SEARCH · Search PubMed

Results for “bivalent”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,423 records · Page 79Linked to original sources

PubMed2001

Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses.

Optimal immune responses require both an antigen-specific and a co-stimulatory signal. The shared ligands B7-1 and B7-2 on antigen-presenting cells deliver the co-stimulatory signal through CD28 and CTLA-4 on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it. Numerous animal studies and recent clinical trials indicate that manipulating these interactions holds considerable promise for immunotherapy. With the consequences of these signals well established, and details of the downstream signalling events emerging, understanding the molecular nature of these extracellular interactions becomes crucial. Here we report the crystal structure of the human CTLA-4/B7-1 co-stimulatory complex at 3.0 A resolution. In contrast to other interacting cell-surface molecules, the relatively small CTLA-4/B7-1 binding interface exhibits an unusually high degree of shape complementarity. CTLA-4 forms homodimers through a newly defined interface of highly conserved residues. In the crystal lattice, CTLA-4 and B7-1 pack in a strikingly periodic arrangement in which bivalent CTLA-4 homodimers bridge bivalent B7-1 homodimers. This zipper-like oligomerization provides the structural basis for forming unusually stable signalling complexes at the T-cell surface, underscoring the importance of potent inhibitory signalling in human immune responses.

Abatacept↗

PubMed1993

Mechanical basis of meiotic metaphase arrest.

Control of the metaphase to anaphase transition is a central component of cell-cycle regulation. Arrest at either metaphase I or II before fertilization is a common component of oogenesis in many organisms. In Drosophila melanogaster females, this arrest occurs at meiosis I with the chiasmate bivalents tightly massed at the metaphase plate and the nonexchange chromosomes positioned between the plate and the poles on long tapered spindles. Meiosis resumes only after passage through the oviduct. Thus, metaphase arrest defines an important checkpoint in the meiotic cell cycle. We report here that this arrest results from the balancing of chiasmate bivalents at the metaphase plate. Two meiotic mutations, mei-9b and mei-218a4, both of which greatly reduce the frequency of chiasma formation, bypass the metaphase block and allow stage 14 oocytes to finish both meiotic divisions without arrest. We conclude that metaphase arrest results from the balancing of kinetochore forces due to chiasmata.

Animals↗

PubMed2001

Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II--peptide chimera.

As the number of drugs with potential therapeutic use for T-cell-mediated diseases increases, there is a need to find methods of delivering such drugs to T cells. The major histocompatibility complex (MHC)--peptide complexes are the only antigen-specific ligands for the T-cell receptor (TCR) expressed on T cells, and they may be an appropriate drug delivery system. We engineered a soluble bivalent MHC class II-peptide chimera on the immunoglobulin scaffold (I-E(d)alpha beta/Fc gamma 2a/HA110-120, DEF) that binds stably and specifically to CD4 T cells recognizing the HA110-120 peptide. Doxorubicin, a powerful antimitogenic anthracycline, was enzymatically assembled on the galactose residues of a DEF chimera. The DEF-gal-Dox construct preserved both the binding capacity to hemagglutinin (HA)-specific T cells, and the drug toxicity. Brief exposure of HA-specific T cells to DEF-gal-Dox construct in vitro was followed by drug internalization in the lysosomes, translocation to the nucleus, and apoptosis. Administration of DEF-gal-Dox to mice expressing the TCR-HA transgene reduced the frequency of TCR-HA T cells in the spleen and thymus by 27% and 42%, and inhibited HA proliferative capacity by 40% and 60%, respectively. It has not been demonstrated previously that pharmacologically active drugs able to modulate T-cell functions can be delivered to T cells in an antigen-specific manner by soluble, bivalent MHC II-peptide chimeras.

Animals↗

PubMed1975

Chiasma frequency variation with altitude in Cepaea hortensis (můll.).

Populations of Cepaea hortensis have been sampled from an area of 121 sq km on the north slopes of the Brendon Hills, Somerset, and analysed for chiasma frequency. Variation in chiasma frequency is due to variation in a single large bivalent--the A group bivalent. In 12 populations studied during 1973 no association between chiasma frequency and ecological factors could be detected. In particular, there is no evidence of a negative correlation of population density with chiasma frequency which is known to exist in populations of C. nemoralis within the area. In 1974, 17 populations, four of which were utilised in the 1973 analysis, were studied. Negative correlations of interstitial (but not total or terminal) chiasma frequency and between-cell variance with altitude were found. It is likely that the correlation of between-cell variance with altitude is due to the strong correlation of variance with chiasma frequency which exists in these populations. There is evidence from several populations that chiasma frequency is stable between years. The implications of the negative correlation of chiasma frequency with altitude and the lack of a correlation with population density are discussed.

Altitude↗

PubMed1987

A model for quantifying genetic recombination in chromosome polymorphisms due to supernumerary heterochromatic segments.

Heterochromatic supernumerary segments can modify chiasma distribution in the affected bivalents. A model is developed for quantifying the genetic recombination in populations polymorphic for such segments. This paper describes this model for a monochiasmate bivalent, and its application in different populations of the grasshopper Chorthippus parallelus. The observations suggest that these polymorphic systems have evolutionary implications.

Animals↗

PubMed1991

Positional control of chiasma distribution in the house mouse. Chiasma distribution in mice homozygous and heterozygous for an inversion in chromosome 1.

An examination of the chiasma distribution in chromosome 1 of male mice homozygous and heterozygous for a distal inversion In(1) 12Rk and in normal males was carried out. No differences in chiasma distribution were found between homozygotes for the inversion and homozygotes for normal chromosome 1. A significant decrease in the frequency of bivalents bearing chiasmata in the pretelomeric region was found in heterozygotes. This, in its turn, produced a redistribution of chiasmata in the proximal non-inverted part of bivalent 1. These results could be interpreted as evidence for positional control of the chiasma distribution pattern: the distance of certain parts of the chromosome from the telomere and chiasmata interference are more important for determination of the chiasma frequency in a given region than its genetic content.

Animals↗

PubMedDate not supplied

Crossing over analysis at pachytene in man.

The distribution of anti-MLH1 (MutL homologue 1) antibody labelling was studied in human prophase meiocytes. A labelling pattern consisting of distinct foci, always associated with the synaptonemal complex (SC) and never in closely juxtaposed pairs, was observed. Comparison of the number and general positions of autosomal foci with previous studies of the number and positions of autosomal chiasmata indicates that the anti-MLH1 antibody marks sites of crossing over in human pachytene spermatocytes. A mean number of 50.9 autosomal foci was observed from 46 human pachytene spermatocytes corresponding to a genetic length of 2545 cm. Division of these spermatocytes into sub-stages revealed that the number of foci remains stable throughout pachytene. A focus was found on the XY bivalent in 56.5% of the nuclei. The presence or absence of foci from the XY bivalent could not be correlated to pachytene sub-stage.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice.

Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t(1/2) and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG(1) heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG(1)-Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentration-dependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

Animals↗

PubMed2005

Evolutionary implications of permanent odd polyploidy in the stable sexual, pentaploid of Rosa canina L.

In Rosa canina (2n = 5x = 35), the pollen and ovular parents contribute, respectively, seven and 28 chromosomes to the zygote. At meiosis I, 14 chromosomes form seven bivalents and 21 chromosomes remain as univalents. Fluorescent in situ hybridization to mitotic and pollen mother cells (PMC) of R. canina showed that 10 chromosomes (two per genome) carry ribosomal DNA (rDNA) loci. Five chromosomes carry terminal 18S-5.8S-26S rDNA loci; three of these also carry paracentric 5S rDNA loci and were designated as marker chromosomes 1. Five chromosomes carry only 5S rDNA loci and three of these were designated as marker chromosomes 2. The remaining four of the 10 chromosomes with rDNA loci were individually identifiable by the type and relative sizes of their rDNA loci and were numbered separately. At PMC meiosis, two marker chromosomes 1 and two marker chromosomes 2 formed bivalents, whereas the others were unpaired. In a gynogenetic haploid of R. canina (n = 4x = 28), obtained after pollination with gamma-irradiated pollen, chromosomes at meiosis I in PMC remained predominantly unpaired. The data indicate only one pair of truly homologous genomes in R. canina. The 21 unpaired chromosomes probably remain as univalents through multiple generations and do not recombine. The long-term evolutionary consequence for the univalents is likely to be genetic degradation through accumulated mutational change as in the mammalian Y chromosome and chromosomes of asexual species. But there is no indication that univalents carry degenerate 5S rDNA families. This may point to a recent evolution of the R. canina meiotic system.

Chromosome Banding↗

PubMed2006

Heterovalent selectivity and the combinatorial advantage.

Libraries of monovalent compounds can be reacted with each other to give libraries of bivalent ones. If those reactions are efficient, and if the products do not need to be purified, large numbers of bivalent compounds can be produced rapidly, and one might say there is a "combinatorial advantage" to doing so. However, selective formation of heterobivalent products must be possible otherwise statistical mixtures will form. This tutorial review describes methods that will give heterobivalent compounds almost exclusively. Although there are relatively few methods that will give that desired selectivity, such methods are becoming increasingly important as the potential applications of bi- and multivalent compounds emerge.

Journal Article↗

PubMed1967

The ion-binding characteristics of reconstituted collagen.

The ion-binding capacity of highly purified reconstituted calf-skin collagen, and the effects of these ions on the precipitation and solubility of the collagen, were studied with a variety of salt solutions at ionic strength 0.16 and pH7.4. Only a small percentage of the total theoretically available anionic and cationic groups was available for ion-binding. In view of this, it appears that most of the ionizable groups of collagen are involved in intramolecular or intermolecular linkages, or both. Nevertheless, marked differences in the binding of the various ions by collagen were observed. Bivalent cations were bound in extremely small but remarkably similar quantities. In contrast, sodium was bound both in much higher and more variable quantities. Of the anions, pyrophosphate and sulphate were bound in the largest quantities, followed by phosphate, fluoride and chloride, in that order. Despite the minimal uptake by collagen of bivalent cations, they prevented the aggregation of tropocollagen into fibrils, and disaggregated fibrillar collagen. In the presence of multivalent anions, tropocollagen aggregated readily and its fibrillar stability was maintained. On the basis of the imbalance in the binding of ion pairs by the sodium pyrophosphate- and sodium phosphate-treated collagens, it was apparent that a reduced number of side-chain carboxyl groups were dissociated in the presence of these salts.

Journal Article↗

PubMed1967

The origin of the polydispersity in sedimentation patterns of rapidly labelled nuclear ribonucleic acid.

1. A study was made of the sedimentation properties of purified preparations of the rapidly labelled RNA in the nucleus and the cytoplasm of the HeLa cell. The sedimentation of the rapidly labelled nuclear RNA was very sensitive to changes in ionic strength and bivalent cation concentration. Under the conditions usually used in sucrose-density-gradient centrifugation the rapidly labelled nuclear RNA showed extreme polydispersity, and much of it sedimented more rapidly than the 28s RNA. At low ionic strength and after removal of Mg(2+), however, the rapidly labelled nuclear RNA sedimented as a single peak at about 16s. The conversion of the polydisperse material into the 16s form did not involve degradation of the RNA, since the effect could be reversed by increasing the ionic strength of the solution. 2. The cytoplasm did not contain any RNA that showed polydisperse sedimentation under the usual conditions of sucrose-density-gradient centrifugation, or that had the same sensitivity as the rapidly labelled nuclear RNA to changes in ionic strength. All the radioactivity in the cytoplasmic RNA sedimented with the 28s, 16s and 4s components over a wide range of physical conditions, but these components did contain a labelled fraction with some of the features of the rapidly labelled nuclear RNA on columns of methylated albumin on kieselguhr. 3. In both nucleus and cytoplasm the RNA detected by ultraviolet absorption could also be converted into a 16s form by removal of bivalent cations at low ionic strength; this effect was again, within certain limits, reversible. The nuclear RNA as a whole was more susceptible to changes in ionic strength than the cytoplasmic RNA. 4. It thus appears that all the RNA in the cell, except the 4s RNA, can be prepared, without degradation, as a single peak sedimenting at about 16s. The relationship of these various 16s components to each other is discussed.

Albumins↗

PubMed1967

The reversal of phenylarsenoxide inhibition of keto acid oxidation in mitochondrial and bacterial suspensions by lipoic acid and other disulphides.

1. Inhibition of pyruvate oxidation in suspensions of Aerobacter aerogenes cells and of isolated mitochondria from rat heart and liver by phenylarsenoxide is prevented by an excess of lipoic acid, whereas inhibition due to certain bivalent cations is not. 2. In both systems inhibition persists when the bacteria and mitochondria are recovered and resuspended in fresh media in the absence of the inhibitor. Persistent inhibition due to preincubation with phenylarsenoxide, but not with the metal ions, is reversed by lipoic acid and by certain other disulphides. 3. 2,3-Dimercaptopropan-1-ol prevents the inhibition of pyruvate oxidation by phenylarsenoxide and by bivalent cations in both mitochondria and bacterial cells. 4. In aerobic suspensions of mitochondria and bacteria disulphides such as lipoic acid are reduced rapidly to dithiols. Reduction is inhibited by Co(2+), Ni(2+), Cd(2+) and Zn(2+), but not by phenylarsenoxide. 5. It is concluded that the inability of lipoic acid to prevent the action of the metal ions on pyruvate oxidation is due to the inhibition of its reduction to the effective dithiol.

Animals↗

PubMed1968

Effect of cations on structure-linked sedimentability of lysosomal hydrolases.

1. A partially purified lysosomal preparation was obtained from mouse liver sucrose homogenates by differential and discontinuous gradient centrifugation. 2. Triton X-100 or repeated freezing and thawing of the lysosomal suspension (subfraction B) allowed comparison of free and activated values for acid phosphohydrolase, beta-glucuronidase and N-acetylglucosaminidase in the presence and absence of ascorbate. 3. The distribution of hydrolase activities between supernatant and pellet after high-speed centrifugation was measured and the percentages of total enzyme found in the supernatant were: acid phosphohydrolase, 40.7; beta-glucuronidase, 51; N-acetylglucosaminidase, 39.4. 4. Differential rates of elution of the three hydrolases from the membrane fraction occurred with increasing Na(+) and K(+) concentrations, whereas complex biphasic elution curves were obtained as a function of bivalent cation concentration with Ca(2+) and Mg(2+). 5. Sucrose-density-gradient centrifugation of frozen-and-thawed subfraction B demonstrated highly significant changes in the protein gradient profile in the presence of a low concentration of bivalent cation, indicating membrane aggregation and enzyme-membrane association. 6. The data provide further evidence for the nature of lysosomal enzyme binding and indicate the presence of different enzyme-membrane bonds conferring structure-linked latency upon individual lysosomal enzymes.

Acid Phosphatase↗

PubMed1970

Physical properties of ribosomal ribonucleic acid isolated from bacteria deficient in ribonuclease I.

1. Bacteria deficient in ribonuclease I were used as a source of stable ribosomal RNA. RNA was isolated from a ribosome fraction of Pseudomonas fluorescens N.C.I.B. 8248 and acetone-treated cells of Escherichia coli M.R.E. 600 by the method developed by Robinson & Wade (1968). 2. The s(20,w) of the 16S and 23S components can vary from 21S and 28S down to 4S depending on the RNA macro-ion concentration and the extent to which charge is suppressed by univalent Na(+) and tris(+) counter-ions or neutralized through the binding of bivalent Mg(2+) to phosphate groups. 3. The primary charge effect in sedimentation and the frictional coefficient (which increases as the molecular conformation expands) both increase with charge and cause a decrease in s value. 4. RNA solutions heated to 80 degrees C for 10min show minor changes in s value and a detectable increase in polydispersity. Millimolar concentrations of Mg(2+) promote heat-instability and so does treatment of RNA solutions with the nuclease adsorbent macaloid, which was found to contaminate the solutions with Mg(2+). 5. The stabilization of secondary structure by univalent and bivalent cations was investigated by optical methods. 6. The sedimentation properties of 30S and 50S ribosomal subunits and their constituent 16S and 23S RNA components were compared and discussed from the viewpoint of unfolding.

Binding Sites↗

PubMed1972

Assay and properties of dititonin-activated bilirubin uridine diphosphate glucuronyltransferase from rat liver.

1. The bilirubin UDP-glucuronyltransferase assay described by Van Roy & Heirwegh (1968) has been improved. 2. Extraction of final azo-derivatives is rendered more simple and efficient by thorough emulsification and by cooling. 3. Pretreatment of homogenates and cell fractions with digitonin increases the sensitivity of the assays and gives less variable results than those with untreated preparations. The activation procedure is flexible. 4. Blank values (obtained from incubation mixtures from which activating bivalent metal ion and UDP-glucuronic acid were omitted) are low. No endogenous conjugate formation could be detected except with untreated, fresh liver homogenates. Control incubation mixtures containing the latter preparations are preferably kept at 0 degrees C. 5. With activated microsomal preparations, rates of breakdown of UDP-glucuronic acid (as monitored by release of P(i)) were low. Little if any increase in enzyme activity was found when UDP-N-acetylglucosamine was included in the incubation mixtures. 6. Slight deviation from Michaelis-Menten kinetics with respect to bilirubin observed at low substrate concentrations is probably related to the use of binding protein in the assay mixtures. Michaelis-Menten kinetics were followed with respect to UDP-glucuronic acid. Part of the enzyme in microsomal preparations from rat liver functioned independently of added bivalent metal ions. Mn(2+) was slightly more, and Ca(2+) somewhat less, stimulatory than Mg(2+). The Mg(2+)-dependent fraction showed Michaelis-Menten kinetics with respect to the added Mg(2+). 7. The enzyme activities found were higher than values reported in the literature for untreated or purified preparations from rat liver. They were above reported values of the maximal biliary excretion rate of bilirubin.

Animals↗

PubMed1974

Purification and properties of 3-hexulose phosphate synthase and phospho-3-hexuloisomerase from Methylococcus capsulatus.

3-Hexulose phosphate synthase and phospho-3-hexuloisomerase were purified 40- and 150-fold respectively from methane-grown Methylococcus capsulatus. The molecular weights of the enzymes were approximately 310000 and 67000 respectively, as determined by gel filtration. Dissociation of 3-hexulose phosphate synthase into subunits of molecular weight approx. 49000 under conditions of low pH or low ionic strength was observed. Within the range of compounds tested, 3-hexulose phosphate synthase is specific for formaldehyde and d-ribulose 5-phosphate (forward reaction) and d-arabino-3-hexulose 6-phosphate (reverse reaction), and phospho-3-hexuloisomerase is specific for d-arabino-3-hexulose 6-phosphate (forward reaction) and d-fructose 6-phosphate (reverse reaction). A bivalent cation is essential for activity and stability of 3-hexulose phosphate synthase; phospho-3-hexuloisomerase is inhibited by many bivalent cations. The pH optima of the two enzymes are 7.0 and 8.3 respectively and the equilibrium constants are 4.0x10(-5)m and 1.9x10(2)m respectively. The apparent Michaelis constants for 3-hexulose phosphate synthase are: d-ribulose 5-phosphate, 8.3x10(-5)m; formaldehyde, 4.9x10(-4)m; d-arabino-3-hexulose 6-phosphate, 7.5x10(-5)m. The apparent Michaelis constants for phospho-3-hexuloisomerase are: d-arabino-3-hexulose 6-phosphate, 1.0x10(-4)m; d-fructose 6-phosphate, 1.1x10(-3)m.

Aldehyde-Lyases↗

PubMed1975

Adenosine 3':5'-cyclic monophosphate-dependent and plasma-membrane-associated protein kinase(s) from bovine corpus luteum.

Plasma-membrane fractions FI and FII isolated from bovine corpus luteum by discontinuous sucrose-density-gradient centrifugation, at sucrose-density interfaces of 1.14/1.16 and 1.16/1.18 respectively, contained membrane-associated protein kinases that phosphorylated both the structural proteins of membranes as well as exogenously added protein substrates. Both fractions were characterized with respect to endogenous and exogenous protein substrate specificity, pH-dependence, effect of bivalent metal ions and sensitivity toward cyclic nucleotides. These membrane-associated kinases showed an optimum pH of 6.0 and had an absolute requirement for bivalent metal ions such as Mg2+, Mn2+, or Co2+ that cannot be replaced by Ca2+. Both the activities were stimulated two- to four-fold by cyclic AMP in vitro with an apparent Km of 83 and 50 nM for fractions FI and FII respectively. Other cyclic 3':5'-nucleotides were effective only at higher concentrations, but even the most effective, cyclic IMP, showed a stimulation nearly an order of magnitude lower than that of cyclic AMP. In contrast, stimulation by cyclic dTMP and cyclic dAMP was very weak. Cyclic AMP showed no significant effect on the apparent Km value of both enzymes for histone and MgCl2 but it somewhat decreased the Km value for ATP. Nucleoside triphosphates like GTP, CTP and UTP inhibited the transfer of [32P]Pi from [gamma-32P]ATP into mixed histone catalysed by membrane-associated kinases either in the presence or in the absence of cyclic AMP. In addition to protein kinases, these membrane fractions also possessed cyclic AMP-binding activities. The apparent association constant (Kalpha) for cyclic AMP binding was 1.0 X 10(10) and 2.6 X 10(10) M for FI and FII membrane fractions respectively.

Adenosine Triphosphate↗