A pivotable folding utility table includes a table top having a pair of support pedestals pivotally attached thereto. A first pivotal support brace including a distal end and a proximal end attached to the first support pedestal. A second pivotal support brace including a distal end and a proximal end attached to the second support pedestal. The distal ends of the first and second pivotal support braces pivotally attached to a retaining assembly preferably mounted in relation to the table top. Specifically, the retaining assembly includes a cross-brace member operably disposed through openings formed in the distal ends of the first and second pivotal support braces, thus providing a pivotal engagement in relation to the table top. Alternatively, a second retaining assembly including a cross-brace member may be mounted in relation to the table top, wherein the distal end of the first pivotal support brace pivotally engages the first retaining member and the distal end of the second pivotal support brace pivotally engages the second retaining member. In addition, the first and second support pedestals may comprise at least one support leg, wherein each support leg of the first and second support pedestals are laterally offset from each other so as to permit an offset displacement of the support legs when the support pedestals are disposed in a collapsed position.

1. The Field of the Invention The present invention is related to a utility table, and more particularly, to a portable folding utility table having one or more center support assemblies and off-set support legs that selectively support the utility table above a surface.
2. Technical Background
Portable folding utility tables are indispensable for groups or organizations that have limited floor space usable for multiple purposes. For example, foldable utility tables can be placed in a pre-determined configuration to meet the space requirements of a school gymnasium, a church multi-purpose room, or a hotel conference meeting room. Afterward, the tables can be neatly stored away and the conference or meeting room used for a different purpose. Thus, portable folding utility tables allow a group or organization to maximize the efficiency and utility of a particular space.
Foldable utility tables can also provide an immediate temporary work space in a garage, tool shed, and the like. The portability and foldability of these utility tables allows a user to conveniently set up, take down, and store the table whenever and wherever the user chooses.
A major drawback with many portable folding utility tables of the prior art, however, is their inherent size and bulkiness. Many such utility tables require two people to collapse and store the table after use. Moreover, some prior art portable folding utility tables are heavy enough to cause injury if dropped or mishandled. These unwieldy tables are usually made from hardwood, particle board, or similarly heavy materials. In an attempt to overcome this weight and bulkiness problem, some prior art portable utility tables are formed of lighter-weight materials. However, many of these lightweight utility tables generally lack the sturdiness of the heavier-weight prior art utility tables.
Another disadvantage to prior art utility tables is the means used for attaching the table support legs or two or more support pedestals to the underside of the table. As will be appreciated, prior art table support legs are typically attached to the table top using threaded screws or bolts that are drilled into the underside of the table top. This means of attachment may compromise the integrity of the table top thereby making it weaker at the point of attachment between the table support legs and the table top. Other attachment mechanisms may include a form of bonding the table support legs as support pedestals directly against the surface of the table top. Often, however, this means of attachment by bonding weakens the structural integrity of the table top. Thus, when the table support legs fail, a portion of the material forming the table top may pull away at the point of the bonded attachment thereby making the table costly, if not impossible to repair.
In an attempt to overcome the foregoing disadvantages, prior art utility tables were developed by those skilled in the art that are equipped with complex or heavy-duty attachment mechanisms that facilitate a secure attachment between the table support legs or the support pedestals and the table top. These types of attachment mechanisms, however, are normally heavier, more costly, more difficult to install, and typically require additional time to manufacture.
The previously stated disadvantages are compounded by the fact that many prior art utility tables incorporate a separate and distinct attachment mechanism for attaching each table support leg or pedestal to the table top. As appreciated, most existing portable folding utility tables have two sets of support legs or pedestal supports, one at each end of the table. Each of these supports is typically attached to the underside of the table top at two places or points of contact. Correspondingly, many of these types of utility tables have at least four separate points of attachment, each attachment between the support legs or pedestal supports facilitated by a separate attachment mechanism. One particular problem with utility tables having separate and distinct attachment mechanisms is that they are generally susceptible to bowing in the center of the table top under stress. This is especially true with larger banquet style tables.
Yet another drawback with many prior art utility tables is that the hard materials used to maintain a sufficient rigidity and sturdiness of the table top often have sharp edges which may be uncomfortable for the user to lean against or rest their arms upon. Further, these materials may also be susceptible to damage or degradation from the elements of nature.
In addition, smaller utility tables that are found in the prior art usually comprise shortened support legs that fail to provide sufficient height to the table top in relation to the underlying surface, thus these types of table are generally uncomfortable to users. In particular, when these prior art utility tables are configured in the folded position for storage, the table support legs are required to be short enough so not to interfere with each other when folded in a conventional fashion underneath the table top. Small folding utility tables of the prior art are also typically bulky when disposed in the folded position because complex and unwieldy mechanisms are generally required to accommodate the use of longer support legs that may be incorporated to overcome the inherent height deficit found in most smaller utility tables.
From the foregoing, it will be appreciated that it would be an advancement in the art to provide a portable folding utility table that is durable enough to withstand the increased wear and tear that portable utility tables are subjected to over long periods of time and sturdy enough to support varying sized loads that will be placed on the table, while at the same time being light-weight enough to be easily set up and taken down.
It would be another advancement in the art to provide a portable folding utility table having a leg or support pedestal attachment mechanism that does not involve a complex design, heavy duty attachment hardware, or need to be screwed, bolted, or bonded to the under side of the table top. It would be a further advancement in the art to provide a portable folding utility table that minimizes the points of attachment to the surface of the table top and facilitates attachment mechanisms that interrelate with each other to support the table top above an underlying surface.
Furthermore, it would be an advancement in the art to provide a portable folding utility table that may provide a smaller working surface than larger utility table, but that is comfortable to work at in relation to its height disposition and which is capable of withstanding the elements of nature.
Finally, it would be an advancement in the art to provide a portable folding utility table in which the support legs or pedestals, having a length greater than the corresponding length of the table top, can fold against the underside of the table top when disposed for storage without interfering with each other, so that smaller frames and table tops can be used that accommodate a sufficient height disposition in relation to the underlying support surface.
Such a portable folding utility table is disclosed and claimed herein.


A method for monitoring slope lands and buildings on the slope lands includes installing a light transceiver on a slope land and a light emission device on a location or a building corresponding to the light transceiver. When light emitted from the light emission device is received by the light transceiver, the light transceiver does not output signals. The light transceiver does not receive the light emitted from the light emission device when the dislocation or inclination occurs to the slope land and the light transceiver outputs a signal to alert a monitor center.

In recent years many slope lands have been relentlessly cultivated or developed and result in the soils of the slope lands cannot withstand a great amount rainwater seeping into the earth. Consequently the slope lands often crumple to form landslides that become a great threat or cause great damages to people living in the slope land area.
One of the measures to protect people living in the slope area is to construct retaining structure on the slope land. The conventional retaining structure usually is built in the form of embankment. Because of geographic and space constraints, the retaining structure often is constructed by a half-excavation and half-filling approach. And it generally is a man-made platform or construction space. These days many buildings are located on the slope land or below the slope land. Hence the slope land retaining structure becomes very important. A lot of slope land damage cases indicate that prior to the damage occur or pending to occur, many unstable symptoms such as small or obvious inclination or dislocations or cracking take place. However due to the present regulations do not have mandatory decree or budget constraint, no monitor systems or continuous monitoring have been established for those unstable slope lands. As a result, crumpling or dislocation of the slope land often aggravates and finally inflicts a great damage or disaster.
Therefore to establish a safety monitor structure or system for the community on the slope land area is an urgent issue.
To ensure the stability of the slope land retaining structure, besides giving additional reinforcement to the retaining structure, setting up a monitor apparatus on the slope land retaining structure to monitor the slope land condition also is important. FIG. 1 illustrates a conventional monitor system for such purpose. It includes a building gradient tray A, a landslide meter B, a gradient observation duct C, a sinking observation spot D, and a crevice meter E. While the monitor devices mentioned above can monitor the slope land conditions, they are very expensive. To install those equipment on the slope land retaining structure also is costly and time-consuming.

Method for monitoring slope lands and buildings on the slope lands


A frame-type computer cooling device for installation in a host computer is provided. The host computer has a heat-generating source and a slot compartment. The slot compartment communicates with the inside of the host computer and the outside of the host computer. The frame-type computer cooling device includes a frame and a cooling circulation device. The frame is insertedly disposed in the slot compartment and includes a receiving recess. The cooling circulation device includes an evaporator, a compressor, a condenser, and an expansion valve connected to one another by a pipeline filled with a coolant. The compressor, the condenser, and the expansion valve are received in the receiving recess. The evaporator adjoins the heat-generating source. Accordingly, the cooling circulation device is easy to install, and heat dissipation of the heat-generating source is swift and efficient.

1. Field of the Invention
The present invention relates to frame-type computer cooling devices, and more particularly, to a frame-type computer cooling device easy to install and efficient in dissipating heat from a heat-generating source in a host computer.
2. Description of Related Art
Recent years see evolution of ever-changing technologies, and thus computers are indispensable to the handling of routine at both an individual level and a corporate level. To be increasingly versatile, computers nowadays are equipped with an increasing number of electronic components more complicated than ever before, for example, CPU, chips, and expansion cards. All the electronic components in operation generate heat and thereby become so-called heat-generating sources. The heat generated by the electronic components is ever-increasing because of a continuous increase in both the data processed by computers and the speed thereof.
Usual means to heat dissipation of the aforesaid heat-generating sources are, namely cooling fans, cooling fins, heat pipes, and other heat-dissipating components. In this regard, a cooling circulation device is one of the feasible means to enhancement of efficiency in heat dissipation.
Nonetheless, cooling circulation devices are composed of various components, namely evaporators, compressors, condensers, expansion valves, etc. It is well known that host computers are equipped with a variety of electronic parts and electronic devices, thus leaving little usable space. Despite their high efficiency in heat dissipation, the cooling circulation devices mentioned above pose a challenge in space utilization when installed in host computers.
Accordingly, the purpose of the present invention is to disclose a frame-type computer cooling device easy to install and efficient in dissipating heat from a heat-generating source in a host computer.


A signal converting apparatus for integrating an analog-to-digital converter (ADC) and a digital-to-analog converter (DAC) and an integration unit thereof are provided. The present invention integrates ADC and DAC, that do not operate simultaneously, into a signal converting apparatus (SCA), wherein a control signal decides whether an analog-to-digital mode or a digital-to-analog mode is selected. By sharing the operational amplifiers and other components in the SCA, the chip area and the cost are significantly reduced. In addition, in the integration unit, by switching a plurality of capacitor sets with various capacitances, the capacitance coefficients required for switching ADC and DAC are obtained.

1. Field of Invention
The present invention relates to a signal converting apparatus (SCA) between an analog signal and a digital signal, and particularly to a signal converting apparatus (SCA) for integrating an analog-to-digital converter (ADC) and a digital-to analog converter (DAC) and an integration unit thereof.
2. Description of the Related Art
FIG. 1 is a block diagram showing a conventional processing structure of analog and digital signals. In general, an ADC 110 and a DAC 130 are two independent analog circuits designed separately. For converting an analog signal A1 into a digital signal D1, the analog signal A1 should be converted into a digital signal D1 by the ADC 110 first, then sent to a processor 120 (for example, a digital signal processor DSP) to process the digital signal. If the digital signal D2 output from the processor 120 is to be converted into an analog signal A2, the DAC 130 converts the digital signal D2 from the processor 120 into an analog signal A2 for output.
In real practice, however, there is little chance to conduct signal converting of both ADC and DAC simultaneously. In other words, only one converter, either the ADC 110 or the DAC 130, converts signals, while the other converter is idle. Thus, the circuit utility rate is low.

Signal converting apparatus for integrating analog-to-digital converter and digital-to-analog converter and integration unit


The invention features methods of treating or preventing congestive heart failure by administering a polypeptide containing an epidermal growth factor-like domain encoded by a neuregulin gene.

Congestive heart failure, one of the leading causes of death in industrialized nations, results from an increased workload on the heart and a progressive decrease in its pumping ability. Initially, the increased workload that results from high blood pressure or loss of contractile tissue induces compensatory cardiomyocyte hypertrophy and thickening of the left ventricular wall, thereby enhancing contractility and maintaining cardiac function. However, over time, the left ventricular chamber dilates, systolic pump function deteriorates, cardiomyocytes undergo apoptotic cell death, and myocardial function progressively deteriorates.
Factors that underlie congestive heart failure include high blood pressure, ischemic heart disease, exposure to cardiotoxic compounds such as the anthracycline antibiotics, and genetic defects known to increase the risk of heart failure.
Neuregulins (NRGs) and NRG receptors comprise a growth factor-receptor tyrosine kinase system for cell-cell signalling that is involved in organogenesis in nerve, muscle, epithelia, and other tissues (Lemke, Mol. Cell. Neurosci. 7: 247-262, 1996 and Burden et al., Neuron 18: 847-855, 1997). The NRG family consists of three genes that encode numerous ligands containing epidermal growth factor (EGF)-like, immunoglobulin (Ig), and other recognizable domains. At least 20 (perhaps 50 or more) secreted and membrane-attached isoforms may function as ligands in this signalling system. The receptors for NRG ligands are all members of the EGF receptor (EGFR) family, and include EGFR (or ErbB1), ErbB2, ErbB3, and ErbB4, also known as HER1 through HER4, respectively, in humans (Meyer et al., Development 124: 3575-3586, 1997; Orr-Urtreger et al., Proc. Natl. Acad. Sci. USA 90: 1867-71, 1993; Marchionni et al., Nature 362: 312-8, 1993; Chen et al., J. Comp. Neurol. 349: 389-400, 1994; Corfas et al., Neuron 14: 103-115, 1995; Meyer et al., Proc. Natl. Acad. Sci. USA 91:1064-1068, 1994; and Pinkas-Kramarski et al., Oncogene 15: 2803-2815, 1997).
The three NRG genes, Nrg-1, Nrg-2, and Nrg-3, map to distinct chromosomal loci (Pinkas-Kramarski et al., Proc. Natl. Acad. Sci. USA 91: 9387-91, 1994; Carraway et al., Nature 387: 512-516, 1997; Chang et al., Nature 387: 509-511, 1997; and Zhang et al., Proc. Natl. Acad. Sci. USA 94: 9562-9567, 1997), and collectively encode a diverse array of NRG proteins. The most thoroughly studied to date are the gene products of Nrg-1, which comprise a group of approximately 15 distinct structurally-related isoforms (Lemke, Mol. Cell. Neurosci. 7: 247-262, 1996 and Peles and Yarden, BioEssays 15: 815-824, 1993). The first-identified isoforms of NRG-1 included Neu Differentiation Factor (NDF; Peles et al., Cell 69, 205-216, 1992 and Wen et al., Cell 69, 559-572, 1992), Heregulin (HRG; Holmes et al., Science 256: 1205-1210, 1992), Acetylcholine Receptor Inducing Activity (ARIA; Falls et al., Cell 72: 801-815, 1993), and the glial growth factors GGF1, GGF2, and GGF3 (Marchionni et al. Nature 362: 312-8, 1993).
The Nrg-2 gene was identified by homology cloning (Chang et al., Nature 387:509-512, 1997; Carraway et al., Nature 387:512-516, 1997; and Higashiyama et al., J. Biochem. 122: 675-680, 1997) and through genomic approaches (Busfield et al., Mol. Cell. Biol. 17:4007-4014, 1997). NRG-2 cDNAs are also known as Neural- and Thymus-Derived Activator of ErbB Kinases (NTAK; Genbank Accession No. AB005060), Divergent of Neuregulin (Don-1), and Cerebellum-Derived Growth Factor (CDGF; PCT application WO 97/09425). Experimental evidence shows that cells expressing ErbB4 or the ErbB2/ErbB4 combination are likely to show a particularly robust response to NRG-2 (Pinkas-Kramarski et al., Mol. Cell. Biol. 18: 6090-6101, 1998). The Nrg-3 gene product (Zhang et al., supra) is also known to bind and activate ErbB4 receptors (Hijazi et al., Int. J. Oncol. 13:1061-1067, 1998).
An EGF-like domain is present at the core of all forms of NRGs, and is required for binding and activating ErbB receptors. Deduced amino acid sequences of the EGF-like domains encoded in the three genes are approximately 30-40% identical (pairwise comparisons). Further, there appear to be at least two sub-forms of EGF-like domains in NRG-1 and NRG-2, which may confer different bioactivities and tissue-specific potencies.
Cellular responses to NRGs are mediated through the NRG receptor tyrosine kinases EGFR, ErbB2, ErbB3, and ErbB4 of the epidermal growth factor receptor family. High-affinity binding of all NRGs is mediated principally via either ErbB3 or ErbB4. Binding of NRG ligands leads to dimerization with other ErbB subunits and transactivation by phosphorylation on specific tyrosine residues. In certain experimental settings, nearly all combinations of ErbB receptors appear to be capable of forming dimers in response to the binding of NRG-1 isoforms. However, it appears that ErbB2 is a preferred dimerization partner that may play an important role in stabilizing the ligand-receptor complex. Recent evidence has shown that expression of NRG-1, ErbB2, and ErbB4 is necessary for trabeculation of the ventricular myocardium during mouse development.
In view of the high prevalence of congestive heart failure in the general population, it would be highly beneficial to prevent or minimize progression of this disease by inhibiting loss of cardiac function, and ideally, by improving cardiac function for those who have or are at risk for congestive heart failure.

Methods for treating congestive heart failure


A photosensitive monolayer is self-assembled on an oxide surface. The chemical compound of the photosensitive monolayer has three components. A first end group provides covalent bonds with the oxide surface for self assembly on the oxide surface. A photosensitive group that dissociates upon exposure to ultraviolet radiation is linked to the first end group. A second end group linked to the photosensitive group provides hydrophobicity. Upon exposure to the ultraviolet radiation, the dissociated photosensitive group is cleaved and forms a hydrophilic derivative in the exposed region, rendering the exposed region hydrophilic. Carbon nanotubes or nanocrystals applied in an aqueous dispersion are selectively attracted to the hydrophilic exposed region to from electrostatic bonding with the hydrophilic surface of the cleaved photosensitive group.

With the realization that end of scaling for conventional CMOS integrated circuits is fast approaching in the semiconductor industry, alternative nanostructures and materials have been investigated. Of such nanostructures and materials, carbon nanotubes (CNTs) offer excellent intrinsic properties that are suitable for high performance nanoscale devices. Research in the replacement of semiconductor based field effect transistors and optoelectronic devices and sensors with carbon nanotube based nanoscale devices has been producing promising results in this field.
A key advantage of CNTs over conventional CMOS devices is that scaling limitations of MOSFETs due to boundary scattering of electrons from imperfect interfaces are solved naturally in CNTs which have a smooth, well coordinated graphene structure with no bonds to the outside. This enables CNTs to retain excellent transport properties to much smaller lateral dimensions than silicon. The small radius and possibility of completely surrounding the CNT by a gate provide excellent electrostatic confinement of channel electrons, enabling the channel length to be scaled down to very small dimensions, and their small size would enable high packing densities.
Although single, isolated CNT based field effect transistors and other devices have been demonstrated, many challenges remain in the construction of an integrated circuit employing CNTs as an active material. One such challenge is reliable placement of CNTs on a substrate surface with alignment, i.e., placement of the CNTs in a predefined region for fabrication of a CNT based device.
Several methods for selective placement of CNTs on a surface have been disclosed in the prior art. An exemplary prior art method employs the steps of:
prepatterning the surface into a metal oxide region and a silicon oxide region;
applying alkylphosphonic acids or alkylhydroxamic acids on the prepatterned surface, wherein the alkylphosphonic acids or alkylhydroxamic acids self-assemble on the silicon oxide region, while not assembling on the metal oxide region; and
applying functionalized CNTs on the prepatterned surface containing the patterned alkylphosphonic acids or alkylhydroxamic acids, wherein the functionalized CNTs are selectively attracted to the metal oxide region.
The exemplary prior art method has the drawback of requiring at least one lithographic step for formation of the metal oxide region and the silicon oxide region, in which a photoresist needs to be applied directly on the surface to be patterned, thus making the cleaning of residual photoresist material from the surface difficult and thereby degrading the effectiveness and fidelity of the pattern to be formed on the surface.
In view of the above, there exists a need for a method for patterning a surface into hydrophobic regions and hydrophilic regions without direct contact of a photoresist with the surface so that residual material from the photoresist does not produce adverse effects on the pattern, and a chemical compound for effecting such a method.

Photosensitive self-assembled monolayer for selective placement of hydrophilic structures

International Business Machines Corporation


According to the present invention, techniques, including a method and system, for restoring and/or validating data and/or associated signature log entries are provided. One embodiment of the present invention provides a method for validating a restored message, having an entry generated in a signature log for a message, where the entry includes cryptographic information associated with the message; Next, when said message is lost, the restored message is generated responsive to a request; and the restored message is validated using the signature log. In another embodiment a method for validating a selected log entry by using a signature log having a plurality of recorded log entries is provided. The method includes: computing a cryptographic value for the selected log entry; and determining if the cryptographic value is part of another recorded log entry.

The present invention generally relates to recovering data and more specifically to restoring and/or validating digitally signed data.
The use of the Internet for both business and personal communications has grown dramatically over the past few years, especially in the area of E-commerce. This large increase in message traffic along with the increased complexity of hardware and software, has increase the chance of losing data. Many systems today provide for back-up, as the number of computer crashes is rising.
While there are many conventional data recovery methods, the problem arises for the user in that how does she know if the information recovered has been tampered with? Especially when there have been several well publicized accounts of computer break-ins. One conventional technique to detect if there has been tampering to a message, and hence to the recovered message, is a digital signature. The US government has established a standard for digital signatures, which is given in Federal Information Processing Standards Publications (FIPS PUB) 186, which is incorporated by reference in its entirety.
FIG. 1 illustrates a conventional digital signature technique. The sender of a Message (M) 110 has a Signature Generation Unit 112. The receiver of the message 110 has a Signature Verification Unit 114. The Signature Generation Unit 112 takes message 110 and performs a secure hash 116 on M 110 to produce H(M) 118. H(M) 118 and Private Key 120 are inputted into Digital Signature Algorithm (DSA) Sign 122 to produce a digital signature for H(M) 118, i.e., Sign(H(M)) 124. M 110 and Sign(H(M)) 124 are sent from Signature Generation Unit 112 at a user sender to Signature Verification Unit 114 at a user receiver. M 110 at Signature Verification Unit 114 is then hashed 130 to produce H(M) 132. The secure hash 130 is the same function as secure hash 116. H(M) 132 and Sign(H(M)) 124 are inputted into DSA Verify 136 along with Public Key 134 to validate the message content. A "no" result means the message 110 has been tampered with, while a "yes" result indicates, but does not insure, no tampering. In addition the digital signature authenticates the message, i.e., it assures the recipient that the message is from the source that the message claims to be from.
However, the digital signature relies on a known algorithm that assumes that is very difficult but not impossible to crack. This assumption is becoming weaker and weaker with the rapid increase in computer power. In addition the digital signature assumes that the private key is secret. If the private key is compromised, the security is lost in present, as well as, recovered data. Thus there needs to be better techniques to validate recovered data.

Method and system for recovering the validity of cryptographically signed digital data


The invention relates to a portable digital Computer with an in-built coupling device which is arranged in order to receive mouse Signals from a radio mouse provided with a battery and fed by said battery. Said digital Computer comprises an in-built current source and an electric interface which is installed in a fixed manner and which is connected to the current source, the electric interface being arranged such that the battery can be charged. The invention also relates to an input device for a portable digital Computer comprising a radio mouse and an additional slide pad which is arranged on the top side of said radio mouse. The invention further relates to a special coupling bay comprising a recess which is a notebook. Said coupling bay is used for mechanically coupling a Cursor control device which is disposed below a notebook keyboard and in order to reconfigure the Cursor control device in a rear-sided Operation in order to use a notebook in a book-type and handheld form, whereby a flat mouse with annular-shaped finger Supports is provided in order to improve the handling and Operation thereof, in addition to a Cursor control device which is provided with an identification and locking function. Additionally, a notebook is disclosed, comprising a decoupling Cursor control device and a keyboard which can be decoupled. A desktop PC can be configured by means of a configuration via a hinge foldable functional part of a notebook.

1. Field of the Invention
The invention relates to an input device for mobile, and particularly portable digital computers, and to a portable digital computer with input device.
2. Description of Related Art
Portable digital computers have recently become widely used. These portable digital computers include, in particular, the so-called notebooks, by which two-leaf portable digital computers are meant in which a lid part containing a display device and a base part provided with a keyboard are moveably coupled with one another by means of a hinge device so that they can be opened and shut like a book. Apart from this, there are, in particular, so-called Tablet PC computers which are constructed to be single-leafed. Finally, a large variety of portable digital computers constructed as mini devices have conquered the markets in the form of so-called personal digital assistants (PDA).
In this context, so-called e-book readers must not be forgotten which frequently also utilize mouse functions. Such technologies have been described, in particular, in the earlier printed documents International Patent Application Publications WO 2001073673 A2 and WO 1999015982 A1; the content of these printed documents is expressly incorporated by reference herein.
Portable devices are always also meant to be "mobile" devices in the sense of the present patent. This also includes devices which can be used in means of transport such as motor vehicles.
The numerous situations of application in connection with the practical use of these portable digital computers outlined above that is required that the user can move and position a pointer, commonly called "cursor", on the screen of the display device by means of a suitable input device. The traditional aid for this is the so-called "mouse". A mouse is a moveable input device which enables the user to position and/or to select objects shown on the display device in interaction with an operating system and other software. Such a mouse is known, for example, from the document U.S. Pat. No. 5,805,144.
A mouse typically consists of a sliding part which can be gripped by the user with the fingers of one hand or also with a flat hand and pushed to and fro on a level surface, for example a table surface. A sensor device provided in the sliding part detects the movement of the mouse in accordance with path length and path direction relative to the surface on which the mouse is moved, and conveys these movement quantities in a suitable manner with a digital computer via a cable link. The digital computer then interprets these movement quantities by processing certain data processing programs which are usually components of the operating system and/or of application programs. Typical mouse-controlled functionalities are the following:                1. Selecting functions by positioning the mouse pointer on the display device in a screen area which, in accordance with suitable conventions, is considered by the user as a graphic symbolization of a function.        2. Actuating functions, i.e. single or rapidly successive double-activation of a mouse key when the mouse pointer is located over a screen area which, in accordance with suitable conventions, is considered by the user as a "button" on the display device;        3. Marking information items between a first position on the screen and a second position on the screen within the framework of a predetermined geometric model, i.e. positioning the mouse pointer on the display device at a first position, then operating and keeping a mouse key operated and then, whilst keeping the mouse key operated, moving the mouse pointer to a second position, finally releasing the mouse key, wherein the geometric model can be, for example, a rectangle, a linear arrangement, an ellipse or the like;        4. Scrolling functions;        5. Inserting selection information such as, for example, context menus.The above list of functions is only intended to be by way of example; the context of this patent specification also includes all functions possible by means of a mouse pointer.
Almost all programs which have a graphical user interface provide the user at least optionally with the possibility of performing the entire navigation in the program functions by means of a mouse or equivalent input devices. Examples of this are the navigational concept of the "Windows" operating system software by Microsoft or the navigational concept of the user interface "KDE" for computers which are operated under the Linux operating system. The expert knows these user interfaces and no further explanation will therefore be provided here.
Mice in which a roller ball arranged on the underside of the sliding part and freely rotatably rolls along on the support on which the mouse is moved are in widespread use, the relative motion between roller ball and sliding part housing produced as a result being detected in a suitable manner, for example by means of measuring rollers and converted into an electrical signal. Since the roller ball is mechanically sensitive and, moreover, is susceptible to soiling, there are also attempts to detect the motion of the sliding part over the surface on which the mouse is pushed, contactlessly optically in that optically detect able surface patterns present in any case or arranged on a mouse support are detected by optical sensing means and converted into motion signals.
In principle, mice provided with a roller ball can also be used in an alternative mode in which the housing is located stationary on a support, for example a table top, the roller balls being rotated with fingers or at the ball of the thumb of one hand of the user. Mouse devices optimized for this operating mode are also called "trackball".
It is usually found to be expedient to provide mice or, respectively, trackball devices, with keys, adjusting wheels and other operating elements at a suitable place on the housing in order to be able to carry out, for example, complete selection processes in a simple and clearly understood manner by the user.
In the practical use of portable digital computers, mice and trackball devices provided with cables have always been found to be unwieldy in as much as the user, in addition to the actual digital computer, must also carry the mouse or the trackball device, respectively, as a further object. A mouse or trackball device, respectively, provided with a sufficiently long cable presents problems since, on the one hand, the cable must be wound up before being transported or secured in another manner against being twisted and, on the other hand, requires a corresponding unwinding process before being used. During operation, the cable can become caught on other objects located in the vicinity and present discomfort and inconvenience to the user. To deal with these problems, so-called "cableless" mice or trackball devices are known in which the motion data of the sliding part are transferred to the digital computer wirelessly via a short-range radio link or by infrared data transmission.
For the user of a portable digital computer, however, the use of such a cableless mouse or of a cableless trackball device means that he has to carry along three parts, namely the portable digital computer, a base station provided with a short cable stub for connection to the digital computer, and the sliding or trackball part. In practice, it has been found to be problematic always having to pack up and reliably carry along all three parts during the transport.
The power supply represents a further problem because either sufficient batteries must be kept in stock which can rapidly become discharged due to frequent use and thus have to be frequently replaced, or a charging device must be carried along as a further component in the case of a rechargeable battery.
An approach at remedying these problems, known from the prior art, consists in dispensing completely with the mouse or the trackball device as an independent part and instead installing a sensor for transmitting location and displacement data directly into the portable digital computer. A widely used exemplary embodiment of this approach is the so-called "slide pad". A "slide pad" is a small area with sides of a few centimeters' length which is equipped with suitable sensors in such a manner that during a sliding contact with a fingertip moving on the area, a signal representing the motion path and motion direction can be detected and processed further by the digital computer. Solutions are also known in which a pin slightly protruding from the keyboard plane is arranged in the keyboard which can be bent in one direction via the full force acting on it with a fingertip. This action of the force is measured by suitable sensors and transmitted as motion direction and motion length signal to the digital computer. Finally, solutions are known in which a trackball device is permanently installed in the portable digital computer.
Although these approaches at improvement considerably simplify the transport problem for the user since now only a single part, namely the portable digital computer must be packed up and transported; according to experience, however, the ergonomic characteristics of such permanently installed mouse substitutes considerably lag behind those of an external mouse or of an external trackball device, respectively, because of the close proximity to the keyboard and due to the mechanical housing dimensions which are always kept small.
From U.S. Pat. No. 5,126,955, a notebook is known which exhibits a scanner mouse unit connected by means of a cable. It is only intended to store the scanner mouse part in the storage part for purposes of transport. There is no mouse functionality in the storage part of the keyboard. The cable restricts the freedom of motion and limits the possibilities. A roller ball is used for the mouse function.
From U.S. Pat. No. 5,049,863, a keyboard unit is known which, although it can be applied with PCs and notebooks and specifies an infrared connection instead of a cable connection, a part-keyboard segment is used for it in order to create, due to a possibility of decoupling the key segment, a mouse which generates mouse signals via a roller ball. On the top, the removed keyboard segment is only equipped with the cursor keys of the keyboard which does not offer a functionally equivalent alternative to an integrated notebook mouse due to its arrangement and its restricted usefulness. An integrated mouse would have to be constructed in addition. Moreover, the removable key unit is fed with a non-rechargeable dry battery which would have to be replaced more frequently, especially with more intensive use. In this context, it is very disadvantageous always to have to keep spare batteries in stock. A further disadvantage is the infrared link which can also restrict the freedom of movement. Moreover, it is disadvantageously provided expressly that when the keyboard segment is inserted into the keyboard, it operates a switch which switches off the power supply for the keyboard segment.
From U.S. Pat. No. 5,546,334, a decoupleable keyboard and a decoupleable integrated trackball mouse is known which, however, are only to be decoupled for repair purposes or when the notebook is to be used without trackball. Neither the keyboard nor the trackball mouse are electrically connected to the notebook and functionally operable after the mechanical decoupling.
From U.S. Pat. No. 5,726,684, a notebook with a decoupleable integrated mouse with trackball is known, wherein these can be operated both by cable, infrared or radio. For this purpose, the decoupled mouse, after removal from the notebook housing is turned over so that the roller ball can generate mouse signals by being moved over a level surface. Here, too, a non-rechargeable dry battery is provided which must be replaced after having been used up.
From printed document U.S. Pat. No. 6,476,795 A, a notebook is known by means of which it is possible to charge up radio mice. However, this is done in a complex manner with the aid of a module to be inserted for this purpose into a drive bay of the notebook, for example for inserting a CD ROM drive. In this arrangement, a radio mouse can be charged up via an intermediate battery in the auxiliary module. It is intended, however, to charge up conventional radio mice. The solution shown does not have the aim of decoupling an integrated mouse so that it can also be used as external mouse. Instead, the mouse must be transported and stored as second external mouse. The charging module can remain in the notebook but this blocks the coupling interface for modules which may be more important. Any permanent integration of the module would, therefore, be rather disadvantageous for space and cost reasons.
From U.S. Patent Application Publication 2001/0033267 A1, a notebook having a number of coupling possibilities for function modules such as an external infrared mouse is known which can be wirelessly effectively connected to the notebook. However, this is shown as additional possibility to a permanently integrated mouse. The notebook mouse cannot be removed from the notebook. The solution is based on the placement of IR transmitters at various points on the notebook in order to increase the freedom of movement with a radio mouse shown externally. The charging up of a coupleable mouse module is not shown.

Input device for portable digital computers and portable digital computer with a multi-functional mouse

Brands & Products IPR Holding GmbH & Co. KG


Provided herein are the 3′3′ cyclic phosphonate dinucleotides of general formula J, their pharmaceutically acceptable salts, a pharmaceutical composition containing them and combinations of said substances and other medicaments or pharmaceuticals. The disclosure also relates to the use of said compounds for the treatment or prevention of diseases or conditions modifiable by STING protein modulation, such as cancer or viral, allergic and inflammatory diseases. In addition, these substances can be used as adjuvants in vaccines.

The innate immune system recognizes the presence of pathogen or disruption of the homeostasis of the host by a battery of Pattern Recognition Receptors (PRRs) which detect a small set of ligands associated with pathogens or damage. These ligands are generally called Pathogen or Damage Associated Molecular Patterns (PAMPs and DAMPs) (Takeuchi O et al, Cell, 2010:140, 805-820). A number of PRRs have been identified over the past two decades including Toll-like receptors, retinoic acids inducible gene (RIG-I)-like receptors, nucleotide-binding oligomerization domain-like (NOD) receptors, C-type lectin receptors and cytosolic DNA sensors (Brubaker S W et al, Annu Rev Immunol, 2015:33, 257-290). Recognition of PAMPs and DAMPs by PRRs ultimately leads to the upregulation of cytokines and chemokines, including interferons, and recruitment of immune cells to the sites of infection. All these processes slow down pathogen replication and contribute to the development of adaptive immunity.
Cellular DNA is normally restricted to the nucleus and mitochondria of healthy cells. DNA present in cytosol, therefore, represents a signal indicating the presence of pathogen or disruption of the host homeostasis. The sensing of exogenous DNA is initiated by several DNA sensors such as DNA-dependent activator of IRFs (DAI) or DEAD box polypeptide 41 (DDX41). They signal via adaptor protein STING (Stimulator Of Interferon Genes, also called TMEM173, MITA, ERIS) (Unterholzner L, Immunology, 2013: 218, 1312-1321) by recruiting protein kinase TBK1 that triggers activation of the transcription factors NFκ-B (nuclear factor kappa B) and IRF-3 (interferon regulatory factor 3). Activation of STING ultimately results in release of type I and III interferons and variety of cytokines and chemokines such as IL-6, TNF-α and INF-γ.
Alternatively, STING can be activated by the second messenger cyclic dinucleotides (CDNs)(Burdette et al. Nature 2011: 478, 515-518). CDNs with affinity to STING contain two purine nucleotide monophosphates linked with either two 3′-5′ (3′3′-CDNs), two 2′-5′ (2′2′-CDNs) or 2′-5′ and 3′-5′ phosphodiester bonds (2′3′-CDNs). The prototype 2′3′ cGAMP (c[G(2′,5′)pA(3′,5′)p]) is a product of the activation of host cGAS in the presence of pathogen or self dsDNA and it has the highest binding affinity to STING of all linkage isomers (Zhang et al, Molecular Cell 2013:51, 226-235).
The type I interferons (IFNs) are immune-regulatory cytokines that play a pivotal role in viral immunity. They induce dendritic cell (DC) and macrophage maturation and activation (Galluci et al, Nat Med, 1999:5, 1249-1255) and promote T- and B-cell survival, activation and differentiation. Furthermore they activate numerous intracellular pathways that inhibit virus replication. The clinical utility of type I interferons has been demonstrated by their usefulness in treatment of chronic hepatitis B and C (Lin and Young, Cytokine Growth Factor Rev, 2014:25, 369-376).
In addition, interferons have shown utility in treatment of human cancers (Cohen et al, N Engl J Med, 2005:353, 2477-2490, Tsao et al, N Engl J Med, 2004:351, 998-1012). They can directly inhibit proliferation of tumor cells and may be synergistic with many approved anticancer agents. Furthermore, type-I-IFNs can act on immune cells to induce antitumor response (Musella et al, Oncoimmunology 2017:6:e1314424). Type I IFN signaling was shown to be important in tumor-initiated T cell priming in mice and animals lacking the IFN-α/β receptor in dendritic cells were unable to reject immunogenic tumors, and were defective in antigen cross-presentation to CD8+ T cells (Fuertes et al, J Exp Med, 2011:208, 2005-2016, Diamond et al, J Exp Med, 2011:208:1989-2003). Consistently with these observations, intratumoral injection of STING agonists has been recently shown to induce regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory (Corrales et al, Cell Rep, 2015:11, 1018-1030).
CDNs are believed to promote priming of both cellular and humoral immunity. For example, CDNs were shown to be an effective adjuvant in animal models (Dubensky et al, Ther Adv Vaccines, 2013:1, 131-143.
Patent publications WO 2014/093936, WO 2014/189805, WO 2013/185052, US 2014/03441976, WO 2015/077354, WO 2015/185565, WO 2016/145102, WO 2017/093933, WO 2017/027646, WO 2017/027645, WO 2017/175156, WO 2017/175147, WO 2017/123657, WO 2018/013908, WO 2018/013887, WO2018/009652, WO 2018/009648, and WO 2018/009466 disclose certain CDNs and their use in inducing an immune response.

This patent is subject to a terminal disclaimer.

3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein

INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY ASCR, V.V.I.


The present invention dedicates to detect nephritis in early stage of either primary or secondary nephritis using an anti NC1 monoclonal antibody. The present invention dedicates to provide useful information for diagnosis of renal function to detect NC1 by immunofluorescent stain method in renal biopsy section obtained at early stage where immunoglobulins do not deposit yet in renal GBM etc, or by antigen-antibody reaction in urine or serum specimens. Furthermore, the present invention comprises to utilize for therapeutic use.

Main conventional parameters to detect or diagnose nephritis using the urine sample include the presence and/or level of a protein, albumin, type IV collagen (three chains-domain) and β 2M etc. Further, conventional definite diagnostic method for nephritis depends on a method of staining renal slice samples obtained by renal biopsy in order to observe the deposit of immunoglobulin (hereafter referred to as Ig) or formation of crescents. For example, in order to diagnose IgA nephropathy, detecting "granular deposit of IgA mainly in diffused mesangial region of kidney" may need to be done, for example, as described in p. 1071 of Laboratory Examination (2001˜2002; published by BUNKO-DO). The foregoing detecting granular deposit of IgA can be done by an immunofluorescence assay or enzyme immunoassay, however, it may necessarily require the renal biopsy procedures.


There is provided an image processing apparatus and an image processing method that are capable of suppressing an increase in loads when a point cloud is generated from a mesh. Point cloud data is generated by positioning points at intersection points between a surface of a mesh and vectors each including, as a start origin, position coordinates corresponding to a specified resolution. For example, intersection determination is performed between the surface of the mesh and each of the vectors, and in a case where the surface and the vector are determined to intersect each other, the coordinates of the intersection point are calculated. The present disclosure can be applied to an image processing apparatus, electronic equipment, an image processing method, a program, or the like.

In the related art, for example, coding with an Octree is available as a method for coding 3D data representative of a three-dimensional structure such as a point cloud (for example, see NPL 1).
In recent years, there has been a proposal that, after a target 3D object is voxelized, coding is performed by using a combination of Octree coding and mesh coding (Triangle soup) (see, for example, NPL 2).

Image processing apparatus and method using point cloud generation and a surface of a mesh


A reinforcement learning method executed by a computer includes calculating a degree of risk for a state of a controlled object at a current time point with respect to a constraint condition related to the state of the controlled object, the degree of risk being calculated based on a predicted value of the state of the controlled object at a future time point, the predicted value being obtained from model information defining a relationship between the state of the controlled object and a control input to the controlled object; and determining the control input to the controlled object at the current time point, from a range defined according to the calculated degree of risk so that the range becomes narrower as the calculated degree of risk increases.

Conventionally, in a technique of reinforcement learning, a policy for optimizing a value function defining a value of a control input to a controlled object is learned based on a cumulative cost or a cumulative reward from the controlled object by referring to an immediate cost or an immediate reward from the controlled object corresponding to the control input to the controlled object. The value function is a state action value function (Q function) or a state value function (V function), etc.
In a conventional technique, for example, a method of generating a control signal applied to a plant is autonomously learned so that a cost evaluation value obtained by evaluating a plant operation cost is optimized. In another technique, for example, a search range of a control parameter is determined based on knowledge information in which an amount of change of the control parameter used for calculating an operation signal is correlated with an amount of change of a state of a plant. In another technique, for example, a correction signal for an operation signal is generated when a second error defined as an error from a target value of a second measurement signal of a plant is larger than a first error defined as an error from a target value of a first measurement signal of the plant. For examples of such techniques, refer to Japanese Laid-Open Patent Publication No. 2012-53505, Japanese Laid-Open Patent Publication No. 2017-157112, and Japanese Laid-Open Patent Publication No. 2009-128972.

Reinforcement learning method, recording medium, and reinforcement learning system


Systems and methods for announcing audio calling identification information associated with an incoming communications signal from a calling party to a wireless communications device are disclosed. The invention makes use of a translatable telephone number associated with a wireless communications device of a subscribing customer. The translatable telephone number includes a wireless telephone number of a wireless communications device and also includes an access telephone number that is associated with an access address serviced by a communications network. The wireless communications device is typically serviced by a separate wireless communications network that connects with the communications network over a communications link. The calling party dials the access telephone number and the incoming communications signal is detected, decoded, and processed to generate an audio communication by the communications network. The communications network also maps the access address with the wireless telephone number and presents the audio calling identification information to the wireless communications network.

1. Field of the Invention
This invention relates generally to the field of communications. More particularly, this invention relates to a system and method for audio delivery of caller identification information to wireless communications devices.
2. Description of the Related Art
Telecommunications has experienced explosive growth, and more growth is planned as telecommunication access and numerous communications devices improve. This explosive growth is revolutionizing special services offered to subscribing customers. Of the special service offerings, the most relevant to this invention is the caller identification or Caller ID service. A customer or a user of a telephone that is served by the Caller ID service is able to screen incoming calls by knowing what telephone number is calling before the user answers the phone. Presently available Caller ID systems provide a calling party's telephone number and a billing name associated with the calling party's telephone number (if available) when an incoming caller line identification (ICLID) signal can be detected, decoded, and transmitted to the serviced telephone or other display device associated with the serviced telephone. In recent years, telephony providers and manufacturers have tried to achieve vocalized announcement of the calling party's number and/or name to the serviced telephone.
For example, U.S. Pat. No. 5,796,806 entitled "Apparatus and Method for Spoken Caller Identification Using Signals of the Advanced Intelligent Network," discloses an apparatus and method for audio presentation of a calling party's name in a cellular environment. When a caller places a call to a cellular phone serviced by Caller ID, the cellular switch triggers identification of the caller by sending the ICLID signal along with the cellular telephone number to a data server located in cellular switching center. The user of the cellular phone can pre-record a list of names associated with phone numbers that are expected to originate calls to the cellular phone and the data server can fetch the caller's prerecorded name if there is a match with the ICLID. If the ICLID does not match any of the expected callers, then the telephone number of the caller can be spoken by the user answering the cellular phone by an Intelligent Peripheral attached to the cellular switch. Alternatively, if an ICLID signal is not detected, the data server can play a pre-recorded message of "unknown caller" or prompt the calling party to state his/her name and play the recorded calling party announcement to the user answering the cellular phone. The 5,796,806 patent, however, has several drawbacks that include necessitating expensive, specialized hardware and equipment in the cellular or mobile switching network, necessitating cooperation from the user to pre-record names and associate those names with telephone numbers of expected callers, and limiting the audio announcement to only the name or the number of the calling party.

Audio delivery of callerid information to a wireless communications device


Systems are described for use in removing toxic airborne contaminants from a waxing environment where wax is being applied to sporting equipment. The systems include a base, at least one platform coupled to the base and an airflow generator. The at least one platform is configured to securely receive sporting equipment to be waxed. Each platform includes a first surface that is in contact with the waxing environment, an opposing second surface and at least one opening that extends between the first and second surfaces of each platform. The airflow generator is configured to generate an airflow for pulling harmful airborne contaminants through the at least one opening in each platform in a direction from the first surface to the second surface.

Fluoropolymers are widely used in industry for a variety of applications. Example applications include mechanical and electrical components; fiberoptics; as a non-stick agent in the manufacturing of cooking utensils and as oil, water and stain repellents in upholstery production. Inhalation of airborne fumes during manufacturing of any of the example applications can cause polymer flume fever. Within hours of exposure to airborne fumes, symptoms of polymer flume fever can include dyspnoea, pyrexia, nausea, vomiting, unproductive cough, pulmonary edema, peripheral blood leucocytosis, hypoxaemia, alveolitis and alveolar collapse. Within days of exposure, reactive airway dysfunction and acute respiratory distress syndrome can occur.
Hydrocarbon based waxes are commonly used in ski waxes. Oftentimes the hydrocarbons are used alone or together in combination with fluorocarbons and other chemical products to reduce the friction between the sporting device and the surface with which it makes contact (snow, water, etc). For example, waxes are often applied to equipment for use in skiing, boarding, bobsledding, rowing, sailing and etc. When wax is applied to sporting equipment, release of the hydrocarbon molecules creates an environment similar to that of smoking. Hydrocarbon levels in these environments are several hundred times more than the acceptable safe limits for inhalation (based on governmental industrial hygiene standards).
Application of waxes to sporting equipment is generally accomplished through application of heat, such as by iron, torch, hot air and etc. Oftentimes, overheating of waxes can occur when applying the waxes to sporting equipment. If waxes containing fluropolymers are overheated, the molecular bond of the fluoropolymer breaks down and a fluorine ion becomes airborne. Free airborne fluorine is toxic and carcinogenic.
In general, application of fluoropolymer and hydrocarbon waxes are accomplished by individuals and/or wax technicians in enclosed spaces in various environments, such as individuals' homes, equipment rental businesses, huts located near recreational areas where the equipment is used and at major sporting competitions, such as the Olympics and World Cup events. In a typical competition scenario, each team is given an enclosed space for applying waxes to their equipment. This space (often an individual room) is an area that is separated from other teams. Privacy in regard to waxing techniques and products are highly desirable and necessary for each team so as to protect individual team waxing strategies. Therefore, a typical wax environment has athletes and wax technicians from the same team sharing the same enclosed space.
At this time, very few international enclosed spaces for waxing have ventilation systems. However, sometimes these enclosed spaces are supplied with a conventional updraft exhaust system. Updraft exhaust systems simply draw toxins into the breathing path of the wax technician and out into an environment external to the wax application environment. Since fluoropolymer particles degrade to produce phosgene, fluorine, hydrofluoric acid and other toxic byproducts, wax fumes are mostly invisible, odorless and tasteless. The wax technician is only aware of the removal of other airborne particles, such as hydrocarbons or smoke, which are toxic in of themselves.
These conventional exhaust systems have proven to remove a high percentage of hydrocarbons as can be seen with the naked eye, however, it is unknown how effective the updraft exhaust system is in removing invisible, odorless and tasteless particles that are also toxic. In particular, it is unknown how effective an updraft exhaust system is in removing fluorine ion particles, which are heavier than ambient air. In addition the external exhausting of these particles poses a substantial health and environmental risk to persons and wildlife in the vicinity of the exhaust ports. Although wax technicians could use respirators when applying fluoropolymer waxes, respirators are cumbersome, hot, uncomfortable and visually impair one's ability to see work in detail. The respirators are also often not maintained adequately in terms of frequency of cartridge filtration changes so as to render them effectively useless. Respirators are also are not fitted properly or maintained in a manner that effectively protects a user.
The discussion above is merely provided for general background information and is not intended to be used as an aid in determining the scope of the claimed subject matter.

Systems for removing toxic airborne contaminants in waxing environments


A method for forming a metal matrix composite within a mold of investment material. The method comprises the steps of forming a preform mixture of liquid flow medium, binding agent and reinforcement into the desired shape of a metal matrix composite. Then, allowing the preform mixture to solidify into desired shape. Next, encasing the preform mixture within a container of investment material. Then, heating the preform mixture at a controlled rate which first allows any fluid, such as water, to evaporate, then allows removal of the flow medium. Next, sintering the remaining reinforcement material and binder to form a solid preform. Then, disposing molten metal on top of the solid preform within the container such that the molten metal forms a seal with the container. Next, pressurizing the molten metal such that it is forced into said preform. Next, solidifying the molten metal to form a metal matrix composite in the shape of this preform; and removing the investment material from metal matrix composite. Additionally, there is a method comprising the steps of connecting a preform, which has been previously prepared for infiltration of molten material and having a binding agent, to a sprue system. Next, encasing the preform and sprue system within a container of investment material. Then, melting out the sprue system to form piping which allows the metal to flow to the preform. Next, sintering said preform with said binding agent therein to form a solid preform. Then, disposing molten metal on top of the preform within the container such that molten metal form a seal with the container. Next, pressurizing the molten metal such that it is found through the sprue system and into the preform. Then, solidifying the molten metal to form a metal matrix composite in the shape of the preform; and removing the investment material from metal matrix composite.

Investment casting, also known as the lost wax method, is one of the oldest processes for the forming of metal. It was used extensively by the ancient craftsman, to form jewelry and is currently the preferred method for casting complex parts for aircraft engines. Patterns are typically formed by pressure injection of wax or plastic into a precision metal die. Patterns, either singly or in groups, are fitted with wax gates and risers and encased in an investment material such as a slurry of refractory material. The wax or plastic patterns are then melted out of the investment material thereby leaving molds of the parts to be cast connected by a series of gates and risers. The preferred molten metal is then caused to fill the hollow impressions through the piping of the gates and risers. After solidification, the investment material is removed from the metal parts.
In the past, metal matrix composites have been investment casted by first mixing the metal with the reinforcement and then introducing the molten mixture to the mold. There is no known method that allows the infiltration of the reinforcement material within a mold of investment material.

Investment casting of metal matrix composites


The present invention is directed to conopeptides having 6-45 amino acids, including one or more bromo-tryptophan residues. More specifically, the present invention is directed to conopeptides having the general formula: R-(Cys).sub.n -R.sup.1 -B-R.sup.2 -Cys-R.sup.3, wherein R is a peptide chain of 0-24 amino acids, R.sup.1 is a peptide chain of 0 to 31 amino acids, R.sup.2 is a peptide chain of 0-29 amino acids, R.sup.3 is a peptide chain of 0 to 26 amino acids, B is 6-bromo-tryptophan, n is 0 or 1 and the total length of the conopeptide is from about 6 to about 45 amino acids. The invention also includes pharmaceutically acceptable salts of the conopeptides. These bromo-tryptophan containing conopeptides invention are useful as antihelminthic agents, anti-vomiting agents, sleep-inducing agents, adjuncts to anesthesia, anticonvulsant or neuroprotective agents.

This invention relates to relatively short peptides about 6-45 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogs to the naturally available peptides, and which include one or more bromo-tryptophan residues.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
Mollusks of the genus Conus produce a highly toxic venom that enables them to carry out their unique predatory lifestyle. Prey are immobilized by the venom that is injected by means of a highly specialized venom apparatus, a disposable hollow tooth that functions both in the manner of a harpoon and a hypodermic needle.
Few interactions between organisms are more striking than those between a venomous animal and its envenomated victim. Venom may be used as a primary weapon to capture prey or as a defense mechanism. These venoms disrupt essential organ systems in the envenomated animal, and many of these venoms contain molecules directed to receptors and ion channels of neuromuscular systems.
The predatory cone snails (Conus) have developed a unique biological strategy. Their venom contains relatively small peptides that are targeted to various neuromuscular receptors and may be equivalent in their pharmacological diversity to the alkaloids of plants or secondary metabolites of microorganisms. Many of these peptides are among the smallest nucleic acid-encoded translation products having defined conformations, and as such, they are somewhat unusual. Peptides in this size range normally equilibrate among many conformations. Proteins having a fixed conformation are generally much larger.
The cone snails that produce these toxic peptides, which are generally referred to as conotoxins or conotoxin peptides, are a large genus of venomous gastropods comprising approximately 500 species. All cone snail species are predators that inject venom to capture prey, and the spectrum of animals that the genus as a whole can envenomate is broad. A wide variety of hunting strategies are used, however, every Conus species uses fundamentally the same basic pattern of envenomation.
Several peptides isolated from Conus venoms have been characterized. These include the .alpha.-, .mu.- and .omega.-conotoxins which target nicotinic acetylcholine receptors, muscle sodium channels, and neuronal calcium channels, respectively (Olivera et al., 1985). Conopressins, which are vasopressin analogs, have also been identified (Cruz et al. 1987). In addition, peptides named conantokins have been isolated from Conus geographus and Conus tulipa (Mena et al., 1990; Haack et al., 1990). These peptides have unusual age-dependent physiological effects: they induce a sleep-like state in mice younger than two weeks and hyperactive behavior in mice older than 3 weeks (Haack et al., 1990). Recently, peptides named contryphans containing D-tryptophan residues have been isolated from Conus radiatus (U.S. Ser. No. 60/).
The N-methyl-D-aspartate (NMDA) receptor is a postsynaptic ionotropic receptor which is responsive to the excitatory amino acids glutamate and glycine and the synthetic compound NMDA, among others. The NMDA receptor controls the flow of both divalent (Ca.sup.2+) and monovalent (K.sup.+, Na.sup.+) ions into the postsynaptic neural cell through a receptor associated channel (Foster and Fagg, 1987; Mayer and Miller, 1990).
The NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience dependent synaptic modifications. In addition, NMDA receptors are also thought to be involved in long term potentiation, Central Nervous System (CNS) plasticity, cognitive processes, memory acquisition, retention and learning. The NMDA receptor has also drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. For example, during brain ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen deprived neurons. This excess glutamate binds to the NMDA receptor which opens the ligand-gated ion channel thereby allowing Ca.sup.++ influx producing a high level of intracellular Ca.sup.++ which activates biochemical cascades resulting in protein, DNA and membrane degradation leading to cell death. This phenomenon, known as excitotoxicity, is also thought to be responsible for the neurological damage associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there are reports indicating similar involvement in the chronic neurodegeneration of Huntington's, Parkinson's and Alzheimer's diseases. Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures.
In addition to the effect of glutamate on the NMDA channel, it is also regulated by glycine. This amino acid increases NMDA-evoked currents in various tissues Johnson and Ascher, 1987; Kleckner and Dingledine, 1988! by increasing the opening frequency of the NMDA channel Johnson and Ascher, 1987!. Thus, NMDA-induced calcium influx and intracellular accumulation may therefor also be stimulated by glycine Reynolds et al., 1987; Wroblewski et al., 1989!, which interacts with its own distinct site Williams et al., 1991!.
Neuropsychiatric involvement of NMDA receptor has also been recognized. Blockage of the NMDA receptor Ca.sup.2+ channel by the animal anesthetic PCP (phencyclidine) produces a psychotic state in humans similar to schizophrenia (Johnson and Jones, 1990). NMDA receptors have also been implicated in certain types of spatial learning (Bliss et al., 1993). Interestingly, both the spatial and temporal distribution of NMDA receptors in mammalian nervous systems have been found to vary. Thus, cells may produce NMDA receptors at different times in their life cycles and not all neural cells may utilize the NMDA receptor.
Specifically, it has been shown that neurotransmission mediated through the NMDA receptor complex is associated with seizures Bowyer, 1982; McNamara et al., 1988!, ischemic neuronal injury Simon et al., 1984; Park et al., 1988! and other phenomena including synaptogenesis Cline et al., 1987!, spatial learning Morris et al., 1986! and long-term potentiation Collinridge et al., 1983; Harris et al., 1984; Morris et al., 1986!. Regulation of these neuronal mechanisms by NMDA-mediated processes may involve activation of a receptor-gated calcium ion channel Nowak et al., 1984; Mayer et al., 1987; Ascher and Nowak, 1988!.
Epilepsy is a recurrent paroxysmal disorder of cerebral function characterized by sudden brief attacks of altered consciousness, motor activity, sensory phenomena or inappropriate behavior caused by abnormal excessive discharge of cerebral neurons. Convulsive seizures, the most common form of attacks, begin with loss of consciousness and motor control, and tonic or clonic jerking of all extremities but any recurrent seizure pattern may be termed epilepsy. The term primary or idiopathic epilepsy denotes those cases where no cause for the seizures can be identified. Secondary or symptomatic epilepsy designates the disorder when it is associated with such factors as trauma, neoplasm, infection, developmental abnormalities, cerebrovascular disease, or various metabolic conditions. Epileptic seizures are classified as partial seizures (focal, local seizures) or generalized seizures (convulsive or nonconvulsive). Classes of partial seizures include simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Classes of generalized seizures include absence seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures (grand mal) and atonic seizures. Therapeutics having anticonvulsant properties are used in the treatment of seizures. Most therapeutics used to abolish or attenuate seizures demonstrate act at least through effects that reduce the spread of excitation from seizure foci and prevent detonation and disruption of function of normal aggregates of neurons. Anticonvulsants which have been utilized include phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, clonazepam and valproate. For further details of seizures and their therapy (see Rall & Schleifer (1985) and The Merck Manual (1992)).
The development of drugs acting at the NMDA receptor is described in U.S. Pat. Nos. 4,904,681; 5,061,721 and 5,086,072 and in PCT application publication numbers WO 94/07914 and WO 96/11698. It is desired to identify additional compounds which target the NMDA receptor. It is further desired to identify compounds which are useful as anticonvulsant or neuroprotective agents.