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Suitcase, especially a pilot suitcase |
In a case, in particular a pilot case, comprising a bottom element (2), a cover element (4) and side as well as front wall elements (6,8), the cover element (4) is made up of a plurality of hingedly interconnected strips (10). |
1. Case, in particular pilot case, comprising a bottom element (2), a cover element (4) and side as well as front wall elements (6, 8), wherein the cover element (4) comprises a plurality of hingedly interconnected strips (10), characterized in that the cover element (4, 4a, 4b) is of bipartite configuration and, in the closed position, the free front edges of both cover parts (4a, 4b) abut on each other, and the two cover elements (4a, 4b) are coupled to each other via a linkage (20) to allow synchronous movement. 2. Case according to claim 1, characterized in that the cover element (4) is guided in lateral guides (12) of the side wall elements (6). 3. Case according to claim 1, characterized in that the cover element (4, 4a, 4b) comprises one or a plurality of lock elements (16) at the free front edge. 4. Case according to claim 1, characterized in that the cover element (4, 4a, 4b) is movable along the lateral guides (12) into a position essentially parallel to the front wall elements (8) thus assuming an open position. 5. Case according to claim 1, characterized in that in the cover element (4, 4b) a handle (18) is provided. 6. Case according to claim 2, characterized in that the lateral guides (12) are made from a profile with a U-shaped cross-section. 7. Case according to claim 6, characterized in that the profile with the U-shaped cross-section at least partially surrounds and receives the side wall element (6). 8. Case according to claim 2, characterized in that the lateral guides (12) for the cover element (4, 4a, 4b) are arcuately bent by 90° in the upper portion of the case. 9. Case according to claim 1, characterized in that the linkage (20) comprises two swivel arms (22, 24) and a coupling element (26), wherein each cover part (4a, 4b) is rigidly coupled with one swivel arm (22, 24) and the coupling element (26) hingedly connects the two swivel arms. 10. Case according to claim 9, characterized in that the swivel arms (22, 24) are supported in the side wall elements (6) in a plane extending in parallel to the side wall elements (6). 11. Case according to claim 9, characterized in that the swivel arms (22,24) are connected with each other by a spring element (28) promoting the closing movement. 12. Case according to claim 1, characterized in that the bottom, wall and cover elements (2, 4, 4a, 4b, 6, 8) are made of plastic and/or metal, preferably aluminum. 13. Case according to claim 1, characterized in that the strips (10) have a width of approximately 15 to 25 mm, preferably 23 mm. 14. Case according to claim 2, characterized in that the cover element (4, 4a, 4b) comprises one or a plurality of lock elements (16) at the free front edge. 15. Case according to claim 10, characterized in that the swivel arms (22,24) are connected with each other by a spring element (28) promoting the closing movement. |
7-Amino triazolopyrimidines for controlling harmful fungi |
The invention relates to 7-amino triazolopyrimidines of formula (I), in which the substituents have the following meanings: R1, R2 represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphthyl; or 5-membered or 6-membered heterocyclyl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom; or 5-membered or 6-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, or R1 and R2 can, together with the nitrogen atom, which binds them, form a 5-membered or 6-membered ring containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom; R3 represents alkyl, alkenyl, alkynyl, cycloalkyl, phenylalkyl and alkyl halide; whereby R3 and R2 can be unsubstituted or partially or completely substituted according to the description; X represents halogen, cyano, alkoxy, alkyl halide, phenyl or phenyl that is substituted by Ra. The invention also relates to methods and intermediate products for producing said compounds, to agents containing the same, and to their use. |
1. A 7-aminotriazolopyrimidine of the formula I, where: R1, R2 are hydrogen, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C3-C8-cycloalkyl, phenyl, naphthyl; or 5- or 6-membered heterocyclyl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom; or 5- or 6-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, where R1 and R2, independently of one another, may, if they are not hydrogen, be partially or fully halogenated and/or may carry one to three radicals from the group Ra Ra is cyano, nitro, hydroxyl, C1-C6-alkyl, Cl-C6-haloalkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-alkylamino, di-C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkenyloxy, C2-C6-alkynyl, C3-C6-alkynyloxy and unhalogenated or halogenated oxy-C1-C4-alkyleneoxy; or R1 and R2 together with the linking nitrogen atom may form a 5- or 6-membered ring which contains one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom and which may be substituted by one to three radicals from the group Ra; R3 is C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl-, C3-C8-cycloalkyl, phenyl-C1-C10-alkyl, where R3 may be unsubstituted or partially or fully halogenated and/or may carry one to three radicals from the group Ra, or C1-C10-haloalkyl which may carry one to three radicals from the group Ra; X is halogen, cyano, C1-C4-alkoxy, C1-C4-haloalkyl, phenyl or Ra-substituted phenyl; and its salts. 2. A 7-aminotriazolopyrimidine of the formula I as claimed in claim 1 in which X is halogen. 3. A process for preparing 7-aminotriazolopyrimidines of the formula I as claimed in claim 1 in which X is halogen, cyano or C1-C4-alkoxy, which comprises cyclizing dicarbonyl compounds of the formula II.1, where A1 and A2 are C1-C10-alkoxy, with 3-amino-1,2,4-triazole of the formula III to give hydroxytriazolopyrimidines of the formula IV.1 halogenating the hydroxytriazolopyrimidines of the formula IV.1 with a halogenating agent to give halotriazolopyrimidines of the formula V.1 where Hal is halogen, followed by reaction with an amine of the formula VI to give 7-aminotriazolopyrimidines of the formula I in which X is halogen, and, to prepare 7-aminotriazolopyrimidines of the formula I in which X is cyano or C1-C4-alkoxy, reacting with a compound of the formula VII M-X′ VII in which M is an ammonium, tetraalkylammonium, alkali metal or alkaline earth metal cation and X′ is cyano or alkoxy. 4. A process for preparing compounds of the formula I as claimed in claim 1, in which X is C1-C4-haloalkyl or unsubstituted or Ra-substituted phenyl, which comprises cyclizing dicarbonyl compounds of the formula II.2 where A1 is C1-C10-alkoxy and X is C1-C4-haloalkyl or unsubstituted or Ra-substituted phenyl with 3-amino-1,2,4-triazole of the formula III as claimed in claim 3 to give 7-hydroxytriazolopyrimidines of the formula IV.2 halogenating the 7-hydroxytriazolopyrimidines of the formula IV.2 with a halogenating agent to give 7-halotriazolopyrimidines of the formula V.2 where Hal is halogen, followed by reaction with an amine of the formula VI as claimed in claim 3 to give 7-aminotriazolopyrimidines of the formula I. 5. A composition suitable for controlling harmful fungi, which comprises a solid or liquid carrier and a 7-aminotriazolopyrimidine of the formula I as claimed in claim 1. 6. The use of the 7-aminotriazolopyrimidines of the formula I as claimed in claim 1 for preparing a composition suitable for controlling harmful fungi. 7. A method for controlling harmful fungi, which comprises treating the fungi or the materials, plants, the soil or the seeds to be protected against fungal attack with an effective amount of the 7-aminotriazolopyrimidines of the formula I as claimed in claim 1. |
Article with droplet-like coating and method for making same |
The invention concerns a method for making adherent relief coating surface simulating the appearance of liquid droplets, comprising direct transfer application (and preferably by screen-printing) of a curable liquid material on the surface so as to form on the surface projecting discrete drops which are then cured: Drops of different sizes are applied, preferably in ordered manner. |
1. A method for making on a surface of an article an adherent relief coating which simulates the appearance of liquid droplets, said method comprising application of a curable liquid material onto the surface so as to form on the surface projecting discrete drops which are then cured, wherein application is performed by direct transfer. 2. The method as claimed in claim 1, wherein the application is performed by screen printing. 3. The method as claimed in claim 1 wherein the surface and the liquid material exhibits a difference in surface tension which results in a low level of wetting. 4. The method as claimed in claim 1, wherein drops of different sizes are applied onto the surface. 5. The method as claimed in claim 4, wherein the drops of different sizes are applied in an ordered manner. 6. An article comprising an adherent relief coating simulating the appearance of liquid droplets, resulting from the application of a curable liquid material onto the surface so as to form on the surface projecting discrete drops which are then cured, wherein application has been performed by direct transfer as claimed in any one of claims 1 to 5. 7. The method as claimed in claim 2, wherein the surface and the liquid material exhibit a difference in surface tension which results in a low level of wetting. 8. The method as claimed in claim 7, wherein drops of different sizes are applied onto the surface. 9. The method as claimed in claim 8, wherein the drops of different sizes are applied in an ordered manner. |
Method for using auxiliary filtering agents for filtration purposes |
The invention relates to a method for filtering liquids, especially biological liquids. A filter (1) is deposited with the auxiliary filtering agent during a pre-deposition phase. In an ensuing filtration phase, the infiltrate is filtered by adding an auxiliary filtering agent. The auxiliary filtering agent forms a filter cake during the pre-deposition phase and the filtration phase. The auxiliary filtering agent is deposited during the pre-deposition phase, the proportion of regenerated auxiliary filtering agent being 30%, especially 0%. During the filtration phase, an auxiliary filtering agent is added, consisting predominantly, especially almost fully, of regenerated auxiliary filtering agent. The regenerated auxiliary filtering agent is treated with a medium over the whole pH value spectrum. |
1. A method for filtering liquids, in which a filter is precoated with filter aid in a precoating phase and feed is filtered while adding filter aid in a subsequent filtration phase, where the filter aid forms a filter cake on the filter in the precoating phase and the filtration phase, wherein in the precoating phase, filter aid is deposited in which the amount of regenerated filter aid is <30%, and filter aid is added in the filtration phase that chiefly consists of regenerated filter aid, where the regenerated filter aid has been treated with an agent in the range of the overall pH spectrum. 2. A method as in claim 1, wherein in the filtration phase filter aid is added that consists nearly entirely of regenerated filter aid. 3. A method as in claim 1, wherein diatomaceous earth is used as filter aid. 4. A method as in claim 1, wherein cellulose and/or perlite with or without diatomaceous earth is used as filter aid. 5. A method as in claim 1, wherein silica gel and/or PVPP is added to the filter aid. 6. A method as in claim 1, wherein the method includes a regeneration phase, in which the filter aid is regenerated. 7. A method as in claim 6, wherein the regeneration is carried out in the filter. 8. A method as in claim 6, wherein the regeneration phase includes the treatment of the filter aid with an alkali solution. 9. A method as in claim 8, wherein the alkali solution is sodium hydroxide solution in a concentration of 0.1 to 2%. 10. A method as in claim 8, wherein the regeneration with alkali solution is carried out at a temperature from 60° C. to 90° C. 11. A method as in claim 8, wherein the filter cake is rinsed with hot water before the treatment with alkali solution. 12. A method as in claim 11, wherein the hot water has a temperature from 40° C. to 90° C. 13. A method as in claim 8, wherein after treatment with alkali solution the alkali solution is displaced with hot water and with cold water. 14. A method as in claim 6, wherein the filter aid is treated with an acid. 15. A method as in claim 14, wherein the filter aid is treated with nitric aid. 16. A method as in claim 14, wherein the treatment with acid is carried out after displacing the alkali solution with hot water and with cold water. 17. A method as in claim 14, wherein the acid is displaced with cold water and the acid is then allowed to drain from the filter. 18. A method as in claim 6, wherein the filter aid is resuspended at the end of the regeneration phase. 19. A method as in claim 1, wherein the method is carried out in combination with a method for stabilizing tannin-containing liquids. |
Sensor device for measuring vital parameters of a fetus during birth |
The invention relates to a sensor device as part of a measurement appliance with a measurement device for the measurement of vital parameters of a foetus during labor and delivery, in particular the oxygen content of the blood of the foetus. Such sensor devices should be applied to the tissue of the foetus in a secure and light-tight manner, and furthermore at least the carrier or sensor should be able to be fitted to the foetus gently and easily. According to the invention, the sensor device comprises a shell-type carrier, which is subdivided into an approximately centrally arranged attachment zone and a surrounding zone, which can be brought into contact with the tissue of the foetus, and the attachment zone is provided with a spiral-type attachment element for attaching the carrier to the leading part of the foetus, and the rotational axis of the attachment element is arranged approximately perpendicular to the surface of the carrier to be fitted to the leading part of the foetus. The surrounding zone comprises at least one light emitter and at least one receiver, whereby the attachment element is supported for rotation with respect to the surrounding zone. |
1. Sensor device as part of a measurement appliance with a measurement device for the measurement of vital parameters of a foetus during labor and delivery, in particular the oxygen content of the blood of the foetus, whereby the sensor device comprises a shell-type carrier, which is subdivided into an approximately centrally arranged attachment zone and a surrounding zone, which can be brought into contact with the tissue of the foetus, and the attachment zone is provided with a spiral-type attachment element for attaching the carrier to the leading part of the foetus, whereby the axis of rotation of the attachment element is arranged approximately perpendicular to the surface of the carrier to be fitted to the leading part of the foetus, and the surrounding zone comprises at least one light emitter and at least one receiver, whereby the attachment element is supported for rotation with respect to the surrounding zone. 2. Sensor device according to claim 1, wherein the attachment zone comprises a rotational body to which the attachment element is attached. 3. Sensor device according to claim 1, wherein the leads transferring the signal to the measurement device are arranged branching off from the surrounding zone. 4. Sensor device according to claim 1, wherein a rotary handle is provided, whereby the carrier can be releasably connected to the rotary handle for moving and fitting the sensor device to the leading part of the foetus and leads of the carrier are arranged branching off towards the outside from the front end section of the rotary handle. 5. Sensor device according to claim 4, wherein the rotary handle exhibits a protective bell for accommodating the carrier and the bell wall exhibits an opening through which the leads are brought out. 6. Sensor device according to claim 5, wherein the opening for routing the leads runs into the funnel opening of the protective bell facing the leading part of the foetus. 7. Sensor device according to claim 4, wherein the rotary handle exhibits a rotating bar which can be connected to the attachment zone, said rotating bar being mounted for rotation in a tube-type sleeve, whereby the leads run outside of the tube-type sleeve. 8. Sensor device according to claim 1, wherein the attachment element is in electrically conducting contact with a slip-ring contact of the surrounding zone. 9. Sensor device according to claim 1, wherein the attachment zone is supported on the carrier for rotation via an annular shoulder supported in an annular groove and is axially fixed. 10. Sensor device according to claim 1, wherein the attachment zone is latched axially on the carrier. |
<SOH> BACKGROUND OF THE INVENTION <EOH>This kind of sensor device known from EP 611 548 A1 exhibits a round shell-type carrier in which an approximately central attachment zone is provided which is fitted with a spiral-type attachment element for attaching the carrier to the leading part of the foetus. Here, the rotational axis of the attachment element is approximately perpendicular to the surface of the carrier which is to be attached to the leading part of the foetus. The carrier also exhibits a marginal zone which can be brought into contact with the tissue of the foetus, the said marginal zone exhibiting a light emitter and a receiver. The marginal zone is formed as a spring element, whereby it presses flexibly onto the tissue of the foetus under the stressing of the spring. This ensures a reliable transmission of light from the emitter through the tissue of the foetus to the receiver, whereby good signals are obtained for evaluation. For fitting the sensor device to the tissue of the foetus, the carrier is pressed against the tissue of the foetus and the sensor device rotated about the axis and in the rotational direction of the wire spiral, so that it screws into the galea of the foetus. The screwed-in wire spiral provides the counterpoint for the spring force with which the marginal zone presses onto the tissue of the foetus. From U.S. Pat. No. 5,199,432 and U.S. Pat. No. 5,373,843 it is known that a cylindrical CTG sensor (cardiotocography) is provided at its front end with a wire spiral and is fastened by the wire spiral penetrating into the tissue of a person. For fitting, the cylindrical sensor is joined at its rear end to a rotating bar which is supported for rotation in a tube. The leads leaving the sensor extend longitudinally through the hollow space of the rotating bar and are brought out at the back. When feeding in the sensor, the sensor is first arranged withdrawn inside the tube. Once the tube is placed on the human tissue, the sensor is pushed axially towards the front with the aid of the rotating bar and then twisted. The problem arises in that the handling of the leads running through the rotating bar and the tube is cumbersome in practice, in particular when the sensor is fitted to the tissue and the rotating bar and the tube are withdrawn when they are no longer required. An analogous method of attachment with a wire spiral is suggested in U.S. Pat. No. 4,644,957 with which the same problems arise. With these sort of arrangements there is also the disadvantage that the tubes are often filled with amniotic fluid which contaminates the leads and plug contacts. Due to the electrolyte content of the amniotic fluid, an electrically conductive film remains which can negatively affect the sensor signals. U.S. Pat. No. 6,058,321 describes a measurement appliance for the continuous monitoring of a foetal electrocardiogram and for the intermittent monitoring of a blood pH value of the foetal scalp during a delivery. A spiral-shaped needle for screwing into the scalp protrudes from a flat bottom of the appliance. A hollow needle of the pH probe is stored withdrawn within the appliance during the screw-in process, so that it has no contact with the tissue of the foetus. A rotatable retention ring with a receiving recess for the hollow needle of the pH probe is arranged around the base element, the said retention ring being locked onto the base element when the spiral needle is screwed in. When the spiral needle is securely attached in the scalp of the foetus, the pH probe with the retention ring can be screwed in at various spaced measurement positions from which the hollow needle of the pH probe can be extended to extract a blood sample from the foetal scalp. |
<SOH> SUMMARY OF THE INVENTION <EOH>The object of the invention is to develop the known sensor device of the type mentioned at the beginning, such that the existing advantages such as the secure attachment and light sealing on the tissue of the foetus are retained and furthermore, at least the carrier (sensor) can be applied to the foetus more gently and easily. For the solution of this object the invention provides a sensor device as part of a measurement appliance with a measurement device for the measurement of vital parameters of a foetus during labor and delivery, in particular the oxygen content of the blood of the foetus, whereby the sensor device comprises a shell-type carrier which is subdivided into an approximately centrally arranged attachment zone and a surrounding zone which can be brought into contact with the tissue of the foetus, and the attachment zone with a spiral-type attachment element is provided for attaching the carrier to the leading part of the foetus, whereby the rotational axis of the attachment element is arranged approximately perpendicular to the surface of the carrier to be applied to the leading part of the foetus, and the surrounding zone comprises at least one light emitter and at least one receiver, whereby the attachment element is supported for rotation with respect to the surrounding zone. Due to the shell-type formation of the carrier, the surrounding zone is already positioned on the tissue of the foetus during the attachment of the spiral-type attachment element and it retains its position also when the attachment element is screwed into the tissue of the foetus. The measures according to the invention ensure that when fitting the carrier to the tissue of the foetus the already contacting parts of the carrier do not need to be also rotated with the attachment element when overcoming the frictional force, i.e. the application of the carrier occurs significantly more sensitively and with more protection of the tissue. This handling of the carrier is simplified still further if the attachment zone exhibits a rotational body to which the attachment element is mounted. Here it is of advantage if the leads transferring signals to the measurement device from the surrounding zone are arranged branched. Then the leads cannot be of hindrance when the attachment element is screwed in. According to a preferred embodiment, the carrier can be releasably joined to a rotary handle for passing and fitting the sensor device to the leading part of the foetus and the carrier leads can be arranged branching outwards from the front end section of the rotary handle. This means that the leads can be brought out already from the front end of the rotary handle and routed further as is most practicable for the user. In particular the leads are therefore freed from the largest part of the rotary handle and are less affected by the rotary movement. According to a particular embodiment of the invention, the rotary handle can exhibit a protective bell for accommodating the carrier and the bell wall can exhibit an opening through which leads are brought out. The carrier can be arranged in the protective bell when the sensor is passed and applied, so maternal tissue is held at a distance and protected from the carrier. This facilitates trouble-free fitting of the carrier on the tissue. Leads are brought out through the opening in the bell wall and they can be then routed as required by the user. It is suggested that the opening for bringing out the leads opens into the funnel opening of the protective bell facing the leading part of the foetus. When releasing the rotary handle from the carrier applied to the foetus, the leads are released from the protective bell via the mouth of the opening in the bell wall towards the funnel opening and can be arranged depending on the application. According to a special embodiment of the invention, the rotary handle may comprise a rotating bar which can be joined to the attachment zone, the rotating bar being supported for rotation in a tube-type sleeve, whereby the leads run outside of the tube-type sleeve. Whereas in the state of the art the leads ran within the sleeve and the rotating bar and with the rotation of the rotating bar an undesirable twisting of the leads with even binding of the leads or the rotating bar in the sleeve could occur, with this special embodiment of the invention undisturbed rotation of the rotating bar in the sleeve is possible. The leads can be routed outside of the sleeve. For example, it is conceivable that they are connected or clipped on outside of the sleeve, whereby this connection can also be released again where necessary. In a particular manner the attachment element can be in electrically conducting contact with a slip-ring contact of the surrounding zone. This facilitates the use of the attachment element as an electrode despite its rotation with respect to the surrounding zone, the said electrode deriving its electrical potential via the slip-ring contact to the surrounding zone, from where it is passed on via leads. In this way for example, a wire spiral can be used as a CTG electrode. In a particular manner the attachment zone can be supported for rotation and axially fixed via an annular shoulder held in an annular groove on the carrier. This ensures good rotating properties of the attachment zone on the carrier, whereby pressure forces in the direction of the rotational axis are also transferred to the carrier. This is particularly favourable with sensors whose surrounding zone presses on the tissue of the foetus under the stress of a spring in order to establish a good light transferring contact to the tissue of the foetus. Particularly advantageously, the attachment zone can be latched axially on the carrier. The initially separate attachment zone can be mounted on the carrier via the latch connection, whereby the latch connection is strong enough for the forces to be transferred between the attachment zone and the carrier. |
Methods for the identification of peptidyl compounds interacting with extracellular target molecules |
The present invention provides libraries expressing peptide libraries on the extracellular cell surface of host cells and methods for identifying peptides that bind extracellular target molecules under the physiological conditions encountered in biological fluids and secretions. The present invention is also directed to vectors for expressing gene fusion proteins and for targeting those fusion proteins to the extracellular cell surface. |
1. A method for identifying peptides that specifically bind to extracellular target molecules, comprising: introducing an expression library comprising a plurality of oligonucleotides, at least a majority of the oligonucleotides having different sequences encoding different peptides, into a first plurality of mammalian host cells, the host cells expressing and displaying the peptides on an extracellular cell surface; contacting the host cells displaying the peptides with at least one extracellular target molecule under substantially physiological conditions; selecting from the first plurality of host cells displaying the peptides a first subset of cells displaying peptides that bind to the at least one target molecule, and recovering from the first subset of host cells a first sub-library of the expression library comprising at least one oligonucleotide that encodes a peptide that binds to the at least one target molecule. 2. The method of claim 1, wherein the contacting is performed in the presence of a complex biological fluid. 3. The method of claim 2, wherein the complex biological fluid is blood, serum, plasma, sweat, tears, urine, semen, vaginal fluid or mucous. 4-6. (canceled) 7. The method of claim 1, further comprising: introducing the first sub-library into a second plurality of host cells, the second plurality of host cells expressing peptides encoded by the first sub-library and displaying the peptides on the extracellular cell surface; contacting the second plurality of host cells displaying the peptides with the at least one extracellular target molecule; selecting from the second plurality of host cells a second subset of host cells displaying peptides that bind to the at least one target molecule; and recovering from the second subset of selected host cells a second sub-library comprising at least one oligonucleotide that encodes the peptide that binds to the at least one target molecule. 8. (canceled) 9. The method of claim 1, wherein the target molecule is an extracellular protein, a carbohydrate, or a lipid. 10. The method of claim 9, wherein the extracellular protein is a peptide, protein, antibody, glycoprotein, phosphoprotein, glycophosphoprotein, proteoglycan, or a polymeric complex thereof. 11-12. (canceled) 13. The method of claim 1, wherein the target molecule is displayed on an extracellular surface of a target cell. 14. The method of claim 13, wherein binding of the peptide to the target molecule results in a change in a detectable phenotype of the target cell. 15. The method of claim 14, wherein the change in detectable phenotype is (a) a change resulting from altering a function of a mutant protein; (b) an alleviation of factor-dependent growth; or (c) a change in apoptotic state of the target cell. 16-17. (canceled) 18. The method of claim 1, wherein the target molecule is displayed on an extracellular surface of an animal cell. 19. The method of claim 18, wherein the animal cell is a mammalian cell. 20. The method of claim 18, wherein the selecting comprises contacting the animal cell with a detectably labeled antibody that binds a marker on the animal cell and detecting the bound, labeled antibody. 21. The method of claim 18, wherein the selecting comprises contacting the host cells with a detectably labeled antibody that binds a marker on the host cells and detecting the bound, labeled antibody. 22-23. (canceled) 24. The method of claim 1, wherein the target molecule is (a) a molecule that binds to a cell surface receptor; (b) an antibody, wherein the binding of the peptide to the antibody reduces binding of the antibody to an antigen; (c) an extracellular enzyme, wherein the binding of the peptide to the enzyme alters the activity of the enzyme; or (d) a tumor-specific antigen or a tumor-associated antigen. 25. The method of claim 24, wherein the target molecule is a cytokine, a chemokine, or a secreted factor; and the binding of the peptide to the target molecule, alters binding of the target molecule to the cell surface receptor. 26. The method of claim 25, wherein the binding of the target molecule to the cell surface receptor is reduced. 27. (canceled) 28. The method of claim 24, wherein the antibody is an autoantibody. 29. (canceled) 30. The method of claim 24, wherein (i) the peptide binds to an active site of the extracellular enzyme, thereby inhibiting activity of the enzyme; or (ii) the peptide binds to an allosteric regulatory site on the extracellular enzyme. 31. The method of claim 24, wherein the peptide is a competitive inhibitor of substrate binding to the extracellular enzyme. 32-33. (canceled) 34. The method of claim 1, wherein the target molecule is displayed on an extracellular surface of a target cell. 35. The method of claim 34, wherein the target molecule is a mutant protein, and binding of the peptide alters a function of the mutant protein. 36. The method of claim 34, wherein peptide binding alleviates factor-dependent growth; changes an apoptotic state of the target cell; or causes increased or decreased sensitivity to a cytotoxic drug. 37-38. (canceled) 39. The method of claim 1, wherein the peptides are displayed as a fusion protein with a presentation molecule. 40. The method of claim 39, wherein the presentation molecule is CD24 or IL-3. 41. (canceled) 42. The method of claim 39, wherein the fusion protein further comprises an epitope. 43. The method of claim 42, wherein the epitope is polyhistidine, V5, FLAG, or myc. 44. The method of claim 39, wherein the fusion protein further comprises a signal for a glycophosphatidylinositol anchorage. 45. The method of claim 1, wherein the selecting comprises use of a flow sorter to identify the first subset of cells exhibiting binding to the target molecule. 46. The method of claim 34, wherein the target cells are coupled to magnetic beads and the selecting comprises collection of the first subset of cell bound to the target cells. 47. The method of claim 1, wherein the target molecule is detectably labeled and the selecting comprises identifying host cells bound to the labeled target molecule. 48. The method of claim 1, wherein the target molecule comprises detectably labeled antibody and the selecting comprises identifying host cells bound to the labeled antibodies. 49. The method of claim 1, wherein the target molecule is a protein associated with an autosomal dominant disease, with an oncogenic disease, or with normal cellular function. 50. A peptide display library, comprising: a plurality of at least one type of expression vector, each expression vector having a first nucleic acid sequence encoding a signal sequence, a presentation molecule comprising modified CD24 or modified IL-3 receptor, and a transmembrane domain, and a cloning site for insertion of a second nucleic acid sequence distal to the transmembrane domain, the second nucleic acid sequence encoding an amino acid sequence; whereby fusion proteins are expressed and displayed on an extracellular surface of a host cell. 51. The library of claim 50, wherein the second nucleic acid sequence encodes peptides having up to 20 amino acids. 52. A library peptide displayed as an extracellular membrane protein fusion, comprising: modified CD24 comprising a signal sequence, a library peptide inserted within CD24 amino acid sequence, and a transmembrane domain; whereby the peptide is displayed on an extracellular cell surface such that the peptide can interact with extracellular target molecules under substantially physiological conditions. 53. A plasmid expression vector, comprising: an SV40 origin of replication; and a nucleic acid sequence comprising SV40 early promoter region and SV40 Large T antigen coding region, the SV40 early region promoter promoting transcription of the Large T antigen coding region; whereby replication of the plasmid is self-regulating. 54-68. (canceled) 69. The method of claim 2, wherein the complex biological fluid is substantially undiluted. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Intercellular function is mediated by protein interactions with macromolecules in the extracellular space. For example, cell-surface proteins and soluble proteins secreted by cells bind extracellularly to their cognate ligands, receptors, enzymatic substrates, or other extracellular macromolecules to initiate intracellular signaling cascades, release cell-surface proteins from the plasma membrane, localization of cells to target sites, or to produce other changes in the extracellular environment. Such proteins include, for example, antibodies that mediate immune responses; cytokines or chemokines that regulate diverse cell growth, differentiation, or cell death pathways; enzymes of the major blood cascade pathways; and the like. Because these responses are involved in normal cell function, inappropriate induction, disruption, or stabilization of extracellular protein interactions play a key role in disease pathogenesis. Screening methods have been developed to identify peptides that affect cellular processes through perturbation of protein interactions. These methods involve the development of large peptide libraries, such as phage display libraries (see, e.g., Scott and Smith, Science 249:386-90 (1990)), combinatorial libraries, peptide mimetic libraries, and one-bead-one structure combinatorial libraries. (See, e.g., al-Obeidi et al., Mol. Biotechnol. 9:205-23 (1998).) Libraries of peptides can be used in in vitro screening assays to identify those peptides that specifically interact with proteins or other macromolecules. Conventional peptide screens suffer from various disadvantages, however, that limit the efficient identification of therapeutically promising peptides, particularly peptides that act within the extracellular space. Most of the screening methods that employ conventional peptide libraries demonstrate only binding to targets in vitro; these methods often fail to identify peptides that bind to extracellular targets with corresponding physiological effects in vivo. Subsequent biological screens of the peptides are required to identify those peptides with an appropriate effect on target protein function in vivo. Such methods are not optimized to identify therapeutically promising peptides because they are ineffective in initial screens in discriminating between weak and strong interactions, and between specific and non-specific binding variants. Also, these methods can screen out promising peptides that demonstrate a relatively weak affinity and yet induce an appropriate physiological response. Such methods also rely upon further costly and time-consuming experimentation to identify effectors of protein activity. Current in vitro screening methods also suffer from the disadvantage that the normal structure, activity, and any necessary regulatory molecule(s) may be lost when proteins or other macromolecules are purified or removed from their native environment. Peptides that would normally be effector molecules of native macromolecules may not bind to structurally altered targets. Non-native targets are also more likely than native targets to non-specifically bind physiologically irrelevant peptides. Further, even if purified target molecules retain native structure and activity, existing screening methods can produce poor or misleading results because the assay conditions are not representative of the local extracellular environment in vivo. Local environments can significantly influence the accessibility of target molecules to peptides or the specificity or avidity of peptide binding. Conventional screening methods also typically utilize target molecules that are attached to non-physiological surfaces, such as plastic, glass, or polymeric matrices. This association with a non-physiological surface introduces impediments to identifying peptides that interact specifically with protein or other macromolecular target molecules. Many macromolecular target molecules that are attached to a non-physiological surface denature onto that surface. Native binding sites on the surface of targets can be lost and other sites not normally displayed on the surface of targets can be unmasked, exposing such physiologically irrelevant sites to the peptides. This problem can result in the identification of peptides that only bind non-specifically to targets. The mode of attachment can also bias how target molecules are exposed on the surface and can result in a spatial orientation where only one set, or a limited set, of potential binding sites are exposed to the peptides. When this occurs, functionally important peptide binding sites on targets can be inaccessible during screening. Another impediment is that the binding kinetics and constants of freely soluble, interacting molecules can be altered when one is attached directly to a non-physiological surface. This problem is a well-known phenomenon that can either increase or decrease the specificity and avidity of peptide binding to targets and can lead to the identification of peptides that are ineffective in subsequent, functional screens (see, e.g., Vijayendran and Leckband, Anal. Chem. 73:471-80 (2001); Butler, Methods 22:4-23 (2000)). Further, chemical-based combinatorial peptide libraries, consisting of small peptides that are not attached to a soluble carrier molecule or a hydrophilic matrix, suffer from the disadvantage that many short peptides are not soluble under physiological conditions, such as in the presence of undiluted blood, plasma, serum, or other complex biological fluids. Organic solvents such as methanol, ethanol, or DMSO have been required in prior screens to maintain the solubility of many peptides in the library. These organic solvents can denature many potential target or non-target proteins and other macromolecules during screening and result in the identification of poor-quality peptide candidates. An additional disadvantage experienced with methods using phage- and bacteria-display peptide libraries is the prevalence of high backgrounds due to nonspecific binding of phage or bacteria to the targets. Such background can occur when screening is conducted in physiologic environments, thereby causing many irrelevant peptide candidates to be selected. Typically, the nonspecific binding of phage and bacteria can be reduced by screening in the presence of high concentrations of salt, denaturants (e.g., urea or guanidine-HCl), protein, or detergent, or other non-physiological conditions (e.g., elevated temperatures, such as above 37° C.). In contrast, physiological screening conditions for the identification of peptides usually replicate the conditions in which the target molecules normally express their activities (e.g., human blood at 37° C.). However, the complexity of macromolecules (e.g., blood) present under physiological conditions can lead to a high level of nonspecific binding of peptide-displaying phage or bacteria, such that the library's diversity can be significantly reduced. Some screening methods have sought to address these limitations, but largely with respect to intracellular target molecules. For example, methods have been developed to screen small peptides and polypeptides intracellularly. Such methods typically utilize intracellular expression of peptides or polypeptides as fusion products, such as in the yeast two hybrid system. (See Fields and Song, Nature 340:245-46 (1989).) Other methods can present peptides and small proteins in vivo in constrained configurations on carrier proteins or displayed within a reporter protein. (See, e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-69 (1992); Lu et al., Biotechnology (NY)13:366-72 (1995); International Patent Publication WO 99/24617; Norman et al., Science 285:591-95 (1999); International Patent Publication WO 98/39483.) For example, International Patent Publication WO 99/24617 discloses peptides displayed as a fusion with green fluorescent protein (“GFP”). In addition, some methods allow identification of small peptides and polypeptides based on their ability, when expressed intracellularly, to alter cell function through perturbation of cellular protein interactions. (See, e.g., International Patent Application WO 98/07886; Caponigro et al., Proc. Natl. Acad. Sci. USA 95:7508-13 (1998).) However, these methods, while preserving the native, cytosolic constituents of intracellular pathways, do not allow for the screening of extracellular target molecules under relevant physiological conditions. Other methods have been described that allow peptide library sequences to be expressed extracellularly on eukaryotic cells, including mammalian and other animal cells (see U.S. Pat. No. 6,153,380; International Patent Application WO 98/39483). These methods still do not allow peptide interactions to be screened under physiological conditions, such as in the presence of undiluted blood, plasma, serum, or other complex biological fluids. For example, one method allows randomized peptides to be inserted into host cells and depending on the fusion construct used, either localized to the extracellular or intracellular cell surface or secreted in soluble form. (See U.S. Pat. No. 6,153,380.) Peptides can then be selected by assaying for their ability to alter the phenotype of either the host cells or, alternatively, of another cell population. While allowing for the identification of peptides that affect extracellular interactions, this method does not address the need for assay conditions that reproduce the target molecule's native physiological conditions. Such conditions, including those that affect molecular conformation, stability, binding kinetics, and the like, can be significant for maintaining normal interactions of the target molecule with other extracellular macromolecules. Analysis of the human genome indicates approximately 1.6% of the gene products are proteases (Southan, FEBS Lett. 498:214-218 (2001)). Therefore, humans produce between 400 to 700 different proteases. Approximately 350 unique human protease mRNAs are found in GenBank, indicating that as many as one-half of all human proteases have not been studied (Southan, J. Pept. Sci. 6:453-458 (2000)). Further, 14% of all known human proteases currently are targets of drug development (Southan, Drug Discovery Today 6:681-688 (2001)). The physiologic functions and pathologic activities of many proteases, even those previously studied, are unknown. Thus, while proteases are important in many biologic processes including fertilization, cellular differentiation, cellular regulation, inflammation, blood coagulation, fibrinolysis, tissue remodeling/repair, host defense systems against pathogens, cancer, programmed cell death and others, the functions of many human proteases are unknown. There is increasing awareness of the potential of protease inhibitors as clinical drugs, stimulated to a large extent by the success of protease inhibitors in HIV treatment. A major impediment in the identification of clinically applicable protease inhibitors has been the absence of a high throughput screening technology capable of identification of inhibitors under physiological conditions. The use of the invention described herein is expected to facilitate the identification of biologically relevant inhibitors of target proteases. Targeted proteases and extracellular displayed peptides can be combined under near physiological conditions to identify the detailed peptide substrate specificity of proteases that may lead to the development of selective inhibitors of the proteases. Alternatively, certain constrained “loop” peptides may act directly as protease inhibitors. Proteases have specific substrate amino acid sequence requirements for physiologic activity. A system of nomenclature to describe protease-substrate interaction was implemented by Schechter and Berger ( Biochem. Biophys. Res. Commun. 27:157-162 (1967)). The bond cleaved is designated: in-line-formulae description="In-line Formulae" end="lead"? P 1 -P 1 ′ in-line-formulae description="In-line Formulae" end="tail"? For proteases that cleave many different peptides and proteins, e.g., trypsin, chymotrypsin, and subtilisin, the nature of the P 1 amino acid residue is the most important specificity element. Proteases involved in regulatory pathways typically have substrates with more complex specificity information. For some proteases, physiologic substrates contain an accessible, unique amino acid sequence defined by as many as 5 or 6 consecutive amino acid residue positions such as: in-line-formulae description="In-line Formulae" end="lead"? P 5 -P 4 -P 3 -P 2 -P 1 - - - P 1 ′ in-line-formulae description="In-line Formulae" end="tail"? An example is enterokinase that cleaves proteins or peptides containing the amino acid residue sequence: in-line-formulae description="In-line Formulae" end="lead"? Asp-Asp-Asp-Asp-Lys - - - P 1 ′ (SEQ. ID NO.: 6) in-line-formulae description="In-line Formulae" end="tail"? Another example is Factor X a that selectively cleaves peptides or proteins containing the following sequence: in-line-formulae description="In-line Formulae" end="lead"? Ile-Glu-Gly-Arg - - - P 1 ′ (SEQ ID NO.: 7) in-line-formulae description="In-line Formulae" end="tail"? Some proteases require substrates with specific amino acid residues at the amino terminal side of hydrolyzed bonds, i.e., at P 1 ′-P 2 ′-P 3 ′ etc. positions. An example of this is the family of aspartic acid proteases. There are corresponding binding sites or “pockets” designated as, e.g., S 3 -S 2 -S 1 , on the surface of the protease molecule to accommodate the side chains of each amino acid residue contributing to specificity. Occasionally, one or a few conservative amino acid substitutions in preferred peptide substrates can be made without significant loss in protease activity. Conventional approaches for determining the substrate specificity of a protease is a difficult, time-consuming and costly procedure, particularly when the physiologic substrate is unknown. Frequently, only a general or partial specificity map is possible. Two conventional approaches have been used to determine protease specificity. The first comprises analytical characterization of peptide products following protease digestion of reduced and denatured proteins of known amino acid sequences, e.g., insulin, ribonuclease, and others (Le Trong et al., Proc. Natl. Acad. Sci. USA 84:364-367 (1987)). This approach provides only a simple description of specificity, concluding, e.g., that a protease has “trypsin-like” activity. The second method comprises the use of synthetic peptide substrates containing a detectable leaving group, e.g., p-nitroaniline that is measured when an appropriate bond is cleaved (Yoshida et al., Biochemistry 19:799-804 (1980)). This tedious, costly approach involves extensive trial and error effort. For example, the determination of a protease's specificity requiring only two amino acid residues, i.e., P 2 -P 1 could require testing as many as 400 different synthetic substrates. A 3 amino acid residue specificity sequence (P 3 -P 2 -P 1 ) may involve testing thousands of substrates. A further complication with this approach is that many short peptide substrates are insoluble under conditions required for optimum protease activity and their solubility may require concentrations of organic solvents that denature the protease or alter enzyme activity. The presentation of random peptide libraries by phage display is a useful approach to search for peptides with biologic activities (Roberge et al., Biochemistry 40:9522-9531 (2001); Kridel et al., Anal. Biochem. 294:176-184 (2001); and Leinonen et al., Scand. J. Clin. Lab. Invest. Suppl. 233:59-64 (2000)). Matthews and co-workers (U.S. Pat. No. 5,846,765) reported a phage display system to search for suitable substrate peptides of a mutant variant of subtilisin. The system displays a fusion protein consisting of phage coat protein attached to the substrate peptides attached to a polypeptide “reporter” that can be bound by specific antibody, receptor or other means. Phage that display appropriate substrate peptides lose the reporter group and can be selected from inappropriate ones via affinity adsorption. Alternatively, the phage can be pre-adsorbed to an affinity surface, incubated with protease and appropriate substrate peptides selected from among those phage particles released from the surface. These investigators suggest that this approach could be used to determine the substrate specificity of proteases in general. In practice, however, the phage peptide display approach may be limited to relatively “robust” proteases that retain activity under non-physiologic screening conditions (e.g., high concentrations of salt, inclusion of detergents and/or EDTA) required to prevent undesired adsorption of phage particles. Also, screening under non-physiologic conditions may alter normal protease specificity and other enzyme properties. Additionally, several reports have emphasized the technical difficulties in implementing polyvalent display phage methods that frequently result in preparations containing mixtures of peptides where the expression level is low, the quality of the peptides is inconsistent and screening is unreliable (see U.S. Pat. No. 5,846,765). Many phage-based screening methods require selection of desired phage from inappropriate ones by affinity adsorption, e.g., with specific antibodies. In other screens selection is based on direct interaction of the macromolecule of interest with peptides displayed on phage. Selection of phage particles by affinity adsorption methods frequently is limited by the inability to distinguish between phage products with high binding affinities from those with low affinities (Cwirla et al., Proc. Nat. Acad. Sci. USA 87:6372-6382 (1990)). The inability to distinguish between peptides with high and low binding affinities in screens results in many false positives. A similar outcome may occur when phage peptide libraries are screened for substrates and inhibitors under conditions of low stringency required for optimal protease activity. Therefore, while phage display methods are innovative approaches, they may result in a high number of poor quality prospects that must be systematically culled from promising ones. There is need in drug development for rapid, more efficient screening approaches, conducted under optimum physiologic conditions, to identify substrate peptides of human proteases, particularly poorly characterized and “orphan” enzymes. Therefore, there remains a need for screening methods that will allow for more efficient identification of peptides that bind to extracellular target molecules by replicating the complex physiological conditions of the extracellular environment. Because screening under physiological conditions is more likely to reduce non-specific binding events, retain native molecular conformations and kinetics, and maintain the presence of regulatory molecules, such physiologically-based screens are more likely to identify molecular interactions associated with normal or disease-related cellular function. Consequently, the development of robust technologies to express peptide libraries of high diversity on the surface of mammalian cells and that allow peptide screening under physiological conditions are needed to facilitate the identification of more effective drugs and therapeutic approaches to disease. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention generally relates to methods for identifying peptides that specifically bind to extracellular target molecules under physiological or substantially physiological conditions. In one aspect, the methods include introducing an expression library into mammalian host cell. The library includes a plurality of oligonucleotides. At least a majority of the oligonucleotides in the library have different sequences encoding different peptides. The host cells express and display the peptides on an extracellular cell surface. The host cells displaying the peptides are contacted with at least one extracellular target molecule under substantially physiological conditions. A first subset of host cells that bind to the target molecule is selected from the first plurality of host cells. A first sub-library (of the expression library) is recovered from the first subset of host cells, the first sub-library including at least one oligonucleotide that encodes a peptide that binds to the target molecule(s). The target molecule can be contacted with the host cells in the presence of a complex biological fluid. Suitable complex biological fluids include, for example, blood, serum, plasma, sweat, tears, urine, semen, vaginal fluid, mucous, and the like. In one embodiment, the oligonucleotides have a length of about 18 to about 60 nucleotides. In another embodiment, the oligonucleotides encode peptides having a length of about 6 to about 20 amino acid residues. The oligonucleotides can optionally have randomized or semi-randomized sequences. For further screening, the first sub-library is introduced into a second plurality of host cells, the second plurality of host cells expressing peptides encoded by the first sub-library and displaying the peptides on the extracellular cell surface. The second plurality of host cells is contacted with the at least one extracellular target molecule, and a second subset of host cells is selected that display peptides that bind to the target molecule. A second sub-library is recovered from the second subset of selected host cells, the second sub-library including at least one oligonucleotide that encodes the peptide that binds to the target molecule(s). In certain embodiments, the host cells express and display a high copy number of the peptides on the extracellular cell surface. The target molecule can be an extracellular protein, such as, for example, a peptide, protein, a tumor-specific antigen, a tumor-associated antigen, an antibody, a glycoprotein, a phosphoprotein, a glycophosphoprotein, a proteoglycan, a carbohydrate, a lipid, or a polymeric complex thereof. The target molecule is displayed on an extracellular surface of a target cell or can be soluble in a complex biological fluid. The target cell can be an animal cell, a mammalian cell, a bacterial cell, a fungal cell, or the target molecule can be on a virus, phage, parasite, isolated subcellular organelle, and the like. The target molecule also can be a protein associated with an autosomal dominant disease, an oncogenic disease, or with normal cellular function. The binding of the peptide to the target molecule can result in a change in a detectable phenotype of the target cell. Such a change in a detectable phenotype can result from, for example, altering a function of a mutant protein, an alleviation of factor-dependent growth, a change in apoptotic state of the target cell, and the like. In certain embodiments, the first subset of host cells is selected by contacting animal cells with a detectably labeled antibody that binds to a marker on the target cells and detecting the bound, labeled antibody. In other embodiments, the first subset of host cells is selected by contacting the host cells with a detectably labeled antibody that binds a marker on the host cells and detecting the bound-labeled antibody. Alternatively, the first subset of host cells can be selected by contacting bacterial cells, fungal cells, viruses, phage, parasites, or isolated subcellular organelles with a detectably labeled antibody that binds a marker on the bacterial cells, fungal cells, viruses, phage, parasites, or isolated subcellular organelles and detecting the bound labeled antibody. In an embodiment, the target molecule can be, for example, a cell surface receptor, such as a cytokine, a chemokine, a secreted factor, and the like. The peptide can bind to the target molecule, thereby altering (e.g., increasing or decreasing) binding of the target molecule to its cell surface receptor. In another embodiment, the target molecule can be an antibody, and the peptide binds to the antibody, thereby reducing binding of the antibody to an antigen. The antibody can be, for example, an autoantibody. The peptide can be an extracellular enzyme or protease and peptide binding to the enzyme or protease altering the activity of the enzyme or protease. For example, the peptide can bind to an active site of the enzyme or protease, thereby inhibiting activity of the enzyme or protease. The peptide can be a competitive inhibitor of substrate binding to the enzyme or protease. The peptide can also bind to an allosteric regulatory site on the enzyme or protease. In a particular embodiment wherein the enzyme is a protease the peptide can be a substrate of the protease resulting in cleavage of the peptide. A selectable marker placed at the amino-terminus of peptides tethered to a presenting cell will be released from the cell when the protease cleaves a displayed peptide. The target molecule can be displayed on an extracellular surface of a target cell. The target molecule can be a mutant protein, and binding of the peptide alters a function of the mutant protein. Alternatively, the target molecule can cause other alterations of function, such as, for example, alleviating factor-dependent growth, changing an apoptotic state of the target cell, increasing or decreasing sensitivity to a cytotoxic drug, and the like. In certain embodiments, the peptides can be displayed as fusion proteins with a presentation molecule. Suitable presentation molecules include, for example, CD24 or Interleukin 3 receptor. The fusion protein can optionally further include an epitope, such as, for example, polyhistidine, V5, FLAG, or myc. The fusion protein can also optionally include a signal for glycophosphatidylinositol anchorage or a transmembrane domain. In certain embodiments, the peptides can be displayed as a fusion proteins consisting of thioredoxin and one or two tag elements in addition to the random peptide sequence. For example, a protease substrate random peptide sequence is positioned at the amino-terminal end of thioredoxin between two markers, FLAG and V5, with FLAG as the amino-terminus of the fusion protein. In a particular embodiment, the screen for protease susceptible sequences selects cells lacking the amino terminal FLAG marker due to protease activity that cleaves peptides in the library. Plasmids from selected cells are recovered, amplified in bacteria, reintroduced into naïve cells, the cells are incubated with protease, and screening selects an enriched population of candidates as compared to the first round results. The process is repeated for several rounds until a relatively restricted family of related peptides is obtained. DNA sequence analysis of the selected clones establishes the substrate preference of the selected protease. In a particular embodiment, a specific amino acid sequence, e.g., Ile-Glu-Gly-Arg-X (SEQ ID NO: 7), that is a restricted substrate of the protease Factor X a is inserted at the random peptide site. In certain embodiments, the first subset of host cells is selected by using a flow sorter to identify the first subset of cells exhibiting binding to the target molecule. Alternatively, the target cells can be coupled to magnetic beads; the first subset of host cells can be selected by collecting host cells bound to the target cells on the beads. In other embodiments, the target molecule is detectably labeled and the first subset of host cells is selected by identifying cells bound to the labeled target molecule. For example, the target molecule can be a detectably labeled antibody, and the first subset of host cells is selected by identifying host cells bound to the labeled antibody. In another aspect a peptide display library is provided, the peptide library including a plurality of at least one type of expression vector. Each expression vector has a first nucleic acid sequence encoding a signal sequence, a presentation molecule, a transmembrane domain, and a cloning site for insertion of a second nucleic acid sequence distal to the transmembrane domain, the second nucleic acid sequence encoding an amino acid sequence. The encoded fusion protein(s) is expressed and displayed on an extracellular surface of a host cell. The presentation molecule can encode, for example, modified CD24, modified IL-3 receptor, and the like. The second nucleic acid optionally can encode peptides having up to 20 amino acids. In yet another aspect, a library peptide displayed as an extracellular membrane protein fusion is provided. The library peptide includes modified CD24 having a signal sequence and a transmembrane domain. The library peptide is inserted within the CD24 amino acid sequence. The peptide is displayed on an extracellular cell surface such that the peptide can interact with extracellular target molecules under substantially physiological conditions. In another aspect, a plasmid expression vector is provided. The expression vector includes an SV40 origin of replication and a nucleic acid sequence including an SV40 early promoter region and an SV40 Large T antigen coding region, the SV40 early region promoter promoting transcription of the Large T antigen coding region; the replication of the plasmid is self-regulating. In another aspect, a method is provided for identifying peptides that specifically bind to extracellular target molecules. The method generally includes introducing an expression library into a first plurality of mammalian host cells. The expression library has a plurality of oligonucleotides, at least a majority of the oligonucleotides having different sequences encoding different peptides. The host cells express and display the peptides on an extracellular cell surface. The host cells displaying the peptides are contacted with at least one extracellular target molecule in a substantially undiluted complex biological fluid. A first subset of cells displaying peptides that bind to the target molecule is selected, and a first sub-library of the expression library is recovered from the first subset of host cells. The first sub-library includes at least one oligonucleotide that encodes a peptide that binds to the target molecule. The substantially undiluted complex biological fluid can be, for example, blood, plasma, serum, a tissue secretion, sweat, tears, vaginal fluid, mucous, seminal fluid, urine, and the like. In yet another aspect, a method is provided for identifying peptides that specifically bind to extracellular target molecules. The method generally includes introducing an expression library into a first plurality of host cells. The expression library includes a plurality of oligonucleofides, at least a majority of the oligonucleotides having different sequences encoding different peptides. The host cells express and display the peptides on an extracellular cell surface of the host cells. The host cells are contacted with at least one extracellular target molecule in a complex biological fluid. A first subset of host cells is selected that display peptides that bind to target molecules. A first sub-library is recovered from the first subset of host cells, the first sub-library including at least one oligonucleotide that encodes a peptide that binds to the target molecule(s). The target molecule can be displayed on the extracellular surface of host or non-host animal cells, on bacterial cells, fungal cells, viruses, phage, parasites, isolated subcellular organelles, and the like. In an embodiment, the complex biological fluid can be substantially undiluted. A further understanding of the nature and advantages of the invention will become apparent by reference to the remaining portions of the specification. |
Preparing preforms for fibre fabrication |
This invention relates to a method of producing a preform for an optical fibre. More particularly, the present invention relates to a method of preparing preforms for the production of holey optical fibres. The invention provides a method of producing an optical fibre, said method comprising applying heat to the interior of a preform and subsequently drawing said optical fibre from said preform. The invention also provides a method of producing an optical fibre, said method comprising preparing a preform comprising a body of optically suitable material and removing material at predetermined locations in the body so as to provide a plurality of holes within the body, applying heat to the interior of the preform and subsequently drawing said optical fibre from said preform. |
1. A method of producing an optical fibre, said method comprising applying heat to the interior of a preform and subsequently drawing said optical fibre from said preform. 2. A method of producing an optical fibre, said method comprising preparing a preform comprising a body of optically suitable material and removing material at predetermined locations in the body so as to provide a plurality of holes within the body, applying heat to the interior of the preform and subsequently drawing said optical fibre from said preform. 3. The method as claimed in claim 1 or 2 wherein the preform is of a relatively large diameter. 4. The method as claimed in claim 3 wherein the diameter of the preform is 50 mm or greater. 5. The method as claimed in any one of claims 1 to 4 wherein the preform includes one or more holes which facilitate the heating of the interior of the preform. 6. The method as claimed in claim 5 wherein said one or more holes in the preform permit the ingress of a heating fluid into the preform to facilitate the heating of the interior of the preform. 7. The method as claimed in claim 5 or 6 wherein the holes in the preform have parallel axes and extend parallel to the principal axis of the preform. 8. The method as claimed in any one of claims 2 to 6 wherein the holes extend through the preform. 9. The method as claimed in claim 6 wherein the heated fluid passes through the preform so as to heat the interior of the preform. 10. The method as claimed in any one of claims 6 to 9 wherein the heating fluid is a gas. 11. The method as claimed in any one of claims 6 to 9 wherein the heating fluid is a liquid. 12. The method as claimed in any one of claims 1 to 11 wherein the preform is formed from a polymer material. 13. The method as claimed in any one of claims 1 to 11 wherein the preform is formed from a glass material. 14. The method as claimed in claim 1 or 2 wherein heating of the interior of the preform is achieved by the application of lasers, microwaves, infrared or other forms of electromagnetic radiation. 15. The method as claimed in claim 14 wherein the heating is achieved by the application of a plurality of lasers configured such that intersecting beams from the lasers produce a higher intensity of heating at the centre of the preform. 16. A method of producing a polymer optical fibre, said method comprising drawing said optical fibre from a preform wherein both an exterior surface and interior of the preform are heated to assist in drawing the preform. 17. A method of preparing a preform for a holey fibre comprising providing a body of optically suitable material and removing material at predetermined locations in the body so as to provide a plurality of holes within the body. 18. The method as claimed in claim 17 wherein said holes are mutually parallel longitudinally extending holes arranged generally around the fibre axis. 19. The method as claimed in claim 16 wherein a first stage preform is heated and drawn to a second stage preform of reduced cross-section. 20. The method as claimed in claim 16 comprising a series of draws of the preform to successively reduce the cross-section of the preform. 21. The method as claimed in claim 20 further including the step of sleeving the preform between draws so as to produce a fibre with a microstructure of desired dimensions. 22. The method as claimed in claim 17 wherein the holes in the preform are heated by pins or protrusions. 23. The method as claimed in claim 17 wherein the pins are heated and inserted into the holes in the preform to produce the desired temperature gradient across the preform to facilitate the subsequent drawing process. 24. The method as claimed in claim 23 wherein pins or protrusions can form part of a mould in which the first stage preform is cast. 25. The method as claimed in claim 1 or 2 wherein a relatively large diameter initial preform is heated both internally, using holes in the preform to duct hot air, and locally from the outside, which is then drawn down to second stage preform. 26. The method as claimed in any one of the preceding claims wherein there is a relatively high drawing ratio in drawing the preform to form said optical fibre. 27. The method as claimed in claim 17 wherein the holes are formed by drilling. 28. The method as claimed in claim 17 wherein the holes are formed by sonic drilling. 29. The method as claimed in claim 17 wherein the holes are formed by laser. 30. The method as claimed in claim 17 wherein the holes are formed by punching. 31. The method as claimed in claim 17 wherein the material is chemically removed at predetermined locations in the body so as to provide a plurality of holes within the body. 32. The method as claimed in any one of the preceding claims wherein the hole structure is not restricted to a particular lattice structure. 33. The method as claimed in any one of the preceding claims wherein after a hole is produced in the preform, a rod or wire of a predetermined shape is inserted and the preform collapsed around it by heating together with pressure or tension. 34. A preform formed according to the method defined in any one of claims 1 to 33. 35. A preform formed according to any one of claims 1 to 33 wherein a plurality of holes are formed in the preform in predetermined locations, said holes having predetermined diameters, such that upon drawing of the preform the resulting fibre guides light in a multi-mode manner, the hole positions and sizes in the fibre resulting in a graded refractive index profile. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field. Glass Microstructured Optical Fibres (MOFs) (also known as “photonic crystal fibres” or “holey fibres”) were first developed in 1974 by Bell labs. They have attracted much more attention since 1996 when a group from the University of Bath published a paper on an “endlessly” singlemode photonic crystal fibre and a large effort has been devoted throughout the world researching their guiding properties and developing new devices. MOF's guide light in the core using an array of microscopic holes that extend along the entire length of the fibre. By changing the hole structure, a large range of fibre properties such as dispersion, birefringence and nonlinearities can be tailored to the required application. The first single mode Microstructured Polymer Optical Fibre (OF) operating in the visible optical spectrum was reported in 2001 by Martijn A. van Eijkelenborg, Maryanne C. J. Large, Alexander Argyros, Joseph Zagari, Steven Manos, Nader A. Issa, Ian Bassett, Simon Fleming, Ross C. McPhedran, C. Martijn de Sterke and Nicolae A. P. Nicorovici, in “Microstructured polymer optical fibre”, Optics Express Vol. 9, No. 7, pp. 319-327 (2001). MPOFs can be fabricated with greater flexibility than silica using techniques such as casting and extrusion and hence can offer a greater variety of structures. It is known to produce optical fibres by means of a drawing process wherein a length of fibre is drawn from an initial preform. It is also known to heat the preform so as to facilitate the drawing process. However, the materials from which optical fibres are typically manufactured are poor heat conductors. This results in a temperature gradient across the cross-section of the preform and subsequently leads to problems in the drawing process which to date has restricted the size of preforms which can be used. It is therefore an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. |
<SOH> SUMMARY OF THE INVENTION <EOH>To this end, one aspect of the present invention provides a method of producing an optical fibre, said method comprising applying heat to the interior of a preform and subsequently drawing said optical fibre from said preform. Unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”. Advantageously, by applying heat to the interior of the preform to produce the desired temperature within the interior of the preform the drawing process is assisted. This in turn facilitates the use of larger sized preforms. In one preferred embodiment, the preform includes one or more holes which facilitate the heating of the interior of the preform by the application of a heating fluid. More particularly, the holes in the preform permit the ingress of the heating fluid into the preform to facilitate the heating of the interior of the preform. The heating fluid may comprise either a liquid or a gas, although in a practical embodiment of the invention a gas is preferred. A further aspect of the present invention provides a method of producing an optical fibre, said method comprising applying heat to both an exterior surface and the interior of the preform and subsequently drawing said optical fibre from said preform. A further aspect of the present invention provides a method of producing an optical fibre, said method comprising drawing said optical fibre from a preform wherein both an exterior surface and interior of the preform are heated to assist in drawing the preform. A further aspect of the present invention provides a method of preparing a preform for a holey fibre comprising providing a body of optically suitable material and removing material at predetermined locations in said body so as to provide a plurality of holes within the body. Whilst the various aspects of the present invention are particularly applicable to the process of making polymer holey fibres, it is to be noted that they are also applicable to the production of fibres made from other materials, such as glass. The present invention is particularly suitable for producing holey fibres or photonic crystal fibres. These fibres contain, for example, a plurality of mutually parallel, longitudinally extending holes arranged generally around the fibre axis. Advantageously, the holes in the preform serve not only their ultimate functional purpose in the optical fibre, but also serve as conduits for the heating fluid in the preform. This assists in achieving a suitable temperature gradient across the cross-section of the preform for drawing of the preform. Another surprising advantage has arisen from the present invention insofar as the invention has permitted the use of relatively large preforms (that is, preforms of 50 mm diameter or greater) in comparison with conventional preforms. The preform is heated by the aforementioned technique, and then drawn. This provides a number of significant advantages over the prior art. For example, the increase in size and volume of the preform increases the length of optical fibre which can be ultimately drawn from the preform. In turn this provides advantages by reducing the number of fibre connections necessary for long distance optic fibre installations, such connections being a potential source of leakage. Additionally, by being able to use preforms of a larger size, it is possible to incorporate a greater number of holes into the cross-section of the preform, thereby increasing the possibilities for the design of an optical fibre with desired transmission characteristics. Alternatively, by using a larger preform more cladding material can be provided around the central core structure of the preform, which enhances the protection of the core structure. Additionally, the present invention enables a large draw ratio which in turn leads to a reduction in the defect size in the resulting optical fibre. Furthermore, as a result of being able to use relatively large preforms a variety of industrial techniques can be used to produce the preform rather than the more demanding and specialised techniques required when working with very small scaled preform structures. |
Interleukin-1 beta antibodies |
The present invention encompasses high affinity antibodies that neutralize IL-1β activity in vivo. These antibodies can be used to treat various diseases such as rheumatoid arthritis and osteoarthritis. |
1-39. (canceled) 40. An antibody that specifically binds mature human IL-1β wherein the antibody binds the same epitope on mature human IL-1β as mouse monoclonal antibody Mu007 or humanized antibody Hu007. 41. The antibody of claim 40 that specifically binds mature human IL-1β with an affinity constant that is within ten-fold the affinity constant of mouse monoclonal antibody Mu007 for human IL-1β. 42. The antibody of claim 40 wherein the antibody comprises at least one complementarity determining region having a sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID No:10. 43. The antibody of claim 42 wherein the antibody comprises a light chain variable region having the sequence of SEQ ID NO:27. 44. The antibody of claim 42 wherein the antibody comprises a heavy chain variable region having the sequence of SEQ ID NO:28. 45. A humanized antibody which specifically binds mature human IL-1β comprising a humanized light chain which is comprised of three light chain complementarity determining regions (CDRs) having sequences that correspond to SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7 and a humanized heavy chain which is comprised of three heavy chain CDRs having sequences that correspond to SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10. 46. The humanized antibody of claim 45 comprising a light chain variable region having the sequence of SEQ ID NO:27. 47. The humanized antibody of claim 45 comprising a heavy chain variable region having the sequence of SEQ ID NO:28. 48. The humanized antibody of claim 45 comprising a light chain variable region having the sequence of SEQ ID NO:11 and a heavy chain variable region having the sequence of SEQ ID NO:15. 49. The humanized antibody of claim 48 comprising a light chain having the sequence of SEQ ID NO:13 and a heavy chain having the sequence of SEQ ID NO:17. 50. An antibody that specifically binds human IL-1β wherein the variable domains of the antibody have framework regions which correspond to one or more human immunoglobulin heavy or light chain variable domain germline sequences and complementarity determining regions (CDRs) having sequences that correspond to: SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10. 51. An antibody of claim 40 comprised of complementarity determining regions (CDRs) wherein said CDRs are a modified form of the CDRs that correspond to the CDRs of antibody Mu007 wherein said modification improves binding affinity or biological activity compared to the binding affinity or biological activity of the Hu007 antibody. 52. An antibody fragment obtainable by enzymatic cleavage of the antibody of claim 40. 53. The antibody fragment of claim 52 which is a Fab or F(ab′)2 fragment. 54. An antibody fragment obtainable by enzymatic cleavage of the antibody of claim 45. 55. The antibody fragment of claim 54 which is a Fab or F(ab′)2 fragment. 56. An antibody fragment obtainable by enzymatic cleavage of the antibody of claim 50. 57. The antibody fragment of claim 56 which is a Fab or F(ab′)2 fragment. 58. The antibody of claim 40, which is a single chain antibody. 59. The antibody of claim 45, which is a single chain antibody. 60. The antibody of claim 50, which is a single chain antibody. 61. The antibody of claim 40 wherein the antibody has an IgG isotype. 62. The antibody of claim 61 wherein the isotype is selected from the group consisting of IgG1 and IgG4. 63. The antibody of claim 62 wherein the isotype is IgG1. 64. The antibody of claim 45 wherein the antibody has an IgG isotype. 65. The antibody of claim 64 wherein the isotype is selected from the group consisting of IgG1 and IgG4. 66. The antibody of claim 65 wherein the isotype is IgG1. 67. The antibody of claim 50 wherein the antibody has an IgG isotype. 68. The antibody of claim 67 wherein the isotype is selected from the group consisting of IgG1 and IgG4. 69. The antibody of claim 68 wherein the isotype is IgG1. 70. The antibody of claim 40 wherein the antibody has a binding affinity for mature human IL-1β which is within 5-fold of the binding affinity of Mu007 for mature human IL-1β. 71. The antibody of claim 70, which is within 3-fold the binding affinity of Mu007. 72. The antibody of claim 45 wherein the antibody has a binding affinity for mature human IL-1β which is within 5-fold of the binding affinity of Mu007 for mature human IL-1β. 73. The antibody of claim 72, which is within 3-fold the binding affinity of Mu007. 74. The antibody of claim 50 wherein the antibody has a binding affinity for mature human IL-1β which is within 5-fold of the binding affinity of Mu007 for mature human IL-1β. 75. The antibody of claim 74, which is within 3-fold the binding affinity of Mu007. 76. The antibody of claim 40 wherein the heavy chain or light chain variable framework region has at least 80% sequence identity with the corresponding framework region of the antibody Mu007. 77. The antibody of claim 45 wherein the heavy chain or light chain variable framework region has at least 80% sequence identity with the corresponding framework region of the antibody Mu007. 78. The antibody of claim 50 wherein the heavy chain or light chain variable framework region has at least 80% sequence identity with the corresponding framework region of the antibody Mu007. 79. The antibody of claim 40 wherein the antibody has an IC50 for mature human IL-1β within 10-fold the IC50 of Mu007 for mature human IL-1β. 80. The antibody of claim 79 wherein the antibody has an IC50 within 5-fold that of Mu007. 81. The antibody of claim 80 wherein the antibody has an IC50 within 3-fold that of Mu007. 82. The antibody of claim 45 wherein the antibody has an IC50 for mature human IL-1β within 10-fold the IC50 of Mu007 for mature human IL-1β. 83. The antibody of claim 82 wherein the antibody has an IC50 within 5-fold that of Mu007. 84. The antibody of claim 83 wherein the antibody has an IC50 within 3-fold that of Mu007. 85. The antibody of claim 50 wherein the antibody has an IC50 for mature human IL-1β within 10-fold the IC50 of Mu007 for mature human IL-1β. 86. The antibody of claim 85 wherein the antibody has an IC50 within 5-fold that of Mu007. 87. The antibody of claim 86 wherein the antibody has an IC50 within 3-fold that of Mu007. 88. An isolated nucleic acid, comprising a polynucleotide encoding an antibody of claim 40. 89. The nucleic acid of claim 88 comprising one or more polynucleotides having a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, and SEQ ID NO:17. 90. The nucleic acid of claim 89 comprising a polynucleotide having a sequence which corresponds to SEQ ID NO:13 and SEQ ID NO:17. 91. An expression vector comprising a nucleic acid according to claim 88. 92. A host cell stably transfected with the expression vector of claim 91. 93. The host cell of claim 92 wherein the host cell is selected from the group consisting of a Chinese Hamster Ovary cell, SP2/0 myeloma cell, NS0 Myeloma cell, a syrian hamster ovary cell, and an embryonic kidney cell. 94. The host cell of claim 93, which is a Chinese Hamster Ovary cell. 95. A process for producing an antibody comprising culturing the host cell of claim 94 under conditions suitable for expression of said antibody and recovering said antibody from the cell culture. 96. A pharmaceutical composition comprising the antibody of claim 40. 97. A pharmaceutical composition comprising the antibody of claim 45. 98. A pharmaceutical composition comprising the antibody of claim 50. 99. A method of treating rheumatoid arthritis or osteo-arthritis, comprising administering to a subject an effective amount of the antibody of claim 40. 100. A method of treating rheumatoid arthritis or osteo-arthritis, comprising administering to a subject an effective amount of the antibody of claim 45. 101. A method of treating rheumatoid arthritis or osteo-arthritis, comprising administering to a subject an effective amount of the antibody of claim 50. 102. A method of inhibiting the destruction of cartilage, comprising administering to a subject in need thereof an effective amount of the antibody of claim 40. 103. A method of inhibiting the destruction of cartilage, comprising administering to a subject in need thereof an effective amount of the antibody of claim 45. 104. A method of inhibiting the destruction of cartilage, comprising administering to a subject in need thereof an effective amount of the antibody of claim 50. 105. The use of the antibody of claim 40 for the manufacture of a medicament to treat a subject with rheumatoid arthritis or osteo-arthritis. 106. The use of the antibody of claim 40 for the manufacture of a medicament to inhibit cartilage destruction in a subject in need thereof. 107. The use of the antibody of claim 45 for the manufacture of a medicament to treat a subject with rheumatoid arthritis or osteo-arthritis. 108. The use of the antibody of claim 45 for the manufacture of a medicament to inhibit cartilage destruction in a subject in need thereof. 109. The use of the antibody of claim 50 for the manufacture of a medicament to treat a subject with rheumatoid arthritis or osteo-arthritis. 110. The use of the antibody of claim 50 for the manufacture of a medicament to inhibit cartilage destruction in a subject in need thereof. |
Feeder for high moisture content coal |
A feeder for high moisture content carbonaceous material, especially lignite, includes a housing (1) having an inlet (2) for introducing the carbonaceous material to the housing (1). The housing (1) has one or more converging sections (12a-12e) that are preferably of frusto-conical shape. A shaft (6) extends through the housing. Auger sections (8) define screw flights for transporting the carbonaceous material through the housing. Auger sections (8) do not extend through the converging sections (12a-12e). At least one radially extending paddle extends from the shaft in each converging section. The feeder can be used to feed carbonaceous material to a high pressure environment, such as a boiler. |
1. A feeder for high moisture content carbonaceous material comprising a housing having an inlet for introducing the carbonaceous material to said housing, said housing having a converging section, a shaft extending through said housing, said shaft having one or more radially extending auger sections defining a screw flight for transporting the carbonaceous material through the housing said radially extending auger sections on said shaft extending at least to an entrance of but not through the converging section of the housing, and at least one paddle extending radially from said shaft within said converging section. 2. A feeder as claimed in claim 1 wherein the converging section is essentially frusto-conicular in shape. 3. A feeder as claimed in claim 1 further comprising a plurality of paddles extending radially from said shaft within the converging section of the housing, said paddles being arranged with a plan that is perpendicular to a longitudinal axis of the shaft. 4. A feeder as claimed in claim 1 wherein the screw flight for transporting the carbonaceous material through the housing is of helical shape. 5. A feeder as claimed in claim 4 wherein the screw flight comprises a single, radially extending auger section extending from the inlet of the housing to the converging section. 6. A feeder as claimed in claim 1 further comprising a plurality of converging sections within the housing, the shaft extending through said housing and having a number of screw flighted regions comprising one or more radially extending auger sections for conveying carbonaceous material from inlet and between the converging sections. 7. A feeder is claimed in claim 6 wherein each of the converging sections is provided with at least one paddle extending generally radially from the shaft within the converging sections. 8. A feeder as claimed in claim 1 further comprising a transport screw for discharging the carbonaceous material from the feeder, said transport screw being located downstream of the converging section or sections. 9. A feeder as claimed in claim 8 wherein said transport screw is provided on a shaft of increasing diameter towards a material discharge to provide compression of the carbonaceous material. 10. A feeder as claimed in claim 8 wherein said transport screw comprises a variable pitch screw for compressing the carbonaceous material. 11. A feeder as claimed in claim 8 wherein the transport screw is at least partly surrounded by a perforated or foraminate section to allow moisture to be removed from the carbonaceous material. 12. A feeder for high moisture content solid carbonaceous material comprising a housing having an inlet for introduction of carbonaceous material into said housing and one or more converging section or stages through which carbonaceous material passes, a shaft extending through said housing having one or more radially extending auger sections, said auger sections defining at least one screw flighted region extending from said inlet up to a first of said one or more converging sections or between adjacent converging sections, and at least one paddle extending radially from said shaft within the one or more converging sections. 13. A feeder as claimed in claim 12 wherein the converging sections are frusto-conicular in shape. 14. A feeder as claimed in claim 12 further comprising a transport screw extending to an outlet of the housing for transporting the carbonaceous material from a last of the converging sections to the outlet. 15. A feeder as claimed in claim 12 further comprising one or more injectors for injecting hot fluid into the housing. 16. A feeder as claimed in claim 15 wherein the hot fluid is saturated steam. 17. A feeder as claimed in claim 12 wherein the carbonaceous material exits the feeder as a dense plug and the feeder further comprises a shredder to produce fine shavings from the dense plug as it leaves the housing. 18. (canceled) |
Method and device for flocculating setting |
The present invention has an object to provide a compact aggregation precipitation method and an apparatus therefor which prevent the outflow of flocs and do not deteriorate the turbidity elimination performance even in start-up early stages. As the means to accomplish such an object, the present invention provides a method of adding an inorganic flocculant and, optionally, an organic polymer flocculent to the water to be treated and agitating the resulting mixture to effect aggregation precipitation treatment which comprises introducing the agitated solution into a first chamber of a separation tank where flocs are allowed to grow to effect solid-liquid separation and, simultaneously, the separated water is discharged out of the separation tank. |
1. A method of aggregation precipitation treatment by adding an inorganic flocculant to the water to be treated and agitating the resulting solution, which comprises introducing the agitated solution into a first chamber of a separation tank where flocs are allowed to grow and subjected to solid-liquid separation and, simultaneously, the separated water is discharged out of the tank, allowing the flocs grown in the first chamber and part of the separated water to flow down into a second chamber provided below the first chamber at a velocity higher than the settling velocity of the flocs as such, concentrating the grown flocs, discharging the concentrated slurry in the second chamber, and simultaneously withdrawing the separated water formed by the concentration of the flocs and the separated water in the first chamber which has been introduced into the second chamber together with the flocks from the upper part of the second chamber as the separated water. 2. The method of claim 1 comprising adding an organic polymer flocculent together with the inorganic polymer flocculant to the water to be treated. 3. The method of claim 1 comprising controlling the amounts of introducing the flocs and the separated water in the first chamber into the second chamber from the first chamber by regulating the amount of the separated water to be withdrawn from the second chamber. 4. The method of claim 1 comprising introducing the flocs and the separated water in the first chamber into the second chamber from the first chamber by a floc transfer pipe and inhibiting the fragmentation of the flocs in the lower part of the floc transfer pipe by regulating the total discharge flow rate of the separated water and the slurry in the second chamber so as to render the flow velocity in the floc transfer pipe to 5 m/min or lower. 5. The method of claim 1 comprising introducing the flocs and the separated water in the first chamber into the second chamber from the first chamber by a floc transfer pipe and automatically controlling the effluent amount of the separated water in the second chamber as an index of the turbidity or the suspended substance concentration of the separated water in the second chamber, so as to render the upward flow velocity above the lower end of the floe transfer pipe in the second chamber lower than the settling velocity of the flocs. 6. An apparatus for subjecting a solution obtained by adding an inorganic flocculant to the water to be treated and agitating the resulting mixture to aggregation precipitation treatment, which comprises a separation tank; a partition wall which divides the separation tank into the upper part of a first chamber and the lower part of a second chamber, the first chamber having an effluent section for the separated water in the first chamber in the upper part and an influent section for the water to be treated in the lower part, the second chamber having an effluent section for the separated water in the second chamber in the upper part and a slurry drainage section in the lower part: a vertical floc transfer pipe which penetrates the first chamber and the second chamber and has both open ends, the upper end of the floc transfer pipe positioning between the effluent section for the separated water in the first chamber and the lower end positioning between the effluent section for the separated water in the second chamber and the slurry drainage section in the second chamber, and a valve or a pump to regulate the amount of the flowage water from the effluent section for the separated water in the second chamber. 7. The apparatus of claim 6, wherein an inorganic flocculant is added together with an organic polymer flocculant. 8. The apparatus of claim 6, wherein a filtering medium layer is installed in the upper part of the first chamber. |
<SOH> BACKGROUND ART <EOH>Of methods of separating suspended substances present in raw water, a method comprising adding a flocculant to the raw water, allowing the raw water to flow as an upward flow in a separation tank to aggregate pollutants and settling and separating them as coarse particles (flocs), is broadly used. The treatment velocity in the conventional aggregation precipitation method of the upward flow type (the term “treatment velocity” means herein a flow velocity found by dividing the water amount of the water to be treated by the sectional area of a tank) is restrained by the settling velocity of flocs and cannot be faster than the settling velocity of the flocs. Further, even if the treatment velocity is lower than the settling velocity of the floes, when the flow velocity is not uniform, the settling of flocs is hindered. Particularly, the upward flow velocity in the neighborhood of the influent section of the raw water is higher than the settling velocity of the flocs, and not only hinders the settling of flocs but also invites the fragmentation of flocs. This can be said independently of whether or not the formation of a blanket layer, in other words, a retention layer of coarse flocs is caused in the course of treatment. In the aggregation precipitation of the upward flow type accompanying the formation of a blanket layer of floes, fine flocks and an unaggregated turbidity component are brought into contact with flocs forming the blanket layer and trapped in passing through the blanket layer and as a result, the elimination of turbidity is accelerated, and simultaneously the settling properties of flocs are improved. However, when the blanket layer is formed to improve the settling properties, with increased treatment velocities, the formation of the blanket layer is hindered to cause an overflow of floes. On the other hand, as the treatment system which makes the treatment velocity higher than that of the conventional aggregation precipitation treatment, there is a system of installing a concentration tank below a separation tank and connecting the separation tank with the concentration tank by a floc transfer pipe. The flocs formed in the separation tank settle in the flock transfer pipe by the descending flow caused by the settling of flocks as such, and are transferred to the concentration tank, then concentrated and discharged. The separated water to be formed by the concentration process is affected by the above-described descending flow of flocs and returned as a flow to the separation tank. However, according to this system, the transfer of flocs and water from the separation tank to the concentration tank depends on the descending flow caused by the settling of the flocs as such, and accordingly it is impossible to arbitrarily control the amount of water to be transferred from the separation tank to the concentration tank, and the treatment velocity must depend on the settling velocity of flocs. Furthermore, the function of the concentration tank is only to gravitationally concentrate the influent flocs flown from the separation tank and has no function of positively effecting solid-liquid separation to obtain clear separated water as the separation tank. As a problem different from the above described problem in the aggregation precipitation method of the upward flow type, the deterioration of the turbidity elimination performance in start-up early stages of the apparatus can be mentioned. This deterioration is a very serious problem in the treatment system accompanying the formation of a blanket layer. Once the blanket layer is formed, fine flocs are brought into contact with large flocs forming the blanket layer, integrated with the flocs, and removed. But in order to form such a blanket layer, it is necessary for fine flocs to repeatedly associate with one another. Thus, on start-up of the apparatus, the treatment is started in a state in the absence of in the blanket layer, and accordingly the property of the treated water is deteriorated until the blanket layer is formed. The present invention solves the above described problems of the conventional technique and has an object to provide a compact aggregation precipitation method and an apparatus therefor which prevent the outflow of flocs even in the circumstances that the treatment velocity is higher than the settling velocity of flocs and, simultaneously, do not deteriorate the turbidity elimination performance even in start-up early stages of the apparatus. |
Pressure regulation by transfer of a calibrated gas volume |
Pressure regulation in a liquid reservoir such as ink of a jet printing head, is obtained by transferring a calibrated gas volume through an auxiliary reservoir (12), said regulation being applied to installations manufacturing intelligent portable objects and more particularly to graphic customization stations. |
1. A method of regulating negative or positive pressure in a reserve of liquid also containing a gas, comprising the following steps: a) defining a set pressure value around which the gas present in the reserve is to be maintained; b) measuring the instantaneous pressure of the gas present in the reserve; c) comparing the measurement of the instantaneous pressure of the gas present in the reserve with the set pressure value; d) in cases where the measurement of the instantaneous pressure of the gas present in the reserve is higher than the set pressure value, creating a calibrated volume of gas under negative pressure and then putting it in communication with the reserve ; and e) in cases where the measurement of the instantaneous pressure of the gas present in the reserve is less than the set pressure value, creating a calibrated volume of gas under pressure and then putting it in communication with the reserve. 2. A method according to claim 1, wherein the steps of measuring (b) and comparing (c) and those of creating a calibrated volume and then putting it in communication (d or e) are repeated successively at regular intervals. 3. A method according to claim 2, further including the step of defining a new set pressure value, and wherein the steps of measuring (b) and comparing (c) and those of creating a volume and then putting it in communication (d or e) are performed successively, taking into account the new set pressure value. 4. A method according claim 1, further including, before the measuring step (b), a step of: a1) defining a minimum threshold pressure value for rapid regulation and a maximum threshold pressure value for rapid regulation, these two values framing the set pressure value; and, before the comparison step (c), the steps of: b1) comparing the measurement of the instantaneous pressure of the gas present in the reserve with the minimum and maximum threshold pressure values for rapid regulation; b2) in cases where the instantaneous pressure of the gas present in the reserve is higher than the maximum threshold pressure for rapid regulation, connecting the reserve to a continuous source of gas under negative pressure until a pressure close to the set pressure value is obtained in the reserve; and b3) in cases where the instantaneous pressure of the gas present in the reserve is lower than the minimum threshold pressure for rapid regulation, connecting the reserve to a continuous source of gas under pressure until a pressure close to the set pressure value is attained in the reserve. 5. A method according to claim 1, wherein the set pressure value comprises a minimum set threshold pressure value and a maximum set threshold pressure value. 6. A regulation device for putting under negative or positive pressure a reserve of liquid that also contains a gas, comprising: a related reserve; means of charging the related reserve with gas under pressure or negative pressure; means of transferring volumes of gas between the related reserve and the reserve of liquid; means for measuring the instantaneous pressure in the reserve of liquid; and control means connected with the measuring means and actuating the charging means and the transfer means; so that an absolute pressure is maintained around a defined set pressure value. 7. A regulation device according to claim 6, further comprising means for selecting the set pressure value to be maintained in the reserve of liquid, said means also making it possible to modify the set value during the functioning of the regulation device. 8. A regulation device according to claim 6, further comprising means of putting the charging means in direct connection with the reserve of liquid. 9. A regulation device according to claim 6, wherein the transfer means comprise a solenoid valve that selectively connects the related reserve with either the charging means or the reserve of liquid. 10. A regulation device according to claim 8, wherein the means of putting the charging means in direct connection with the reserve of liquid comprise a solenoid valve that selectively connects the charging means with either the related reserve or directly the liquid reserve. 11. A regulation device according to claim 6, wherein the set pressure value has a value lower than atmospheric pressure so that a negative pressure is maintained in the reserve. 12. A regulation device according to claim 6, wherein the set pressure value has a value higher than atmospheric pressure so that an overpressure is maintained in the reserve. 13. A device for putting a print head under negative or positive pressure, in which a reserve of liquid to be printed also contains a gas, comprising: a supply of gas under pressure; a supply of gas under negative pressure; and a regulation device according to claim 6. 14. A pressure regulating device according to claim 13, wherein the charging means comprise a third solenoid valve receiving as an input the gas supply under pressure and gas supply under negative pressure, and delivering as an output one or the other of these supplies. 15. A machine for printing on a plastic medium, comprising a print head with a reserve and provided with an opening to contain a liquid to be printed as well as a gas, and a regulation device according to claim 6. 16. An installation for manufacturing intelligent portable objects, comprising at least one graphical personalisation station having a machine according to claim 15. |
High purity metallurgical silicon and method for preparing same |
The invention concerns a silicon designed in particular for making solar cells containing a total of impurities ranging between 100 and 400 ppm, a boron content ranging between 0.5 and 3 ppm, a phosphorus/boron content ratio ranging between 1 and 3, and a content of metal elements ranging between 30 and 300 ppm. The invention also concerns a method for making such a silicon from an oxygen- or chorine-refined metallurgical silicon containing at least 500 ppm of metal elements, and comprising: refusion under neutral atmosphere of the refined silicon, in an electric furnace equipped with a hot crucible; transferring the molten silicon, to provide a plasma refining, in an electric furnace equipped with a hot crucible; plasma refining with as plasma-forming gas a mixture of argon and of at least a gas belonging the group consisting of chlorine, fluorine, HCI and HF; casting under controlled atmosphere in an ingot mould wherein is produced segregated solidification. |
1. Method for making a photovoltaic quality silicon from an oxygen or chlorine refined metallurgical silicon containing less than 500 ppm of metal elements and comprising: remelting of the refined silicon, under a neutral atmosphere, in an electric furnace equipped with a hot crucible, transfer of the remelted silicon for plasma refining, in an electric furnace equipped with a hot crucible, plasma refining of the molten silicon with a mixture of argon and at least one gas from the group consisting of chlorine, fluorine, hydrochloric acid and hydrofluoric acid, as plasma-forming gas, the mix containing from 5 to 90% of argon, casting under controlled atmosphere in an ingot mould, in which segregated solidification takes place. 2. Method according to claim 1, characterised in that the silicon is prepared with less than 500 ppm of metallic elements, using a segregated solidification operation to concentrate the metallic impurities in the liquid fraction. 3. Method according to claim 1, characterised in that remelting is done on successive batches. 4. Method according to claim 1, characterised in that remelting and plasma refining of silicon are done in two different workstations. 5. Method according to claim 1, characterised in that silicon is transferred between the remelting operation and the plasma refining operation by displacement of an assembly composed of the casing of the furnace, the induction coil, the crucible, and liquid silicon. 6. Method according to claim 1, characterised in that plasma refining is done using an HF-argon and/or HCl-argon gas mix containing between 50% and 70% argon. 7. Method according to claim 1, characterised in that the plasma source is an inductive torch powered by an electricity source at a frequency of between 100 kHz and 4 MHz. 8. Method according to claim 2, characterised in that the first segregated solidification, before plasma refining, is controlled so that the solidification front advance velocity is below 2×10−5 m/s. 9. Method according to claim 1, characterised in that the segregated solidification, after plasma refining, is controlled so that the solidification front advance velocity is below 10−5 m/s. 10. Method according to claim 9, characterised in that the solidification front advance velocity is below 5×10−6 M/s. 11. Method according to claim 1, characterised in that segregated solidification operations take place in a reverberatory furnace. 12. Method according to claim 1, characterised in that electric furnaces used for silicon remelting and plasma refining operations are induction furnaces. 13. Method according to claim 1, characterised in that electric furnace crucibles used for silicon remelting and plasma refining operations are made either of silica, carbon, graphite, or silicon carbide. 14. Silicon designed in particular for making solar cells, with a total content of impurities ranging between 100 and 400 ppm, a boron content ranging between 0.5 and 3 ppm, and a phosphorus/boron ratio ranging between 1 and 3, and a content of metallic elements between 30 and 300 ppm. 15. Silicon according to claim 14, characterised by a total content of impurities ranging between 100 and 250 ppm, a boron content ranging between 0.5 and 2 ppm, and a content of metallic elements between 30 and 150 ppm. 16. Silicon according to claim 14, characterised by an iron content ranging between 10 and 20 ppm. 17. Method according to claim 2, characterised in that remelting is done on successive batches. 18. Method according to claim 2, characterised in that remelting and plasma refining of silicon are done in two different workstations. 19. Method according to claim 3, characterised in that remelting and plasma refining of silicon are done in two different workstations. 20. Silicon according to claim 15, characterised by an iron content ranging between 10 and 20 ppm. |
<SOH> FIELD OF THE INVENTION <EOH>The invention relates to a high purity metallurgical silicon with different applications including the manufacture of panels for conversion of light energy, and particularly solar energy, into electrical energy. The invention also relates to the process for making this material called photovoltaic silicon. |
Terminal device, content acquisition method, content providing method, and information input medium |
Using a camera 3 included in a terminal 1, an image of an information-including region in an information input medium 43 is captured. Captured image information is processed to detect the direction of rotation of an image pattern and to recognize a code for specifying an image that can be provided as content. On the basis of the recognized code, the image serving as the corresponding content is obtained from, for example, a site on the Web or a storage medium. Accordingly, a terminal capable of obtaining content, such as a background image to be pasted on a display screen, from the Web or the like using a simple process is provided. |
1. A terminal comprising: a display unit that can display an image; image capturing means for capturing an image of an information-including region in an information input medium including information for specifying an image that can be provided as content, the information being encoded by the direction of rotation of a predetermined image pattern; recognition means for determining, on the basis of image information captured by the image capturing means, the direction of rotation of the image pattern and recognizing the information for specifying the image, which can be provided as the content; and content obtaining means for obtaining the image serving as the corresponding content on the basis of the information recognized by the recognition means. 2. A terminal according to claim 1, further comprising: detection means for detecting the movement of the terminal; and scrolling means for moving, when displaying an image larger than a display screen of the display unit on the display screen, the position of the image displayed on the display screen in accordance with the movement of the terminal, the movement being detected by the detection means. 3. A terminal according to claim 2, further comprising: table obtaining means for obtaining a table for assigning individual functions to a plurality of partial regions constituting the image obtained as the content by the content obtaining means; and execution means for executing, on the basis of the table obtained by the table obtaining means, a function assigned to a region displayed on the display screen by moving the image by the scrolling means. 4. A content obtaining method for a terminal having a display unit that can display an image and an image capturing unit for capturing an image, the method comprising: a step of capturing an image of an information-including region in an information input medium including information for specifying an image that can be provided as content, the information being encoded by the direction of rotation of a predetermined image pattern; a step of determining, on the basis of captured image information, the direction of rotation of the image pattern and recognizing the information for specifying the image, which can be provided as the content; and a step of obtaining the image serving as the corresponding content on the basis of the recognized information. 5. A content obtaining method for a terminal having a display unit that can display an image, a scrolling function of moving, when displaying an image larger than a display screen of the display unit on the display screen, the position of the image displayed on the display screen, and an image capturing unit for capturing an image, the method comprising: a step of capturing an image of an information-including region in an information input medium including information for specifying an image that can be provided as content, the information being encoded by the direction of rotation of a predetermined image pattern; a step of determining, on the basis of captured image information, the direction of rotation of the image pattern and recognizing the information for specifying the image, which can be provided as the content; a step of obtaining the image serving as the corresponding content on the basis of the recognized information; a step of displaying the image obtained as the content on the display screen; a step of obtaining a table for assigning individual functions to a plurality of partial regions constituting the image obtained as the content; and a step of executing, on the basis of the obtained table, a function assigned to a region displayed on the display screen by moving the image by the scrolling function. 6. A content providing method for providing content to a terminal having a display unit that can display an image and an image capturing unit for capturing an image, the method comprising: providing an information input medium including information for specifying an image that can be provided as content, the information being encoded by the direction of rotation of a predetermined image pattern; and causing the image capturing unit of the terminal to capture an image of an information-including region in the information input medium; causing the terminal to recognize the information on the image, which can be provided as the content, on the basis of captured image information; and providing the image serving as the corresponding content to the terminal in response to a request based on the recognition result from the terminal. 7. A content providing method for providing content to a terminal according to claim 6, wherein the terminal is charged a fee for the content provided. 8. A content providing method for providing content to a terminal having a display unit that can display an image, a scrolling function of moving, when displaying an image larger than a display screen of the display unit on the display screen, the position of the image displayed on the display screen, and an image capturing unit for capturing an image, the method comprising: providing an information input medium including information for specifying an image that can be provided as content, the information being encoded by the direction of rotation of a predetermined image pattern; and causing the image capturing unit of the terminal to capture an image of an information-including region in the information input medium; causing the terminal to recognize the information on the image, which can be provided as the content, on the basis of captured image information; providing the image serving as the corresponding content to the terminal in response to a request based on the recognition result from the terminal; and providing a table for assigning individual functions to a plurality of partial regions constituting the image and for executing a function assigned to an arbitrary region displayed on the display screen by the scrolling function. 9. A content providing method for providing content to a terminal according to claim 8, wherein the terminal is charged a fee for the content provided. 10. An information input medium including information for specifying an image that can be provided as content to a terminal having a display unit that can display an image and an image capturing unit for capturing an image, the information being encoded by the direction of rotation of a predetermined image pattern. |
<SOH> BACKGROUND ART <EOH>In general, the amount of information that can be displayed on a display screen of a mobile terminal, such as a hand-held terminal or a cellular phone, is limited. To display an image larger than a display screen on the display screen, a function that is generally referred to as scrolling display is used. Although this scrolling display is generally employed in personal computers and the like, it is unrealistic to provide a mobile terminal with operation means equivalent to that of personal computers. In most cases, such a mobile terminal lets the user use not only a scrolling display, but also all functions only by operating buttons. A method of improving the user-friendliness of a scrolling display of a mobile terminal is disclosed in, for example, Japanese Unexamined Patent Application Publication No. 2002-7027. This patent document discloses a technique in which longitudinal and lateral movement of the terminal is detected by, for example, an acceleration sensor; and, on the basis of the detection result, a displayed image is scrolled simultaneously in the direction in which the terminal is moving. This technology liberates the user from burdensome button operations involved in the above-mentioned scrolling display and provides a scrolling display that is intimately associated with human instincts. When such a mobile terminal obtains various types of content, such as an image, music, and a document, from the Web or the like, the user must look the Web for a site or a page within a site that provides desired content by continuously scrolling a small display screen. Although the scrolling display itself becomes user-friendlier by the above-mentioned technique, the user must take a long time to perform complicated operations to obtain the desired content. In accordance with the above-described circumstances, it is an object of the present invention to provide a terminal that can obtain desired content by a simple process, a content obtaining method, a content providing method, and an information input medium. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a perspective view that schematically shows the appearance of a terminal according to an embodiment of the present invention. FIG. 2 is a block diagram showing the hardware configuration of this terminal. FIGS. 3A and 3B are block diagrams showing part of the structure of a program and data for the terminal. FIGS. 4A and 4B are illustrations for describing a scrolling display function of the terminal. FIG. 5 is an illustration showing an example of a content table. FIG. 6 is an illustration showing an example of an information input medium including recognition target images. FIG. 7 is an illustration showing an example of a recognition target image. FIG. 8 is an illustration showing the relationship between a code and a rotation mode of an image pattern included in a recognition target image. FIG. 9 is an illustration showing the flow of a process of recognizing a code from a recognition target image, which is included in the information input medium. FIG. 10 is an illustration showing a process of extracting image patterns. FIG. 11 is an illustration showing an example of a direction-and-characteristics table. FIG. 12 is an illustration showing an example of a candidate code group for use in determining the code recognition result. FIG. 13 is an illustration showing an example of a code conversion table. FIG. 14 is an illustration showing the configuration of a network system that provides a background image, a content table, and content to the terminal. FIGS. 15A and 15B are flowcharts showing the operation of the terminal. FIG. 16 shows other examples of image patterns. detailed-description description="Detailed Description" end="lead"? |
Apparatus and method for inputting alphabet characters |
The invention shows that words or phrases may be input without ambiguity in some languages and with a little ambiguity in most languages by applying (language restricted) RSM and CVSK. Moreover, this invention proposes an innovative system which recognizes in early stage of input whether an input value is a simple code or a full code by CIM (i.e. Language Restricted CIM) with a language restricted input method as FIM. |
1. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or symbols, the method comprising: (a) detecting a selection of button on which at least one of alphabet characters are arranged; and (b) recognizing a target word or phrase using available alphabet character combination excluding unavailable alphabet character combination when the number of button selection is two or more. 2. (canceled) 3. The method of claim 1, wherein consonant buttons of the keypad are separated from vowel buttons of the keypad, each consonant button arranging one or more consonants and each vowel button arranging one or more vowels. 4. The method of claim 1, wherein the target word or phrase is composed of Chinese characters, the step (b) recognizes the target word or phrase using a language restriction rule (i.e., word production rule or character coupling rule) which same consonant or vowel of Roman alphabet should not succeed in the Chinese Pinyin. 5. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or symbols, the method comprising: wherein consonant buttons of the keypad are separated from vowel buttons of the keypad, each consonant button arranging one or more consonants and each vowel button arranging one or more vowels, the method comprising: (a) detecting a selection of vowel button or consonant button; and (b) recognizing a target word or phrase responsive to the selection of the button. 6. The method of claim 5, wherein the consonant button or vowel button arranges consonants or vowels based on similarity of pronunciation. 7. The method of the claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, wherein vowel “a” and vowel “i” are not grouped into a same group and are arranged on different vowel buttons. 8. The method of claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, wherein vowel “e” and vowel “i” are not grouped into a same group and are arranged on different vowel buttons. 9. The method of the claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, wherein vowel “o” and vowel “u” are not grouped into a same group and are arranged on different vowel buttons. 10. The method of claim 5, wherein the consonant button or the vowel button is to enter Chinese Pinyin, one or more alphabet characters selected from alphabet character group including vowel “a”, “e”, “o” and one or more alphabet characters selected from the alphabet character group including vowel “i” and “u” are arranged on different vowel buttons. 11. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or symbols, the method comprising: (a) detecting a selection of button arranging one or more alphabet characters; (b) determining whether the selected button is available alphabet character combination or not, based on language restriction rule of a specific language when the number of button selection is two or more; and (c) processing the selected button value as simple code when the selected button is determined as unavailable alphabet character combination. 12. The method of claim 11, wherein the selected button value is processed as a predetermined full code when the phrase corresponding selected button value is determined not to exist in index. 13. The method of claim 11, wherein step (c) further comprises: recognizing an available alphabet character combination corresponding to the selected button; deriving the alphabet character combination from the word or phrase stored in the index on the basis of the type of a predefined simple code; and processing the simple code by comparing the recognized alphabet character combination with the derived alphabet-character combination. 14. The method of claim 11, wherein step (c) processes the simple code by comparing the selected button value with a specific simple code stored in index. 15. The method of claim 11, wherein step (c) further comprises: recognizing an available alphabet character combination corresponding to the selected button; and processing the simple code by comparing the recognized alphabet character combination with alphabet character combination stored in index based on specific simple code. 16. The method of claim 11, wherein the language restriction rule is based on word production rule of the Chinese Pinyin, wherein step (c) processes the selected button value as simple code or full code using the language restriction rule that consonants do not appear in succession from the start of word except “ch..”, “sh..”, “zh”. 17. The method of claim 11, wherein the language restriction rule is to enter alphabet character using Roman alphabet, wherein step (c) processes the selected button value as simple code or full code using the language restriction rule that consonants do not appear in succession from the start of word except “st..”, “sp..”. 18. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or symbols, the method comprising: (a) detecting a selection of button on which at least of alphabet characters is arranged; (b) counting the number of button selection; and (c) processing as simple code when the button selection number is no more than a predetermined number and processing as full code when the button selection number is larger than the predetermined number. 19. A method for inputting characters from a keypad, which is to construct an index of simple code, the method comprising: (a) dividing the syllables from a word or phrase which is input by the user; (b) extracting predefined type of a simple code from each syllables; and (c) storing simple code corresponding to the word or phrase. 20. (canceled) 21. (canceled) 22. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or controls, the method comprising: (a) detecting input of simple code; and (b) processing the simple code by comparing the recognized alphabet character combination by the simple code with alphabet character combination stored in index based on specific simple code. 23. The method of claim 22, wherein consonant buttons of the keypad are separated from vowel buttons of the keypad, and each consonant button arranging one or more consonants and each vowel button arranging one or more vowels. 24. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or controls, the method comprising: (a) detecting input of simple code; (b) deriving the alphabet character combination from the word or phrase stored in the index on the basis of the type of a predefined simple code; and (c) processing the simple code by comparing the recognized alphabet character combination by the simple code with the derived alphabet character combination. 25. The method of claim 24, wherein consonant buttons of the keypad are separated from vowel buttons of the keypad, and each consonant button arranging one or more consonants and each vowel button arranging one or more vowels. 26. A method for entering characters from a keypad, which has a plurality of buttons, each button arranging at least one of alphabet characters or controls, the method comprising: wherein consonant buttons of the keypad are separated from vowel buttons of the keypad, each consonant button arranging one or more consonants and each vowel button arranging one or more vowels, the method comprising: (a) detecting input of simple code; and (b) processing the simple code by comparing the inputted simple code with simple code stored in index. 27. The method of claim 5, wherein the consonant button or the vowel button is to enter Hindi, and short vowels (i.e., basic vowels) are not grouped into a same group and are arranged on different vowel buttons. 28. The method of claim 27, wherein the consonant button or the vowel button is to enter Hindi, and “a short sound vowel (i.e., a basic vowel)”, “a long sound vowel”, and “compound vowel(s)” are grouped into a group and arranged on a button. 29. The method of claim 5, wherein the consonant button or the vowel button is to enter Hindi, and vowels arranged in a button are selected according to the number of times of pressing the button in the order of “a short sound vowel (i.e., a basic vowel)-a long sound vowel-compound vowel(s).” 30. The method of claim 5, wherein the consonant button or the vowel button is to enter Hindi, and compound vowels are input by the predefined combination of short sound vowel or long sound vowel. 31. The method of claim 5, wherein the consonant button or the vowel button is to enter Russian, and vowels “a(a)”, “o(o)” which can be regarded as strong vowels are grouped into same group and arranged in the same button and vowels “y(u)”, “3(e)”, and “(i)” which can be regarded as weak vowel are not grouped with strong vowels group. 32. The method of claim 5, wherein the consonant button or the vowel button is to enter Indonesian, and vowel “a” and vowel “i” are not grouped into a same group and are arranged on different vowel buttons. 33. The method of claim 5, wherein the consonant button or the vowel button is to enter Indonesian, and vowel “a” and vowel “u” are not grouped into a same group and are arranged on different vowel buttons. 34. The method of claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, and vowel “a” and vowel “i”, and vowel “e” and vowel “i” are not grouped into a same group and are arranged on different vowel buttons. 35. The method of claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, and vowel “e” and vowel “i”, and vowel “o” and vowel “u” are not grouped into a same group and are arranged on different vowel buttons. 36. The method of claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, and vowel “o” and vowel “u”, and vowel “a” and vowel “i” are not grouped into a same group and are arranged on different vowel buttons. 37. The method of claim 5, wherein the consonant button or the vowel button is to enter a language (including Chinese Pinyin) using Roman alphabet, and vowel “a” and vowel “i”, vowel “e” and vowel “i”, and vowel “o” and vowel “u” are not grouped into a same group and are arranged on different vowel buttons. |
<SOH> BACKGROUND OF THE INVENTION <EOH>(a) Field of the Invention The present invention relates to an apparatus and method for inputting characters from a keypad. More specifically, the present invention relates to an apparatus and method for inputting characters from a keypad having a small number of buttons such as a telephone keypad. (b) Description of the Related Art With the progress of mobile communications, a function of receiving and sending digital information such as text messages is added to a mobile station chiefly used for voice calls. Hence, the keypad provided on the mobile station for the entry of a telephone number additionally has a function of entering characters, thus reducing the size of the keypad used as an input means in the mobile station and hence limiting the number of buttons included on the keypad. Alphabets of every language are usually much more than 12 keys on the keypad. Therefore a need exists to represent every character with buttons on a telephone keypad alone or in combination of two or more different types. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention disclosed in the prior documents published by the present applicant (i.e., Application No. 10-2000-0031879 and PCT/KR00/00601) can be summarized as follows. First, so-called “Part-Whole Selection Method (PWSM)” assigns characters to a given number of lattices provided to every button on the keypad in correspondence to the arrangement of buttons on the keypad, so that the user can enter a desired character (hereinafter, referred to as “target character”) by pressing a first button for the target character in combination with a second button provided on the keypad in correspondence to the arranged position of the character in the lattices of the first button. For example, the user may enter“A=[1]+[2]” in FIG. 1-1 . The core of PWSM is using part of the lattice elements of every button including a base lattice element (BLE), for which the first button is identical to the second one, and particularly, in the Order of Proximity to a BLE that is most convenient in button combination. As such, the base lattice element forms the core of PWSM and a keypad making the use of the conception of the Base Lattice Element is called “Base Keypad (BK)”. Next, so-called “Base Repeat Selection Method (BRSM)” enables the user to select an character depending on the number of times of pressing a button on a Base Keypad designed to use PWSM in the order of proximity to a BLE, i.e., the Convenient Order of Button Combination (COBC) in PWSM. BRSM makes the user of a Repeat Selection Method (RSM) on the Base Keypad. Expediently, a keypad using only RSM is called “Plain Keypad (PK)”, and a method of using RSM in a PK as is usual is referred to as “Simple Repeat Selection Method (SRSM)”. There is also a “Control Processing Method (CPM)”, which includes an “Affix Control Processing Method (ACPM)” and a “Succession Control Processing Method (SCPM)”. The affix control processing method is to enter affixed characters by a combination of affix control and basic character. The succession control processing method defines a group of characters assigned to a button as the relation among a representative character and its succession characters, and compounds the representative character and the priority associated with the representative character. For example, the user may enter as in FIG. 4-1 . The Affix Control Processing Method (ACPM) is in substance similar to the Succession Character Control Processing (SCPM). The latter is more general than the former, because a specific character group also includes affixed characters belonging to basic characters in a defined sequent order in SCPM. The ACPM has a close connection with the character group in shape because affixed characters are decomposed into an affix and a basic character, while SCPM is closely connected to sequent order and pronunciation. The CPM are advantageous in that succession (or affixed) characters are not displayed on the keypad through the relation between a basic character and its succession (or affixed) characters to provide a simple arrangement of the keypad and enter character without ambiguity. A keypad that excludes succession characters is called “Succession Keypad (SK)” and one excluding affixed characters is called “Abbreviated Keypad (AK)”. Both SK and AK are referred to as “Concise Keypad (CK)”. A keypad that displays all succession (or affixed) characters in contrast to CK is called “full keypad (FK)”. The full keypad also enables the entry of succession (or affixed) characters using CPM, while CK allows the user who memorizes the arrangement of the full keypad to perform the entry procedure on the full keypad. As described above, CK can be expanded to the FK and the user can expediently enter succession characters by CPM, which guarantees compatibility characteristic of the prior document. The control processing method not only removes ambiguity but also simplifies the arrangement of the keypad by “hiding” the succession characters via the relation between a representative character and its succession characters as described in the prior documents. Expediently, this is called “Hiding Control Processing Method (HCPM)”. The succession (or affixed) characters may be input by CPM even on the full keypad on which the succession (or affixed) characters are displayed, as described in the prior documents. Expediently, this is called “Non-hiding Control Processing Method (NCPM)”. The present invention suggests the improvement of the prior documents of the applicant (Application No. 10-2000-0031879 and PCT/KR00/00601). More particularly, it provides (a) a method for entering commonly used words with a small number of strokes, (b) a method for entering all target characters using a concurrent input method (CIM) that involves both a short-cut input method (SIM) and a full input method (FIM), to reduce input strokes and thereby enhance the convenience in entering characters, (c) a method for entering various symbols on a keypad, and (d) a method for using a move button, not frequently used in the character input mode, as a control button. |
Medium purity metallurgical silicon and method for preparing same |
The invention concerns a method for producing a medium purity silicon comprising: preparing, by carbothermic reduction of silica in a submerged arc-furnace a silicon with low boron content; refining the liquid silicon with oxygen or chlorine; treating the refined silicon under reduced pressure from 10 to 100 Pa with neutral gas injection; segregated solidification. The invention also concerns a medium purity silicon designed to serve as raw material for making silicon of electronic or voltaic quality, and having (in weight fractions): a total of impurities ranging between 100 and 400 ppm, with the content in metallic elements ranging between 30 and 300 ppm; a boron content from 1 to 10 ppm; a phosphorus/boron ratio ranging between 0.5 and 1.5. |
1. Process for making medium-purity silicon to be used as a raw material for making photovoltaic quality or electronic quality silicon, and comprising: production of a silicon with a low content of boron, by carbothermal reduction in a submerged electric arc furnace, refining of liquid silicon with oxygen or chlorine, treatment of liquid silicon refined under low pressure between 10 and 100 Pa with injection of neutral gas, segregated solidification. 2. Process according to claim 1, characterised in that the segregated solidification is followed by remelting of the solid fraction obtained and is then repeated. 3. Process according to claim 1, characterised in that, in the first step of carbothermal reduction of silica, the power density used expressed as the (Pe/Do3)/3 ratio is between 2 and 3 MW/m3, and that the weighted average specific area S of the reduction agents used is between 20 and 40 m2/g. 4. Process according to claim 1, characterised in that the first segregated solidification is carried out at a solidification front advance velocity below 2×10−5 m/s. 5. Process according to claim 2, characterised in that the second segregated solidification is carried out at a solidification front advance velocity below 10−5 m/s. 6. Process according to claim 5, characterised in that the solidification front advance velocity is below 5×10−6 M/s. 7. Process according to claim 1, characterised in that the segregated solidification operations are carried out in a reverberatory furnace. 8. Process according to claim 2, characterised in that the remelting operation is carried out in an induction furnace. 9. Process according to claim 7, characterised in that electric furnace crucibles used for silicon remelting operations are made of silica, carbon, graphite, or silicon carbide. 10. Silicon to be used as a raw material for making photovoltaic or electronic grade silicon, characterised in that it comprises a total content of impurities ranging between 100 and 400 ppm, with a content of metallic elements between 30 and 300 ppm, a boron content ranging between 1 and 10 ppm, and a phosphorus/boron ratio ranging between 0.5 and 1.5. 11. Silicon according to claim 10, characterised in that its iron content is between 10 and 40 ppm. 12. Silicon according to claim 10, characterised in that the total content of impurities is between 100 and 300 ppm, with a content of metallic impurities between 30 and 200 ppm. 13. Silicon according to claim 10, characterised in that the boron content is between 1 and 3 ppm. 14. Process according to claim 2, characterised in that, in the first step of carbothermal reduction of silica, the power density used expressed as the (Pe/Do3)/3 ratio is between 2 and 3 MW/m3, and that the weighted average specific area S of the reduction agents used is between 20 and 40 m2/g. 15. Process according to claim 2, characterised in that the first segregated solidification is carried out at a solidification front advance velocity below 2×10−5 m/s. 16. Process according to claim 3, characterised in that the first segregated solidification is carried out at a solidification front advance velocity below 2×10−5 m/s. 17. Process according to claim 8, characterised in that electric furnace crucibles used for silicon remelting operations are made of silica, carbon, graphite, or silicon carbide. 18. Silicon according to claim 11, characterised in that the total content of impurities is between 100 and 300 ppm, with a content of metallic impurities between 30 and 200 ppm. 19. Silicon according to claim 11, characterised in that the boron content is between 1 and 3 ppm. 20. Silicon according to claim 12, characterised in that the boron content is between 1 and 3 ppm. |
<SOH> FIELD OF THE INVENTION <EOH>The invention relates to a medium-purity metallurgical silicon that will be used as a raw material for making electronic quality or photovoltaic quality silicon. The invention also relates to the process for making this material. |
Computerized portable handheld means |
The invention relates to a computerized portable handheld means (10) with a screen (16) for the display of objects (19) to be manipulated, and a method therefore. It has two type of means for manipulation; one for a hand holding it, and one when it is placed on another surface. A tactile providing means provides a tactile feedback to a hand holding a pointing means (20) when manipulating an object (19). It thus provides an enhanced browsing through available objects (19) by the use of at least the two human senses seeing and feeling. |
1. A computerized portable handheld means (10) with a screen (16) displaying images of objects (19) to be manipulated, whereby a manipulation of objects connects a link to a sub-object or function to be performed, comprising: a first manipulating means for said objects, controlling the manipulation of said objects by movement of a hand holding said manipulating means; a second manipulating means for said objects, controlling the manipulation of said objects by a pointing device (20) when it is placed on another surface than a hand; and a means for providing tactile feedback to said hand for every successful possible manipulation of said objects, thereby providing a push-button free manipulation of objects and a feeling for the manipulation, thus enhancing the speed of manipulation by involving at least the two senses of seeing and feeling, and providing at least two functions of manipulating objects (19) on a screen in accordance with said first and second means. 2. A handheld means according to claim 1, wherein it is provided with a gyro, whereby the degree of tilting it, constitutes an input signal to said first and second manipulating means which controls the degree of manipulation of objects (19). 3. A handheld means according to claim 1, wherein a zero base for a manipulation is provided by an agreement action provided by a bearer of it, no matter in what direction or angle it is held when said action is provided. 4. A handheld means according to claim 2, wherein a tilting of it in a vertical plane to its length axis determines the degree of manipulation of an object, and where a rotation of it around its axis determines an approval of the manipulation. 5. A handheld means according to claim 1, wherein a position detecting means for a 3-D determination of said pointer device (20) stylus position in space is an ultrasonic receiver/transmitter means (14). 6. A handheld means according to claim 1, wherein a position detecting means for a 3-D determination of said pointer device stylus position in space is a miniaturized camera means. 7. A handheld means according to claim 1, wherein a 3-D image provides a skin layer with menus. 8. A handheld means according to claim 7, wherein said first and second manipulating means is locked to a skin layer when having provided a tactile feedback, whereby said manipulating means is used for browsing on the skin layer surface, thus preventing slipping to an adjacent skin layer. 9. A handheld means according to claim 1, whereby it is a cellular phone. 10. A handheld means according to claim 1, whereby it is a palm-top-computer or the like. 11. A handheld means according to claim 1, wherein said screen is of an auto-stereoscopic type. 12. A method for a computerized portable handheld means (10) with a screen (16) displaying images of objects (19) to be manipulated, whereby a manipulation of objects connects a link to a sub-object or function to be performed, comprising the steps of: providing a first manipulating means for said objects, controlling the manipulation of said objects by movement of a hand holding said manipulating means; providing a second manipulating means for said objects, controlling the manipulation of said objects by a pointing device (20) when it is placed on another surface than a hand; and providing a means for tactile feedback to said hand for every successful possible manipulation of said objects, thereby providing a push-button free manipulation of objects and a feeling for the manipulation, thus enhancing the speed of manipulation by involving at least the two senses of seeing and feeling, and providing at least two functions of manipulating objects on a screen in accordance with said first and second means. 13. A method according to claim 12, wherein it is provided with a gyro, whereby the degree of tilting it, constitutes an input signal to said first and second manipulating means which controls the degree of manipulation of objects. 14. A method according to claim 12, wherein a zero base for a manipulation is provided by an agreement action provided by a bearer of it, no matter in what direction or angle it is held when said action is provided. 15. A method according to claim 13, wherein a tilting of the handheld means in a vertical plane to its length axis determines the degree of manipulation of an object, and where a rotation of it around its axis determines an approval of the manipulation. 16. A method according to claim 12, wherein a position detecting means for a 3-D determination of said pointer device (20) stylus position in space is an ultrasonic receiver/transmitter means (14). 17. A method according to claim 12, wherein a position detecting means for a 3-D determination of said pointer device (20) stylus position in space is a miniaturized camera means. 18. A method according to claim 12, wherein a 3-D image provides a skin layer with menus. 19. A method according to claim 18, wherein said first and second manipulating means is locked to a skin layer when having provided a tactile feedback, whereby said manipulating means is used for browsing on the skin layer surface, thus preventing slipping to an adjacent skin layer. 20. A method according to claim 12, whereby the handheld means is a cellular phone. 21. A method according to claim 12, whereby the handheld means is a palm-top-computer or the like. 22. A method according to claim 12, wherein said screen is of an autostereoscopic type. |
<SOH> BACKGROUND ART <EOH>Portable handheld computerized devices, such as palm-top-computers, PDA (Personal Digital Assistance) and cellular phones, have a drawback in displaying objects due to their relatively small screen for display. This means that a user of such a device has to push or activate a lot of buttons in order to browse through, for example, all available menus that allow a handheld device to be user-friendly. A browsing through such menus is thus very time consuming, and the possibility to rapidly display a multiple choice of menus is highly restricted. Another drawback with current portable handheld devices relates to tactile feed-back when manipulating widgets on a screen, for example, it is not practically accomplished to tilt such a device when it is placed on a surface other than a palm of a human being in order to manipulate a widget on a screen. Hence there is a need for at least two procedures when manipulating a widget; one for the device when held in a palm, and one for it when it lies down on another surface. Further, it should be appreciated that a selection of, for example, a menu could be verified so that a user of a handheld computerized device is provided an indication of a selection. Patent document US-A-5 657 054 by Files et al discloses the determination of a pen location on a two-dimensional display apparatus, for example a computer screen, through piezoelectric point elements. The patent document US-A-5 500 492 by Kobayashi et al discloses a coordinate input apparatus for detecting an input vibration from a vibration pen. Coordinates are determined only in two dimensions. In the U.S. patent document US-A-5 818 424 by Korth a rod-shaped device for spatial data acquisition is described. The position of the device in three-dimensions is determined through an optical system. The patent document US-A-4 246 439 by Romein describes an acoustic writing combination including a stylus with an associated writing tablet. The stylus is provided with an ultrasonic sound source emitting pulse signals which are picked up by at least two microphones arranged on the writing table to determine the position of the stylus in two dimensions. Embodiments of the present invention with its advantages are described through the attached independent claims. Further embodiments and advantages are described through the attached dependent sub-claims. |
<SOH> SUMMARY OF THE DISCLOSED INVENTION <EOH>It is a subject of the present invention to provide a computerized portable handheld means with a stereoscopic screen for 2-D and/or 3-D browsing and manipulation with two manipulating means; one used when holding the means in a palm such as during walking, and one for placing it on another surface, such as a table. In order to achieve aims and subjects of the present invention it sets forth a computerized portable handheld means with a screen displaying images of objects to be manipulated, whereby a manipulation of objects connects a link to a sub-object or function to be performed, comprising: a first manipulating means for said objects, controlling the manipulation of said objects by movement of a hand holding said manipulating means; a second manipulating means for said objects, controlling the manipulation of said objects by a pointing device when it is placed on another surface than a hand; and a means for providing tactile feedback to said hand for every successful possible manipulation of said object, thereby providing a push-button free manipulation of objects and a feeling for the manipulation, thus enhancing the speed of manipulation by involving at least the two senses of seeing and feeling, and providing at least two functions of manipulating objects on a screen in accordance with said first and second means. In one embodiment of the present invention it is provided with a gyro, whereby the degree of tilting it constitutes an input signal to said first and second manipulating means which controls the degree of manipulation of objects. Another embodiment comprises that a zero base for the manipulation is provided by an agreement action provided by a bearer of it, no matter in what direction or angle it is held when said action is provided. A tilting of the portable handheld means in a vertical plane to its length axis determines the degree of manipulation of an object in one embodiment, and where a rotation of it around its axis determines an approval of the manipulation. In another embodiment of the invention a position detecting means for a 3-D determination of said pointer device stylus position in space is an ultrasonic receiver/transmitter means. In a further embodiment the position detecting means is a miniaturized camera means. Further in one embodiment a 3-D image provides a skin layer with menus. The manipulating means is locked to a skin layer when having provided a tactile feedback, whereby the manipulating means is used for browsing on the skin layer surface, thus preventing slipping to an adjacent skin layer. A still further embodiment of the present invention comprises that it is a cellular phone. Yet another embodiment provides that it is a palm-top-computer or the like. A further embodiment sets forth that the screen is of an auto-stereoscopic type. The present invention also sets forth a method for a computerized portable handheld means with a screen displaying images of objects to be manipulated, whereby a manipulation of objects connects a link to a sub-object or function to be performed, comprising the steps of: providing a first manipulating means for said objects, controlling the manipulation of said objects by movement of a hand holding said manipulating means; providing a second manipulating means for said objects, controlling the manipulation of said objects by a pointing device when it is placed on another surface than a hand; and providing a means for tactile feedback to said hand for every successful possible manipulation of said object, thereby providing a push-button free manipulation of objects and a feeling for the manipulation, thus enhancing the speed of manipulation by involving at least the two senses of seeing and feeling, and providing at least two functions of manipulating objects on a screen in accordance with said first and second means. The method of the present invention is able to perform embodiments relating to the embodiments of the handheld portable means, especially in accordance with the attached set of method sub-claims. |
Treatment of nail infections with no |
Nitrogen oxide generating compositions are useful in the treatment of subungual infections, as NO has surprisingly been found to be able to penetrate the nail to exert an anti-fungal effect. |
1. A method for the treatment or prophylaxis of a subungual infection, the method comprising: generating nitrogen oxide by combining a nitrite and an organic acid, wherein the nitrite and the organic acid are separately disposed from each other prior to being combined, and combining the nitrite and the organic acid forms a composition. 2. The method according to claim 1, wherein the organic acid is present in sufficient quantity that the composition formed by combining the nitrite and the organic acid is at a pH of 5.5, or below. 3. The method according to claim 1, wherein the organic acid is selected from: formic acid, malic acid, maleic acid, acetic acid, lactic acid, citric acid, benzoic acid, tartaric acid and salicylic acid, ascorbic acid, ascorbyl palmitate, and mixtures thereof. 4. The method according to any preceding claim 1, wherein the nitrite is selected from the alkali metal nitrites and the alkaline earth metal nitrites. 5. The method according to claim 4, wherein the nitrite is selected from: sodium, potassium, magnesium and barium nitrites. 6. The method according to claim 1, wherein the organic acid comprises citric acid and the nitrite comprises sodium nitrite, at least one being present in an aqueous vehicle. 7. The method according to claim 1, wherein the subungual infection is onychomycosis. 8. The method according to claim 1, wherein the nitrite is formulated with an excipient selected from: Eudragits, carbopol, carboxymethylcellulose, hydroxymethylcellulose, and mixtures thereof. 9. The method according to claim 1, wherein the organic acid is formulated with an excipient selected from: carbopol, carboxymethylcellulose, hydroxymethylcellulose, methylcellulose, and mixtures thereof. 10. The method according to claim 1, wherein the organic acid and the nitrite are separately disposed in aqueous based formulations prior to being combined. 11. The method according to claim 10, wherein each preparation is in a form separately selected from gels, creams, lotions, ointments and paints suitable for mixing each with the other. 12. The method according to claim 1, wherein the organic acid and the nitrite are each separately formulated as a gel, paint or lacquer prior to being combined. 13. The method according to claim 1, wherein, prior to being combined, the organic acid and the nitrite are each separately formulated as a liquid or gel which, when mixed, solidify or form a gel or paint. 14. The method according to claim 1, wherein the nitrite is approximately 0.5 to 30%, by weight, of the composition formed by combining the nitrite and the organic acid. 15. The method according to claim 14, wherein the nitrite is 5 to 15%, by weight, of the composition formed by combining the nitrite and the organic acid. 16. The method according to claim 1, wherein the organic acid is approximately 5 to 30%, by weight, of the composition formed by combining the nitrite and the organic acid. 17. The method according to claim 16, wherein the organic acid is approximately 10 to 15%, by weight, of the composition formed by combining the nitrite and the organic acid. 18. (Cancelled). 19. The method according to claim 1, wherein the composition formed by combining the nitrite and the organic acid is applied to an infected nail in an effective amount. 20. A kit comprising: a nitrite; and an organic acid kept separate from the nitrite, wherein the kit is configured so that the nitrite and the organic acid can be combined to generate nitrogen oxide, and the nitrogen oxide can be used for the treatment or prophylaxis of a subungual infection. 21. A kit according to claim 20, comprising an aqueous preparation of the nitrite and an aqueous preparation of the organic acid, separately disposed one from each other, the two preparations each being suitable to apply to a nail to be treated such that the nitrite and acid can react to release nitrogen oxides for penetration into the nail. 22. A kit according to claim 21, wherein each preparation is in a form selected from lotions, gels, creams and lacquers. 23. A kit according to claim 21, wherein the preparations are provided in resealable containers. |
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