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At least 163 records · Page 9Linked to original sources
PubMed2006

Application of a fluorescent cobalamin analogue for analysis of the binding kinetics. A study employing recombinant human transcobalamin and intrinsic factor.

Fluorescent probe rhodamine was appended to 5' OH-ribose of cobalamin (Cbl). The prepared conjugate, CBC, bound to the transporting proteins, intrinsic factor (IF) and transcobalamin (TC), responsible for the uptake of Cbl in an organism. Pronounced increase in fluorescence upon CBC attachment facilitated detailed kinetic analysis of Cbl binding. We found that TC had the same affinity for CBC and Cbl (K(d) = 5 x 10(-15) m), whereas interaction of CBC with the highly specific protein IF was more complex. For instance, CBC behaved normally in the partial reactions CBC + IF(30) and CBC + IF(20) when binding to the isolated IF fragments (domains). The ligand could also assemble them into a stable complex IF(30)-CBC-IF(20) with higher fluorescent signal. However, dissociation of IF(30)-CBC-IF(20) and IF-CBC was accelerated by factors of 3 and 20, respectively, when compared to the corresponding Cbl complexes. We suggest that the correct domain-domain interactions are the most important factor during recognition and fixation of the ligands by IF. Dissociation of IF-CBC was biphasic, and existence of multiple protein-analogue complexes with normal and partially corrupted structure may explain this behaviour. The most stable component had K(d) = 1.5 x 10(-13) m, which guarantees the binding of CBC to IF under physiological conditions. The specific intestinal receptor cubilin bound both IF-CBC and IF-Cbl with equal affinity. In conclusion, the fluorescent analogue CBC can be used as a reporting agent in the kinetic studies, moreover, it seems to be applicable for imaging purposes in vivo.

Binding Sites↗
PubMed1991

Binding kinetics of Clostridium difficile toxins A and B to intestinal brush border membranes from infant and adult hamsters.

This study was undertaken to determine if the relative resistance of neonates and infants to Clostridium difficile-associated intestinal disease can be related to age-dependent differences in intestinal receptors for C. difficile toxins A and B. Brush border membranes (BBMs) from the small intestines of adult and infant hamsters were examined for their ability to bind radiolabeled toxins A and B. [125I]toxin A bound to both infant and adult hamster BBMs at physiological temperature, whereas [125I]toxin B did not bind to the BBMs under any of the conditions examined. The number of [125I]toxin A molecules bound at saturation was approximately 4 x 10(10) per micrograms of membrane protein for adult BBMs and 1 x 10(11) per micrograms of membrane protein for infant BBMs. Scatchard plot analysis suggested the presence of a single class of toxin A binding sites on both infant and adult hamster BBMs. Maximal binding capacity and Kd values were 0.63 pmol/mg of protein and 66.7 nM, respectively, for the infant BBMs, and 0.24 pmol/mg of protein and 27 nM, respectively, for the adult BBMs. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analyses of extracted BBM proteins revealed differences in the proteins of infant and adult BBMs. However, there were not any detectable differences in the protein bands which bound [125I]toxin A between infant and adult hamsters. The results from these investigations indicate that differences in the binding kinetics of toxins A and/or B to infant and adult hamster BBMs do not account for the observed differences in their susceptibility to C. difficile-associated intestinal disease.

Age Factors↗
PubMed1996

Modulation of hippocampal synaptic transmission by low concentrations of cell-permeant Ca2+ chelators: effects of Ca2+ affinity, chelator structure and binding kinetics.

Calcium chelators are commonly used for fluorescence and electrophysiological studies of neuronal Ca2+ signalling. Recently, they have also been used as neuroprotectants. Since they buffer calcium ions, these agents also modify the same signals which are being studied. These properties may be used to modulate Ca2+ signals such as those involved in synaptic transmission, and may explain their neuroprotective mechanism. To define factors which govern the modulation of synaptic transmission by Ca2+ chelators, we examined their actions on synaptic responses evoked in CA1 neurons of rat hippocampal slices. We used a spectrum of cell-permeant Ca2+ chelators having different structures, Ca(2+)-binding kinetics and Ca2+ affinities, as well as an impermeant, intracellularly perfused chelator salt. Application of the cell-permeant 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetate acetoxymethyl ester (50 microM) markedly attenuated evoked synaptic responses. This application produced an intracellular chelator accumulation of 79-125 microM, as estimated using 14C-labelled chelator. The actions of a Ca2+ chelator on synaptic responses were dependent on the chelator's Ca2+ affinity, Ca(2+)-binding rate and Ca2+ selectivity, because 1,2-bis(2-amino-5-nitrophenoxy)ethane-N,N,N',N'-tetra-acetate acetoxymethyl ester (a low Ca2+ affinity analogue), ethyleneglycolbis(beta-aminoethyl ether)-N,N,N',N'-tetra-acetate acetoxymethyl ester (a slow buffer with similar Ca2+ affinity to 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetate) and the selective Zn2+ chelator, tetrakis(2-pyridylmethyl)ethylenediamine, were ineffective. The intrinsic cell membrane properties, including the post-spike train afterhyperpolarization, were not significantly affected by any of the Ca2+ chelators used in this study. Intracellular perfusion of 100-200 microM 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetate salt through patch pipettes into postsynaptic cells did not affect synaptic potentials, suggesting a presynaptic action of cell-permeant Ca2+ chelators on transmitter release. Other cell-permeant, fast Ca(2+)-binding chelators reduced synaptic responses according to their Ca2+ affinities, and not their chemical structure: those chelators with Kd values < or = 25 microM attenuated synaptic responses, whereas chelators of lesser affinity did not. These data support the ideas that [Ca2+]i rises to high (micromolar) levels during transmitter release, and that Ca2+ chelators may be used to attenuate excitotoxicity by attenuating excitatory neurotransmission without affecting Ca2+ signalling in the submicromolar [Ca2+]i range.

Animals↗
PubMed2003

An unusual form of the association binding kinetics of N-[3H]methylscopolamine to the split muscarinic M2trunk/M2tail receptor.

The muscarinic M(2) receptor was split at the third cytoplasmic loop into two fragments: the one containing the first five transmembrane regions and the N-terminal part of the third cytoplasmic loop was named M(2trunk), while the other, which contained the last two transmembrane regions and the C-terminal part of the third cytoplasmic loop, was named M(2tail). As seen in many other G protein-coupled receptors, when these two fragments were transfected together in COS-7 cells they rescued the pharmacological profile and the functional activity of the wild-type M(2) receptor. Conversely, N-[(3)H]methylscopolamine ([(3)H]NMS) association binding experiments showed a substantial difference between the wild-type M(2) and the split M(2trunk)/M(2tail) receptors. The progression of the association binding kinetic of the M(2trunk)/M(2tail) receptor was strictly dependent upon the amount of the fragment DNA transfected. When the amount of transfected DNA was 4 microg/plate and the B(max) of [(3)H]NMS at equilibrium was around 200 fmol/mg protein the form of the association was that of classical saturation, but when the amount of transfected DNA was lower the [(3)H]NMS association reached a maximum binding point and then declined to a lower equilibrium binding level. The form of the association was temperature-dependent: as the temperature was lowered, the maximum binding point tended to be higher. We suggest that this peculiar form of the [(3)H]NMS association binding to the muscarinic M(2trunk)/M(2tail) receptor is attributable to a less stable interaction between the trunk and the tail fragments of the split receptor.

Adenylyl Cyclases↗
PubMed2006

Binding kinetics and duration of in vivo action of novel prolyl oligopeptidase inhibitors.

Prolyl oligopeptidase (POP) is a serine protease that specifically hydrolyses small peptides at the carboxyl end of the proline residue. POP has gained pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties in rat. We examined the effect of the 2(S)-substituents CN and COCH(2)OH at the P1 site of the parent inhibitors isophthalic acid 2(S)-(cyclopentanecarbonyl)pyrrolidine-l-prolyl-pyrrolidine amide and 4-phenylbutanoyl-l-prolyl-pyrrolidine and bulky 5-t-butyl group at the P2 site l-prolyl residue of the parent inhibitor 4-phenylbutanoyl-l-prolyl-pyrrolidine on the binding kinetics to the enzyme. In addition, we studied the duration of POP inhibition in the rat tissues in vivo after i.p. administration. CN and COCH(2)OH substituents at the P1 site pyrrolidine group were found to greatly increase the affinity of the inhibitor and the enzyme-inhibitor complex half-life. In addition, 5-t-butyl group at the P2 site l-prolyl residue increased the dissociation half-life of the enzyme-inhibitor complex, without much affecting the inhibitory potency. The duration of the inhibition in the rat tissues followed the inhibition kinetic properties in that the compounds with fast dissociation produced shorter inhibition in the rat tissues than the compounds with slow dissociation. The duration of POP inhibition of compounds was evidently not governed by their serum clearance. The fact that the in vivo pharmacodynamic behaviour of POP inhibitors can be predicted by their in vitro-properties may be of importance when designing therapeutically useful POP inhibitors.

Animals↗
PubMed1999

In vitro characterization of the erythrocyte distribution of methazolamide: a model of erythrocyte transport and binding kinetics.

The rate and extent of binding of methazolamide to human erythrocytes was studied in vitro. All experiments were carried out at physiological temperature (37 C) and pH (7.4). Methazolamide (MTZ) buffer concentrations were analyzed by HPLC. Distributional equilibrium between buffer and washed red blood cells was achieved after 1 hr. Results of equilibrium studies were consistent with two classes of binding sites for MTZ within the erythrocyte: a low affinity, high capacity site (CA-I) and a high affinity, low capacity site (CA-II). A two-binding site model was fitted to experimental data generating estimates for binding parameters Ka1 (0.0017 +/- 0.00022 microM-1) nM1 (636 +/- 5.23 microM), Ka2(0.46 +/- 0.0083 microM-1), and nM2(80.9 +/- 0.389 microM). Based upon these findings, kinetic studies were performed in order to characterize the rate of drug distribution. The rate of erythrocyte uptake of MTZ was mathematically modeled using a series of differential equations describing drug diffusion across the red blood cell membrane and subsequent complexation with intracellular binding sites. The model assumed that penetration of MTZ into the red blood cells was passive but drug binding to the carbonic anhydrase isozymes was not instantaneous. Using a novel curve fitting technique, parameter estimates of RBC membrane permeability (0.0102 +/- 0.000618 cm/min), and binding rate constants k-1(0.254 +/- 0.0213 min-1), k1 (0.0022 +/- 0.00020 ml/microgram-min), k-2(1.59 +/- 0.0358 min-1), and k2(3.1 +/- 0.035 ml/microgram-min) were obtained. The model characterized the observed biphasic decline of MTZ buffer concentrations over time and may help explain the prolonged residence of MTZ in vivo.

Binding Sites↗
PubMed2000

Specificity and binding kinetics of murine lupus anti-DNA monoclonal antibodies implicate different stimuli for their production.

The origin and relative biological importance of the many different DNA-reactive antibodies that appear in systemic lupus erythematosus are not well understood. A detailed analysis of their fine specificity and binding characteristics with DNA is a necessary step in understanding their biology. We have examined here two monoclonal antibodies (mAb) IV-228 and V-88 that are, respectively, characteristic of antibodies, which bind exclusively to single-stranded (ss) DNA and to both double-stranded (ds) DNA and ssDNA. By surface plasmon resonance (SPR) on BIAcore, we characterized the kinetics of binding of each antibody to synthetic ss and ds oligonucleotides. Antibody V-88 and IV-228 showed different patterns of reactivity for both ss and ds oligonucleotides, characterized by distinctly different kinetic parameters. Analysis of their binding kinetics indicates the importance of base composition in defining DNA epitopes, and shows that some epitopes, such as that recognized by mAb V-88, are expressed on dsDNA and ssDNA, whereas others, as recognized by IV-228, are not. The base preferences of V-88 for ds GC-rich structures over AT-rich, and of IV-228 for ss T-rich structures, also reveal distinct differences between these antibodies. We conclude that the different binding properties of the antibodies will relate to their biological activities. The base preferences of the antibodies suggest that they might be induced by different immunological stimuli, such as those that could be provided by the various DNA fragments and structures released during programmed cell death.

Animals↗
PubMed1990

The effect of temperature on the binding kinetics and equilibrium constants of monoclonal antibodies to cell surface antigens.

The effect of temperature on the kinetic association and dissociation binding parameters, and equilibrium constants of four monoclonal antibodies to the murine Ly-2.1 and Ly-3.1 antigens has been studied using flow cytometry. All four monoclonal antibodies were conjugated to FITC and their association to, and dissociation from, the surface of murine thymoma cells was observed at 15 sec intervals, at temperatures between 1 and 37 degrees C. The initial association rate constant and the dissociation rate constant for each antibody at each temperature were calculated from graphs of the first-order reactions and it was demonstrated that an increase in temperature caused an increase in both association rate and dissociation rate of the antibodies. Generally the increase in association rate with temperature was less than the increase in dissociation rate. Differences between antibodies to the same antigen (Ly-2.1) suggest that changes in membrane fluidity were not solely responsible for the changes in association rate. However, the equilibrium constants (Keq) did not always show a simple relationship of increasing temperature causing decreasing values for Keq. For one antibody the highest value for Keq was seen at 17 degrees C rather than at 37 degrees C and differences in Keq between individual antibodies were greater at 1 degree C than at 37 degrees C. Kinetic rate constants are usually measured at 4 degrees C or room temperature, therefore for antibodies under consideration for in vivo use, measurements at 37 degrees C are more appropriate.

Animals↗
PubMed1982

Stopped-flow studies on drug-protein binding. Analog-computer analysis of the pH-dependent binding kinetics of warfarin and human serum albumin.

Binding curves obtained by the stopped-flow method for the association of warfarin and human serum albumin (HSA) at pH 6.0 and 9.0 have been analysed with digital- and analog computers. The first association product (WHSA') at pH 6-9 does not contribute to the observed fluorescence enhancement during warfarin-HSA complex formation. A similar consecutive relaxation process leads to a more stable warfarin-HSA complex, with HSA in the neutral (N)-form (pH 6) and base (B)-form (pH 9). This rearrangement can be measured by stopped-flow (k 2 = 31 s-1 at pH 6; K'2 = 63 s-1 at pH 9). At pH 6 a further concentration dependent relaxation process has been observed indicating that the complex of warfarin with the N-form of HSA gets partially converted into its B-form with a half-time for this N leads to B transition in the range of 0.2-0.4 s. A drug such as warfarin can act as effector molecule for conformational changes of the HSA tertiary and quaternary structure during the formation of a high affinity complex.

Computers, Analog↗
PubMed2006

Modeling micropatterned antigen-antibody binding kinetics in a microfluidic chip.

The reaction kinetics of antigen-antibody binding in the electrokinetically controlled microfluidic heterogeneous immunoassays has been investigated by numerical simulations. A two-dimensional computational model was employed to include the mass transport (convection and diffusion) and binding reaction between the antigen in the bulk flow and the immobilized antibody at the channel surface. The influence of the bulk velocity, the concentrations of the antibody and antigen, and the geometry of the microchips was studied for a variation of conditions and the guidance for designing of microfluidic immunoassay was provided. The model also shows that electrokinetically driven immunoassays have better reaction kinetics than pressure-driven ones, resulting from the plug-like velocity profile. Finally, a multi-patch immunoassay chip was analyzed and the reaction kinetics was optimized by rearranging the reaction patches at the channel surfaces.

Antigen-Antibody Complex↗
PubMed1987

Interaction of amide inhibitors with the active site of carbonic anhydrase: metal-induced deprotonation of the bound amide group is indicated by slow binding kinetics, by visible spectra of complexes with cobalt enzyme, and by pH effects on binding affinity.

Most carbonic anhydrase (CA) inhibitors bind at the active site metal and either are anions or are capable of deprotonation to yield anions. Much less is known about the interaction of CA with inhibitors that have hitherto been considered to bind as neutral species. We report a study of the reversible amide inhibition of Co(II)-substituted CA by iodoacetamide and ethyl carbamate (urethane), as well as the ambivalent oxamate, the monoamide of oxalate. Visible cobalt spectral changes indicate coordination of all these inhibitors to the metal. The pH dependence of the affinity of carbonic anhydrase isozyme I (CA I) for ethyl carbamate and iodoacetamide is formally consistent with their binding either as anionic species to the acid form of the enzyme or as neutral species to the basic form of the enzyme. The former view is in better accord with the spectral data. Most strikingly, reversible binding of iodoacetamide and ethyl carbamate leads to uniquely slow kinetics of ligand association and dissociation that could be followed by simple mixing. The slow association kinetics suggest the involvement of energetically unfavorable deprotonation of the amide group preceding final coordination. The complex pH profile for inhibition of CA I by the ambivalent oxamate is consistent with coordination through the carboxylate group at low pH and through the deprotonated amide group at high pH. The visible spectrum of the complex of Co(II)CA I with oxamate shows a parallel dependence on pH, reflecting this dual coordination mode. Similarly, oxamate dissociation kinetics were biphasic and could be correlated with the pH-dependent spectral changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2005

Meningococcal transferrin-binding proteins A and B show cooperation in their binding kinetics for human transferrin.

Neisseria meningitidis, a causative agent of bacterial meningitis and septicemia, obtains transferrin-bound iron by expressing two outer membrane-located transferrin-binding proteins, TbpA and TbpB. A novel system was developed to investigate the interaction between Tbps and human transferrin. Copurified TbpA-TbpB, recombined TbpA-TbpB, and individual TbpA and TbpB were reconstituted into liposomes and fused onto an HPA chip (BIAcore). All preparations formed stable monolayers, which, with the exception of TbpB, could be regenerated by removing bound transferrin. The ligand binding properties of these monolayers were characterized with surface plasmon resonance and shown to be specific for human transferrin. Kinetic data for diferric human transferrin binding showed that recombined TbpA-TbpB had K(a) and K(d) values similar to those of copurified TbpA-TbpB. Individual TbpA and TbpB also displayed K(a) values similar to those of copurified TbpA-TbpB, but their K(d) values were one order of magnitude higher. Chemical cross-linking studies revealed that TbpA and TbpB, in the absence of human transferrin, formed large complexes with TbpA as the predominant species. Upon human transferrin binding, a complex was formed with a molecular mass corresponding to that of a TbpB-human transferrin heterodimer as well as a higher-molecular-mass complex of this heterodimer cross-linked to TbpA. This indicates that TbpA and TbpB form a functional meningococcal receptor complex in which there is cooperativity in the human transferrin binding kinetics. However, iron loss from the diferric human transferrin-TbpA-TbpB complex was not greater than that from human transferrin alone, suggesting that additional meningococcal transport components are involved in the process of iron removal.

Dimyristoylphosphatidylcholine↗
PubMed1991

Comparison of the effects of hypertonic sucrose and intracellular potassium depletion on growth hormone receptor binding kinetics and down-regulation in IM-9 cells: evidence for a sequential block of receptor--mediated endocytosis.

To better understand the complex kinetics of human GH (hGH) binding to its receptors, we have further investigated, in IM-9 cultured human lymphocytes, the cellular locus corresponding to the slowly dissociating component of hormone binding, and to the homologous down-regulation of hGH receptors. First, we have detailed the biphasic kinetics of dissociation of bound hormone in control cells at 30 C. When the association at 30 C was extended from 0.5 to 3 h, the time required for half-dissociation of the fast component was slightly decreased (from 30 to 15 min) but that of the slow component increased considerably (from 6 h to 30 h). Concomitantly, the size of the slowly dissociating component increased from 50 to 80% of total. This indicates a maturation of bound hormone, from a rapidly to a slowly dissociating pool and, in the latter, an increase in the apparent affinity that may reflect a molecular rearrangement. Next, we have compared the effect of two procedures reported to inhibit receptor-mediated endocytosis at the level of coated pits. As previously reported, depletion of intracellular K+ abolished the slowly dissociating component and the down-regulation of hGH receptors. In contrast, upon incubation with 0.4 M sucrose, which like K+ depletion virtually abrogated hGH internalization, the dissociation kinetics remained non-first order, and the down-regulation of hGH-receptor was only slightly reduced. Thus, these procedures appear to block receptor-mediated endocytosis at two successive compartments of the cell surface. In conclusion, we propose that some conformational change of hGH-receptor at the cell surface (possibly associated with clustering) may considerably slow down their dissociation and may be sufficient for down-regulation.

Cell Line↗
PubMed1998

Equilibrium and kinetic binding analysis of the N-terminal domain of the Pf1 gene 5 protein and its interaction with single-stranded DNA.

The Pf1 gene 5 protein is a single-stranded DNA-binding protein that binds cooperatively to the viral strand of Pf1 DNA during replication. A variety of N-terminal fragments of the Pf1 gene 5 protein have been expressed and purified. We have identified an N-terminal single-stranded DNA-binding domain (residues 1 to 105) that is much more globular than the intact protein (1 to 144). Larger fragments (1 to 115) as well as smaller fragments (1 to 91) were unable to bind DNA effectively. Analysis of the truncated proteins by gel retardation and fluorescence anisotropy indicates that the N-terminal domain binds DNA with a reduced affinity, due principally to a reduction in cooperativity, and that binding is highly concentration-dependent. Kinetic analysis shows that the rates of association and dissociation of the N-terminal domain from the complex with DNA are faster than those observed for the intact protein. The results suggest that the flexible C-terminal domain of the Pf1 gene 5 protein plays an important role in protein-protein interactions that stabilise adjacent protein dimers in the DNA-protein complex.

Biosensing Techniques↗
PubMed1995

Point mutations in Staphylococcus aureus PBP 2 gene affect penicillin-binding kinetics and are associated with resistance.

In Staphylococcus aureus, penicillin-binding protein 2 (PBP 2) has been implicated in non-PBP 2a-mediated methicillin resistance. The PBP 2 gene (pbpB) was cloned from an expression library of a methicillin-susceptible strain of S. aureus (209P), and its entire sequence was compared with that of the pbpB gene from strains BB255, BB255R, and CDC6. Point mutations that resulted in amino acid substitutions near the conserved penicillin-binding motifs were detected in BB255R and CDC6, two low-level methicillin-resistant strains. Penicillin binding to PBP 2 in both BB255R and CDC6 is altered, and kinetic analysis indicated that altered binding of PBP 2 by penicillin was due to both lower binding affinity and more rapid release of bound drug. These structural and biochemical changes may contribute to the strains' resistance to beta-lactam antibiotics.

Amino Acid Sequence↗
PubMed1985

Age-dependent, ovary-independent decrease in the nuclear binding kinetics of estrogen receptors in the brain of the C57BL/6J mouse.

To further define the role of aging of the brain in the induction of reproductive acyclicity, we put to death intact as well as castrated female C57BL/6J mice of various ages before and from 0.5 to 24 hours after subcutaneous injection of 0.2 micrograms of 17 beta-estradiol. Pooled hypothalamic and pituitary tissues were dissected and cytosolic/nuclear estrogen receptors were assayed in buffer that consisted of 10 mmol/L Tris(hydroxymethylaminomethane) hydrochloride, 1.5 mmol/L ethylenediaminetetraacetic acid, and 0.5 mmol/L dithiothreitol and contained molybdate (25 mmol/L) and inhibitors of proteases. Our results in intact animals indicated that baseline cytosolic concentration of estrogen receptors remained constant at 60 to 77 fmol/mg of protein (range) throughout aging, whereas nuclear levels of estrogen receptors decreased from 1.2 to 1.6 fmol/micrograms of deoxyribonucleic acid (range) to nondetectable levels after the onset of ovarian acyclicity. No age-related changes in the Ka were observed. After subcutaneous challenge with estrogen, nuclear binding of hypothalamic-pituitary axis estrogen receptors revealed a significant age-related decrease which was already evident at 10 to 14 months of age and prior to the onset of anestrous. Castration, whether performed neonatally or at 8 months of age, reduced the hypothalamic-pituitary axis concentration of estrogen receptors in middle-aged and aged animals, but did not prevent this blunted kinetics of nuclear binding. One week of daily injection of 17 beta-estradiol to intact and castrated mice of all age groups prior to binding kinetic studies induced maximal (five fold) increases in the content of hypothalamic-pituitary axis estrogen receptors in young animals which readily bound to the nucleus. After similar therapy to middle-aged and aged mice, minimal changes or even no changes were observed in both cellular estrogen receptor contents, despite similar increments in plasma levels of estrogen. These findings suggest an age-dependent decrease in the kinetics of hypothalamic-pituitary axis estrogen receptors manifested by a reduced synthesis of functional estrogen receptors in the brain of mice.

Aging↗