The present invention relates to a carbonic acid ester compound of the following formula (1):

The present invention relates to a new compound which can be used as an amino-protecting group, a process for preparing the same, and a process for synthesizing peptides using the same. More specifically, the present invention relates to a carbonic acid ester compound of the following formula (1):
in which
X represents para-nitrophenyloxy, imidazolyl, Cl, or Br,
Y represents S or SO2, and
Ar represents aryl group containing fluorine(s), which can be easily combined with the amino group of amino acids (capping or protection; xe2x80x98cappingxe2x80x99 below) or removed therefrom (decapping or deprotection; xe2x80x98decappingxe2x80x99 below) under mild conditions, whereby the amino group can be effectively protected during peptide synthesis, a process for preparing the same, and a use of the same. Since the amino acid derivatives thus protected have high thermal and chemical stabilities and good solubility for organic solvents, peptides can be synthesized at a low cost with a high yield.
Typically known functional groups used for protecting the amino group of amino acids when preparing peptide compounds include tert-butoxycarbonyl (tBoc), 9-fluoroenylmethoxycarbonyl (Fmoc), 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc), etc.
Among them, tBoc has a fatal demerit that it cannot be used for the amino acids having functional groups sensitive to acid because it should be removed by an acid.
Fmoc can be easily decapped from the amino group under weak basic conditions, which makes the peptide synthesis possible under much milder conditions than tBoc. However, Fmoc also has some fatal demerits. First, the amino acid derivatives protected by Fmoc have low thermal and chemical stabilities, which are particularly lowered in the case of amino acids containing aromatic groups. Therefore, in order to increase the yield of peptide synthesis from the aromatic amino acid derivatives protected by Fmoc group, short reaction time and excess amount of amino acid should be applied. Second, when it is used as a protecting group of amino acids containing a heterocycle, the low solubility of the amino acids in organic solvents may not be improved to a satisfactory level. Third, differently from tBoc, methyl or ethyl ester of amino acid cannot be used as a starting material, and t-butyl ester or carboxylic acid should be used as a starting material. Particularly, since decarboxylation may easily occur in the case of heterocycle compounds, carboxylic acid cannot be used, and t-butyl ester should be used. Since this t-butyl group should be removed under strong acidic conditions, however, it is practically impossible to use the protecting group of Fmoc for the heterocycle-containing amino acids. Fourth, the base piperidine used in the decapping step of Fmoc has weak reactivity with the resulting dibenzofulvene (DBF), and so has a limit in reducing side reactions by DBF by removing side products through a reaction.
On the other hand, since Nsc is more stable than Fmoc, it is useful for peptide synthesis. However, Nsc also has the disadvantage that it is inappropriate for the synthesis on a solid phase due to the low solubility in organic solvents depending on the kind of protected compounds.
Thus, the present inventors have extensively studied to provide a process for effectively synthesizing peptides, and so have identified that the new compound of formula (1) as defined above meets the inventor""s requirements as an amino-protecting group. This new compound has the features that it has the advantage of Fmoc or Nsc, synthesis of peptides under weak basic conditions, and at the same time it cures the disadvantages thereof as illustrated above. That is, the amino acid derivatives protected by the amino-protecting group provided by the present invention have high thermal and chemical stabilities and good solubility for organic solvents; the cheap methyl or ethyl ester of amino acid can be used as a starting material in the peptide synthesis; and any side reaction by the products formed in the reaction for removing the protecting group does not occur.
Therefore, the object of the present invention is to provide the compound of formula (1) used as an amino-protecting group.
It is another object of the present invention to provide a process for preparing the compound of formula (1).
It is also another object of the present invention to provide a process for synthesizing peptides using the compound of formula (1) as a protecting group.
It is also another object of the present invention to provide an amino acid derivative protected by the compound of formula (1).
First, the present invention relates to a new carbonic acid ester compound of the following formula (1):
in which
X represents para-nitrophenyloxy, imidazolyl, Cl, or Br,
Y represents S or SO2, and
Ar represents aryl group containing fluorine(s).
In the compound of formula (1), the substituent Ar defined as aryl group containing fluorine(s) preferably represents a radical selected from the following group:
The carbonic acid ester compound of formula (1) according to the present invention, {circle around (1)} enables peptide synthesis under strong basic conditions, {circle around (2)} produces amino acid derivatives protected thereby, which have high thermal and chemical stabilities and good solubility for organic solvents, {circle around (3)} enables use of the cheap methyl or ethyl ester of amino acid as a starting material in the peptide synthesis, {circle around (4)} makes it easy to convert the peptides to unstable derivatives under basic conditions for easy decapping of the protecting group, and {circle around (5)} does not cause any side reaction by the products formed in the decapping reaction.
The carbonic acid ester compound of formula (1) according to the present invention can be prepared by a process characterized in that a fluorinated derivative of aryl halide of the following formula (2):
Arxe2x80x94Lxe2x80x83xe2x80x83(2)
in which Ar is defined as above and L represents a leaving group, preferably halogen, is reacted with mercaptoethanol to give a fluorinated derivative of 2-(arylsulfanyl)-ethanol of the following formula (3):
in which Ar is defined as above; and the resulting fluorinated derivative of 2-(arylsulfanyl)-ethanol of formula (3) is reacted with a compound of the following formula (4):
in which X is defined as above and Lxe2x80x2 represents a leaving group, preferably halogen, in order to introduce the para-nitrophenyloxy, imidazolyl, Cl, or Br group. Therefore, the present invention also relates to the above process for preparing the compound of formula (1).
Specifically, the fluorinated derivative of aryl chloride of formula (2) is dissolved in an organic solvent, mercaptoethanol is added thereto, and the mixture is reacted for 10xcx9c30 hours at 20xcx9c160xc2x0 C. to give the fluorinated derivative 2-(arylsulfanyl)-ethanol of formula (3) (Step 1). Then, the compound of formula (3) thus obtained is dissolved in an organic solvent, the compound of formula (4) is added thereto, and the mixture is reacted for 1xcx9c5 hours at 0xcx9c100xc2x0 C. to give the novel compound of formula (1) of the present invention (Step 2). For example, the reaction wherein 4-nitrophenyl chloroformate is used as the compound of formula (4) may be depicted as the following Reaction Scheme 1:
The present invention also provides a compound of the following formula (5),
in which Ar and Y are defined as above, and R represents an amino acid except for the amino group combined with the xcex1-carbon atom, which is an amino acid derivative of which amino group is protected by the carbonic acid ester compound of formula (1).
As stated in the following explanation on the capping step, the above compound of formula (5) is formed in the step of preparing a carbamate derivative of amino acid by reacting the compound of formula (1) according to the present invention with the amino group of an amino acid. When Y is S, the compound of formula (5) wherein Y is SO2 may be obtained by additional oxidation reaction using a suitable oxidant.
The present invention also relates to a process for synthesizing peptides using the compound of formula (1) as an amino-protecting group. That is, the present invention relates to a process for synthesizing peptides comprising
(A) the step of capping wherein the amino group of an amino acid is protected by the carbonic acid ester compound of formula (1) according to the present invention;
(B) the step of carboxylic acid formation wherein the amino acid derivative of which amino group is protected is hydrolyzed in case it is in the form of an ester;
(C) the step of peptide formation wherein carboxyl group of the amino acid derivative in the form of a carboxylic acid is coupled with amino group of another amino acid;
(D) the optional step of oxidation wherein S group at the position of Y in the capping moiety is oxidized to SO2 group in case the position of Y in the capping moiety is S group; and
(E) the step of decapping wherein the carbonic acid ester moiety is removed under basic conditions from the compound formed through the peptide formation step.
However, the oxidation step (D) may be positioned anywhere between the capping step (A) and the decapping step (E), and further the oxidation step (D) may be carried out simultaneously with the decapping step (E).
The peptide synthesizing process according to the present invention may be roughly divided into capping step, peptide formation step, and decapping step, which will be more specifically explained step by step below.
(1) Capping Step: Formation of Ttc Group
This step provides a carbamate derivative of an amino acid wherein the amino group is protected by the compound of formula (1).
In this capping step, the carbonic acid ester compound of formula (1) according to the present invention is reacted with an amino acid of formula (6) to give a carbamate derivative of an amino acid as represented by the above formula (5). This step may be more specifically depicted as Reaction Scheme 2 below:
in which R1 and R2 each represent a substituent such as hydrogen, alkyl, aryl, or heterocycle which can be included in amino acids.
The capping group exemplified in the above Reaction Scheme 2 is 2-(4-trifluoromethylphenylthio)ethoxycarbonyl (xe2x80x98Ttcxe2x80x99 below) which is stable against a base.
(2) Carboxylic Acid Formation Step
When the right side terminal of the above compound of formula (5), a carbamate derivative of capped amino acid, is not carboxylic acid, that is, when R2 group is not hydrogen, the terminal is converted to carboxylic acid using a base. This step may be depicted, for example, as the following Reaction Scheme 3. In the following Reaction Scheme 3, the capping group is Ttc.
(3) Peptide Formation Step
Then, the carboxylic acid at the right terminal of the compound of formula (5) is reacted with an amino group of another amino acid to form a peptide bond and to give an amino acid dimer derivative such as the compound of the following formula (7).
in which
Ar and R1 are each defined as above, and
R1xe2x80x2 represents a substituent such as hydrogen, alkyl, aryl, or heterocycle which can be included in amino acids.
As the agent that can be used in the peptide bond formation of the above compound of formula (7), tetramethylfluoroformamidinium hexafluorophosphate(TFFH), bromo-tris-pyrrolidino-phosphonium-hexafluorophosphate(PyBroP), etc. may be mentioned, but not restricted thereto.
The above explained two steps (carboxylic acid formation step+peptide formation step) are repeated until the desired amino acid polymer (peptide) is obtained and finally the right terminal of the peptide derivative is converted to carboxylic acid.
(4) Oxidation Step: Formation of Tsc Group
At any time after the capping step, in case Y is S in the compound of formula (5), it can be oxidized to SO2 in order to increase the sensitivity of the cap (carbonic acid ester compound) to the base. That is, as depicted in the following Reaction Scheme 4, the S moiety of the Ttc group is oxidized to SO2 moiety.
Specifically, the starting compound containing a thio group (xe2x80x94Sxe2x80x94) is treated by hydrogen peroxide or a mixture of hydrogen peroxide and other oxidant in an organic solvent at a temperature ranging from xe2x88x9210xcx9c100xc2x0 C. to give an oxidized product containing a sulfonyl group (xe2x80x94SO2xe2x80x94). The oxidized product as exemplified in the above Reaction Scheme 4 is a compound containing 2-(4-trifluoromethyl-benzenesulfonyl)ethoxycarbonyl (xe2x80x98Tscxe2x80x99 below) group, of which carbamate bond becomes very weak against a base.
The oxidation step can be performed at any time after the capping step, and if necessary, carried out simultaneously with the following decapping step.
(5) Decapping Step
To the compound obtained from the above explained oxidation step is added a secondary base such as piperidine, or a tertiary or aromatic base in an organic solvent in order to decompose the carbamate bond and to give a peptide of the following formula (8) in the decapping step:
in which R1 and R1xe2x80x2 are each defined as above.
That is, in this step, the peptide compound synthesized through the peptide formation step is hydrolyzed under basic conditions as the case of Nsc, Fmoc, etc. to remove the carbonic acid ester moiety. For example, the Tsc group can be removed via xcex2-hydrogen elimination reaction with 20%(v/v) piperidine in DMF solvent.
For reference, after the protecting group Tsc is decapped by piperidine, the resulting products are analyzed by NMR. As a result, as depicted in the following Reaction Scheme 5, only the compound of formula (10) is detected as the decapping product, and the compound of formula (9), a side product of the xcex2-hydrogen elimination reaction, is not.
Therefore, since such compounds that may cause side reactions in the decapping step as the compound of formula (9) are not produced in the process according to the present invention, the desired peptide can be more effectively obtained than in the previous process using the Fmoc group.
The present invention will be more specifically explained in the following examples. However, it should be understood that the following examples are intended to illustrate the present invention but not to limit the scope of the present invention in any manner. Further, a person skilled in the art may easily modify the reactants and reaction conditions in the following examples within a reasonable range, and such modifications also fall within the technical scope of the present invention.
Usually, there is a problem of solubility decrease of the reactants (intermediates) to the solvent in the artificial synthesis of peptides. Therefore, in order to confirm that there is no problem caused by the solubility decrease of the reactants (intermediates) in the process of the present invention, amino acids having such N-containing heterocycles as pyrrole or imidazole, that is, those having low solubility, are particularly selected and used as the reactants in the following examples.
The full names of the abbreviations used in the following examples are as follows:
EA: ethyl acetate
DMF: dimethylformamide
DCM: dichloromethane
DIEA: diisopropylethylamine
HOBt: 1-hydroxybenzotriazole
THF: tetrahydrofuran
TFFH: tetramethylfluoroformamidinium hexafluorophosphate
DMAP: 4-(N,N-dimethylamino)pyridine
PyBroP: bromo-tris-pyrrolidino-phosphonium-hexafluorophosphate

Compound used as an amino-protecting group, process for preparing the same, and synthetic method of a peptide using the same

Abstract: in which X, Y, and Ar are defined in the specification, which can be easily combined with the amino group of an amino acid or removed therefrom under mild conditions, whereby the amino group can be effectively protected during peptide syntheses, process for preparing the same, and use of the same. Since the amino acid derivatives thus protected have high thermal and chemical stabilities and good solubility for organic solvents, peptides can be synthesized at a low cost with a high yield.


A system for on-site collection of evaluation data at a vehicle repair site installation is disclosed. Generally the system includes a mobile computing tool wirelessly connected to a database, a workflow operations guiding module that runs on the mobile computing tool, an evaluation module, a comparison module, a data-mining module, a certification module, a legal compliance module, and a repair procedure compliance module. As a vehicle is repaired, the workflow operations guiding module prompts a coach with questions. The evaluation module performs a quantitative analysis of the answers provided by the coach and the comparison module compares the result of the quantitative analysis against aggregated or averaged information. The certification module compares information from the comparison module against predetermined certification criteria and the data mining module identifies correlations, trends or patterns in collected data by the system.

Modern automotive maintenance and repair processes require the intensive use of information. As automobile models and the technology they use change from year to year, repair facilities need to constantly acquire and manage new data and knowledge on the appropriate technologies, procedures, and equipment used in repair and maintenance processes. This challenge is compounded by parallel changes in the tools and techniques used for the automobile industry. Many components of the automotive repair industry face these challenges, from collision repair, to inspection procedures, to mechanical repair.
One category of challenges involves the coaching of technical personnel performing the maintenance, inspection, and repairs of automobiles. As procedures change and as new personnel enter the industry or expand the scope of the work they perform, managers need to reliably review and improve the skills of their technical personnel and ensure that a high level of competence is maintained among the technical professionals in the industry.

Data management systems for collision repair coaching


A file directory structure and retrieval system for use in a computer that operates according to an operating system program and an application program. The memory of the computer stores files in a directory structure. A document locator module maps the directory structure of the files stored in the memory to a real world hierarchical file structure of files and directories. The mapping is independent of conventions of the operating system. The document locator module can create, move and delete files and directories without exiting the application program. An open module operates in the background of the application program and intercepts control of the processor when a command is executed to cause a file to be opened. The open module displays on the output device an open card to allow entry of information relating to the contents of the file and location of the file in the real world hierarchical file structure of the file. It causes the file to be opened. A save module operates in the background of the application program and intercepts control of the processor when a command is executed to cause the application program to request information about a file to be saved. The save module displays on the output device a save card to allow entry of information relating to the file. It also causes the file to be saved.

Computer systems generally comprise physical devices including a processing unit, a memory device, a monitor and input-output devices such as a keyboard and a mouse. Computer systems are utilized by users to perform specific tasks or to solve specific problems. Typically, the computer system is programmed to perform these tasks or solve these problems. Such a program is referred to as an application program. Examples of common application programs include word processing programs, data base programs, spread sheet programs, and graphics programs. Application programs, as well as carrying out the programmed function of the application, also provide the user with an interface to enable the user of the application program to communicate with the program. The interface of an application program allows a user to give commands to execute the program's instructions (for example, to underline a word or plot a graph) and to interact with the computer system's operating system (for example, to retrieve a file from memory).
Thus, application programs run in conjunction with the computer system's operating system. The operating system is a program to control the operation of the computer's physical devices. For example, the operating system determines where in memory a piece of information is to be stored, coordinates the sending of information to a printer to be printed, and commences the operation of an application program. Operating systems also provide the user with an interface to communicate with the operating system. Commonly, the operating system's interface is a command line on the computer's monitor where the user can enter an instruction from the operating system's instruction set.
The instruction set usually contains simple instructions to manipulate memory, control peripheral devices and run applications programs. For example, operating systems often have instructions that allow the user to do such things as display the contents of a memory device on a computer screen, delete items of information from a memory device, place items of information in a memory device, organize the information stored in a memory device into simple structures such as hierarchical directories, run application programs and have information printed. A common operating system for personal computers is the MS-DOS operating system (Microsoft Disk Operating System).
Users often find such operating systems difficult to use. The types of commands available are few and unsophisticated. Commands are often abbreviated words, making it difficult for users to remember what a command does and when to use it. Additionally, the user has limited methods to store and structure the user's information in the memory device and limited ways of identifying (or naming) such information. The methods used to store the information are often not user friendly and the data structures in which the information is stored are difficult to manipulate.
The user's information, stored in a memory device, such as a hard disk drive, is often represented by less than meaningful names identifying that information. For example, in the MS-DOS operating system a user's information is stored as a file of information, and that file is identified by a string of up to eight characters followed by a period followed by three characters representing the type of information stored. A typical file identifier in the MS-DOS operating system would thus be "Leonlet.doc", where the first part of the file name is an identifier selected by the user and the second part of the file name identifies the type of file and is generally determined by the operating system or application program. In the example above, the second part of the file name identifies the file as a word processing document.
When using such cryptic file identifiers, many users find it difficult to remember in which file a particular piece of information is stored. The file identifier gives little information to the user about the kind of information stored in the file. Further, the `dot convention` used in identifying MS-DOS operating system files is unfamiliar to most users, who do not understand what each suffix in the file identifier means. Others operating systems have equally cryptic file naming conventions. It should be noted that application programs are named and stored by the operating system using the same conventions. The file name for the Wordperfect brand word processor application program, for example, is "WP.EXE". This file stores the code for the Wordperfect application program. Additionally, the file name is used as an operating system command to execute that application program.
A further problem user's find when interfacing with an operating system is the way the operating system allows the user to structure stored information. To enable a user to retrieve a file from memory and to provide additional information about the contents of a file (apart from the information given by the file name), operating systems often allow a user to structure the way the files are stored. It is common to provide users with the ability to create directories and subdirectories so that files of information can be grouped in storage with related information.
For example, a user may decide that a directory called "customer" and another directory called "vendors" is desirable. The user can create those directories and then "put" files in those directories. By "putting" a file in a directory, the user is in effect enlarging the filename for the file. For example, the identifier for a file called "address.wrd" stored in the "vendors" directory would be "c: vendors address.wrd." (The "c" at the beginning of the file name specifies in which storage device the file is stored.) If subdirectories are used, the file name is even more complex. Although providing the user with more information about a file (i.e. that the addresses filed stores the addresses of the user's vendors), the notation used is difficult for inexperienced users to understand. When identifying a file, the user must generally give the full name of the file, thus requiring the user to remember in which directory and subdirectory the file is placed. However, when many files have been stored in a memory device, each with such a cryptic name, it is difficult to locate the desired file and to determine the contents of the various files.
Further, users are given no help in determining what directories and subdirectories are needed, in creating the directories structure and in deciding which files should be placed in which subdirectory. Many users, finding the process of creating directories and placing files in directories too complex, do not bother to use the operating system's directory features. Accessing and creating different directories and subdirectories is clumsy, using meaningless commands such as "cd . . .". When a list of files is displayed, all files are displayed at the one level. The hierarchical directory structure is not explicit in such a listing of files. The notation used in the directory structure, moreover, consists of a series of directory names and file identifiers joined by "/" and ":" characters. Such notation does not relate to the user's real world environment.
To overcome the problem that inexperienced users find when communicating with an operating system program, other programs have been written to provide an easier user interface that performs operating systems functions. The most successful of these advanced operating systems is Microsoft's Windows brand program that provides a graphical user interface for the MS-DOS operating system. Windows is a shell program that converts the MS-DOS operating system environment into a graphical environment. Functions such as "save," "copy," "create directory," "run a program," and the like are simplified by giving the user a graphical interface which the user can operate by means of a cursor on the monitor moved by a physical device such as a mouse. The user's commands from the graphical interface are converted into MS-DOS operating system commands by the Windows program. The program is easy to learn and simple to use. The user needs no knowledge of the difficult MS-DOS operating system conventions and commands. A further advantage of the Windows system is that it offers a standard interface that can be used by various application programs. Application programs can be written to take advantage of the Windows program so that the user sees and operates the same Windows graphical interface for each application program used. In that way, the user can use one series of "graphical commands" for both the operating system and all application programs.
For example, the graphical user interface of the Windows program allows a user to access files stored in memory from both an application program or from an operating system screen using the same command. At the top of each screen on the computer's monitor is a menu bar giving groups of possible commands. When the cursor is placed up on the word "file" on the menu bar and the button on the mouse is activated, different file command options such as "open," "new," "save," and "exit" are displayed below the word "file" on the menu bar. By moving the mouse so that cursor is placed on the required command, which is highlighted, the user can activate a button on the mouse to select that command. In this way, the user does not need to learn difficult MS-DOS operating system command abbreviations because all possible commands are displayed in natural language in the menu. In addition, the same operating system functions can be accessed from various application programs using the same method.
However, software utilizing the Windows program or other graphical user interfaces are limited by the underlying operating system. For example, the Windows program operating under the MS-DOS operating system is limited by certain characteristics of the MS-DOS operating system. Even though file manipulation functions such as "new," "open," "close," "save" and "save as" are presented to the user in a graphical way, the file identifiers used in conjunction with these commands are still the dot notation identifiers of the MS-DOS operating system. The Windows program graphical user interface makes it easier for the user to activate file manipulation commands, but the names used to identify the files are still those that are used by the MS-DOS operating system.
For example, when the user selects the "open" command from the Windows program, a box appears on the screen listing a mixture of MS-DOS operating system files and directories in no particular order or structure. The user is able to open one of these files by placing the cursor on the file name and activating a button on the mouse. The directory structure is not graphically displayed on the screen. The listing just shows a mixture of directories and files, not giving any information about the contents of these directories or files apart from that of the cryptic MS-DOS operating system file identifier. Even though the graphical user interface of the Windows program is based on the principal that commands should be based on actions manipulating graphical worldly metaphors rather than entering cryptic commands, the file names and retrieval operations presented to the user do not create an environment molded to match the user's physical world.
The Windows program does not provide an easy to use tool to create a meaningful real world based file storage structure. For example, a user who wishes to save a document in a file is given no help as to how to name the file, is limited as to the format of the file's name, and is not encouraged to place the file in a relevant directory. More troublesome, the user cannot create a directory using the Windows program from an application program, as explained below. Further, properly arranging the secondary memory into a meaningful directory structure using the file manager programs currently provided by operating systems, such as the MS Windows File Manager program, is a lengthy manual process which requires a good operating knowledge of the operating system. This presents a difficult and challenging task for a novice user. Most users will end up working with a disorganized data and file structure.
This situation results in nonefficient management of secondary memory, creating serious difficulties for the user in retrieving and storing files. As more and more files are stored on the computer, secondary memory becomes cluttered with unrecognizable documents and misleading file directories. Extensive (and expensive) disk space will be occupied by files that the user does not know the contents or relevance of, and which may be obsolete, reducing the efficient use of the computer as a file storage device.
When a user is operating the computer from the operating system level, a common requirement is to locate a file of data, open that file and operate upon it using an application program. Interfaces such as those of the MS-DOS operating system and the Windows program do not help users find the required file. All that is provided to the user is a list of almost meaningless file names. The contents of each file is a mystery to the user until the file is opened. Thus, to locate a relevant file, the user must look at a list of meaningless file names, and open each file in conjunction with the respective application program until the right file is located. When many files are involved, this is a time consuming process. No information, apart from the file name, length of the file and date of first creation is presented to the user about a file when examining the contents of a memory device.
A further problem encountered by users is using an operating system's file management techniques from inside an application program. Once the application program is in use, manipulation of the file structure is very difficult. Even sophisticated graphical user interface programs operating in conjunction with application programs do not allow users to create directories and delete groups of files or directories while inside the application program. For example, if a user is using a word processing program and decides to save the document but the directory the user wishes to save the document in has not been created, the user is unable to both create a new directory and save the document without leaving the word processing application program. In addition, if the user wishes to delete a directory and all the files of information stored within that directory, the user must delete each file individually and then leave the application program to delete the directory.
Not all computers, of course, have the same graphical user interface. A user can save a file on a secondary storage device, such as a floppy disk, and move that file ("the exported file") to another computer that does not use the same interface. As yet, no program has allowed users to automatically transfer, along with the exported file, a file containing information about the exported file. When on another computer system, the only information about the exported file transferred to this system is the minimal information supplied by operating system.

File directory structure generator and retrevial tool with document locator module mapping the directory structure of files to a real world hierarchical file structure


The present invention discloses the cloning of a new cDNA, HGFIN, from stimulated bone marrow stromal cells that was retrieved with a probe specific for the neurokinin-1 (NK-1) receptor. The novel gene, HGFIN, encodes a protein receptor that is involved in the regulation of hematopoietic proliferation and differentiation. HGFIN is implicated in the treatment of hyperproliferative disorders, particularly bone and breast cancer, because it acts to suppress the proliferating cells.

Bone Marrow is the major source of both lymphocytes (immune cells) and erythrocytes in the adult. Among the various cells that constitute the bone marrow are primitive hematopoietic pluripotent stem cells and progenitor cells. An important property of stem cells is their ability to both proliferate, which ensures a continuous supply throughout the lifetime of an individual, and differentiate into the mature cells of the peripheral blood system. When necessary, a pluripotent stem cell can begin to differentiate, and after successive divisions become committed, thus losing the capacity for self-renewal, to a particular line of development. All of the circulating blood cells, including erythrocytes, leukocytes or lymphocytes, granulocytes and platelets originate from various progenitor cells that are themselves derived from precursor stem cells.
The morphologically recognizable and functionally capable cells circulating in the blood include erythrocytes (red blood cells), leukocytes (white blood cells including both B and T cells), non B- and T-lymphocytes, phagocytes, neutrophilic, eosinophilic and basophilic granulocytes, and platelets. These mature cells are derived, on demand, from dividing progenitor cells, such as erythroblasts (for erythrocytes), lymphoid precursors, myeloblasts (for phagocytes including monocytes, macrophages and neutrophils), promyelocytes and myelocytes (for the various granulocytes) and megakaryocytes for the platelets. As stated above, these progenitor cells are themselves derived from precursor stem cells.
A complex network of soluble factors as well as inter- and intra-cellular interactions regulate the proliferation and differentiation of a finite pool of hematopoietic stem cells (HSC). Adult bone marrow consists of a finite number of self-renewing HSCs that replenish the immune system throughout life. Proliferation and differentiation of hematopoietic cells are regulated by hormone-like growth and differentiation factors designated as colony-stimulating factors (CSF) (Metcalf (1989) Nature 339:27-30). CSF can be classified into several factors according to the stage of the hematopoietic cells to be stimulated and the surrounding conditions as follows: granulocyte colony-stimulation factor (G-CSF), granulocyte-macrophage colony-stimulation factor (GM-CSF), macrophage colony-stimulation factor (M-CSF), and interleukin 3 (IL-3). Hematopoiesis is also regulated by inter-cellular and intra-cellular interactions that involve several adhesion molecules.
The stromal cells are a major compartment of the bone marrow microenvironment. These cells exert functional plasticity by producing molecules that belong to classes that include cytokines, neurotrophic factors, neuropeptides and extracellular matrix proteins. Stromal cells provide a niche for HSC at a site close to the endosteal region. At this site, the oxygen level is the lowest in the bone marrow and perhaps, HSC could be protected from oxygen radicals, insults from chemical compounds and from other insults.
Small amounts of certain hematopoietic growth factors account for the differentiation of stem cells into a variety of blood cell progenitors, for the tremendous proliferation of those cells, and for their differentiation into mature blood cells. For instance, G-CSF participates greatly in the differentiation and growth of neutrophilic granulocytes and plays an important role in the regulation of blood levels of neutrophils and the activation of mature neutrophils (Nagata (1990) "Handbook of Experimental Pharmacology", volume "Peptide Growth Factors and Their Receptors", eds. Sporn & Roberts, Spring-Verlag, Heidelberg, Vol. 95/1, pp. 699-722; Nicola, et al. (1989) Annu. Rev. Biochem. 58:45-77). It is also reported that G-CSF stimulates the growth of tumor cells such as myeloid leukemia cells (Nicola & Metcalf (1984) Proc. Natl. Acad. Sci. USA 81:3765-3769; Begley et al. (1987) Leukemia 1:1-8). Other growth factors include, erythropoietin (EPO), which is responsible for stimulating the differentiation of erythroblasts into erythrocytes and M-CSF responsible for stimulating the differentiation of myeloblasts and myelocytes into monocytes.
Growth factors are part of a family of chemical messengers known as the cytokines. Cytokines are among the factors that act upon the hematopoietic system to regulate blood cell proliferation and differentiation. Cytokines are also important mediators of the immune response being secreted by both B and T cells, as well as other various lymphocytes. Cytokines encourage cell growth, promote cell activation, direct cellular traffic, act as messengers between cells of the hematopoietic system, and destroy target cells (i.e., cancer cells). Tachykinins are among the various components involved in the modulation and regulation of the hematopoietic system that cytokines play a role in modulating.
The tachykinins are immune and hematopoietic modulators that belong to a family of peptides encoded by a single copy of the evolutionarily conserved preprotachykinin-I (PPT-1) gene (Quinn, et al. (2000) Neuropeptides 34:292-302). PPT-1 is alternatively spliced into four possible transcripts and is ubiquitously expressed. The tachykinins can be released in the bone marrow and other lymphoid organs as neurotransmitters or from the resident bone marrow immune cells (Rameshwar (1997) supra; Ho, et al. (1997) J. Immunol. 159:5654-5660; Maggi (1996) Pharmacol. Res. 33:161-170; 2-6). In the bone marrow, PPT-1 and other hematopoietic growth factors regulate expression of each other through autocrine and paracrine activities. It is believed that various cytokines induce the expression of the PPT-1 gene in bone marrow mesenchymal cells (Rameshwar (1997) supra). The tachykinin family of peptides exerts pleiotropic functions such as neurotransmission and immune/hematopoietic modulation.
PPT-1 peptides exert both stimulatory and inhibitory hematopoietic effects by interacting with different affinities to the G-protein coupled receptors: NK-1, NK-2 and NK-3 (Krause, et al. (1992) J. Invest. Dermatol. 98:2S-7S). NK-1 and NK-2 expression has been reported in bone marrow cells (Rameshwar, et al. (1997) Leuk. Lymphoma 28:1-10), whereas NK-3 has not been detected. NK-1 is induced in bone marrow cells by cytokines and other stimulatory hematopoietic regulators. NK-2 is constitutively expressed in bone marrow cells that are unstimulated or stimulated with suppressive hematopoietic regulators. NK-1 and NK-2 are not co-expressed in bone marrow cells because NK-1 induction by cytokines is correlated with the down regulation of NK-2. NK-1 and NK-2 are co-expressed in breast cancer, however. In bone marrow cells, NK-1 expression requires cell stimulation whereas its expression in neural tissue is constitutive (Rameshwar (1997) supra; Yao, et al. (1999) Mol. Brain. Res. 71:149-158; Abrahams, et al. (1999) J. Neurochem. 73:50-58). It is believed that a particular cytokine discriminates between the expression of NK-1 and NK-2, which directs the type of bone marrow functions: stimulatory vs. inhibitory (Rameshwar, et al. (1997) supra).
PPT-1 is constitutively expressed in several cancers including breast cancer (Singh, et al. (2000) Proc. Natl. Acad. Sci. USA 97:388-393), but its expression requires induction in normal mammary epithelial cells (Rameshwar, et al. (1997) supra; Rameshwar & Gascon (1997) Acta Haematol. 98:59; Qian et al. (2001) J. Immunol. 166:2553). PPT-1 peptides protect cancer cells from radiation damage (Aalto et al. (1998) Peptides 19:231), prevent apoptosis (Reeve et al. (1994) Biochem. Biophy. Res. Comm. 199:1313), enhance breast cancer cell proliferation (Miura, et al. (2000) Blood 96:1733-1739) and could be produced by hypoxia (Fan et al. (1993) Br. J. Pharmacol. 110:43; Qian et al. (2001) J. Immunol. 167:4600). The association between PPT-1 overexpression in cancers that show preference for bone marrow (Gluck (1995) Canadian J. Oncol. 1:58; Malawer & Delaney (1993) In Cancer. Principles and Practice of Oncology. DeVita et al. (eds.) J. B. Lippincott, Philadelphia, p 2225) could provide insights into bone marrow metastasis.
Substance P (SP), the major tachykinin released in the bone marrow, stimulates hematopoiesis through interactions with the neurokinin-1 (NK-1) receptor, which is resident on bone marrow stroma, immune cells and other lymphoid organ cells. Hence, the expression of NK-1 determines the hematopoietic response of the tachykinins. NK-2 inhibits hematopoiesis by interacting with neurokinin-A, another tachykinin encoded for by the PPT-1 gene. The present inventors have discovered that the stimulatory effects mediated by NK-1 can be changed to hematopoietic inhibition in the presence of the amino terminal of SP, a fragment found endogenously in the bone marrow due to enzymatic digestion of SP by endogenous endopeptidases. Further, dysregulated expression of the PPT-1 gene has been associated with different pathologies such as cancer.
Typically, cancer is due to failure of the immune surveillance system in an individual. Even immunocompetent individuals can succumb to aggressive tumors. However, most endocrine cancers (such as cervical, neuroblastoma, breast, prostate), lung and colon cancers have homing preference for the bone marrow, although breast cancer is linked predominantly to bone marrow. Breast cancer metastasis to the bone marrow is a clinical dilemma since the prognosis for the patient is generally poor. Through the functioning presence of different families of growth factors and other molecules, the bone marrow microenvironment is conducive to the survival and transient changes of breast cancer cell function from an aggressive type tumor cell to a more benign-type cell. This reduction in short-term aggression is part of what allow the breast cancer cell to survive and remain undetectable in the bone marrow for prolonged periods.
Despite the emphasis on regular mammograms and self-examination, a breast cancer patient could present with metastasis with cells from the bone marrow to tertiary site for up to ten years after the start of remission. A major reason for breast cancer evasion in the bone marrow is that therapeutic intensity is limited by toxicity to the finite and limited number of hematopoietic stem cells in the bone marrow. It is believed that breast cancer cells are located in the marrow compartment during early phase of cancer and during remission. The cancer cells from the marrow can invade the bone and other distant organs during metastasis. To develop proper drugs to target cancer cells, two areas of cancer entry to the marrow could be targeted: during entry and at "seeding."
Breast cancer cells have shown increased expression of PPT-1 and its receptor NK-1 as compared to normal mammary epithelial cells. Specific NK-1 antagonists have inhibited breast cancer cell proliferation, suggesting autocrine and/or intercrine stimulation of breast cancer cells by PPT-1 peptides. Thus, PPT-1 and NK-1 are thought to be important in breast cancer development. Further, since PPT-1 peptides are considered hematopoietic modulators, the relationship of PPT-1 peptides and NK-1 receptor with breast cancer may assist in understanding the early integration of breast cancer cells in the bone marrow (Rameshwar, et al. (2000) Proc. Natl. Acad. Sci. USA 97: 388-393).
Under normal circumstances, the bone marrow is able to respond quickly to an increased demand for a particular type of cell. The pluripotential stem cell is capable of creating and reconstituting all the cells that circulate in the blood, including both red and white blood cells and platelets. As stated, progenitor cells that derive from stem cells can replicate and differentiate at an astounding, if not alarming rate. On average, 3-10 billion lymphocyte cells can be generated in an hour. The bone marrow can increase this by ten-fold in response to need. However, in the throes of a diseased state, the bone marrow may not produce enough stem cells, may produce too many stem cells or various ones produced may begin to proliferate uncontrollably. Further complications arise when these stem cells or their associated progenitors are not able to differentiate into the various morphologically recognizable and functionally capable cells circulating in the blood.
Lymphoproliferative syndromes consist of types of diseases known as leukemia and malignant lymphoma, which can further be classified as acute and chronic myeloid or lymphocytic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. These diseases are characterized by the uncontrollable multiplication or proliferation of leukocytes (primarily the B-cells) and tissue of the lymphatic system, especially lymphocyte cells produced in the bone marrow and lymph nodes.
Lymphocytes (also called leukocytes) are core components of the body's immune system, which is one of the principal mechanisms by which the body attacks and controls cancers. Lymphocytes, or their derivatives, recognize the foreign antigenic nature of cancer cells or of antibodies associated therewith and attack the cancer cells. Upon exposure to a foreign antigen in the human body, lymphocytes naturally proliferate or multiply to combat the antigen.
B and T cells are two broad sub-types of lymphocyte cells, derived from the bone marrow. T cells undergo a process of maturation in the thymus gland. Mature lymphocytes all have a similar appearance. They are small cells with a deeply basophilic nucleus and scanty cytoplasm. B and T cells circulate in the blood and through body tissues. B cells primarily work by secreting soluble substances called antibodies. Each B cell is programmed to make one specific antibody. When a B cell encounters its triggering antigen, it goes through a process wherein it is changed into many large plasma cells. Hence, B cells give rise to plasma cells, which secrete a specific immunoglobulin (antibodies). T cells also respond to antigens. Some of them (CD4+) secrete lymphokines that act on other cells, thus regulating the complex workings of the immune response. Others (CD8+, cytotoxic) directly contact infected cells and are able to cause lysis thereby destroying the infected cells.
Leukemia and other such B-cell malignancies, such as acute and chronic myeloid and lymphocytic leukemia as well as the B-cell subtype of Hodgkins and non-Hodgkin's lymphoma, are examples of lymphoproliferative syndromes that are significant contributors to cancer mortality. In fact, the majority of chronic lymphocytic leukemias are of B-cell lineage (Freedman (1990) Hematol. Oncol. Clin. North Am. 4:405).
Leukemia can be defined as the uncontrolled proliferation of a clone of abnormal hematopoietic cells. Leukemias are further typically characterized as being myelocytic or lymphocytic. Myeloid leukemias affect the descendents of the myeloid lineage, whereas the lymphocytic leukemias involve abnormalities in the lymphoid lineage. Most B cell leukemias and lymphomas are monoclonal, meaning that all of the related tumor cells are derived from one particular aberrant cell.
Generally, leukemia is a neoplastic disease in which white corpuscle maturation is arrested at a primitive stage of cell development. The disease is characterized by an increased number of leukemic blast cells in the bone marrow and by varying degrees of failure to produce normal hematopoietic cells. The condition may be either acute or chronic. Acute myelocytic leukemia (AML) arises from bone marrow hematopoietic stem cells or their progeny. The term "acute myelocytic leukemia" subsumes several subtypes of leukemia, e.g., myeloblastic leukemia, promyelocytic leukemia and myelomonocytic leukemia and is a form of cancer that affects the cells producing myeloid blood cells in the bone marrow. As stated above, myeloid cells are red blood cells, platelets and all white blood cells (which include: neutrophils, monocytes, macrophages, eosinophils and basophils). Primarily, AML involves abnormal white blood cells of the neutrophil type. Production of blood cells is obstructed and immature cells known as "blast cells" accumulate in the bone marrow. These cells are unable to mature and differentiate properly leading to a significant reduction of normal blood cells in the circulation. The accumulation of blast cells in the bone marrow prevents production of other cell types resulting in anemia and low platelet blood counts. Acute lymphocytic leukemia (ALL) arises in lymphoid tissues and ordinarily first manifests its presence in bone marrow. ALL is primarily a form of cancer that affects the lymphocytes and lymphocyte-producing cells in the bone marrow.
Chronic myelogenous leukemia (CML) is characterized by abnormal proliferation of immature granulocytes, for example, neutrophils, eosinophils and basophils, in the blood, bone marrow, the spleen, liver and sometimes in other tissues. A large portion of chronic myelogenous leukemia patients develop a transformation into a pattern indistinguishable from the acute form of the disease.
This change is known as the "blast crises". Chronic lymphocytic leukemia (CLL) is a form of leukemia in which there is an excess number of mature, but poorly functioning, lymphocytes in the circulating blood. It is to be noted that the rate of production of lymphocytes is not significantly increased and may in fact even be slower than normal. CLL has several phases. In the early phase, it is characterized by the accumulation of small, mature functionally-incompetent malignant B-cells having a lengthened life span. The late stages of CLL are characterized by significant anemia and/or thrombocytopenia.
The two main types of lymphoma are Hodgkin's and non-Hodgkin's lymphoma. Hodgkin's disease is a cancer of the lymphatic system, the network of lymph glands and channels that occurs throughout the body. The defining feature of Hodgkin's disease is the presence of a distinctive abnormal lymphocyte called a Reed-Sternberg cell. There are five. recognized sub-groups of Hodgkin's disease including lymphocyte rich, nodular sclerosing, mixed cellularity, lymphocyte depleted and nodular lymphocyte predominant (which predominantly affects one isolated lymph node). All other types of lymphoma are collectively known as non-Hodgkin's lymphoma. There are thirty sub-types of non-Hodgkin's type lymphoma.
Traditional methods of treating these B-cell malignancies, which include chemotherapy and radiotherapy, have limited utility due to toxic side effects. Short-term side effects of chemotherapy may include significant toxicity, extreme nausea, vomiting, and serious discomfort. The long-term side effects may include diabetes, other forms of B-cell malignancies, other forms of cancer, heart, lung or other organ disease, fatal bleeding during remission induction, and myelodysplasia. The short-term side effects of radiotherapy may include extreme nausea, vomiting, serious discomfort, sterility and infertility. The long-term side effects of radiotherapy may include other forms of B-cell malignancies, cancer, thyroid gland, spleen or other organ failure. These side effects may be moderated by reduced dosages, however, this also increases the risk of remission.
Another traditional method for treating B-cell malignancies includes either bone marrow or stem cell transplantation. However, these procedures are plagued with exorbitant cost and high rates of failure. It is both difficult and costly to locate a sufficient donor and even when one is located, rejection of the transplanted cells often takes place, which in turn can lead to graft versus host disease. Most often, these treatments also include a combination of both chemo and radiotherapies, hence, the concomitant risks involved therein would apply here as well.
There is, therefore, a need for a more non-evasive treatment for lymphoproliferative diseases related to either an increase or decrease in differentiation, as well as uncontrolled proliferation. The present invention meets this need in the art.

Method of reversing carboplatin resistance by inhibition of HGFIN

University of Medicine and Dentistry of New Jersey


Synchronizing mobility messaging includes receiving an Internet Protocol (IP) address at a Dynamic Host Configuration Protocol (DHCP) server. The IP address is sent by a home agent of a mobile client, where the home agent has a mobility binding for the mobile client. A DHCP request requesting an IP address for the mobile client is received from the mobile client. The DHCP server assigns the IP address to the mobile client. A DHCP acknowledgement comprising the assigned IP address is sent to the mobile client.

An endpoint, such as an mobile client, may use a system of communication networks to communicate during communication sessions. In certain situations, the mobile client may not support protocols used by the communication networks. Certain known techniques may be used to accommodate the mobile node. These known techniques, however, are not efficient in certain situations.

Synchronizing DHCP and mobile IP messaging


When a print screen for transmitting a print job to a printing apparatus is displayed, an information processing apparatus transmits a disable command of disabling a power saving mode to the printing apparatus. The printing apparatus receiving the disable command temporarily disables the power saving mode.

1. Field of the Invention
The present invention relates to a data transmission apparatus capable of making wireless communication, a method for controlling the data transmission apparatus, and a storage medium.
2. Description of the Related Art
In recent years, many devices with a wireless local area network (LAN) conforming to the IEEE802.11 standard have been produced. As a technique for reducing power consumption of a wireless communication unit for making wireless communication, there is known a power saving mode of a wireless LAN discussed in Japanese Patent Application Laid-Open No. 2002-300175. The power saving mode will be described with reference to FIGS. 1, 2, and 3.
FIG. 1 illustrates processing performed when the power saving mode is disabled. FIG. 1 illustrates a printing apparatus as an example of a device with a wireless LAN. When the power saving mode is disabled in the printing apparatus, a wireless communication unit of the printing apparatus is always in an Awake state, or in a power-supplied state. When the wireless communication unit is in the Awake state, the printing apparatus can transmit data to an external device or receive data transmitted from an external device by use of wireless communication.
When an access point receives data addressed to the printing apparatus from an information processing apparatus such as a personal computer (PC) (101), the access point transmits the data to the printing apparatus (102). The access point transmits a signal called beacon at constant intervals to a peripheral device, and the data transmission illustrated at 102 of FIG. 1 is performed irrespective of the beacon intervals.
Processing performed when the power saving mode is enabled will be described below with reference to FIG. 2. When the power saving mode is enabled, the wireless communication unit repeats a transition between the Awake state and a Doze state. The Doze state is a state in which power supplying to the wireless communication unit is blocked or reduced, and when the wireless communication unit is in the Doze state, the printing apparatus cannot transmit data to an external device or receive data transmitted from an external device by use of wireless communication.
When the power saving mode is enabled, the wireless communication unit intermittently transitions from the Doze state to the Awake state in synchronization with the beacon intervals of the access point (201 to 203). The access point which receives data (data addressed to the printing apparatus) transmitted from the information processing apparatus uses information such as Traffic Indication Message (TIM) or Delivery Traffic Indication Message (DTIM) to notify, to the printing apparatus, that the data addressed to the printing apparatus is present (204, 205). TIM is directed for notifying, to the printing apparatus, that data addressed to the printing apparatus is present. DTIM is a type of TIM, and indicates that data to be transmitted is for multicast or broadcast.
The printing apparatus which transitions to the Awake state at timing 206 in FIG. 2 receives TIM notified at timing 205. The printing apparatus requests the access point to transmit the data (207). The access point which receives the request at timing 207 transmits data 1 to the printing apparatus (208).
When the power saving mode is enabled, the wireless communication unit transitions from the Awake state to the Doze state under a condition that data is not transmitted nor received between the printing apparatus and the access point in the Awake state for a predetermined time (half the beacon interval, for example). In FIG. 2, when a predetermined time 209 elapses after the printing apparatus receives the data 1, the wireless communication unit transitions from the Awake state to the Doze state (210). After transitioning to the Doze sate, the wireless communication unit intermittently transitions from the Doze state to the Awake state in synchronization with the beacon intervals of the access point similarly as at 201 to 203. The condition that the wireless communication unit transitions from the Awake state to the Doze state is not limited to an elapse of the predetermined time 209. The wireless communication unit may transition from the Awake state to the Doze state under a condition that no accumulation of data addressed to the printing apparatus is confirmed by the beacon.
The power saving mode of the wireless LAN is enabled thereby to reduce power consumption of the wireless communication unit. However, when the power saving mode of the wireless LAN is enabled, a communication delay easily occurs when the printing apparatus receives data (such as print job) transmitted from the access point. The reason why a delay easily occurs will be described with reference to FIG. 3.
When the information processing apparatus transmits a large amount of data (large-size data) to the printing apparatus via the access point, the large amount of data is divided to be transmitted. FIG. 3 illustrates an example in which a large amount of data is divided into data 1, data 2, and data 3 to be transmitted. The access point receives the data 1 transmitted from the information processing apparatus at 301. When the power saving mode is disabled, the access point can immediately start to transmit the data 1 to the printing apparatus, but the power saving mode is enabled, and thus the access point waits until a next beacon timing and then transmits the data 1 to the printing apparatus. That is, a communication delay with time 302 occurs unlike when the power saving mode is disabled.
The wireless communication unit of the printing apparatus which has completely received the data 1 transitions from the Awake state to the Doze state at timing 303 if data is not transmitted nor received for a predetermined time. If a timing when the access point receives the data 2 from the information processing apparatus is later than 303 as illustrated in FIG. 3, the access point waits until a next beacon timing and then transmits the data 2 to the printing apparatus. That is, a communication delay with time 304 occurs also when the access point transmits the data 2 to the printing apparatus. A communication delay with time 305 similarly occurs also when the access point transmits the data 3 to the printing apparatus.
FIG. 3 illustrates the example in which a large amount of data is divided into three items of data, but the number of items of divided data to be actually transmitted is enormous, and thus a communication delay is more conspicuous. As a technique for solving the issue, Japanese Patent Application Laid-Open No. 2009-071385 discusses therein a communication terminal device for disabling a power saving mode of a wireless LAN on receiving streaming data such as moving images or sounds. The communication terminal device discussed in Japanese Patent Application Laid-Open No. 2009-071385 disables the power saving mode of the wireless LAN on receiving streaming data such as moving images or sounds, thereby preventing a communication delay with 304 or 305 of FIG. 3 from occurring.
The communication terminal device discussed in Japanese Patent Application Laid-Open No. 2009-071385 can prevent a communication delay from occurring on receiving streaming data such as moving images or sounds in the power saving mode of the wireless LAN. However, the communication terminal device discussed in Japanese Patent Application Laid-Open No. 2009-071385 needs to be provided with a special structure of determining whether received data is streaming data, and if the data is streaming data, disabling the power saving mode. The communication terminal device discussed in Japanese Patent Application Laid-Open No. 2009-071385 cannot disable the power saving mode if the received data is not streaming data such as moving images or sounds, even if a communication delay easily occurs in the received data.

Data transmission apparatus, method for controlling data transmission apparatus, and storage medium


The disclosed device is a solid state organic semiconductor VCSEL in which the microcavity is composed of metal and dielectric mirrors and the gain layer is only λ/2n thick. The gain layer comprises a thermally evaporated 156.7 nm thick film of the laser dye DCM doped (2.5% v/v) into an Alq3 host matrix. The microcavity consists of 2 mirrors, a dielectric Bragg reflector (DBR) sputter-coated onto a quartz substrate as the mirror through which the organic gain layer is optically excited and laser emission is collected and a silver mirror that is thermally evaporated on top of the Alq3:DCM film. The device exhibits laser action from the DCM both when the DCM molecules are excited directly at 535 nm and via Förster Resonance Energy Transfer (FRET) from the Alq3 (excited at 404 nm) with laser thresholds of 4.9 μJ/cm2 and 14.2 μJ/cm2 respectively.

1. Field of the Invention
The disclosure relates to a method and apparatus for producing super radiant laser in a half wavelength thick organic semiconductor microcavity.
2. Description of Related Art
Microcavity lasers that utilize solid state organic semiconductors as the gain medium hold promise for a wide range of applications, including chemical sensors and single molecule detectors for biological applications. Such devices also serve as a platform for investigating fundamental physical phenomena such as energy transfer and room temperature condensation of excitons, and a test-bed for developing electrically pumped solid state organic lasers. The very large absorption cross sections of organics suggest that these materials may also be useful as part of communications switching elements and compact sources of non-classical light (e.g., quantum optics).
A number of research groups investigated the lasing properties of organic laser dyes in optical microcavities. The laser dyes were dissolved in solutions which were then flowed into the space between two dielectric (sputter-coated) minors. The spacing between the minors was adjusted either through piezoelectric nano-positioners or through metal spacer layers of precision thickness, such that the gain region thickness had a value equal to λ/2n or an integer multiple thereof.
One observation was an anomalously low lasing threshold, which was attributed to XYZ/super-radiance physical effects and even reported "thresholdless" lasing in the device which had λ/2n thick gain region. The lack of a distinct threshold in the input-output power dependence of the λ/2n has been confirmed. They also determined that there was nevertheless a clear threshold associated with the polarization of the emitted light and that above a given pump pulse energy, the polarization of the emitted light followed the polarization of the pump laser.
In the late 1990's, researchers began developing organic-based microcavity lasers using solid state materials. For example, lasing was achieved in a metal dielectric Bragg reflector ("DBR") based microcavity that contained the laser dye molecule 4-dicyanomethylene-2-methyl-6-p-dimethylamino-styryl-4H-pyran ("DCM") as the gain material which was doped into an Alq3 host matrix. The Alq3 host was optically pumped with a 337 nm Nitrogen laser, which in turn excited the DCM molecules via the so-called Forster resonance energy transfer ("FRET"). The gain layer thickness needed to be on the order of 1.5λ/n to provide sufficient gain in order to reach a threshold, which was measured to be 0.3 mJ/cm2. Lasing with the fluorescent conjugated polymer PPV in an all dielectric (2 DBR based) λ/2n microcavity showed 80% polarized emission above a threshold of 15 μJ/cm2. The reduced threshold was attributed to the high quality factor ("Q") of the microcavity (i.e., Q value of about 1200).
More recently, Alq3:DCM gain layer with thickness of about 1.5λ/n was integrated into an all dielectric microcavity and demonstrated lasing with a threshold of 20 μJ/cm2, using a frequency doubled pulsed Ti:Sapphire laser. The reduction in threshold compared to the metal-DBR based microcavity described above can be attributed to the high Q of the all-dielectric microcavity (i.e., Q of about 4500). There remains a need for a microcavity lasing device with Q value which can overcome the optical losses and achieve lasing. There is also a need for a method and apparatus to reduce the Q value.

Method and apparatus for super radiant laser action in half wavelength thick organic semiconductor microcavities


When a central pixel having a red component is generated by interpolation, mixing is performed using red-component pixels lying along the diagonal directions thereof. When a central pixel having a green component is generated by interpolation, mixing is performed using green-component pixels located above, below and to the left and right thereof. When a central pixel having a blue component is generated by interpolation, no mixing processing is executed. A reduction in image size is performed at the same time as pixel interpolation.

FIG. 24a illustrates part of the photoreceptor surface of a solid-state electronic image sensing device 1. The solid-state electronic image sensing device 1 is provided with a number of optoelectronic transducers 2 in the horizontal and vertical directions. Formed on the photoreceptor surfaces of the optoelectronic transducers 2 are color filters R having a characteristic that transmits a light component of the color red, color filters G having a characteristic that transmits a light component of the color green, or color filters B having a characteristic that transmits a light component of the color blue. In FIG. 24a, the color filters R, G or B are formed on the photoreceptor surfaces of the optoelectronic transducers 2 in an array referred to as the "Bayer array". FIG. 24b illustrates the manner in which an image having a period that corresponds to three columns of the optoelectronic transducers 2 of the solid-state electronic image sensing device 1 is formed on the solid-state electronic image sensing device 1. The level of the white-color portions is 255 if expressed by eight bits and the level of the portions indicated by the hatching is 0 if expressed by eight bits. If subsampling processing, which is for reading out signal charge that has accumulated in a (3n+1)th row (where n is a positive integer), is executed in a case where such an image has been formed, high-frequency components repeat and a bright, flat Moiré image is produced, as shown in FIG. 24c.
FIG. 25 illustrates one row of optoelectronic transducers of the solid-state electronic image sensing device 1 shown in FIG. 24a. Signal charge that has accumulated in optoelectronic transducers 2 on which color filters having identical characteristics have been formed are mixed along the horizontal direction.
Since every other color filter has the same characteristic, the resolution of the image after the pixels are mixed declines as if it were passed through a low-pass filter.
Furthermore, if, in a case where an image having a period that corresponds to the columns of the optoelectronic transducers 2 of the solid-state electronic image sensing device 1 is formed on the solid-state electronic image sensing device 1, as shown in FIG. 26a, signal charge is mixed every block of 3×3 pixels of the optoelectronic transducers 2, as shown in FIG. 26b, then the red level within the block will be 255 in terms of eight bits, the green level will be 128 in terms of eight bits, and the blue level will be 0, and an orange color will result (a color Moiré), as depicted in FIG. 26c.
Conventionally, the occurrence of color Moiré is suppressed by placing an optical low-pass filter in front of the photoreceptor surface of the solid-state electronic image sensing device and removing the high-frequency components of the image of the subject. However, there is a decline in resolution.
In order to deal with this, there is a technique (Japanese Patent Application Laid-Open No. 2000-308080) in which the filter array of the solid-state electronic image sensing devices is made a three-color random array that satisfies an array limit condition, namely that any pixel of interest adjoin three colors, which include the color of this pixel of interest, at any of four sides of this pixel of interest. However, it is necessary to optimize synchronization processing for every random pattern. This is troublesome. In addition, this technique is not effective in dealing with false colors ascribable to high-frequency components.
Further, there is also a sensor (Japanese Patent Application Laid-Open No. 2005-136766) having a plurality of filters of different spectral sensitivities, in which first and second filters among these are arranged alternately at a first predetermined period along one diagonal direction of an image grid and alternately at a second predetermined period only the other diagonal direction. However, the precision of pixel reproduction is not high. There is also a technique (U.S. Pat. No. 4,350,706) for applying optimum interpolation also to patterns other than horizontal and vertical edges.
Furthermore, in cases where, owing to subsampling of pixels, the amount of data is reduced and the frame rate raised, pixel interpolation processing is executed after subsampling processing and, hence, processing is inevitably complicated. In addition, false signals are produced as well.

Color imaging apparatus having color imaging element, method of controlling operation of same and image sensing system


Provided is a clutch device configured so that different desired torque values can be set without influence between assist torque and slipper torque. A clutch device 100 includes a center clutch 105 holding clutch plates 104 arranged facing friction plates 103 to be rotatably driven by a drive shaft, and a pressure clutch 111. The center clutch 105 includes center-side assist cam surfaces 106a and center-side slipper cam surfaces 106b. The pressure clutch 111 includes pressure-side assist cam surfaces 112a and pressure-side slipper cam surfaces 112b. A contact surface between the center-side assist cam surface 106a and the pressure-side assist cam surface 112a and a contact surface between the center-side slipper cam surface 106b and the pressure-side slipper cam surface 112b are formed at different positions in a radial direction.

Typically, in a vehicle such as a two-wheel vehicle or a four-wheel vehicle, a clutch device has been used for transmitting rotary drive force of a motor to a drive target body or block such transmission, and is arranged between the motor such as an engine and the drive target body such as a wheel. Generally, in the clutch device, multiple friction plates to be rotated by the rotary drive force of the motor and multiple clutch plates coupled to the drive target body are arranged facing each other, and transmission or blocking of the rotary drive force can be performed as necessary by close contact or separation of the friction plates and the clutch plates.
For example, Patent Literature 1 below discloses a clutch device including cam surfaces for quickly performing transmission or blocking of rotary drive force, and these cam surfaces are provided at opposing surfaces of a clutch member (a center clutch) and a pressure member (a pressure clutch) approaching each other or separating from each other with clutch plates being held. This clutch device is configured such that the clutch member and the pressure member quickly approach each other or separate from each other by assist torque or slipper torque. Such assist torque or slipper torque is generated when a pressure-member-side first cam surface (a pressure-side assist cam surface) and a pressure-member-side second cam surface (a pressure-side slipper cam surface) formed at the pressure member move over a clutch-member-side first cam surface (a center-side assist cam surface) and a clutch-member-side second cam surface (a center-side slipper cam surface) formed at the clutch member.


The invention provides an apparatus and method for positioning solder balls in a desired array on a substrate. A positioning means is provided for positioning the solder balls in positions corresponding to the array of positions the solder balls are to take up on the substrate. A container for receiving a plurality of solder balls and which is movable between a first position remote from the positioning means and a second position directly thereover supplies solder balls to the positioning means. Means are provided to bias the solder balls in the direction of movement of the container from the first to the second position whereby to reduce or obviate damage to the solder balls during such movement.

The present invention relates to an apparatus and method for automatically placing an array of solder balls onto a substrate, such as a ball-grid array (BGA) substrate.
The use of BGA packages as semiconductor integrated circuits is becoming more popular and common. One method of manufacturing BGA packages is to firmly attach solder balls to solder pads (or electrodes) found on a BGA substrate such that electrical conductivity is maintained between electrical connections manufactured on the BGA substrate and external devices with corresponding electronic circuits. Such a manufacturing process typically involves solder ball placement and solder ball reflow. The former involves locating the positions of the solder pads and placing the solder balls onto these positions, and the latter is a process in which solder balls melt, wet and reflow onto the solder pads of the BGA substrate to create the electrical conductivity.
Current systems for solder ball placement usually apply xe2x80x9csweepingxe2x80x9d and xe2x80x9cgravity rollingxe2x80x9d concepts to locate and place the solder balls onto the solder pads. Several examples from the prior art will illustrate the concept of sweeping.
U.S. Pat. No. 5,655,704 for a xe2x80x9cMethod and Apparatus for Mounting Soldering Balls onto Electrodes of a Substrate or a Comparable Electronic Componentxe2x80x9d describes a ball-filling device using a xe2x80x9csweepingxe2x80x9d concept. The ball-filling device include a container which has a supply of solder balls, which fill up apertures of a ball-receiving element when the container is moved over the area of the apertures. Due to the storage of a large number of solder balls in the container, significant forces are generated due to the weight of the plurality of solder balls which are exerted on one another, and these forces act to restrain the solder balls from falling freely under the influence of gravity into the apertures. In addition, there is a high risk that solder balls that are partially engaged in empty apertures are sheared by the edges of the container as the container is moved over the apertures.
Another example of a ball-filling device is described in PCT publication number 00/564921 for a xe2x80x9cFilling Device and Method for Filling Balls in the Apertures of a Ball-Receiving Elementxe2x80x9d. It comprises housing including an opening at a lower surface thereof and defining in part a chamber for containing a supply of balls. The housing is movably disposed over an array of apertures, and distribution means disposed within the housing distributes balls contained in the chamber so that limited number of layers of the balls are spread over the apertures. Although the described device alleviates the problem of shearing of solder balls during filling of the solder pads as compared to the prior art, the soft solder balls can still be damaged by the distribution means, which in itself, has edges and produces undesired forces on the solder balls that can cause damage.
Another example of the use of these concepts is U.S. Pat. No. 6,229,210 which describes a xe2x80x9cDevice and method for attaching and soldering pre-formed solder spheres to the BGA integrated circuit package attachment sites in high volume.xe2x80x9d In this design, the placement device comprises a pre-formed stencil having a pattern of through holes corresponding to contact pads of a BGA substrate. By brushing the solder balls or by the use of a U-shaped blade, the balls are made to fall into the apertures. The problem is that since the solder balls are exposed to the atmosphere, they can be oxidized more easily and contamination may easily occur from the surroundings and/or the blade. Furthermore, the soft solder balls may be damaged by the blade.
As another example, U.S. Pat. No. 5,918,792 describes an xe2x80x9cApparatus and method for filling a ball grid arrayxe2x80x9d. A ball-filling device comprises a solder bin that is moved along side rails over a stencil allowing solder balls to fill apertures in the stencil and thereby settling on corresponding solder pads, before being fixed by adhesive. As explained above, the problem is that solder balls may be damaged by the edges of the side walls of the solder bin and also by the edges of the many apertures.
It Is an objective of the present Invention to provide an improved apparatus for automated placement of solder balls onto a substrate, so that damage and/or oxidation of solder balls are reduced as compared to the prior art.
According to a first aspect of the invention there is provided an apparatus for positioning solder balls in a desired array on a substrate comprising a positioning means for positioning the solder balls in positions corresponding to the array of positions the solder balls are to take up on the substrate, a container for receiving a plurality of solder balls and which is movable between a first position remote from the positioning means and a second position directly thereover, and means to bias the solder balls in the direction of movement of the container from the first to the second position whereby to reduce or obviate damage to the solder balls during such movement.
According to a second aspect of the invention there is provided a method for positioning solder balls in a desired array on a substrate, comprising providing positioning means for positioning the solder balls in positions corresponding to the array of positions the solder balls are to take up on a substrate, providing a container for receiving a plurality of solder balls, providing means to move the container between a first position remote from the positioning means and a second position directly thereover, and providing means to bias the solder balls to move in the direction of movement of the container whereby damage to the solder balls is reduced or obviated.
According to a third aspect of the invention there is provided a substrate on which a plurality of solder balls so arranged in a desired array according to an apparatus or a method as hereinbefore defined.
Using the invention it is possible to provide an apparatus and method in which a force, usually gravitational force, will be provided which is independent of the force generated on the solder balls by the walls of the container during said movement whereby to bias the solder balls In the direction of movement of the container.
It will be convenient to hereafter describe the invention in greater detail by reference to the accompanying drawings which illustrate one embodiment of the invention. The particularity of the drawings and the related description is not to be understood as superseding the generality of the broad identification of the invention as defined by the claims.

Apparatus and method of placing solder balls onto a substrate


In one embodiment, a power supply controller utilizes a plurality of reference signals that operate at different frequencies to form a switching signal that is suitable to control a power device to regulate an output voltage.

The present invention relates, in general, to electronics, and more particularly, to methods of forming semiconductor devices and structure.
In the past, the semiconductor industry utilized various methods and structures to produce switching power supply controllers such as pulse width modulated (PWM) power supply controllers. The system typically supplied a current and a regulated output voltage to a load. During the operation of these PWM power supply controllers, it was possible for the current requirements of the load to change requiring transitions between supplying increased and decreased amounts of current. Typically, the response time of the power supply controllers was limited which resulted in a poor transient response. The poor transient response resulted in variations in the value of the output voltage supplied to load and also limited the value of the current that could be supplied to load during the transient.
Accordingly, it is desirable to have a power supply controller that has improved response to variations in the current required by the load.
For simplicity and clarity of illustration, elements in the figures are not necessarily to scale, and the same reference numbers in different figures denote the same elements. Additionally, descriptions and details of well-known steps and elements are omitted for simplicity of the description. As used herein current carrying electrode means an element of a device that carries current through the device such as a source or a drain of an MOS transistor or an emitter or a collector of a bipolar transistor or a cathode or anode of a diode, and a control electrode means an element of the device that controls current through the device such as a gate of an MOS transistor or a base of a bipolar transistor. Although the devices are explained herein as certain N-channel or P-Channel devices, a person of ordinary skill in the art will appreciate that complementary devices are also possible in accordance with the present invention. It will be appreciated by those skilled in the art that the words during, while, and when as used herein are not exact terms that mean an action takes place instantly upon an initiating action but that there may be some small but reasonable delay between the reaction that is initiated by the initial action.

Power supply controller and method therefor

Semiconductor Components Industries, L.L.C.


A platform for managing delivery of content originating from one or more content providers to users is provided. The platform includes a portal that is configured to support access through a plurality of access channels configured to receive requests through one or more access channels. A request for content is received from an access device through an access channel. An identity management module is configured to determine a user associated with the message. A content manager is configured to manage content for delivery through the plurality of access channels and configured to determine eligible content for the user. A billing module is configured to process billing for the user and content provider based on the content provided to the user. The content manager is then configured to deliver the requested content to the user's access device through the access channel.

The present invention generally relates to telecommunications and more specifically to a platform for management of multichannel delivery of multi-types of content.
Content can be delivered through a growing number of channels. Traditionally, content, such as videos, movies, etc., were delivered through wireline systems, such as cable. With the advent of next generation telecommunication networks, such as 3G, this content may be delivered to mobile devices. Accordingly, for example, video and data, may be sent to users using their mobile devices, such as cellular phones, personal digital assistants, etc.
The wireless and wireline systems that delivered the content are typically different. For example, telecommunication operators typically use different platforms to deploy systems that allow mobile download of content than systems used to provide content through wireline networks. Accordingly, content management and delivery is difficult when combining delivery across both wireline and wireless networks. There is redundancy at integration points due to various network elements and resources, difficulty in cross selling due to disparate content management systems, inflexibility in supporting new content types for the future, and difficulty in extending or customizing the functionality to add new capabilities. The potential for generating new revenue streams by providing content across wireless systems is great. However, the mobile space includes many devices that communicate through many different channels. Accordingly, it is difficult to provide content to all the devices communicating through all the channels.

Platform and service for management and multi-channel delivery of multi-types of contents


A pinball machine comprises a frame which carries a playfield, a chute and a driver for launching balls onto the playfield through the chute. A spent ball-receiving aperture in the playfield communicates with a sloped trough positioned under the playfield. The trough is of a length to hold a plurality of balls, preferably more than three balls. An upper end of the trough communicates with the aperture, while the lower end of the trough is positioned adjacent to and below the chute and the ball driver for launching. A solenoid or the like is positioned to vertically elevate the ball occupying the trough lower end, typically by striking it to cause the ball to fly to a new position in the chute for launching. Sensors are present to determine the number of balls in the trough. A microprocessor and other electronics are present for actuating the solenoid or the like for vertically elevating the ball to the chute for launching. Balls may be automatically launched, being fed from the trough, in a manner responsive to events taking place on the playfield.

Pinball machines are currently in use which have multiple ball systems. Typically, such machines have the capability of automatically putting three balls into play at the same time, as the result of a score or other event that takes place during the pinball game. The balls are automatically launched, although the player also may have the capability of launching balls manually.
With such a multiple ball system, the pinballs which are waiting to be launched reside on a 3-ball track which is positioned on the playfield near the player's end, with the track being of the shape of an inverted V. Other balls may be held in eject holes on the playfield until they are released by the game program. At one end, the track communicates with the ball driver and the chute which is used for launching the pinballs onto the playfield. At the other end of the track there is a "kicker" for propelling the balls from that end of the track to the other.
By this invention, a pinball machine is provided having a multiple ball feed unit capable of feeding more than three balls into the game, for example six balls, in automatic sequence for increased game excitement.

Multiple ball feed unit for pinball machine


An implantable cardiac stimulation device classifies ventricular tachyarrhythmias as either a ventricular tachycardia or ventricular fibrillation and applies appropriate therapy. The device include sensing circuits that provide right and left ventricular electrogram signals, a detector that detects an accelerated ventricular arrhythmia, and a classifying circuit that measures relative correspondence between the right and left ventricular electrogram signals to classify a detected accelerated ventricular arrhythmia as either ventricular tachycardia or ventricular fibrillation. A therapy circuit is responsive to the classifying circuit and applies appropriate therapy to the heart based upon the tachyarrhythmia classification.

Implantable cardiac defibrillators (ICD's) are well known in the art. These devices, encapsulated in a conductive housing or enclosure, are generally implanted in a pectoral region of a patient and electrically connected to the heart with one or more electrode carrying leads. An arrhythmia detector detects accelerated arrhythmias, such as tachycardia or fibrillation. When such a tachyarrhythmia is detected, a pulse generator delivers electrical therapy to the patient's heart. A therapy for tachycardia may be anti-tachycardia pacing and a therapy for fibrillation may be a defibrillating shock. Such therapies are well known.
With ventricular tachycardia (VT) the ventricles of the heart beat abnormally fast. Though often unpleasant for the patient, a ventricular tachycardia is typically not immediately fatal. However, ventricular fibrillation (VF) is an immediately life threatening tachyarrhythmia, wherein the heart beats chaotically such that there is little or no net flow of blood from the heart to the brain and other organs.
With atrial tachycardia (AT), the atria of the heart beat rapidly at an abnormally high rate. This can cause the ventricular to in turn beat at a high rate. Cardiac output is downed. The patient may experience dizziness or feel fatigued. Although not immediately life threatening, it can also be unpleasant to a patient.
Atrial fibrillation is a common atrial tachyarrhythmia and can occur suddenly. It results in rapid and chaotic activity of the atrial of the heart. The chaotic atrial activity in turn causes the ventricular activity to become rapid and variable. Although not life threatening, it is associated with strokes thought to be caused by blood clots forming in areas of stagnant blood flow as a result of prolonged atrial fibrillation. In addition to strokes, symptoms of atrial fibrillation may include fatigue, syncope, congestive heart failure, weakness and dizziness.
From the foregoing, it may be readily understood that it is most desirable to treat tachyarrhythmias as quickly as possible to return the heart to normal sinus rhythm (NSR). Tachycardia may be treated quite effectively with ATP while fibrillation generally requires a defibrillating shock. However, defibrillating shocks can cause discomfort and trauma to a patient while ATP is generally not perceptible. Hence, to achieve the most effective and the quickest return of tachyarrhythmias to NSR with the least amount of discomfort to the patient, it would be desirable to match the therapy to the tachyarrhythmia.
The need for therapy matching techniques becomes even more apparent in view of some recent research which has shown that the majority of very fast rhythms, normally treated as VF with a defibrillating shock, are actually monomorphic VT. These arrhythmias have traditionally been treated as a VF in ICDs because there was no reliable means of separating VFs, which require shocking, from VTs, which may be treated with ATP. Such research showed that approximately 50% of these high-rate tachyarrhythmias were, in fact, monomorphic tachycardias, and not VF.
Hence, there is a need in the art for an implantable cardiac stimulation device capable of distinguishing tachycardias from fibrillation and providing an appropriate therapy. There is also a need to accomplish the foregoing which assures that the patient is receiving the most appropriate therapy in the shortest possible time.

This patent is subject to a terminal disclaimer.

Implantable cardiac stimulation device and method that discriminates between and treats ventricular tachycardia and ventricular fibrillation