jan. 26, 1971), and Miller et al., U.S. Pat. No. 3,887,009 (Jun. 3, 1975). However, such techniques, while presumably operable, have failed to achieve commercialization even after the passage of many years. Another attempt in this direction is described in Wyant et al., U.S. Pat. No. 3,499,491 (Mar. 10, 1970), wherein Portland cement is used in an aqueous drilling fluid to produce a mud concrete. Portland cement, however, is very sensitive to the water/solids ratio. Even under ideal conditions, only small increases in the amount of solids results in a very viscous mass. On the other hand, and only a slight decrease in the amount of solids results in a composition which sets up to give a very weak structure. These problems are amplified when attempting to use Portland cement in a drilling mud. Thus, while this technique has been used commercially, it has serious drawbacks.
Expanded use of extended reach drilling and slim hole drilling has increased the problem of removing an incompatible drilling fluid before cementing, because the more narrow annulus created in these techniques create makes conventional cementing far more difficult.
Generally, drilling fluids are tailored to the characteristics of the formation into which the borehole is being drilled so far as density and rheological properties such as viscosity are concerned. Thus, even if the composition is tolerant of substantial variations in solids to liquid ratio so far as strength and viscosity are concerned, the density is still changed by the addition of a cementitious material to the composition.
Finally, when the drilling operation is complete there remains the problem of disposing of the used drilling fluid.

Dilution of drilling fluid in forming cement slurries


The present invention provides novel crystalline hydrochloride salt of darunavir, process for its preparation and to pharmaceutical composition comprising it. The present invention also provides novel process for preparation of darunavir amorphous form and pharmaceutical composition comprising it.

Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly, inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections. Darunavir has HIV protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Among them darunavir, chemically (1S,2R,3′R,3′aS,6′aR)-[3′-hexahydrofuro[2,3-b]furanyl-[3-(4-aminobenzenesulfonyl)isobutylamino]-1-benzyl-2-hydroxypropyl]carbamate. Darunavir is represented by the following structure:

Darunavir and its pharmaceutical acceptable salts such as hydrochloride were described in EP 715618.
Processes for the preparations of darunavir were disclosed in EP 715618, WO 99/67417, U.S. Pat. No. 6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998, "Potent HIV protease inhibitors incorporating high-affinity P2-igands and (R)-(hydroxyethylamino)sulfonamide isostere", all of which are incorporated herein by reference.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Darunavir or its hydrochloride salt can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. Patent Application No. 2005/0250845 described amorphous form, form A (ethanolate), form B (hydrate), form C (methanolate), form D (acetonate), form E (dichloromethanate), form F (ethylacetate solvate), form G (1-ethoxy-2-propanolate), form H (anisolate), form I (tetrahydrofuranate), form J (isopropanolate) and form K (mesylate) of darunavir.
Darunavir C5-C8 alcohol solvate and process for its preparation was disclosed in co-pending Application No. PCT/IN2009/000724. According to the application also disclosed a process for the preparation of darunavir amorphous form which comprises a solution of darunavir C5-C8 alcohol solvate in dichloromethane, removing the solvent from the solution to obtain a residue, slurrying the residue with cyclohexane and isolating.
We have discovered novel crystalline hydrochloride salt of darunavir and also discovered novel process for the preparation of darunavir amorphous form.
Thus, one object of the present invention is to provide novel crystalline hydrochloride salt of darunavir, process for its preparation and to pharmaceutical compositions comprising it.
The salt of the present invention may also serve as intermediates for preparation of darunavir amorphous form and other polymorphs of darunavir.
Another object of the present invention is to provide a novel process for preparation of darunavir amorphous form and pharmaceutical compositions comprising it.

Crystalline hydrochloride salt of darunavir


The present invention is methods and compositions for reducing and preventing the excess accumulation of extracellular matrix in a tissue and/or organ or at a wound site using a combination of agents that inhibit TGFβ, or using agents that inhibit TGFβ in combination with agents that degrade excess accumulated extracellular matrix. The compositions and methods of the invention are used to treat conditions such as fibrotic diseases and scarring that result from excess accumulation of extracellular matrix, impairing tissue or organ function or skin appearance in a subject.

Excess deposition and accumulation of extracellular matrix (ECM) is found in diseases such as fibrosis of the kidney or lung. Although the cytokine transforming growth factor Beta (TGFβ) regulates extracellular matrix deposition for tissue repair, overproduction of TGFβ clearly underlies tissue fibrosis caused by excess deposition of extracellular matrix resulting in disease (Border and Ruoslahti, J. Clin. Invest. 90:1-7 (1992)). TGFβ's fibrogenic action results from simultaneous stimulation of matrix protein synthesis (Border et al., Kidney Int 37:689-695 (1990), inhibition of matrix degradation and turnover and enhanced cell-matrix interactions through modulation of integrin receptors that facilitate ECM assembly. Overproduction of TGFβ has been demonstrated in glomerulonephritis (Okuda et al., J. Clin. Invest. 86:453-462 (1990)), diabetic nephropathy and hypertensive glomerular injury and in related fibrotic disorders of the lung, liver, heart, arterial wall, skin, brain, joints and bone marrow (Border and Noble, N. Eng. J. Med. 331:1286-1292 (1994)). In addition to the kidney, blocking the action of TGFβ with an agent such as antibody or the proteoglycan decorin has been shown to be therapeutic in fibrosis and scarring of the skin, lung, central nervous system and arterial wall (Border and Noble, Kidney Int. 51:1388-1396(1997)).
Suppression of the production of ECM and prevention of excess accumulation of mesangial matrix in glomeruli of glomerulonephritic rats has been demonstrated by intravenous administration of neutralizing antibodies specific for TGFβ (Border et al., Nature 346:371-374 (1990)) or administration of purified decorin, a proteoglycan (Border et al., Nature 360:361-364 (1992)) and by introduction of nucleic acid encoding decorin, a TGF-inhibitory agent, into a rat model of acute mesangial glomerulonephritis (Isaka et al., Nature Med. 2:418-423 (1996)). Inhibition of TGFβ activity, using for example anti-TGFβ antibodies, has been shown to to disrupt TGFβ overproduction (Sharma et al., Diabetes 45:522-530 (1996)).
Dermal scarring following dermal injury results from excessive accumulation of fibrous tissue made up of collagen, fibronectin and proteoglycans at a wound site. Because the fibrous extracellular matrix lacks elasticity, scar tissue can impair essential tissue function as well as result in an undesirable cosmetic appearance. TGFβ is believed to induce the deposition of fibrous matrix at the wound site (Shah et al., Lancet 339:213-214 (1992)).
One explanation for persistent TGFβ overexpression in progressive fibrotic kidney disease is that repeated or multiple episodes of tissue injury, such as occurs in chronic diseases such as hypertension, diabetes or immune complex disease lead to continuous overproduction of TGFβ and extracellular matrix resulting in tissue fibrosis (See Border and Noble, N. Eng J. Med. 331:1286-1292 (1994)). Another possible explanation for persistent TGFβ overexpression is the presence of a biologically complex interconnection between TGFβ and the renin-angiotensin system (RAS) in the kidney as part of an emergency system that responds to the threat of tissue injury as discussed further herein.
Renin is an aspartyl proteinase synthesized by juxtaglomerular kidney cells and mesangial cells in humans and rats. (Chansel et al., Am. J. Physiol. 252:F32-F38 (1987) and Dzau and Kreisberg, J. Cardiovasc. Pharmacol. 8 (Suppl 10):S6-S10 (1986)). Renin plays a key role in the regulation of blood pressure and salt balance. Its major source in humans is the kidney where it is initially produced as preprorenin. Signal peptide processing and glycosylation are followed by secretion of prorenin and its enzymatically active form, mature renin. The active enzyme triggers a proteolytic cascade by cleaving angiotensinogen to generate angiotensin I, which is in turn converted to the vasoactive hormone angiotensin II by angiotensin converting enzyme ("ACE").
The sequence of the human renin gene is known (GenBank entry M26901). Recombinant human renin has been synthesized and expressed in various expression systems (Sielecki et al., Science 243:1346-1351 (1988), Mathews et al., Protein Expression and Purification 7:81-91 (1996)). Inhibitors of renin's enzymatic site are known (Rahuel et al., J. Struct. Biol. 107:227-236 (1991); Badasso et al., J. Mol. Biol. 223:447-453 (1992); and Dhanaraj et al., Nature 357:466472 (1992)) including an orally active renin inhibitor in primates, Ro 42-5892 (Fischli et al., Hypertension 18:22-31 (1991)). Renin-binding proteins and a cell surface renin receptor on human mesangial cells have been identified (Campbell and Valentijn, J. Hypertens. 12:879-890 (1994), Nguyen et al., Kidney Internat. 50:1897-1903 (1996) and Sealey et al., Amer. J. Hyper. 9:491-502 (1996)).
The renin-angiotensin system (RAS) is a prototypical systemic endocrine network whose actions in the kidney and adrenal glands regulate blood pressure, intravascular volume and electrolyte balance. In contrast, TGFβ is considered to be a prototypical cytokine, a peptide signaling molecule whose multiple actions on cells are mediated in a local or paracrine manner. Recent data however, indicate that there is an intact RAS in many tissues whose actions are entirely paracrine and TGFβ has wide-ranging systemic (endocrine) effects. Moreover, RAS and TGFβ act at various points to regulate the actions of one another.
In a systemic response to an injury such as a wound, the RAS rapidly generates All that acts by vasoconstriction to maintain blood pressure and later stimulates the secretion of aldosterone, resulting in an increase in intravascular volume. In the wound, TGFβ is rapidly released by degranulating platelets and causes a number of effects including: 1) autoinduction of the production of TGFβ by local cells to amplify biological effects; 2) chemoattraction of monocyte/macrophages that debride and sterilize the wound and fibroblasts that begin synthesis of ECM; 3) causing deposition of new ECM by simultaneously stimulating the synthesis of new ECM, inhibiting the proteases that degrade matrix and modulating the numbers of integrin receptors to facilitate cell adhesion to the newly assembled matrix; 4) suppressing the proinflammatory effects of interleukin-1 and tumor necrosis factor; 5) regulating the action of platelet derived growth factor and fibroblast growth factor so that cell proliferation and angiogenesis are coordinated with matrix deposition; and 6) terminating the process when repair is complete and the wound is closed (Border and Noble, Scientific Amer. Sci. & Med. 2:68-77 (1995)).
Interactions between RAS and TGFβ occur at both the systemic and molecular level. It has been shown that TGFβ's action in causing ECM deposition in a healing wound is the same action that makes TGFβ a powerful fibrogenic cytokine. (Border and Noble, New Engl. J. Med. 331:1286-1292 (1994); and Border and Ruoslahti, J. Clin. Invest. 90:107 (1992)). Indeed, it is the failure to terminate the production of TGFβ that distinguishes normal tissue repair from fibrotic disease. RAS and TGFβ co-regulate each other's expression. Thus, both systems may remain active long after an emergency response has been terminated, which can lead to progressive fibrosis. The kidney is particularly susceptible to overexpression of TGFF. The interrelationship of RAS and TGFβ may explain the susceptibility of the kidney to TGFβ overexpression and why pharmacologic suppression of RAS or inhibition of TGFβ are both therapeutic in fibrotic diseases of the kidney. (Noble and Border, Sem. Nephrol., supra and Border and Noble, Kidney Int. 51:1388-1396 (1997)).
Activation of RAS and generation of angiotensin II (AII) are known to play a role in the pathogenesis of hypertension and renal and cardiac fibrosis. TGFβ has been shown to be a powerful fibrogenic cytokine, acting simultaneously to stimulate the synthesis of ECM, inhibit the action of proteases that degrade ECM and increasing the expression of cell surface integrins that interact with matrix components. Through these effects, TGFβ rapidly causes the deposition of excess ECM. AII infusion strongly stimulates the production and activation of TGFβ in the kidney. (Kagami et al., J. Clin. Invest. 93:2431-2437 (1994)). Angiotensin II also upregulates TGFβ production and increases activation when added to cultured vascular smooth muscle cells (Gibbons et al, J. Clin. Invest. 90:456-461 (1992)) and this increase is independent of pressure (Kagami et al., sira). AII also upregulates TGFβ receptors, even in the presence ofexogenously added TGFβ which normally down-regulates its own receptors, leading to enhanced TGFβ signalling and enhanced fibronectin production (Kanai et al., J. Am. Soc. Nephrol. 8:518A (1997)). Blockade of AII reduces TGFβ overexpression in kidney and heart, and it is thought that TGFβ mediates renal and cardiac fibrosis associated with activation of RAS (Noble and Border, Sem. Nephrol. 17(5):455-466 (1997)), Peters et al., Kidney International 54 (1998)). Blockade of AII using inhibitors of ACE slow the progression of renal fibrotic disease (see, e.g., Anderson et al., J. Clin. Invest. 76:612-619 (1985) and Noble and Border, Sem. Nephrol. 17(5):455-466(1997)). What is not clear is whether angiotensin blockade reduces fibrosis solely through controlling glomerular hypertension and thereby glomerular injury, or whether pressure-independent as well as pressure-dependent mechanisms are operating. While ACE inhibitors and AII receptor antagonists have been shown to slow the progress of fibrotic diseases, they do not halt disease and TGFβ levels remain somewhat elevated. (Peters et al., supra).
Thus, RAS and TGFβ can be viewed as powerful effector molecules that interact to preserve systemic and tissue homeostasis. The response to an emergency such as tissue injury is that RAS and TGFβ become activated. Continued activation may result in chronic hypertension and progressive tissue fibrosis leading to organ failure. Because of the interplay between the RAS and TGFβ, and the effects of this interplay on tissue homeostasis, blockade of the RAS may be suboptimal to prevent or treat progressive fibrotic diseases such as diabetic nephropathy.
Components of the renin-angiotensin system act to further stimulate production of TGFβ and plasminogen activator inhibitor leading to rapid ECM accumulation. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates with the suppression of TGFβ production. (Noble and Border, Sem. Nephrol., supra; and Peters et al., supra).
The renin molecule has been shown to enzymatically cleave angiotensinogen into Angiotensin I. The angiotensin I is then converted by Angiotensin Converting Epiyme ("ACE") to Angiotensin II which acts as an active metabolite and induces TGFβ production. Angiotensin II is an important modulator of systemic blood pressure. It has been thought that if you decrease hypertension by blocking AII's vasoconstrictor effects fibrotic disease is reduced.
In the glomerular endothelium, activation of RAS and TGFβ have been shown to play a role in the pathogenesis of glomerulonephritis and hypertensive injury. Volume (water) depletion and restriction of potassium have been shown to stimulate both production of renin and TGFβ in the juxtaglomerular apparatus (JGA) of the kidney (Horikoshi et al., J. Clin. Invest. 88:2117-2122 (1992) and Ray et al., Kidney Int. 44:1006-1013 (1993)). Angiotensin blockade has also been shown to increase the production of renin. TGFβ has been shown to stimulate the release of renin from kidney cortical slices and cultured JG cells (Antonipillai et al., Am. J. Physiol. 265:F537-F541 (1993); Ray et al., Contrib. Nephrol. 118:238-248 (1996) and Veniant et al., J. Clin. Invest. 98:1996-19970 (1996)), suggesting that renin and TGFβ are coregulated. Other interactions between RAS and TGFj) include that AII induces the producton of TGFβ in cultured cells and in vivo (Kagami et al., supra) and AII regulates expression of TGFβ receptors (Kanai et al., 1977, sura). It is thus likely that the fibrogenic effects that have been attributed to AII are actually mediated by TGFβ.
Another interplay between RAS and TGFβ is with the production of aldosterone. Aldosterone overproduction has been linked to hypertension and glomerunosclerosis. AII stimulates the production and release of aldosterone from the adrenal gland. In contrast, TGFβ suppresses aldosterone production and blocks the ability of AII to stimulate aldosterone by reducing the number of AII receptors expressed in the adrenal (Gupta et al., Endocrinol. 131:631-636 (1992)), and blocks the effects of aldosterone on sodium reabsorption in cultured renal collecting duct cells (Husted et al., Am. J. Physiol. _i Renal, Fluid Electrolyte Physiol. 267:F767-F775 (1994)). Aldosterone may have fibrogenic effects independent of AII, and may upregulate TGFβ expression. The mechanism of aidosterone's pathological effects is unknown but might be due to stimulation of TGFβ production in the kidney (Greene et al., J. Clin. Invest. 98:1063-1068 (1996)).
Prorenin or renin may have AII-independent actions to increase fibrotic disease. Prorenin overexpressing rats were found to be normotensive but to develop severe glomerulosclerosis (Veniant et al., J. Clin. Invest. 98:1996-1970 (1996)).
Human recombinant renin added to human mesangial cells induces marked upregulation of production of plasminogen activator inhibitors (e.g. PAI-1 and PAI-2) which block the generation of plasmin, a fibrinolytic enzyme important in the dissolution of clots after wounding generated from plasminogen by two enzymes called plasminogen activators, urokinase (u-PA) and tissue plasminogen activator (t-PA). PAI-1 and 2 regulate U-PA and t-PA in turn. Plasmin appears to be a key mediator of extracellular matrix degradation, carrying out at least three functions important to extracellular matrix degradation. Plasmin directly degrades proteoglycan components of extraceflular matrix, proteolytically activates metalloproteinases (MMPs) that, in turn, degrade collagens and other matrix proteins, and enzymatically inactivates tissue inhibitors of MMPs (TIMPs), releasing MMPs from inhibition of TIMPs, allowing them to proteolytically digest matrix proteins. (Baricos et al., Kidney Int'l. 47:1039-1047 (1995); Baricos et al., J. Amer. Soc. Nephrol. 10:790-795 (1999)). The net generation of active plasmi from the inactive precursor plasminogen results from a balance of the plasminogen activators and PAI-1 and 2, and other factors. PAI-1 binds to vitronectin. (Lawrence et al., J. Biol. Chem. 272:7676-7680 (1997)). Mutant PAI-1 molecules have been developed that have enhanced properties for PAI-1 binding to vitronectin molecules, but do not inhibit either t-PA or u-PA activity, resulting in an increase in the amount of the active form of plasmin. (See, WO 97/39028, Lawrence et al.). PAI-1 is increased in response to added TGFβ (Tomooka et al., Kidney Int. 42:1462-1469 (1992)).
It has been suggested that TGFβ enhances release of renin from storage granules in the juxtaglomerular apparatus of the kidney (Antonipillai et al., Am. J. Physiol. 265:F537-F541 (1993) and Ray et al., Contrib. Nephrol. 118:238-248 (1996)).
Thus, the interactions of RAS and TGFβ production form a complex system which impacts fibrotic ECM accumulation and the incidence of fibrotic disease. Various RAS components such as aldosterone, prorenin and renin may be connected with TGFβ production and fibrotic ECM accumulation. Any successful therapeutic regime must take into account these complex relationships to optimize inhibition of TGFβ to prevent and/or reduce ECM accumulation.
The multiple pathways resulting in TGFβ overexpression and fibrosis proposed from in vitro studies are depicted in FIG. 1. (See, Kagami et al., J. Clin. Invest. 93:2431-2437 (1994); Gibbons et al., J. Clin. Invest. 90:456-461 (1992); Abboud, Kidney Int. 41:581-583 (1992); Ruiz-Ortega et al., J. Am. Soc. Nephrol. 5:683 (1994) abstract; Kim et al., J. Biol. Chem. 267:13702-13707 (1992); Ohno et al., J. Clin. Invest. 95:1363-1369 (1995); Riser et al, J. Clin. Invest. 90:1932-1943 (1992); Riser et al., J. Am. Soc. Nephrol. 4:663 (1993); Ziyadeh et al., J. Clin. Invest. 93:536-542 (1994); Rocco et al., Kidney Int. 41:107-114 (1992); Flaumenhaft et al., Advan. Pharmacol. 24:51-76 (1993); Lopez-Armanda et al., J. Am. Soc. Nepbrol. 5:812 (1994) abstract; Sahai et al., J. Am. Soc. Nephrol. 6:910 (1995); Remuzzi et al., Kidney Int. 1:2-15 (1997); and Remuzzi et al., J. Am. Soc. Nephrol. 9:1321-1332 (1998)). This diagram shows that a large number of factors implicated in kidney injury are believed to increase tbF production of TGFβ.
In fibrotic diseases overproduction of TGFβ results in excess accumulation of extracellular matrix which leads to tissue fibrosis and eventually organ failure. Accumulation of mesangial matrix is a histological indication of progressive glomerular diseases that lead to glomerulosclerosis and end-stage kidney disease (Klahr et al., N. Engl. J. Med. 318:1657-1666 (1988); Kashgarian and Sterzel, Kidney Int. 41:524-529 (1992)). Rats injected with antithymocyte serum are an accepted model of human glomerulonephritis and this model has demonstrated that overproduction of glomerular TGFβ can underlie the development of glomerulosclerosis (Okuda et al., J. Clin. Invest. 86:453-462 (1990); Border et al., Nature (Lond.) 346:371-374 (1990); Kagami et al., Lab. Invest. 69:68-76 (1993); and Isaka et al., J. Clin. Invest. 92:2597-2602 (1993)). Using cultured rat mesangial cells where the effects of Angiotensin II on glomerular pressure are not a factor, Angiotensin II has been shown to induce TGFβ production and secretion by mesangial cells, and this in turn has been shown to stimulate extracellular matrix production and deposition (Kagami et al., J. Clin. Invest. 93:2431-2437 (1994)). Increases in PAI-1 levels result in decreased degradation of extracellular matrix (Baricos et al., Kidney Int. 47:1039-1047 (1995)). Increases in TGFβ result in increased PAI-1 levels (Tomooka et al., Kidney Int. 42:1462-1469 (1992)). It has been demonstrated that decreasing TGFβ overexpression in a rat model of glomerulonephritis by in vivo injection of neutralizing antibodies to TGFβ, reduces TGFβ overexpression (Border et al., Nature 346:371-374(1990)), and reduces PAI-1 deposition into the pathological matrix (Tomooka et al., Kidney Int. 42:1462-1469 (1992)). Therefore, decreases in TGFβ levels should result in decreased PMA-1 levels and increased degradation of extracellular matrix to ameliorate organ impairment and fibrotic disease. However, patients present with fibrotic disease that is well advanced in terms of build-up of extra-cellular matrix (ECM). This is because abnormal organ function is undetectable until ECM accumulation is very advanced. For example, in the kidney, standard diagnostic tests do not provide an abnormal reading until about fifty percent of organ function has been lost.
The treatment of conditions associated with excess accumulation of ECM has also focused on decreasing stimuli to disease such as to, lower blood pressure or, in the case of diabetic nephropathy to reduce plasma glucose levels. For example, current therpies fqr treating fibrotic disease in the kidney are limited to AII blockade using ACE inhibitors such as Enalapril or AII receptor antagonists such as Losartan. In addition, patients are encouraged to follow low protein diets since this regimen has some therapeutic value (Rosenberg et al., J. Clin. Invest. 85:1144-1149 (1992)). These therapies, at best, prolong organ function by only 1-2 years. This may be because of the multiple pathways that result in TGFβ overexpression or enhanced activity. Moreover, it is likely that current therapeutic strategies to reduce TGFβ overproduction may lead to upregulation of other pathways resulting in continued TGFβ overproduction. For example, when the action of AII is blocked, renin is upregulated which itself increases TGFβ production (see co-pending U.S. patent application, U.S. Ser. No. 09/005,255, incorporated in its entirety herein). More recently, treatments aimed to halt the overproduction of TGFβ have been proposed (Border and Noble, Kidney Internatl. 54 (1998); and Peters et al., Kidney Internatl. 54 (1998)).
Therefore, the most promising therapeutic methods will need to increase ECM degradation to restore organ function as well as decrease TGFβ overproduction and/or activity. Enhanced degradation of excess accumulated ECM can be used to optimize overall reduction in levels of accumulated ECM to restore function to tissues and organs. Proteases that are able to degrade ECM are known. For example, the serine protease plasmin degrades ECM proteins and activates pro-metalloproteinases, in addition to degrading fibrin (Baricos et al., supra). One goal of therapeutic intervention to increase ECM degradation for treating fibrosis could be increasing plasmin in the region of excess ECM deposition.
There is a need for improved therapies to normalize TGFβ production, that take into account the multiple pathways that stimulate TGFβ production, to prevent or reduce excess accumulation of ECM, to restore function to tissues and organs in which excess ECM has accumulated and/or to reduce scar formation at a wound site.

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Methods for treating conditions associated with the accumulation of excess extracellular matrix