Biomedical subjects

J Marie

Publications and source records attributed to J Marie.

At least 19 recordsLinked to original sources

PubMed2006

Comparison of the type of substrate oxidation during exercise between pre and post pubertal markedly obese boys.

The aim of this study was to investigate, in markedly obese children, the effect of puberty on substrate oxidation during an acute bout of exercise. Two groups of markedly obese boys (7 pre pubertal, 8 post pubertal, matched for adiposity) performed an exercise-test designed for measuring carbohydrate and fat oxidation with indirect calorimetry, and consisting of five six-minute steady-state workloads at 20, 30, 40, 50, and 60 % of the theoretical maximal aerobic power. Fat oxidation (mg . min (-1)) is correlated to fat free mass (FFM) (r = 0.7, p = 0.02). When expressed in crude flow rate units, fat oxidation is slightly higher in PostP than PreP children (p < 0.05). However, when expressed per unit of FFM or as a percentage of total fuel oxidation, fat oxidation is lower in PostP than PreP children (p < 0.05). Multivariable analysis shows that the influence of age on the ability to oxidize fat at exercise is explained by the pubertal increase in FFM. In markedly obese children during puberty, the ability of each kg of FFM to oxidize fat at exercise decreases (- 28% at 20%Wmax th), but the pubertal increase in FFM overcomes this effect, resulting in an increase in whole body ability to oxidize fat at exercise (+ 17,3% at 20%Wmax th).

Adolescent↗

PubMed2005

Impact of high- and low-intensity targeted exercise training on the type of substrate utilization in obese boys submitted to a hypocaloric diet.

BACKGROUND: We assessed the effect of two programs combining a hypocaloric diet with low-intensity (LI) or high-intensity (HI) exercise training, during two months, on substrate utilization at exercise in obese children. METHODS: Fifteen obese boys participated in a combined program of exercise and caloric restriction-induced weight loss (diet starting two weeks before the training program). The maximal fat oxidation point (Lipox max) was determined to individualize exercise training. Training consisted of cycling at either LI (Lipox max) for seven children or HI (Lipoxmax+40% Lipox max) for eight children. RESULTS: All children exhibited a decrease in weight (LI: -5.2 kg +/- 0.7 (P<0.01), HI: -7 kg +/- 0.7 (P<0.01)). While in the LI group, both fat and CHO oxidation were unchanged after training, HI group oxidize less fat and more CHO after training when exercising at 20% and 30% Wmax th (P = 0.02). DISCUSSION: While a LI exercise training program maintains (but does not improve) the ability to oxidize fat at exercise, HI training actually shifts towards CHO the balance of substrate oxidation during exercise. Thus, a low intensity training protocol seems to counteract to some extent the decline in lipid oxidation at exercise that occurs after a hypocaloric diet, and is thus likely to be synergistic to diet in the weight lowering strategy.

Adipose Tissue↗

PubMed2002

Antimicrobial susceptibility of Streptococcus suis isolated from swine in France and from humans in different countries between 1996 and 2000.

The susceptibility of 135 Streptococcus suis strains isolated from pigs (n = 110) and from humans (n = 25) to 13 antimicrobial agents was studied by microdilution and disc diffusion methods using Mueller-Hinton Agar II (MH) supplemented with either defibrinated sheep blood (MHSB) or horse serum (MHHS). Results were similar for both methods used except for penicillin G whose zone diameters were reduced with MHSB compared with MHHS. When MH was supplemented with sheep blood, 39% of S. suis strains classified as penicillin susceptible by MHHS microdilution showed intermediate susceptibility. Nearly all strains were susceptible to penicillin G (except by disc diffusion in MHSB), amoxicillin, ceftiofur, florfenicol, gentamicin and bacitracin. The least active antimicrobial agents were doxycycline and macrolides/lincosamides. High-level resistance (MIC > 500 mg/L or zone diameters < 10 mm) to streptomycin and kanamycin was detected in only a few strains. The virulence of strains did not seem to be related to antimicrobial resistance because no statistical difference was reported between the proportion of resistant strains of S. suis isolated from pigs with meningitis, septicaemia and arthritis, and those from tonsils and nasal cavities. However, significant differences were found in the proportions of macrolide- or doxycycline-resistant strains between S. suis serotype 2 and other serotypes. The results of antibiotic susceptibility testing presented in this study indicate that beta-lactams can be used in empirical treatment of human and pig S. suis infections in France.

Animals↗

PubMed2001

Control of conformational equilibria in the human B2 bradykinin receptor. Modeling of nonpeptidic ligand action and comparison to the rhodopsin structure.

A prototypic study of the molecular mechanisms of activation or inactivation of peptide hormone G protein-coupled receptors was carried out on the human B2 bradykinin receptor. A detailed pharmacological analysis of receptor mutants possessing either increased constitutive activity or impaired activation or ligand recognition allowed us to propose key residues participating in intramolecular interaction networks stabilizing receptor inactive or active conformations: Asn(113) and Tyr(115) (TM III), Trp(256) and Phe(259) (TM VI), Tyr(295) (TM VII) which are homologous of the rhodopsin residues Gly(120), Glu(122), Trp(265), Tyr(268), and Lys(296), respectively. An essential experimental finding was the spatial proximity between Asn(113), which is the cornerstone of inactive conformations, and Trp(256) which plays a subtle role in controlling the balance between active and inactive conformations. Molecular modeling and mutagenesis data showed that Trp(256) and Tyr(295) constitute, together with Gln(288), receptor contact points with original nonpeptidic ligands. It provided an explanation for the ligand inverse agonist behavior on the WT receptor, with underlying restricted motions of TMs III, VI, and VII, and its agonist behavior on the Ala(113) and Phe(256) constitutively activated mutants. These data on the B2 receptor emphasize that conformational equilibria are controlled in a coordinated fashion by key residues which are located at strategic positions for several G protein-coupled receptors. They are discussed in comparison with the recently determined rhodopsin crystallographic structure.

Amino Acid Sequence↗

PubMed2001

Significance of MDR1, MRP1, GSTpi and GSTmu mRNA expression in acute lymphoblastic leukemia in Indian patients.

Using, semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) in 167 patients of acute lymphoblastic leukemia (ALL) from India at different stages of the disease (presentation 125, remission 33, first relapse nine), MRP1 and GSTpi expression were significantly higher at relapse than presentation (P=0.03 and P=0.01, respectively) and remission (P=0.007 and P=0.003, respectively). MRP1, GSTpi and GSTmu were expressed simultaneously in several samples with significant association of expression levels (P=0.0001). Association with clinicopathological features included higher MDR1 expression with age >15 years (P=0.04) and higher MRP1, GSTpi, GSTmu expression with WBC counts >100x10(9)/l. In 71 patients (age <25 years), inability to achieve CR was associated with a significantly higher MDR1 mRNA expression (P=0.03) indicating a prognostic significance. However, relapse or shorter Event Free Survival was independent of mRNA expression levels of the four genes. In view of the increased mRNA expression of MRP1/GST at the time of relapse and an association with risk factors such as a high WBC count, further studies directed towards investigating the functional aspects of GSH/GST/MRP1 mediated drug transport are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Identification of an RNA binding specificity for the potential splicing factor TLS.

The TLS/FUS gene is involved in a recurrent chromosomal translocation in human myxoid liposarcomas. We previously reported that TLS is a potential splicing regulator able to modulate the 5'-splice site selection in an E1A pre-mRNA. Using an in vitro selection procedure, we investigated whether TLS exhibits a specificity with regard to RNA recognition. The RNAs selected by TLS share a common GGUG motif. Mutation of a G or U residue within this motif abolishes the interaction of TLS with the selected RNAs. We showed that TLS can bind GGUG-containing RNAs with a 250 nm affinity. By UV cross-linking/competition and immunoprecipitation experiments, we demonstrated that TLS recognizes a GGUG-containing RNA in nuclear extracts. Each one of the RNA binding domains (the three RGG boxes and the RNA recognition motif) contributes to the specificity of the TLS.RNA interaction, whereas only RRM and RGG2-3 participate to the E1A alternative splicing in vivo. The specificity of the TLS.RNA interaction was also observed using as natural pre-mRNA, the G-rich IVSB7 intron of the beta-tropomyosin pre-mRNA. Moreover, we determined that RNA binding specificities of TLS and high nuclear ribonucleoprotein A1 were different. Hence, our results help define the role of the specific interaction of TLS with RNA during the splicing process of a pre-mRNA.

Animals↗

PubMed1999

Specific nonpeptide photoprobes as tools for the structural study of the angiotensin II AT(1) receptor.

The aim of this work was to obtain photoactivatable nonpeptide antagonists of the angiotensin II AT(1) receptor. Based on structure-function relationships, two chemical structures as well as appropriate synthetic schemes were chosen as a frame for the design of radiolabeled azido probes. The feasibility of the strategy was first assessed by the synthesis of two tritiated ligands 21 and 22 possessing a high affinity for the AT(1) receptor and a low nonspecific binding to membrane or cell preparations. We then prepared two unlabeled azido derivatives 7 and 14 which retained a fairly high affinity for the AT(1) receptor. The latter compound proved to be suitable for receptor irreversible labeling and was prepared in its tritiated form 28. This tritiated azido nonpeptide probe displayed a K(d) value of 11.8 nM and a low nonspecific binding. It was suitable for specific and efficient covalent labeling of the recombinant AT(1A) receptor stably expressed in CHO cells. The electrophoretic pattern of the specifically labeled entity was strictly identical to that of purified receptor photolabeled with a biotinylated peptidic photoactivatable probe. This new tool should be useful for the mapping of the nonpeptide receptor binding site. These potential applications are discussed in light of the current knowledge of molecular mechanisms of G-protein coupled receptor activation and inactivation.

Angiotensin II↗

PubMed1999

N-glycosylation requirements for the AT1a angiotensin II receptor delivery to the plasma membrane.

The purpose of this work was to investigate the role of N-glycosylation in the expression and pharmacological properties of the the rat AT1a angiotensin II (AII) receptor. Glycosylation-site suppression was carried out by site-directed mutagenesis (Asn-->Gln) of Asn176 and Asn188 (located on the second extracellular loop) and by the removal of Asn4 at the N-terminal end combined with the replacement of the first four amino acids by a 10 amino acid peptide epitope (c-Myc). We generated seven possible N-glycosylation-site-defective mutants, all tagged at their C-terminal ends with the c-Myc epitope. This double-tagging strategy, associated with photoaffinity labelling, allowed evaluation of the molecular masses and immunocytochemical cellular localization of the various receptors transiently expressed in COS-7 cells. We showed that: (i) each of the three N-glycosylation sites are utilized in COS-7 cells; (ii) the mutant with three defective N-glycosylation sites was not (or was very inefficiently) expressed at the plasma membrane and accumulated inside the cell at the perinuclear zone; (iii) the preservation of two sites allowed normal receptor delivery to the plasma membrane, the presence of only Asn176 ensuring a behaviour similar to that of the wild-type receptor; and (iv) all expressed receptors displayed unchanged pharmacological properties (Kd for 125I-sarcosine1-AII; sarcosine1-AII-induced inositol phosphate production). These results demonstrate that N-glycosylation is required for the AT1 receptor expression. They are discussed in the light of current knowledge of membrane-protein maturation and future prospects of receptor overexpression for structural studies.

Amino Acid Sequence↗

PubMed1999

Functional expression of receptors for calcitonin gene-related peptide, calcitonin, and vasoactive intestinal peptide in the human thymus and thymomas from myasthenia gravis patients.

The molecular and functional expression of serpentine membrane receptors for vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and calcitonin (CT) were characterized in human thymus and thymomas from myasthenia gravis (MG) patients and thymic epithelial cells either in primary culture (PTEC) or transformed by the simian virus 40 large T (SV40LT) oncogene (LT-TEC). Using RT-PCR combined with Southern analysis, we identified the PCR products corresponding to the receptor (-R) transcripts for VIP, CGRP, and CT in thymus from control subjects and MG patients with either hyperplasia or thymoma. Similar expressions of the VIP- and CGRP-R transcripts were observed in PTEC, whereas the CT-R message was not detected. In LT-TEC, the signals for VIP-R, CGRP-R, and CT-R transcripts were seen with a lower intensity than those in control and MG thymus. In agreement with our molecular analysis, 1) VIP was the most potent peptide among VIP-related peptides (VIP > PACAP > PHM > PHV) to stimulate cAMP production through specific type 1 VIP receptors in both PTEC and LT-TEC; 2) cAMP generation was induced by CGRP in PTEC and by CT in LT-TEC; 3) in frozen thymic sections and by flow cytometry, type 1 VIP-R, CGRP-R, and CT-R were localized in epithelial cells; and 4) in parallel, the transcription of the acetylcholine receptor alpha subunit (the main autoantigen in MG) was induced by CGRP and CT in PTEC and LT-TEC, respectively. Our data suggest that the neuroendocrine peptides VIP, CGRP, and CT may exert functional roles during MG and malignant transformation of the human thymus.

Adolescent↗

PubMed1999

Constitutive activation of the human bradykinin B2 receptor induced by mutations in transmembrane helices III and VI.

We report that mutation of specific residues in the human B2 bradykinin (BK) receptor induces its marked constitutive activation, evaluated through inositol phosphate production in COS-7 cells expressing the wild-type or mutant receptors. We provide evidence for a strikingly high constitutive activation of the B2 receptor induced by alanine substitution of the Asn113 residue, located in the third transmembrane domain. These results are reminiscent of our previous finding that mutation of the homologous Asn111 residue induces constitutive activation of the AT1 angiotensin II receptor. BK overstimulation of the constitutively activated mutant N113A receptor was also observed. Phe replacement of the Trp256 residue, fairly conserved in transmembrane domain VI of G protein-coupled receptors, also induced a less prominent but significant constitutive activation. Interestingly, the peptidic HOE 140 compound and an original nonpeptidic compound LF 16 0335, which both behaved as inverse agonists of the wild-type receptor expressed in COS-7 cells, became potent and efficient agonists of the two constitutively activated mutant N113A and W256F receptors. These parallel changes observed for two chemically unrelated series can serve as a basis for future studies of structure-function relationships and modeling of activation processes, based on a detailed analysis of the network of helix-helix interactions, which stabilize the inactive receptor conformation and undergo rearrangements on transition to activated states.

Animals↗

PubMed1997

The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the beta-tropomyosin alternative exon 6A.

Exons 6A and 6B of the chicken beta-tropomyosin gene are mutually exclusive and selected in a tissue-specific manner. Exon 6A is present in non-muscle and smooth muscle cells, while exon 6B is present in skeletal muscle cells. In this study we have investigated the mechanism underlying exon 6A recognition in non-muscle cells. Previous reports have identified a pyrimidine-rich intronic enhancer sequence (S4) downstream of exon 6A as essential for exon 6A 5'-splice site recognition. We show here that preincubation of HeLa cell extracts with an excess of RNA containing this sequence specifically inhibits exon 6A recognition by the splicing machinery. Splicing inhibition by an excess of this RNA can be rescued by addition of the SR protein ASF/SF2, but not by the SR proteins SC35 or 9G8. ASF/SF2 stimulates exon 6A splicing through specific interaction with the enhancer sequence. Surprisingly, SC35 behaves as an inhibitor of exon 6A splicing, since addition to HeLa nuclear extracts of increasing amounts of the SC35 protein completely abolish the stimulatory effect of ASF/SF2 on exon 6A splicing. We conclude that exon 6A recognition in vitro depends on the ratio of the ASF/SF2 to SC35 SR proteins. Taken together our results suggest that variations in the level or activity of these proteins could contribute to the tissue-specific choice of beta-tropomyosin exon 6A. In support of this we show that SR proteins isolated from skeletal muscle tissues are less efficient for exon 6A stimulation than SR proteins isolated from HeLa cells.

Alternative Splicing↗

PubMed1997

Mutation of Asn111 in the third transmembrane domain of the AT1A angiotensin II receptor induces its constitutive activation.

A preliminary model of the rat AT1A angiotensin II (AII) receptor (Joseph, M. P., Maigret, B., Bonnafous J.-C., Marie, J., and Scheraga, H. A. (1995) J. Protein Chem. 14, 381-398) has predicted an interaction between Asn111 located in transmembrane domain (TM) III and Tyr292 (TM VII) in the nonactivated receptor; a disruption of this interaction upon AII activation would allow Tyr292 to interact with the conserved Asp74 (TM II). The previous verification that Tyr292 is essential for receptor coupling to phospholipase C (Marie, J., Maigret, B., Joseph, M. P., Larguier, R., Nouet, S., Lombard, C., and Bonnafous, J.-C. (1994) J. Biol. Chem. 269, 20815-20818) prompted us to check the possible alterations in receptor properties upon Asn111 --> Ala mutation. The mutated receptor (N111A) displayed: (i) strong constitutive activity, with amplification of the maximal phospholipase C response to AII; (ii) agonist behavior of the AT2-specific ligand CGP 42112A, [Sar1, Ile8]AII, and [Sar1,Ala8]AII, antagonists of the wild-type receptor; (iii) inverse agonism behavior of the non-peptide ligands DuP 753, LF 7-0156, and LF 8-0129. The results are discussed in the light of the allosteric ternary complex models and other described examples of constitutive activation of G protein-coupled receptors.

Alanine↗

PubMed1996

Tissue-specific splicing of two mutually exclusive exons of the chicken beta-tropomyosin pre-mRNA: positive and negative regulations.

Alternative splicing of premessenger RNA (pre-mRNA) is a widespread process used in higher eucaryotes to regulate gene expression. A single primary transcript can generate multiple proteins with distinct functions in a tissue- and/or developmental-specific manner. A central question in alternative splicing concerns the selection of splice sites in different cell environments. In this review, we present our results on the alternative splicing of the chicken beta-tropomyosin gene which provides an interesting model for understanding mechanisms involved in splice site selection. The beta-tropomyosin gene contains in its central portion a pair of exons (6A and 6B) that are used mutually exclusively in a tissue and developmental stage-specific manner. Exon 6A is present in mRNA of non-muscle and smooth muscle tissues while exon 6B is only present in mRNA of skeletal muscle. Regulation of both exons is necessary to ensure specific expression of beta-tropomyosin gene in non-muscle cells. Several cis-acting elements involved in the repression of exon 6B and activation of exon 6A have been identified. In addition, we show that the tissue-specific choice of exon 6A is mediated through interaction with a specific class of splicing factors, the SR proteins. In the last part of this review we will focus on possible mechanisms needed to switch to exon 6B selection in skeletal muscle tissue. We propose that tissue-specific choice of exon 6B involves down regulation of exon 6A and activation of exon 6B. A G-rich enhancer sequence downstream of exon 6B has been defined that is needed for efficient recognition of the exon 6B 5' splice site. Moreover, we suggest that alteration of the ratio between proteins of the SR family contributes to tissue-specific splice site selection.

Animals↗

PubMed1995

A T to G mutation in the polypyrimidine tract of the second intron of the human beta-globin gene reduces in vitro splicing efficiency: evidence for an increased hnRNP C interaction.

In a patient with a beta-thalassemia intermedia, a mutation was identified in the second intron of the human beta-globin gene. The U-->G mutation is located within the polypyrimidine tract at position -8 upstream of the 3' splice site. In vivo, this mutation leads to decreased levels of the hemoglobin protein. Because of the location of the mutation and the role of the polypyrimidine tract in the splicing process, we performed in vitro splicing assays on the pre-messenger RNA (pre-mRNA). We found that the splicing efficiency of the mutant pre-mRNA is reduced compared to the wild type and that no cryptic splice sites are activated. Analysis of splicing complex formation shows that the U-->G mutation affects predominantly the progression of the H complex towards the pre-spliceosome complex. By cross-linking and immunoprecipitation assays, we show that the hnRNP C protein interacts more efficiently with the mutant precursor than with the wild-type. This stronger interaction could play a role, directly or indirectly, in the decreased splicing efficiency.

Base Sequence↗

PubMed1995

An intronic (A/U)GGG repeat enhances the splicing of an alternative intron of the chicken beta-tropomyosin pre-mRNA.

Computer analysis of human intron sequences have revealed a 50 nucleotide (nt) GC-rich region downstream of the 5' splice site; the trinucleotide GGG occurs almost four times as frequently as it would in a random sequence. The 5' part of a beta-tropomyosin intron exhibits six repetitions of the motif (A/U)GGG. In order to test whether these motifs play a role in the splicing process we have mutated some or all of them. Mutated RNAs show a lower in vitro splicing efficiency when compared with the wild-type, especially when all six motifs are mutated (> 70% inhibition). Assembly of the spliceosome complex B and, to a lesser extent, of the pre-spliceosome complex A also appears to be strongly affected by this mutation. A 55 kDa protein within HeLa cell nuclear extract is efficiently cross-linked to the G-rich region. This protein is present in the splicing complexes and its cross-linking to the pre-mRNA requires the presence of one or several snRNP. Altogether our results suggest that the G-rich sequences present in the 5' part of introns may act as an enhancer of the splicing reaction at the level of spliceosome assembly.

Alternative Splicing↗

PubMed1995

beta-Tropomyosin pre-mRNA folding around a muscle-specific exon interferes with several steps of spliceosome assembly.

The chicken beta-tropomyosin pre-mRNA is spliced in a tissue-specific manner. Internal exons 6B and 6A are specifically used in skeletal muscle and non-skeletal muscle cells, respectively. Pre-mRNA secondary structure around exon 6B has been shown to be part of the mechanism that inhibits exon 6B to 7 splicing in HeLa nuclear extract. We analyse the influence of pre-mRNA folding on the different steps of spliceosome assembly under different conditions. At 3 mM MgCl2, conditions that favour RNA structure formation, the interactions of U1, U2, U4, U5 and U6 small nuclear ribonucleoprotein particles (snRNPs) with the pre-mRNA are all affected. The study of several mutants destabilising some proposed stem-loop structures shows that the in vitro splicing activation is correlated with an increased binding of snRNPs on pre-mRNA molecules. At 1 mM MgCl2, conditions that allow a partial relaxation of the inhibitory structure, U1 snRNP binding on exon 6B 5' splice site occurs very efficiently. Nonetheless, if this first step of spliceosome assembly is derepressed, U2, U4, U5 and U6 snRNP interaction processes remain inhibited. Altogether, these results suggest that the choice between exon 6A and 6B donor sites is a complex process not simply directed by a difference in the efficiency of interaction between U1 snRNP and alternative 5' splice sites.

Alternative Splicing↗

PubMed1995

In vitro splicing deficiency induced by a C to T mutation at position -3 in the intron 10 acceptor site of the phenylalanine hydroxylase gene in a patient with phenylketonuria.

A previous study has identified a C-->U mutation at position -3 in the 3' splice site of intron 10 of the phenylalanine hydroxylase pre-mRNA in a patient with phenylketonuria. In vivo, this mutation induces the skipping of the downstream exon. This result is puzzling because both CAG and UAG have been reported to function equally as 3' splice sites. In this report, we show that the C-->U mutation affects predominantly the first step of the splicing reaction and that it blocks spliceosome assembly at an early stage. The 3' region of the phenylalanine hydroxylase intron 10 has two unusual characteristic features: multiple potential branch sites and a series of four guanosine residues, which interrupt the polypyrimidine tract at positions -8 to -11 from the 3' splice site. We show that the mutation precludes the use of the proximal branch site, while having no effect on the remote one. We also show that in the UAG transcript, the four guanosine residues inhibit the splicing of intron 10. The substitution of these purine residues by one cytosine residue, regardless of the position, increases the splicing efficiency of the mutant UAG precursor while having no effect on the wild-type CAG precursor. Substituting the four purine residues by four pyrimidines relieves the inhibition and rescues the use of the proximal branch site. These results demonstrate that according to the context, the C and U nucleotides preceding the AG are not equivalent for the splicing reaction.

Base Sequence↗

PubMed1995

Amino acids of the third transmembrane domain of the AT1A angiotensin II receptor are involved in the differential recognition of peptide and nonpeptide ligands.

The differential role of amino acids of the third transmembrane domain on peptide and nonpeptide recognition by the AT1 angiotensin II receptor has been evidenced. The mutation of Ser105 into alanine completely abolished peptide agonist and antagonist binding, while the binding of nonpeptide ligands, including the original radioligands [3H] LF 7-0156 and [3H] LF 8-0129, was more moderately affected. Reverse pharmacological changes, i.e., unchanged affinities for peptide agonists or antagonists and drastically reduced affinities for nonpeptide antagonists, were observed upon alanine replacement of Asn111. These results confirm that the binding sites for peptide and nonpeptide molecules are not totally overlapping and delineate new amino acids as candidates for the selective receptor interaction with the two categories of ligands. Their integration in topographical studies is discussed.

Amino Acids↗