The present invention is directed to novel peptides and polypeptides that specifically bind to target cells and may have anti-cancer activity, especially blood-related cancers. The present invention includes a peptide or polypeptide comprising an Fv molecule, having a heavy variable chain comprising CDR3, CDR2 and CDR1 regions comprising the amino acid sequences SEQ ID NOS:8, 115 and 114, respectively.

Tissue-selective targeting of therapeutic agents is an emerging discipline in the pharmaceutical industry. New cancer treatments based on targeting have been designed to increase the specificity and potency of the treatment, while reducing toxicity, thereby enhancing overall efficacy. Mouse monoclonal antibodies (MAb's) to tumor-associated antigens have been employed in an attempt to target toxin, radionucleotide, and chemotherapeutic conjugates to tumors. In addition, differentiation antigens, such as CD 19, CD20, CD22 and CD25, have been exploited as cancer specific targets in treating hematopoietic malignancies. Although extensively studied, this approach has several limitations. One limitation is the difficulty of isolating appropriate monoclonal antibodies that display selective binding. A second limitation is the need for high antibody immunogenicity as a prerequisite for successful antibody isolation. A third limitation is the elicitation in the patient of an immune response against murine antibodies (human anti-mouse antibody-HAMA response) that often results in a shorter serum half-life, and prevents repetitive treatments, thus diminishing the therapeutic value of the antibody. This latter limitation has stimulated interest both in engineering chimeric or humanized monoclonal antibodies of murine origin, and in discovering human antibodies.
There are many factors that influence the therapeutic efficacy of monoclonal antibodies (Mabs) for treating cancer. These factors include specificity of antigen expression on tumor cells, level of expression, antigenic heterogeneity, and accessibility of the tumor mass. Leukemia and lymphoma have been generally more responsive to treatment with antibodies than solid tumors, such as carcinomas. MAbs rapidly bind to leukemia and lymphoma cells in the bloodstream and easily penetrate to malignant cells in lymphatic tissue, thus making lymphoid tumors excellent candidates for MAb-based therapy. An ideal system would entail identifying a MAb that recognizes a marker on the cell surface of stem cells that produce malignant progeny cells.
To aid in the discovery/production of Mabs, phage libraries have been used to select random single chain Fvs (scFvs) that bind to isolated, pre-determined target proteins such as antibodies, hormones and receptors. In addition, the use of antibody display libraries in general, and phage scFv libraries in particular, facilitates an alternative means of discovering unique molecules for targeting specific, yet unrecognized and undetermined, cell surface moieties.
Leukemia, lymphoma, and myeloma are cancers that originate in the bone marrow and lymphatic tissues and are involved in uncontrolled growth of cells. Acute lymphoblastic leukemia ("ALL") is a heterogeneous disease that is defined by specific clinical and immunological characteristics. Like other forms of ALL, the definitive cause of most cases of B-cell ALL ("B-ALL") is not known, although in many cases, the disease results from acquired genetic alterations in the DNA of a single cell, causing it to become abnormal and multiply continuously
Acute Myelogenous Leukemia (AML) is a heterogeneous group of neoplasms with a progenitor cell that, under normal conditions, gives rise to terminally differentiated cells of the myeloid series (erythrocytes, granulocytes, monocytes, and platelets). As in other forms of neoplasia, AML is associated with acquired genetic alterations that result in replacement of normally differentiated myeloid cells with relatively undifferentiated blasts, exhibiting one or more type of early myeloid differentiation. AML generally evolves in the bone marrow and, to a lesser degree, in the secondary hematopoietic organs. AML primarily affects adults, peaking in incidence between the ages of 15–40, but it is also known to affect both children and older adults. Nearly all patients with AML require treatment immediately after diagnosis to achieve clinical remission, in which there is no evidence of abnormal levels of circulating undifferentiated blast cells.
To date, a variety of monoclonal antibodies have been developed that induce cytolytic activity against tumor cells. A humanized version of the monoclonal antibody MuMAb4D5, directed to the extracellular domain of P185—growth factor receptor (HER2)—was approved by the FDA and is being used to treat human breast cancer (U.S. Pat. Nos. 5,821,337 and 5,720,954). Following binding, the antibody is capable of inhibiting tumor cell growth that is dependent on the HER2 growth factor receptor. In addition, a chimeric antibody against CD20, which causes rapid depletion of peripheral B cells, including those associated with lymphoma, was recently approved by the FDA (U.S. Pat. No. 5,843,439). The binding of this antibody to target cells results in complement-dependent lysis. This product has recently been approved and is currently being used in the clinic to treat low-grade B-cell non-Hodgkin's lymphoma.
Several other humanized and chimeric antibodies are under development or are in clinical trials. In addition, a humanized Ig that specifically reacts with CD33 antigen, expressed both on normal myeloid cells as well as on most types of myeloid leukemic cells, was conjugated to the anti-cancer drug calicheamicin, CMA-676 (Sievers et al., Blood Supplement, 308, 504a (1997)). This conjugate, known as the drug MYLOTARG®, has recently received FDA approval (Caron et al., Cancer Supplement, 73, 1049–1056 (1994)). In light of its cytolytic activity, an additional anti-CD33 antibody (HumM 195), currently in clinical trials, was conjugated to several cytotoxic agents, including the gelonin toxin (McGraw et al., Cancer Immunol. Immunother, 39, 367–374 (1994)) and radioisotopes 131I (Caron et al., Blood 83, 1760–1768 (1994)), 90Y (Jurcic et al., Blood Supplement, 92, 613a (1998)) and 213Bi (Humm et al., Blood Supplement, 38:231P (1997)).
A chimeric antibody against the leukocyte antigen CD-45 (cHuLym3) is in preclinical phase for treatment of human leukemia and lymphoma (Sun et al., Cancer Immunol. Immunother., 48, 595–602 (2000)) as a conditioning for bone marrow transplantation. In in vitro assays, specific cell lysis was observed in ADCC (antibody dependent cell-mediated cytotoxicity) assays (Henkart, Immunity, 1, 343–346 (1994); Squier and Cohen, Current Opin. Immunol., 6, 447–452 (1994)).
Although these preliminary results seem promising, they have the following limitations. The final product comprises non-human sequences, resulting in a problematic immune response to non-human material, such as HAMA. This HAMA response prevents repetitive treatments and results in a shorter serum half-life for the product. In addition, the above methods allow for the isolation of a single antibody species only, and only allow for the isolation of antibodies against known and purified antigens. Further, these methods are not selective insofar as they allow for the isolation of antibodies against cell surface markers that are present on normal cells as well as on malignant cells.
Thus, a method, which overcomes these above discussed limitations, would be desirable. Further, such method would ideally enable the identification of target ligands or markers on cancer cells or cells involved in mediating metastis of cancer cells, for example. Additionally, such method would also enable the production of antibodies to such targets. Phage display technology appears to offer such abilities.
The use of phage display technology has enabled the isolation of scFvs comprising fully human sequences. For example, fully human antibody against the human TGFb2 receptor based on a scFv clone derived from phage display technology was recently developed. This scFv, converted into a fully human IgG4 that is capable of competing with the binding of TGFb2 (Thompson et al., J. Immunol Methods, 227, 17–29 (1999)), has strong anti-proliferative activity. This technology, known to one skilled in the art, is more specifically described in the following publications: Smith, Science, 228, 1315 (1985); Scott et al, Science, 249, 386–390 (1990); Cwirla et al., PNAS, 87, 6378–6382 (1990); Devlin et al., Science, 249, 404–406 (1990); Griffiths et al., EMBO J., 13(14), 3245–3260 (1994); Bass et al., Proteins, 8, 309–314 (1990); McCafferty et al., Nature, 348, 552–554(1990); Nissim et al., EMBO J., 13, 692 –698 (1994); U.S. Pat. Nos. 5,427,908, 5,432,018, 5,223,409 and 5,403,484, lib.
Using this phage display technology, the inventors of the present invention have identified cell markers present on or cells in diseased or malignant state. Therefore, it is an objective of the present invention to identify peptides and polypeptides that recognize cell markers that are substantially exposed or over-expressed, particularly on or in cells in a diseased or malignant state.
It is a further objective of the present invention to use and expand phage display technology as an aid to identify such peptides and polypeptides.
It is a further objective of the present invention to identify such peptides and polypeptides by immuno-cross-reactivity.
It is a still further objective of the present invention that such peptides and polypeptides be of fully human origin.
It is a still further objective of the present invention that such peptides and polypeptides be isolated against antigens that may not necessarily be immunogenic.
It is a still further objective of the present invention to provide peptides or polypeptides that prevent, retard or cure cancer, particularly blood-related cancers including leukemia or lymphoma.
It is a still further objective of the present invention to provide for local targeting of cancerous cells with such peptides and polypeptides alone, or associated with, or coupled to, an anti-cancer agent and/or a diagnostic label or marker.
It is a still further objective of the present invention to provide a method for producing a targeting agent against desired ligands.
It is a still further objective of the present invention to identify specific motifs that provide for the recognition of cell markers that are over-expressed in the malignant state and that can be used in the construction of a targeting or diagnostic label or marker for an anti-cancer agent.
It is a still further objective of the present invention to provide a composition comprising an effective amount of such peptides, polypeptides or motifs associated with, or coupled to, an anti-cancer agent or to a diagnostic label or marker.
It has been established that scFv penetrate tissues and are cleared from the blood more rapidly than a full size antibody because they are smaller in size. Adams, G. P., et al., Br. J. Cancer 77, 1405–1412 (1988); Hudson, P. J., Curr. Opin. Immunol. 11(5), 548–557 (1999); Wu, A. M., et al., Tumor Targeting 4, 47 (1999). Thus, scFv are often employed in diagnostics involving radioactive labels such as tumor imaging to allow for a more rapid clearance of the radioactive label from the body. A number of cancer targeting scFv multimers have recently undergone pre-clinical evaluation for in vivo stability and efficacy. Adams, G. P., et al., Br. J. Cancer 77, 1405–1412 (1988); Wu, A. M., et al., Tumor Targeting 4, 47 (1999).
Single chain Fv (scFv) fragments are comprised of the variable domains of the heavy (VH) and light (VL) chains of an antibody tethered together by a polypeptide linker. The linker is long enough to allow the (VH) and the (VL) domains to fold into a functional Fv domain enabling the scFv to recognize and bind its target with the similar or increased affinity of the parent antibody. A commonly used linker comprises glycine and serine residues to provide flexibility and protease resistance.
Typically, scFv monomers are designed with the C-terminal end of the VH domain tethered by a polypeptide linker to the N-terminal residue of the VL. Optionally an inverse orientation is employed: the C-terminal end of the VL domain is tethered to the N-terminal residue of VH through a polypeptide linker. Power, B., et al., J. Immun. Meth. 242, 193–204 (2000). The polypeptide linker is typically around twelve amino acids in length. When the linker is reduced to about three to twelve amino acids, the scFvs can not fold into a functional Fv domain and instead associate with a second scFv to form a diabody. Further reducing the length of the linker to less than three amino acids forces the scFv association into trimers or tetramers, depending on the linker length, composition and Fv domain orientations. B. E. Powers, P. J. Hudson, J. Immun. Meth. 242 (2000) 193–194.
Recently, it has been discovered that mulitvalent antibody fragments such as scFv dimers, trimers, and tetramers often provide higher apparent ffinity over the binding of the parent antibody to the target. This higher affinity offers many advantages including ideal pharmaco-kinetics for tumor targeting applications.
The greater binding affinity of these multivalent forms is therefore desirable in diagnostics and therapeutic regimens. For example, a scFv may be employed as a blocking agent to bind a target receptor and thus block the binding of the "natural" ligand. In such instances, it is desirable to have a high affinity association between the scFv and the receptor to decrease chances for disassociation, which may allow an undesirable binding of the natural ligand to the target. In addition, this high affinity is especially critical when the target receptors are involved in adhesion and rolling or when the target receptors are on cells present in areas of high sheer flow, such as platelets.
Therefore, an object of the invention is multivalent forms of Y1 and Y17 scFv. These multivalent forms include, but are not limited to dimers, trimers and tetramers, sometimes referred to herein as diabodies, triabodies, and tetrabodies, respectively.

Specific human antibodies for selective cancer therapy


There are provided an image generating system and program which can generate an image of an object variable in its state depending on an impacted position, in real-time with less amount of data and reduced load in computation. The image generating system generates an image of an aggregate object formed by a plurality of part objects. The image generating system comprises: an object determination section (120) which determines part objects within a predetermined area in the aggregate object as objects to be changed in display form when an impact is applied to the aggregate object and the impacted position is included within the predetermined area; and an image generation section (160) which changes at least one of shape, color, position, rotation angle, direction, moving direction and moving speed of the part objects determined as objects to be changed and generates an image. The aggregate object may be formed by assembling a plurality of part objects having different shapes without any gaps. The image of the aggregate object may be generated as an image of a single object before the impact is applied thereto and as an image of an aggregate object after the impact.

There is known an image generating system which can generate an image as viewed within a virtual three-dimensional or object space from a given viewpoint. Such a system is very popular since one can experience a so-called virtual reality through it. Now considering a image generating system for playing a gun game, a player (or operator) can enjoy a three-dimensional shooting game by manipulating a gun-shaped controller (or shooting device) to shot targets such as enemy characters (or model objects) and the like which are displayed on a screen.
In order to improve the virtual reality for a player in such an image generating system, it was an important technical problem to produce more realistic images. It is thus desired that when, for example, a glass plate is broken by impact such as a bullet, the broken glass may more realistically be represented.
In the conventional image generating systems, however, when a bullet has hit a glass plate, the image is simply replaced by an image representing the broken glass plate which was previously provided. Independent of the hit position or the power of a bullet, the same image of a broken glass plate is shown. The representation is monotonic and lacks in reality.
According to such a technique, once a glass plate was broken by a first bullet, the image will not change even if the glass plate is hit by the succeeding bullets. Consequently, the representation was insufficient when it is possible that the glass plate is hit by many bullets in high-speed continuous shooting.


A method and an apparatus of producing natural salt or fresh water by treating sea water in an extremely short period of time and with high efficiently. The distilled water and salt components are treated for expediting crystallization of the salt components by evaporating water components by atomizing sea water and blowing warm wind thereto. During this treatment, there are provided a method and an apparatus of arranging net or cloth at one stage or a plurality of stages in a midway of a flow of the evaporated water components and adhering the salt components on the net or the cloth when the evaporated water components pass through the net or the cloth.

1. Field of the Invention
The present invention relates to a method and apparatus for producing natural salt by treating sea water.
2. Description of Related Art
According to a currently known method of producing natural salt, a number of pieces of bamboo with branches are hung upside down in a tower formed by piling up blocks, sea water is sprinkled from thereabove and water is evaporated by wind and solar heat while flowing down on the surface of bamboo by which sea water is condensed and water is evaporated on evaporating shelves for three through seven days, thereafter, brine is moved to crystallizing shelves of a green house type and salt is crystallized. Successively, the brine is separated into salt and bittern. According to the salt production process, there is provided an advantage in which compared with a process of boiling it in a kettle, various rare substances are not changed in respect of the qualities or vanished by intense heat.
Meanwhile, as a process of producing drinking water artificially from sea water, there has been known a desalination apparatus by a reverse osmosis membrane process which is used in a district having a small amount of rainfall or a district having a small number of dams.
According to the salt producing process mentioned above, salt component is crystallized over a number of days and therefore, the efficiency is poor and the process is not suitable for mass production. As a result, expensive natural salt is brought about.
Further, according to the process of producing fresh water from sea water by the reverse osmosis membrane process, a very complicated and high degree of technology is required and the installation cost becomes high. Further, the efficiency is poor and the process is not suitable for mass production of fresh water.
It is the technological problem of the invention to realize a treating method and a treating apparatus of sea water capable of producing natural salt with no need of an expensive equipment, in an extremely short period of time and efficiently by paying attention to such problems.
The technical problem of the invention is revolved by the following means.
Invention according to a first through a seventh aspect relates to a method of treating sea water for producing salt by means of atomizing sea water by rotating a centrifugal generator and of evaporating a water component to crystallize the salt by blowing warm wind thereto, wherein between a treating chamber and an outflow portion for the evaporated water component there is arranged at least one of net and cloth in one stage or a plurality of stages, the salt component is adhered to at least one of the net and the cloth when the evaporated water component passes through at least one of the net and the cloth, and thereafter the adhered salt component is peeled and dropped from at least one of the net and cloth.
When the net and the cloth are respectively used in a plurality of stages, the respective nets and cloths may be directly overlapped or may be spaced with an interval being kept therebetween. Further, also when both the net and the cloth are used, they may be mutually overlapped or may be spaced. In this case, either may be laid above.
When sea water is atomized in this way, innumerable small particles of sea water are composed and therefore, the surface area in contrast to the volume becomes large and vaporization of the water component is facilitated. As a result, vaporization of the water component from the salt crystal can efficiently be carried out. Further, warm wind is blown thereto and therefore, vaporization of the water component is expedited by thermal energy and wind and natural salt can inexpensively be produced. Further, sea water is brought into very fine mist and therefore, natural salt having very fine particles can be provided. Distilled water can be recovered and utilized as fresh water. Accordingly, at least one or both of fresh water and salt can be produced.
Particularly, between the treating chamber and the outflow portion of the evaporating water component there is arranged at least one of net (first screen) and cloth (second screen) is arranged in one stage or a plurality of stages and accordingly, when the evaporated component passes through at least one of the net and the cloth, the salt component is prevented from passing therethrough and is adhered to at least one of the net and the cloth. Here, within the context of the present invention, the phrase of xe2x80x9cat least one of net and clothxe2x80x9d is used to mean either (1) net, (2) cloth, or (3) net and cloth. The cloth (second screen) has a mesh size smaller than that of the net (first screen).
As a result, it is possible to prevent the salt component separated from the water component and the condensed sea water from being discharged wastefully. Further, the salt component and the condensed sea water are hampered by at least one of the net and the cloth to suppress discharges therefrom. Therefore, an amount of the salt component contained in the discharged water component is reduced and accordingly, water obtained becomes more resembled to fresh water.
And, since the salt component adhered to the net and the cloth is peeled and dropped therefrom, only the salt component is efficiently recovered and mass-production of salt becomes possible.
According to the second aspect of the invention, there is provided a method of treating sea water according to the first aspect, wherein at least one of the net and the cloth is made to hang on a side portion of the treating chamber and the salt component is adhered thereto.
In this way, according to the method wherein at least one of the net and the cloth is made to hang also on a side portion of the treating chamber and the salt component is adhered thereto, also the salt component floating in the vicinity of a side wall of the treating chamber is adhered to the net and the cloth, so that salt is produced more efficiently by peeling and dropping the adhered salt component.
According to the third aspect, there is provided the method of treating sea water according to the first or second aspect, wherein a number of strings are made to hang on a lower side of at least one of the net and the cloth and the salt component is adhered to the number of strings. In this way, when a number of strings are made to hang below the net or the cloth for preventing the salt component from passing through without stopping and the salt component is adhered thereto, salt crystal can be provided before reaching the net or the cloth and by knocking or shaking the number of strings or knocking or shaking them after collecting them to one place, the salt component can easily be collected to one place.
According to the fourth aspect, there is provided the method of treating sea water according to the second aspect or the third aspect, wherein the salt component adhered to at least one of the net and the cloth is recovered by washing off the salt component by sea water or by other method. Further, in respect of a method of separating the salt component adhered onto at least one of the net and the cloth from the net or the cloth, there can be provided a method of knocking, shaking it down by applying vibration other than a method of washing it off by sea water.
In this way, when the salt component or the condensed sea water adhered to the net or the cloth by being prevented from passing therethrough can be recovered in the treating chamber when it is washed off or shaken off by spraying sea water and accordingly, the salt component separated from the water component or the condensed sea water can be utilized for salt production and salt production can be carried out efficiently.
According to the fifth aspect of the invention, there is provided a method of treating sea water according to any one of the first through the fourth aspects, wherein the atomization of the sea water is carried out by means of applying a centrifugal force to the sea water by rotating an impeller in which arcuate blades are radially provided in a space between two circular disks and which has a water injection port at its center.
In mass production of fresh water or natural salt, sea water needs to convert into small particles in a large amount such that small particles thereof as fine as possible are produced and according to a method of producing a mist by a centrifugal force produced by an impeller in which arcuate blades are radially provided in a space between two circular disks and which has a water injection port at its center as proposed by inventors of the invention in Japanese Patent Application No. 8-297129 and Japanese Patent Application No. 8-220618, a large amount of sea water can easily be finely atomized and a large amount of salt or fresh water can be produced.
According to the sixth aspect of the invention, there is provided a method of treating sea water in accordance with any one of the first through the fifth aspects, wherein sea water is atomized by scattering sea water in a treating chamber, warm wind is blown thereto, an evaporated water component is discharged to outside of the treating chamber and a crystallized salt component is stored in the treating chamber. In this way, by adopting the method of atomizing sea water and blowing warm wind thereto in a space of the treating chamber and discharging the evaporated water component to outside of the treating chamber, a large amount of fresh water and natural salt can be separated and therefore, mass production of natural salt or fresh water can easily be carried out. As a result, natural salt and fresh water can be supplied inexpensively.
According to the seventh aspect of the invention, there is provided the method of treating sea water according to any one of the first through the sixth aspects, wherein the sea water is atomized after preheating the sea water at a temperature to a degree by which components in the sea water are not altered. In this way, since the thermal energy is applied on sea water by preheating it when the sea water is made fine and scattered, vaporization of sea water and crystallization of natural salt are further expedited. In this case, sea water is heated at a temperature to a degree by which components in sea water are not altered and accordingly, quality of natural salt is not deteriorated.
Accordingly, when the fan 34 is rotated in a state in which the heat generating body 31 of, for example, a heater is operated, air sucked by the fan 34 is heated by the heat generating body 31, blown into the treating chamber 1 and also blown to the heating chamber 25. As a result, vaporization of fine particles of sea water in the treating chamber 1 is expedited and heating of air in the heating chamber 25 is expedited. Further, the heating achieves power particularly when the weather is deteriorated and solar energy cannot be expected.
An eighth aspect through a twenty-second aspect of the invention relate to an apparatus of treating sea water. According to the eighth aspect, there is provided an apparatus of treating sea water for producing salt by means of atomizing sea water by rotating a centrifugal generator and of evaporating a water component to crystallize the salt by blowing warm wind thereto wherein between a treating chamber and an outflow portion for the evaporated water component there is arranged at least one of net and cloth in one stage or a plurality of stages, and there is provided means for peeling and dropping the salt component adhered to at least one of the net and the cloth from at least one of the net and the cloth.
In this way, one stage or plural stages of at least one of the net and the cloth for preventing the salt component from escaping are arranged between the treating chamber and the outflow portion for the evaporated water component and accordingly, in producing salt by treating sea water, the salt component or the condensed sea water is hampered by the net or the cloth and the discharge is restrained and therefore, only the water component passes through the net or the cloth and is discharged.
And, there is provided means for peeling and dropping the salt component adhered to the net and the cloth and accordingly, the salt component and the condensed sea water can be separated more effectively from the water component to produce salt in mass-production basis, and the water component can be utilized as flesh water.
Different from the net, the cloth is not provided with gaps (meshes) and therefore, the salt component can effectively be prevented from passing therethrough without stopping, however, it is also effective to use the cloth along with the net. However, considerable effect is achieved even only with a net. In the case of installing plural stages of the net, when the respectives of net are constituted to directly overlap each other, the meshes are substantially made fine and the salt component or the condensed sea water can firmly be adhered thereto and recovered. Further, when they are installed at intervals, the salt component or the condensed sea water passes through the respectives of the net at plural times and the salt component or the condensed sea water can be adhered and recovered further effectively.
According to the ninth aspect of the invention, there is provided the apparatus of treating sea water according to the eighth aspect, wherein a number of strings are made to hang on a lower side of at least one of the net and the cloth for adhering the salt component. In this way, when a number of strings are made to hang below the net or the cloth for preventing the salt component from passing therethrough without stopping, before the salt component reaches the net or the cloth, the floating salt component is adhered to the large number of strings and accordingly, recovery of the salt component is facilitated which is suitable for mass production.
According to the tenth aspect of the invention, there is provided the apparatus of treating sea water according to the eighth aspect or the ninth aspect, wherein means for washing off the salt component by spraying the sea water at least on one of the net and the cloth is arranged on an upper side of at least one of the net and the cloth.
In this way, owing to the structure in which the salt component or the condensed sea water adhered to the net or the cloth is washed off by scattering sea water to the net or the cloth, the salt component or the condensed sea water adhered to the net or the cloth can be recovered and utilized in salt production. As a result, the salt component or the condensed sea water can be prevented from wastefully discharging and the yield of salt production is promoted.
According to the eleventh aspect of the invention, there is provided an apparatus of treating sea water comprising means for atomizing and scattering sea water into a treating chamber and warm wind blowing means for blowing warm wind to mist of the sprayed sea water, wherein a duct hole for exhausting vapor produced by being vaporized in a treating chamber to outside of the treating chamber is provided at a roof portion of the treating chamber. The roof portion of the treating chamber indicates a wall portion closing an upper portion of the treating chamber. The warm wind blowing means includes a structure in which the atomizing means serves also as the warm wind blowing means by supplying warm air to an intake side of the scattering means and means exclusive for blowing warm wind installed separately from the scattering means.
And, net is provided so as to cover the duct hole, and means for peeling and dropping the salt component adhered to the net is provided.
In this way, means for atomizing and scattering sea water in the treating chamber is provided and therefore, sea water can be atomized in the treating chamber and can be scattered into a wide space such that vaporization of the water component is facilitated. Further, the warm wind blowing means is provided and therefore, thermal energy and wind can be applied to small particles of sea water. Vaporized vapor rises since its specific weight is light and the duct hole for exhausting is opened at the roof portion of the treating chamber and accordingly, only the water component can smoothly be discharged from the treating chamber and can be separated from crystals of natural salt.
Further, the net is provided so as to cover the duct of the roof portion for discharging the water vapor vaporized in the treating chamber, and means for peeling and dropping the salt component adhered to the net is provided and accordingly, it is possible to peel and drop the salt component adhered to the net and the condensed sea water by such means as washing off with the sea water, so that it is suitable for efficiently producing salt in mass-production basis.
According to the twelfth aspect of the invention, there is provided the apparatus of treating sea water according to the eleventh aspect, wherein at least one stage of at least one of a net and a cloth for adhering a salt component is arranged at a midway or on a lower side of the duct hole and means for washing off a salt component by scattering the sea water to at least one of the net and the cloth is arranged on an upper side of at least one of the net and the cloth.
In this way, owing to the constitution in which the net or the cloth for adhering the salt component is arranged in a midway or on a lower side of the duct hole opened between inside of the treating chamber and outside of the treating chamber, the net or the cloth having a comparatively small area is sufficient and means for washing off the salt component or the condensed sea water adhered to the net or the cloth is sufficient with a small scale. Further, all the salt component or the condensed sea water discharged from inside of the treating chamber to outside thereof passes through the duct hole and accordingly, the salt component or the condensed sea water can efficiently be recovered.
According to the thirteenth aspect of the invention, there is provided the apparatus of treating sea water according to the eleventh or the twelfth aspect, wherein an outer roof is provided above a roof portion of the treating chamber and an outer wall is provided at outside of side walls of the treating chamber, wherein means for scattering the sea water is provided above the outer roof, and wherein a water distributing constitution in which the sea water recovered from above the outer, roof is supplied to the atomizing means is constituted. Sea water recovered from above the outer roof is not necessarily be supplied directly to the atomizing means. Accordingly, the aspect includes also a case in which sea water is supplied to the atomizing means via a preheating unit.
In this way, sea water is scattered on the outer roof, the water component is evaporated by solar ray and wind and concentration of the salt component is increased and thereafter, sea water is supplied to the atomizing means and fine mist of sea water is produced in the treating chamber and therefore, separation of the water component from the salt component can efficiently be carried out. Further, by scattering sea water on the upper roof and cooling a space between the outer roof and the roof of the treating chamber, vapor which has been vaporized in the treating chamber and flows in the space is cooled and condensed and accordingly, the space constitutes negative pressure. As a result, an effect of sucking smoothly vapor in the treating chamber into the space can also be achieved.
Further, when vapor is cooled and liquefied to constitute liquid, thermal energy absorbed in the treating chamber as vaporization heat is discharged as liquefaction heat. The discharged heat can expedite condensation by warming sea water scattered on the outer roof and can contribute to vaporization of small particles of sea water by being transferred also into the treating chamber.
According to the fourteenth aspect of the invention, there is provided the apparatus of treating sea water according to the eleventh, the twelfth or the thirteenth aspect, wherein at least one stage of at least one of the net and the cloth for adhering the salt component is arranged at least one of a lower side of the roof portion of the treating chamber (inner roof) and inner sides of the side walls.
In this way, owing to the constitution in which the net or the cloth for adhering the salt component is arranged on the lower side of the inner roof of the treating chamber or on the inner sides of the side walls, the net or the cloth can be stretched in a wide region and the salt component or the condensed sea water can be caught in a wide area and accordingly, the efficiency of recovering the salt component or the condensed sea water is increased.
According to the fifteenth aspect of the invention, there is provided the apparatus of treating sea water according to the fourteenth aspect, wherein a number of strings are made to hang from a lower side of at least one of the net and the cloth for adhering the salt component. In this way, in the inside of the treating chamber, owing to the constitution in which the number of strings are made to hang below the net or the cloth for preventing the salt component from passing therethrough without stopping, the salt component adheres to the number of strings before reaching the net or the cloth and accordingly, the salt component adhered to the strings can be shaken off and recovery of the salt component is facilitated which is suitable for mass production.
According to the sixteenth aspect of the invention, there is provided the apparatus of treating sea water according to the fourteenth or the fifteenth aspect, wherein means for washing off the salt component by scattering the sea water to at least one of the net and the cloth is arranged on an upper side of at least one of the net and the cloth on the lower side of the roof portion of the treating chamber. In this way, owing to the constitution in which sea water is scattered from the upper side of the net on the lower side of the inner roof to thereby wash off the salt component, a large amount of the salt component or the condensed sea water adhered to the net or the cloth in a wide region can efficiently be recovered and utilized in salt production.
According to the seventeenth aspect of the invention, there is provided the apparatus of treating sea water according to any one of the eleventh through the sixteenth aspects, further comprising a preheating unit for heating the sea water supplied to the means for atomizing the sea water at a temperature to a degree by which components in the sea water are not alterated.
In this way, before supplying sea water to the atomizing means, owing to the preheating unit of sea water, sea water accompanied by thermal energy is supplied to the atomizing means and therefore, vaporization of water component of mist of sea water is further expedited.
According to the eighteenth aspect of the invention, there is provided the apparatus of treating sea water according to any one of the eleventh through the seventeenth aspects, wherein a heating chamber is installed at a distance from the side wall of the treating chamber, wherein the sea water preheating means is installed in the heating chamber, and wherein heated air in the heating chamber is blown by blowing means from an opening opened at the side wall into the treating chamber. The blowing means includes exclusive blowing means and blowing means provided to the mist scattering device.
In this way, the heating chamber is installed at a distance from the side wall of the treating chamber and warm wind in the heating chamber is blown to inside of the treating chamber and accordingly, a large amount of thermal energy can be provided to fine mist of sea water in the treating chamber and vaporization of the water component is further expedited. Further, the preheating unit of sea water according to the seventeenth aspect is installed in the heating chamber and extra heat produced from the sea water preheating unit is utilized which is economical.
According to the nineteenth aspect of the invention, there is provided the apparatus of treating sea water according to any one of the eleventh through the eighteenth aspects, further comprising a heating facility for supplying warm air into the treating chamber. In this way, owing to the constitution capable of supplying warm air produced in the heating facility into the treating chamber, even when solar energy cannot be utilized as in, for example, rainy weather, thermal energy is provided to small particles of sea water in the treating chamber and the water component and the salt component can smoothly be separated from each other.
According to the twentieth aspect of the invention, there is provided the apparatus of treating sea water according to any one of the thirteenth through the nineteenth aspects, wherein a water distributing structure capable of supplying the sea water to the preheating unit without via the outer roof is constituted. When the processing of condensing sea water by natural energy on the outer roof cannot be carried out owing to rainy weather, the sea water is supplied as it is to the preheating unit, and can be supplied into the treating chamber after being provided with thermal energy and accordingly, natural salt and fresh water can be produced without being controlled by weather.
According to the twenty-first aspect of the invention, there is provided the apparatus of treating sea water according to any one of the thirteenth through the twentieth aspects, wherein a water distributing structure for scattering the sea water in a sea water tank for storing sea water by recovering the sea water scattered on the outer roof, guiding and scattering the sea water again onto the outer roof is constituted. In this way, owing to the structure in which sea water the salt component of which is condensed by scattering the sea water on the outer roof, is guided and scattered again on the outer roof, the sea water can be condensed by natural energy on the upper roof over a plurality of times. Therefore, it is suitable for the case of mass production of natural salt.
According to the twenty-second aspect of the invention, there is provided the apparatus of treating sea water according to any one of the thirteenth through the twenty-first aspects, wherein at least the roof of the treating chamber and the outer roof comprise transparent bodies. In this way, by constituting the outer roof and the roof of the treating chamber by transparent bodies, solar energy can reach the inside of the treating chamber to thereby heat it and accordingly, in fair weather, vaporization of fine mist of sea water in the treating chamber can efficiently be carried out.
In this way, according to salt or condensed sea water including salt provided by the invention, by removing bittern by reducing the water component, only crystals of salt can be separated.

Method and apparatus for desalinating sea water, natural salt and fresh water


A mobile computing platform for a mobile device, which has an interface for a remote connection to a backend server, includes a mobile analytics engine. The mobile analytics engine is configured to implement a mobile analytics model, which defines data, query and report structures for analytics of business data stored on the backend server. The mobile analytics engine uses model metadata to provide a generic reporting and analytics interface to support diverse mobile business analytics applications.

Mobile and connected devices (e.g., smart phones, tablets, etc.), which provide Internet connectivity to device users on the move, are transforming patterns of social and business behavior. Consumers are increasingly integrating mobile behaviors into their lifestyles. There is a growing use of mobile applications, not merely mobile browsers, for diverse purposes. Business applications (e.g., transactional business applications) have become relevant to mobile device use. As use of mobile devices continues to grow, consumers may expect business applications running on the mobile devices to have increasing functions and capabilities. The functions and capabilities of applications running on mobile computing platforms may be affected by features (e.g., limited data transfer rates, limited processing power, and temporary and unpredictable connectivity to the web) that are associated with the mobile devices. Yet, consumers may expect applications running on the mobile devices to have the same or similar capabilities as applications running on larger or immobile enterprise computing platforms. For example, consumers may want business applications running on mobile computing platforms to have the same analytical features or capabilities (e.g., reports or queries) associated with business applications (e.g., reporting or descriptive analytics, modeling or predictive analytics, data-driven strategy, clustering, affinity grouping, etc.) running on enterprise computing platforms.
Each mobile business application running on a mobile device may be affected differently and respond differently to operating conditions and features (e.g., limited data transfer rates, limited processing power, and temporary and unpredictable connectivity to the web) that are associated with the mobile devices.
Consideration is now being given to a common infrastructure for development of business applications on mobile computing platforms.


Powder coating apparatus (10) comprises an enclosure or booth (12) in which an article to be powder coated is locatable. Spray heads (24) are provided in the booth (12) to spray water over the inside of the booth (12) to remove over-spray powder coat material from the booth (12), following coating of an article, and removal thereof from the booth (12). Material washed from the booth (12) can be collected for recovery from the water.

Powder coating is a technique of coating a metallic article with paint or a similar substance. The paint is sprayed in dry powder form onto the article through a spray gun. The gun charges the powder particles with static charge such that they are attracted to the metal. The article is then passed into an oven, where the powder coating melts to form a flat coating on the article.
Spraying articles in this way results in a considerable amount of powder missing the article (so called overspray) and settling in the enclosure or booth in which the article is being sprayed. It is therefore desirable to recover this material for re-spraying.
Moreover, it is important that this material is recovered from the enclosure or booth when the colour of material to be sprayed is changed, otherwise cross contamination of colours of material will occur.
Conventionally, recovery of such material is done by either sucking the excess powder into an airline, or alternatively by blowing the powder with an airline into a collecting chamber. These techniques have the drawbacks of causing the powder to become airborne and thus difficult to recover. Moreover airborne powder coat material presents both health and environmental hazards.
Further, using such airlines to collect overspray tends to increase the static charge of the particles, and hence their affinity to the walls of the enclosure and other metal items thereby increasing the difficulty of their recovery.

Cutnall Green Droitwich, Worcestershire, WR9 OPQ


Compositions and methods for identifying new treatments for Facioscapulohumeral muscular dystrophy (FSHD), and uses thereof.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. There is currently no effective treatment available for FSHD and clinical trials with novel therapeutics have been discouraged by the lack of a recognized mouse model. Clinical trials have also been discouraged by the fact that FSHD is a highly variable and slowly progressing disease whereas the efficacy of therapeutic interventions is ideally established over short periods of time. Therefore, molecular biomarkers of FSHD that could be used to assay responsiveness to therapy would greatly facilitate FSHD therapeutic development and clinical research. High-density oligonucleotide arrays reliably quantify the expression levels of thousands of genes simultaneously and enable identification of such biomarkers.

Compositions and methods for characterizing and treating muscular dystrophy


A glass composition employing as its colorant portion at least iron (total iron expressed as Fe2O3), erbium (e.g., Er2O3), and holmium (e.g., Ho2O3). The glass may be grey or otherwise colored in different embodiments. In certain example embodiments the colorant portion may include, by weight percentage:

This invention relates to glass compositions and methods of making the same.
More particularly, this invention relates to glass compositions including at least erbium (Er) and holmium (Ho), which have low light transmittance in the UV (ultraviolet) and IR (infrared) ranges and high light transmittance in the visible range. Such glass compositions are useful, for example, in windows and windshields in the automotive industry and also in architectural applications. Glasses herein may be grey, or otherwise colored.
The automotive industry, for a number of years, has desired glass having grey color (sometimes called xe2x80x9cneutral greyxe2x80x9d) for automotive window applications. At the same time, it is also desirable for transmission in the UV and/or IR ranges of the light spectrum to be minimized. Moreover, certain Governmental regulations in the automotive industry have been known to require that visible light transmittance be at least 70% in certain vehicular windows when provided by the original equipment manufacturer of the vehicle (e.g. GM, Ford, Chrysler etc.) in the U.S.A. Accordingly, there exists a need in the automotive industry for a glass which achieves these properties (a similar need may also exist in other industries such as the architectural glass industry).
A glass window or other glass article is said to have the desirable color xe2x80x9cgreyxe2x80x9d when it has a dominant wavelength of from 435 nm to 570 nm (this dominant wavelength range defines the color xe2x80x9cgreyxe2x80x9d herein). Moreover, grey glass often has an excitation purity of less than about 4.5%. In certain embodiments, it may be preferable to have a dominant wavelength of from 470 nm to 570 nm, or even from 480-560 nm, with purity of from about 0.2 to 4.5%.
While glass having xe2x80x9cgreyxe2x80x9d color is often desirable, there sometimes also exists a need or desire to achieve certain levels of light transmission defined conventionally by:
Lta as visible light transmission,
UV as ultraviolet light transmission, and
IR as infrared light transmission.
Glass thickness ranges of from about 1-6 mm, more preferably from about 3-mm, are typically used when measuring the aforesaid characteristics. These thickness ranges are generally recognized as conventional thicknesses for glass sheets made by the float glass process, as well as recognized thickness ranges in the automotive industry.
For automotive windows (including windshields) it is often desirable for glass to have one or more of the following characteristics at any or all of the aforesaid thicknesses:
Lta: at least about 70%
UV no greater than about 43%, more preferably no greater than 40%
IR: no greater than about 46%, more preferably no greater than about 42%
Classically formulated grey glasses often include low levels of iron (i.e., less than 0.2% total iron) along with cobalt and nickel oxides. Unfortunately, while this type of glass may achieve satisfactory coloration in certain instances, it typically suffers from undesirable solar characteristics. Certain nickel-free grey glasses combine selenium (Se) and cobalt (Co) oxide with iron oxide, but also suffer from poor solar performance characteristics.
Certain known green solar control float glasses are formulated so as to achieve desirable solar characteristics due in large part to their use of large quantities of total iron (e.g., 0.60 to 0.84% total iron). Unfortunately, the green coloration of such glasses does not always harmonize well with certain exterior automotive paints and sometimes affects vehicle interiors when viewed through the glass.
In view of the above, it is apparent that there exists a need in the art for a new glass composition which overcomes the above problems while achieving one or more of desired grey color and desired solar management property(ies) of the particular application in which it is to be used.
An object of this invention is to provide a grey glass (i.e., having a dominant wavelength of from 435 nm to 570 nm) including a colorant portion which may include at least from 0.20 to 2.50%, by weight, erbium oxide (e.g., Er2O3), from about 0.10 to 0.90%, by weight total iron (expressed as Fe2O3), and from about 0.10 to 1.60%, by weight, holmium oxide (e.g., Ho2O3). The combination of erbium oxide, iron oxide, and holmium oxide provides for desirable color and/or solar characteristics in different embodiments of this invention.
Generally speaking, certain example embodiments of this invention fulfill one or more of the above-listed need(s) or object(s) by providing a glass comprising a colorant portion including:
In certain embodiments, the colorant portion may further include:
Certain other example embodiments fulfill one or more of the above listed needs and/or objects by providing a glass comprising:
the glass formed so as to have a dominant wavelength in the range of from 435 nm to 570 nm, and an excitation purity (Pe) of no greater than about 4.5%; and
wherein a colorant portion of the grey glass comprises iron oxide and at least three different lanthanide oxides, where a sum total of all of the lanthanide oxides in the glass is from 1.0 to 5.0%, by weight.
Still further example embodiments of this invention fulfill one or more of the above-listed object(s) and/or need(s) by providing a glass comprising:
a base glass portion comprising:
and a colorant portion comprising (or consisting essentially of in other embodiments):
In certain embodiments, the glass may be grey in color and have an excitation purity (Pe) of no greater than about 4.5%, and a dominant wavelength in the range of from 435 nm to 570 nm.
In certain exemplary embodiments, the glass or glass composition is substantially free of cerium and/or nickel. In certain embodiments, the amount of Se may be from 0.0 to 0.0010%.
While grey color is preferred in certain embodiments, this invention is not so limited. Colorant portions herein may be used in conjunction with other glass colors in alternative embodiments of this invention.
Glasses according to different embodiments of this invention may be used, for example, in the automotive industry (e.g., windshields, backlites, side windows, etc.), in architectural applications, and in other suitable applications. Such glasses may be grey, or otherwise colored in different embodiments of this invention.
Certain glasses according to this invention utilize soda-lime-silica flat glass as their base composition/glass, to which is added certain ingredients making up a unique colorant portion. An exemplary soda-lime-silica base glass according to certain embodiments of this invention, on a weight percentage basis, includes the following basic ingredients:
Other minor ingredients, including various conventional and refining aids, such as SO3, carbon, gypsum, CaSO4 and the like may also be included in the base glass. In certain embodiments, for example, glass herein may be made from batch raw materials silica sand, soda ash (or NaOH as a soda source), dolomite, limestone, with the use of salt cake (SO3) and/or Epsom salts (e.g., about a 1:1 combination of both) as refining agents. Reducing agent(s) such as Si (metallic), Si, silicon monoxide, SiO, sucrose, and/or carbon may also be used. Preferably, soda-lime-silica base glasses herein include by weight from about 10-15% Na2O and from about 6-12% CaO. While a soda-lime-silica base glass set forth above is preferred in certain embodiments of this invention, this invention is not so limited. Thus, other base glasses (e.g., borosilicate glass) may instead be employed in alternative embodiments.
To the base glass (e.g., see Table 1 above), the instant invention adds a colorant portion which may cause the resulting glass to be grey in color (e.g., dominant wavelength of from 435 nm to 570 nm) and/or achieve desirable solar management properties (e.g., low UV and IR transmission coupled with high visible transmission). In certain preferred embodiments, the resulting glass is grey in color and has a dominant wavelength of from 480 nm-560 nm (nanometers). Moreover, the resulting glass preferably has an excitation purity (Pe) no greater than about 4.5%, and most preferably from 0.2% to 4.5%.
In certain embodiments of this invention, an exemplary colorant portion that is added to the base glass is substantially free of cerium and nickel (i.e., no more than 0.0030% Ce, CeO, and/or CeO2, and no more than 0.0010% Ni and/or NiO), and is characterized in final glasses as set forth in Table 2 below (in terms of weight percentage of the total glass composition):
It should be appreciated that small amounts of other materials (e.g., refining aids, melting aids, and/or impurities) may be present in the glass such as chromium, manganese, molybdenum, tin, chlorine, zinc, zirconium, Si, sulfate, fluorine, lithium and strontium, without taking away from the purpose(s) and/or goal(s) of the instant invention. It is also noted that up to about 2.0% total iron may be used in certain embodiments of this invention.
The total amount of iron present in the glass and in the colorant portion thereof is expressed herein in terms of Fe2O3 in accordance with standard practice. This, however, does not imply that all iron is actually in the from of Fe2O3. Likewise, the amount of iron in the ferrous state is reported herein as FeO, even though all ferrous state iron in the glass may not be in the form of FeO. The proportion of the total iron in the ferrous state (i.e., FeO) is used to determine the redox state of the glass, and is expressed as the ratio FeO/Fe2O3, which is the weight percentage (%) of iron in the ferrous state (expressed as FeO) divided by the weight percentage (%) of total iron (expressed as Fe2O3). Thus, Fe2O3 herein means total iron and FeO means iron in the ferrous state. According to certain embodiments of this invention, the colorant portion of the glass composition herein is characterized by a redox value (i.e., FeO/Fe2O3) of from 0.10 to 0.25, more preferably from 0.12 to 0.20.
Moreover, it is noted that glass according to this invention is often made via the known float process in which a tin bath is utilized. It will thus be appreciated by those skilled in the art that as a result of forming the glass on molten tin in certain exemplary embodiments, small amounts of tin or tin oxide may migrate into surface areas of the glass on the side that was in contact with the tin bath during manufacture (i.e., typically, float glass may have a tin oxide concentration of 0.05% or more (wt.) in the first few microns below the surface that was in contact with the tin bath).
Glasses of this invention, as stated above, may in certain non-limiting embodiments achieve a true grey or neutral grey color. Such a true xe2x80x9cgreyxe2x80x9d color is best defined, as aforesaid, by referring to: (1) xe2x80x9cdominant wavelengthxe2x80x9d, and/or (2) xe2x80x9cexcitation purity.xe2x80x9d Other colors are also possible in other embodiments of this invention. In certain embodiments, glasses herein include one or more of the following color/solar characteristics when measured at a nominal thickness of from about 1 mm-6 mm (and preferably for most uses, at about 3 mm-4 mm):
When used in the automotive market for windows and/or windshields that must conform to certain minimal visible light transmission properties, certain example glass articles of this invention (e.g., at 3 mm thicknesses for purposes of reference) preferably have an Lta of at least 70% and, in certain embodiments of least about 72%, and in still further instances at least about 75%; and/or an IR transmission percentage (%) of no greater than 46%. Additionally, in certain exemplary embodiments, glasses herein have a UV transmission percentage (%) of no greater than about 43%. These optical characteristics relate to example embodiments only, and are not limiting upon the invention as a whole.
The glasses of this invention achieve the above unique characteristics (i.e., desired color in combination with desired solar management properties, e.g., Lta, UV, IR) in base glasses (e.g., silicate glasses such as soda-lime-silica, or borosilicate glasses) through the use of the unique colorant portions discussed herein. Erbium acts as a pink colorant, holmium as a pale yellow colorant, and the FeO aspect of the total iron acts as a blue colorant. As discussed above, selenium and cobalt may be utilized in the colorant portion for coloration purposes to achieve the desired grey color.
With regard to Se, in certain embodiments Se may be introduced into the glass batch in amounts of, for example, from 5-20 ppm. In order to increase retention of Se and to improve homogeneity of the glass through a more uniform Se distribution in the melt, compositions of this invention may use various sources of Se, such as sodium and/or calcium selenites, iron and/or cobalt selenides, and/or metallic Se powder. Moreover, while Se often combines with iron as iron selenide (FeSe) in glass to produce brown color, and does so in certain embodiments of this invention, selenium is referred to in the colorant portion herein as xe2x80x9cSexe2x80x9d which is meant to include, for example, its state as Se as well as other states in glass such as FeSe. While the use of Se is preferred in the colorant portion as discussed above, it is noted that in some embodiments Se need not be present. Thus, in some embodiments, the colorant portion of final glasses herein may include Se in the amount of 0.0 to 0.0020% by weight, more preferably from 0.0002 to 0.0010%.
Regarding cobalt (Co), this blue colorant may be added to the glass batch in amounts of, for example, 10-30 ppm. Moreover, it is believed that much of the cobalt in the glass is in the oxide state of Co3O4. However, other oxide states of CoO are also possible in glasses according to this invention. Thus, unless expressly stated to the contrary, the terms cobalt oxide, CoO and Co3O4 as used herein include not only cobalt in this/these particular oxide state(s), but also include(s) cobalt which may be present in other oxide state(s).
Holmium oxide acts as a pale yellow colorant, as does thulium oxide due to its absorption band at the blue end of the visible spectrum. Moreover, it is believed that much of the holmium in the glass is in the oxide state of Ho2O3. However, other oxide states of HoO are also possible in glasses according to this invention. Thus, unless expressly stated to the contrary, the terms holmium oxide, HoO and Ho2O3 as used herein include not only holmium in this/these particular oxide state(s), but also include(s) holmium which may be present in other oxide state(s). In a similar manner, it is believed that much of the thulium in the glass is in the oxide state of Tm2O3. However, other oxide states of TmO are also possible in glasses according to this invention. Thus, unless expressly stated to the contrary, the terms thulium oxide, TmO and Tm2O3 as used herein include not only thulium in this/these particular oxide state(s), but also include(s) thulium which may be present in other oxide state(s). Also, with regard to Er, unless expressly stated to the contrary, the terms erbium oxide, ErO and Er2O3 as used herein include not only Er in this/these particular oxide state(s), but also include(s) Er which may be present in other oxide state(s).
Ytterbium (Yb) and Lutetium (Lu) oxides also define absorption bands/regions in the visible region, and are referred to as colorants herein. It is believed that much of the Yb and Lu in the glass is in the oxide state(s) of Yb2O3 and Lu2O3, respectively. However, other oxide states are also possible in glasses according to this invention. Thus, unless expressly stated to the contrary, the terms ytterbium oxide, YbO and Yb2O3 as used herein include not only Yb in this/these particular oxide state(s), but also include(s) Yb which may be present in other oxide state(s). Likewise, unless expressly stated to the contrary, the terms lutetium oxide, LuO and Lu2O3 as used herein include not only Lu in this/these particular oxide state(s), but also include(s) Lu which may be present in other oxide state(s).
Colorant elements Ho, Er, Tm, Yb and Lu are all lanthanides or rare earth elements. Thus, as can be seen herein, in certain preferred embodiments up to five different lanthanides (or rare earth elements) are used in the glass composition together with iron in order to achieve the desired glass color. This is advantageous in that lanthanides are often grouped together when mined, and thus the ability to use multiple lanthanides together as a colorant portion is more cost efficient than previous methods of adding colorants such as Er. In some embodiments of this invention five or more lanthanides combine with at least iron in order to achieve the desired glass color and/or solar characteristics. For purposes of example only, and without limitation, a five element Er inclusive concentrate available from Pacific Industrial Development Corp., Ann Arbor, Mich. (e.g., rare earth oxide concentrate), may be used to add the aforesaid lanthanides. In other embodiments of this invention, two, three or four different lanthanides may be used together with iron to achieve the desired glass color and/or solar characteristics. In certain embodiments of this invention, the wt. % of all lanthanides or rare earth elements (including the lanthanide oxides listed above) in the glass composition put together is from 1.0 to 5.0%, more preferably from 1.4 to 4.0%. In certain preferred embodiments, glass compositions herein have more erbium oxide (Er2O3) than any of holmium oxide (Ho2O3), thulium oxide (Tm2O3), ytterbium oxide, or lutetium oxide taken individually. In certain preferred embodiments, glass compositions herein have at least twice as much erbium oxide (Er2O3) as holmium oxide (Ho2O3). In certain embodiments of this invention, glass compositions herein include at least twice as much holmium oxide (Ho2O3) as thulium oxide (Tm2O3), and at least three times as much erbium oxide (Er2O3) as thulium oxide (Tm2O3).

Grey glass composition including erbium and holmium


An interior arrangement used in an expandable room structure includes a first room section having a stationary floor with an upper surface. A second room section is movable relative to the first section between a retracted position and an extended position to expand the interior volume of the vehicle, and the second room section has a floor with a top surface. A pair of substantially parallel outer rails is provided for supporting the first room section, and a pair of substantially parallel inner rails is provided for supporting the second room section. Each of the inner rails is slidably mounted for longitudinal movement relative to one of the outer rails. An operating mechanism selectively moves the inner rails relative to the outer rails to extend and retract the second room section relative to the first room section. The operating mechanism is constructed and arranged to translate inward and outward movement between the inner rails and the outer rails into substantially vertical movement of the second room section relative to the stationary floor. The operating mechanism includes a gear track extending along a sloped path of travel defined by the inner rails so as to align the top surface of the second room section floor with the upper surface of the stationary floor as the second room section is moved to its extended position, and to vertically offset the top surface of the second room section floor relative to the upper surface of the stationary floor as the second room section is moved to its retracted position. The operating mechanism substantially maintains parallelism between a longitudinal axis of the inner rail and the floor of the second room section, and between a longitudinal axis of the outer rail and the stationary floor over the entire range of movement of the second room section relative to the first room section.

In order to increase the available interior space of recreational vehicles or trailers, slide-out rooms or sections can be made integral with the structure of the vehicle or trailer. During transit, these rooms can be retracted and stored in the interior of the vehicle or trailer with the exterior wall of the slide-out room approximately flush with the exterior of the vehicle or trailer. To use the slide-out room, the vehicle is first parked and leveled. The slide-out room is then slid outward from the vehicle to an extended position, increasing the interior space of the vehicle.
In prior art constructions, the floor of the movable slide-out room is typically supported above the floor of the portion of the room which remains stationary when the slide-out room is in its retracted position, and thus forms a portion of the usable interior floor while the vehicle is in transit. The floor of the movable slide-out room is higher than the floor of the stationary room section, which creates a step up from the stationary floor to the floor of the slide-out room when the slide-out room is placed in the expanded position. This step formed by the differential in floor height is undesirable, inconvenient, and may lead to injury from one unwarily tripping or stumbling thereover. Besides limiting the mobility of an occupant of the slide-out room, the step can cause difficulty in furniture placement and detract from the overall aesthetic appearance of the floor.
To address the problems created by this floor height differential, various slide-out structures have been proposed which allow the movable and stationary floors to have flush or coplanar upper surfaces at least when the slide-out room is in the expanded position. One such flat floor slide-out apparatus is disclosed in U.S. Pat. No. 5,491,933 issued Feb. 20, 1996 to Miller et al. In this patent, a sliding inner tube is movable laterally to pivot as the movable and stationary floor slide into the same horizontal plane during movement of the slide-out room section to its extended position. In seeking this position, however, the inner tube supporting the floor of the slide-out room section, which is dropped into flush engagement with the stationary floor, sags or tips downwardly due to the torque exerted by gravity in reaching a cantilevered position. This requires modification of the outer beam to provide a ramped surface, and also places undue stress on the drive element upon which the inner tube directly pivots.
Another factor in the design of an improved expandable vehicle is possible misalignment of the slide-out room during expansion. Chances for misalignment grow proportionately as the length of the slide-out room and the ensuing cantilevered weight exerted thereby increases. Any misalignment in the support mechanism for the slide-out room can lead to binding or skewing problems during movement of the slide-out room section between its extended and retracted positions.
It is an object of the present invention to provide a flat floor arrangement for a slide-out room section of a vehicle which is economical to manufacture and is dependable in use. It is another object of the invention to provide a flat floor arrangement which will ensure a low friction sliding operation without binding or misalignment problems. A further object of the invention is to provide a flat floor arrangement which involves cooperating movement of the support structure beneath the stationary floor and the floor of the slide-out room section.

Expandable room flat floor system utilizing notched inner rails and ramped outer rails


A position calculating apparatus that calculates a position of a moving body by using results of positioning by a GPS satellite and a self-contained sensor includes receiving means for receiving GPS orientation data measured by the GPS satellite and navigation orientation data measured by the self-contained sensor; first determining means for determining a reliability of the GPS orientation data; second determining means for determining a reliability of the navigation orientation data; and movement angle calculating means for calculating a movement angle of the moving body from the GPS orientation data or the navigation orientation data in accordance with the determination results of the first and second determining means.

1. Field of the Invention
The present invention relates to a position calculating apparatus that uses global positioning system (GPS) satellites and a self-contained sensor to calculate a position of a moving body and, more particularly, to a method of determining a movement angle of a moving body.
2. Description of the Related Art
Navigation apparatuses widely use GPS positioning that uses GPS satellites and self-contained navigation that uses, for example, gyro sensors or vehicle-speed sensors mounted in vehicles in order to calculate positions of the vehicles. The GPS positioning can detect absolute positions or orientations but the detection accuracy can be decreased depending on the reception environments. In contrast, the self-contained navigation does not depend on the reception environments but has the disadvantage of accumulated error. The navigation apparatuses use both the GPS positioning and the self-contained navigation in complementary fashion to calculate positions of the vehicles.
Japanese Unexamined Patent Application Publication No. 10-307036 relates to a hybrid navigator system that uses data from a self-contained sensor and a GPS device to yield navigation data about a moving body. The navigator system calculates the navigation data on the basis of data from the self-contained sensor and data received by the GPS device at the same positioning time. Since the GPS device is not provided with a calculation unit that calculates positional data including latitude, longitude, and orientation from the received data, unlike GPS devices in the related art, it is not necessary to perform a calculation for accommodating a difference in time between the data received from the self-contained sensor and the data received by the GPS device in the navigator system.
Japanese Unexamined Patent Application Publication No. 2003-279362 relates to a vehicle position correction device. The vehicle position correction device compares a traveling distance during a certain time period, yielded by self-contained navigation, with a distance between GPS positioning points during a time period corresponding to the certain time period, yielded by GPS positioning. If the difference between the traveling distance yielded by the self-contained navigation and the distance between the GPS positioning points is large, the vehicle position correction device determines that the GPS positioning data has a lower reliability. If the difference is small, the vehicle position correction device determines that the GPS positioning data has a higher reliability. The radius of an error circle indicating a range permitted for the GPS positioning error is decreased if the reliability is high while the radius is increased if the reliability is low.
Japanese Unexamined Patent Application Publication No. 2004-150852 relates to a satellite signal receiver. The satellite signal receiver adds a velocity vector Vn−1 yielded from the previous speed and speed orientation to the previously calculated position Xn−1 to calculate an estimated position Yn, yields the current calculated position Zn at a positioning unit, and calculates the reliabilities of the estimated position Yn and the calculated position Zn. Then, the satellite signal receiver yields a weight Tn to be assigned to the estimated position Yn from the reliabilities of the estimated position Yn and the calculated position Zn to calculate a corrected position Xn. The satellite signal receiver calculates an optimal corrected position from the reliability of the calculated position and the reliability of the estimated position each time the positioning is performed so that the error in speed is not accumulated, in order to improve the positioning accuracy.
As disclosed in Japanese Unexamined Patent Application Publication No. 2004-150852, if the error in the orientation defining the velocity vector is large when the satellite signal receiver calculates the reliability of the estimated position, yielded by adding the velocity vector to the previous calculated position, and the reliability of the current calculated position at the positioning unit to determine the corrected position on the basis of the reliabilities, the error in the estimated position becomes large, thus reducing the accuracy of the corrected position. Accordingly, in order to increase the accuracy of the corrected position, it is necessary to improve the accuracy of the orientation or movement angle defining the velocity vector.
The speed orientation defining the velocity vector can be obtained from absolute orientation data yielded by GPS positioning or relative orientation data yielded by self-contained navigation. The absolute orientation data is yielded by Doppler shift. The absolute orientation data that is almost correct can be obtained in a case where the positioning is performed in a good positioning environment, as in the open air. However, the error in positioning becomes large in a case where the vehicle is stopped or in a case affected by, for example, multipath, as in a shielded environment. In contrast, the relative orientation data does not depend on the reception environment, unlike the GPS positioning, and offers a variation in orientation that is almost correct. However, the error is accumulated in the case of continuous use for a long time or in a ease where the orientation varies significantly, as in a winding route.
In order to overcome the disadvantages of both the absolute orientation data and the relative orientation data, it is desired that the orientation data having a higher reliability, of the absolute orientation data and the relative orientation data, be adopted for the velocity vector each time the positioning is performed.

Position calculating apparatus, position calculating method, and program


The present invention includes composition and methods for making and using a combinatorial library to identify modified thioaptamers that bind to, and affect the immune response of a host animal, transcription factors such as IL-6, NF-κB, AP-1 and the like. Composition and methods are also provided for the treatment of viral infections, as well as, vaccines and vaccine adjuvants are provided that modify host immune responses.

Virtually all organisms have nuclease enzymes that degrade rapidly foreign DNA as an important in vivo defense mechanism. The use, therefore, of normal oligonucleotides as diagnostic or therapeutic agents in the presence of most bodily fluids or tissue samples is generally precluded. It has been shown, however, that phosphoromonothioate or phosphorodithioate modifications of the DNA backbone in oligonucleotides can impart both nuclease resistance and enhance the affinity for target molecules, such as for example the transcriptional activating protein NF-κB.
Recent world events have heightened the awareness of possible bioterrorist threats. Hemorrhagic fever viruses (category A bioweapon agents) have reportedly been weaponized by the former Soviet Union and the United States (Borio et al., 2002; Hawley & Eitzen, 2001). Despite the awareness of the potential of Viral Hemorrhagic Fever viruses (Lassa, Junin), Encephalitic viruses (West Nile, VEE) and other agents both as bioweapons and as emerging viral diseases, few therapeutic options are available to those infected. Apart from supportive therapy, the only drug for treating Arenavirus infections is Ribavirin and it is only partially effective (McCormick et al, 1986a; Shulman, 1984; Enria et al., 1987) while there are no efficacious drugs to treat victims of West Nile infections (Peterson and Marfin, 2002). There is an urgent need to expand the current therapeutic armamentarium, which is hindered, at least in part, by a lack of in-depth knowledge concerning the mechanisms of Arenaviral pathogenesis (Peters & Zaki, 2002).
Arenavirus pathogenesis stems from host immune response dysregulation and endothelial dysfunction (Peters & Zaki, 2002; Ignatyev et al., 2000; McCormick & Fisher-Hoch, 2002; Walker et al., 1982; McCormick et al., 1986b; Marta et al., 1999). West Nile pathogenesis is associated with the inability of host immune response to limit virus replication to levels below that required for viral invasion of the CNS (Solomon and Vaughn, 2002).
Lassa fever, a human arenavirus hemorrhagic fever virus endemic in West Africa, affects up to 300,000 people annually and is responsible for up to 3000 deaths (McCormick, et al., 1987). Lassa Fever virus is difficult to study due to its hazardous nature (a BSL4 agent) Junin Virus is the causative agent of Argentine hemorrhagic fever (AHF). The annual incidence varies between 100-4000 cases/yr. AHF has a case fatality rate of 15-30% and is also a BSL4 agent. A well-established animal model that resembles Lassa Fever, using the non-pathogenic New World Arenavirus, Pichinde virus (Jahrling et al., 1981) has been used to study this class of pathogens. Serial passage of Pichinde virus in guinea pigs was used to develop a virulent variant that produces a disease in guinea pigs that mimics human Lassa Fever in many important respects including: viremia correlates with disease outcome (Johnson et al., 1987; Aronson et al., 1994), a relative paucity of pathologic findings in lethally infected animals (Walker, et al., 1982; Connolly, et al., 1993), terminal vascular leak syndrome (Katz & Starr, 1990) and distribution of viral antigens within the host (Connolly et al., 1993; Shieh et al., 1997; Aronson, unpublished data). Macrophage responses to the attenuated Pichinde virus, P2, with the virulent Pichinde variant, P18 as well as reassortants of the two variants (Zhang et al., 1999; Zhang et al., 2001; Fennewald et al., 2002) may be used to compare and modify the immune response to viral infection.
West Nile virus (Category B virus) is a mosquito-borne flavivirus that is a neuropathogen in humans, equines and avians (Solomon and Vaughn, 2002; Petersen and Marfin, 2002). Humans become infected by the bite of an infected mosquito. The viruses are then thought to replicate in the skin before being transported to the local lymph nodes. West Nile may then spread via the blood to other organs including the liver, spleen, heart and kidney and eventually the brain. West Nile virus may spread to the CNS via either hematogenous spread or via the olfactory mucosa where there is no blood-brain barrier. West Nile is an emerging pathogen in the US, spreading across the country since it was first identified in New York in 1999. As of Oct. 3, 2002, the CDC has reported 2530 cases of West Nile virus infection with 125 deaths in 32 states. West Nile is also responsible for major outbreaks in other countries including Tunisia, Romania, Algeria, Russia and Israel among others. Case fatality rates range from 4-29%. Age is a risk factor in the development of severe West Nile disease with many patients exhibiting substantial morbidity. Presently, treatment for West Nile is limited to supportive intervention. There is no evidence that either interferon or Ribavirin treatment is efficacious (Petersen and Marf1in, 2002).
Arenavirus Hemorrhagic Fevers, such as Lassa fever, Junin, Argentine hemorrhagic fever, Bolivian hemorrhagic fever and Venezuelan hemorrhagic fever, have several features in common with sepsis and the systemic inflammatory response syndrome, including fulminant clinical course, fever, shock, capillary leak syndrome, decreased myocardial contractility, abnormalities of coagulation and platelet function, and elevated serum levels of TNFα (Aronson et al., 1994; Cummins, 1990). Arenaviruses are non-cytopathic viruses with a tropism for macrophages and other reticuloendothelial cells (Cummins, 1990; Peters et al., 1987); the pathogenesis of these diseases is believed to involve excessive production of pro-inflammatory cytokines (Aronson et al., 1995; Peters et al., 1987). Unpublished data (Bausch et al., CDC) show cytokines to be massively activated in human Lassa fever, and also confirm that Lassa virus can directly induce cytokine secretion by infecting human macrophages in vitro (Mahanty et al., CDC, unpublished). Alternatively, there is evidence that a swift elaboration of pro-inflammatory cytokines and early engagement of the (innate) immune response may help protect of the infected host from lethal disease in various hemorrhagic fever syndromes (Peters et al., 1987).
Endotoxic shock results from an innate, anaphylactic response to bacterial lipopolysaccharide (LPS). The NF-κB transcription factor, in conjunction with other cellular transcription factors, plays a critical role in gene activation, especially in acute phase and inflammatory responses (Baeuerele, 1998; Barnes and Karin, 1997), and in particular endotoxic shock, a complex pathophysiological state which is considered to be an exaggerated or dysregulated systemic acute inflammatory response syndrome initiated by the binding of bacterial LPS complexed with lipopolysaccharide binding protein (LBP) to the CD14 receptor on macrophages. A series of intracellular signaling events, in which NF-κB activation figures importantly leads to enhanced transcription of proinflammatory mediators, including TNFα, IL-1 and inducible nitric oxide synthase, ultimately promoting vasodilatation, capillary leakiness, and myocardial suppression (Murphy et al., 1998). In well-established mouse endotoxemia models, rapid transient increases in NF-κB DNA-binding activity can be detected in the nuclei of macrophages and other cell types (Boher, et al., 1997); similar observations have been made in human sepsis (Velasco et al., 1997).
The AP-1 transcription factor family include the dimeric basic region leucine zipper proteins that belong to the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1, Fra-2) Maf (c-Maf, MafB, MafA, MafG/F/K, Nrl) and ATF/CREB (CREB, CREBP-2, ATF1, ATF2, LRF1/ATF3, ATF4, ATFa, ATF6, B-ATF, JDP1, JDP2) subfamilies which recognize either 12-O-tetradecanoylphorbol-13-acetate (TPA) response elements (5′-TGAG/CTCA-3′) or cAMP response elements (CRE, 5′-TGACGTCA-3′) (Chinenov and Kerppola, 2001; Shaulian and Karin, 2002). These transcription factor binding sites are elements in the promoters and enhancers of numerous mammalian genes including IL-2, IL-3, IL-4, IL-5, IFNβ, TNFα and GM-CSF (Chineov and Kerppola, 2001). The c-Jun protein is the most potent transcription factor. The c-Fos proteins, which cannot homodimerize can form heterodimers with c-Jun and thereby enhance their DNA binding activities. The c-Fos, and FosB proteins contain transactivation domains, however, Fra1, Fra2 and some splice variants of FosB do not. CREB and ATF1 can form homodimers and heterodimers but do not combine with other ATF proteins. ATF2, ATFa, CREBP-2, ATF3, ATF4 and ATF6 combine both with themselves and with specific Jun and/or Fos family members. C-Fos and Fra1 can heterodimerize with ATF4, but not with ATF2 and ATF3.
There are numerous other possible homodimers and heterodimers possible among this large group of BZIP proteins. Jun, Fos and ATF family members can also bind to DNA upon association with certain Maf, C/EBP and non-bZIP member factors like NF-κB, NFAT and Smad. This can direct AP-1 components to promoter sequences that only slightly resemble consensus AP-1 and ATF motifs. This variation in dimer partner and DNA binding site specificity is assumed to provide AP1 subunits with a high level of flexibility in gene regulation. The regulation of AP-1 family of transcription factor activity is complex but briefly regulation occurs through: 1) changes in jun and fos gene transcription and mRNA turnover, 2) Fos and Jun protein turnover, 3) post-translational modifications of both Fos, Jun other family proteins that modulate their activities, and 4) interactions with other transcription factors (Shaulian and Karin, 2001,2002). AP-1 activity is induced by growth factors, cytokines, neurotransmitters, polypeptide hormones, cell/matrix interactions, bacterial and viral infections and a variety of environmental stresses. These activators stimulate a series of signaling events that involve a variety of protein kinases including MAPKs, ERKs and JNKs. Members of the Fos and Jun protein families participate in the regulation of a variety of cellular processes including cell proliferation, differentiation, apoptosis, oncogenesis, inflammation, and immunity (Chinenov and Kerppola, 2001).

This patent is subject to a terminal disclaimer.

Structure based and combinatorially selected oligonucleoside phosphorothioate and phosphorodithioate aptamer targeting AP-1 transcription factors

Board of Regents, The University of Texas System


The present invention provides an application-independent and engine-independent middleware layer between applications and engines. The middleware provides speech-related services to both applications and engines, thereby making it far easier for application vendors and engine vendors to bring their technology to consumers.

The present invention deals with services for enabling speech recognition and speech synthesis technology. In particular, the present invention relates to a middleware layer which resides between applications and engines (i.e., speech recognizers and speech synthesizers) and provides services, on an application-independent and engine-independent basis, for both applications and engines.
Speech synthesis engines typically include a decoder which receives textual information and converts it to audio information which can be synthesized into speech on an audio device. Speech recognition engines typically include a decoder which receives audio information in the form of a speech signal and identifies a sequence of words from the speech signal.
In the past, applications which invoked these engines communicated directly with the engines. Because the engines from each vendor interacted with applications directly, the behavior of that interaction was unpredictable and inconsistent. This made it virtually impossible to change synthesis or recognition engines without inducing errors in the application. It is believed that, because of these difficulties, speech recognition technology and speech synthesis technology have not quickly gained wide acceptance.
In an effort to make such technology more readily available, an interface between engines and applications was specified by a set of application programming interfaces (API's) referred to as the Microsoft Speech API version 4.0 (SAPI4). Though the set of API's in SAPI4 specified direct interaction between applications and engines, and although this was a significant step forward in making speech recognition and speech synthesis technology more widely available, some of these API's were cumbersome to use, required the application to be apartment threaded, and did not support all languages.
The process of making speech recognition and speech synthesis more widely available has encountered other obstacles as well. For example, many of the interactions between the application programs and the engines can be complex. Such complexities include cross-process data marshalling, event notification, parameter validation, default configuration, and many others. Conventional operating systems provide essentially no assistance to either application vendors, or speech engine vendors, beyond basic access to audio devices. Therefore, application vendors and engine vendors have been required to write a great deal of code to interface with one another.

Middleware layer between speech related applications and engines