The proposed steam turbine rotor extends along an axial extent and includes: an outer side which adjoins an outer space which is intended to receive a main flow of a fluid working medium, a first location along the outer side, at which a first blade is held, a second location along the outer side, at which a second blade is held, the second location being arranged behind the first location along the axial extent. To ensure sufficient cooling, there is at least one integrated passage, which extends continuously at least between a first region arranged in front of the first location and a second region arranged behind the second location The invention proposes a method and a use in which a fluid cooling medium is guided in a corresponding way.

When hot steam is applied to a steam turbine as working medium, targeted cooling of highly loaded components is desirable in order to increase the steam temperatures which can be reached. Where possible, this targeted cooling encompasses shielding and dissipation of heat through corresponding levels of cooling. In the context of the present application, a steam turbine is to be understood as meaning any turbine or part-turbine through which a working medium in the form of steam flows. By contrast, gas turbines have gas and/or air flowing through them as working medium, but this medium is subject to completely different temperature and pressure conditions than the steam in a steam turbine. Unlike in gas turbines, in steam turbines the working medium flowing to a part-turbine, for example, reaches its highest pressure at the same time as it is at its highest temperature. Therefore, an open cooling system cannot be realized without a cooling medium being supplied from the outside of the part-turbine. It has consequently proven impossible for cooling measures which are known from gas turbines to be transferred to steam turbines in the form which is known for gas turbines and is only suitable for gas turbines.
A casing of a steam turbine is to be understood as meaning in particular the stationary casing component of a steam turbine or part-turbine, which along the axial extent of the steam turbine has an inner space which is intended for the working medium steam to flow through. Depending on the particular type of steam turbine, this may be an inner casing and/or a guide vane carrier. A steam turbine casing is also to be understood as meaning a turbine casing which does not have an inner casing or a guide vane carrier.
A rotor fitted with blades is arranged rotatably along the axial extent in the inner space, so that when heated and pressurized steam flows through the inner space the steam makes the rotor rotate by means of the blades. The blades of the rotor are also known as rotor blades. Furthermore, a steam turbine has stationary guide vanes which penetrate into the spaces between the rotor blades and are held by the inner casing/guide vane carrier. A rotor blade is usually held along an outer side of a steam turbine rotor. It usually forms part of a ring of rotor blades which comprises a number of rotor blades which are arranged along an outer circumference on the outer side of the steam turbine rotor. The main blade part of each rotor blade faces radially outward. A ring of rotor blades is also referred to as a row of rotor blades. A number of rows of rotor blades are usually positioned behind one another. Accordingly, a further, second ring of blades is held along the outer side of the steam turbine rotor at a second location behind the first location along the axial extent.
With the cooling methods which have been disclosed hitherto, in particular for a steam turbine rotor, a distinction has to be drawn between active cooling and passive cooling. In the case of active cooling, cooling is brought about by a cooling medium which is fed to the steam turbine rotor separately, i.e. in addition to the working medium. By contrast, passive cooling is brought about only by suitably guiding or using the working medium in the main flow. Standard cooling of a steam turbine rotor is restricted to passive cooling.
By contrast, it is known from U.S. Pat. No. 6,102,654 and WO 97/49901 for cool steam which has already expanded to flow through a rotor of a steam turbine. In this case, cooling medium is passed through a substantially central cavity along an inner rotor wall and is then fed from there to the outside, in particular to regions of the casing which are to be cooled, via separate radial branch channels. Since the central cavity and the branch channels are arranged at the location where the component is subject to the highest levels of loading, this is highly disadvantageous for the rotor strength. It has the further drawback that a temperature difference across the rotor wall has to remain limited, since otherwise the rotor would be excessively thermally deformed in the event of an excessive temperature difference. For these reasons, a concept of this nature has not yet achieved widespread use. Although heat is dissipated as it flows through the rotor, the dissipation of heat takes place relatively far away from the location where the heat is supplied. Hitherto, it has not been possible to achieve sufficient dissipation of heat in the immediate vicinity of where the heat is supplied.
Further, passive cooling can be achieved by suitably guiding and using the expansion of the steam of the working medium. In this case, the steam which flows to a steam turbine is first of all expanded by exclusively stationary parts, e.g. a ring of guide vanes or radially acting guide vanes, before it is applied to rotating components. In the process, the steam is cooled by approximately 10 K. However, this method can only achieve a very limited cooling action on the rotor.
U.S. Pat. No. 6,102,654 realizes active cooling of a steam turbine rotor to only a very restricted extent, and moreover the cooling is limited to the inflow region of the hot working medium. As shown in FIG. 1 of this application, according to U.S. Pat. No. 6,102,654 cooling medium is passed through the casing onto a protective shield and onto a first ring of guide vanes, in order to reduce the thermal load on the rotor and the first ring of guide vanes. Some of the cooling medium is admixed with the working medium. Aside from the fact that the cooling is restricted to the inflow region, cooling is only supposed to be brought about by flow onto the components which are to be cooled. The cooling effect on the rotor which can be achieved as a result is limited, since it is restricted to the inflow region of the main flow.
It is known from WO 97/49901 for a single ring of guide vanes to be cooled selectively through a separate radial channel in the rotor, fed from a central cavity. For this purpose, cooling medium is admixed with the working medium via the channel, and cooling medium flows selectively onto the ring of guide vanes which is to be cooled. The cooling effect on the rotor is still in need of improvement. Furthermore, the bore disadvantageously increases the rotor stresses significantly compared to the configuration without a bore.
EP 1154123 has described a possible way of removing and guiding a cooling medium from other regions of a steam system and the supply of the cooling medium in the inflow region of the working medium.
To achieve higher efficiency levels in the generation of power using fossil fuels, there is a need to employ higher steam parameters, i.e. higher pressures and temperatures, than has hitherto been customary. In this context, if steam is used as the working medium, pressures of over 250 bar and temperatures of over 540° C. are intended. Steam parameters of this nature are described in detail in the article "Neue Dampfturbinen-konzepte für höhere Eintrittsparameter und längere Endschaufeln" [Novel steam turbine concepts for higher entry parameters and longer end blades] by H. G. Neft and G. Franconville in the Journal VGB Kraftwerks-technik, No. 73 (1993), Volume 5. The content of disclosure of this article is hereby incorporated by reference in the description of the present application. In particular, examples of higher steam parameters are cited in FIG. 13 of the article. In the abovementioned article, a cooling steam supply and passage of the cooling steam through the first guide vane stage and if appropriate also through the second guide vane stage is proposed in order to improve the cooling of a steam turbine rotor. This provides active cooling only for the steam turbine casing. Moreover, the cooling is restricted to the main flow region of the working medium and is still in need of improvement.
Therefore, all the methods which have been disclosed hitherto for cooling a steam turbine rotor, if they are active cooling methods at all, at best provide for a directed flow onto a separate turbine part which is to be cooled and are restricted to the inflow region of the working medium. When higher steam parameters are applied to standard steam turbines, an increased thermal load may result over the entire turbine, and this load could only be alleviated to an insufficient degree by standard cooling of the rotor as described above. Steam turbines which use higher steam parameters in order to achieve higher efficiencies, for example, require improved cooling, in particular of the rotor, in order to sufficiently break down the higher thermal loads on the steam turbine. This gives rise to the problem that when turbine materials which have hitherto been customary are employed, the increasing load on the rotor resulting from increased steam parameters may lead to a disadvantageous thermal load on the rotor and to an unacceptable increase in the temperature of the rotor.

Steam turbine rotor, steam turbine and method for actively cooling a steam turbine rotor and use of active cooling


The present invention relates to a composition for and a method of treating hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, hepatitis D virus (HDV) infection or a proliferative disorder in a patient using an effective amount of a compound selected from the group consisting of formulas [I]–[IV] below and mixtures of two or more thereof:

This invention relates to a process for preparing a 3′- or 2′-hydroxymethyl substituted nucleoside derivative, compounds and pharmaceutical compositions for, and a method of treating hepatitis virus infections and/or proliferative disorders in patients using 3′-hydroxymethyl and 2′-hydroxymethyl substituted nucleosides and structurally related nucleosides of general formulas [I]–[IV] and their L-nucleoside counterparts.
wherein the substituents are as defined herein.
Hepatitis B virus (HBV) infection is the most prevalent form of hepatitis and is the second most common infectious disease worldwide. Approximately 5% of the world's population is chronically infected with HBV. The virus is transmitted through blood transfusions, contaminated needles, sexual contact and transmission from mother to child. Moreover, a significant number of people are infected by unknown means.
Carriers of the hepatitis B virus can exhibit various forms of disease, one of which is chronic hepatitis B. Approximately 50% of the carriers show chronic inflammatory changes in the liver and, of these, about 50% have histopathologic changes, which are termed "chronic active hepatitis," which may lead to fibrosis and ultimately to cirrhosis and progressive liver failure. Carriers without chronic inflammatory changes may also develop chronic active hepatitis, while liver cancer develops in about 10 to 30% of hepatitis B carriers. It has been estimated that approximately 4 million carriers of hepatitis B virus die each year from liver cancer or cirrhosis.
HBV, also known as the Dane particle, is a member of the Hepadonaviridae and is a 42 nm complex spherical particle composed of an outer lipoprotein coat (hepatitis B surface antigen HBsAg) and an inner core (hepatitis B core antigen, HBcAg). (Ganem, D., Fundamental Virology, 3rd Ed., Lippincott-Raven Pub., Philadelphia, 1996, p. 1199) This core contains partially double stranded DNA of 3.2 kb maintained as a circular structure by 5′ cohesive ends. (Chu, C. K., Therapies for Viral Hepatitis, Schinazi, et al., Eds., International Medical Press, 1998) The viral minus strand is full length, while the plus strand is less than full length. The 5′ ends of both strands contain short (11 nucleotide) direct repeats. These repeats are involved in priming the synthesis of their respective strands. Remarkably, viral DNA is synthesized in a reverse transcription of an RNA template. (Mason, W. S., Adv. Virus. Res., 1987, 32, 35) Following viral infection, the viral replication cycle begins with translocation of nucleocapsids from the cytoplasm to the nucleus. (Eckart, S. G., J. Virol., 1991, 65, 575) The partially duplex genomic DNA is converted to fully duplex covalently closed supercoiled DNA, which persists as an episomal minichromosome and functions as a reservoir of the viral genome. This feature provides a difficult challenge to therapeutic attack on the virus.
The episomal DNA is transcribed by the host RNA polymerase II and viral proteins are translated from the transcription products. Among the transcripts are full length pregenomic RNAs which are encapsulated by the viral structural proteins together with the viral polymerase. Synthesis of both viral DNA strands by the viral polymerase occurs within these structures. The polymerase contains both a reverse transcriptase and an RNAse H domain. Minus strand synthesis proceeds in two distinct steps (Zolim, F., J. Virol., 1994, 68, 3536). In the first, the polymerase binds to the direct repeat at the 5′ end of the pregenomic RNA and serves as a covalent primer for the synthesis of a 4 nucleotide element. The priming hydroxyl group is the side chain of a tyrosine residue on the polymerase and is linked to a dGMP residue. A sequence in the bulge of a stem loop structure in the RNA template serves as the template for this step. This reaction is particular to the virus and is not mimicked in any cellular DNA synthesis reaction. Agents which target this step would have the potential for a high degree of specificity. Following this step the polymerase-nucleotide complex translocates to the other end of the RNA template and complete reverse transcription of the strand takes place. (It has been proposed that there may be proteolytic cleavage of polymerase and RNAse domains away from the portion of the polymerase bound to the tetranucleotide primer. (Bartenschlager, R., EMBO J. 1988, 7, 4185). First strand synthesis is accompanied by the degradation of the RNA in the RNA:DNA hybrid by the RNAse H of the polymerase. Synthesis of the second strand, also mediated by the viral polymerase, is generally incomplete, giving rise to the partially duplex DNA found in the virion.
It is now clear that there are three separate phases in replication and that the first reverse transcription step is of particular interest for therapeutic intervention. It should be noted that an agent that inhibits the reverse transcriptase of other retroviruses does not necessarily have activity against HBV. For example, Zidovudine (or AZT) as its 5′-triphosphate is a potent inhibitor of reverse transcriptase of human immunodeficiency virus and has been widely used in the treatment of HIV-infected patients. However, this agent is inactive against HBV. On the other hand, certain 2′-fluoro-D-arabino nucleosides, such as Fiacitabine (FIAC) and Fialuridine (FIAU), are devoid of activity against HIV although they effectively inhibit replication of HBV.
Hepatitis C virus (HCV), the second major cause of viral hepatitis, is present in an estimated 170 million carriers worldwide, 3.9 million of whom reside in the United States. HCV is considered the most common blood-borne infection in the United States, where it is one of the leading causes for liver transplantation among adults. Most people infected with HCV do not exhibit any acute signs or symptoms of hepatitis. In fact, unless they have a blood test, most people remain unaware that they are infected with HCV for the first 10–20 years.
Aside from direct blood contact, HCV is a very difficult agent to transmit. Maternal-to-fetal transmission is quite low, less than 6% of babies born to infected mothers will carry the virus. Additionally, unlike HBV and human immunodeficiency virus (HIV), evidence of direct sexual transmission of HCV is inconclusive.
HCV is a small, enveloped virus in the Flaviviridae family, with a positive single-stranded RNA genome of ˜9.6 kb within the nucleocapsid. The genome contains a single open reading frame (ORF) encoding a polyprotein ofjust over 3,000 amino acids, which is cleaved to generate the mature structural and nonstructural viral proteins. ORF is flanked by 5′ and 3′ non-translated regions (NTRs) of a few hundred nucleotides in length, which are important for RNA translation and replication. The translated polyprotein contains the structural core (C) and envelope proteins (E1, E2, p7) at the N-terminus, followed by the nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The mature structural proteins are generated via cleavage by the host signal peptidase. The junction between NS2 and NS3 is autocatalytically cleaved by the NS2/NS3 protease, while the remaining four junctions are cleaved by the N-terminal serine protease domain of NS3 complexed with NS4A. The NS3 protein also contains the NTP-dependent helicase activity which unwinds duplex RNA during replication. The NS5B protein possesses RNA-dependent RNA polymerase (RDRP) activity, which is essential for viral replication. It is emphasized here that, unlike HBV or HIV, no DNA is involved in the replication of HCV. Recently in in vitro experiments using NS5B, substrate specificity for HCV-RDRP was studied using guanosine 5′-monophosphate (GMP), 5′-diphosphate (GDP), 5′-triphosphate (GTP) and the 5′-triphosphate of 2′-deoxy and 2′,3′-dideoxy guanosine (dGTP and ddGTP, respectively). The authors claimed that HCV-RDRP has a strict specificity for ribonucleoside 5′-triphosphates and requires the 2′- and 3′—OH groups. Their experiments suggest that the presence of 2′- and 3′-substituents would be the prerequisite for nucleoside 5′-triphosphates to interact with HCV-RDRP and to act as substrates or inhibitors. The present invention on the development of anti-HCV agents is based on this rationale.
Hepatitis D virus (HDV) is classified separately from other hepatitis viruses, but it is often found in association with hepatitis B virus. The host range of HDV is limited to those species that support the replication of a hepadnavirus capable of supplying a helper function. These include the chimpanzee (hepatitis B virus), the eastern woodchuck (woodchuck hepatitis virus) and possibly the Pekin duck (duck hepatitis virus). The successful replication of HDV is dependent on the replication of the helper hepadnavirus. Inhibition of hepatitis B virus, therefore, should result in inhibition of HDV. Also, while HDV appears to employ the host RNA polymerase, it is not clear if the virus causes some modification of the polymerase enabling it to replicate the HDV genome more efficiently. Thus, nucleosides that inhibit the HBV polymerase or the modified host RNA polymerase would be expected to inhibit the replication of HDV.
The synthesis of some related compounds has been disclosed in the literature (Acton, E. M., et al., J. Med. Chem., 1979; 22:518; Fiandor, J., et al., Nucleosides Nucleotides, 1989; 8:1107; Bamford, M. J., et al., J. Med. Chem., 1990; 23:2494; Svansson, L., et al., J. Org. Chem., 1991; 56:2993; Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991; 10:291; Svansson, L., et al., Nucleosides Nucleotides, 1992; 11:1353; Kvamstrom, I., et al., Nucleosides Nucleotides, 1992; 11:1367; Tseng, C. K-H., et al., J. Med. Chem., 1991; 34: 343; Lin, T-S., et al., J. Med. Chem., 1993; 36:353; Wengel, J., et al., Bioorg. Med. Chem., 1995; 3:1223; Lee-Ruff, E., et al., J. Med. Chem., 1996; 39:5276; Jorgensen, P. N., et al., Nucleosides Nucleotides, 1997; 16:1063; Jeong, L. S., et al., Nucleosides Nucleotides, 1997; 16:1059;). Moreover, these references also disclose anti-viral test results of some of these compounds against herpes virus (HSV) or human immunodeficiency virus (HIV). Only 2′,3′-dideoxy-3′-hydroxymethyl-cytidine and adenosine show good activity against HIV and 2′,3′-dideoxy-3′-hydroxymethyl-cytidine (Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991, 10, 291) and 5-bromovinyl-1-(3-deoxy-3-hydroxymethyl-D-arabinofuranosyl)-uracil (Svansson, L., et al., J. Org. Chem., 1991, 56, 2993) are active against HSV.
Although it would not have been expected that an anti-herpes virus agent or anti-HIV agent would also be effective in the treatment of hepatitis, the compounds of the present invention have surprisingly been found to be useful as anti-hepatitis agents. Some of these compounds are particularly favorable in the treatment of hepatitis because they unexpectedly cause less toxic side effects. For example, we discovered that 3′-deoxy-3′-hydroxymethylthymidine, which, though devoid of activity against murine leukemia virus (MuLV), HIV, HSV-1, HSV-2, human cytomegalovirus (HCMV), Varicella zoster virus (VZV) and Epstein Barr virus (EBV)( Sterzycki, R. Z., et al., Nucleosides Nucleotides, 1991, 10, 291), is a potent agent against HBV.
It is therefore an object of the present invention to provide compounds and compositions useful for the treatment of hepatitis.
It is a further object of the present invention to provide a method for treating hepatitis using the compounds of the present invention.
It is another object of the present invention to provide compositions for treating hepatitis comprising the compounds of the present invention in combination with other anti-hepatitis agents.
It is another object of the present invention to provide a method for treating hepatitis using the compounds of the present invention in combination with other anti-hepatitis agents.
It is still another object of the present invention to provide compounds and compositions useful for the treatment of proliferative disorders.
It is still another object of the present invention to provide a method for treating proliferative disorders using the compounds of the present invention.
It is still another object of the present invention to provide a process for preparing 3′- or 2′-hydroxymethyl substituted nucleoside derivatives.

3′-or 2′-hydroxymethyl substituted nucleoside derivatives for treatment of hepatitis virus infections

Abstract: wherein the substituents are as defined herein. Pharmaceutical compositions comprising these compounds in combination with other HBV, HCV, or HDV agents is also disclosed.


A personal cleansing composition comprising. a. at least about one wt % of soap, and PA1 b. a sufficient amount of a compound to provide at least about 0.03 wt. % of a free fatty carboxylic acid, said compound of the formula ##STR1## wherein R is hydrogen or CH.sub.2 COOH, R.sub.a is hydrogen or carboxyl, and R.sub.b is hydrogen or methyl provided that when R is hydrogen, then R.sub.a is carboxyl and when R is CH.sub.2 COOH then R.sub.a is hydrogen.

Soaps have been used for hundreds of years to remove soil from skin. Continual efforts have been made to improve the actions of soaps while increasing mildness, shelf life, lather and the like.
A new method has been discovered which can bring about a combination of increased lather, superfatting, and shelf life compared with previously modified compositions. This is accomplished by the presence in the solid or liquid formulation of a member of a specific family of compounds which has at least two of these effects.


Implementations set forth herein relate to conditionally caching responses to automated assistant queries according to certain contextual data that may be associated with each automated assistant query. Each query can be identified based on historical interactions between a user and an automated assistant, and—depending on the query, fulfillment data can be cached according to certain contextual data that influences the query response. Depending on how the contextual data changes, a cached response stored at a client device can be discarded and/or replaced with an updated cached response. For example, a query that users commonly ask prior to leaving for work can have a corresponding assistant response that depends on features of an environment of the users. This unique assistant response can be cached, before the users provide the query, to minimize latency that can occur when network or processing bandwidth is unpredictable.

Humans may engage in human-to-computer dialogs with interactive software applications referred to herein as "automated assistants" (also referred to as "digital agents," "chatbots," "interactive personal assistants," "intelligent personal assistants," "conversational agents," etc.). For example, humans (which when they interact with automated assistants may be referred to as "users") may provide commands and/or requests using spoken natural language input (i.e., utterances) which may in some cases be converted into text and then processed, and/or by providing textual (e.g., typed) natural language input.
In some instances, a user can interact with an automated assistant through any assistant device of an ecosystem of assistant devices. An ecosystem of assistant devices can refer to one or more devices that each include a local assistant client application and/or that are each associated with a corresponding assistant account that is controlled by one or more users. This ecosystem of assistant devices can include portable assistant device(s) that the user carries with them as they travel, home assistant device(s) that remain in different rooms of their home or other structure, and/or in-vehicle device(s).
In order for the automated assistant to provide accurate and relevant responses to various user queries, a client device can retrieve data from a server that manages the data that is accessible to the automated assistant. In some instances, in response to a user query, a client automated assistant can request data from the server, but a response from the server can be delayed as a result of network and/or processing constraints. As a result, an interaction between a user and an automated assistant can be prone to delays and/or otherwise inconsequential. When such interactions occur for a population of users, computational resources for the corresponding pool of client devices can be wasted. For example, when a population of users in a city frequently ask, around the same time of day, about a local news event (e.g., construction-related traffic), a server network associated with the city can exhibit a decrease in available bandwidth. Various client devices relying on the server network can exhibit latency and other operational deficiencies as a result.

Conditional response fulfillment cache for locally responding to automated assistant inputs


A method for finding L internal reference vectors for classification of L chromosomes or portions of chromosomes of a cell, the L chromosomes or portions of chromosomes being painted with K different fluorophores or combinations thereof, wherein K basic chromosomes or portions of chromosomes of the L chromosomes or portions of chromosomes are each painted with only one of the K different fluorophores, whereas the other L-K of the L chromosomes or portions of chromosomes are each painted with a different combination of the K different fluorophores, the method comprising the steps of (a) using a multi-band collection device for measuring a first vector for each pixel of each of the L chromosomes or portions of chromosomes; (b) identifying pixels belonging to each of the K basic chromosomes or portions of chromosomes and defining the pixels as basic pixels, so as to obtain K basic classes of basic pixels; (c) using at least one basic pixel from each of the K basic classes for obtaining K basic vectors, the K basic vectors being K internal reference vectors; (d) using the K basic vectors for identifying pixels belonging to the other L-K chromosomes or portions of chromosomes; and (e) using the pixels belonging to the other L-K chromosomes or portions of chromosomes for calculating the other L-K internal reference vectors, thereby finding all of the L internal reference vectors. A method for classification of L chromosomes or portions of chromosomes of a cell similarly painted using the above method for finding L internal reference vectors, and using the L reference vectors for classification of each of the pixels into one of L classification classes. And, images presenting color chromosomes.

The present invention relates to classification of in situ painted chromosomes into a color (spectral) karyotype. More particularly, the present invention relates to a method for identifying prominent internal reference spectra to effect such classification.
The use of fluorescent dyes (i.e., fluorescent probes, fluorophores, fluorochromes, all are used interchangeably in this document), is one of the most powerful and common tools for analyzing tissues and cells. Fluorescence microscopy is therefore one of the most important experimental methods used in light microscopy Lakowicz (1983) Principles of fluorescence spectroscopy, Plenuni Press, New York, London!.
The power of fluorescent probes, is mainly due to the great variety of biological structures to which specific dyes can be bound Waggoner (1986) Applications of fluorescence in the biomedical sciences, Eds. Taylor et al., New York: Alan R. Liss, Inc. pp. 3-28!. For a detailed review of fluorescent probes see, Mason, editor (1993) Fluorescent and Luminescent Probes for Biological Activity, Biological Techniques Series, edited by Sattelle, Academic Press Limited, London; and, Ploem and Tanke (1987) Introduction to Fluorescence Microscopy, Oxford University Press, Royal Microscopical Society.
The rapid development of new and more sophisticated multicolor fluorescent dye molecules continues to create a need for more advanced fluorescence imaging techniques that can utilize the full potential of these dyes. For a discussion of the revolutionary impact fluorescent dyes have had, and will continue to have, on the way research is conducted today, refer to Taylor et al. (1992) The New Vision of Light Microscopy, American Scientist, Vol. 80, pp. 322-335.
An important example where the detection of multiple fluorescent probes can be of significant advantage is FISH (fluorescent in situ hybridization) Emanuel (1993) Growth Genetics and Hormones 9, pp. 6-12!, which is used to analyze genes at the chromosome level, and find possible genetic defects such as gene/chromosome amplification, deletion, translocation, rearrangement and other abnormalities associated with genes and/or chromosomes.
Certain diseases and disorders, including many cancers and birth defects, are genetic disorders caused by defects (i.e., mutations) in one or more genes. Many other diseases are known or believed to have a genetic component(s), that is, there exists a genetic defect(s) that does not alone cause the disease but contributes to it, or increases the probability of developing the disease later in life, phenomena known in the art as multifactorial diseases and genetic predispositions.
Correlation of visible genetic defects with known diseases would allow physicians to make definitive diagnoses, and permit early detection and treatment of many diseases. Genetic counseling could alert prospective parents and at-risk individuals to the possibility of potentially serious medical problems in the future. permitting appropriate intervention.
More than 8,000 genetic disorders have now been identified, many of which are associated with multiple genetic defects. Following the discovery that chromosomes are the carriers of hereditary information. scientists reasoned that it should be possible to document visible defects in chromosomes that were responsible for specific disorders.
In the 1960's, staining techniques were developed for microscopy-based classification of metaphase chromosomes spreads. For several decades, visual analysis of chromosomes banding patterns has been used to correlate human genetic disorders with observed structural abnormalities in metaphase chromosomes. Chromosomes are typically examined by brightfield microscopy after Giemsa staining (G-banding), or by fluorescence microscopy after fluorescence staining (R-banding), to reveal characteristic light and dark bands along their length. Careful comparison of a patient's banding pattern with those of normal chromosomes can reveal abnormalities such as translocations (exchange of genetic material between or within chromosomes), deletions (missing chromosome(s) or fragment(s) thereof), additions, inversions and other defects that cause deformities and genetic diseases. Yet conventional chromosome banding techniques are limited in resolution.
Fluorescent in situ hybridization (FISH) has evolved over the past 25 years through the improvement of a number of complementary techniques. Its emergence has been driven by the desire of cytogeneticists to develop better tools for mapping the precise location of genes on chromosomes, and to detect very small genetic defects not visible by gross staining of chromosomes.
The human genome project (HGP), a bold initiative to identify and map all human genes, has identified interest in FISH and has hastened the development of much-needed DNA probes. Current FISH techniques have also been made possible by the concurrent development of powerful immunological probes, a growing variety of excellent fluorescent dyes for microscopy and spectroscopy, and dramatic improvements in the objectives, illuminators and filters used for fluorescence microscopy.
The power and utility of FISH is due to many factors: (1) FISH can be used not only on isolated chromosomes and nucleus, but also whole cells within fixed, paraffin-embedded tissue sections; (2) it can detect relatively small defects (ability of detecting smaller defects constantly increases); (3) it can provide results relatively fast; (4) its moderate cost allows it to be used in most diagnostic and research laboratories; (5) adaptation can be developed for various probes and specimen types; and, (6) high specificity and sensitivity can be achieved; (7) within a short time, typically in the range of two hours.
Many FISH applications merely require from the cytogeneticist to look through the eyepieces of a microscope, or at the image on the monitor, and to determine whether a fluorescent label is present or absent. With somewhat more complex specimens, a simple count of one or two colored labels may be done. However, the ability to process digital images and extract numerical data from them adds a vast new set of capabilities to FISH techniques.
An appropriate imaging method, can enhance very faint FISH images so that labeled chromosomes and loci are clearly identifiable. Under readily achieved experimental conditions, the number of labeled sites can be automatically counted. In addition, the intensity at each labeled site can be measured and the amount of DNA calculated to reveal, for example, the number of copies present of a particular gene.
As discussed above, FISH can provide information on the location of the labeled probe, the number of labeled sites on each chromosome, and the intensity of labeling (the amount of genetic material) at each site. Centromeric (repetitive DNA) probes and chromosome paints are used to tag and count the number of copies present of each targeted chromosome. Locus-specific probes are used to map the location of small regions of genetic material. These types of probes can be used on intact interphase nucleus as well as metaphase chromosome spreads, and can be counted visually or automatically by a suitable algorithm. They are routinely used to identify genetic diseases characterized by having too many or too few copies of a specific chromosome, chromosome fragment, or gene.
In very early stages of some cancers, long before the cells are recognized as abnormal, there may be an increase in the number of specific genes, phenomenon known in the art as gene amplification, that are detectable using locus-specific probes as homogeneously stained regions (HSR) and/or double minute chromosomes. Using FISH to detect chromosome abnormalities in cancerous cells may point out the developmental stage of the disease, and therefore to enable selecting the most suitable treatment(s), many of which are stage specific in their effectiveness.
It is possible to uniformly label the entire surface of one specific chromosome by isolating the chromosome (using flow cytometry, for example), physically (e.g., by sonication) or enzymatically (e.g., by endonucleases) chopping it up, and generating a set of probes against all of the fragments. Whole chromosome probes, also known as chromosome paints, fluorescently label all copies of their target chromosome. One important application of chromosome painting is the detection of translocation of genetic material between two chromosomes, as characteristically occurs in early stages of certain cancers, yet other chromosome aberrations are also detectable.
For example, if chromosome A is specifically labeled with a green paint and chromosome B is labeled with a red paint, translocation of genetic material from A to B will appear as a green area juxtaposed to a red area (and vice versa).
Typically, chromosome paints generated from normal chromosomes are used to detect deletions or translocations on abnormal (patient) chromosomes. Reverse chromosome painting uses probes generated from an abnormal chromosome to identify DNA from various normal chromosomes which contributed material to the abnormal chromosome.
The method of the present invention, as exemplified hereinbelow in the Examples section, enables to paint the 24 different chromosomes comprising the human karyotype (i.e., genome), each in a different color, and simultaneously detect, identify and meaningfully display a color human karyotype, using a single hybridization procedure followed by a single short measurement.
A remarked improvement in multicolor fluorescent dyes used for labeling chromosome paints is the introduction of combinatorial fluorescent strategies (e.g., combinatorial labeling and combinatorial hybridization) which employ various combinations of few basic fluorescent dyes. For further details on combinatorial labeling see, Ried et al., (1992) Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc. Natl. Acad. Sci. USA 89, 1388-1392; and, Ried (January 1994) Fluoreszenz in situ Hybridizierung in der genetischen Diagnostik, Faculty of theoretical medicine, Ruprecht-Karls University Heidelberg, both are incorporated by reference as if fully set forth herein. For further details about combinatorial hybridization see du-Manoir et al. (1993) Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum. Genet. 90, 590-610, which is incorporated by reference as if fully set forth herein.
Numerous methods are available to label DNA probes for use in FISH assays, including indirect methods whereby a hapten such as biotin or digoxigenin is incorporated into DNA using enzymatic reactions. Following hybridization to a metaphase chromosome spread or interphase nucleus, a fluorescent label is attached to the hybrid through the use of immunological methods. More recently, fluorescent dyes have been directly incorporated into probes and detected without the use of an intermediate step. Standard FISH dyes include fluorescein, rhodamine, Texas-Red and cascade blue, and multiprobe FISH analysis can be accomplished by labeling different probes with different haptens or fluorescent dyes and combinations thereof, known in the art as combinatorial labeling see, Ried et al., (1992) Simultaneous visualization of seven different DNA probes by in situ hybridization using combinatorial fluorescence and digital imaging microscopy. Proc. Natl. Acad. Sci. USA 89, 1388-1392; and, Ried (January 1994) Fluoreszenz in situ Hybridizierung in der genetischen Diagnostik, Faculty of theoretical medicine, Ruprecht-Karls University Heidelberg, both are incorporated by reference as if fully set forth herein!. Alternatively, a pool of a given probe may be divided into sub-pools, each labeled with a different fluorophore, after which the sub-pools are regrouped to yield otherwise similar hybridization results, a method known in the art as combinatorial hybridization see, du-Manoir et al. (1993) Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum. Genet. 90, 590-610, which is incorporated by reference as if fully set forth herein!. According to both labeling strategies obtained are combinatorial probes. Thus, when any of the terms "combination of fluorophores" or "combinatorial fluorescent strategy" is used herein in this document and especially in the claims below, it refers both to combinatorial labeling and to combinatorial hybridization, as described above.
The use of combinatorial fluorophores for chromosome painting and karyotyping, multicolor chromosome banding and comparative genome hybridization is described in details in U.S. Pat. No. 5,817,462, and in Science magazine E. Schroeck et al. (1996) Multicolor spectral karyotyping of human chromosomes. Science, 273, 494-497!, both are incorporated by reference as if fully set forth herein.
The main progress described in Science is that whole genome scanning by spectral imaging allows instantaneous visualization of defined emission spectra for each human chromosome after fluorescence in situ hybridization (FISH). By means of computer separation (classification) of spectra, spectrally-overlapping chromosome-specific DNA probes are resolved and all human chromosomes are simultaneously identified.
This spectral imaging approach therein described combines Fourier spectroscopy, charge coupled device (CCD)-imaging, and optical microscopy to measure simultaneously at all points in the sample emission spectra in the visible and near-infrared spectral range. This allows the use of multiple spectrally overlapping probes. The approach is based on the measurement of a discrete spectrum (identified from a sequence of intensities at every pixel measured at many different wavelengths), which facilitates the discrimination of multiple fluorophores. In dramatic contrast to conventional epifluorescence microscopy in which fluorochrome discrimination is based on the measurement of the fluorescence intensity through a small number of narrow band fluorochrome specific optical filters see, Speicher et al. (1996) Nature Genetics. 12:368-375!, the use of spectral karyotyping, as therein described, allows all the available information present in the emitted photons within the spectrum of emitted light, to be used for analysis.
The spectral-based method for discriminating spectrally overlapping fluorophores (classification) is readily extended to a large number of fluorochromes, provided there are measurable and consistent differences in the emission spectrum of each fluorochrome.
Simultaneous identification of each human chromosome in metaphase preparations, an approach referred to as spectral karyotyping, is also reported. To this end, chromosome-specific composite libraries generated by polymerase chain reaction (PCR) from flow-sorted human chromosomes are directly labeled with nucleotides conjugated to five different fluorophores or combinations thereof A composite probe set containing all 24 chromosomes is then hybridized to metaphase chromosomes. Chromosome-specific labeling is achieved by suppression hybridization. Specifically, repetitive sequences in the composite libraries are blocked by the addition of an excess of unlabeled human Cot-1 DNA.
The hybridization is presented in both RGB display and classification colors. Display colors allow all human chromosomes to be readily visualized after spectral imaging, and based on spectral measurements at each pixel, a chromosome classification algorithm is applied to spectrally karyotype all human chromosomes. One of the most important analysis algorithms is the spectral-based classification algorithm that enables multiple different spectra in the image to be identified and highlighted in classification-colors. This allows assignment of a specific classification-color to all human chromosomes based on their spectra. This algorithm assumes that the (reference) spectrum of each chromosome has been measured and stored in a reference library in the computer. A distinguishing classification-color is assigned to each pixel in the image according to the classification-color assigned to the reference spectrum that is most similar to the spectrum at that given pixel. A minimal square error algorithm as shown in Equation 1: ##EQU1## is computed for every pixel, in which I.sub.x,y (.lambda.) is the normalized spectrum at pixel coordinates x,y and I.sub.n (.lambda.) represents the normalized reference spectrum for each of the chromosome n=1, 2, . . . , 23, 24. After calculating the value of S.sub.x,y,n for all reference spectra, the smallest value is chosen and an artificial classification-color is assigned to that pixel in accordance with the classification-color assigned to the most similar reference spectrum.
The potential of spectral karyotyping as a screening method for chromosomal aberrations was further explored by analyzing clinical samples from multiple laboratories where conventional banding methods or FISH with chromosome painting probes had been previously performed. In all cases, G-banding and spectral karyotyping revealed consistent results. In some cases, Giemsa-banding was not sufficient to entirely interpret the chromosomal aberrations. In these cases, the diagnosis of chromosomal aberrations by spectral karyotyping was confirmed with conventional dual-color FISH analysis. The smallest discernible aberration analyzed for this report was a translocation t(1;11)(q44;p15.3) in which the reciprocal translocation was unrecognizable by conventional banding analysis. The origin of the chromosomal material that contributed to the reciprocal translocation was correctly classified. The translocated segments on chromosomes 1 and 11 had been confirmed by subtelomere specific cosmid probes for chromosomes 1q and 11p. On the basis of the location of the probes utilized, the size of the alteration was estimated to be >1,500 kbp. In a second case, banding analysis suggested a translocation of a segment of chromosome 4 to chromosome 12. Spectral karyotyping unambiguously identified and classified the origin of the additional chromosomal material as being derived from chromosome 4. To determine the limit of sensitivity of spectral karyotyping, a case with a submicroscopic translocation (unrecognizable in both metaphase and prometaphase chromosomes) involving chromosomes 16 and 17 was examined. This t(16;17) had been previously demonstrated by FISH with cosmid probes and the reciprocal interchange of chromatin estimated at approximately 500 kbp. Spectral karyotyping with metaphase chromosomes from this patient failed to identify the known t(16;17) suggesting that the limit of sensitivity for metaphase chromosome analysis with currently available painting probes to be between 500-1,500 kbp.
To demonstrate that spectral karyotyping is an approach that can be used to complement conventional banding analysis, hybridization on previously G-banded chromosomes was performed. Probably due to the trypsin digestion that is required for G-banding, the signal intensity was slightly reduced as compared to metaphases that were not previously G-banded. The loss of signal intensity was approximately 10%, and could therefore easily be compensated for by prolonged exposure times. A slightly increased noise at the edges of previously G-banded chromosomes compared to non G-banded chromosomes was also observed. However, the classification of the metaphase could be readily achieved.
Thus, according to the above described approach, first, chromosomes of a single normal karyotype are identified by a conventional chromosome banding technique (e.g., G-banding or R-banding). Second, the same chromosomes are hybridized with chromosome paints as described above. Third, the average spectrum characterizing pixels attributed to any chromosome type (e.g., 1-22, X and Y in human male) as previously determined by chromosome banding is calculated and the resulting spectra (e.g., 24 for human) form a library of reference spectra. Fourth, the reference spectra are thereafter used for classification of pixels of new karyotypes into their chromosomes.
Nevertheless, as was experimentally observed, this approach is not always successful. In other words, in some cases new karyotypes do not appropriately classify. This is especially the case when abnormal or aberrant karyotypes, such as karyotypes of cancer cells, are analyzed. This may be due to one or more of the following reasons. First, differential hybridization efficiency. Second, chromosomes of different sources consistently behave in a different manner with respect to the hybridization, light emission, etc. And third, the measurement device is not identically calibrated in each measurement.
Nevertheless, it was further observed that when the reference spectra were used for karyotyping the chromosomes from which they were derived, best classification results were achieved. In other words, best results are achieved when the reference spectra employed are internal spectra. As described above, this, however, requires identification of the chromosomes via the conventional chromosome banding technique prior to classification. This, in turn, limits the scope of use of the classification method since (i) the method is not readily automateable; (ii) a highly trained cytogenetecist is required for analysis of the conventional banding pattern of the chromosomes; and (iii) in many cases of aberrant karyotypes, such as cancer cells karyotypes, the conventional banding pattern is not informative and therefore not conclusive.
The present invention is of a method for identifying more prominent reference spectra for chromosome classification, which reference spectra are calculated substantially automatically for each karyotype from spectral information derived from each karyotype. In other words, the present invention is of method for identifying internal reference spectra for chromosome classification, which reference spectra are calculated substantially automatically for each karyotype. Using internal reference spectra for classification overcomes the above described limitations of the prior art.


A street light may include a pole and a head attached to the pole. The head may include a lighting module. The lighting module may include a light-emitting device configured to emit light, a thermal interface configured to conduct heat away from the light-emitting device, an optical element configured to transmit the emitted light in a light distribution pattern on an area located a distance away from the lighting module, and a reflective surface configured to redirect a portion of the light transmitted by the optical element.

The present disclosure relates to light sources and, more particularly, to a lighting module.
A light-emitting device, such as a light-emitting diode (LED), is an attractive candidate for replacing conventional light sources such as incandescent, halogen and fluorescent lights. LEDs have substantially higher light conversion efficiencies than incandescent and halogen lights and longer lifetimes than these types of conventional light sources. Some types of LEDs have higher conversion efficiencies than fluorescent light sources. LEDs require lower voltages than fluorescent lights and contain no mercury or other dangerous materials. Some light-emitting devices have been used to replace high-intensity discharge (HID) lights to provide high levels of light over large areas that require greater energy efficiency or light intensity. Such areas include roadways, parking lots, pathways, large public areas, and other outdoor applications.


A method of enforcing security rules for a packet on a host is provided. The method at a security service dispatcher, determines a dispatching action on a packet for each of a group of security services. Each security service is for enforcing a set of security rules on each packet. The method for each security service, sends the packet to the security service when the dispatch rule for the security service indicates that the set of security rules of the security service has to be enforced on the packet. The method for each security service, bypasses the enforcement of the security rules of the security service when the dispatch rule for the security service indicates that the set of security rules of the security service has to be bypassed for the packet.

A flow-based software switch operates on a host by matching incoming packets with one or more flow entries. Each flow entry includes a set of matching criteria and a set of actions. The matching criteria specify a subset of the packet header values for which it requires a match. When a packet matches the set of matching criteria of a flow entry, the action or actions specified by the corresponding set of actions are performed on the packet.
Distributed firewalls provide the ability to specify firewall rules for enforcement at different enforcement points within a network. Distributed firewall rules are specified at the management plane of the flow-based software switch and pushed down to the virtualization software of the host. It is desirable to allow third party networking services to provide security and firewall rules and enforce them in the same pipeline that enforces the distributed firewall rules on the host.

Third-party service chaining using packet encapsulation in a flow-based forwarding element


A multi-axis machine includes a horizontally-displaceable carriage, a vertically-displaceable column, a spindle supported distally of the column, a motor configured to change a position of at least one of the carriage, the column, or the spindle; and an impact detection mechanism. The impact detection mechanism includes a first plate, a second plate secured distally of the first plate, and a sensor configured to detect a motion of the second plate with respect to the first plate.

CNC machines, such as CNC routers, are used to rout, cut, drill, shape, or perform other processes on various materials, such as wood, plastic, phenolics, aluminum, or others, forming one or more desired objects. Some CNC machines, which are referred to as "5-axis" machines, have the ability to move in five different degrees of freedom. At least some 5-axis machine employ a stationary base, which has considerable size and weight to stabilize the machine. An upright, stationary gantry is typically mounted to the stationary base, which rests on the floor. Some machines include one or more moving tables that are mounted to the top of the stationary base. The stationary or fixed gantry must have a sufficient size and stiffness, which can be considerable, in order to adequately support components such as a movable column, which can be attached to the stationary gantry, and a machining head at the end of the column. When one or more moveable tables are included in the machine, these tables may move on bearings attached to rail ways in a linear degree of freedom. During operation, the carrier moves on the gantry in a linear direction parallel to the gantry. The column itself moves up and down with respect to the gantry in another linear direction. The machining head carrier rotates in a first plane, while the machining spindle rotates in another plane. The machining head carrier rotates in a third plane.
If, during operation, one or more of the axes experiences an out of tram state, or out of alignment state, due to a collision or other impact, the program executed on the controller for controlling the CNC machine may produce an item that is unusable. When unusable items are produced, a significant amount of time and material are wasted. Also, out of tram conditions cause loss of time, in terms of both production and manpower, to have a skilled mechanic to realign the machine so it is back in tram. Realignments also increase cost. Therefore, a design that would prevent at least some collisions from producing an out of tram state would be beneficial.

Method and system for z-axis impact resistance for machining


A modulator including a waveguide propagating an electromagnetic wave of given wavelength (λ) with absorption. Means such as an electrical junction enable the residence time of the electromagnetic wave in the guide to be modified. A corresponding modulation method is also provided.

Modulators are devices the object whereof is to control the transmission of a wave, for example the transmission of light in the case of optical modulators. This concept therefore covers devices that can vary the intensity of the wave transmitted continuously, or discontinuously, for example on an all or nothing basis in the case of switches.
At present the aim is to design modulators with a structure such that they can be integrated into components fabricated in silicon-based materials with a view to simplification of the fabrication of the whole and reduction of the size thereof.
In this context, it has already been proposed to modify the refractive index of a material by injection or depletion of charge carriers, for example as described in the document European Patent No. EP 1 403 684. Such modification of the index can lead to spectral displacement of a resonance of the waveguide or a shifting of the phase of the wave, which is then generally made to interfere with a wave that has not been phase-shifted (Mach-Zehnder device).
One such Mach-Zehnder device is described in U.S. Patent Application No. 2003/161565, for example, according to which the group velocity is caused to vary in one branch of the device in order to obtain a phase-shift of the signal in that branch relative to the signal that is traveling in the other branch of the device.
In both cases (displacement of a resonance or interference of phase-shifted waves), the resulting wave, and in particular its intensity, varies as a function of the density of the charge carriers, which can itself be controlled by an electrical voltage.
However, because of the physical phenomena utilized, modulation is obtained in these devices only over a narrow frequency band. Moreover, Mach-Zehnder devices have a relatively complex structure because they utilize two branches that must additionally be coupled to the main guide of the electromagnetic wave.
Modulating the absorption of a material so as to modulate directly the intensity of the wave that passes through it has also been proposed. For example, such solutions have been proposed in the papers "Current induced intersubband absorption in GaAs/GaAlAs quantum wells", A. Fenigstein et al., PPL. Phys. Lett. 66 (19), 8 May 1995, and "Electromodulation of the interband and intraband absorption of Ge/Si cells assembled islands", M. Elkurdi et al. Physica E16 (2003) 450/454.
However, the low absorption of silicon-based materials rules out the generation of high modulation of the intensity of the transmitted wave using known techniques, which therefore make the production of an efficient and compact modulator impossible.

Waveguide modulator and related modulation method


A method for operating a motor vehicle diesel engine having an exhaust emission control system is provided. The emission control system includes an oxidation catalytic converter, a particle filter, and an SCR catalytic converter, in which the exhaust gas that is discharged from the diesel engine is passed through the oxidation catalytic converter before passing through the particle filter and the SCR catalytic converter. A regeneration of the particle filter with thermal soot burn-off is occasionally carried out, during which the diesel engine is operated at an air-fuel ratio having a lambda value (λ) of at least approximately 1.0, and air is added to the exhaust gas after it exits the oxidation catalytic converter and before it enters the particle filter air, so that soot deposited on the particle filter is burnt-off.

Exemplary embodiments of the present invention relate to method for operating a motor vehicle diesel engine having an exhaust emission control system, comprising an oxidation catalytic converter, a particle filter, and an SCR catalytic converter, in which exhaust gas discharged from the diesel engine is passed through the oxidation catalytic converter before passing through the particle filter and the SCR catalytic converter.
PCT Patent Publication WO 99/39809 A1 describes an exhaust emission control system provided for a diesel engine, having an oxidation catalytic converter, a particle filter, and an SCR catalytic converter situated one behind the other.
In exhaust emission control systems having a particle filter and an SCR catalytic converter, it is generally problematic that, due to the operating conditions, nitrogen oxides (NOx) are emitted to the surroundings largely unconverted during thermal regeneration of a particle filter in which soot is burnt-off.
Exemplary embodiments of the present invention are directed to a method for operating a motor vehicle diesel engine having this type of exhaust emission control system, the method allowing a reduction in NOx even when a thermal particle filter regeneration with soot burn-off is performed.
For the method according to the invention, a regeneration of the particle filter with thermal soot burn-off is occasionally carried out, and during the regeneration of the particle filter, the diesel engine is operated at an air-fuel ratio having a lambda value of at least approximately 1.0, and air is added to the exhaust gas after it exits the oxidation catalytic converter and before it enters the particle filter air, so that burn-off of soot deposited on the particle filter is made possible.
The invention is based on the finding that typical diesel oxidation catalytic converters are able to convert NOx as well as reducing exhaust gas components such as carbon monoxide (CO) and hydrocarbons (HC) into harmless components, even at high exhaust gas temperatures, when the diesel engine is operated at an air-fuel ratio having a λ value of at least approximately 1.0. Catalyst formulations for diesel oxidation catalytic converters with or without oxygen storage capacity are known to those skilled in the art, so that no particular discussion of such is provided herein. In any case, coated supported catalysts, in which a metal or ceramic substrate is provided with a washcoat coating containing noble metal, are typical. Preferred noble metals are those of the platinum group, in particular platinum itself.
The SCR catalytic converter is a catalytic converter that is able to selectively and continuously reduce NOx under oxidizing conditions, i.e., at λ>1.0, using ammonia (NH3).
In this regard, the λ value characterizing the air-fuel ratio is understood to mean, as is customary, a ratio of the quantity of oxygen actually present in the combustion air-fuel mixture to the minimum quantity of oxygen theoretically required for complete combustion of the fuel. A lean air-fuel mixture having excess air therefore has a λ value of greater than one. On the other hand, a rich air-fuel mixture having excess fuel has a λ value of less than one. In the absence of oxygen sources or sinks in the exhaust gas system, the lambda value in the exhaust gas (exhaust gas λ) corresponds to the lambda value of the air-fuel mixture (combustion λ) with which the engine is operated. For simplicity, therefore, reference is made below only to a λ value, or λ for short, when differentiation is not necessary.
Due to the addition of air to the exhaust gas according to the invention before the exhaust gas enters the particle filter, the particle filter is enriched with oxygen to a greater or lesser degree, so that a soot burn-off that regenerates the particle filter may proceed, a prerequisite being a prior temperature increase to an appropriately high temperature. A temperature of the exhaust gas or of the particle filter of greater than 550° C. is typically necessary for thermal soot burn-off. A burn-off rate that is customarily sought is usually achieved only above 650° C. At such high exhaust gas temperatures, the effectiveness of an SCR catalytic converter, also provided in the exhaust emission control system, with regard to NOx conversion is already greatly reduced. This is particularly true when the SCR catalytic converter is situated relatively close to the particle filter. In the present case, however, the oxidation catalytic converter may take over this function during the particle filter regeneration. As a result, removal of NOx from the exhaust gas is achieved even during a particle filter regeneration.
A so-called wallflow filter based on silicon carbide or aluminum titanate, which may optionally have a catalytically active coating on the channel walls, is preferably used as a particle filter.
A secondary air pump may be used for supplying air to the exhaust gas between the oxidation catalytic converter and the particle filter. It is likewise possible to withdraw air from a compressed air store, or to provide air by branching off from an intake tract by means of a turbocharger. A device for variably, in particular controllably, providing quantities of air is preferred.
In one embodiment of the invention, an oxidation catalytic converter having a three-way catalyst coating is used. This involves a catalyst material, which in a narrow range around λ=1.0, is able to catalyze a conversion of NOx as well as reducing exhaust gas components such as CO and HC to harmless products. The catalyst coating typically contains platinum and/or palladium as well as rhodium, and also a material such as cerium oxide that is able to store and release oxygen. Appropriate catalyst formulations are known to those skilled in the art, in particular from applications regarding exhaust gas emission control of gasoline engines. As a result of this design, particularly effective removal of harmful exhaust gas components, NOx in particular, specifically when carrying out a particle filter regeneration, is achieved.
In another embodiment of the method, during a regeneration of the particle filter the addition of air is carried out with a mass flow such that the burn-off of soot deposited on the particle filter occurs at a predefinable rate. The soot burn-off rate is preferably determined by means of a temperature sensor that is able to detect, directly downstream from and/or in the particle filter, a quantity of heat released during the soot burn-off due to the resulting temperature development. Since the rate of the soot burn-off is a function of the oxygen partial pressure of the exhaust gas, the soot burn-off may be controlled or regulated via the added quantity of air. In this way, for example overheating of the particle filter is avoidable in that the added quantity of air, and thus the soot burn-off rate, is reduced or kept low. Supplying air which is regulated or controlled by means of a lambda sensor for achieving a desired soot burn-off rate is likewise possible. Since the air which promotes soot burn-off is supplied from an external source, engine operation which is independent from the air flow rate is made possible.
In another embodiment of the method, outside operating phases of a particle filter regeneration, the diesel engine is operated with excess air that is typical for normal diesel engine operation, and ammonia or a reducing agent, in particular an aqueous urea solution, which is capable of splitting ammonia is added to the exhaust gas before it passes through the SCR catalytic converter. NOx reduction occurs with the aid of the SCR catalytic converter. At the same time, removal of the oxidizable exhaust gas components by means of the oxidation catalytic converter is made possible.
In another embodiment of the method the exhaust gas is led through the SCR catalytic converter before and/or after passing through the particle filter. The SCR catalytic converter may be provided as a separate component upstream and/or downstream from the particle filter. In another particularly advantageous embodiment of the invention the exhaust gas is led through an SCR catalytic converter designed as a coating of the particle filter. The coating of the particle filter with an SCR catalyst material may be provided on the uncontrolled gas side or the clean gas side of the filter-active channel walls of the particle filter. It is preferred that the clean gas side is provided, at least on the downstream portion of the particle filter, with a coating containing an SCR catalyst material.
Further advantages, features, and particulars of the invention result from the following description of preferred exemplary embodiments, and with reference to the drawings. The features and feature combinations mentioned above in the description, as well as the features and feature combinations mentioned below in the description of the figures and/or shown in the figures alone, are usable not only in the particular stated combination, but also in other combinations or alone without departing from the scope of the invention.

Method for operating a motor vehicle diesel engine


A liquid crystal panel device, being able to transfer heat generation within each of cells building up a panel, into an outside thereof, effectively, therefore being suitable for use in a liquid crystal projection, etc., comprises: a TFT substrate 30, which is formed with semiconductor portions 24 and pattern layers 28 in large numbers on the surface thereof; an opposed substrate 29; and a liquid crystal layer 27 hermetically enclosed between them, wherein heat interruption layers 31 are formed on a surface of the opposed substrate, in opposite to the liquid crystal layer, at the same positions to those of the semiconductor portions, which are formed on the FTF substrate 30, and further comprises an anti-dust glass plate 23 disposed at the light-inlet side thereof, so as to define a space, including a gap 11 and grooves 32, for receiving a cooling liquid 11 therein, on the opposite side surface of the opposed substrate, in vicinity of the heat interruption layers, thereby achieving cooling, effectively, so as to obtain the liquid crystal panel device being long in the lifetime and high in reliability thereof.

The present invention relates to a cooling structure of a liquid crystal panel device, in particular, to the cooling structure of the liquid crystal panel device for use in a liquid crystal projector or the like, accompanying heat generation within an inside thereof, and it further relates to an apparatus, into which such the liquid crystal panel is applied.
In various kinds of apparatuses, each of which applies the liquid crystal panel therein, and in particular, in the liquid crystal panel, which is applied into the liquid crystal projector, etc., for example, since it intercepts and/or absorbs the light from a light source, the liquid crystal panel generates heat within an inside thereof; therefore, there is pointed out a problem that it shorten the lifetime of the liquid crystal therein. For this reason, conventionally, a cooling device is provided for the purpose of protecting the liquid crystal panel from such the heat generation. As such the cooling structure for the liquid crystal panel, in particular, applying therein a cooling method of being superior in cooling efficiency, there is already known the structure of sticking a cooling liquid container onto the liquid crystal panel, in which a cooling liquid is hermetically filled up with, as is shown in the following Patent Document 1. And, as is shown in the following Patent Document 2, there is also already known the structure of sticking a cooling liquid container, being transparent and sheet-like, between the liquid crystal device and a polarizing plate located at an inlet side or an outlet side.
Patent Document 1: Japanese Patent Laying-Open No. Hei 5-107519 (1993); and
Patent Document 2: Japanese Patent Laying-Open No. Hei 7-248480 (1995).
Also, as other cooling structure than those, as is shown in the following Patent Document 3, for example, there is also known the structure, in which a liquid crystal panel unit is stuck up between two (2) sets of hermetically sealed containers, each of which is built up with two (2) pieces of transparent glass plates and hermetically filled up with a cooling liquid within an inside thereof.
Patent Document 3: Japanese Patent Laying-Open No. Hei 11-202411 (1999).
Moreover, as is shown in the following Patent Document 4, there is already known a liquid crystal projector having the cooling structure, in which the transparent sealed containers are disposed, respectively, being stuck on the liquid crystal panels, in particular, on the light source side thereof, building up a plural number of liquid crystal bulbs in a projector apparatus, wherein a liquid is circulated within an inside thereof, so as to absorb the heat generated in the liquid crystal panel therein, thereby discharging the heat through a heat exchanger provided in an outside of the liquid crystal panel.
Patent Document 4: Japanese Patent Laying-Open No. Hei 5-264947 (1993).
However, with such the conventional arts as was mentioned above, they capture the heat generation within the liquid crystal panel device, from a macro viewpoint thereof, i.e., the liquid crystal panel is considered to be only a heat generation body. Namely, with such the conventional arts mentioned above, the consideration was not paid sufficiently on the mechanism of generating the heat within a portion of the liquid crystal panel in the liquid crystal projector, etc., for example, and for this reason it is not sufficient for achieving the cooling of the liquid crystal panel device at high efficiency.

Liquid crystal panel device having a cooling medium within grooves which are formed vertically/horizontally along the heat interruption layer


Clamping device and method of connecting clamping device that includes a clamping band having a first end and a second end and an engagement geometry on at least one surface; and a tensioning head having a housing attached to the clamping band in the region of the first end and through which the second end of the clamping band is guidable, and an engagement element in the housing that is engageable with the engagement geometry. The engagement element is connected to the housing by a flexible connection, so that the engagement element is swivelable between a pull-through position, in which the clamping band may be pulled through the housing, and an engagement position, in which the clamping screw may engage with the engagement geometry.

1. Field of the Invention
The invention relates to a clamping device with a clamping band having a first end and a second end and a tensioning head having a housing attached to the clamping band in the region of the first end and through which the second end of the clamping band can be guided. The clamping band has an engagement geometry on at least one surface that can be engaged with an engagement element in the housing.
2. Discussion of Background Information
A clamping device of this type is for example used as a cable tie in order to consolidate a bundle of cables or lines or to attach a bundle of this type or only a single cable to a holder. For this purpose, the clamping band is guided around the parts that are to be connected to one another. The second end of the clamping band is then inserted into the housing of the tensioning head and pulled through the housing so that the engagement element engages with the engagement geometry on the surface of the clamping band. In most cases, this engagement cannot be released again or can only be released again with considerable effort. In most cases, only a limited tension force can be applied radially inwards using the clamping band, which is easily sufficient for the consolidation of cables but may no longer suffice for other purposes of use. This also applies if a tool, for example pliers, is used to tighten the clamping band.
However, a clamping device of this type has the advantage that the space bordered by the clamping hand that is inserted into the housing can be quickly varied in a simple manner within relatively wide limits. This variation occurs simply by pulling the second end of the clamping band through the housing.


A process for preparing a 2-cyanobiphenyl compound represented by the formula (II): ##STR1## wherein R.sup.1 is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or hydrogen atom, from a phenylmagnesium chloride compound represented by the formula (I): ##STR2## wherein R.sup.1 is as defined above. According to the process, a 2-cyanobiphenyl compound represented by the formula (II) can be economically, simply, industrially and advantageously prepared.

1. Field of the Invention
The present invention relates to a process for preparing a 2-cyanobiphenyl compound. More particularly, the present invention relates to a process for preparing a 2-cyanobiphenyl compound, which is useful as an intermediate of pharmaceuticals such as antihypertensives.
2. Discussion of the Related Art
Conventionally, there have been known processes for preparing 2-cyanobiphenyl compounds, including (A) a method of reacting a phenylmagnesium halide compound with a 2-halobenzonitrile in the presence of a manganese(II) halide (Japanese Patent Laid-Open No. Hei 6-9536); and (B) a method of reacting a phenylmagnesium halide compound with a 2-halobenzonitrile in the presence of a metal manganese and trimethylchlorosilane (Japanese Patent Laid-Open No. Hei 8-109143).
In the process (A), however, since the manganese(II) halide has hygroscopic property, there arises such a problem that much care is necessitated in handling.
In the process (B), since it is necessary to add an equimolar amount of a metal manganese to the 2-halobenzonitrile, the metal manganese has to be treated after terminating the reaction, thereby industrial wastes are generated. Therefore, this method is not industrially advantageous.
In addition, there have been known processes for preparing 4'-methyl-2-cyanobiphenyl, which is one of the 2-cyanobiphenyl compounds, including (C) a process for preparing 4'-methyl-2-cyanobiphenyl comprising treating a 4-methylphenylmagnesium halide and a 2-halobenzonitrile with a Ni catalyst in the presence of a zinc halide and an amine compound (Japanese Patent Laid-Open No. Hei 8-231454); and (D) a process for preparing 4'-methyl-2-cyanobiphenyl comprising reacting a phenylmagnesium halide with a zinc halide, and treating the resulting product with 4-bromobenzonitrile in the presence of a Ni catalyst (J. Org. Chem. 42. 1821, (1977)).
However, in the process (C), an expensive tertiary amine has to be used as an amine compound in order to give a reaction yield of at least 80%, and thereby there arise economical disadvantages.
In addition, in the process (D), an expensive bromide or iodide has to be used as a halide, which is a reaction substrate, and thereby there arise economical disadvantages as in the process (C).
In view of the problems in the prior art mentioned above, an object of the present invention is to provide a method for economically, advantageously, simply and industrially preparing a 2-cyanobiphenyl compound.
These and other objects of the present invention will be apparent from the following description.

Process for preparing 2-cyanobiphenyl compound


The present disclosure is a method of dynamic creation of games, the method comprising the steps of receiving keyword(s) from a user, performing a search operation comprising of the keyword(s) to generate a set of search result(s), selecting at least one search result and dynamically creating said game from the said search result.

The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
Search engines such as Google, Bing, and Yahoo Search are well known in the art and are used by users to find information on any topic. Such search engines instantly return relevant documents from vast data sources such as the Internet. In order to use a search engine, a user seeking information on a desired topic generally inputs a search query consisting of keyword(s) or phrase(s) relevant to the topic into the search interface of the search engine. In response, the search engine typically displays a report with a prioritized list of links pointing to relevant documents containing the search keywords. Oftentimes, a short summary of text i.e., extract/snippet is also included for each result. The extract/snippet is that portion or portions of the text in the document that contain the keywords from the search query.
A user may want to play games online for a variety of reasons. Some of the games that the user may play online may be question and answer games. The user is presented with a question and based on how close his answer is to the actual answer he/she may be awarded point(s). Such online games generally suffer from several drawbacks. The question/answers are composed manually and may not be available in the topic that the user may be interested in. Further, the question and answers may become stale within a short time and need to be manually updated constantly.
Thus, there is a need to create games dynamically that do not become stale and are not limited to few topics.

System and method for creating dynamic games making use of a search engine


The invention provides polypeptides of transcription factor DP-3 which exists in four isoforms produced by alternative splicing of mRNA, nucleic acid encoding the polypeptides and the use of such nucleic acid and polypeptides in assays. Two isoforms of DP-3 contain a region, designated the E region, which is a nuclear localization signal and is involved in a further level of regulation of DP-3 and its ability to bind to E2F-1 and regulate the cell cycle.

A wealth of cell cycle research supports the idea that the cellular transcription factor DRTF1/E2F plays a pivotal role in coordinating early cell cycle events by integrating transcription with cell cycle progression (Nevins, 1992; La Thangue, 1994). For example, the negative effects on cellular proliferation exerted by the retinoblastoma tumour suppressor gene product (pRb) appear to be mediated in part through the ability of pRb to regulate the transcriptional activity of DRTF1/E2F (Heibert et al., 1992; Zamanian and La Thangue, 1992). Since many target genes encode proteins which contribute to cell cycle progression, pRb may influence proliferation through a regulation of DRTF1/E2F. The importance of this pathway in cell cycle control is underscored by the fact that natural mutations in Rb, which frequently occur in human tumour cells, encode proteins which fail to bind to DRTF1/E2F and that the oncogene products of certain tumour viruses, such as adenovirus Ela, human papilloma virus E7 and SV40 large T antigen bind pRb, an interaction which correlates with a potential to mediate cellular transformation (Nevins, 1992; La Thangue, 1994).
Other members of the pRb family (known generically as `pocket proteins`) interact with DRTF1/E2F and regulate its transcriptional activity. Two other members of the family, plO7 and p130, associate with DRTF1/E2F in temporally distinct fashions during cell cycle progression, p130 predominantly during G0 and p107 in late G1 and into S phase (Shirodkar et al., 1992; Cobrinik et al., 1993). Like pRb, the physical association of p107 leads to transcriptional inactivation (Schwarz et al., 1993; Zamanian and La Thangue, 1993), and p107 can negatively regulate cell cycle progression (Zhu et al., 1993) but in contrast to Rb is not known to be mutated in tumour cells.
Several other molecules involved in regulating the cell cycle interact with DRTF1/E2F. Either cyclin A or E, together with the catalytic kinase subunit cdk2, can stably interact in a fashion which is dependent upon the presence of p107 or p130; again these events are under temporal control during the cell cycle (Lees et al., 1992; Cobrinik et al., 1993; Li et al., 1993). The physiological role of the cyclin A/cdk2 and cyclin E/cdk2 kinase in this context is unknown. In contrast, there is persuasive evidence that cyclins A and E influence the growth regulating capacity of pRb (Hinds et al., 1992). An alternative type of interaction can occur between a cyclin A-dependent kinase and DRTF1/E2F (Dynlacht et al., 1994; Krek et al., 1994). The biochemical consequence of this interaction is reduced DNA binding activity which is believed to be involved with the physiological control of transcription at later times during the cell cycle.
Progress has been made in understanding the molecular composition of DRTF1/E2F. Specifically, generic DRTF1/E2F DNA binding activity arises when members of two distinct families of proteins interact as DP/E2F heterodimers (Lam and La Thangue, 1994), the prototype molecules of each family being E2F-1 (Helin et al., 1992; Shan et al., 1992; Kaelin et al., 1992) and DP-1 (Girling et al., 1993). Heterodimerization between DP and E2F proteins (Bandara et al., 1993; Helin et al., 1993; Krek et al., 1993; Girling et al., 1994) allows a variety of combinatorial interactions to generate an array heterodimers.
Information on the properties of E2F family members suggests that they perform a physiological role in dictating the nature of the pocket protein which physically interacts with the heterodimer. From the E2F family members characterised, it is believed that E2F-1, -2 and -3 interact with pRb (Ivey-Hoyle et al., 1993; Lees et al., 1993), E2F-4 with p107 (Beijersbergen et al., 1994; Ginsberg et al., 1994) and E2F-5 with p130 (Buck et al., 1995). An extreme C-terminal region in these E2F proteins required for the physical association of pocket proteins is interdigitated with a potent trans activation domain (Helin et al., 1993; Flemington et al., 1993). It is likely therefore that the temporally regulated association of pocket proteins with DRTF1/E2F during cell cycle progression reflects its dynamically changing composition.
In many types of cells DP-1 is a frequent component of DRTF1/E2F, for example in 3T3 cells where it is present in DNA binding complexes which occur throughout the cell cycle (Bandara et al., 1994). Another member of the DP family, DP-2, is expressed in a tissue-restricted fashion (Girling et al., 1994). However, apart from this distinction the biochemical and functional properties of DP-1 and DP-2 are similar (Girling et al., 1994).
Recently, two publications have documented the existence of a further member of the DP family of proteins (Wu et al., 1995; Zhang and Chellappan, 1995). The cDNA sequence presented in Wu et al. (1995) is derived from the human DP-3 locus. Zhang and Chellappan (1995) report an identical sequence apart from the addition of a single glutamine at position 97.

Transcription factor DP-3 and isoforms thereof


A keyword creation method and its apparatus to simply create keywords in user's retrieving a desired item of information from a vast amount of information. The habitual situation characteristics and the degree of typical liking tendency of a user are calculated on the basis of answers on daily items of the user, typical situation dependent keyword(s) of the user in one or more individual typical situations previously prepared is(are) created in accordance with the degree of typical liking tendency of the user and typical situation dependent keyword(s) is(are) revised in accordance with the habitual situation characteristics of the user, so that keyword(s) according to the actual situation of the user can be created.

1. Field of the Invention
The present invention relates to a keyword creation method and its apparatus, and is appropriately applied, for example, to a program retrieval system for retrieving the programs necessary for a viewer from many TV programs distributed via a broadcasting satellite.
2. Description of the Related Art
With a satellite broadcast system wherein TV programs are distributed via a broadcasting satellite to viewer, TV signals are digitalized and a vast number of programs are simultaneously distributed. In such a system, the number of programs selected by a viewer increases markedly.
Besides, with a system for providing various items of information from the host side to computer terminals via a telephone line or private line, a user on the terminal side selects the necessary item of information from a vast amount of information and requests it to the host side.
In an attempt to select such TV programs, items of information using a computer or the like, a viewer or user must retrieve a desired program or information item from a vast number of programs or a vast amount of information. In this case, a viewer or user selects a word or the like related to the genre of the program to be selected or the information item to be selected as the keyword and retrieves a desired program or information item by referring to it.
In a way of a viewer or user to directly input a keyword to a retrieval system, however, a viewer or user need to always learn and renew a knowledge concerning an up-to-date keyword or genre classification method of information repeatedly according as programs or information items are renewed and has difficulty in readily selecting a desired keyword.
Besides, there is a method comprising storing keywords such as genres or words selected by a viewer or user in the past as a selection history and using them as keywords at the time of future retrieval. At a first time of using a retrieval system according to this method, no history information is present and a viewer or user is compelled to directly select and input a keyword to the system and has such difficulty in readily selecting a keyword as the above-mentioned case.
In such a manner, there was a problem that the retrieval operation of a viewer or a user is complicated and it is difficult to readily select a required program or information item.

Keyword creation method and its apparatus


A thumb body is pivotally connected to a first mount, and a stiff-arm anchor is connected to and extends between the first mount and a second mount. The stiff-arm anchor is selectively removable from the first and second mounts. A stiff-arm support link includes a first end connected to the thumb body and a second end connected to the stiff-arm anchor. The thumb can be converted from a hydraulic mode to a stiff-arm or fixed mode by disconnecting the first end of a hydraulic cylinder actuator from the thumb body and disconnecting the second end of the hydraulic cylinder actuator from the second mount, and by installing the stiff-arm anchor and stiff-arm support link.

Thumbs for excavators are well known (the term "excavator" as used herein is intended to encompass excavators, backhoes, and other machines having an arm or "dipper stick" that carries a bucket or other work implement). These thumbs are secured to the arm of the excavator and are arranged relative to the bucket or other work implement so as to provide an opposable member to aid in grasping large or odd-shaped objects and/or for other purposes. The thumb includes a body having an inner end secured to the excavator arm and an outer end that is spaced outwardly from the arm. The outer end can have any of a wide variety of shapes and sizes, depending upon the work being performed, e.g., carrying logs, carrying demolition debris, lifting large rocks or metal plates, and similar activities.
Known thumbs are either a fixed or "stiff-arm" type that is set to a desired operative position, or a continuously remotely adjustable "hydraulic" type in which the angular position of the thumb body relative to the excavator arm is selectively continuously adjustable using a remotely controlled hydraulic cylinder or other actuator controlled by the machine operator from the operator's cab. These known thumbs cannot be quickly and conveniently changed from one type to the other once installed on an excavator, because the stiff-arm thumb requires a different base mounting structure to be installed on the excavator arm as compared to a hydraulic thumb.