A method for visualizing an image combining an image (Ic) of a real object (200) originating from a video capture system (300) with digital information (In) originating from a three-dimensional model of the equipment, comprising: carrying out a processing operation to superimpose, in real time, a reference point (402) of the three-dimensional model with a reference point (302) of the video capture system and an object reference point (202) of the real object, and displaying at least some of the digital information superimposed on the image captured by the video capture system, further comprising: an initial step (Ei) of recording the reference texture (T200) of the real object, and a step (Ea) of analyzing the images transmitted by the video capture system, the analysis step comprising: generating a synthesis image from the captured image, and from the three-dimensional model of the equipment textured using the recorded texture; a step of calculating a composite image by mixing the synthesis image and the captured image.

Various augmented reality systems are known for extending the perception of the visual reality, and, in particular, visualization systems using a viewing screen, a tablet, or augmented reality glasses displaying a combination of image capture of the real object, and data in the form of a digital image of the virtual mockup of the associated object.
These augmented reality solutions make it possible to improve the effectiveness of manual work steps in manufacture, assembly and maintenance, and, at the same time, the quality of the work. The precise transmission of information, for example, the state of digital planning (CAO model), directly to an item of equipment, makes the transmission complex and makes the construction plans subject to error, by using dispensable models and other measuring instruments. A visual variance comparison can be carried out at any time, and in a manner intuitive for a user. Moreover, work instructions, for example, step-by-step instructions, may be provided directly on the work object or in the user's field of vision, i.e., exactly where they are actually necessary. Typical scenarios of application of the present disclosure include worker assistance systems for displaying assembly and maintenance instructions, and information for quality assurance. For example, the assembly positions or the drilling holes may be marked precisely, or weld points or supports to be verified may be identified. The system is also capable of providing assistance to maintenance personnel on-site, by non-resident experts.
In the prior art, U.S. Pat. No. 9,436,993 is known, which describes an augmented reality system comprising an image processing system; a first imaging module comprising one or more cameras in communication with the image processing system, in which the image processing system is designed to:                receive secondary image data originating from a second imaging device;        segment the secondary image data in order to determine a first surface of interest;        receive imaging data in real time from the first imaging module, the imaging data in real time originating from the camera or cameras comprising images of one or more of: a second surface of interest, an anchoring marker, and an orientation of the surface, a plurality of early or late markers, and tools;        calculate a recording transformation of the first surface of interest with respect to the second surface of interest, using one or more from: the anchor marker, the plurality of early or late markers, or the second surface;        calculate a tracking location of the first imaging module with respect to the first surface of interest, using one or more of the following elements: the anchor marker, the plurality of early or late markers, the second surface, or features of the second surface; and        create an improved image by combining information originating from imaging data in real time, with corresponding information calculated from the secondary image data on the basis of the location of the first imaging module.
In order to ensure perfect synchronization of the referential of the virtual image and a real object, a method for camera location and 3D reconstruction in a partially known environment is known from the European Patent No. 2715662. The method of locating a camera and 3D reconstruction of the static environment in which it develops, comprises an object of interest, the 3D model of which is known, which method comprises the following steps:                a/ calculating an initial placement of the camera in the surroundings, and an initial reconstruction,        b/ calculating the placement of the camera for each new image by matching 3D primitives of the surroundings with 2D primitives of the image, and reconstructing 3D primitives of the surroundings by triangulation,        c/ simultaneous optimization of the placements of the camera and the 3D primitives by minimizing a reprojection error on a plurality of images.
The 3D model is a geometric description of the object of interest, the reprojection error not comprising two types of terms, a first type of terms associated with primitives limited by the 3D model, and a second type of terms associated with primitives of the environment other than the object, and the step of optimization comprises a sub-step of association of the primitives with the environment or the 3D model.
The prior art solutions are not entirely satisfactory, since they do not allow for the visualization of the augmented reality information on the masked parts of the real object, for example, by the operator's hand, a robot arm, or a processing tool being interposed between the camera and the object.
In the solutions of the prior art, the digital information appears in an overlaid manner, not with the object but with the image of the element interposed between the camera and the object, which reduces the usefulness of the information.

Method and system for augmented reality visualisation


A bulk high temperature superconductor single crystal having the formula MBa.sub.2 Cu.sub.3 O.sub.7-x wherein M is selected from the group consisting of Y, Sm, Eu, Gd, Dy, Ho, Er, and Yb; and, x has a number value from about 0.1 to about 1.0; are produced by a novel process incorporating: i) starting powders produced by combustion spray pyrolysis, ii) a novel setter powder, and/or iii) a monitored isothermal growth process.

Continuing scientific and technological advances in the area of high-temperature superconducting ceramic (HTSC) materials are expected to have a significant economic impact in the next century. Numerous applications involving the use of these materials as thin and thick films, in wire form, and in bulk form are being explored. Applications based on HTSC thin films--e.g., filters for advanced communications systems, probe coils for magnetic resonance systems, and squids for non-destructive evaluation (NDE) and biomagnetism instruments--are progressing the most rapidly because thin films possess the necessary high current-carrying capacity. In contrast, applications requiring bulk superconductors have advanced at a slower pace because bulk materials having high critical current density are difficult to process. Only with significant increases in critical current density and the development of economically viable processing methods will the many potential applications of bulk HTSC materials be realized. These applications include bearings for superconducting motors, rails for magnetic levitation systems, components for high-efficiency generators, electromagnetic pumping, magnetic heat pumps, magnetic separation, and many other special-purpose devices. Early developmental work involving the use of bulk HTSC materials in an experimental generator, superconducting flywheel for long-term energy storage, and in high-temperature superconducting bearings have recently been reported.
For most applications requiring bulk HTSC material, the flux-trapping capacity is of primary importance in determining its utility, particularly when the material is to be used as a permanent magnet. To achieve a high flux-trapping capacity, the material must be able to carry a circulating current throughout the bulk form at high critical current density. In polycrystalline HTSC materials, achieving high critical current density is greatly inhibited by crystalline misalignments introduced at grain boundaries and the presence of other defects. For a given HTSC composition, the highest critical current density can thus be expected to occur in single crystals. The growth of high-quality superconducting single crystals, however, presents material processing challenges, both in fabricating required precursor materials and in optimizing the crystal growth process.
Specific targeted applications for these single crystals are superconducting clamping devices, electromagnetic superconductive dent pullers for use in the aircraft industry, bearings for flywheels, and advanced rivet guns. Even the simplest of these devices--an electromagnetic clamp--requires single crystals at least 3 cm in diameter able to trap a magnetic field of more than 1 T.
For most other applications, more stringent requirements must be met. Single crystals as large as 10 cm in diameter.times.2 cm thick and capable of trapping at least 3 T(J.sub.c >2400 A/cm.sup.2) will be needed. Meeting this need will require significant advances in the materials and processes involved in producing HTSC single crystals, as well as an improved understanding of fundamental aspects of the overall crystal growth process.
Although the mechanisms for the peritectic reaction and growth of aligned grains in HTSC materials are well-documented, the growth of high-quality, large single crystals remains a challenging task. Early attempts to form bulk materials followed traditional ceramic processing methods such as the solid-state sintering of powder compacts containing appropriate mixtures of Y.sub.2 O.sub.3 CuO.sub.3 and BaCO.sub.3 Measured critical current densities were typically less than 1000 A/cm.sup.2 and dropped off sharply in the presence of small magnetic fields (>0.5 T). Subsequent attempts involved the growth of 123 crystalline domains from a melt. As the superconducting 123 phase (YBa.sub.2 Cu.sub.3 O.sub.7) is heated above its peritectic melting temperature of about 1010.degree. C., it melts incongruently to form a non-superconducting 211 phase (Y.sub.2 BaCuO.sub.5) and a liquid phase rich in barium and copper. When the two-phase mixture is cooled below the peritectic temperature, the 211 phase and the liquid phase react to form 123: EQU Y.sub.2 BaCUO.sub.5 +3 BaCU.sub.2 +2 CuO!(liquid).fwdarw.YBa.sub.2 CU.sub.3 O.sub.7-x
Other crystal growth processes rely on solid state reactions between Lanthanide, Ba, and Cu oxides to produce the starting materials. The solid state reaction of oxide powders to requires several heating and grinding steps before phase pure powders are obtained. The powders in other works are also frequently mixed with platinum by ball milling or with a mortar and pestle. Platinum also has been introduced using the melt-powder-melt-growth technique.
A number of processes for producing bulk material have been explored based on this melting and reaction behavior. Reported approaches include the melt-textured growth (MTG) process, the quench-melt-growth (QMG) process, and the melt-powder-melt-growth (MPMG) process. The MTG approach does not yield large crystals. In the other two processes, the starting powders are first melted at temperatures above the peritectic temperature in platinum crucibles, cooled or quenched, and then reheated under various conditions to HTSC. Aligned polycrystalline structures typically result. Although such process variations have demonstrated some ability to influence phase formation and distribution in the resulting materials, none of these approaches has resulted in high critical current densities and trapped fields in large samples. For example, materials produced by the MTG method were reported to have critical current values of up to 17,000 A/cm.sup.2 in the absence of an applied magnetic field. Crystals as large as 8 cm in diameter have reportedly been grown by the MPMG process, and use of the process was claimed to be essential to such success.
Currently all single crystal growth processes slowly cool the sample, utilizing temperature and/or composition gradients to reduce the probability of nucleation away from the seed. While other processes require complex layering steps to make compacts with compositional gradients and/or the careful placement of a single sample in a specially designed furnace so that the temperature gradient in the furnace will align with the desired direction of growth in the sample.
Prior work has shown that high temperature ceramic superconductors as large as 8 cm in diameter can be grown by heating a pressed compact (usually in disk shape) of YBa.sub.2 Cu.sub.3 O.sub.7 (123) powder above the YBa.sub.2 Cu.sub.3 O.sub.7 .fwdarw.Y.sub.2 BaCuO(211)+Liquid peritectic temperature of 1010.degree. C. to achieve a homogeneous distribution of 211 particles within the liquid matrix and then nucleating the 123 crystal at a predetermined nucleation site of SmBa.sub.2 Cu.sub.3 O.sub.7 seed crystal while the sample is slowly cooled below 1010.degree. C. At a temperature range below 1010.degree. C., the crystal growth is initiated and completed while the samples are cooled through this range at a cooling rate of 0.01.degree. C./min. For a successful growth, platinum is added into the 123 powder compact in order to refine the 211 particles during the homogenization heat treatment above 1035.degree. C. and a temperature gradient is introduced into the compact in order to prevent the nucleation of 123 anywhere else other than the SmBa.sub.2 Cu.sub.3 O.sub.7 seed crystal.
Several problems associated with this process include: (i) the use of temperature gradient limits the number of samples that can be processed in a gradient furnace; (ii) continuous cooling limits the sample size to kinetically defined range; and (iii) samples lose considerable amount of liquid (>25 wt %) as a result of chemical reactions with the substrate and consequently the crystal growth is arrested after a critical amount of liquid is lost.
Another problem in growing single crystals is the difficulty of removing some samples from the MgO substrates. This demonstrates the importance of a suitable setter powder. Without an effective setter powder, separating the sample from the substrate is not only a processing nuisance but there is also risk of damaging the sample. Furthermore, the inert setter powder should not act as a nucleation site for the sample. This is important in the processing of single crystals and in inhibiting the nucleation of crystals away from the primary seed. Better setter powders are needed to facilitate bulk HTSC growth.
The ceramic powders used to make the HTSC materials can have a dramatic effect on the resulting product. Traditional multi-component ceramic powder processing usually relies upon solid-state reactions to produce powders having the desired final phase(s). The overall process typically involves wet or dry mixing and grinding of constituent powders as oxides or carbonates, followed by an appropriate calcination step to form the desired material. Due to the nonoptimal distribution of individual constituents within the batch, the resulting powder may be non-homogeneous and contain undesirable secondary phases and/or unreacted components. Repeated mixing/grinding and calcining steps are frequently required to achieve acceptable homogenization and phase-pure powders.
Various alternative powder processing methods have been developed for producing ceramic powders having greater compositional uniformity. Many of these techniques also yield much finer particles, which facilitate reactions and densification during sintering into useful components. One of these techniques is called spray pyrolysis. It consists of a solution/precipitation process much more amenable to process control than traditional solid-state powder processing methods. A detailed review of ceramic powder synthesis using this general approach has been provided by Messing et al., J.Am. Ceram. Soc. 76, p.2702 (1993). The process allows for the production of particles having controlled morphology, composition and reproducibility provided process variables are well understood.

Method for producing ceramic superconductor single crystals


A computer system and method for automated discovery of topic relatedness are disclosed. According to an embodiment, topics within documents from a corpus may be discovered by applying multiple topic identification (ID) models, such as multi-component latent Dirichlet allocation (MC-LDA) or similar methods. Each topic model may differ in a number of topics. Discovered topics may be linked to the associated document. Relatedness between discovered topics may be determined by analyzing co-occurring topic IDs from the different models, assigning topic relatedness scores, where related topics may be used for matching/linking a feature of interest. The disclosed method may have an increased disambiguation precision, and may allow the matching and linking of documents using the discovered relationships.

Using multiple topic models without determining their relatedness offers limited value. It becomes more difficult to find and discover a feature of interest as the collective knowledge continues to be digitized and stored in the form of news, blogs, Web pages, scientific articles, books, images, sound, video, and social networks. New computational tools to help organize, search, and understand these vast amounts of information are needed. Current tools to work with online information include search and links, automated and human generated topics.
One of the limitations of automatically generating topics is that models may be too broad or too specific, decreasing analytics accuracy that may be achieved as a result. In addition, automatically generated topics do not strongly define any taxonomy, ontology or other semantic meaning
One of the limitations of human generated topics is they have human-bias, thus, topics and taxonomies represent a specific viewpoint. Human generated topics and topic taxonomies may be expensive and time consuming to create and maintain. In addition to being difficult and expensive to create and maintain, human generated topics may not meet the needs of various users.
Therefore, there is still a need for automatically discovering related topics from a corpus ranging from broad topics to more specific topics based on the content of a large corpus. Automatically discovered topic relationships can improve search results, content navigation and provide increased precision for text analytics tasks including entity disambiguation and document linking using the discovered topic relationships.

Method of automated discovery of topics relatedness


An embodiment of an integrated scanner apparatus, includes a support surface for objects to be scanned, a scanner unit to perform a scanning movement relative to the support surface to capture images of portions of objects to be scanned, and a printer unit carried by a carriage mobile with respect to said support surface, wherein said scanner unit is carried by said carriage carrying said printer unit to be imparted said scanning movement by said carriage.

A key part of printers and other conventional image-sensor devices is the Contact Image Sensor (CIS) scan bar, which transforms an image on paper into an electronic image. A CIS scan bar may be widely used for facsimile (fax) machines, optical scanners, and portable applications e.g. portable scanners.
Over the years, the cost of CMOS imaging-sensor arrays has decreased, and their performance level increased: these sensors may thus be used in the place of conventional CIS scan bars, giving rise to cheaper solutions without any adverse impact on scanner size.
Different solutions have been proposed in order to use CMOS/CCD imaging-sensor arrays to scan a document.
For instance, DE-A-102006010776, which is incorporated by reference, discloses an arrangement including four fixed CCD-sensors, which are located under a glass for supporting the documents to be scanned and which operate on the basis of a pre-calibrated evaluation algorithm to form an entire image.
Various documents disclose different kinds of image-sensor carriages for mounting image reading means in combination with a drive unit (driving motor) to move the carriage.
For instance, GB-A-2336734, which is incorporated by reference, discloses an image sensor arranged parallel to the short sides of a rectangular lower frame to capture the image of a scanned object placed on a transparent plate mounted on a rectangular upper frame. A rod-like guiding member is provided orthogonal to the longitudinal holder to guide the movement of the image sensor.
In the solution disclosed in JP-A-2005331533, which is incorporated by reference, an image scanner is equipped with a carriage on which an image sensor is mounted. A driving motor moves the carriage in a sub-scanning direction via a toothed timing belt.
US-A-2006/098252, which is incorporated by reference, discloses a drive device for a scanner which includes an elongate guiding unit mounted in a base and disposed under an image sensor carriage. A roller unit is mounted on a bottom side of the image sensor carriage and a driving unit drives the image sensor carriage in a second direction with respect to the base.
Documents such as US-A-2008/174836 and JP-A-20060245172, which are incorporated by reference, disclose a scanner device adapted to scan an object and generate image data; the scanner device includes an image sensor and a movement unit which moves in a sub-scan direction a carriage carrying the image sensor.
EP-A-0 886 429, which is incorporated by reference, discloses an image input/output apparatus capable of printing and reading images and a cartridge carriage for reading an original with a simple control: the system uses a camera module which replaces the ink cartridge, sharing the same circuitry, which may turn out to be critical for maintaining the same speed for printing and as regards manual replacement of the cartridges.
Document CN-A-201286132, which is incorporated by reference, discloses a planar-image sensor, high-speed scanner with a reading function, and a copying machine containing an image part, at the bottom of a workbench, which includes n sets of image detection parts and a set of image reading parts; a light-source part above the image part; and a reflection part above the light-source part. A main drawback of this solution may lie in that too many cameras may be needed to cover the entire document area.
Document US-A-2009/0021798, which is incorporated by reference, discloses a scanner operating system with a single camera module. Such an arrangement is implemented in an "All-in-One" (AiO) product traded by Lexmark® under the commercial designation Genesis, which uses a single fisheye lens. A main drawback of this arrangement lies in the negative impact on system height.
In brief, the idea of using one or more sensors (fixed or in motion) to scan an image (or part of an image) has been largely adopted. If the image sensor is intended to be moved in operation, these arrangements almost inevitably involve the use of an additional carriage for the sensor.

Scanner apparatus having printing unit and scanning unit, related method and computer program product


Norvaline derivative of the formula [I] or pharmaceutically acceptable salt thereof, method for preparing the same, pharmaceutical composition containing the same, and use of the compound for inhibiting transporting activity of glycine transporter type 2 (GlyT2)

Glycine is one of inhibitory neurotransmitters. Glycine shows an inhibitory activity on sensory nerves through strychnine-sensitive glycine receptors (ssGlyRs) in the spinal cord and the brain stem of a vertebrate.
It has been reported that a pain threshold is elevated by intrathecal administration of glycine, while it is lowered by intrathecal administration of strychnine having a glycine receptor antagonistic activity. Those results suggest that a pain threshold may be kept at a certain level or higher by stimulation of strychnine-sensitive glycine receptors by glycine in the spinal cord.
On the other hand, for many neurotransmitters, there are reuptake systems into cells. Specific transporters are participated in those reuptake systems, whereby concentration of the neurotransmitter is controlled.
As glycine-specific transporters, there have been known two classes such as glycine transporter type 1: GlyT1 (including subtypes: GlyT1a, GlyT1b, GlyT1c) and glycine transporter type 2: GlyT2 (including subtypes: GlyT2a, GlyT2b), and genes thereof were cloned one after another in the 1990s [Guastella et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 7189; Liu et al., FEBS Lett., 1992, 305, 110; Smith et al., Neuron, 1992, 8, 927; Borosky et al., Neuron, 1993, 10, 851].
Among these transporters for glycine, GlyT1 is widely distributed in the central nervous system: CNS, and existing mainly in glia cells and it has been considered that GlyT1 has a role to maintain a low concentration of glycine in an extracellular fluid.
On the contrary, GlyT2 exists locally in the brain stem and the spinal cord. GlyT2 takes a role in the reuptake system of glycine acting as a neurotransmitter in the brain stem and the spinal cord, and removes glycine from a synaptic space and inactivates glycinergic neuro-activity. Further, GlyT2 has the same distribution pattern as strychnine-sensitive glycine receptor: ssGlyR, and closely relates to the inhibitory system through strychnine-sensitive glycine receptors. Based upon this knowledge, it has been considered that the synaptic glycine level in the intrathecal space is elevated by inhibition of GlyT2 activity, and whereby the function of inhibitory neuron expressing ssGlyR is activated and then pain-related neurotransmission should be limited. Further, compounds which inhibit the transporting activity of GlyT2 (GlyT2 inhibitor) have been considered as being useful as a muscle relaxant, an anesthetic, an analgesic, etc. for treatment of muscle spasticity, tinnitus, epilepsy, neuropathic pain, etc. [Isaac et al., Bioorg. Med. Chem. Lett. 2001, 11, 1371-1373; WO2003/1013-2 (Akzo Nobel); Caulfield et al., J. Med. Chem., 2001, 44: 2679-2682; Ho et al., Bioorganic & Medicinal Chemistry Letters, 2004, 14, 545-548; Friauf et al., J. Comp. Neurol., 1999, 412, 17; Simpson et al., Neurochem. Res., 1996, 21, 1221; Huang et al., Neurol. Res., 2000, 22, 160; Gomeza et al., Curr. Opin. Drug Discovery Dev., 2003, 6, 675; Aragon., Eur. J. Pharmacol., 2003, 479, 249-262].
Further, it has actually been reported that a compound which inhibits the transporting activity of GlyT2 (GlyT2 inhibitor) shows an effect of improving hyperalgesia by increasing a pain threshold in neuropathic pain models [Houghton et al., 31st Society of Neuroscience Meeting Abstracts 2001, 27 (Abs 283.1)].
Further, GlyT2 inhibitors are considered as being useful for treatment of urological disorders [WO 2005/94808 (Bayer Healthcare)].
Consequently, GlyT2 inhibitors have been expected to be developed as an excellent medicament. Particularly, neuropathic pain syndromes are difficult to be cured, and available medicaments for neuropathic pain such as μ-Opioid, etc. often show side effects to the central nervous system, and thus, it has strongly been demanded to develop an excellent medicament therefor.
As to compounds which inhibit the transportation activity of GlyT2 (GlyT2 inhibitor), the following reports have been found.
For instance, amino acid derivatives having GlyT2 inhibiting activity are disclosed in the literature of Isaac et al. (Isaac et al, Bioorg. Med. Chem. Lett. 2001, 11, 1371-1373) (NPS); benzamide derivatives such as N-[(1-dimethylaminocycloalkyl)methyl]benzamide derivatives, 2-(aminomethyl)benzamide derivatives, etc. are disclosed in WO 2003/10132 (Akzo Nobel), the literature of Caulfield et al. (Caulfield et al., Journal of Medicinal Chemistry, 2001, 44, 2679-2682) and the literature of Ho et al. (Ho et al., Bioorganic & Medicinal Chemistry Letters, 2004, 14, 545-548).
Further, α, β and γ amino acid derivatives are disclosed in the literatures of Wolin et al. (Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4477-4492; Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4493-4509) and WO 2005/044810 (Janssen Pharmaceutica).
Still further, aryl piperidine amide derivatives are disclosed in the literatures of Wolin et al. (Wolin et al., Bioorganic & Medicinal Chemistry, 2004, 12:4511-4532) and WO 2005/021525 (Janssen Pharmaceutica).

Norvaline derivative and method for preparation thereof

Abstract: wherein X is —CH2—, —O—, —S— or single bond; Ar is optionally substituted aryl or lower cycloalkyl; n is 0 to 2; R1 and R2 are (i) each is hydrogen or lower alkyl; (ii) R1 and R2 are combined to form lower alkylene; or (iii) R1 is hydrogen or lower alkyl and R2 is combined with R4 or R6 to form lower alkylene;    R3 and R4 are (i) each is hydrogen or lower alkyl; (ii) R3 and R4 are combined to form lower alkylene; or (iii) R3 is hydrogen or lower alkyl and R4 is combined with R2 or R6 to form lower alkylene;    R is

Abstract: or —OR7;    R5 and R6 are (i) each is optionally substituted lower alkyl, or hydrogen; (ii) R5 and R6 are combined to form aliphatic 5- to 6-membered heterocyclic group; or (iii) R5 is optionally substituted lower alkyl or hydrogen and R6 is combined with R2 or R4 to form lower alkylene; R7 is lower alkyl.


Disclosed and claimed are methods for the isolation and use of stem cell modulating factors for regulating stem cell cycle and for accelerating the post-chemotherapy peripheral blood cell recovery. Also disclosed and claimed are the inhibitors and stimulators of stem cell proliferation.

Most end-stage cells in renewing systems are short-lived and must be replaced continuously throughout life. For example, blood cells originate from a self-renewing population of multipotent hematopoietic stem cells (HSC). Hematopoietic stem cells are a subpopulation of hematopoietic cells. Hematopoietic cells can be obtained, for example, from bone marrow, umbilical cord blood or peripheral blood (either unmobilized or mobilized with an agent such as G-CSF), hematopoietic cells include the stem cell population, progenitor cells, differentiated cells, accessory cells, stromal cells and other cells that contribute to the environment necessary for production of mature blood cells. Hematopoietic progenitor cells are a subset of stem cells which are more restricted in their developmental potency. Progenitor cells are able to differentiate into only one or two lineages (e.g., BFU-E and CFU-E which give rise only to erythrocytes or CFU-GM which give rise to granulocytes and macrophages) while stem cells (such as CFU-MIX or CFU-GEMM) can generate multiple lineages and/or other stem cells. Because the hematopoietic stem cells are necessary for the development of all of the mature cells of the hematopoietic and immune systems, their survival is essential in order to reestablish a fully functional host defense system in subjects treated with chemotherapy or other agents.
Hematopoietic cell production is regulated by a series of factors that stimulate growth and differentiation of hematopoietic cells, some of which, for example erythropoietin, GM-CSF and G-CSF, are currently used in clinical practice. One part of the control network which has not been extensively characterized, however, is the physiological mechanism that controls the cycling status of stem cells (Eaves et al. Blood 78:110–117, 1991; Lord, in Stem Cells (C. S. Potten, Ed.) pp 401–22, 1997 (Academic Press, NY)).
Early studies by Lord and coworkers showed the existence of soluble protein factors in normal and regenerating bone marrow extracts which could either inhibit or stimulate stem cell proliferation (reviewed in: Lord and Wright, Blood Cells 6:581–593, 1980; Wright and Lorimore, Cell Tissue Kinet. 20:191–203, 1987; Marshall and Lord, Int Rev. Cyt. 167:185–261, 1996). These activities were designated stem cell inhibitor (SCI) and stem cell stimulator (SCS), respectively.
To date, no candidate SCS molecules have been purified from bone marrow extracts prepared as described by Lord et al. (reviews referenced above). Purification of either SCS or SCI from primary sources was not accomplished due to the difficulties inherent in an in vivo assay requiring large numbers of irradiated mice. In an attempt to overcome these problems Pragnell and co-workers developed an in vitro assay for primitive hematopoietic cells (CFU-A) and screened cell lines as a source of the inhibitory activity (see Graham et al. Nature 344:442–444, 1990). As earlier studies had identified macrophages as possible sources for SCI (Lord et al. Blood Cells 6:581–593, 1980), a mouse macrophage cell line, J774.2, was selected (Graham et al. Nature 344:442–444, 1990). The conditioned medium from this cell line was used by Graham et al. for purification; an inhibitory peptide was isolated which proved to be identical to the previously described cytokine macrophage inflammatory protein 1-alpha (MIP-1α). Receptors for MIP-1α have been cloned; like other chemokine receptors, these MIP-1α receptors are seven-transmembrane domain (or "G-linked") receptors which are coupled to guanine nucleotide (GTP) binding proteins of the Ginhibitory subclass ("Gi") (reviewed in Murphy, Cytokine & Growth Factor Rev. 7:47–64, 1996). The "inhibitory" designation for the Gi subclass refers to its inhibitory activity on adenylate cyclase.
MIP-1α was isolated from a cell line, not from primary material. While Graham et al. observed that antibody to MIP-1α abrogated the activity of a crude bone marrow extract, other workers have shown that other inhibitory activities are important. For example, Graham et al. (J. Exp. Med. 178:925–32, 1993) have suggested that TGFβ. not MIP-1α, is a primary inhibitor of hematopoietic stem cells. Further, Eaves et al. (PNAS 90:12015–19, 1993) have suggested that both MIP-1α and TGFβ are present at sub optimal levels in normal bone marrow and that inhibition requires a synergy between the two factors.
Recently, mice have been generated in which the MIP-1α gene has been deleted by homologous recombination (Cook et al., Science 269:1583–5, 1995). Such mice have no obvious derangement of their hematopoietic system, calling into question the role of MIP-1α as a physiological regulator of stem cell cycling under normal homeostatic conditions. Similarly, although transforming growth factor beta (TGFβ) also has stem cell inhibitory activities, the long period of time it takes for stem cells to respond to this cytokine suggests that it is not the endogenous factor present in bone marrow extracts; further, neutralizing antibodies to TGFβ do not abolish SCI activity in bone marrow supernatants (Hampson et al., Exp. Hemat. 19:245–249, 1991).
Other workers have described additional stem cell inhibitory factors. Frindel and coworkers have isolated a tetrapeptide from fetal calf marrow and from liver extracts which has stem cell inhibitory activities (Lenfant et al., PNAS 86:779–782, 1989). Paukovits et al. (Cancer Res. 50:328–332, 1990) have characterized a pentapeptide which, in its monomeric form, is an inhibitor and, in its dimeric form, is a stimulator of stem cell cycling. Other factors have also been claimed to be inhibitory in various in vitro systems (see Wright and Pragnell in Bailliere's Clinical Haematology v. 5, pp. 723–39, 1992 (Bailliere Tinadall, Paris); Marshall and Lord, Int Rev. Cyt. 167:185–261, 1996).
Tsyrlova et al., SU 1561261 A1, disclosed a purification process for a stem cell proliferation inhibitor.
Commonly owned applications WO 94/22915 and WO96/10634 disclose an inhibitor of stem cell proliferation, and are hereby incorporated by reference in their entirety.
To date, none of these factors have been approved for clinical use. However, the need exists for effective stem cell inhibitors. The major toxicity associated with chemotherapy or radiation treatment is the destruction of normal proliferating cells which can result in bone marrow suppression or gastrointestinal toxicity. An effective stem cell inhibitor will protect these cells and allow for the optimization of these therapeutic regimens. Just as there is a proven need for a variety of stimulatory cytokines (i.e., cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-1, IL-13, IL-14, IL-15, G-CSF, GM-CSF, erythropoietin, thrombopoietin, stem cell factor, flk2/flt3 ligand, etc., which stimulate the cycling of hematopoietic cells) depending upon the clinical situation, so too it is likely that a variety of inhibitory factors will be needed to address divergent clinical needs.
Further, there is a need to rapidly reverse the activity of such an inhibitor. The original studies of Lord et al. (reviews referenced above) demonstrated that the inhibitory activity could be reversed by addition of the stimulatory activity. While a variety of stem cell stimulatory cytokines has been identified (see above), none has been demonstrated to represent the activity described by Lord and coworkers as being present in bone marrow extracts and of being able to reverse the activity of the inhibitor.
Hematopoietic progenitors and stem cells primarily reside in the bone marrow in normal adults. Under certain conditions, for example chemotherapy or treatment with cytokines such as G-CSF, large numbers of progenitors and stem cells egress into the peripheral blood, a process referred to as "mobilization" (reviewed in Simmons et al., Stem Cells 12 (suppl 1): 187–202, 1994; Scheding et al. Stem Cells 12 (suppl 1):203–11, 1994; Mangan, Sem. Oncology 22:202–9, 1995; Moolten, Sem. Oncology 22:271–90, 1995). Recent published data suggest that the vast majority of mobilized progenitors are not actively in cell cycle (Roberts and Metcalf, Blood 86:1600-, 1995; Donahue et al., Blood 87:1644-, 1996; Siegert and Serke, Bone Marrow Trans. 17:467- 1996; Uchida et al., Blood 89:465–72, 1997).
Hemoglobin is a highly conserved tetrameric protein with molecular weight of approximately 64,000 Daltons. It consists of two alpha and two beta chains. Each chain binds a single molecule of heme (ferroprotoporphyrin IX), an iron-containing prosthetic group. Vertebrate alpha and beta chains were probably derived from a single ancestral gene which duplicated and then diverged; the two chains retain a large degree of sequence identity both between themselves and between various vertebrates (see FIG. 16A). In humans, the alpha chain cluster on chromosome 16 contains two alpha genes (alpha1 and alpha2) which code for identical polypeptides, as well as genes coding for other alpha-like chains: zeta, theta and several non-transcribed pseudogenes (see FIG. 16B for cDNA and amino acid sequences of human alpha chain). The beta chain cluster on chromosome 11 consists of one beta chain gene and several beta-like genes: delta, epsilon, G gamma and A gamma, as well as at least two unexpressed pseudogenes (see FIG. 16C for cDNA and amino acid sequences of human beta chain).
The expression of these genes varies during development. In human hematopoiesis, which has been extensively characterized, embryonic erythroblasts successively synthesize tetramers of two zeta chains and two epsilon chains (Gower I), two alpha chains and two epsilon chains (Gower II) or two zeta chains and two gamma chains (Hb Portland). As embryogenesis proceeds, the predominant form consists of fetal hemoglobin (Hb F) which is composed of two alpha chains and two gamma chains. Adult hemoglobin (two alpha and two beta chains) begins to be synthesized during the fetal period; at birth approximately 50% of hemoglobin is of the adult form and the transition is complete by about 6 months of age. The vast majority of hemoglobin (approximately 97%) in the adult is of the two alpha and two beta chain variety (Hb A) with small amounts of Hb F or of delta chain (Hb A2) being detectable.
Several methods have been used to express recombinant hemoglobin chains in E. coli and in yeast (e.g., Jessen et al., Methods Enz. 231:347–364, 1994; Looker et al. Methods Enz. 231:364–374, 1994; Ogden et al., Methods Enz. 231:374–390, 1994; Martin de Llano et al., Methods Enz. 231:364–374, 1994). It has thus far not been possible to express isolated human alpha chain in high yields by recombinant methods (e.g., Hoffman et al., PNAS 87:8521–25, 1990; Heman et al., Biochem. 31:8619–28, 1992). Apparently, the isolated alpha chain does not assume a stable conformation and is rapidly degraded in E. coli. Co-expression of beta chain with alpha chain results in increased expression of both (Hoffman et al. and Hernan et al., op. cit.). While the alpha chain has been expressed as a fusion protein with a portion of the beta chain and a factor Xa recognition site (Nagai and Thorgersen, Methods Enz. 231:347–364, 1994) it is expressed as an insoluble inclusion body under these conditions.
Both the beta chain and the alpha chain contain binding sites for haptoglobin. Haptoglobin is a serum protein with extremely high affinity for hemoglobin (e.g., Putnam in The Plasma Proteins—Structure, Function and Genetic Control (F. W. Putnam, Ed.) Vol. 2, pp 1–49 (Academic Press, NY); Hwang and Greer, JBC 255:3038–3041, 1980). Haptoglobin transport to the liver is the major catabolic pathway for circulating hemoglobin. There is a single binding site for haptoglobin on the alpha chain (amino acids 121–127) and two on the beta chain (amino acid regions 11–25 and 131–146) (Kazim and Atassi, Biochem J. 197:507–510, 1981; McCormick and Atassi, J. Prot. Chem. 9:735–742, 1990).
Biologically active peptides with opiate activity have been obtained by proteolytic degradation of hemoglobin (reviewed in Karelin et al., Peptides 16:693–697, 1995). Hemoglobin alpha chain has an acid-labile cleavage site between amino acids 94–95 (Shaeffer, J. Biol. Chem. 269:29530–29536, 1994).
Kregler et al. (Exp. Hemat. 9:11–21, 1981) have disclosed that hemoglobin has an enhancing activity on mouse bone marrow CFU-C progenitor colonies. Such assays demonstrate effects on CFU-GM and CFU-M progenitor populations as opposed to stem cells such as CFU-MIX. The authors observed activity in both isolated alpha and beta chains of hemoglobin. This activity was abolished by treatment with N-ethylmaleimide, which suggested to Kregler et al. that sulfhydryl groups were necessary. This observation, coupled with the fact that the stimulatory activity was resistant to trypsin digestion, suggested to Kregler et al. that the C-terminal hydrophobic domain or "core" region was responsible for the activity. Moqattash et al. (Acta. Haematol. 92:182–186, 1994) have disclosed that recombinant hemoglobin has a stimulatory effect on CFU-E, BFU-E and CFU-GM progenitor cell number which is similar to that observed with hemin. Mueller et al. (Blood 86:1974, 1995) have disclosed that purified adult hemoglobin stimulates erythroid progenitors in a manner similar to that of hemin.
Petrov et al. (Bioscience Reports 15:1–14, 1995) disclosed the use of a "nonidentified myelopeptide mixture" in the treatment of congenital anemia in the Wv/Wv mouse. The mixture increased the number of spleen colonies, especially those of the erythroid type.
Heme and hemin have been extensively examined with regard to their influences on hematopoiesis (see S. Sassa, Seminars Hemat. 25:312–20, 1988 and N. Abraham et al., Int. J. Cell Cloning 9:185–210, 1991 for reviews). Heme is required for the maturation of erythroblasts; in vitro, hemin (chloroferroprotoporphyrin IX—i.e., heme with an additional chloride ion) increases the proliferation of CFU-GEMM, BFU-E and CFU-E. Similarly, hemin increases cellularity in long-term bone marrow cultures.
"Opiates" are substances with analgesic properties similar to morphine, the major active substance in opium. Opiates can be small organic molecules, such as morphine and other alkaloids or synthetic compounds, or endogenous peptides such as enkephalins, endorphins, dynorphins and their synthetic derivatives. Endogenous opiate peptides are produced in vivo from larger precursors—pre-proenkephalin A for Met- and Leu-enkephalins, pre-proopiomelanocortin for α, β, and γ endorphins, and pre-prodynorphin for dynorphins A and B, α-neoendorphin and β-neoendorphin. In addition, peptides with opiate activity can be obtained from non-classical sources such as proteolysis or hydrolysis of proteins such as α or β casein, wheat gluten, lactalbumin, cytochromes or hemoglobin, or from other species such as frog skin (dermorphins) or bovine adrenal medulla. Such peptides have been termed "exorphins" in contrast to the classical endorphins; they are also referred to as a typical opiate peptides (Zioudrou et al., JBC 254:2446–9, 1979; Quirion and Weiss, Peptides 4:445, 1983; Loukas et al. Biochem. 22:4567, 1983; Brantl, Eur. J. Pharm. 106:213–14, 1984; Brantl et al., Eur. J. Pharm. 111:293–4, 1985; Brantl et al., Eur. J. Pharm. 125:309–10, 1986; Brantl and Neubert, TIPS 7:6–7,1986; Glamsta et al., BBRC 184:1060–6, 1992; Teschemacher, Handbook Exp. Pharm. 104:499–28, 1993; Petrov et al., Bioscience Reports 15:1–14, 1995; Karelin et al., Peptides 16:693–7, 1995). Other endogenous peptides, such as the Tyr-MIF-1 family, have also been shown to have opiate activity (Reed et al., Neurosci. and Biobehav. Rev. 18:519–25, 1994).
Opiates exert their actions by binding to three main pharmacological classes of endogenous opiate receptors—mu, delta, and kappa. Receptors representing each pharmacological class have been cloned and shown to be G-linked receptors coupled to Gi (reviewed in: Reisine and Bell, TINS 16: 506–510, 1993; Uhl et al., TINS 17:89–93, 1994; Knapp et al., FASEB J. 9:516–525, 1995; Satoh and Minami, Pharm. Ther. 68:343–64, 1995; Kieffer, Cell. Mol. Neurobiol. 15:615–635, 1995; Reisine, Neuropharm. 34:463–472, 1995; Zaki et al., Ann. Rev. Pharm. Toxicol., 36:379–401, 1996).
Specific agonists and antagonists are available for each receptor type—e.g., for mu receptors (which are selectively activated by DAIMGO and DALDA and selectively antagonized by CTOP and naloxonazine), for kappa receptors (which are selectively activated by GR 89696 fumarate or U-69593 and selectively antagonized by nor—binaltorphimine hydrochloride) and for delta receptors (which are selectively activated by DADLE and DPDPE and selectively antagonized by natrindole). In addition, there are broad-spectrum antagonists (such as naloxone) and agonists (such as etorphine) which act on all three receptor subtypes.
Both classical and a typical opiate peptides can be chemically altered or derivatized to change their specific opiate receptor binding properties (reviewed in Hruby and Gehrig, Med. Res. Rev. 9:343–401, 1989; Schiller, Prog. Med. Chem. 28: 301–40, 1991; Teschemacher, Handbook Exp. Pharm. 104:499–28, 1993; Handbook of Experimental Pharmacology, A. Hertz (Ed.) volumes 104/II and 104/II, 1993, Springer Verlag, Berlin; Karelin et al., Peptides 16:693–7, 1995). Examples include derivatives of dermorphin (e.g., DALDA) and enkephalins (e.g., DADLE, DAIMGO or DAMME). Peptides which do not normally bind to opiate receptors, such as somatostatin, can also be derivatized to exhibit specific opiate receptor binding (e.g., CTOP (Hawkins et al., J. Pharm. Exp. Ther. 248:73, 1989)). Analogs can also be derived from alkaloids such as morphine with altered receptor binding properties (e.g., heroin, codeine, hydromorphone, oxymorphone, levorphanol, levallorphan, codeine, hydrocodone, oxycodone, nalorphine, naloxone, naltrexone, buprenorphine, butanorphanol and nalbuphine); in addition, small molecules structurally unrelated to morphine can also act on opiate receptors (e.g., meperidine and its congeners alphaprodine, diphenoxylate and fentanyl) (see Handbook of Experimental Pharmacology, op. cit.; Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th Ed., A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad (Eds.) 1985 Macmillan Publishing Co. NY).
The endogenous opiate peptides (enkephalins, endorphins and dynorphins) have a conserved N-terminal tetrapeptide Tyr-Gly-Gly-Phe, followed by Leu or Met and any remaining C-terminal sequence. Removal of the hydroxyl group on the N-terminal Tyr (resulting in an N-terminal Phe) results in a dramatic loss of activity for Met-enkephalin. These structural data led to the "message-address" hypothesis whereby the N-terminal "message" confers biological activity while the C-terminal "address" confers specificity and enhanced potency (Chavkin and Goldstein, PNAS 78:6543–7, 1981). Exorphins generally have a Tyr-Pro replacing the N-terminal Tyr-Gly of classical opiate peptides; the proline residue is thought to confer higher stability against aminopeptidase degradation (Shipp et al., PNAS 86: 287-, 1989; Glamsta et al., BBRC 184:1060–6, 1992).
Recently an orphan receptor ("ORL1") was cloned by virtue of sequence relatedness to the mu, delta and kappa opiate receptors (Mollereau et al., FEBS 341:33–38, 1994; Fukuda et al., FEBS 343:42–46, 1994; Bunzow et al., FEBS 347:284–8, 1994; Chen et al., FEBS 347:279–83, 1994; Wang et al., FEBS 348:75–79, 1994; Keith et al., Reg. Peptides 54 143–4, 1994; Wick et al., Mol. Brain Res. 27: 37–44, 1994, Halford et al., J. Neuroimmun. 59:91–101, 1995). The ligand for this receptor, variously called nociceptin or orphanin FQ (referred to hereafter as "nociceptin") has been cloned and shown to be a heptadecapeptide which is derived from a larger precursor (Meunier et al., Nature 377:532–535, 1995; Reinscheid et al., Science 270:792–794, 1995). It was demonstrated to have pronociceptive, hyperalgesic functions in vivo, as opposed to classical opiates which have analgesic properties. Nociceptin has a Phe-Gly-Gly-Phe . . . N-terminal motif in contrast to the Tyr-Gly-Gly-Phe . . . N-terminal motif of classical opiate peptides discussed above. In keeping with the requirement for an N-terminal Tyr for opiate activity in classical opiate peptides, nociceptin exhibits little or no affinity for the mu, kappa or delta opiate receptors. Similarly, the broad-spectrum opiate antagonist naloxone has no appreciable affinity for ORL1.
Enkephalins have been observed to have effects on murine hematopoiesis in vivo under conditions of immobilization stress (Goldberg et al., Folia Biol. (Praha) 36:319–331, 1990). Leu-enkephalin inhibited and met-enkephalin stimulated bone marrow hematopoiesis. These effects were indirect, Goldberg et al. believed due to effects on glucocorticoid levels and T lymphocyte migration. Krizanac-Bengez et al. (Biomed. & Pharmacother. 46:367–43, 1992; Biomed. & Pharmacother. 49:27–31, 1995; Biomed. & Pharmacother. 50:85–91, 1996) looked at the effects of these compounds in vitro. Pre-treatment of murine bone marrow with Met- or Leu-enkephalin or naloxone affected the number of GM progenitor cells observed in a colony assay. This effect was highly variable and resulted in suppression, stimulation or no effect; further, there was no clear dose-response. This variability was ascribed by Krizanac-Bengez et al. to circadian rhythms and to accessory cells.
Recently, it has been demonstrated that mice in which the mu opiate receptor has been deleted by homologous recombination have elevated numbers of CFU-GM, BFU-E and CFU-GEMM per femur. Marrow and splenic progenitors were more rapidly cycling in these mu receptor knockout mice compared to normal mice. It was not determined if these effects were due to a direct or indirect effect on bone marrow stem cells resulting from the absence of the mu receptor in these animals (Broxmeyer et al., Blood 88:338a, 1997).
I. Chemotherapy and Radiotherapy of Cancer
Productive research on stimulatory growth factors has resulted in the clinical use of a number of these factors (erythropoietin, G-CSF, GM-CSF, etc.). These factors have reduced the mortality and morbidity associated with chemotherapeutic and radiation treatments. Further clinical benefits to patients who are undergoing chemotherapy or radiation could be realized by an alternative strategy of blocking entrance of stem cells into cell cycle thereby protecting them from toxic side effects. The reversal of this protection will allow for rapid recovery of bone marrow function subsequent to chemo- or radiotherapy.
II. Bone Marrow and Stem Cell Transplantation, Ex Vivo Stem Cell Expansion and Tumor Purging
Bone marrow transplantation (BMT) is a useful treatment for a variety of hematological, autoimmune and malignant diseases. Current therapies include hematopoietic cells obtained from umbilical cord blood, fetal liver or from peripheral blood (either unmobilized or mobilized with agents such as G-CSF or cyclophosphamide) as well as from bone marrow; the stem cells may be unpurified, partially purified (e.g., affinity purification of the CD34+ population) or highly purified (e.g., through fluorescent activated cell sorting using markers such as CD34, CD38 or rhodamine). Ex vivo manipulation of hematopoietic cells is currently being used to expand primitive stem cells to a population suitable for transplantation. Optimization of this procedure requires: (1) sufficient numbers of stem cells able to maintain long term reconstitution of hematopoiesis; (2) the depletion of graft versus host-inducing T-lymphocytes and (3) the absence of residual malignant cells. This procedure can be optimized by including a stem cell inhibitor(s) and/or a stem cell stimulator(s).
The effectiveness of purging of hematopoietic cells with cytotoxic drugs in order to eliminate residual malignant cells is limited due to the toxicity of these compounds for normal hematopoietic cells and especially stem cells. There is a need for effective protection of normal cells during purging; protection can be afforded by taking stem cells out of cycle with an effective inhibitor.
III. Peripheral Stem Cell Harvesting
Peripheral blood stem cells (PBSC) offer a number of potential advantages over bone marrow for autologous transplantation. Patients without suitable marrow harvest sites due to tumor involvement or previous radiotherapy can still undergo PBSC collections. The use of blood stem cells eliminates the need for general anesthesia and a surgical procedure in patients who would not tolerate this well. The apheresis technology necessary to collect blood cells is efficient and widely available at most major medical centers. The major limitations of the method are both the low normal steady state frequency of stem cells in peripheral blood and their high cycle status after mobilization procedures with drugs or growth factors (e.g., cyclophosphamide, G-CSF, stem cell factor). An effective stem cell inhibitor will be useful to return such cells to a quiescent state, thereby preventing their loss through differentiation.
IV. Treatment of Hyperproliferative Disorders
A number of diseases are characterized by a hyperproliferative state in which dysregulated stem cells give rise to an overproduction of end stage cells. Such disease states include, but are not restricted to, psoriasis, in which there is an overproduction of epidermal cells, premalignant conditions in the gastrointestinal tract characterized by the appearance of intestinal polyps, and acquired immune deficiency syndrome (AIDS) where early stem cells are not infected by HIV but cycle rapidly resulting in stem cell exhaustion. A stem cell inhibitor will be useful in the treatment of such conditions.
V. Treatment of Hypoproliferative Disorders
A number of diseases are characterized by a hypoproliferative state in which dysregulated stem cells give rise to an underproduction of end stage cells. Such disease states include myelodysplatic syndromes or aplastic anemia, in which there is an underproduction of blood cells, and conditions associated with aging where there is a deficiency in cellular regeneration and replacement A stem cell stimulator will be useful in the treatment of such conditions.
VI. Gene Transfer
The ability to transfer genetic information into hematopoietic cells is currently being utilized in clinical settings. Hematopoietic cells are a useful target for gene therapy because of ease of access, extensive experience in manipulating and treating this tissue ex vivo and because of the ability of blood cells to permeate tissues. Furthermore, the correction of certain human genetic defects can be possible by the insertion of a functional gene into the primitive stem cells of the human hematopoietic system.
There are several limitations for the introduction of genes into human hematopoietic cells using either retrovirus vectors or physical techniques of gene transfer: (1) The low frequency of stem cells in hematopoietic tissues has necessitated the development of high efficiency gene transfer techniques; and (2) more rapidly cycling stem cells proved to be more susceptible to vector infection, but the increase of the infection frequency by stimulation of stem cell proliferation with growth factors produces negative effects on long term gene expression, because cells containing the transgenes are forced to differentiate irreversibly and lose their self-renewal. These problems can be ameliorated by the use of a stem cell inhibitor to prevent differentiation and loss of self-renewal and a stem cell stimulator to regulate the entry of stem cells into cycle and thereby facilitate retroviral-mediated gene transfer.


A walking stick includes an upper section and a lower section connected by a boss assembly. The upper section comprises three elongate arm members each pivotal about a hinge located on an upper surface of the boss assembly between a first position in which it is generally upstanding and lies generally parallel with the other two elongate members and a second position in which it is inclined at an angle to the other two elongate arm members. The lower section comprises three elongate leg members each having an upper end positioned for pivotal movement relative to the boss assembly between a first position in which it is generally upstanding and lies generally parallel to the other two elongate leg members and a second position in which it is inclined at an angle to the other two elongate leg members. A foldable seat member is secured to and between each of the three elongate arm members of the upper section which, when the elongate arm members of the upper section which, when the elongate arm members are in their inclined positions, defines a seat.

Shooting sticks are known which comprise a walking stick formed with a foldable seat of canvas or like material. These sticks have proved to be popular but suffer from the disadvantage that when used as a seat they make only single point contact with the ground. They are therefore inherently unstable and are of limited use to the elderly or others with relatively limited personal stability.
Examples of walking sticks which can be converted into multi-legged seats can be seen from CN101214099, U.S. Pat. Nos. 484,334, 391,901, 389,810, 763,166, 542,609 and CH48155. All of these proposed walking sticks suffer from the disadvantage that, when in their seat configurations, no independent adjustment of the seat legs is possible. This means that when positioned on uneven ground, there is a strong possibility that the seat will be unstable.
Tripod stands for such items as cameras and guns are also known, some of which include a leg or support of adjustable height. Examples of these are to be found in EP1936436, U.S. Pat. Nos. 7,845,602 and 8,146,876.
One object of this invention is to provide a walking stick which can readily be converted to a seat which has three height adjustable points of contact with the ground whether the ground is flat or uneven.


An electric earth-moving vehicle, particularly for poorly ventilated locations, comprising an electric motor drive for driving wheels of the vehicle, a hydraulic unit which is actuated by a further electric motor drive for equipment installed on the vehicle, at least two sets of batteries for the motor drives, a control unit for connecting the motor drives to the two sets of batteries which is adapted to connect the motor drives individually or simultaneously to one set of batteries or the other or to both, and a supporting chassis which has, in a median and downward region, a tunnel for inserting one of the two sets of batteries.

The present invention relates to an electric earth-moving vehicle, particularly for poorly ventilated locations.
Small vehicles are known for earth-moving in confined spaces or for low power levels which preferably have a hydraulic drive which is controlled by a pump which is driven by an internal-combustion engine: in particular, some vehicles can be fitted, at the front or at the rear, with buckets, loading shovels, blades, lifting forks, excavators, mills, drills, rotating brushes or equipment of any kind which will be designated hereinafter generically as equipment and which is usually hydraulically powered.
Vehicles of this kind are extremely effective, but when used in confined spaces, such as mines, basements, ship holds, industrial buildings, historical city centers, cemeteries or the like, they have the drawback that their internal-combustion engines emit exhaust gases and produce noise at levels which are particularly unwanted in such environments.
In practice, there is the need for vehicles which reduce the coefficients of acoustic and chemical aggressiveness and which in giving broad assurances of environment-friendliness have a gentle impact on the user and on the citizens involved.
On the other hand, differently from battery-powered electric-drive vehicles known as fork-lift trucks, which are meant to usually work on level ground and on the same site, earth-moving vehicles must be able to travel for significant stretches on roads, including unpaved roads, without stations for recharging or replacing the batteries.
The aim of the present invention is to provide an electric earth-moving vehicle, particularly for poorly ventilated locations, which can travel over significant distances on roads, can operate without emitting toxic gases, can be fitted with equipment of any kind which can be actuated hydraulically and has a significant operating range.
Within the scope of this aim, an object of the present invention is to achieve the above aim with a structure which is simple, relatively easy to provide in practice, safe in use, effective in operation and relatively modest in cost.
This aim, this object and others which will become apparent hereinafter are achieved by an electric earth-moving vehicle particularly for poorly ventilated locations, according to the present invention, characterized in that it comprises an electric motor drive for driving wheels of the vehicle, a hydraulic unit which is actuated by a further electric motor drive for the equipment installed on the vehicle, at least two sets of batteries for said motor drives, a control unit for connecting said motor drives to said sets of batteries which is adapted to connect the motor drives individually or simultaneously to one set of batteries or the other or to both, and a supporting chassis which has, in a median and downward region, a tunnel for inserting one of said sets of batteries.

Electric earth-moving vehicle particularly for poorly ventilated locations


A tool changer for a machine includes a disc having a number of protrusions extended radially outward and a number of grooves formed between the protrusions. A rod has a projection for engaging with the grooves of the disc and for precisely rotating the disc step by step when the rod is rotated. The protrusions each includes a curved rib. The rod includes a stud and one or more stops for engaging with the curved rib and for retaining the curved rib and the disc in place when the projection does not rotate the disc.

1. Field of the Invention
The present invention relates to a tool changer, and more particularly to a tool changer for a machine.
2. Description of the Prior Art
Typical machines, such as drilling machines, milling machines etc., comprise a chuck for engaging with tool bits and for driving the tool bits to conduct drilling or milling operations. For most of the machining operations, a number of tool bits of various sizes are required. However, it is difficult and complicated to change the tool bits, and it wastes a lot of time for changing the tool bits manually.
The present invention has arisen to mitigate and/or obviate the afore-described disadvantages of the conventional tool bits exchanging problems.


Provided is an image forming apparatus including an apparatus electric-contact that is connectable to a cartridge electric-contact of a cartridge, which is equipped with a memory that stores information related to the cartridge, such that the information is transmitted from the cartridge to a main apparatus body of the image forming apparatus; a connector having the apparatus electric-contact and a first engaging unit that is engageable with the cartridge so as to position the cartridge electric-contact and the apparatus electric-contact in a predetermined direction; and a connector holder that holds the connector in a movable manner. The connector holder has a second engaging unit that is engageable with the cartridge. The connector is movable in the predetermined direction.

1. Field of the Invention
The present invention relates to image forming apparatuses, and particularly, to an image forming apparatus that uses a cartridge equipped with a memory.
2. Description of the Related Art
A known electrophotographic image forming apparatus, which is a kind of an image forming apparatus, uses a process cartridge formed by combining an electrophotographic photosensitive drum and process units into a single cartridge unit. With this process-cartridge method, maintenance of the electrophotographic image forming apparatus can be performed by the user instead of a serviceman. This significantly improves the ease of use. Thus, this process-cartridge method has been widely used in electrophotographic image forming apparatuses.
A known process cartridge (referred to as "cartridge" hereinafter) is equipped with a memory (such as an integrated-circuit (IC) memory) that stores information to be transmitted to the main apparatus body of the electrophotographic image forming apparatus. When the cartridge is inserted in the main apparatus body, information can be exchanged between the main apparatus body and the cartridge. Thus, a controller of the main apparatus body can be notified of the status, such as the usage condition, of the cartridge (see U.S. Pat. No. 5,937,239).
Information, such as the lot number of the cartridge, the characteristics of the image forming apparatus, and the characteristics of the process units, is registered in the memory equipped in the cartridge. This facilitates maintenance of the main apparatus body or the cartridge. Moreover, image forming operation is controlled in accordance with the information stored in the memory so that the image forming operation can be performed under better conditions.
A contact-type electric connection technique is a known technique for electrically connecting the memory equipped in the cartridge of the image forming apparatus to the main apparatus body. In this technique, the memory and the main apparatus body are electrically connected to each other by using a connector or a contact formed of a spring, which have simple configurations and are advantageous in terms of cost (see US Patent Laid-Open No. 2003-0123896).
However, when strong impact force is applied to a positioning boss of the connector due to strong impact force or vibration applied to the main apparatus body during physical distribution, such as during transport, there is a possibility that the boss may break. Even if the connector were to be given a predetermined movable range for compensating for positional variations between the connector and the cartridge, the moving distance of the cartridge, which has a large mass, may exceed that movable range due to the strong impact. In this case, for example, the positioning boss of the connector, which serves as a positioning section for the connector and the cartridge, receives extremely large impact force. As a result, compact engagement sections, such as the positioning boss, may break or deform, possibly causing the connection state between an electric contact of the cartridge and an electric contact of the main apparatus body to deteriorate. On the other hand, expanding the movable range of the connector or increasing the strength of the positioning member would lead to an increase in size of the apparatus electric-contact mechanism.

Image forming apparatus having a movable connector


The present invention relates to an apparatus for playing ball sports including softball. More particularly, the present invention relates to an apparatus for deterring the modification of ball bats. The bat comprises a barrel, a sweet spot, a transition area, a handle, and an end knob. Within the barrel are found supports used to reinforce the structural integrity of the bat to deter users from crushing the bat, causing the bat to fall outside the legal classification of bats allowed by the Amateur Softball Association of America (ASA). The supports are made out of a lightweight durable composition. The supports are held in place by a retaining member. Multiple supports and retaining members may be used.

(a) Field of the Invention
The present invention relates to an apparatus for playing ball sports, such as, for example, softball. More particularly, the present invention relates to an apparatus for deterring the modification of ball bats.
(b) Background of the Invention
In the field of ball bat technology, a known problem is "rolling". An issue presently exists in softball where players will purchase a softball bat and then modify that bat such that its performance ability is altered and may exceed the standards of the Amateur Softball Association of America (ASA). Persons will perform a process known as "rolling" where they will take a fiber bat and "squeeze" the barrel between large rolling tubes separated by a distance smaller than the diameter of the bat being rolled. The bat is rolled back and forth between these tubes fracturing fibers within the bat so that the bat becomes softer and more elastic. A bat that is so rolled is referred to as "hot" because it has the capacity to send the ball from the bat at a faster pace than a bat not so rolled. Certain regulations are in place under the ASA that make such rolled bats improper for use in any ASA regulated competition. Tests are conducted under the authority of the ASA to determine the rate of speed at which a ball will exit a bat when struck by a batter. Those bats with exit speeds in excess of 98 miles per hour (mph) when using the ASTM F2219 standard test method are illegal under the current rules of the ASA.
The Inventor is not aware of any prior art addressing the problem of deterring any portion of a ball bat from being rolled.

This patent is subject to a terminal disclaimer.

Apparatus for deterring modification of sports equipment


To provide a ferrite thin film-forming composition material that is a composition material for forming a ferrite thin film by using the sol-gel method which can form a thin ferrite thin film having a uniform thickness and, furthermore, has excellent long-term storage stability, a method of forming a ferrite thin film using the above composition material, and a ferrite thin film formed by using the above method. A ferrite thin film-forming composition material is a composition material for forming a NiZn ferrite, CuZn ferrite, or NiCuZn ferrite thin film by using a sol-gel method, in which the composition material is formed by dissolving metallic raw materials in a solvent including acetonitrile, and the fraction of acetonitrile is 30 mass % to 60 mass % with respect to 100 mass % of the composition material.

In recent years, there has been an abrupt demand for a decrease in size and weight of a variety of electronic devices, and thus there is a demand for a decrease in size or thickness of a condenser, an inductor, or the like which is embedded in an IPD chip having a plurality of passive elements formed on a substrate. For a decrease in the thickness of an inductor, compared to a wirewound inductor of the related art having a structure in which a wire is wound in a bulk magnetic material, for example, a thin film inductor or the like having a structure in which a spiral planar coil is inserted in a magnetic material such as a ferrite is proposed.
Since a magnetic material used in an inductor generally shows a high magnetic permeability in a high frequency range, a ferrite thin film or the like formed by using a ferrite-based material has been thus far used widely. Thus far, as a method of manufacturing a ferrite thin film, researches and developments have been made mainly for a forming method in which a vacuum process such as a sputtering method or chemical vapor deposition is required; however, in this method, it was necessary to introduce an expensive apparatus to the process, and thus there was a problem with costs such as an increase in initial investment. Meanwhile, while a forming method or the like by using a spin spraying method to which non-electrolytic plating is applied has been also studied; however, in the spin spraying method, while there is a merit that a ferrite film can be formed by using a relatively cheap apparatus, since a liquid including a large amount of a raw material is used during forming of a film, there was a problem in terms of the environment.
Therefore, a sol-gel method is attracting attention as a method of forming a ferrite thin film, which is not a spin spraying method and replaces a sputtering method or the like. In the sol-gel method, a vacuum process, which is used in the sputtering method or the like, is not required, and a ferrite thin film can be formed by using relatively simple and low-cost processes of preparation, coating, drying, and firing of a composition material. As a method of forming a ferrite thin film by using the sol-gel method, in the past, a method of forming a NiCuZn ferrite thin film by coating a mixed solution including iron nitrate, nickel nitrate, N,N-dimethylformamide, zinc acetate, and copper nitrate on a Si substrate on which SiO2 is formed by using a spin coating method, drying the Si substrate on which the mixed solution is coated at 120° C. for 10 minutes so as to remove the solvent, and heating the resultant at 400° C. for 30 minutes so as to be thermal decomposed was disclosed (for example, refer to Non Patent Document 1).

Ferrite thin film-forming composition material, method of forming ferrite thin film, and ferrite thin film formed using the same


A textile system for producing heat comprises a panel of heating textile, the heating textile comprising a non-woven three-dimensional network of non-electrically conductive fibers and strands of electrically conductive fibers consolidated therewith. Electrodes are conductively connected to the panel of heating textile at opposite ends. A circuit is formed at least by the panel of heating textile and the electrodes, the circuit being adapted to be connected to a power source to heat the heating textile.

It is commonly known to heat textiles by passing an electric current through a circuit within a textile. For instance, heated blankets and jackets are commonly used. However, existing heated textiles typically comprise wires arranged in coil configurations, to produce the heat. The presence of such wires therefore may a negative impact on the practicality of the textile, for instance by adding rigidity and/or weight. Moreover, wires may be fragile and may be damaged by bending, and do not supply a homogeneous heat.


An impeller pump which can be connected for use with hot-water serving systems. By the rotation of an impeller, liquids are sucked through a suction port which is connected with a container of the hot-water serving system and discharged through a discharge port for the intended supply. A guide port is provided nearby the suction port to let escape bubbles from the pump chamber, thereby assuring that the hot-water supply capacity performance is kept constant.

a) Field of the Invention
This invention relates to an impeller pump for use with hot-water serving systems to supply hot water.
b) Description of the prior art
An impeller pump is used to supply hot water from the hot water serving system, such as a jar and pot. As shown in FIG. 1, the impeller pump has a suction port connected through a connecting member 34 with a bottom opening of a hot water container 20. In FIG. 1, the impeller pump comprises a pump casing 21, a partition plate 22 for gas-tightly separating a pump chamber 23 from a driving device 24, and a shaft 25 supported by a supporting member 26. A retaining member 27 is used to keep an impeller 28, which is rotatably placed on the shaft 25, and a driven magnet 29, respectively. A driving magnet 30 is rotated by an electric motor 31.
In the impeller pump of FIG. 1, the driving magnet 30 is rotated by the electric motor 31. The driven magnet 29 is then rotated by the magnetic coupling action between the driving magnet 30 and the driven magnet 29, thereby causing the impeller 28 to rotate. Thus, due to the rotation of the impeller, hot water in the container 20 is sucked into the pump chamber 23 through the inlet port 32, and then discharged out of the pump through a discharge port 33 for the intended supply.
When hot water is being supplied by using such an impeller pump, there is a problem that bubbles are generated in the pump chamber. Particularly, the pressure in a region around the impeller's axis of rotation becomes lower than elsewhere. Thus, bubbles generated tend to gather around the axis of rotation and choke off the suction port, thereby obstructing the flow of hot water, substantially lowering the hot water supply capacity and often stopping the hot water supply.

Centrifugal pump for supplying hot liquid from a container


Absorbent articles such as sanitary napkins, panty liners, and incontinence pads are disclosed that have undergarment covering components (or "side wrapping elements") that extend from the main body portion of the absorbent article and automatically fold along the sides of a wearer's panties and provide an alternative to conventional side flaps. The side wrapping elements have at least one zone of extensibility and a region therein that is stiffer and less extensible than the zone of extensibility. The absorbent article preferably comprises at least three regions with different bending moduli to control the location of the absorbent article about which the side wrapping elements will bend.

Absorbent articles such as sanitary napkins, pantiliners, and incontinence pads are devices that are typically worn in the crotch region of an undergarment. These devices are designed to absorb and retain liquid and other discharges from the human body and to prevent body and clothing soiling. Sanitary napkins are a type of absorbent article worn by women in a pair of panties that is normally positioned between the wearer's legs, adjacent to the perineal area of the body. Sanitary napkins both with and without side flaps (or wings) are disclosed in the literature and are available in the marketplace.
Generally when sanitary napkins are provided with flaps, the flaps extend laterally from a central absorbent means and are intended to be folded around the edges of the wearer's panties in the crotch region. Commonly, the flaps are provided with an attachment means for either affixing the flaps to the underside of the wearer's panties or to the opposing flap. The flaps are generally effective for preventing exudates from soiling the edges of the wearer's panties.
Sanitary napkins having flaps of various types are disclosed in U.S. Pat. No. 5,267,992 entitled "Shaped Sanitary Napkin With Flaps", which issued Dec. 7, 1993; U.S. Pat. No. 4,687,478, entitled "Shaped Sanitary Napkin With Flaps", which issued to Van Tilburg on Aug. 18, 1987; U.S. Pat. No. 4,608,047, entitled "Sanitary Napkin Attachment Means", which issued to Mattingly on Aug. 26, 1986; U.S. Pat. No. B1 4,589,876, entitled "Sanitary Napkin", which issued to Van Tilburg, Certificate of Reexamination issued Apr. 27, 1993; U.S. Pat. No. 4,285,343, entitled "Sanitary Napkin", which issued to McNair on Aug. 25, 1981; U.S. Pat. No. 3,397,697, entitled "Disposable Sanitary Shield For Undergarments", which issued to Rickard on Aug. 20, 1968; and, U.S. Pat. No. 2,787,271, entitled "Sanitary Napkin", which issued to Clark on Apr. 2, 1957.
While sanitary napkins having flaps are commonly viewed as providing better protection against soiling as compared to sanitary napkins without flaps, some women find applying sanitary napkins having flaps to be inconvenient for various reasons. For instance, some women find it to be difficult to attach the flaps to the underside of the crotch of their panties. This can be due to factors such as the tendency for the adhesive fasteners on the flaps to stick to themselves or to other parts of the sanitary napkin. As a result, some women still prefer a sanitary napkin without flaps. In addition, some women who generally prefer a sanitary napkin with flaps, occasionally (such as during periods of light flow) prefer a sanitary napkin without flaps. Therefore, there is a need for a sanitary napkin which provides an alternative to sanitary napkins having conventional side flaps while still providing the protection of side flaps.
Several variations of sanitary napkins having conventional flaps that attempt to solve some, but not all of these problems are disclosed in the patent literature. For example, U.S. Pat. No. 4,911,701 issued to Mavinkurve discloses a sanitary napkin having elastic strands for providing a greater convex shape to the body-facing portion of the central absorbent and for enabling adhesive-free placement of the flaps of a winged napkin embodiment into a pair of panties. The sanitary napkin described in the Mavinkurve patent, however, still appears to require the user to manipulate the flaps (by first flipping the flaps upward and then placing the flaps in her panties and flipping the flaps back down) since the flaps appear to be pre-disposed to be in a downward folded condition. The Mavinkurve patent also requires that individual elastic strands be attached in a contracted condition to the central absorbent portion of the napkin and/or to its wings or flaps. The napkins described in the Mavinkurve patent can, therefore, be difficult and expensive to manufacture.
U.S. Pat. No. 5,125,918 issue to Seidy is directed to sanitary napkins having flaps with a "specially designed" resilient hinge means for disposing the flaps in an acute angular relation with the undergarment facing side of the absorbent element of the sanitary napkin. The resilient hinge, however, is described as one which tends to return to its original position after deformation. U.S. Pat. Nos. 5,154,715 and 5,221,275 issued to Van Iten are directed to absorbent articles, such as sanitary napkins, that have a "clasp means" for fastening the absorbent article to an adjacent undergarment. The clasp means of the Van Iten patents includes two relatively stiff portions (that are more rigid than the absorbent pad) which are joined together by a hinge which permits bending of one portion relative to the other portion. At least one of the portions has an arcuate portion that is designed to pivot on the hinge and "forcefully press" the undergarment towards the first member when the absorbent article is worn. Such a clasp may, thus, tend to forceably alter the configuration of the undergarment. Further, the stiffness of the clasp means may tend to make the absorbent article uncomfortable to wear.
U.S. Pat. No. 4,940,462 issued to Salerno discloses a sanitary napkin with longitudinally expandable flaps. The flaps are designed to fold over the exterior of the wearer's panty and then to expand to conform with the contour of the panties. The sanitary napkin described in the Salerno patent, however, appears to require conventional adhesive fasteners to retain the flaps in place on the underside of the wearer's panties.
Thus, a need exists for an absorbent article, such as a sanitary napkin, that is provided with an alternative to conventional flaps. In particular, a need exists for a sanitary napkin which provides the protection from soiling of conventional flaps and which can conveniently and efficiently solve the problems caused when attempting to attach conventional flaps to the underside of the wearer's panties.
It is, therefore, an object of the present invention to provide an absorbent article, such as a sanitary napkin, that is able to provide coverage to the wearer's panties to reduce side soiling (i.e., staining of the edges of the panty crotch) without the use of conventional flaps.
It is another object of the present invention to provide an absorbent article, such as a sanitary napkin, that automatically folds around the sides of the wearer's panties by the simple action of the wearer pulling up her panties.
It is still another object of the present invention to provide an absorbent article, such as a sanitary napkin, that is able to fold around the sides of the wearer's panties and stay without providing flaps having panty fasteners thereon, and without attaching separate elastic strands to the sanitary napkin.
These and other objects of the present invention will be more readily apparent when considered in reference to the following description and when taken in conjunction with the accompanying drawings.

Absorbent articles having undergarment covering components especially suited for folding around the edges of an undergarment


A Class-D audio amplifier is disclosed which accepts a digitized audio signal input and drives a load such as a loudspeaker without digital-to-analog conversion. The amplifier preferably comprises (1) means for processing a plurality of digital audio input values to create a plurality of deviation values respectively based on the deviation of the input value""s relationship from a previous audio input value, (2) means for producing a carrier signal, (3) modulation means for using the deviation values to responsively modulate the carrier signal by varying the frequency of its waveform inversely with the magnitudes of the deviation values, and (4) filter means operative on the modulated carrier to produce an analog voltage capable of driving the load.

Audio amplifiers have been manufactured using class-A and class A-B configurations since the earliest days of radio. These amplifiers are the simplest to implement and have been manufactured using vacuum tubes and transistors. These class A and class A-B amplifiers, while simple and easy to manufacture, are inefficient. Their output stages operate at about 40% efficiency. resulting in heat generation. This means that for each 100 watts of input power, they only put out about 40W.
The concept of class-D amplifiers (often referred to as switching amplifiers) has been known for many decades. and class-D amplifiers have been used in control systems, where relatively low carrier frequencies are acceptable, since the 1960s. In the mid 1970s one of the co-inventors herein developed the first commercially successful class-D analog input audio amplifier. Class-D has the advantage of high efficiency, cooler operation and, ultimately, improved sound quality. Disadvantages have been the increased complexity and RF emissions. Implementing part of the class-D amplifier in an integrated circuit form and housing the amplifier in a sheet metal box has reduced the complexity and RF emissions, respectively.
Class-D amplifiers with analog inputs have been in manufacture for many years. During the late 1990s there has, in fact, been surge of activity in analog-input audio class-D amplifiers. The use of less energy and the generation of less heat are important considerations in multi-channel home theater amplifiers, for example, where five or more audio channels are typically found.
Audio sources are now migrating towards digital; the phonograph record has been almost completely replaced by the compact disk (hereinafter, xe2x80x9cCDxe2x80x9d) and digital audio tape (hereinafter, xe2x80x9cDATxe2x80x9d), and video tape is being replaced by the digital video disk (hereinafter, xe2x80x9cDVDxe2x80x9d). TV is becoming digital with the advent of direct broadcast TV. Computer audio is digital by nature.
This invention is accordingly directed to an amplifier that can accept the digital output of a digital source (e.g., CD, DVD, DAT) without digital/analog conversion. Audio amplifiers which can directly accept the digital output of CDs, DATs, and DVDs, as well as future formats of future media, are very desirable because they eliminate the need to have a digital-to-analog converter and thereby offer improved sound quality.
It is a further object of this invention to provide such an amplifier having a preferred design that can be implemented in one low-cost digital integrated circuit.
The invention herein is a digital class-D audio amplifier which accepts digital audio inputs and amplifies them without the use of a D/A converter. Briefly, the digital audio input is processed to create an error value of the audio input""s relationship with the previous audio input. The error value is used to pulse-width modulate a carrier signal, and the digitally modulated carrier is low pass filtered so that the amplifier output comprises an analog voltage capable of driving a speaker.
These and other features of the invention will become apparent from the following description of the preferred embodiment, of which the drawing is a part.


A method and apparatus for transferring data across a network protocol bridge is disclosed. In one embodiment, a multi-processing engine configuration is used wherein processing engines are tasked with carrying out specific data transfer operations. In another embodiment, this multi-processing engine configuration is implemented in a protocol bridge in which data is being transferred between Fibre Channel and a network bus that is coupled to a host system. In one embodiment, the network bus is a PCI/PCI-X bus.

1. Field of the Invention
The present invention relates in general to data networks and more particularly, to a method and apparatus for transferring data across a protocol bridge.
2. Background Information
Fibre Channel is a computer communications protocol designed to provide for higher performance information transfers. Fibre Channel allows various existing networking protocols to run over the same physical interface and media. In general, Fibre Channel attempts to combine the benefits of both channel and network technologies.
A channel is a closed, direct, structured, and predictable mechanism for transmitting data between relatively few entities. Channels are commonly used to connect peripheral devices such as a disk drive, printer, tape drive, etc. to a workstation. Common channel protocols are Small Computer System Interface (SCSI) and High Performance Parallel Interface (HIPPI).
Networks, however, are unstructured and unpredictable. Networks are able to automatically adjust to changing environments and can support a larger number of connected nodes. These factors require that much more decision making take place in order to successfully route data from one point to another. Much of this decision making is done in software, making networks inherently slower than channels.
Fibre Channel has made a dramatic impact in the storage arena by using SCSI as an upper layer protocol. Compared with traditional SCSI, the benefits of mapping the SCSI command set onto Fibre Channel include faster speed, connection of more devices together and larger distance allowed between devices. In addition to using SCSI, several companies are selling Fibre Channel devices that run Internet Protocol (IP).
Fibre Channel continues to expand into the storage markets, which will make use of its benefits over traditional channel technologies such as SCSI. Being able to access mass storage devices quicker and from greater distances is very attractive to such applications as multimedia, medical imaging, and scientific visualization. One of the issues with transferring data across a protocol bridge, such as a bridge between Fibre Channel and a peripheral component interconnect (PCI) bus operating in accordance with the PCI-X standard, which is commonly referred to in the art as a PCI-X bus, is the lack of available bandwidth afforded by prior art systems. Thus, there is a need for an improved system of data transfer in which bandwidth is maintained.

Method and apparatus for transferring data across a protocol bridge