The invention concerns methods and constructs for producing retroviral particles, in vitro, ex vivo or in vivo. It also concerns the use of said methods and constructs for transferring nucleic acids into cells. More particularly, the invention concerns a composition comprising the whole set of genetic elements required for constituting a retroviral particle, incorporated in one or several recombinant adenoviruses defective for all or part of the regions E1 and E4 at least (adenoviral/retroviral chimeric vectors).

The present invention relates to the field of biotechnology. More particularly, it concerns methods and constructs for producing retroviral particles in vitro, ex vivo or in vivo. It also concerns the use of such methods and constructs for transferring nucleic acids into cells.
Retroviruses are currently one of the main types of vector for transferring nucleic acids into cells. They are used for example for transferring nucleic acids in vitro or ex vivo (experimental studies, study of regulation, production of recombinant proteins, introduction of resistance genes or toxicity genes) or directly in vivo (establishment of animal pathological models, labeling or bioavaiiability studies, therapeutic use by grafting producer cells or injecting purified virus, etc.).
For all these utilizations, it is therefore important to have effective methods available for producing and administering retroviruses. In this respect, conventional methods are based on the use of packaging cell lines. Such cell lines are constructed in vitro and express the whole set of proteins required for constituting and packaging a defective retroviral vector in a retroviral particle. Such cell lines are exemplified by the cell lines PSICRIP [Danos and Mulligan, PNAS (1988) 85: 6460], PA317 [Miller and Buttimore, Mol. Cell. Biol. (1986) 6: 2895], or GP+ Env AM12 [Markowitz et al., Virology (1988) 167: 400]. However, the use of such cell lines can pose certain problems, related first to their construction and second, to their use.
For example, such cell lines must be stable, that is, express the retroviral functions in a continuous manner, without genetic rearrangements or loss of expression. In addition, such cell lines must be compatible with the potential pharmacological use of the retroviruses, and must therefore be established from cells that can be cultured, having little or no immunogenicity, etc.
Furthermore, it is important that the cell lines used produce fairly high viral titers free of replication-competent virus (RCV). The methods of retroviral preparation by means of packaging cell lines therefore necessarily comprise quality controls on both the viral stocks produced and the cell lines used. Finally, depending on the desired application, these production methods may have to be carried out under a high level of confinement, further complicating the industrial scalability of such methods.
To address these drawbacks, patent application WO 95/22617 proposed a new concept for producing retroviral particles that avoids the use of retrovirus packaging cells. This new concept consists in transforming a target cell in vitro, ex vivo or directly in vivo to a retrovirus producing cell, by introducing into this cell the whole set of genetic elements required for constituting a retroviral particle. This application provides in particular for transferring these elements by means of plasmid constructs or viral vectors of different origin. As a matter of fact, Feng et al. [Nature Biotechnology (1997) 15: 866] have described a specific embodiment of this new approach, using two first generation recombinant adenoviruses (i.e. defective for the E1 region) into which the retroviral genetic elements have been distributed in a precise arrangement.
The present application now describes a further improvement to the retroviral particle production methods described hereinabove, and the use for transferring nucleic acids.
The present application is based in particular on the use of recombinant adenoviruses for delivering to cells, in vitro, ex vivo or in vivo, the whole set of genetic elements required for constituting a retroviral particle. As compared to previously described works, the present application is based in part on the use of specific types of recombinant adenovirus and/or on a specific distribution of the retroviral genetic elements. As demonstrated in the present application, the methods and constructs according to the invention make it possible to obtain high levels of retroviral particle production, are effective, and display increased safety in vitro, ex vivo as well as in vivo. Furthermore, the defective recombinant retroviruses so produced are infectious, and are capable of transferring a nucleic acid into a cell with high efficiency.
A first subject of the invention therefore concerns a composition comprising the whole set of genetic elements required for constituting a retroviral particle, incorporated in one or several recombinant adenoviruses defective for all or part of the E1 and E4 regions at least.
In the context of the invention, the term xe2x80x9cgenetic elements required for constituting a retroviral particlexe2x80x9d refers to the whole set of nucleic acid sequences, coding and regulatory, which in cis or in trans are necessary and sufficient to constitute a retroviral particle, that is, a physical particle expressing the retroviral envelope at its surface, and inside of which are found the different proteins required to carry out a retroviral replication cycle, and a genome in a form which allows it to be reverse transcribed.
The organization of the retroviral genome is well understood, and comprises primarily the following elements:
An LTR region located at each end of the retroviral genome, serving in particular as origin of transcription and transcriptional promoter. This LTR region more specifically contains elements designated U3, R and U5 (see FIG. 5, for example). The U5 sequence, together with the U3 sequence, plays a key role during provirus integration.
A packaging sequence (Psi or "psgr"), involved in packaging the retroviral genome in the viral particle. The packaging sequence may further contain a region extending to certain elements of the gag gene, which have been reported to improve packaging efficiency.
Three coding regions, named gag, pol and env, coding for the core proteins (gag), enzymes (reverse transcriptase, protease, integrase), and the retroviral envelope (env), respectively.
To constitute a recombinant retroviral particle, a retroviral vector is generally constructed comprising genetic elements acting in cis, i.e., the LTR regions and the packaging sequence, and in which all or part of the gag, pol and/or env coding regions (acting in trans) have been deleted. Normally, such a retroviral vector also comprises a nucleic acid of interest (transgene). The coding regions not present or inactive in the retroviral vector are provided in trans (complementation functions) so as to be able to reconstitute a retroviral particle.
In a specific embodiment of the invention, the genetic elements therefore comprise a retroviral vector and nucleic acids coding for retroviral complementation functions (that is, for functions defective in the retroviral vector, eg., gag, pol and/or env).
In a more particular embodiment of the present invention, the genetic elements comprise:
a nucleic acid coding for a retroviral gag protein,
a nucleic acid coding for a retroviral pol protein,
a nucleic acid coding for an envelope protein, for example a retroviral env protein, and
a nucleic acid comprising, between two LTR regions, a retroviral packaging sequence and a nucleic acid sequence of interest.
To carry out the present invention, the genetic elements may be derived from different types of retrovirus, such as ecotropic and/or amphotropic viruses. In particular, these may be retroviruses belonging to the family of oncoviruses, lentiviruses or spumaviruses. In the oncovirus family, particular examples include the slow oncoviruses, which do not carry an oncogene, such as for example MoMLV, ALV, BLV or MMTV, and rapid oncoviruses, such as RSV for example. In the lentivirus family, examples include HIV, SIV, FIV or CAEV.
Furthermore, the LTR region or regions used may either be complete retroviral LTR regions, or subdomains allowing reconstitution of complete LTR regions after reverse transcription. Thus, the LTR regions used may comprise deletions of domains such as U3 and U5 for example. In a specific embodiment of the invention, the retroviral vector comprises a 5xe2x80x2 LTR deleted for the U3 region and a 3xe2x80x2 LTR deleted for the U5 region. The use of this type of construct allows in particular to stabilize the vector during the construction steps and to lower the risks of recombination. The genetic elements may be directly prepared from isolated retroviruses, according to methods known to those skilled in the art, and/or synthesized artificially. Such elements may be amplified in culture, as described in the examples. Moreover, the nucleic acids used may be DNA or RNA.
In a preferred variant, the genetic elements are such that they code for the retroviral gag and pol proteins and for an envelope protein allowing infection of human cells. More preferably still, the gag and pol proteins are proteins from retroviruses chosen from among MoMLV, ALV, BLV, MMTV or RSV, and the envelope protein is a protein from viruses chosen from A4070, GALV, RD114, VSV-G or rabies virus. It is understood that the invention may also be carried out by using variants or mutants of these proteins, having conserved their biological activity, or chimeric or hybrid proteins allowing to modify the tropism of the retroviral particle, especially by giving it specificity for certain cell types.
In a particular embodiment, the envelope protein is therefore a viral or cellular protein, allowing the retroviral particles to infect human cells. It is preferably a protein from a virus such as A4070, GALV, RD114, VSV-G or rabies virus. The preferred viral envelopes are A4070, GALV or VSV-G. The preferred gag and pol proteins come from the MoMLV retrovirus.
According to a specific embodiment of the invention, the genetic elements allow constitution of a lentivirus particle, and therefore derive, at least in part, from a lentivirus, such as HIV, SIV, FIV or CAEV in particular. The use of recombinant retroviruses prepared from lentiviruses has been described in the literature and offers certain advantages for transferring genes into quiescent cells [Poeschia et al., Nature Medicine (1998) 4: 354]. The present invention now makes it possible to exploit this property to achieve, under improved conditions, gene transfer by lentiviruses.
The disposition of the retroviral genetic elements in the adenovirus or adenoviruses may be accomplished in several ways.
Thus, in one variant embodiment, the invention concerns a composition comprising the whole set of genetic elements required for constituting a retroviral particle distributed into three separate recombinant adenoviruses.
In this particular embodiment, a composition according to the invention comprises for example a first recombinant adenovirus comprising, incorporated in its genome, the nucleic acid or acids encoding gag and pol; a second adenovirus comprising, incorporated in its genome, a nucleic acid encoding the envelope protein; and a third recombinant adenovirus comprising, incorporated in its genome, the retroviral vector.
In another, preferred variant embodiment, the invention concerns a composition comprising the whole set of genetic elements required for constituting a retroviral particle distributed into two separate recombinant adenoviruses. In this respect, an especially preferred composition in the context of the invention comprises:
a first recombinant adenovirus comprising, incorporated in its genome, one or several nucleic acids coding for the retroviral proteins gag and pol, and
a second recombinant adenovirus comprising, incorporated in its genome, a nucleic acid coding for an envelope protein such as defined hereinabove, and a nucleic acid comprising, between two complete LTR regions or subdomains allowing reconstitution of complete LTRs following reverse transcription, a retroviral packaging sequence and a nucleic acid sequence of interest.
The use of such a composition is illustrated in a general way in FIG. 1. As shown in the examples, this specific distribution of retroviral genetic elements makes it possible to obtain high titers of infectious retroviral particles, capable of efficiently and stably transferring a transgene into the cells of interest.
In this respect, a specific subject of the present application concerns
any defective recombinant adenovirus, characterized in that it comprises, incorporated in its genome, one or several nucleic acids coding for the retroviral proteins gag and pol, and
any defective recombinant adenovirus, characterized in that it comprises, incorporated in its genome, a nucleic acid coding for an envelope protein, and a nucleic acid comprising, between two LTR regions complete or not, a retroviral packaging sequence and a nucleic acid sequence of interest.
In particular, such adenoviruses may be defective for all or part of the E1 (E1A and/or E1B), E2, and/or E4 region, for example.
A further specific subject of the invention concerns a composition comprising two adenoviruses such as set forth hereinabove.
Another, equally preferred variant embodiment of the invention concerns a composition comprising the whole set of genetic elements required for constituting a retroviral particle, incorporated in a single recombinant adenovirus.
The special advantage of this embodiment is based notably on its simplified implementation due to the use of a single adenovirus.
It is understood that the compositions according to the invention can be adapted by those skilled in the art according to the structure of the retroviral vector, and particularly the defective retroviral genes therein. Thus, the vector used may be defective for one, two or all the retroviral genes gag, pol and env. Depending on the case, the composition and distribution of adenoviruses in the compositions of the invention may be readily adapted. However, a preferred embodiment is that in which the retroviral vector is defective for the whole set of genes gag, pol and env, as illustrated in the examples, and that adapted to producing recombinant lentiviruses.
In the compositions of the invention, the nucleic acid used coding for a retroviral protein gag, pol or env generally comprises a transcriptional promoter located 5xe2x80x2 of the coding region, and a transcriptional terminator located 3xe2x80x2 of the coding region. The promoters used may vary in their nature, origin and properties. The choice of promoter depends in fact on the desired use and on the transgene, in particular. Thus, the promoter may be constitutive or regulated, strong or weak, ubiquitous or tissue/cell-specific, or even specific of physiological or pathophysiological states (activity dependent on the state of cell differentiation or the step in the cell cycle). The promoter may be of eukaryotic, prokaryotic, viral, animal, plant, artificial or human, etc., origin. Specific examples of promoters are the promoters of the genes PGK, TK, GH, EF1-xcex1, APO, CMV, etc. or artificial promoters, such as those for p53. E2F or cAMP.
Preferably, the promoter controlling the expression of gag, pol and env is a strong constitutive promoter. Moreover, the promoter may also comprise an xe2x80x9cenhancerxe2x80x9d region to increase the efficiency of expression. The choice of the terminator region may also be effortlessly made by those skilled in the art, particularly among the terminators of the genes GH, SV40, EF1-xcex1, etc., widely described in the literature. Finally, the nucleic acids coding for gag and pol are often used in the form of a bicistronic unit, controlled by a single promoter and terminator, as is the case in the retroviral genome.
As noted hereinabove, the advantages of the present invention derive notably from the distribution of the retroviral genetic elements in the adenoviruses, and/or from the type of adenovirus used. In this respect, as underscored above, the adenoviruses used in the context of the present invention are primarily defective for all or part of the E1 region and the E4 region at least. As illustrated in the examples, together with an advantageous distribution of retroviral genetic elements, this organization of the adenoviral genome procures high safety and efficiency. Furthermore, the genomic structure of the recombinant adenoviruses used also allows the production of original and advantageous distributions of the retroviral genetic elements, such as notably the use of a single adenovirus or of a combination of two adenoviruses as illustrated hereinabove. The results show, in an especially advantageous manner, that the use of this type of adenovirus and/or of specific distributions of retroviral genetic elements according to the invention makes it possible to obtain high titers of infectious retroviral particles and long-term stability of the transgene (beyond 3 months). These entirely advantageous results are surprising in so far as the absence of the viral E4 region has been described as having a negative effect on the expression of sequences introduced into an adenoviral vector. Furthermore, the results presented show that, in vivo, the compositions according to the invention induce at least a 10- to 50-fold increase in the number of transduced tumor cells, as compared to administration of an adenovirus alone. These results thus confirm the advantageous and surprising properties of the present invention for transferring nucleic acids into cells.
The adenoviruses used to carry out the present invention are therefore advantageously defective for all or part of the E1 and E4 regions at least.
Advantageously these are so-called third generation defective recombinant adenoviruses, i.e. defective for all or part of the E1 and E4 regions, and possibly for the E3 region.
Specific variants of the invention comprise the use of adenoviruses harboring deletions affecting all or a functional part of the following regions:
E1, E4 and E3,
E1, E4 and E2,
E1, E4, E2 and E3,
the regions hereinabove as well as all or part of the genes encoding the adenovirus late functions (L1 to L5), or further still,
all the viral coding regions.
The genomic structure of adenoviruses has been largely described in the literature. In this respect, the genome of adenovirus Ad5 has been fully sequenced and is accessible from data bases (see notably GeneBank M73260). Likewise, parts or even all of other adenovirus genomes (Ad2, Ad7, Ad12, canine to adenovirus CAV-2, etc.) have also been sequenced. Furthermore, the construction of defective recombinant adenoviruses has also been described in the literature. Thus, applications WO 94/28152, WO 95/02697 and WO 96/22378, for example, describe different deletions in the E1 and E4 regions. Similarly, application WO 96/10088 describes vectors bearing a modification in the Iva2 gene, application WO 94/26914 describes animal adenoviruses, and application WO 95/29993 describes deletions in the adenoviral E2 region.
Advantageously, the recombinant adenovirus used in the context of the invention comprises a deletion in the E1 region of its genome affecting the E1a and E1b regions. A specific example is provided by deletions affecting nucleotides 454-3328, 382-3446 or 357-4020 (with reference to the Ad5 genome).
Furthermore, the deletion in the E4 region preferentially affects all the open reading frames, such as for example deletions 33466-35535 or 33093-35535, or only part of the E4 region (ORF6 or ORF3 for example), as described in applications WO95/02697 and WO96/22378, incorporated herein as reference.
As for adenoviruses further deleted for late functions (xe2x80x9cminimumxe2x80x9d vector) or for all coding regions (xe2x80x9cgutlessxe2x80x9d vector), their construction has been described for instance by Parks et al., PNAS (1996) 93: 13565 and Lieber et al., J. Virol. (1996) 70: 8944.
The retroviral genetic elements may be inserted at different sites in the recombinant adenoviral genome. They may be inserted in the E1, E3 or E4 region, by replacing the deleted sequences or in addition. They may also be inserted at any other site, apart from sequences required in cis for virus production (ITR sequences and packaging sequence).
Moreover, the recombinant adenoviruses may be of human or animal origin. As far as adenoviruses of human origin are concerned, those in group C may preferentially be cited, in particular the adenoviruses type 2 (Ad2), type 5 (Ad5); or adenoviruses type 7 (Ad7) or 12 (Ad12). Adenoviruses of animal origin are preferentially exemplified by the canine adenoviruses, and particularly all the strains of adenovirus CAV2 [Manhattan strain or A26/61 (ATCC VR-800), for example]. Other adenoviruses of animal origin are given notably in application WO94126914, incorporated herein as reference.
The recombinant adenoviruses are produced in packaging cells, i.e. a cell line that can complement in trans one or several of the deficient functions in the recombinant adenoviral genome. Among the packaging cells familiar to those skilled in the art, an example is cell line 293 in which part of the adenovirus genome has been integrated. More specifically, cell line 293 is a human embryonic kidney cell line containing the left extremity (approximately 11-12%) of the genome of adenovirus serotype 5 (Ad5), containing the left ITR, the packaging region, the E1 region, including E1a and E1b, the region encoding the pIX protein and part of the region encoding the plVa2 protein. This cell line is able to trans-complement recombinant adenoviruses defective for the E1 region, i.e. deleted of all or part of the E1 region, and produce viral stocks at high titers. This cell line can also produce, at permissive temperature (32xc2x0 C.), stocks of virus further comprising the temperature-sensitive E2 mutation. Other cell lines capable of complementing the E1 region have been described, based notably on human lung carcinoma cells A549 (WO94/28152) or on human retinoblasts [Hum.
Gen. Ther. (1996) 215]. Moreover, cell lines capable of trans-complementing several adenoviral functions have also been described. Specific examples comprise the cell lines complementing the E1 and E4 regions [Yeh et al., J. Virol. (1996) 70: 559-565; Cancer Gen. Ther. (1995) 2: 322; Krougliak et al., Hum. Gen. Ther. (1995) 6: 15751 and cell lines complementing the E1 and E2 regions (WO94/28152, WO95/02697, WO95/27071) or cell lines derived therefrom that can be used for producing minimum adenoviruses, especially since they also express site-specific recombinase activity involved in the construction of such viruses.
The recombinant adenoviruses are normally produced by introducing viral DNA into the packaging cells, followed by cell lysis after about 2 or 3 days (the adenoviral replication cycle being 24 to 36 hours). To carry out the method, the introduced viral DNA may be the complete recombinant viral genome, possibly constructed in bacteria (WO96/25506) or yeast (WO95/03400), transfected into the cells. It may also be a recombinant virus used to infect the packaging cells. The viral DNA may also be introduced in the form of fragments each bearing a part of the recombinant viral genome and a region of homology which, after introduction into the packaging cell, allows reconstitution of the recombinant viral genome by means of homologous recombination between the different fragments.
Following cell lysis, the recombinant viral particles can be isolated by any known method such as cesium chloride gradient centrifugation or chromatography. An alternative method was notably described in application FR 9608164, incorporated herein as reference.
The compositions according to the invention may comprise variable amounts of recombinant adenovirus, easily adaptable by those skilled in the art according to the desired application (in vitro, ex vivo or in vivo, for instance).
Generally, the compositions comprise approximately 105 to 1015 v.p. of each recombinant adenovirus, preferably 107 to 1012 v.p.
The term v.p. corresponds to the number of viral particles present in the compositions.
Furthermore, the compositions of the invention may also be in different forms, such as solutions, gels, powder, etc. They are generally solutions, preferably sterile, such as for instance saline solutions (monosodium phosphate, disodium phosphate, sodium, potassium, calcium or magnesium chloride, etc., or mixtures of these salts), isotonic, or dry compositions, particularly lyophilizates which, by addition of sterile water or ohysiological serum, as the case may be, form reconstituted solutions. Other excipients may be used such as for example a hydrogel. Such a hydrogel may be prepared from any biocompatible, non-cytotoxic (homo or hetero) polymer. Such polymers are described in application WO93/08845 for example.
In addition, the compositions of the invention may be packaged in any suitable type of device, such as a bottle, tube, ampoule, bag, syringe, balloon, etc. Further, in compositions of the invention comprising at least two types of recombinant adenovirus, the latter may be packaged either as a mixture or individually.
As indicated hereinabove, the compositions of the invention may be used in vitro, ex vivo or in vivo.
For in vitro or ex vivo use, the cells may simply be incubated, in any suitable device (plate, dish, bag, etc.) in the presence of a composition such as described hereinabove. As shown in FIG. 1 for a composition comprising two types of recombinant adenovirus, incubation of the cells causes the cells to be infected by the two adenoviruses, after which the coinfected cell can produce infectious retroviral particles. For this type of application, the compositions may be used at multiplicities of infection (MOI) of between 10 and 5000 v.p. per cell, for instance, preferably between 100 and 2000, as shown in particular in the examples.
In this respect, the invention equally concerns a method for producing retroviral particles in vitro comprising incubating cells in the presence of a composition such as described hereinabove, possibly followed by recovery and/or purification of the retroviruses produced. The cells that can be used in this method may be any type of cell permissive to adenovirus. These may be primary cultures or cell lines, particularly mammalian, and particularly of human origin. The use of cells of human origin (embryonic kidney cells, A549, retinoblasts, HeLa, KB, etc.) is especially advantageous because it gives the retroviral particles heightened resistance to the complement system. As shown in the examples, the method of the invention makes it possible to obtain high retroviral titers, without the use of packaging cell lines.
For it vivo use, the compositions of the invention may be formulated in is view of administration by the topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous, intraocular, transdermal, intratumoral, etc. route.
In this respect, the invention further concerns a method for transferring a nucleic acid in vivo comprising administering a composition such as described hereinabove. The invention may be used for instance in animals, to establish pathological models, or for the study of gene regulation, and also in humans, in labeling or bioavailability studies, or for medical purposes. The invention is also directed to the use of the compositions described hereinabove for producting infectious retroviral particles in vivo.
According to the nucleic acid of interest (transgene) inserted in the retroviral vector, the present invention may be used in a large number of applications. Thus, among the products of interest in the context of the present invention, more specific examples include enzymes, blood products, hormones such as growth hormone, cytokines, lymphokines:intedeukins, interferons, TNF, etc. (French patent 92 03120), growth factors, for example angiogenic factors such as VEGF or FGF, neurotransmitters or their precursors or synthesis enzymes, trophic factors, particularly neurotrophic factors for the treatment of neurodegenerative diseases or nervous system trauma, or macular degeneration :BDNF, CNTF, NGF, IGF, GMF aFGF, NT3, NT5, HARP/pleiotrophin, or bone growth factors, hematopoietic factors, etc., dystrophin or minidystrophin (French patent 91 11947), genes encoding coagulation factors:factors VII, VIII, IX, suicide genes (thymidine kinase, cytosine deaminase), proteins involved in the cell cycle such as p21, or other kinasedependent inhibitor proteins, Rb, Gas-1, Gas-6, Gas-3, Gad 45, Gad 153, cyclins A, B, D, or further still the GAX protein inhibiting smooth muscle cell proliferation (treatment of restenosis), apoptosis-inducing proteins or other tumor suppressors such as p53, Bax, BcIX-s, Bad or any other antagonist of Bcl2 and BcIX-1, genes for hemoglobin or other transport proteins, genes for proteins involved in lipid metabolism, of the apolipoprotein type chosen from among apolipoproteins A-I, A-II, A-IV, B, C-I, C-II, C-II, D, E, F, G, H, J and apo(a), metabolic enzymes such as for instance lipoprotein lipase, hepatic lipase, cholesterol lecithin acyltransferase, 7-alpha-cholesterol hydroxylase, phosphatidyl acid phosphatase, or still lipid transport proteins such as cholesterol ester transport protein and phospholipids transport protein, HDL binding protein or further still a receptor chosen from the LDL receptors, chylomicron-remnant receptors and scavenger receptors, etc.
Among the products of interest it is important to point out antibodies, antibody single chain variable fragments (ScFv) or any other antibody fragment with recognition capabilities for its use in immunotherapy, for example in the treatment of infectious diseases, tumors (anti-RAS, anti-p53 or anti-GAP antibodies), autoimmune diseases such as multiple sclerosis (anti-idiotype antibody).
Non-limiting examples of other proteins of interest are the soluble receptors, such as for instance the soluble CD4 receptor or the soluble TNF receptor for anti-HIV therapy, the soluble acetylcholine receptor for the treatment of myasthenia gravis; peptides which are enzyme inhibitors or substrates, or peptides which agonize or antagonize receptors or adhesion proteins such as for instance for the treatment of asthma, thrombosis and restenosis:synthetic, chimeric or truncated proteins. Among the hormones of primary interest one may cite insulin in the case of diabetes, growth hormone and calcitonin.
The nucleic acid may also be a gene or an antisense sequence, whose expression in the target cell enables control of gene expression or transcription of cellular mRNA. Such sequences may, for instance, be transcribed in the target cell to RNA complementary to cellular mRNA, thereby lo blocking its translation to protein, according to the method described in European patent 140 308. Therapeutic genes equally comprise sequences coding for ribozymes, able to selectively destroy target RNAs (European patent 321 201).
The nucleic acid may also comprise one or several genes coding for an antigenic peptide, that can elicit an immune response in humans or animals. In this particular embodiment, the invention therefore allows the production either of vaccines, or of immunotherapy treatments for use in humans or animals, notably against microorganisms, viruses or cancers. In particular these may be antigenic peptides specific of Epstein Barr virus, HIV virus, hepatitis B virus (European patent 185 573), pseudo-rabies virus, xe2x80x9csyncitia forming virusxe2x80x9d, other viruses or yet tumor-specific antigens such as MAGE proteins (European patent 259 212).
The nucleic acid may also code for a product toxic to cells. particularly a conditional toxicity (eg., thymidine kinase, cytosine deaminase, etc.).
Other genes of interest have notably been described by Mc Kusick, V. A. Mendelian [Inheritance in man, catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes, Eighth edition. John Hopkins University Press (1988)], and by Standbury, J. B. et al. [The metabolic basis of inherited disease, Fifth edition. McGraw-Hill (1983)]. The genes of interest comprise the proteins involved in the metabolism of amino acids, lipids and other components of the cell.
Finally, the nucleic acid may comprise several coding regions, possibly separated by an IRES, allowing the production of several products of interest.
Furthermore, the transgene generally comprises a transcriptional promoter (located 5xe2x80x2) and a transcriptional terminator (located 3xe2x80x2), which may be chosen by those skilled in the art, as described hereinabove. In addition, the transgene may be present in the retroviral vector in the same or the opposite orientation to the direction of LTR transcription. Finally, in a particular embodiment, the adenoviral genomes of the invention may also be delivered to cells in the form of plasmids, together with adenoviral complementation functions.
Other advantages and applications of the present invention will become more apparent from the following examples, which are given for purposes of illustration and not by way of limitation.

Methods and compositions for producing viral particles


A large capacity (1-2 MkVA) driving system for variable-speed-driving an AC motor by a power converter (inverter, converter) in which GTO (gate turn-off) thyristors are used as switching devices. In this system, high frequency GTO thyristors are connected in series, power converters are multiplexed, the AC motor is used in its plural phases, instantaneous spatial vector PWM (pulse width modulation) control is performed, vector control for the motor is performed, and a circuit for recovering snubber energy for GTO thyristors and a power factor adjusting circuit are provided. Thus, this driving system provides a torque ripple of 1% or less, speed response of 60 rad/sec or more, efficiency of 95% or more and a power factor of 98% or more.

The present invention relates to a variable speed driving system for an AC electric motor, and more particularly to a large capacity variable speed driving system for driving an AC electric motor using a power converter device provided with a GTO (gate turn-off) thyristor.
A previously proposed variable speed driving system for an AC electric motor with the largest capacity using an inverter is a system with 4000 kVA for general industry such as a pump and a fan. An example of this system is disclosed in e.g. "Toshiba Review" Vol. 43, No. 3 (1983) page 253.
On the other hand, in the field of driving a roller of a rolling mill system, for example, that requires high response with a large capacity, an AC electric motor variable speed driving system based on a cycloconverter is adopted. Its examples are disclosed in Hitachi Hyoron Vol. 72, No. 5 (1990), pp. 441-446; Toshiba Review Vol. 43, No. 3 (1988), p. 256; and Mitsubishi Electric Technical Report Vol. 62, No. 6 (1988), pp. 501-506. An inverter in the field of large-capacity high speed -response such as one used to drive a roller, has not been published.
When conventional systems require a large capacity inverter, a GTO thyristor is used as a switching device in a main circuit of a high- voltage large current device. But, when the device capacity is increased, the permissible switching frequency of the device is reduced (the present limit is 100-150 Hz) so that even when a GTO thyristor is used, harmonics of the output wave from the inverter are increased, the torque ripple of a motor is increased, and loss in the snubber circuit for the GTO is increased (at the rate of square of the voltage).
On the other hand, in the case of the cycloconverter, the only convention device that can be applied to the field of large-capacity high response, the power factor in a power source is limited to around 0.6. In order to improve this power factor, a capacitor with a large capacitance for improving the power factor is required on the power source side. As a result, the resultant apparatus has a large scale.

Large capacity variable speed PWM spatial vector type sub-harmonic system for driving AC electric motor


Fault isolation for a computer system having multiple FRUs in an FSI chain uses logic embedded in a device driver to determine first failure data and a logical error identifier. The logical error identifier represents a hardware logical area of the fault. The fault is then mapped to a segment of the system based on a self-describing system model which includes FRU boundary relationships for the devices. Operation of the device driver is carried out by a flexible service processor. The device driver uses the first failure data to identify a link at a failure point corresponding to the fault and determine a failure type at the link, then maps the link and the failure type to the logical error identifier. After identifying the segment, the device driver can generate a list of callouts of the field replaceable units associated with the segment which require replacement.

Field of the Invention
The present invention generally relates to computer systems, and more particularly to a method of isolating a fault in a complex computer system having a number of serially-connected (FSI chained) devices.
Description of the Related Art
As computer systems become increasingly complex with more interconnected devices, there are ever greater chances of errors arising within the system, and it becomes more difficult to diagnose the cause of these errors. Hardware-based operating errors can result in a period of downtime in which the computer is unavailable for use. For multi-user (or clustering computing environment) computers, such as mainframe computers, midrange computers, supercomputers, and network servers, the inability to use a particular computer may have a significant impact on the productivity of a large number of users, particularly if an error impacts mission-critical applications (e.g., when processing bank transactions). Multi-user computers are typically used around the clock, and as a result, it is critically important that these computers be accessible as much as possible.
Hardware concurrent maintenance is often utilized to address the problems associated with computer downtime. Hardware concurrent maintenance is a process of performing maintenance on computer hardware while the computer is still running, thereby resulting in minimal impact to user accessibility. Conventional hardware concurrent maintenance typically requires that maintenance personnel physically remove one or more field replaceable units (FRUs) from a computer system. FRUs may be packaged in a very complex fashion and/or require special tools to enable removal without causing hardware damage.
Server systems generally have many field replaceable units (FRUs). FIG. 1 depicts one example of a conventional server system 10. In this particular example, the server is controlled by a hardware management console (HMC) 12. HMC 12 is a dedicated workstation that provides a graphical user interface for configuring, operating, and performing basic system tasks for the server, including tasks related to the management of the physical server components and tasks related to virtualization features such as the logical partition configuration or dynamic reconfiguration of resources. HMC 12 communicates with a system controller 14a via an Ethernet connection to an Ethernet controller integrated into the system controller FSP chip. System controller 14a provides system initialization and node management, including error reporting. Inter-device communications may be implemented in server system 10 using a flexible service processor (FSP) located at the system controller. A flexible service processor is similar to a service processor, and may include for example a PowerPC™ processor having engines to drive communications interfaces. A redundant system controller 14b is provided with a point-to-point FSI link between the FSP chips in the system controllers. A plurality of server nodes 16a-16d carry out the main functions of the server, and may constitute a variety of interconnected devices, including multiple processors (primary and support), system memory and cache memories, fabric repeaters, sensors, etc.
FIG. 1 shows how an FSP can have a downstream fanout to other components via a serial link referred to as an FRU support interface (FSI) which is used to reach the endpoint controls (similar interconnections from the FSP in redundant system controller 14b are not shown for simplicity). In this example the endpoints are common FRU access macros (CFAMs) which may be integrated into the microprocessors or other devices such as input/output (I/O) application-specific integrated circuits (ASICs). CFAMs have a standardized interconnect design, and provide FRU support for a variety of control interfaces such as JTAG, UART, I2C (IIC), GPIO, etc. CFAMs can have multiple FSI slaves with a hardware arbiter to allow multiple FSI masters on the support processors, etc., to access the downstream components. The components may be interconnected via multiple CFAMs acting as hubs or links. Hub links are high function links used specifically between processors. Accordingly, instead of an engine in the FSP directly controlling a device, multiple engines linked serially can pass control data to the device (FSI chaining).
In the case of a hardware failure within server system 10, code running on one of the system controllers generates an error log that includes one or more components suspected of being defective (the FRU callout list). A service call is then made to replace hardware associated with those FRUs. A typical FRU callout list includes any FRU having hardware associated with the failure, and may include FRUs that are not actually defective. Typically a platform-specific hard-coded look-up list is used to generate the FRU callout list. This approach is very static. For example, an error's callout may include all associated hardware along a path from a source (e.g., a service processor) to a destination (e.g., a thermal sensor or dual in-line memory module (DIMM)). The FRU callout list would have a minimum of one element with the upper bound determined by the hardware FRU boundaries crossed between the source and destination wiring of the interface.
Another method of generating FRU callout lists is to have the error monitoring application take the industry device driver error number ("errno") and algorithmically try to isolate hardware failures. Often this is done by going to associated hardware (via different methods such as boundary scan or scom) to read hardware registers, states, or status to determine a logical reason for failure. Applications may also try to isolate the failure by communicating to other devices before and after a hub, or on another hub, trying deterministically to limit the FRUs on the callout list.

This patent is subject to a terminal disclaimer.

Device driver error isolation on devices wired via FSI chained interface

International Business Machines Corporation


The present invention relates to detoxified and immunologically active proteins (“mutant LTs”) having mutated amino acid sequences of heat-labile enterotoxin of E. coli, DNA sequences encoding the mutant LTs, recombinant expression vectors comprising the DNAs, recombinant microorganisms transformed with the recombinant expression vectors, process for preparing the mutant LTs and pharmaceutical application of the said protein as immunogenic antigens for vaccination and as adjuvants for anti-body production. In contrast to wild-type LT, the mutant LTs did not induce any toxic activities. The mutant LTs elicited high and comparable levels of anti-LT antibodies when delivered either intragastrically or intranasally, inducing systemic and local responses in serum and fecal extracts. Thus, they might be useful for the development of a novel diarrheal vaccine in humans and animals. In addition, the antibody production ability using mutant LTs as an adjuvant may be effective for prevention and treatment of various diseases.

1. Field of the Tnvention
The present invention relates to detoxified and immunologically active proteins ("mutant LTs"), more specifically, to mutant LTs having mutated amino acid sequences of heat-labile enterotoxin of E. coli, DNA sequences encoding the mutant LTs, recombinant expression vectors comprising the DNAs, recombinant microorganisms transformed with the recombinant expression vectors, process for preparing the mutant LTs and pharmaceutical application of the said proteins as immunogenic antigens for vaccination and as adjuvants for antibody production.
2. Description of the Prior Art
Enterotoxigenic Escherichia coli ("ETEC") strain causes diarrheal disease in humans and animals due to production of toxin such as heat-labile enterotoxin ("LT") (see: Spangler, B. D., Microbiol. Rev., 56:622-647(1992)). LT is a multimeric protein composed of two functionally distinct domains: an enzymatically active A subunit ("LTA") of ˜30,000 daltons with ADP-ribosylating activity, and a pentameric B subunit ("LTB") of ˜11,600 daltons that contains GM1 (momosialoganglioside) receptor-binding site (see: Bäckström, M. et al., Mol. Microbiol., 24:489-497(1997)). Upon thiol reduction, the A subunit dissociates into two polypeptide chains, i.e., A1 (Mr, 23,000 daltons) and A2 (Mr, 6,000 daltons) (see: Tsuji, T. et al., J. Biol. Chem., 260:8552-8558(1985); Grant C. C. R. et al., Infect. Immun., 62:4270-4278(1994)). The A1 subunit, in particular, intoxicates eucaryotic cells by catalyzing ADP-ribosylation of Gs, a GTP-binding protein that regulates the levels of the second messenger cAMP (see: Guerrant, R. L. et al., Infect. Immun., 10:320-327(1974); Field, M. et al., N. Engl. J. Med., 321:800-806(1989)). The resulting increase in cAMP level causes secretion of water and electrolytes into the small intestine through interaction with two cAMP-sensitive ion transport mechanisms including (i) NaCl co-transport across the brush border of villous epithelial cells and (ii) electrogenic Na+-dependent Cl− secretion by crypt cells (see: Guidry, J. J. et al., Infect. Immun., 65:4943-4950(1997)).
Both the cholera toxin ("CT") from Vibrio cholerae and heat-labile enterotoxin from ETEC belong to the most potent mucosal adjuvants and immunogens known to date by oral and other mucosal routes, via which most of antigens are unable to induce immune responses (see: Jackson, R. J. et al., Infect. Immun., 61:4272-4279(1993); Takahashi, I. et al., J. Infect. Dis., 173:627-635(1996)). However, their toxicities have precluded their clinical use in humans (see: Douce, G. et al., Proc. Natl. Acad. Sci., USA, 92:1644-1648(1995)). One approach to overcome the problem of toxicity is the generation of genetically detoxified derivatives of LT (see: Lobet, Y. et al., Infect. Immun., 59:2870-2879(1991); Dickson, B. L. and Clements, J. D., Infect. Immun., 63:1617-1623(1995)) and CT (see: Fontana, M. R. et al., Infect. Immun., 63:2356-2360(1995); Yamamoto, S. et al., Proc. Natl. Acad. Sci., USA, 94:5267-5272(1997b)) by site-directed mutagenesis of amino acids which are located on the β-strand that constitutes the 'floor' of NAD-binding cavity.
The most important factor for immunogenicity is shown to be the ability to bind to the receptor on eucaryotic cell (see: Nashar, T. O. et al., Proc. Natl. Acad. Sci., USA, 93:226-230(1996)). In fact, a non-binding mutant of the B subunit of LT was found to be non-immunogenic (see: Guidry, J. J. et al., Infect. Immun., 65:4943-4950(1997)). In addition, another group found that the ADP-ribosylating activity is unnecessary for immunogenicity because nontoxic derivatives of LT obtained by site-directed mutagenesis of the A subunit retained the immunological properties of the wild-type LT (see: Pizza, M. et al., J. Exp. Med., 180:2147-2153(1994)).
The attempt to define the role of ADP-ribosylating activity in adjuvanticity of LT has generated conflicting results. For example, it was reported that a nontoxic derivative of LT (LTE112K) when co-administered with keyhole limpet hemocyanin (KLH) by an oral route in mice, lacked the adjuvant properties, thus suggesting that the adjuvanticity of LT is linked to its ADP-ribosylating activity (see: Lycke, N. et al., Eur. J. Immunol., 22:2277-2281(1992)). However, more recently, the adjuvant activity of the LTE112K was found to be identical to that of the LT holotoxin when delivered with influenza virus surface antigen by an intranasal route (see: Verweij, W. R et al., Vaccine, 16:2069-2076(1998)). On the other hand, other investigators showed that another LT derivatives, LTK63, lacking enzymatic activity and toxicity was still able to elicit antibody responses against the co-administered antigen in mice immunized orally, intranasally, or intravaginally (see: Di Tommaso, A. et al., Infect. Immun., 64:974-979(1996); Giuliani, M. M. et al., J. Exp. Med., 187:1123-1132(1998); Marchetti, M. et al., Vaccine, 16:33-37(1998)).
Under the circumstances, the present inventors, based on the findings that detoxified LT derivatives may induce antibody responses, tried to explore an efficient immunogenic antigen and mucosal adjuvant for vaccination, which can be applied for the development of a mucosal vaccine as well as a novel diarrheal vaccine for humans and animals.


A plasma deposition system comprising a wafer platform, a second electrode, a first electrode, a first high voltage pulser, and a second high voltage pulser. In some embodiments, the second electrode may be disposed proximate with the wafer platform. In some embodiments, the second electrode can include a disc shape with a central aperture; a central axis, an aperture diameter, and an outer diameter. In some embodiments, the first electrode may be disposed proximate with the wafer platform and within the central aperture of the second electrode. In some embodiments, the first electrode can include a disc shape, a central axis, and an outer diameter. In some embodiments, the first high voltage pulser can be electrically coupled with the first electrode. In some embodiments, the second high voltage pulser can be electrically coupled with the second electrode.

Producing high voltage pulses with fast rise times and/or fast fall times is challenging. For instance, to achieve a fast rise time and/or a fast fall time (e.g., less than about 50 ns) for a high voltage pulse (e.g., greater than about 5 kV), the slope of the pulse rise and/or fall must be incredibly steep (e.g., greater than 1011 V/s). Such steep rise times and/or fall times are very difficult to produce especially in circuits driving a load with low capacitance. Such pulses may be especially difficult to produce using standard electrical components in a compact manner; and/or with pulses having variable pulse widths, voltages, and repetition rates; and/or within applications having capacitive loads such as, for example, a plasma.
In addition, wafer yield can determine whether a process was successful. Often, chips on the edge of a wafer may not be usable because of various defects that may occur at the edge of a wafer. These defects increase waste and decrease wafer yield.

Spatially variable wafer bias power system


An object of the invention is to provide an optical multiplexing method and an optical multiplexer, capable of fixing lights of different wavelengths at required wavelengths to stably multiplex them with a simple optical circuit configuration. To this end, in the present optical multiplexer, there is provided a tilted FBG, which is formed on an optical fiber through which a first light is propagated, with a grating direction thereof being tilted to an axial direction of the optical fiber, and has the sufficiently high reflectance to a second light (multiplexed light) of a wavelength different from that of the first light. The multiplexed light emitted from a light source is irradiated to the tilted FBG, via a free space from an angle direction determined according to a grating pitch of the tilted FBG and the wavelength of the multiplexed light, to be coupled within the optical fiber. Further, a low reflective FBG reflecting light coupled within the optical fiber is formed on the optical fiber, to achieve a resonance structure between the low reflective FBG and the light source, thereby stabling the wavelength of the multiplexed light.

1. Field of the Invention
The present invention relates to an optical multiplexing method and an optical multiplexer, for multiplexing lights of different wavelengths which are utilized in various optical communication systems, and an optical amplifier using the same. In particular, the present invention relates to a technique for realizing the multiplexing of lights with a simple optical circuit configuration.
2. Related Art
An optical amplifier is one of key components realizing the long distance and large capacity of optical communication system. Types of optical amplifier are classified into a laser amplifier using stimulated emission from a population inversion medium, and an amplifier based on a nonlinear optical effect such as Raman scattering or Brillouin scattering. As the laser amplifier, there are a rare earth element doped fiber amplifier and a semiconductor laser amplifier using a semiconductor amplification medium, the former being operated with the photo excitation and the latter being operated with the inlet current excitation. Among these optical amplifiers, the rare earth element doped fiber amplifier has a high advantage in performance, for example, bit rate free, high gain, low noise, broad band, low coupling loss, low polarization dependence, high efficiency and the like. Among the rare earth element doped fiber amplifiers, an erbium (Er) doped fiber amplifier (to be referred to as EDFA herebelow) is typical, and is now in practical use in optical fiber communication systems. The performance (gain, NF) and cost of such an optical amplifier for optical communication represented by EDFA and the like are key factors of optical communication systems, and it is important how the reduction of cost is achieved while maintaining the required performance.
The cost required for a pumping light source and a multiplexing system thereof constitutes a large proportion of the cost of optical amplifier for optical communication. As one of means for achieving the cost reduction of pumping light source, there has been known a technique in which a low cost semiconductor laser (LD) for commercial-off-the-shelf (for example, DVD or CD-R) is adopted (refer to Japanese Unexamined Patent Publication No. 6-318750).
However, in order to make it possible to apply an optical amplifier using a pumping light source which is at low cost although having less reliability, as the optical amplifier for optical communication in which the strict reliability (duration of life) is required, it becomes important to improve the reliability up to a predetermined value while keeping a cost merit.
As one method for improving the reliability of pumping light source utilizing low cost LD, it is effective to adopt a redundant configuration improving the reliability up to a predetermined level by applying multiple pumping LDs, although such an LD has less reliability when used in a simple body. In the redundant configuration of known optical amplifier, even if the unit cost of pumping LD is low, the cost required for optical components of multiplexing system corresponding to the redundant configuration is high. Therefore, it is difficult to expect the cost-reduction of the whole optical amplifier. Specifically, with an increase of the number of pumping LDs, the cost is increased due to the addition of high-cost optical multiplexer (including an increase of assembly cost with the increase of the number of components), and also required output power of single pumping LD is increased due to an increase of insertion loss. Therefore, it is desirable that the number of components of multiplexing system can be reduced to realize the low cost.
As conventional techniques for multiplexing lights of different wavelengths, there has been proposed a technique multiplexing light utilizing a tilted grating (refer to Japanese Unexamined Patent Publication No. 8-171031 and Japanese National Patent Publication No. 2001-516468). The tilted grating is formed such that a direction of grating (a direction perpendicular to a plane where the rise of refractive index occurs) is tilted to an axial direction of optical path of an optical fiber, optical waveguide or the like, and is sometimes called a slanted grating.
Specifically, Japanese Unexamined Patent Publication No. 8-171031 discloses an optical apparatus in which a grating coupler is disposed in a waveguide arranged on a silicon substrate on which a photodiode is formed, a semiconductor laser and an optical fiber are disposed on positions opposite to the grating coupler, a transmission light emitted from the semiconductor laser is incident on the grating coupler at an incident angle of 45° and totally reflected by the grating coupler, to be sent to the optical fiber, and also a reception light of a wavelength different to that of the transmission light is output from the optical fiber to be incident on the grating coupler at an incident angle of 45°, and excited in the waveguide by the grating coupler, to be received by the photodiode. Further, Japanese National Patent Publication No. 2001-516468 discloses an optical apparatus in which a lens is formed on a cladding surface of an optical fiber, on which is written with titled fiber Bragg grating (FBG), to be coupled with the FBG, and a light guided in the optical fiber via the lens is reflected by the tilted FBG, to be guided into the core.
The optical multiplexing method using the tilted grating as described above is considered to be one of techniques effective for reducing the number of components of pumping light multiplexing system in the optical amplifier, since lights of a plurality of wavelengths can be multiplexed with a simple configuration, compared with the case where a plurality of pumping lights is multiplexed sequentially in a three using WDM couplers, polarization combining devices and the like in a pumping system of the optical amplifier (for example, refer to FIG. 18).
However, in the case where the conventional optical multiplexing technique using the tilted grating described above is applied to the pumping light multiplexing system of the optical amplifier, there is caused the following problem. Namely, when the optical multiplexing technique disclosed in Japanese Unexamined Patent Publication No. 8-171031 is applied to the optical amplifier, the pumping lights are multiplexed by means of a bulk type grating formed on the waveguide. The amplification medium used in the optical amplifier such as EDFA and the like is typically of a fiber type, and a combination thereof with the bulk type grating has a possibility of an increase of insertion loss to increase required output power of a simple pumping LD. Therefore, such a combination is not necessarily effective for the cost reduction.
Further, in the case where the optical multiplexing technique disclosed in Japanese National Publication No. 2001-516468 is applied to the optical amplifier, the pumping light is introduced into the tilted grating formed in the optical fiber via the external optical fiber and the lens. Therefore, the optical circuit configuration for introducing the pumping light into such a tilted grating becomes complicated, leading a possibility of a drop of the reduction effect of the number of components by the utilization of tilted grating.
Moreover, in the above described conventional optical multiplexing technique, it is necessary to coincide high accurately the wavelengths of lights to be multiplexed with the reflective wavelength of the tilted grating, in order to obtain the high coupling efficiency. However, since the output wavelengths of the pumping light source and the reflective wavelength of the tilted grating are changed due to external factors, such as individual differences between components or a temperature variation, it becomes difficult to obtain required pumping light power. Further, in order to stably operate the optical amplifier, a function for fixing the wavelengths of the pumping lights to be multiplexed is demanded. However, the realization of such a function leads the increase of number of components and an increase of cost.

Optical multiplexing method and optical multiplexer, and optical amplifier using same


A method and system are described for performing photorefractive keratectomy procedure employing pulses of photoablative radiation to selectively ablate corneal tissue of a patient's eye in an ablation zone on the anterior corneal surface to produce a desired refractive correction in the corneal tissue. The method and system employ control of the effect of ocular fluid at the corneal surface so as to reduce the disturbance of such fluid on the desired ablation process while maintaining hydration of the corneal tissue. Controlling the average repetition rate of the radiation pulses applied to the corneal surface so as to reduce intrapulse fluid accumulation at the corneal surface without dehydrating the corneal tissue, selecting an increased fluence level of the pulse applied to the corneal surface to reduce the effect of fluid accumulation at the corneal surface, and applying evaporative energy to the site of incidence of a pulse of an ablative beam prior to incidence of said pulse at said site are shown as ways to effect this control. Application of the new method and system to wide area ablation techniques and to scanning techniques are described Reduction of irregularities when ablating large areas, e.g., grater than 5.5 cm is made possible in either case.

This invention relates to improvements in photorefractive keratectomy (PRK).
In PRK, corneal tissue is removed in a controlled fashion to shape the surface of the cornea of a patient's eye to treat, e.g., myopia, hyperopia, presbyopia or astigmatism
The cornea comprises transparent avascular tissue that forms the anterior portion of the eye. The cornea functions as both a protective membrane and a "window" through which light passes as it proceeds to the retina. The transparency of the cornea is due to its uniform structure, avascularity, and deturgescence, which is the state of relative hydration of the corneal tissue.
A major proportion of the refractive power of the eye is determined by the curvature of the anterior surface of the cornea, so that changing the shape of the cornea offers a way to significantly reduce a refractive problem in the eye.
Various techniques have been proposed for shaping the cornea of a patient's eye. Some techniques include removing the epithelium, and then shaping the underlying Bowman's and stroma layers. In PRK, photoablation is employed using e.g., ultraviolet radiation from an excimer laser, e.g., at 193 nm wavelength, or infrared laser radiation that has a wavelength in the range of about 2.9 to 3.2 .mu.m.
In one technique, described in Marshall et al., U.S. Pat. No. 4,941,093 (assigned to Summit Technology Inc.), the shape and size of the area of the corneal surface which is irradiated by laser radiation is selected and controlled so that some areas of the corneal surface become more eroded than others and a desired corneal shape is achieved.
Another technique, described in Muller, U.S. Pat. No. 4,856,513 (assigned to Summit Technology Inc.), uses a laser and an erodible mask. The mask, with a predefined profile of resistance to erosion by laser radiation, is disposed between the laser and the corneal surface. A portion of the laser radiation is absorbed by the mask, while another portion is transmitted to the corneal surface in accordance with the mask profile, thereby enabling the selective photoablation of the corneal surface into a desired shape.
There are circumstances in which it is desired to accomplish the PRK treatment with the ablated zone larger than 5 mm in diameter. With such zones, under usual operating conditions it has been observed that the final surface achieved by the ablation process differs from the expected shape. Surface irregularity and significant refractive error have been observed post-operatively in the corneal topographies of some patients treated for PRK. These irregularities may lead to visual disturbances such as diplopia, blurred vision, and loss of Best Corrected Visual Acuity (i.e., the vision obtained with the best possible lens correction).
The PRK procedure has achieved a clinically accepted level. However the possibility of achieving even better results with larger ablation zones has been somewhat elusive. The present invention provides a new insight into conditions that can occur in PRK and provides techniques that address these conditions to enable enhanced predictability, stability, and safety of the procedure to be achieved.


An additive for a blood collection container is a polyelectrolyte complex having a surface charge which activates clotting of a blood sample in the container. A preferred additive is a crosslinked carboxylated cellulose having a negative charge. The invention includes a blood collection tube having a puncturable stopper in an open end and the additive of the invention deployed therein.

1. Field of the Invention
This invention relates to blood collection and, more particularly, relates to a plastic blood sample collection assembly.
2. Background
Blood samples are routinely taken in glass evacuated tubes. One end of a double-ended needle is inserted into a patient's vein. The other end of the needle then punctures a stopper covering the open end of the tube so that the vacuum in the tube draws the blood sample through the needle into the tube. Using this technique, a plurality of samples can be taken using a single needle puncture of the skin.
Plastic tubes have also been proposed for blood collection. Plastic offers a number of advantages over glass such as lower breakage, less weight in shipment, and easier disposal by incineration.
Blood collected in evacuated tubes often must be clotted prior to clinical examination. It is desirable to form a dense clot as rapidly and completely a possible to facilitate clean separation of the clot from the serum layer by centrifugation. To achieve this end, both plastic and glass blood collection tubes frequently employ a clot activator.
Practically all commercial blood collection tubes include particulate activators which lead to dense, crosslinked clots that cleanly separate from the serum in a hematological centrifuge. Clot formation, however, is relatively slow, particularly in plastic, and about 30-60 minutes are required prior to centrifugation. Typical particulate activators used commercially are silica impregnated in fabric, silica particles in small plastic cups or silicate particles applied to the tube wall in polyvinylpyrrolidone (PVP). When blood enters a tube containing silicate-PVP, the PVP dissolves and the silicate particles are released. The PVP enters both the serum and the clot and may interfere with chemical or hematological assays and may foul automated and/or optical instruments.
There is a need in the art for a clot activator which rapidly forms a dense clot which separates cleanly from the serum on centrifugation without contaminating the serum with soluble chemicals. The present invention is directed to fulfilling this need.

Clot activating polyelectrolyte complex and blood collection assembly containing same


A method for displaying physical address of data storage media residing within an automated data storage library. A drive, including a drive processor and a drive display, recognizes a load display request received from a host computer/application that includes an identification of a data storage medium. The drive generates a request for the physical address of the data storage medium corresponding to the identification and transmits the request to a library controller. The library controller looks up the corresponding physical address and transmits it back to the drive, where it is displayed on the drive display.

1. Field of the Invention
This invention is related in general to the field of data management systems. In particular, the invention consists of a method for displaying a physical location of a data storage medium within an automated data storage library.
2. Description of the Prior Art
Automated data storage libraries are used for providing cost effective storage and retrieval of large quantities of data. In an automated data storage library, data is stored on data storage media that are, in turn, stored on storage shelves or the like inside the library in a fashion that renders the media, and its resident data, accessible for physical retrieval. Such media is commonly termed "removable media." Data storage media may comprise any type of media on which data may be stored and which may serve as removable media, including but not limited to magnetic media (such as magnetic tape or disks), optical media (such as optical tap or disks), electronic media (such as PROM, EEPROM, flash PROM, Compactflash TM, Smartmedia TM Memory Stick TM, etc.), or other suitable media.
Typically, the data stored in automated data storage libraries is resident on data storage media that is contained within a cartridge and referred to as a data storage media cartridge. An example of a data storage media cartridge that is widely employed in automated data storage libraries for mass data storage is a magnetic tape cartridge.
In addition to data storage media, automated data storage libraries typically contain data storage drives that store data to, and/or retrieve data from, the data storage media. The transport of data storage media between data storage shelves and data storage drives is typically accomplished by one or more robot accessors (hereinafter termed "accessors"). Such accessors have grippers for physically retrieving the selected data storage media from the storage shelves within the automated data storage library and transporting such media to the data storage drives by moving in the X and Y directions.
Libraries typically use internal addressing to identify cartridge slot locations within the library. The internal addressing of the library is referred to as a library address or a physical address. Libraries typically present cartridge slot locations to host applications by way of an address, commonly referred to as an element address. The hosts' view of library reported address is referred to as a host address or a logical address. In some designs, the library address and the host address for any particular cartridge location may be the same. For example, all physical storage shelves in the library may be assigned a physical address beginning with a starting address and incrementing by one for each sequential slot in the library. This address information is presented by the library to host applications that send commands to the library to move cartridges based on this physical address information.
However, in some designs, the library address and the host address for a particular cartridge location is different. For example, the library may be partitioned into several logical libraries. Each logical library may be assigned to different host computers such that the host associated with one logical library has no awareness of any other logical libraries and associated cartridges. In this example, cartridges associated with one logical library may have the same logical address as seen by its host application as cartridges associated with another logical library as seen by its host application even though the library maintains unique physical addresses for each cartridge.
Virtualization of the storage slots in a library is another example of why the library address and the host address may not be the same. The library maintains a map of host (logical) storage addresses to actual library (physical) addresses when performing move operations and when reporting cartridge locations to a host application. The mapping of the logical address to the actual physical address must be maintained in a consistent fashion by the library so as to ensure proper movement of the intended cartridge. Using virtualization, the library may arbitrarily choose any slot to store media, i.e., the storage slots associated with a range of addresses used by a particular host need to be proximate and/or sequential. Mapping of addresses includes mapping of storage slots with or without media.
A host application manages data in a library using "location-centric" commands, and may utilize a medium changer protocol, such as small-computer systems interface (SCSI). The host application manages cartridge movement by specifying source and destination locations in the system. These source and destination locations are the element addresses reported by the library as host element addresses.
A host element addresses includes a host import/export element address (IEEA) which appears to the host as the address of an input/output slot. Additionally, the host element address includes a host storage element address which appears to the host as a storage slot location. Location-centric commands issued by a host application which include these host element addresses are mapped by the library to physical element addresses of actual media storage slots.
Host computers maintain a host catalog of these host element addresses, cross-referencing host element addresses with library data storage media cartridges. Each data storage media cartridge may be identified by a volume and serial number (VOLSER). Mapping the host element addresses to physical element addresses is managed by the library.
In an exemplary automated data storage library, a data storage media cartridge placed into a library's input/output station by either an automated device or an operator is issued an element address based on the physical location of the input/output station or the storage slot into which the cartridge is subsequently placed. In a library wherein the input/output stations and/or storage cells are segregated into cells, a 5-slot cell station may include a first slot having an element address and each subsequent slot's address would be an incremental increase of the starting slot's address. In this manner, a cartridge placed in the second slot would be given a physical element address one greater than that of the starting element address.
However, the element addresses of import/export elements (IEEs) may be virtualized, resulting in the use of virtual import/export element addresses (VIEEAs). In this manner, multiple hosts may share a single physical library and may utilize differing ranges of VIEE addresses for cartridges within its logical library. For example, a first host may be configured to access 10 import/export element addresses (IEEAs) while a second host may be configured to access 20 IEEAs. However, the physical element address for each cartridge may be reported to each host as a different VIEEA. Utilizing virutalization of the IEEAs, the cartridge placed in the second slot of the 5-cell station may posses a physical element address of 101 but be reported to the first host as VIEEA 106. By mapping the physical element address of each cartridge to a VIEEA, the host may continue to represent a particular data storage media as a single host element address, even if the data storage cartridge is moved to another physical element address.
With the advent of VIEEAs, assignment of element addresses becomes an algorithmic based function of the library firmware rather than a simple mapping of each physical location to a specific element address. When a cartridge is placed into an I/O slot, the volser of the cartridge is first checked to see if it is within a cartridge assignment policy (CAP) for a particular host. If so, the cartridge will be assigned a VIEEA corresponding only to that host and will not become visible to other hosts. If the cartridge's volser is not within any hosts' CAP, it will be assigned a common VIEEA that may be visible to multiple hosts. Volumes may also be stored in virtual storage element addresses (VSEAs), i.e., where the media resides in the library.
Some automated data storage libraries include three modes of operation including Auto, Pause, and Manual. While in manual mode, an operator may move cartridges within the library. The operator may view a manual mode panel to ascertain what actions are to be performed. These actions may include the mounting and ejecting of data storage devices.
For a manual mount operation, a drive used to access the data storage devices may include a drive operator panel which can display the volser and physical location of the cartridge. Alternatively, the operator may utilize a manual mode panel located at the library manager. This panel instructs the operator to place the new cartridge in a particular cell in the library. Demount commands are not displayed as the operator will leave demounted data storage devices in the drive unless another data storage device needs to be mounted. In this case, the demounted data storage device is placed back into the library or is held for insertion after completion of manual mode operation.
However, some automated data storage libraries are not support manual mode operation. For these types of automated data storage libraries, a manual mode must be provided by an external library manager which includes a manual mode panel displaying the volsers of volumes to be mounted.
While some automated data storage libraries are designed so that the library managers maintain both the physical and logical addresses of their data storage devices, other libraries utilize a library controller to manage the mapping of logical addresses to physical addresses. In these types of systems, a command issued by a host to a drive would only include the volser and the logical address. In manual mode, only the volser would be displayed at the drive as the logical address would be useless to an operator. Accordingly, it is desirable, in these types of automated data storage libraries, to have a method for displaying the physical location of data storage media in a manner that can be utilized by an operator.
One approach to this problem would be to utilize a library-specific command created by the library's vendor that works with a pre-defined library configuration. This vendor-specific command may be issued by a particular host configured to interface with a particular automated data storage library. The vendor-specific command may include a volser and a request to the library controller to report the corresponding physical address. A problem occurs, however, if the library configuration changes or if another configuration is desired, as the vendor-specific command will no longer function properly. Accordingly, it is desirable to have a system of issuing non-library specific commands that can be utilized by the drive to initiate a request for a physical address, wherein this non-vendor-specific command may be utilized in a multitude of varying host/library configurations.

Method for displaying cartridge location


Provided is a plasma display panel comprising first and second electrodes, a first barrier rib, and a second barrier rib. The first and second electrodes are formed on an upper substrate. The first barrier rib is formed over a lower substrate to be disposed under the first electrode. The second barrier rib is formed over the lower substrate to be disposed under the second electrode. A barrier rib center point between the first and second barrier ribs is different from an electrode center point between the first and second electrodes.

1. Field of the Invention
The present invention relates to a plasma display panel, and more particularly, to a plasma display panel in which a scan electrode and/or a sustain electrode overlaps with a barrier rib.
2. Description of the Background Art
In general, in a plasma display panel, a barrier rib formed between a front panel and a rear panel forms one discharge cell. Main discharge gas such as neon (Ne), helium (He) or a mixture (He+Ne) of neon and helium and inert gas containing a small amount of xenon (Xe) are filled in each discharge cell. Such a discharge cell is collected in plural, thereby forming one pixel. For example, a red discharge cell, a green discharge cell, and a blue discharge cell are collected and form one pixel.
In such a plasma display panel, when discharge is performed using high frequency voltage, the inert gas generates vacuum ultraviolet rays and excites phosphors provided between the barrier ribs, thereby embodying an image. The plasma display panel is attracting attention as a next generation display apparatus due to its slimness and lightweigtness.
As described above, in the plasma display panel, the discharge is generated in the discharge cell, thereby displaying the image. For example, reset discharge, address discharge, and sustain discharge are generated. The address discharge is discharge for selecting a discharge cell generating the sustain discharge, which is main discharge for displaying the image, from the plurality of discharge cells.
Meantime, the conventional plasma display panel has a drawback of weakly generating the address discharge for selecting the discharge cell generating the sustain discharge.
Accordingly, in the conventional plasma display panel, there is a drawback in that, since the sustain discharge is not generated in the discharge cell in which the sustain discharge should be generated, the image is deteriorated in screen quality or is not even embodied.

Plasma display having barrier ribs that each overlap the bus electrodes of different electrodes only in part


Method and agent for preventing a hostile use of computer resources by an application running on a workstation. A list of services that are not allowed for access by unspecified applications is determined, and when such unspecified application runs on the workstation, direct access to the application is prevented from any resource. Any direct or indirect request for access to specific services is analyzed, to determine whether such request is allowable according to the list. The workstation processes the request if it is allowable. The unspecified application is prevented from accessing the requested resource if the request is not allowable. The resource may be any local or remote resource, such as, memory allocation, files, directories, operations with files and directories, such as copy, delete or compress, or any other operation leading to a permanent change in the workstation or its periphery. A look-up table which includes a list of services that are not allowed for access by unspecified applications, is used to determine whether requests made directly or indirectly by the unspecified application are allowable. The agent comprises a pre-set list of applications including a list of resources that each application may utilize.

The Internet has developed very much both in respect of its contents and of the technology employed, since it began a few years ago. In the early days of the Internet, web sites included text only, and after a while graphics was introduced. As the Internet developed, many compressed standards, such as pictures, voice and video files, were developed and with them programs used to play them (called "players"). Initially, such files were downloaded to the user's workstation only upon his request, and extracted only by the appropriate player, and after a specific order from the user.
When, in the natural course of the development of the World Wide Web the search for a way to show nicer, interactive and animated Web Pages began, Sun Microsystems Inc. developed Java—a language that allows the webmaster to write a program, a list of commands—Network Executables—that will be downloaded to the user workstation most of the time without his knowledge, and executed by his browser at his workstation. The executables are used, e.g., to provide photographic animation and other graphics on the screen of the web surfer. Such executables have ways of approaching the user workstation's resources, which lead to a great security problem. Although some levels of security were defined in the Java language, it was very soon that a huge security hole was found in the language.
Since Java was developed, Microsoft developed ActiveX, which is another Network Executable format, also downloaded into the workstation. ActiveX has also security problems of the same kind.
The Internet has been flooded with "Network Executables" which may be downloaded—deliberately or without the knowledge of the users—into workstations within organizations. These codes generally contain harmless functions. Although usually safe, they may not meet the required security policy of the organization.
Once executed, codes may jam the network, cause considerable irreversible damage to the local database, workstations and servers, or result in unauthorized retrieval of information from the servers/workstations. Such elements may appear on Java applets, ActiveX components, DLLs and other object codes, and their use is increasing at an unparalleled pace. The majority of these small programs are downloaded into the organization unsolicited and uncontrolled. The enterprise has no way of knowing about their existence or execution and there is no system in place for early detection and prevention of the codes from being executed.
The problem is made worse, in some cases, by the existence of large intranets and LANs, which may also be used by unauthorized persons to access workstations and perform hostile activities thereon.
The security problem was solved partially by the browser manufactures which allow the user to disable the use of executables. Of course this is not a reasonable solution, since all the electronic commerce and advertising are based on the use of executables.
In three copending patent applications of the same applicants hereof, IL 120420, filed Mar. 10, 1997, IL 121815, filed Sep. 22, 1997, and IL 122314, filed Nov. 27, 1997, the descriptions of which are incorporated herein by reference, there are described methods and means for preventing undesirable Executable Objects from infiltrating the LAN/WAN in which we work and, ultimately, our workstation and server. IL 122314 further provides a method for enforcing a security policy for selectively preventing the downloading and execution of undesired Executable Objects in an individual workstation.
While much has been done in the abovementioned patent applications toward protecting the individual workstation, one problem yet remained unsolved: the hostile use of local resources by applications which have passed any earlier security check (e.g., a gateway security policy), because they did not contravene such security policy, or by applications which have not passed through an earlier check point (such as a gateway equipped with a security policy check, as described in the aforementioned Israeli patent applications), either because such earlier point of check is not available, or because the application has been loaded directly on the workstation. Such hostile use of CPU resources may lead to damage to the data, operation and hardware of the workstation and, under the conditions contemplated above, may go undetected until the damage is done.
It is an object of the present invention to provide a method and agent which overcomes the aforesaid drawbacks of prior art methods, and which provides effective protection at the workstation level.
It is another object of the present invention to provide a method and an agent which can be used effectively to prevent the hostile use of workstation resources by applications running on said workstation.
Other objects and advantages of the invention will become apparent as the description proceeds.

Method and agent for the protection against the unauthorized use of computer resources


A self-supported nitride semiconductor substrate of 10 mm or more in diameter having an X-ray diffraction half width of 500 seconds or less in at least one of a {20-24} diffraction plane and a {11-24} diffraction plane.

Because the crystal growth of nitride semiconductors in a bulk form from its melt is generally difficult, a self-supported nitride semiconductor substrate is obtained by growing nitride semiconductor layer on a different base substrate such as sapphire and gallium arsenide, and removing layers ranging from the base substrate to leave the nitride semiconductor layer only.
The formation of a nitride semiconductor layer on a different base substrate of sapphire, etc. with large lattice mismatch is usually achieved not by the epitaxial growth of a nitride semiconductor coherent with the lattice of the base substrate, but by growing crystal nuclei in many points on the base substrate to such an extent that they are integrated to a continuous film. Accordingly, a film obtained by integrating such nitride semiconductor crystals does not have a lattice plane completely parallel to that of the substrate (not completely flat surface), resulting in slight deviations of crystal orientations therebetween. It is common to use a diffraction half width determined by an X-ray diffraction method as a method for evaluating crystal quality such as the deviations of crystal orientations, etc.
The quality of nitride semiconductor substrates is conventionally evaluated by a half width of an X-ray rocking curve in a {0002} or {0004} diffraction plane, and the smaller the half width, the higher the quality of the nitride semiconductor. For instance, Japanese patent 3,184,717 discloses a GaN single crystal as thick as 80 μm or more having a half-width of 5 to 250 seconds in a two-crystal X-ray rocking curve, which serves as a substrate, on which a GaN semiconductor crystal layer is grown. JP 10-053495 A discloses a nitride single crystal of 10 mm or more in both length and width and 300 μm or more in thickness, or 20 mm or more in length and 10 μm or more in diameter, which has a half width of 5 minutes or less in an X-ray diffraction rocking curve.

Self-supported nitride semiconductor substrate and its production method, and light-emitting nitride semiconductor device using it


Non-toxic, naturally derived and economical compositions for treating and preventing bacterial or fungal disease in plants, especially citrus canker, wherein such compositions include various combinations of d-limonene, wax and monohydric alcohol are provided. Methods for making and using such compositions are also provided.

As reported by the University of Florida Plant Pathology Department, fungal and bacterial pathogens can lower yields, reduce quality, negatively affect the aesthetic and economic value and even ultimately destroy plants, crops, pre-harvest fruits, trees, vegetables and grasses. In particular, bacterial and fungal diseases in citrus plants create huge economic burdens on the citrus industry worldwide. Citrus canker alone causes severe economic consequences in the world's citrus growing regions. The bacteria which causes citrus canker, Xanthomonas campestris pv. citri, has been found in southern Asia, Japan, the Middle East, Africa, South America and now North America. Historically, citrus canker outbreaks have occurred in North America in the early 1900s and again in 1986. Fortunately, through the use of aggressive eradication techniques, the disease was eliminated in both instances. Citrus canker, however, can be reintroduced when people inadvertantly transport infected citrus fruits and seedlings into citrus growing areas in the U.S. and elsewhere. In the U.S., Florida is by far the state most at risk from citrus canker given its combination of high humidity throughout the year, seasonal hurricanes and frequent thunderstorms accompanied by high wind gusts. (See The University of Florida Plant Pathology Department Report at www.biotech.ufl.edu/PlantContainment/canker.htm)
The University of Florida Extension Service reports that in 1995 citrus canker was again detected in the U.S. in citrus trees in the Miami-Dade County, Florida area. Citrus canker then spread to the commercial groves in southwest Florida. Since 1998 more than 870,000 trees have been destroyed in conjunction with-eradication programs. (See http://edis.ifas.ufl.edu/FE286)
Costs in managing the threat of citrus canker include capital investment for spray equipment, the lost value of affected fruit, costs associated with inspection and eradication, and costs associated with the creation of natural windbreaks and other defensive tactics. Current spraying programs include relatively expensive copper based sprays. The University of Florida Extension Service has estimated that if citrus canker became endemic in Florida, the total cost for countering endemic citrus canker, including the use of copper based sprays, could be more than $300 per acre.
Many types of organic molecules possess antimicrobial properties and can be used to effectively control fungal and bacterial disease in plants. However, many of the currently used pesticides are toxic to humans, animals and the exposed environment which limits large scale application in, for example, citrus orchards. The Environmental Protection Act was established in 1972, in part, to address concerns over the use of potentially toxic materials to control or treat diseases in crops. In 1996 Congress passed the Food Quality Protection Act requiring the Environmental Protection Agency to reassess the safety and efficacy of every existing pesticide by 2006. Concerns about pesticide residues on plants and the exposure of field workers to such residues severely limits the amounts of pesticide that can be applied and the timing of such application. These limitations decrease the potential effectiveness of commonly used pesticides to prevent and treat bacterial and fungal disease in plants in general and citrus canker in particular.
Accordingly, there exists a tremendous need for effective, economical and non-toxic compositions and methods for preventing and treating bacterial and fungal disease in plants. In particular there is a tremendous need for effective, economical and non-toxic compositions and methods for preventing and treating citrus canker.

Compositions and methods for the treatment and prevention of disease in plants


A head core slider including a slider body having an air bearing, and a head core having a ferrite portion providing a closed magnetic circuit with a magnetic gap is disclosed. The ferrite portion of the head core has a recess formed in at least one of two surface areas thereof which are to face the magentic disk and which are located on opposite sides of the magentic gap.

1. Field of the Invention
The present invention relates generally to a head core slider for a rigid magnetic disk drive (RDD) and a method of fabricating the same, and more particularly to a technique for reducing or avoiding a noise in the form of abnormal pulses, which may occur during reproduction or reading of recorded signals, particularly in a magnetic recording head for RDD using a ferrite core slider.
2. Discussion of the Prior Art
As one type of head core slider for a rigid magnetic disk drive (RDD), which includes a slider body having air bearings and a head core having a closed magnetic circuit (path) with a magnetic gap, there is known a ferrite core slider for RDD, in which at least a head core portion constituting the closed magentic circuit is formed of a ferrite material.
Various types of ferrite head core sliders have been proposed for use in a magentic head, for improvements in the output, recording density and other characteristics of the magnetic head. For instance, there are proposed a so-called monolithic type core slider, a so-called composite type core slider and a core slider having a MIG (Metal In Gap) structure. In the monolithic type core slider, the whole body of the core slider is formed of ferrite, and a part of the slider body functions to partially define the closed magnetic circuit. In the composite type core slider, the slider body and the head core are prepared independently of each other, and only the head core portion constituting the closed magnetic circuit is formed of a ferrite.
In operation of the RDD magnetic head having the ferrite core slider of any known type, reproduction outputs may include noise in the form of abnormal pulses (which may be called "Wiggle"), upon reproduction of signals recorded on a magnetic disk. Formerly, this abnormal-pulse type noise did not cause any major problem since the noise has a relatively low output level. Up to the present, therefore, the cause for the occurrence of this type of noise has not been made clear nor discovered, let alone a solution to the problem.
In recent years, however, the RDD magnetic head may suffer from increases in the output level and frequency of occurrence of the abnormal-pulse type noise, due to an increased coercivity of a magnetic disk to meet a need for high-density recording, an increased residual magnetic flux density, and a comparatively narrow spacing between the magnetic head and magnetic disk.

Head core slider for rigid magnetic disk drive