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PubMed1992

The ligand binding domain of the epidermal growth factor receptor is not required for receptor dimerization.

To examine the role of the ligand binding domain of epidermal growth factor receptor in its dimerization, we studied the dimerization of a truncated form of the receptor that resembles v-erbB in that it lacks a ligand binding domain. Receptor dimerization was determined by sedimentation analysis on sucrose density gradients at different concentrations of Triton X-100. At high concentrations of Triton X-100 (0.2%), the truncated receptor occurred as a monomer and displayed low basal autophosphorylation. By contrast, at low concentrations of Triton X-100 (0.01%), it existed as a dimer and exhibited high basal autophosphorylation. The ability of the truncated receptor to dimerize indicates that the ligand binding domain of the epidermal growth factor receptor is not required for receptor dimerization.

Autoradiography↗

PubMed1995

Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm.

Cardioversion of atrial fibrillation carries a serious risk of major thromboembolism and stroke. To determine whether or not the procedure alters plasma levels of fibrin D-dimer (a marker of intravascular fibrin turnover and thrombus formation) and plasma fibrinogen (associated with stroke and thromboembolism), we performed a prospective study in 19 patients with atrial fibrillation in whom cardioversion was attempted: seven patients without prior oral anticoagulant therapy (but with intravenous heparin for 24 h) (Group I), and 12 patients with full oral anticoagulation pre- and post-cardioversion (Group II). Plasma fibrinogen and fibrin D-dimer were measured pre-cardioversion, and at Days 3, 7 and 14 post-cardioversion. In Group I, there was a significant reduction in median plasma fibrin D-dimer levels by 14 days following cardioversion (200 vs. 52 ng/ml; paired Wilcoxon test, P = 0.02). In Group II, there was no change in median plasma fibrin D-dimer levels over the 14 days following cardioversion. There were no significant changes in plasma fibrinogen with cardioversion in either group of patients. The reduction of plasma fibrin D-dimer in Group I suggests a beneficial reduction of intravascular fibrin turnover and thrombogenesis by the cardioversion of patients with atrial fibrillation to sinus rhythm. Furthermore, it strongly suggests that it is atrial fibrillation itself which is the major risk of thromboembolism and that the risk continues for up to 14 days post-cardioversion. In Group II, the low pre-cardioversion fibrin D-dimer levels and lack of change with cardioversion is consistent with the prophylactic effect of warfarin therapy against thromboembolism during the cardioversion of atrial fibrillation.

Adult↗

PubMed1982

The clearance of human fibrinogen fragments D1, D2, D3 and fibrin fragment D1 dimer in mice.

The clearance of human fibrinogen fragments D1, D2, D3 and fibrin fragment D1 dimer were studied in the mouse model. Clearance of these fragments is a complex process involving clearance from blood into three other compartments. The overall clearance of fragment D1 and its dimer were essentially identical. Fragments D2 and D3 cleared at a progressively slower rate. Competition studies were performed between 125I-labeled fragment D1 and large molar excesses of unlabeled human fragments D1, D2, D3, D1 dimer, fragment E, fibrinogen, macroalbumin, mannan and asialoorosomucoid. Of these ligands only the fragment D variants competed for the clearance of 125I-labeled fragment D1. Cross-competition was observed when 125I-labeled fragment D1 dimer was cleared in the presence of a large molar excesses of fragment D1. Autopsies demonstrated that injected fragments D1, D2, D3 and D1 dimer cleared primarily in liver and kidneys. In some clearance studies, livers were perfused with tissue culture fluid, subjected to light microscopic autoradiography, and silver grain counts performed to localize cleared fragment D1. These experiments indicated that 80% of the liver uptake was in hepatocytes. However, when silver grain counts were normalized for the number of parenchymal and nonparenchymal cells, the distribution of silver grains was essentially identical (1.8 and 1.6 grains per cells, respectively). It is concluded that fragments D1, D2, D3 and D1 dimer are recognized by a similar clearance pathway. Since neither fibrinogen nor fragment E competed for the clearance of fragment D1, it is suggested that determinants present in the fragment D domain become exposed after plasmin attack on fibrinogen and are responsible for clearance.

Albumins↗

PubMed1983

Dimers of 5 S RNA and 5.8 S RNA in low molecular weight RNA preparations.

When purified 5 S RNA is exposed to concentrated solutions of sodium chloride or sodium phosphate, it is partly converted to the 5' S conformer but also partly to dimers and oligomers of 5 S RNA which are stable during gel filtration and electrophoresis. Presence of 5 S dimers can not be demonstrated in cellular RNA preparations extracted with phenol. 5.8 S RNA dimers are observed in RNA from cells extracted with phenol at 40-60 degrees C. No 5.8 S dimer is observed when RNA is extracted at 0 degrees C. The amount of dimer increases with the temperature of extraction and may account for about 10% of the total 5.8 S RNA. When RNA extracted at 40-60 degrees C is electrophoresed on polyacrylamide gels under nondenaturing conditions the 5.8 S RNA dimer co-migrates with the low molecular weight RNA component L.

Animals↗

PubMed1987

Structure and in vitro transcription of a mouse B1 cluster containing a unique B1 dimer.

A highly repetitive DNA element located 950 bp upstream from a mouse U2 small nuclear RNA gene has been cloned and characterized. The repetitive element is composed of a simple sequence repeat and a cluster of three B1 sequences. Two of these B1 elements are arranged head-to-tail and are joined by an oligo(dA)-rich linker. This unique B1 dimer, comprised of 339 bp, resembles the dimeric structure of primate Alu-family sequences, particularly that of a prototypic human Alu element. The other B1 element within the mouse cluster is a typical monomeric unit. Transcription studies performed in HeLa cell extracts with deletion mutants of the B1 cluster reveal that the single B1 unit is expressed at least 50 times more efficiently than the B1 dimer region. Furthermore, the B1 dimer which contains mutations in the first polymerase III promoter region is not transcribed end-to-end. We conclude that this B1 dimer is unlikely to give rise to a new dimeric retroposon family in the mouse genome.

Animals↗

PubMed1996

Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers.

BACKGROUND: Genetic engineering can produce novel antibody fragments with improved properties for applications such as tumor targeting in vivo. OBJECTIVES: To produce stable monomeric (27 kDa) and dimeric (55 kDa) forms of a single-chain Fv (scFv) from the anti-carcinoembryonic antigen (anti-CEA) antibody T84.66, and assess the targeting and biodistribution properties in an animal model. STUDY DESIGN: ScFv were constructed with either a 28 or 14 amino acid connecting peptide and expressed by secretion from E. coli. Following affinity purification, proteins were characterized by gel electrophoresis and mass spectrometry. Binding properties were assessed by size exclusion HPLC after incubation with antigen, and affinities determined by surface plasmon resonance. The shorter linker favored formation of dimers (and higher multimers) which showed unusual stability. ScFv were radiolabeled with 125I for tumor targeting and biodistribution studies of monomeric or dimeric forms were conducted in athymic mice bearing LS174T human colorectal carcinoma xenografts. RESULTS: 125I-scFv monomers and dimers targeted exhibited rapid clearance kinetics in tumor-bearing mice. Nevertheless, the anti-CEA scFvs targeted very well to xenografts, leading to high tumor: normal organ ratios (greater than 20:1 at 24 h) for both forms. Tumor localization of the non-covalent dimers was much higher than monomers, reaching 10-15% injected dose per gram at 1 h. CONCLUSION: Non-covalent dimers of scFv (also known as diabodies) are stable, easy to produce and show excellent targeting as compared to monomeric scFv, probably due to increased mass and valency.

Animals↗

PubMed2004

A rapid quantitative turbimetric d-dimer assay has high sensitivity for detection of pulmonary embolism in the ED.

Many rapid d-dimer assays are commercially available with wide ranges of reported sensitivities, often based on small sample sizes. This has limited their intended use as rapid and inexpensive tests to evaluate pulmonary embolism in the low-risk patient. We sought to determine the sensitivity of the STA-Liatest D-Di d-dimer assay in our ED. We performed a retrospective analysis of 103 patients seen in our ED with the admitting diagnosis of known or suspected pulmonary embolism. These charts were assessed to establish if a d-dimer assay was performed within 24 hours. These charts were then reviewed to determine what diagnostic studies were performed and what final diagnosis was reached. Of the 103 charts identified, 55 had d-dimer assays performed within 24 hours. Of those, 38 were diagnosed with pulmonary embolism; none had negative d-dimer assays (<400 ng/mL). Using the exact method, the sensitivity of this assay was calculated to be 100% with a 95% confidence interval (CI) of 91.4% to 100%. Our results suggest that the STA-Liatest D-Di d-dimer assay could have an adequate sensitivity to be used to rule out pulmonary embolism in low-risk patients. Further prospective studies with larger sample sizes are required to validate this observation.

Emergency Service, Hospital↗

PubMed2005

Use of D-dimer to aid in excluding deep venous thrombosis in ambulatory patients.

BACKGROUND: Duplex imaging is currently the gold standard for diagnosing deep venous thrombosis (DVT), but its nonselective use overburdens vasuclar laboratories, particularly during off hours. It is the purpose of this study to determine if a new D-dimer assay could be used as an aid in determing whether duplex imaging could be performed on an elective or emergent basis in patients with suspected DVT. METHODS: D-dimer levels were measured and venous duplex examinations were obtained in all patients. D-dimer assays were performed using the Tina-quant latex agglutination test (Roche Diagnostics, Mannheim, Germany). Venous duplex examinations were performed using colorflow doppler. RESULTS: Between September 1, 2002 and April 30, 2003, 148 patients were seen in the emergency department for suspected DVT. Nineteen patients (12.8%) had positive venous duplex examinations and 129 (87.2%) duplex examinations were negative. None of the 19 patients with positive venous duplex studies had D-dimer levels within of the normal range (0 to 0.49). The sensitivity, specificity, positive predictive value, and negative predictive value of the D-dimer test were 100%, 48.8%, 22.4%, and 100%, respectively. CONCLUSION: The D-dimer test can effectively used without adjuncting risk stratification as an aid in excluding the diagnosis of DVT in ambulatory patients. Its routine use could significantly reduce the need for the performance of emergent venous duplex examinations.

Adolescent↗

PubMed2006

Procyanidin dimer B2 [epicatechin-(4beta-8)-epicatechin] suppresses the expression of cyclooxygenase-2 in endotoxin-treated monocytic cells.

The anti-inflammatory activity of the predominant procyanidin dimer in cocoa, dimer B2, was investigated in this study. Pretreatment of the procyanidin dimer B2 reduced COX-2 expression induced by the endotoxin lipopolysaccharide (LPS) in differentiated human monocytic cells (THP-1) in culture. To further elucidate the underlying mechanism of COX-2 inhibition by procyanidin, we examined their effects on the activation of extracellular signal-regulated protein kinase (ERK), Jun-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), which are upstream enzymes known to regulate COX-2 expression in many cell types. Pretreatment with procyanidin dimer B2 decreased the activation of ERK, JNK, and p38 MAPK. In addition, procyanidin dimer B2 suppressed the NF-kappaB activation through stabilization of IkappaB proteins, suggesting that these signal-transducing enzymes could be potential targets for procyanidin dimer B2. By affecting the expression rather than the activity of COX-2, these in vitro data reported herein give further evidence on the anti-inflammatory protection by procyanidins.

Biflavonoids↗

PubMed1968

-irradiation of thymine dimers in aqueous solution.

Thymine dimers were irradiated in aqueous solution with (60)Co gamma-rays in N(2) or O(2). Thymine and unidentified non-UV-absorbing products appeared. The thymine was identified by spectrophotometry, chromatography, and ability to support the growth of Escherichia coli 15 T(-). Residual dimer was determined by a UV-reversibility assay. The G-values for dimer breakage were approximately equal in N(2) and O(2). At low gamma-doses, about two thymines were produced per dimer broken in N(2), whereas only about one thymine appeared per dimer broken in O(2). For dimer irradiated in frozen solution, the yield of thymine was at least 100 times less than in liquid.

Biological Assay↗

PubMed2000

Dose-adjusted thrombosis prophylaxis in trauma surgery according to levels of D-Dimer.

In 234 trauma surgery patients, thrombosis prophylaxis with Nadroparin-Calcium low-molecular-weight heparin (LMWH) was adjusted according to levels of D-Dimer. Basic prophylaxis was 2,850 IU per day. If D-Dimer concentrations rose above 2 mg/L after the fourth postoperative (p.o.) day, LMWH was administered twice a day. Color Doppler ultrasound was performed between the fifth and seventh p.o. days. Patients were divided into a high-risk (group 1: hip, femur, or knee replacement surgery, n=102) and a moderate-risk group (group 2: other surgery of the knee, tibia, fibula, or foot, n=132). Group 1 showed significantly higher D-Dimer levels than group 2 (p<0.001). Measurement of D-Dimer on days 2 and 4 p.o. showed a sensitivity of 100% and a specificity of 72.8% in identifying patients at risk (i.e., D-Dimer>2 mg/L after day 4 p.o.). The overall deep vein thrombosis (DVT) rate in group 1 was 3.9%, and the rate of proximal DVT was 1.96%. In group 2, one distal DVT (0.8%) occurred. The results show that D-Dimer is a useful marker to monitor p.o. coagulation activation and to manage LMWH prophylaxis in trauma surgery patients.

Adult↗

PubMed2003

Plasma D-dimer for the diagnosis of thromboembolic disorders in dogs.

D-dimer is formed during thrombus formation when factor XIIIa crosslinks the terminal D-domains of fibrin. The D-dimer epitope is exposed when the thrombus is lysed by plasmin. Thus, D-dimer represents both thrombin and plasmin activation and is specific for fibrinolysis. D-dimer concentrations are increased in dogs with DIC or other thromboembolic disorders, but because D-dimer is an indicator of physiologic or pathologic fibrinolysis, values are elevated in other conditions associated with fibrinolysis, including orthopedic surgery, neoplasia, and internal hemorrhage. It can be used as an ancillary test for the diagnosis of DIC but is not recommended as a sole test for this purpose. D-dimer has the potential to be a useful laboratory test for the detection of pulmonary thromboembolism in dogs. Further studies are needed to determine the appropriate applications for this test in veterinary patients to aid in clinical decision making, treatment, and patient care.

Animals↗

PubMed2000

Bedside measurement of D-dimer in the identification of bacteremia in the emergency department.

The objective of this pilot study was to determine the clinical utility of the SimpliRed D-dimer bedside assay to identify patients with bacteremia in a university hospital Emergency Department. We tested 265 patients and compared blood culture results with a novel D-dimer semiquantitative whole blood assay. Bacteremia was confirmed in 25/262 patients. Sensitivity of D-dimer assay was 66.7% for Gram-positive bacteremia and 61.5% for Gram-negative bacteremia with negative predictive value of 98% for Gram-positive and 96% for Gram-negative bacteremia patients. Measurement of D-dimer appears to be of value in identifying patients at low risk for bacteremia and can be accomplished rapidly using a whole blood semiquantitative bedside assay. Although increases in D-dimer are not detected in all patients subsequently documented to have bacteremia on a single sampling, the results of this and other earlier studies suggest assay of D-dimer is useful in rapid differentiation of patients with bacteremia from those who have no bacteremia using blood culture positivity as the standard for bacteremia.

Adult↗

PubMed1994

The structure of an asymmetric dimer relevant to the mode of action of the glycopeptide antibiotics.

BACKGROUND: Glycopeptide antibiotics of the vancomycin group are of crucial clinical importance in the treatment of methicillin resistant Staphylococcus aureus (MRSA)--the often lethal 'super-bug'--characterized by its resistance to a wide range of antibiotics in common use. The antibiotics exert their physiological action by blocking cell wall synthesis through recognition of nascent cell wall mucopeptides terminating in the sequence -D-Ala-D-Ala. Evidence suggests that the antibiotics are able to enhance their biological activity by the formation of homodimers, and this is supported by the observation that dimerization and peptide binding in vitro are cooperative phenomena. The basis of this enhancement is not understood at the molecular level. RESULTS: The first detailed structure of a dimeric glycopeptide antibiotic, that of eremomycin, is presented based upon solution NMR data. The overall structure of the dimer complex is asymmetric. The source of this asymmetry--a parallel alignment and mutual interaction of the disaccharides--appears to promote dimerization through specific sugar-sugar recognition. CONCLUSIONS: A molecular basis for the observed cooperativity of cell wall peptide binding by eremomycin is evident from these studies of the dimer. The carboxylate anion of the cell wall component, which is crucial to binding, forms an amide-mediated ion-pair interaction to the alkylammonium ion of the ring 6 sugar in the other half of the dimer making the structure and positioning of this sugar important in mediating cooperativity.

Amino Acid Sequence↗

PubMed1999

A dimeric ternary complex of FGFR [correction of FGFR1], heparin and FGF-1 leads to an 'electrostatic sandwich' model for heparin binding.

BACKGROUND: Fibroblastic growth factors (FGFs) are a family of cytokines involved in regulation of cell growth, differentiation and chemotaxis in a variety of tissue types. High-affinity FGF receptors (FGFRs) are transmembrane proteins that consist of three extracellular immunoglobulin-like domains, a transmembrane helix and an intracellular protein tyrosine kinase signalling domain. FGFRs are activated through ligand-dependent dimerization that allows trans-autophosphorylation of the tyrosine kinase domains. Heparin or heparin-like molecules, such as heparan sulphate proteoglycans, bind to both FGFs and FGFRs and are required for FGF signal transduction. At present no structure of the ternary complex for FGFR, FGF and heparin exists. RESULTS: We have used the type-1 interleukin-1 receptor-interleukin-1 beta complex crystal structure, in which both the ligand and the receptor are homologous to those of the FGF-FGFR pair, to identify potential interactions in the FGFR-heparin-FGF ternary complex. A key feature of the modelled complex is the 'electrostatic sandwich' that is formed between the positively charged surfaces of FGF and the receptor, with the negatively charged heparin captured in between. The ternary complex places limits on the range of likely modes of receptor dimerization: one of five different dimeric receptor complexes built from the ternary complex correlates best with the experimental data. CONCLUSIONS: The ternary complex of FGFR, FGF and heparin, derived on the basis of the homologous interleukin-1 receptor complex, is in agreement with much of the published experimental data, as is the dimeric receptor complex (FGFR-heparin-FGF)2. This work suggests that the FGF interactions seen in crystal structures, which have previously been used to predict the mode of FGF dimerization, might not be relevant to the biologically active dimeric FGFR-heparin-FGF complex.

Algorithms↗

PubMed1998

Identification of noncovalent dimeric complexes of the recombinant murine S100 protein CP10 by electrospray ionization mass spectrometry and chemical cross-linking.

CP10 is a chemotactic S100 protein expressed by murine myeloid cells. A specific noncovalently linked dimeric complex of recombinant Ala43 CP10 was identified after electrospray ionization mass spectrometry using a nondenaturing solvent of 5-mM ammonium acetate (pH 6.5) and source temperature of 50 degrees C. With a low cone voltage (75 V), major ions were observed at approximately 2075, 2305, and 2613 Da, which were attributed to partially desolvated multiply charged noncovalently linked dimeric species (+10, +9, and +8 charge states, respectively). Deconvolution produced a broad peak centered around 20750 Da corresponding to the approximate mass of dimeric recombinant Ala43 CP10. Increasing the cone voltage, the collisionally activating the complex, gradually reduced the intensity of these dimeric ions, with a concomitant increase in higher and lower charge state monomeric ions. The intensities of these dimeric ions were greatly reduced in spectra recorded with a source temperature of 140 degrees C and cone voltage of 75 V, indicating a thermally unstable noncovalent complex. Similar spectra were obtained using recombinant CP10. Specific noncovalent S100 dimeric complexes were confirmed by chemically cross-linking recombinant Ala43 CP10 or CP10 with bis (sulfosuccinimidyl) suberate, followed by SDS/PAGE. The dominant silver-stained and CP10-immunoreactive component migrated at 20,000 suggested that the complex represents the major isoform in solution.

Animals↗

PubMed1999

Dissociation energies of deoxyribose nucleotide dimer anions measured using blackbody infrared radiative dissociation.

The dissociation kinetics of deprotonated deoxyribose nucleotide dimers were measured using blackbody infrared radiative dissociation. Experiments were performed with noncovalently bound dimers of phosphate, adenosine (dAMP), cytosine (dCMP), guanosine (dGMP), thymidine (dTMP), and the mixed dimers dAMP.dTMP and dGMP.dCMP. The nucleotide dimers fragment through two parallel pathways, resulting in formation of the individual nucleotide or nucleotide + HPO3 ion. Master equation modeling of this kinetic data was used to determine threshold dissociation energies. The dissociation energy of (dGMP.dCMP-H)- is much higher than that for the other nucleotide dimers. This indicates that there is a strong interaction between the nucleobases in this dimer, consistent with the existence of Watson-Crick hydrogen bonding between the base pairs. Molecular mechanics simulations indicate that Watson-Crick hydrogen bonding occurs in the lowest energy structures of (dGMP.dCMP-H)-, but not in (dAMP.dTMP-H)-. The trend in gas phase dissociation energies is similar to the trend in binding energies measured in nonaqueous solutions within experimental error. Finally, the acidity ordering of the nucleotides is determined to be dTMP < dGMP < dCMP < dAMP, where dAMP has the highest acidity (largest delta Gacid).

Algorithms↗

PubMed1995

Thermodynamic studies of the core histones: ionic strength and pH dependence of H2A-H2B dimer stability.

The thermal stability of the core histone dimer H2A-H2B has been studied by high-sensitivity differential scanning calorimetry and circular dichroism spectroscopy. The unfolding transition temperature of the 28 kDa H2A-H2B dimer increases as a function of both the ionic strength of the solvent and the total protein concentration. At neutral pH and physiological ionic strength, the thermal denaturation is centered at about 50 degrees C with a corresponding enthalpy change of about 40 kcal/mol of 14 kDa monomer unit and an excess heat capacity of about 1.4 kcal/(K.mol) of 14 kDa monomer unit. The H2A-H2B dimer is stable mainly between pH 5.5 and 10.5. Below pH 4.0, the system is unfolded at all temperatures. The thermodynamic analysis is performed at low ionic strength where almost complete reversibility is attained, since higher salt conditions seem to promote aggregation and irreversibility of the transitions. Analysis of the data shows that at low ionic strength and pH values between 6.5 and 8.5, the H2A-H2B dimer behaves as a highly cooperative system, melting as a single unit without any detectable intermediates of dissociated, yet folded, H2A and H2B monomers. This is consistent with the observed protein concentration dependence of the midpoint of the thermal denaturation. The two-state unfolding process can be described by the general scheme AB-->2U, indicating that the individual H2A and H2B polypeptides are folded, stable entities only when complexed as the H2A-H2B dimer and that the major contribution to the stabilization of the dimer derives from the coupling between the H2A and H2B interfaces.

Animals↗