Abstract: The present invention concerns the discovery of a new member of the TNF receptor superfamily, referred to herein as the candidate "tvb receptor". Experimental evidence suggests that the instant gene corresponds to the gene of the tvb.sup.s3 locus responsible for mediating certain viral infection. The tvb receptor plays a functional role as the receptor for certain of the avian leukosis/sarcoma viruses (ALSV) in avians, and a likely role as a receptor for tumor viruses in other animals, e.g., the feline leukemia virus and the like. Moreover, inspection of the tvb sequence, particularly in comparison with other TNF receptors, reveals the presence of a "death domain" in the cytoplasmic tail of the tvb receptor, suggesting a role for the tvb receptor in determining tissue fate and maintenance. For instance, the tvb genes and gene products may participate, under various circumstances, in the control of proliferation, differentiation and/or cell death.

Abstract: The present invention relates to the epitopes of hepatitis C virus (HCV) core protein and non-structural 3 protein (NS3), and the epitopes of envelope protein, epitopes of non-structural 4 protein, and the epitopes of HCV non-structural 5 protein and a recombinant protein comprising the same; processes for producing the recombinant proteins; an agent for diagnosing antibodies against hepatitis C virus in a putative serum sample, which comprises said recombinant proteins; and a process for diagnosing hepatitis C by using the agent.

Abstract: An HCV antibody contained in a specimen is measured by an immunoassay method by utilizing the specific binding affinity of a hepatitis C virus (HCV) antibody to an antigenic peptide having the amino acid sequence represented by the following formula (1) or (2):Leu-Ser-Gly-Arg-Pro-Ala-Ile-Val-Pro-Asp-Arg-Glu-Val-Leu-Tyr-Gln-Glu-Phe-Asp -Glu . . . (SEQ ID NO: 1)Val-Asn-Gln-Arg-Ala-Val-Val-Ala-Pro-Asp-Lys-Glu-Val-Leu-Tyr-Glu-Ala-Phe-Asp -Glu . . . (SEQ ID NO: 2)According to the above method, it is possible to determine the serotype of the specimen simply and accurately, while suppressing a cross reaction or a non-specific reaction. As a result, it is also possible to preliminarily predict the effect of interferon treatment in an accurate manner, and to simply observe the course of the curing or treatment for hepatitis C.

Abstract: The present invention relates to polypeptides from clinical isolates of cytomegalovirus encoded by the gB coding region which include at least one amino acid variation which is a substitution, insertion or deletion wherein the polypeptides otherwise retain the character of cytomegalovirus. The amino acid variations include changes to neutralizing epitopes.

Abstract: A protein designated p35 binds to a number of the chemotaxis-stimulating cytokines known as chemokines. p35 may be used to treat conditions that are mediated by chemokines, such as inflammation. p35 is a secreted protein that can be purified from the culture supernatant of cells infected with certain viruses, or produced using recombinant DNA techniques. Isolated DNA sequences encoding p35 are provided, along with expression vectors comprising the p35 DNA, and purified p35 protein.

Abstract: A peptide and veterinarily acceptable salts thereof are disclosed which comprise an amino acid sequence which is derived from foot-and-mouth disease virus (FMDV). The peptide is independent within the FMDV structure of a B-cell epitode and is capable of eliciting T-cell help in an animal susceptible to FMDV infection for production of antibody against an antigen. Optionally, an amino acid in the sequence may be replaced by another amino acid which does not affect the function of the sequence to elicit T-cell help.

Abstract: A polypeptide having immunological activity for use as a diagnostic reagent for the HIV. The polypeptide comprises a substantial portion of each of more than one of the constituent proteins coded for by the HIV-pol gene, namely the amino acid sequences of the reverse transcriptase, RNase H and integrase enzymes coded for by the HIV-pol gene and the amino acid sequences of part of the protease enzyme coded for by the HIV-pol gene, but omitting the active site responsible for proteolytic activity.

Abstract: A variant or so-called "escape mutant" HBsAg protein or fragment thereof displaying the antigenicity of hepatitis B virus surface antigen is disclosed, in which the mutant protein or fragment thereof (mHBsAg) comprises a modified `a` determinant in which at least two amino acids are inserted downstream of position 122 of the wild type HBsAg sequence. A vaccine comprising the mHBsAg is provided, as is a kit for diagnostic in vitro detection of anti-mHBsAg antibodies and an antibody preparation comprising anti-mHBsAg antibodies.

Abstract: Two new isolates of the Hepatitis C virus (HCV), J1 and J7, are disclosed. These new isolates comprise nucleotide and amino acid sequences which are distinct from the prototype HCV isolate, HCV1. Thus, J1 and J7 provide new polynucleotides and polypeptides for use, inter alia, in diagnostics, recombinant protein production and vaccine development.

Abstract: We have cloned human lymphoid cell lines that are susceptible to hepatitis C virus (HCV) infection, and in which infection with HCV results in the development of cytopathic effects, including cell degeneration, induction of cell syncytia and cell death, as well as in the production of progeny virus. Infection was confirmed by the polymerase chain reaction, indirect immunofluorescence of viral antigens, and detection of the viral RNA-dependent RNA polymerase. Progeny virus released from the infected cells into the medium could be serially passaged using the cell-free supernatant fluid as the inoculum. Also described are uses of the cloned cell lines for both intact cell and cell-free assay systems for the effectiveness of candidate anti-HCV drugs.

Abstract: Attenuated recombinant viruses containing DNA encoding a rabies virus antigen in a "cocktail" or combination or multivalent compositions well as methods for making and using the compositions, expression products therefrom, and antibodies generated, are disclosed and claimed. The recombinant viruses can be NYVAC or ALVAC recombinant viruses. The compositions and products therefrom and antibodies generated have several preventive, therapeutic and diagnostic uses.

Abstract: Target cell specificity of delivery vectors is provided by incorporation of a target cell specific binding domain by the use of any binding domain, which binds specifically to a binding site on the target cell. The binding site may be endogenous to the target cell, provided by engineering the target cell, or a suitable binding site may be associated with the target cell. Target cells may also be associated with a CVR polypeptide to provide specificity for the delivery vector. The association of the CVR polypeptide confers target cell specificity for a second virus host cell range, which specificity differs from the viral host cell range of the endogenous target cell or animal host cell viral receptors. The CVR polypeptide may thus comprise a chimeric virus binding site which binds a second virus env binding domain specific for a second virus host cell range, selected from at least one of the group consisting of amphotropic, polytropic, xenotropic, ecotropic and tissue specific.

Abstract: The present invention is directed to a viral capsid polypeptide capable of inhibiting viral packaging, the viral capsid polypeptide consisting of a portion of a viral capsid protein of an RNA virus and including a multimerization domain of the viral capsid protein. The invention further provides an isolated nucleic acid molecule encoding such a viral capsid polypeptide. Expression vectors and host cells comprising the nucleic acid molecules are also provided, as well as a method for inhibiting viral packaging in a host cell by expressing the viral capsid polypeptide. In two preferred embodiments, the RNA virus is the ScVL1 virus or the ScVLa virus of Saccharomyces cerevisiae.

Abstract: Polypeptide antigens are disclosed which are immunoreactive with sera from individuals having a non-A, non-B, non-C, non-D, non-E Hepatitis, herein designated Hepatitis G Virus (HGV). Corresponding genomic-fragment clones containing polynucleotides encoding the open reading frame sequences for the antigenic polypeptides are taught. The antigens are useful in diagnostic methods for detecting the presence of HGV in test subjects. The antigens are also useful in vaccine and antibody preparations. In addition, the entire coding sequences of two HGV isolates are disclosed. Methods are presented for nucleic acid-based detection of HGV in samples and also methods for the isolation of further genomic sequences corresponding to HGV.

Abstract: A multimer of monomers non-covalently held together by interactive peptide linkers is provided for the enhancement of the immunogenicity of a substance. These multimers are useful for stimulating or suppressing the immune system, detecting the presence of antibodies, bypassing MHC restriction in an animal, the effective presentation of antigen, suppressing autoimmune disease, inducing cytokine production, adsorption, treating a defective immune system and for use as an adjuvant.

Abstract: Characterization of the envelope transmembrane protein of human immunodeficiency virus type 2 (HIV-2) was carried out using murine polyclonal and monoclonal antibodies or patient sera specific for HIV-2 proteins. A 80-Mr glycoprotein (gp80) was produced in HIV-2 infected cells along with three other glycoproteins that were recently reported: the extracellular glycoprotein (gp125), the envelope glycoprotein precursor (gp140), and the transient dimeric form of gp140 (gp300). The gp125 and gp80 were detectable after the synthesis of gp140 and the formation of gp300. Among these four glycoproteins, only gp80 and gp125 were associated with HIV-2 virions. As the other glycoproteins, gp8O was recognized by all HIV-2 positive sera. A murine polyclonal antibody raised against the purified gp300 recognized all four glycoproteins.

Abstract: HIV-1 peptides having at least one point mutation between position 593 and 611 of the HIV-1 gp160 amino acid sequence. The point mutation either is at position 604 or 610, or both positions. Immunoassays which utilize these peptides are provided, as well as, diagnostic test kits which contain these peptides.

Abstract: The protease necessary for polyprotein processing in Hepatitis G virus (HGV) is identified, cloned, and expressed. Proteases, truncated protease, and altered proteases are disclosed which are useful for cleavage of specific polypeptides, and for assay and design of antiviral agents specific for HGV.

Abstract: What is described is a modified vector, such as a recombinant poxvirus, particularly recombinant vaccinia virus, having enhanced safety. The modified recombinant virus has nonessential virus-encoded genetic functions inactivated therein so that virus has attenuated virulence. In one embodiment, the genetic functions are inactivated by deleting an open reading frame encoding a virulence factor. In another embodiment, the genetic functions are inactivated by insertional inactivation of an open reading frame encoding a virulence factor. What is also described is a vaccine containing the modified recombinant virus having nonessential virus-encoded genetic functions inactivated therein so that the vaccine has an increased level of safety compared to known recombinant virus vaccines.

Abstract: This invention relates generally to immunoreactive polypeptide compositions comprising hepatitis type C viral epitopes, methods of using the compositions in immunological applications, and materials and methods for making the compositions.

Abstract: A hepatitis C virus antigen polypeptide having a molecular weight of approximately 22 kilodaltons expressed from a hepatitis C virus structural gene region; a production method for a hepatitis C virus antigen polypeptide having a molecular weight of 22 kilodaltons and/or a peptide related thereto, wherein an expression vector having inserted thereinto a cDNA fragment of a hepatitis C virus structural gene region is inserted into a cultured cell line and the transfected cell line thus obtained is cultured; and a detection method for a hepatitis C virus antibody, wherein a hepatitis C virus antigen polypeptide is used as an antigen, and an antibody specific thereto is detected.

Abstract: A first glycoprotein having a molecular weight of approximately 120,000 daltons in the H9/HTLV-III cell line, of which approximately 90,000 daltons is the unglycosylated moiety, is obtained from cells infected with human T-cell leukemia virus, type III. A second glycoprotein having a molecular weight of approximately 160,000 daltons is also obtained from such cells, of which approximately 90,000 daltons is the unglycosylated moiety and is substantially identical to the unglycosylated moiety of the first glycoprotein.The presence, in a biological specimen, of either of these unglycosylated or of the unglycosylated moiety is indicative of the presence of cells infected by human T-cell leukemia virus. An assay for the glycoprotein or its unglycosylated moiety is a useful diagnostic procedure for determining such infection in biological specimens.

Abstract: The present invention provides a method and products for establishing nutrient recognition and improving nutrient utilization and growth in a human or an animal by immunologically stimulating digestion or a gastric cascade within the gastrointestinal tract, by orally or parenterally immunizing the human or animal with an immunizing effective amount of an ingestible antigen or a mixture of ingestible antigens and orally reintroducing the antigen(s). Another aspect of the invention provides a method and products for preventing and treating gastrointestinal disease by immunologically stimulating a gastric cascade, namely, blood flow, production of mucus and release of digestion regulatory factors within the gastrointestinal tract of a human or an animal, by orally or parenterally immunizing the human or the animal with an immunizing effective amount of an ingestible antigen or a mixture of ingestible antigens and orally reintroducing the antigen(s).

Abstract: This disclosure relates to an isolated and cloned DNA from a granulovirus virus which comprises an amino acid sequence of the vital gene encoding a polypeptide isolated from occlusion bodies of certain baculoviruses and which polypeptide possesses the biological activity of enhancing baculovirus infectivity. Such proteins termed herein as "enhancins" are found within the viral occlusion body, have a disruptive effect on the insect peritrophic membrane (PM) proteins, and/or interact with the midgut epithelium in such a manner as to permit the increased adsorption, penetration and uptake of virus particles by midgut cells with a concomitant increase in host mortality. Disclosed herein is a recombinant DNA sequence which codes for the enhancin protein of the Helicoverpa armigera granulovirus virus. The DNA sequence is shown in SEQ. ID. NO.: 1 and the open reading frame is shown in SEQ. ID. NO.: 1: base pairs 271-2976. The amino acid sequence of the enhancin protein is shown in SEQ. ID. NO.: 2.

Abstract: The invention resides in various peptides derived from the envelope glycoprotein of HTLV-1 and conjugates of the peptides. Compositions including the peptides are also included in the invention. The peptides, their conjugates and compositions thereof have use in diagnostic and immunization methods, especially those that are based upon T-helper and/or cytotoxic T lymphocyte function.

Abstract: The present invention is concerned with a new strain of Mareks Disease Virus and to a vaccine for the protection of poultry against Mareks Disease containing the novel strain. The invention also relates to bivalent or polyvalent vaccines comprising in addition other viruses of the Mareks Disease virus group, i.e. HVT.

Abstract: The invention involves an isolated anti prion protein binding protein which has a molecular weight of from about 55 kD to about 65 kD as determined by SDS-PAGE. Also described is a peptide derived from this isolated anti-prion protein binding protein. Diagnostic uses for each of these molecules are discussed.

Abstract: Immunotherapy for the treatment of Herpes Simplex Virus eye infections is disclosed. The invention involves a local therapeutic or prophylactic vaccine for the eye, comprising one or more recombinant HSV-1 glycoproteins or proteins, specifically gB and gD, in combination with at least one adjuvant to reduce the incidence of primary HSV-1 infection and/or decrease spontaneous HSV-1 ocular shedding which in turn, controls recurrent corneal disease.

Abstract: Peptides corresponding to epitopes of HTLV-2 proteins are provided. These peptides are immunologically reactive with HTLV-2 specific antibodies. Several of the peptides are sufficiently unreactive to antibodies to HTLV-1 to distinguish between antibodies which recognize HTLV-1 and those which recognize HTLV-2. Thus HTLV-1 infections can be distinguished from HTLV-2 infections. The peptides are useful in assays for detection of HTLV-2 infection or exposure. The peptides are also useful as vaccine compositions against HTLV-2. Antibodies generated in response to immunization by the peptides are also provided.

Abstract: Vaccines effective in the inhibition of infection caused by the family of retroviruses, HTLV-III, Human T-Cell Leukemia Virus, LAV, Lymphadenopathy-associated virus, ARV-2, AIDS-Related Virus, (AIDS and AIDS-Related Complex) have been developed from an antisera prepared against thymosin .alpha..sub.1 (T.alpha..sub.1), a thymic hormone, as well as from antisera to synthetic peptide fragments of T.alpha..sub.1 and antisera to synthetic peptide fragments inclusive of amino acid positions 92-109 of the p17 gag core protein of HTLV-III, LAV and ARV-2. In this 18 amino acid primary sequence there is a 44 to 50% homology between the gag protein and T.alpha..sub.1. Immunoglobulin (IgG)-enriched preparations of the T.alpha..sub.1 antisera have enhanced activity in blocking vital replication. A diagnostic test capable of directly detecting the presence of HTLV-III, LAV, ARV-2 and related retroviruses associated with AIDS and ARC is also described.

Abstract: Specific peptide fragment from the feline immunodeficiency virus (FIV), and its use as a diagnostic reagent.The said peptide fragment, derived from the Env protein of the Wo strain of the feline immunodeficiency virus (FIV) (peptide P253), corresponds to positions 693-709 of the said Env protein and exhibits the following sequence:Leu-Gly-X-Asn-Gln-Asn-Gln-Phe-Phe-X-Lys-Val-Pro-Ser-Ala-, in which X represents a cysteine or a serine, as follows:Leu-Gly-Cys-Asn-Gln-Asn-Gln-Phe-Phe-Cys-Lys-Val-Pro-Ser-Ala (SEQ ID NO: 1),Leu-Gly-Ser-Asn-Gln-Asn-Gln-Phe-Phe-Ser-Lys-Val-Pro-Ser-Ala (SEQ ID NO: 2),Leu-Gly-Cys-Asn-Gln-Asn-Gln-Phe-Phe-Ser-Lys-Val-Pro-Ser-Ala (SEQ ID NO: 3),Leu-Gly-Ser-Asn-Gln-Asn-Gln-Phe-Phe-Cys-Lys-Val-Pro-Ser-Ala (SEQ ID NO: 4).

Abstract: HIV-2 virus variants, namely virus HIV D194 and virus HIV D205, which can be cloned from the corresponding virus isolate HIV D194 (ECACC V 87122303) or from the infected cell line HUT 194 (ECACC V 87122306) or from the virus isolate HIV D205 (ECACC V 87122304), respectively, and their RNA or RNA-fragments and DNA and DNA-fragments derived therefrom and/or proteins and the use thereof for diagnostics and therapy.

Abstract: BCRF1 proteins are provided for treating conditions associated with excessive production of IFN-.gamma.. Also provided are expression vectors for producing BCRF1 proteins. Compositions of the invention are useful in treating a variety of disorders, including allergy, psoriasis, tissue rejection, and MHC-linked autoimmune diseases.

Abstract: The invention relates to a polypeptide expressed by a DNA molecule, its use in diagnosis and its methods of production. The polypeptide disclosed herein is encoded by a DNA molecule derived from the genome of an HCV, and comprises a hepatitis C virus (HCV) core antigen protein fused to a part of an envelope region of a hepatitis C virus (HCV) protein The polypeptide may be used in the detection of HCV.

Abstract: HIV-1 peptides having at least one point mutation between position 593 and 611 of the HIV-1 gp160 amino acid sequence. The point mutation either is at position 604 or 610, or both positions. Immunoassays which utilize these peptides are provided, as well as, diagnostic test kits which contain these peptides.

Abstract: The invention relates to peptides representing CTL epitopes from the HTLV-I envelope protein. The invention further relates to compositions, comprising the peptides, for priming a T-cell response in a subject. Furthermore, methods for priming a T-cell response by administration of the compositions to a subject and methods for evaluating the T-cell function of a patient are described.

Abstract: This invention relates to E2 trans-activation repressors which interfere with normal functioning of the native full-length E2 transcriptional activation protein of the papillomavirus. This invention also relates to DNA sequences and recombinant DNA molecules encoding such repressors, unicellular hosts transformed with such DNA molecules, and processes for producing and using such repressors. Native full-length E2 trans-activation protein activates transcription of papillomavirus only through binding to DNA, and it binds to DNA only in the form of a pre-formed homodimer--a pair of identical polypeptide subunits held together by non-covalent interactions. The E2 trans-activation repressors of this invention are proteins, polypeptides or other molecules that dimerize with full-length native E2 polypeptides to form inactive heterodimers, thus interfering with the formation of active homodimers comprising full-length native E2 polypeptides, thereby repressing papillomavirus transcription and replication.

Abstract: A vaccine effective against S. zooepidemicus-caused infections is made by enzymatic digestion of S. zooepidemicus and subsequent detergent treatment of the product of this digestion. The antigenic material thus obtained is then combined with an appropriate adjuvant.

Abstract: The present invention provides mammalian cells modified to stably express at least the entire human immunodeficiency virus-1 envelope protein gp160. The invention provides a vaccine comprising the cells of the invention. The invention also provides methods for screening compounds for their ability to inhibit formation of syncytia between cells that express HIV-1 gp160 and cells that express CD4 comprising mixing cells of invention, cells that express CD4 on their surfaces, and a test compound for a length of time sufficient for syncytia to form; and then determining the amount of syncytia formation.

Abstract: The present invention provides a panel of HIV peptides useful in diagnosing whether or not a patient is of vertical HIV transmission status, methods for diagnosing same, methods for identifying epitopes and peptides associated with non-transmission status, and pharmaceutical and vaccine compositions containing same.

Abstract: A chimaeric protein, suitable for incorporation in a vaccine and capable of forming parts of a capsid assembly, comprises the amino acid sequence of the coat protein of phage MS-2, or a conservatively modified variant thereof, or sufficient of said sequence or variant to retain capsid-forming capability, which amino acid sequence has been modified by insertion of a foreign epitope in the region corresponding to a protuberant protein hairpin in the capsid assembly as shown in the crystal structure of the intact phage.

Abstract: A novel gamma retinoic acid receptor is disclosed. The novel receptor is encoded for by cDNA carried on plasmid pGEM-hRAR.gamma., which has been deposited with the American Type Culture Collection for patent purposes. Chimeric receptor proteins are also disclosed. The chimera contain at least one functional domain from the new gamma retinoic acid receptor.

Abstract: What is described is a recombinant poxvirus, such as vaccinia virus, fowlpox virus and canarypox virus, containing foreign DNA from flavivirus, such as Japanese encephalitis virus, yellow fever virus and Dengue virus. In a preferred embodiment, the recombinant poxvirus generates an extracellular particle containing flavivirus E and M proteins capable of inducing neutralizing antibodies, hemagglutination-inhibiting antibodies and protective immunity against flavivirus infection. What is also described is a vaccine containing the recombinant poxvirus for inducing an immunological response in a host animal inoculated with the vaccine.

Abstract: Method for the production of a subunit vaccine against porcine parvovirus (PPV). The method is comprised of a first step wherein a recombinant protein VP2 of PPV is obtained by using the replication of a recombinant baculovirus wherein the gene corresponding to VP2 has been previously inserted in cells of a permissive host. The protein VP2 obtained in this invention has the capacity of forming empty chimeric capsids with high immunogenicity and can be provided as a vaccine formulation for protecting pigs against PPV infection. The recombinant baculovirus AcMNPV.pPPVEx8 expresses the VP2 of PPV in conditions making possible the formation of pseudo-viral capsids.

Abstract: What is described is a modified vector, such as a recombinant poxvirus, particularly recombinant vaccinia virus, having enhanced safety. The modified recombinant virus has nonessential virus-encoded genetic functions inactivated therein so that virus has attenuated virulence. In one embodiment, the genetic functions are inactivated by deleting an open reading frame encoding a virulence factor. In another embodiment, the genetic functions are inactivated by insertional inactivation of an open reading frame encoding a virulence factor. What is also described is a vaccine containing the modified recombinant virus having nonessential virus-encoded genetic functions inactivated therein so that the vaccine has an increased level of safety compared to known recombinant virus vaccines.

Abstract: The present invention relates to C-terminally truncated flavivirus envelope proteins 80-81% in size which are more immunogenic than their counterpart full-length proteins. The present invention further relates to recombinant viruses which encode the truncated protein and to host cells infected therewith. Host cells express the truncated protein on their outer membrane and secrete it into the medium. The present invention further relates to vaccines for use against flavivirus infection. The vaccines include either a recombinant vaccinia virus expressing the truncated envelope protein of the present invention, and the truncated envelope protein produced by a recombinant baculovinis.

Abstract: Cloning and sequencing certain baculovirus genes encoding polypeptides termed enhancins. The polypeptides are isolated from the occlusion body of certain baculoviruses such as Trichoplusia ni granulosis virus and Pseudaletia unipuncta granulosis virus, Hawaiian strain. The polypeptides have the ability of enhancing the infectivity of baculoviruses and are useful ingredients of pest control compositions.

Abstract: The present invention relates to a DNA segment encoding a recombinant HIV p24 protein or HIV p24-gp41 fusion protein and a recombinant DNA (rDNA) molecule capable of expressing either protein. Cells transformed with the rDNA, methods for producing the fusion protein and diagnostic methods and systems using the fusion protein are also described.

Abstract: Medicaments, and methods of identifying the same, are described that are useful for treating papillomavirus diseases that have the characteristics of preventing, interfering with, or reversing the binding of the appropriate papillomavirus proteins E1 or E2 to a nucleotide sequence homologous to a nucleotide sequence present in the papillomavirus genome, or of the formation of a complex consisting of papillomavirus proteins E1 and E2, or the binding of the complex to the nucleotide sequence.

Abstract: The chimeric proteins, and a protential vaccine and diagnostic reagent comprising gag-env chimeric protein particles are disclosed. The preparation comprises linking gag of HIV-2 to env to form the chimeric gene, inserting the obtained chimeric gene into the DNA of a baculovirus, infecting insect cells or insect host with the resulting recombinant virus, culturing it and purifying the obtained chimeric protein. The gag chimeric protein of HIV according to the present invention retains both antigenic and immunogenic properties.