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PubMed2003

Does morality have a biological basis? An empirical test of the factors governing moral sentiments relating to incest.

Kin-recognition systems have been hypothesized to exist in humans, and adaptively to regulate altruism and incest avoidance among close genetic kin. This latter function allows the architecture of the kin recognition system to be mapped by quantitatively matching individual variation in opposition to incest to individual variation in developmental parameters, such as family structure and co-residence patterns. Methodological difficulties that appear when subjects are asked to disclose incestuous inclinations can be circumvented by measuring their opposition to incest in third parties, i.e. morality. This method allows a direct test of Westermarck's original hypothesis that childhood co-residence with an opposite-sex individual predicts the strength of moral sentiments regarding third-party sibling incest. Results support Westermarck's hypothesis and the model of kin recognition that it implies. Co-residence duration objectively predicts genetic relatedness, making it a reliable cue to kinship. Co-residence duration predicts the strength of opposition to incest, even after controlling for relatedness and even when co-residing individuals are genetically unrelated. This undercuts kin-recognition models requiring matching to self (through, for example, major histocompatibility complex or phenotypic markers). Subjects' beliefs about relatedness had no effect after controlling for co-residence, indicating that systems regulating kin-relevant behaviours are non-conscious, and calibrated by co-residence, not belief.

Adolescent↗
PubMed1980

Antigenic analysis of Pasteurella multocida (serotype 1) by crossed immunoelectrophoresis: characterization of cytoplasmic and cell envelope associated antigens.

The application of crossed immunoelectrophoresis to the analysis of a reference cytoplasm and cell envelope preparation from Pasteurella multocida serotype 1 revealed antigenic complexity not previously found. At least 55 cytoplasmic and 19 cell envelope antigens were clearly distinguished. Variation of anticytoplasm immunoglobulin concentration was a major determining factor in resolving the maximum array of cytoplasmic antigens. The use of intermediate gel modification of crossed immunoelectrophoresis permitted the recognition of antibodies in the preimmune rabbit serum against a number of cytoplasmic antigens and a single cell envelope antigen. This technique also demonstrated that reference cytoplasm obtained by 105,000 x g centrifugation of sonically disrupted pasteurellae and repeatedly washed reference cell envelope preparation contained antigens of either origin in amounts sufficient to elicit antibody responses in the host. Antisera to whole cells in the intermediate gel indicated that formalin killed P. multocida were capable of eliciting immune responses to both reference systems.

Animals↗
PubMed1984

Synthesis of a heme fragment of horse cytochrome c which forms a productive complex with a native apofragment.

To investigate the amino acid sequence of apocytochrome c recognized by yeast mitochondrial cytochrome c synthetase, a labeled apofragment containing residues 1 to 25 of horse cytochrome c, N alpha-[3H]acetyl-(1-25), and an analog containing glycine in place of cysteines 14 and 17, N alpha-[3H]acetyl-[14-Gly, 17-Gly] (1-25), have been synthesized using the Merrifield's improved solid phase method (Mitchell, A. R., Ericksen , B. W., Ryabtsev , M. N., Hodges , R. S., and Merrifield, R. B. (1976) J. Am. Chem. Soc. 98, 7357-7362) and then purified to homogeneity. Upon incubation with yeast mitochondria in the presence of hemin, a radioactive species, produced from N alpha-[3H]acetyl-(1-25) and not from N alpha-acetyl-[14-Gly, 17-Gly] (1-25), formed a complex with native apofragment (23-104). This semisynthetic complex was indistinguishable from the native complex in resistance to trypsin upon reduction with ascorbate and by ion-exchange chromatography. The radioactive species, dissociated from the complex was identical with native heme fragment N alpha-acetyl-(1-25)H by reverse-phase high pressure liquid chromatography. Treatment of this radioactive heme fragment with silver sulfate and then with dithiothreitol generated the original apofragment . Thus, if it is assumed that the mitochondrial enzyme catalyzing this covalent attachment of heme to synthetic apo-N alpha-[3H]acetyl-(1-25) is a cytochrome c synthetase, the results may be interpreted as indicating that the amino acid sequence of residues 1 to 25 of horse cytochrome c would contain the principal recognition site of the enzyme.

Amino Acid Sequence↗
PubMed2006

Organic anion recognition of naphthalenesulfonates by steroid-modified beta-cyclodextrins: enhanced molecular binding ability and molecular selectivity.

Two beta-cyclodextrin (beta-CD) derivatives bearing steroid groups (1 and 2) were synthesized by the condensation of mono(6-aminoethylamino-6-deoxy)-beta-CD with cholic acid and deoxycholic acid, respectively, and their original conformations and binding behavior to the organic anion of naphthalenesulfonate derivatives were investigated by using 1H NMR spectroscopy and spectrofluorometric titration in combination with computational methods. The 2D NMR experiments reveal that the steroid groups attached to the beta-CD rim could be deeply embedded in the beta-CD cavity to form the intramolecular (for 1) or intermolecular (for 2) inclusion complexes in aqueous solution. Upon complexation with naphthalenesulfonate derivatives, modified beta-CDs display two obviously different binding modes, that is, the competitive inclusion mode and the induced-fit inclusion mode, which is consistent with the results of molecular modeling study. The two modes and the strict size/shape fitting relationship between the hosts and guests reasonably explain the different binding behaviors and molecular selectivity of host beta-CDs 1 and 2 toward the naphthalenesulfonate guests. Therefore, the cholic acid- or deoxycholic acid-modified beta-CDs could effectively recognize the size/shape of guest molecules as compared with the parent beta-CD, giving good molecular selectivity up to 24.9 for the disodium 2,6-naphthalenedisulfonate/disodium 1,5-naphthalenedisulfonate pair by the host 1.

Anions↗
PubMed1986

Structure of the DNA-Eco RI endonuclease recognition complex at 3 A resolution.

The crystal structure of the complex between Eco RI endonuclease and the cognate oligonucleotide TCGCGAATTCGCG provides a detailed example of the structural basis of sequence-specific DNA-protein interactions. The structure was determined, to 3 A resolution, by the ISIR (iterative single isomorphous replacement) method with a platinum isomorphous derivative. The complex has twofold symmetry. Each subunit of the endonuclease is organized into an alpha/beta domain consisting a five-stranded beta sheet, alpha helices, and an extension, called the "arm," which wraps around the DNA. The large beta sheet consists of antiparallel and parallel motifs that form the foundations for the loops and alpha helices responsible for DNA strand scission and sequence-specific recognition, respectively. The DNA cleavage site is located in a cleft that binds the DNA backbone in the vicinity of the scissile bond. Sequence specificity is mediated by 12 hydrogen bonds originating from alpha helical recognition modules. Arg200 forms two hydrogen bonds with guanine while Glu144 and Arg145 form four hydrogen bonds to adjacent adenine residues. These interactions discriminate the Eco RI hexanucleotide GAATTC from all other hexanucleotides because any base substitution would require rupture of at least one of these hydrogen bonds.

Amino Acids↗
PubMed1989

Recognition of abnormal connections of coronary arteries with the use of Doppler color flow mapping.

Anomalous connection of a coronary artery to a ventricle or pulmonary artery causes shunting of blood from the coronary circuit and may produce myocardial ischemia. Such a coronary anomaly may occur in isolation or with other defects. Doppler color flow mapping and two-dimensional echocardiography were used to diagnose anomalous coronary connections in 13 patients, 1 day to 7 years of age, over a 1 year period. The diagnoses were anomalous origin of the left coronary artery from the pulmonary trunk in five patients, a coronary artery to left ventricle fistula or coronary artery to pulmonary artery fistula in four patients with other complex defects, right ventricular sinusoids in two patients with pulmonary atresia and intact ventricular septum and an isolated coronary artery fistula in two patients. In all cases, the abnormal coronary connection was recognized on the basis of an abnormal, continuous or to and fro flow pattern in the fistula and its connections as demonstrated by scanning in multiple views with Doppler color flow mapping. The low spatial resolution of Doppler color flow mapping limits the anatomic detail available; nonetheless, it is a significant advance in the noninvasive diagnosis of abnormal coronary connections.

Arterio-Arterial Fistula↗
PubMed2004

Antigen recognition properties of a Vgamma1.3Vdelta2-T-cell receptor from a rare variant of polymyositis.

Previously we partially characterized an autoreactive human Vgamma1.3Vdelta2-T-cell receptor (TCR) that had originally been identified in muscle of a patient with an unusual form of polymyositis. This TCR recognizes a muscle-associated auto-antigen in a CDR3-dependent, MHC non-restricted way. Here we show that this TCR also recognizes an antigen from Escherichia coli. Like the muscle-associated mammalian antigen, the bacterial antigen is recognized in a CDR3-dependent, but MHC-non-restricted way. Both antigens have strikingly similar molecular characteristics suggesting that their epitopes are at least very similar. The dissociation kinetics of the bacterial antigen-TCR complexes was investigated by surface plasmon resonance using soluble single-chain TCR molecules produced in COS-7 cells. The measured dissociation rate constant (k(off)=5.7 x 10(-3) s(-1)) shows that the complexes dissociate more slowly than most previously described antigen/alphabeta-TCR complexes, but much faster than antibody/antigen pairs. These results (a) provide further insight into the molecular properties of this unusual TCR, and (b) should help in future attempts to identify the elusive target antigen(s).

Animals↗
PubMed1991

Thermodynamic analysis of the equilibrium, association and dissociation of 2'GMP and 3'GMP with ribonuclease T1 at pH 5.3.

Fluorescence titrations and temperature-jump relaxation experiments were performed as a function of temperature on ribonuclease T1 with the inhibitors 2'GMP and 3'GMP to obtain information on the energetics and molecular events controlling the binding of those inhibitors. Results from the titration and temperature-jump experiments were in agreement concerning the equilibrium constant. The larger equilibrium constant for 2'GMP is enthalpic in origin and is due to both a higher on rate and a lower off rate as compared to 3'GMP. On rates for both inhibitors appear to be below the diffusion controlled limit, apparently due to conformational changes in the portion of the active site responsible for recognition of the guanine base. Comparison of the measured enthalpic and entropic terms associated with the equilibrium constant determined from the fluorescence titrations are in disagreement with those calculated from the on and off rates indicating the presence of an induced conformational change in the 2'GMP-enzyme complex. This second conformational change appears to be due to additional interactions between 2'GMP and the catalytic portion of the active site, which may also be responsible for the differences in the binding constant, the on rate and the off rate between 2'GMP and 3'GMP.

Binding Sites↗
PubMed2004

Primitive complement system--recognition and activation.

The complement system, composed of more than 30 serum and cell surface components, is collaborating in recognition and elimination of pathogens as a part of both the innate and acquired immune systems. The two collagenous lectins, mannose-binding lectin (MBL) and ficolins, are one of the pattern recognition molecules acting in innate immunity and upon recognition of the pathogens, they trigger the activation of the lectin complement pathway through attached serine proteases (MASPs). A similar lectin-base complement system, consisting of the lectin-protease complex and C3, is present in ascidians, our closest invertebrate relatives and functions in an opsonic manner. On the other hand, ongoing genome projects in both vertebrates and invertebrates revealed that most domains used by mammalian complement components are found in both protostomes and deuterostomes. However, the unique combinations of them as found in mammalian complement components are present only in deuterostomes, indicating the deuterostome origin of the complement system. Unexpectedly, the complement system of an invertebrate deuterostome, ascidian, shows a similar level of complexity as that of mammals, suggesting that expansion of complement genes by gene duplications occurred independently both in the ascidian and vertebrate lineages. Although most characteristic domain structures of the mammalian complement components are found in ascidians, detailed evolutionary analysis casts doubt on their mutual reactivity in several points. Thus, another integrative step seems to have been required to establish the modern complement system of higher vertebrates.

Animals↗
PubMed2005

A flexible docking procedure for the exploration of peptide binding selectivity to known structures and homology models of PDZ domains.

PDZ domains are important scaffolding modules that typically bind to the C-termini of their interaction partners. Several structures of such complexes have been solved, revealing a conserved binding site in the PDZ domain and an extended conformation of the bound peptide. A compendium of information regarding PDZ complexes demonstrates that dissimilar C-terminal peptides bind to the same PDZ domain, and different PDZ domains can bind the same peptides. A detailed understanding of the PDZ-peptide recognition is needed to elucidate this complexity. To this end, we have designed a family of docking protocols for PDZ domains (termed PDZ-DocScheme) that is based on simulated annealing molecular dynamics and rotamer optimization, and is applicable to the docking of long peptides (20-40 rotatable bonds) to both known PDZ structures and to the more complicated problem of homology models of these domains. The resulting protocol reproduces the structures of PDZ complexes with peptides 4-8 amino acids long within 1-2 A from the experimental structure when the docking is performed to the original structure. If the structure of the target PDZ domain is an apo structure or a homology model, the docking protocol yields structures within 3 A in 9 out of 12 test cases. The automated docking procedure PDZ-DocScheme can serve in the generation of a structural context for validation of PDZ domain specificity from mutagenesis and ligand binding data.

Models, Molecular↗
PubMed2001

How to unify knowledge. Keynote address.

The central question of general scholarship is whether all of knowledge is intrinsically consilient, that is, whether it can be united by a continuous skein of cause-and-effect explanation and across levels of increasingly complex organization. The answer lies in the recognition that the traditional line separating the great branches of learning (natural sciences, social sciences, and humanities) is not a barrier or even a line, but rather a broad domain of poorly explored material phenomena now being cooperatively entered from all sides. The key to bridge-building is the discovery and analysis of human nature, which consists of the epigenetic rules--the hereditary regularities in mental development. Their study is now well under way, at the biological, social science, and humanities levels. Examples of epigenetic rules include the origin of color vocabularies, incest avoidance, optimum arousal in artistic design, and response to the natural environment. The convergence of the great branches of learning is mostly an empirical process, light on formal logic and theory in its initial stages. The value of the consilience program is that at long last we appear to have acquired the means either to establish the intrinsic truth of the fundamental unity of knowledge, or to discard it. I will argue the likelihood of its existence and early establishment.

Behavior↗
PubMed1984

Macrophage procoagulants.

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Animals↗
PubMed1998

Attention-deficit/hyperactivity disorder: a life-span perspective.

There is increasing scientific recognition that attention-deficit/hyperactivity disorder (ADHD), a heterogeneous disorder that carries a high risk of comorbidity, continues past childhood and adolescence into adulthood in many cases and may be underidentified in girls. The etiology of ADHD is unknown, although evidence from family studies of ADHD suggests a genetic origin for some forms of this disorder. A variety of pharmacologic agents are available in treating ADHD: stimulant medications remain the first-line treatment for noncomorbid ADHD, whereas tricyclic antidepressants and bupropion are recommended for stimulant nonresponders and patients with more than one psychiatric disorder. Complex cases of ADHD, however, may require rational use of combined pharmacotherapy.

Adolescent↗
PubMed1998

Structural origins of gentamicin antibiotic action.

Aminoglycoside antibiotics that bind to the ribosomal A site cause misreading of the genetic code and inhibit translocation. The clinically important aminoglycoside, gentamicin C, is a mixture of three components. Binding of each gentamicin component to the ribosome and to a model RNA oligonucleotide was studied biochemically and the structure of the RNA complexed to gentamicin C1a was solved using magnetic resonance nuclear spectroscopy. Gentamicin C1a binds in the major groove of the RNA. Rings I and II of gentamicin direct specific RNA-drug interactions. Ring III of gentamicin, which distinguishes this subclass of aminoglycosides, also directs specific RNA interactions with conserved base pairs. The structure leads to a general model for specific ribosome recognition by aminoglycoside antibiotics and a possible mechanism for translational inhibition and miscoding. This study provides a structural rationale for chemical synthesis of novel aminoglycosides.

Anti-Bacterial Agents↗
PubMed1997

Antigen recognition characteristics and comparative performance in immunoaffinity purification of two monoclonal antibodies specific for the hepatitis B virus surface antigen.

In this paper we describe the antigen recognition characteristics, variable region base and amino acid sequence, and performance as immunoaffinity chromatography ligands of two MAb specific to the alpha determinant of the HBsAg, derived from the same fusion. We show that the epitope recognized by CB-Hep.0 (IgM) is probably associated to an intrachain disulfide bond in the antigen. On the other hand, CB-Hep.1 (IgG2b) recognizes a heat-resistant non-conformation dependent antigenic determinant on HBsAg. PCR-cloning and sequencing of the variable regions of these two MAb indicated that both heavy chain variable regions were originated from the usage of the same germinal V and J genes. However, the outstanding differences in the size of the VH CDR3, and the absolute difference in the light chain sequences, suggest that the hybridomas were originated from different precursor B lymphocytes. With respect to their use as immunoaffinity chromatography ligands for the purification of a recombinant HBsAg, we found that the IgM immunogel exhibited increased performance with respect to amount of eluted antigen, and final recovery. This difference in overall performance could be attributed to a series of factors: the higher valence number of IgM, a dissimilar distribution of IgM and IgG in the activated gel particles, and differences in antigen recognition between both MAb. Our results suggest that IgM antibodies may be useful in immunopurification, particularly if the antigen is structurally complex and has a high density of repeating epitopes.

Amino Acid Sequence↗
PubMed2006

The receptor concept: pharmacology's big idea.

Chemical signalling is the main mechanism by which biological function is controlled at all levels, from the single cell to the whole organism. Chemical recognition is the function of receptors, which, in addition to recognising endogenous chemical signals, are also the target of many important experimental and therapeutic drugs. Receptors, therefore, lie at the heart of pharmacology. This article describes the way in which the receptor concept originated early in the 20th century, and evolved through a highly innovative stage of quantitative theory based on chemical kinetics, to the point where receptors were first isolated and later cloned, until we now have a virtually complete catalogue of all the receptors present in the genome. Studies on signal transduction are revealing great complexity in the events linking ligand binding to the physiological or therapeutic response. Though some simple quantitative rules of 'receptor theory' are still useful, the current emphasis is on unravelling the pathways that link receptors to responses, and it will be some time before we know enough about them to embark on the next phase of 'receptor theory'.

Animals↗
PubMed2003

Divergent evolutions of trinucleotide polymerization revealed by an archaeal CCA-adding enzyme structure.

CCA-adding enzyme [ATP(CTP):tRNA nucleotidyltransferase], a template-independent RNA polymerase, adds the defined 'cytidine-cytidine-adenosine' sequence onto the 3' end of tRNA. The archaeal CCA-adding enzyme (class I) and eubacterial/eukaryotic CCA-adding enzyme (class II) show little amino acid sequence homology, but catalyze the same reaction in a defined fashion. Here, we present the crystal structures of the class I archaeal CCA-adding enzyme from Archaeoglobus fulgidus, and its complexes with CTP and ATP at 2.0, 2.0 and 2.7 A resolutions, respectively. The geometry of the catalytic carboxylates and the relative positions of CTP and ATP to a single catalytic site are well conserved in both classes of CCA-adding enzymes, whereas the overall architectures, except for the catalytic core, of the class I and class II CCA-adding enzymes are fundamentally different. Furthermore, the recognition mechanisms of substrate nucleotides and tRNA molecules are distinct between these two classes, suggesting that the catalytic domains of class I and class II enzymes share a common origin, and distinct substrate recognition domains have been appended to form the two presently divergent classes.

Adenosine Triphosphate↗
PubMed2006

Perception of complex sounds in budgerigars (Melopsittacus undulatus) with temporary hearing loss.

Songbirds and parrots deafened as nestlings fail to develop normal vocalizations, while birds deafened as adults show a gradual deterioration in the quality and precision of vocal production. Beyond this, little is known about the effect of hearing loss on the perception of vocalizations. Here, we induced temporary hearing loss in budgerigars with kanamycin and tested several aspects of the hearing, including the perception of complex, species-specific vocalizations. The ability of these birds to discriminate among acoustically distinct vocalizations was not impaired but the ability to make fine-grain discriminations among acoustically similar vocalizations was affected, even weeks after the basilar papilla had been repopulated with new hair cells. Interestingly, these birds were initially unable to recognize previously familiar contact calls in a classification task-suggesting that previously familiar vocalizations sounded unfamiliar with new hair cells. Eventually, in spite of slightly elevated absolute thresholds, the performance of birds on discrimination and perceptual recognition of vocalizations tasks returned to original levels. Thus, even though vocalizations may initially sound different with new hair cells, there are only minimal long-term effects of temporary hearing loss on auditory perception, recognition of species-specific vocalizations, or other aspects of acoustic communication in these birds.

Animals↗