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PubMed1978

The mode of action of contractile effects induced by external calcium and its related bivalent cations in the KCl-depolarized rat uterus.

The cumulative log dose-response curve (DRC) isometrically produced by CaCl2 on depolarized uteri of rats in Ca2+-free KCl Ringer's solution (pH 7.8) showed a plateau-shaped type, when responses were plotted as a percent of the maximal tension of 50 micrometer acetylcholine, whereas those produced by BaCl2 or SrCl2 were a simple sigmoid type with the maximal response near the height of the plateau induced by Ca2+. The plateau phase of Ca2+ was inhibited competitively by Mg2+ (0.5--50 mM) and non-competitively by Mn2+ (30 micrometer--1 mM), whereas the maximal contraction of Ca2+ was not inhibited by either ion. Dantrolene (0.1 mM) inhibited both the plateau and the maximal contraction of Ca 2+ and retained the plateau-shaped type. EGTA (2mM) potentiated the plateau to the maximal response level and changed the DRC induced by Ca2+ to the simple sigmoid type. From these results, the plateau of DRC induced by Ca2+ seems to be mainly due to actions of external Ca2+ on the calcium binding of internal surface of cell membrane, suggesting that the internal surface is the site of the bivalent cations tested.

Animals↗
PubMed2000

New bivalent thrombin inhibitors with N(alpha)(methyl)arginine at the P1-position.

A series of bivalent thrombin inhibitors was synthesized, consisting of a d-phenylalanyl-prolyl-N(alpha)(methyl)arginyl active site blocking segment, a fibrinogen recognition exosite inhibitor part, and a peptidic linker connecting these fragments. The methylation of the P1 amino acid led to a moderate decrease in affinity compared with the unmethylated analog. In addition, it prevented the thrombin catalyzed proteolysis, independent of the P1' amino acid used. This is a significant advantage compared to the original hirulogs, which strictly require a proline as P1' amino acid to reduce the cleavage C-terminal to the arginyl residue. Several analogs were prepared by incorporation of different P1' amino acids found in natural thrombin substrates. The most potent inhibitor was I-11 [dCha-Pro-N(Me)Arg-Thr-(Gly)5-DYEPIPEEA-Cha-dGlu] with a Ki of 37 pM. I-11 is highly selective and no inhibition of the related serine proteases trypsin, factor Xa and plasmin was observed. The stability of I-11 in human plasma in vitro was strongly improved compared to hirulog-1. In addition, a significantly reduced plasma clearance of I-11 was observed after intravenous injection in rats. Results from molecular modeling suggest that a strong reorganization of the hydrogen bonds in the active site of thrombin may result in the proteolytic stability found in this inhibitor series.

Amino Acid Sequence↗
PubMed2003

Separation of bivalent anti-T cell immunotoxin from Pichia pastoris glycoproteins by borate anion exchange.

A major problem encountered in the large-scale purification of the bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(G4S), from Pichia pastoris supernatants was the presence of host glycoproteins exhibiting similar charge, size, and hydrophobicity characteristics. We overcame this problem by employing borate anion exchange chromatography. The borate anion has an affinity for carbohydrates and imparts negative charges to these structures. We found that at a concentration of sodium borate between 50 and 100 mM, the nonglycosylated immunotoxin did not bind to Poros 50 HQ anion exchanger resin, but glycoproteins, including aggregates related to the immunotoxin, did. By using this property of the immunotoxin in the presence of sodium borate, we successfully developed a 3-step purification procedure: (i) Butyl-650M hydrophobic interaction chromatography, (ii) Poros 50 HQ anion exchange chromatography in the presence of borate, and (iii) HiTrap Q anion exchange chromatography. The final preparation exhibited a purity of greater than 98% and a yield of greater than 50% from the supernatant. Previously, boronic acid resins have been used to separate glycoproteins from proteins. However, combining borate anion with conventional anion exchange resins accomplishes the separation of the immunotoxin from glycoproteins and eliminates the need to evaluate nonstandard resins with respect to good manufacturing practice guidelines.

Anion Exchange Resins↗
PubMed2004

Evaluation of fetal protection against experimental infection with type 1 and type 2 bovine viral diarrhea virus after vaccination of the dam with a bivalent modified-live virus vaccine.

OBJECTIVE: To evaluate the efficacy of a modified-live virus (MLV) combination vaccine containing type 1 and type 2 bovine viral diarrhea virus (BVDV) in providing fetal protection against challenge with heterologous type 1 and type 2 BVDV. DESIGN: Prospective study. ANIMALS: 55 heifers. PROCEDURE: Heifers were vaccinated with a commercial MLV combination vaccine or given a sham vaccine (sterile water) and bred 47 to 53 days later. Heifers were challenged with type 1 or type 2 BVDV on days 75 to 79 of gestation. Clinical signs of BVDV infection, presence of viremia, and WBC count were assessed for 14 days after challenge. Fetuses were collected on days 152 to 156 of gestation, and virus isolation was attempted from fetal tissues. RESULTS: Type 1 BVDV was not isolated in any fetuses from vaccinated heifers and was isolated in all fetuses from nonvaccinated heifers challenged with type 1 BVDV. Type 2 BVDV was isolated in 1 fetus from a vaccinated heifer and all fetuses from nonvaccinated heifers challenged with type 2 BVDV. CONCLUSIONS AND CLINICAL RELEVANCE: A commercial MLV combination vaccine containing type 1 and type 2 BVDV given to the dam prior to breeding protected 100% of fetuses against type 1 BVDV infection and 95% of fetuses against type 2 BVDV infection. Use of a bivalent MLV vaccine in combination with a comprehensive BVDV control program should result in decreased incidence of persistent infection in calves and therefore minimize the risk of BVDV infection in the herd.

Abortion, Veterinary↗
PubMed1979

Side-by-side pairing of the XY bivalent in spermatocytes and the ubiquity of the H-Y locus.

The pairing mechanism of the XY bivalent, the possibility of crossing-over between X and Y chromosomes during meiotic prophase, and the location of the H-Y locus are of interest with regard to genetic control mechanisms, male gametogenesis, and testicular organization. A whole-mount electron microscope technique has permitted the study of a large number of mouse and hamster spermatocytes to evaluate the spatial relationship of sex chromosomes and autosomes. X and Y chromosomes showed a transient, extensive side-by-side pairing segment along most of the length of the Y chromosome. This extensive pairing segment may cause genetic exchange between X and Y chromosomes. The finding of a small unpaired paracentromeric region of the Y chromosome could be related to a locus of totally sex-linked gene(s) that determine the development of the testis from the undifferentiated embryonic gonad.

Animals↗
PubMed1984

Vaccination against Marek's disease and infectious bursal disease. II. Titration and in vivo efficacy of the coinfection-derived bivalent live vaccine for turkey herpesvirus and infectious bursal disease virus.

The bivalent HVT/IBDV live vaccine, developed by cocultivation of the turkey herpesvirus (HVT) and infectious bursal disease virus (IBDV) vaccine in cell cultures, was quantitated. The titer of each constituent virus could be successfully determined in vitro by pretreatment of the vaccine with anti-IBDV serum or chloroform (CHCl3). Studies in vivo further demonstrated that the anti-IBDV serum-treated HVT/IBDV vaccine lost its immunogenicity by failing to induce IBDV-neutralizing antibody or to protect vaccinates from bursal atrophy after challenge exposure to infectious bursal disease. The CHCl3 treatment significantly reduced the efficacy of the vaccine to protect vaccinates against Marek's disease challenge.

Animals↗
PubMed2002

Positive and negative motivation in nucleus accumbens shell: bivalent rostrocaudal gradients for GABA-elicited eating, taste "liking"/"disliking" reactions, place preference/avoidance, and fear.

Microinjection of the GABA(A) agonist muscimol in the rostral medial accumbens shell in rats elicits appetitive eating behavior, but in the caudal shell instead elicits fearful defensive treading behavior. To further test the hypothesis that rostral shell muscimol microinjections produce positive motivational states, whereas caudal shell muscimol produces negative states, we measured behavioral place preference/avoidance conditioning and affective hedonic and aversive orofacial expressions of taste-elicited "liking" and "disliking" (gapes, etc.) in addition to fear and feeding behaviors. Farthest rostral muscimol microinjections (75 ng) caused increased eating behavior and also caused positive conditioned place preferences and increased positive hedonic reactions to the taste of sucrose. By contrast, caudal shell microinjections elicited negative defensive treading and caused robust negative conditioned place avoidance and negative aversive reactions to sucrose or quinine tastes. Intermediate rostral microinjections elicited effects of mixed positive/negative valence (positive appetitive eating behavior but negative place avoidance and negative taste reactions at mid-rostral sites, and sometimes positive eating simultaneously with fearful defensive treading more caudally). These results indicate that GABAergic neurotransmission in local microcircuits in nucleus accumbens mediates motivated/affective behavior that is bivalently organized along rostrocaudal gradients.

Animals↗
PubMedDate not supplied

[The problem of determining the affinity of bivalent antibodies using ELISA and its mathematical solution].

A new approach for the determination of the affinity of monovalent receptors in direct coordinates could be obtained without using Klotz or Scatchard equations. The mathematical solution of the problem of the determination of the affinity of bivalent antibodies by ELISA gives the following relation between absorbance, measured in ELISA. and antigen concentration: omega + square root of omega 2 + omega = liK, where omega = (Ao-Ai)/Ai, Ai is the absorbance, if Ag concentration is equal li; Ao is the absorbance, if Ag concentration is equal zero, K is an equilibrium constant.

Antibodies, Bispecific↗
PubMed1999

Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial.

The toxicity and therapeutic efficacy of escalating doses of anti-carcinoembryonic antigen x anti-N alpha-(diethylenetriamine-N,N,N',N''-tetraacetic acid)-In bispecific monoclonal antibody (F6-734) and iodine 131-labeled bivalent hapten were determined in a Phase I/II trial. A total of 26 patients with recurrences of medullary thyroid cancer documented by imaging and a rise in serum thyrocalcitonin were enrolled. Twenty to 50 mg of F6-734 and 40-100 mCi of 131I-hapten were injected 4 days apart. Quantitative scintigraphy was performed after the second injection for dosimetry estimations in eight cases. Clinical, biological, and morphological follow-up was carried out for 1 year after treatment. The mean percentage of injected activity per gram of tumor at the time of maximum uptake was 0.08% (range, 0.003-0.26%). The tumor biological half-life ranged from 3 to 95 days, and tumor doses ranged from 2.91 to 184 cGy/mCi. The estimated tumor-to-nontumor dose ratios were 43.8 x 53.4, 29.6 x 35.3, 10.9 x 13.6, and 8.4 x 10.0 for total body, red marrow, liver, and kidney, respectively. Grade III/IV hematological toxicity was observed in seven patients, most of them with bone metastases. Among the 17 evaluable patients, 4 pain reliefs, 5 minor tumor responses, and 4 biological responses with decrease of thyrocalcitonin were observed. Nine patients developed human anti-mouse antibody. Dose-limiting toxicity was hematological, and maximum tolerated activity was 48 mCi/m2 in this group of patients, most of whom had suspected bone marrow involvement. The therapeutic responses observed in patients mainly with a small tumor burden are encouraging for the performance of a Phase II trial with minimal residual disease.

Adolescent↗
PubMed2001

Two-step targeting of xenografted colon carcinoma using a bispecific antibody and 188Re-labeled bivalent hapten: biodistribution and dosimetry studies.

UNLABELLED: Radioimmunotherapy (RIT) is currently being considered for the treatment of solid tumors. Although results have been encouraging for pretargeted 131I RIT with the affinity enhancement system (AES), the radionuclide used is not optimal because of its long half-life, strong gamma emission, poor specific activity, and low beta particle energy. 188Re, though unsuitable for direct antibody labeling, could be used with the AES two-step targeting technique. The purpose of this study was to compare the distribution and dosimetry of a bivalent hapten labeled with 188Re or 125I. For dosimetry calculations and biodistribution data, 125I was substituted for 131I. METHODS: After preliminary injection of a bispecific anticarcinoembryonic antigen (CEA) or antihapten antibody (Bs-mAb F6-679), AG 8.1 or AG 8.0 hapten radiolabeled with 188Re or 125I was injected into a nude mouse model grafted subcutaneously with a human colon carcinoma cell line (LS-174-T) expressing CEA. A dosimetry study was performed for each animal from the concentration of radioactivity in tumor and different tissues. RESULTS: Radiolabeling of AG 8.1 with 125I afforded a 40% yield with a specific activity of 11.1 MBq/nmol after purification. Radiolabeling of AG 8.0 with 188Re afforded a 72% yield with a specific activity of 31.82 MBq/nmol. In all experiments, the percentage of tumor uptake of 125I-AG 8.1 was always significantly greater than that of 188Re-AG 8.0. The corresponding tumor-to-tissue ratios reflected uptake values. The least favorable tumor-to-normal tissue ratios in the dosimetry study were 8.1 and 8.5 for 131I (tumor-to-blood ratio and tumor-to-kidney ratio, respectively) and 2.3 for 188Re (tumor-to-intestine ratio). CONCLUSION: This study indicates that 188Re can be used for radiolabeling of hapten in two-step radioimmunotherapy protocols with the AES technique. 188Re has a greater range than 131I, which should allow the treatment of solid tumors around 1 cm in diameter. Although the method used for hapten radiolabeling did not provide optimal tumor uptake, the use of a bifunctional chelating agent associated with AG 8.1 should solve this problem.

Animals↗
PubMedDate not supplied

ELISA-based method for determining the affinity of bivalent antibodies of two specificities in a mixture.

The problem of the evaluation of the affinity for two types of bivalent antibodies in a mixture is considered. It is shown that the binding curve in appropriate coordinates can be used to compose either a system of four equations with four unknowns or a system of two equations with two unknown variables. The numerical solution of these equation systems yields affinity constants for both antibodies and the relationship between concentrations of antibodies studied in the mixture.

Antibodies, Bispecific↗
PubMedDate not supplied

[Comparison of DNA complexation with antitumor therapeutic cis-DDP and binuclear bivalent platinum compound containing pyrazine].

Conformational properties of DNA molecule upon its complexation with binuclear compounds of bivalent platinum in the cis configuration containing pyrazine ligand were studied by circular dichroism, viscometry, and dynamic birefringence. Comparison with active antitumor therapeutic cis-diamminedichloroplatinum (cis-DDP) was made. Experimental data indicates that interaction of these compounds with DNA results in the formation of coordination bond of platinum with nitrogen bases. The structure of the complex depends on the ratio of platinum and DNA concentrations in initial solution. The study of DNA protonation in complex with the binuclear coordination compound showed that the binding of platinum with DNA bases occurs at the N7 atom of guanine. It was observed a competition between the studied compound and cis-DDP for binding site on DNA. The macromolecule binds stronger to the binuclear platinum compound as compared with cis-DDP.

Antineoplastic Agents↗
PubMed2002

Bivalirudin, a bivalent, thrombin specific anticoagulant as an alternative to heparin in interventional procedures as an alternative to heparin in interventional procedures.

Among the antithrombotic therapies evaluated to date, the synthetic peptide bivalirudin is unique in its ability to reduce both ischemic and bleeding complications associated with percutaneous coronary intervention (PCI). Bivalirudin is a small peptide consisting of 20 amino acid residues that binds thrombin in a direct, reversible, and bivalent fashion. The agent is approved for use in the United States and New Zealand as an anticoagulant in patients with unstable angina undergoing PCI and may also prove beneficial in patients with acute coronary syndromes (ACS), acute myocardial infarction (AMI) and in patients undergoing coronary artery bypass graft (CABG) procedures. This article examines bivalirudin in more detail.

Angioplasty, Balloon, Coronary↗
PubMed1992

Insulin receptors are bivalent as demonstrated by photoaffinity labeling.

Insulin receptors in human placental membranes were photoaffinity-labeled with a radioactive human insulin-like growth factor I (hIGF-I) photoprobe N epsilon B28-monoazidobenzoyl 125I-hIGF-I either alone or together with a non-radioactive insulin photoprobe N epsilon B29-monoazidobenzoyl insulin. Precipitation of the solubilized receptors with anti-insulin antibody showed that receptors labeled with the radioactive hIGF-I photoprobe were detected in the immunoprecipitate only when photolabeling was carried out in the presence of the non-radioactive insulin photoprobe. Comparable results were obtained in converse experiments using a radioactive insulin photoprobe N epsilon B29-monoazidobenzoyl 125I-insulin, a non-radioactive hIGF-I photoprobe N epsilon B28-monoazidobenzoyl hIGF-I, and an antibody to hIGF-I. The amount of radioactive receptors precipitated by either the anti-insulin antibody or the anti-hIGHF-I antibody was close to the expected amount. These observations demonstrate that the insulin receptor is bivalent being capable of binding two molecules of ligand.

Affinity Labels↗
PubMed2006

Induction of neutralizing antibodies specific to dengue virus serotypes 2 and 4 by a bivalent antigen composed of linked envelope domains III of these two serotypes.

There is no vaccine to prevent dengue fever, a mosquito-borne viral disease, caused by four serotypes of dengue viruses. In this study, which has been prompted by the emergence of dengue virus envelope domain III as a promising sub-unit vaccine candidate, we have examined the possibility of developing a chimeric bivalent antigen with the potential to elicit neutralizing antibodies against two serotypes simultaneously. We created a chimeric dengue antigen by splicing envelope domain IIIs of serotypes 2 and 4. It was expressed in Escherichia coli and purified to near homogeneity. This protein retains the antigenic identities of both its precursors. It elicited antibodies that could efficiently block host cell binding of both serotypes 2 and 4 of dengue virus and neutralize their infectivity (neutralizing antibody titers approximately 1:40 and ~1:80 for dengue virus serotypes 2 and 4, respectively). This work could be a forerunner to the development of a single envelope domain III-based tetravalent antigen.

Animals↗
PubMed1991

[The characteristics of the reactogenicity and immunological activity of a new cholera bivalent chemical vaccine based on the results of controlled trials].

The reactogenic properties and immunological potency of modified cholera chemical vaccine (choleragen-toxoid + O-antigens Inaba and Ogawa) were tested in 278 volunteers aged 18 years and over in comparison with those of a commercial batch of monovalent cholera vaccine (choleragen-toxoid + O-antigen Inaba). The cholera vaccine, enriched with O-antigen Ogawa, was found to be safe; vaccination with this vaccine was not accompanied by the development of systemic and local reactions whose frequency and intensity met the requirements for the reactogenic properties of commercial cholera vaccine. The immunological potency of the bivalent vaccine with respect to strain Inaba was not inferior to that of the commercial vaccine; at the same time in persons immunized with the new preparation the titers of vibriocidal antibodies to strain of serovar Inaba were five-fold higher. The conclusion on the expediency of using cholera chemical vaccine enriched with O-antigen Ogawa was made.

Adult↗
PubMed1991

Ligand recognition by influenza virus. The binding of bivalent sialosides.

Infection by influenza virus is initiated by a cellular adhesion event that is mediated by the viral protein, hemagglutinin, which is exposed on the surface of the virion. Hemagglutinin recognizes and binds to cell surface sialic acid residues. Although each individual ligand binding interaction is weak, the high affinity of influenza virus for cells that bear sialic acid residues is thought to result from a multivalent attachment process involving many similar recognition events. To evaluate such binding we have synthesized three series of compounds, each containing two sialic acid residues separated by spacers of different length, and have tested them as ligands for influenza hemagglutinin. No increased binding to the bromelain-released hemagglutinin ectodomain was seen for any of the bivalent compounds as determined by 1H NMR titration. In contrast, however, a spacer length between sialic acid residues of approximately 55 A sharply increases the binding of these bidentate species to whole virus as determined by hemagglutination inhibition assays. The most effective compound containing glycines in the linking chain displayed 100-fold increased affinity for whole virus over the paradigm monovalent ligand, Neu5Ac alpha 2Me.

Animals↗
PubMed1991

Stabilization of PyPuPu triplexes with bivalent cations.

We studied the formation of stable PyPuPu intermolecular triplexes under neutral pH in the presence of bivalent cations (Mg, Ca, Mn, Co, Ni, Cu, Zn, Cd, and Ba) with the help of the photo- and DMS footprinting assays. The cations which stabilize d(C)n.d(G)n.d(G)n and d(TC)n.d(GA)n.d(AG)n triplexes were determined. Among them, Zn++ ions stabilized both triplexes, whereas Mg++ ions stabilize CGG triplexes, but do not stabilize TC.GA.AG triplexes. We have shown that an arbitrary purine sequence forms the PyPuPu triplex in the presence of Zn++ ions, and that the purine third strand is antiparallel with respect to the purine strand within the duplex.

Base Sequence↗