The mechanism of setting the common rhythm of the pacemaker pair in the sinoatrial node

Principal physiological hypotheses concerning the setting of united rhythm in the heart sinoatrial node (SAN) are considered. A mathematical model of SAN is proposed which takes into account properties of individual elementary pacemakers and their interaction. Assuming paired interaction of the pacemakers there are revealed the main P.D. parameters, affecting the setting of the united rhythm. Quantitative expressions are obtained for the united rhythm period, delay and propagation velocity of the excitation. The calculated data are compared with the experimental ones. The hypothesis concerning the setting of the united rhythm as a result of the interaction of SAN pacemakers is confirmed.     

Gene-environment interaction effects on behavioral variation and risk of complex disorders: the example of alcoholism and other psychiatric disorders.

There have been few replicated examples of genotype x environment interaction effects on behavioral variation or risk of psychiatric disorder. We review some of the factors that have made detection of genotype x environment interaction effects difficult, and show how genotype x shared environment interaction (GxSE) effects are commonly confounded with genetic parameters in data from twin pairs reared together. Historic data on twin pairs reared apart can in principle be used to estimate such GxSE effects, but have rarely been used for this purpose. We illustrate this using previously published data from the Swedish Adoption Twin Study of Aging (SATSA), which suggest that GxSE effects could account for as much as 25% of the total variance in risk of becoming a regular smoker. Since few separated twin pairs will be available for study in the future, we also consider methods for modifying variance components linkage analysis to allow for environmental interactions with linked loci.     

Protein interaction: same network, different hubs

Recently, large-scale experiments have provided new insights into the complex protein interaction network in yeast. However, previous analyses have shown that the number of interacting pairs that are common to different methods is extremely low and, therefore, less informative than expected. In this article, we show that comparing the connectivities of individual proteins can reveal that a common tendency between methods has been missed by the pairwise comparison of interactions. We found significant correlations between experimental methods and also between various in silico methods. Exceptionally, a computational method, gene neighbourhood, correlates with both in silico and experimental approaches.     

Electrophysiology of the circadian pacemaker in mammals

The neurons of the mammalian suprachiasmatic nuclei (SCN) control circadian rhythms in molecular, physiological, endocrine, and behavioral functions. In the SCN, circadian rhythms are generated at the level of individual neurons. The last decade has provided a wealth of information on the genetic basis for circadian rhythm generation. In comparison, a modest but growing number of studies have investigated how the molecular rhythm is translated into neuronal function. Neuronal attributes have been measured at the cellular and tissue level with a variety of electrophysiological techniques. We have summarized electrophysiological research on neurons that constitute the SCN in an attempt to provide a comprehensive view on the current state of the art.     

Specificity in the genetic code. The role of nucleotide base-amino acid interaction

The mechanism of the unique and specific association of a given amino acid to its t-RNA is investigated by theoretical methods. Several possible schemes are proposed to explain specificity. The physical forces which act within these mechanisms are illustrated by the computer simulation of probable interactions between glycine and nucleotide bases and base pairs. It is demonstrated that glycine has direct and selective affinities for the nucleotide bases and that these interactions are principally determined by the polar groups. Energies have been calculated for the interaction of glycine with several base pairs. From these, the possibility that specificity arises through direct complexing of an amino acid with its anticodon is evaluated.     

Conduction barriers and pathways of the sinoatrial pacemaker complex: their role in normal rhythm and atrial arrhythmias

Since Keith and Flack's anatomical discovery of the sinoatrial node (SAN), the primary pacemaker of the heart, the question of how such a small SAN structure can pace the entire heart has remained for a large part unanswered. Recent advances in optical mapping technology have made it possible to unambiguously resolve the origin of excitation and conduction within the animal and human SAN. The combination of high-resolution optical mapping and histological structural analysis reveals that the canine and human SANs are functionally insulated from the surrounding atrial myocardium, except for several critical conduction pathways. Indeed, the SAN as a leading pacemaker requires anatomical (fibrosis, fat, and blood vessels) and/or functional barriers (paucity of connexins) to protect it from the hyperpolarizing influence of the surrounding atrium. The presence of conduction barriers and pathways may help explain how a small cluster of pacemaker cells in the SAN pacemaker complex manages to depolarize different, widely distributed areas of the right atria as evidenced functionally by exit points and breakthroughs. The autonomic nervous system and humoral factors can further regulate conduction through these pathways, affecting pacemaker automaticity and ultimately heart rate. Moreover, the conduction barriers and multiple pathways can form substrates for reentrant activity and thus lead to atrial flutter and fibrillation. This review aims to provide new insight into the function of the SAN pacemaker complex and the interaction between the atrial pacemakers and the surrounding atrial myocardium not only in animal models but also human hearts.     

The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer

Germline mutations in two human mismatch repair (MMR) genes, hMSH2 and hMLH1, appear to account for approximately 70% of the common cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Although the hMLH1 protein has been found to copurify with another MMR protein hPMS2 as a heterodimer, their function in MMR is unknown. In this study, we have identified the physical interaction regions of both hMLH1 with hPMS2. We then examined the effects of hMLH1 missense alterations found in HNPCC kindreds for their interaction with hPMS2. Four of these missense alterations (L574P, K616Delta, R659P, and A681T) displayed >95% reduction in binding to hPMS2. Two additional missense alterations (K618A and K618T) displayed a >85% reduction in binding to hPMS2, whereas three missense alterations (S44F, V506A, and E578G) displayed 25-65% reduction in binding to hPMS2. Interestingly, two HNPCC missense alterations (Q542L and L582V) contained within the consensus interaction region displayed no effect on interaction with hPMS2, suggesting that they may affect other functions of hMLH1. These data confirm that functional deficiencies in the interaction of hMLH1 with hPMS2 are associated with HNPCC as well as suggest that other unknown functional alteration of the human MutL homologues may lead to tumorigenesis in HNPCC kindreds.     

The geometries of interacting arginine-carboxyls in proteins

The geometries are reported for interacting arginine-carboxyl pairs obtained from 37 high resolution protein structures solved to a resolution of 2.0 A or better. The closest interatomic distance between the guanidinium and carboxyl is less than 4.2 A for 74 arginine and carboxyl groups, with the majority of these lying within hydrogen-bonding distance (2.6-3.0 A). Interacting pairs have been transformed into a common orientation, and arginine-carboxyl, and carboxyl-arginine geometries have been calculated. This has been defined in terms of the spherical polar angles T theta, T phi, and the angle P, between the guanidinium and carboxyl planes. Results show a clear preference for the guanidinium and carboxyl groups to be approximately coplanar, and for the carboxyl oxygens to hydrogen bond with the guanidinium nitrogens. Single nitrogen-single oxygen is the most common type of interaction, however twin nitrogen-twin oxygen interactions also occur frequently. The majority of these occur between the carboxyl oxygens and the NH1 and NE atoms of the arginine, and are only rarely observed for NH1 and NH2. The information presented may be of use in the modelling of arginine-carboxyl interactions within proteins.     

Functional and physical interaction between WRN helicase and human replication protein A.

The human premature aging disorder Werner syndrome (WS) is associated with a large number of symptoms displayed in normal aging. The WRN gene product, a DNA helicase, has been previously shown to unwind short DNA duplexes (相似文献   

NMR studies of the interaction of bleomycin with (dC-dG)3.

The interaction of bleomycin A2 and Zn(II)-bleomycin A2 with the oligonucleotide (dC-dG)3 has been monitored by nuclear magnetic resonance spectroscopy. Binding of the drug to the oligonucleotide is indicated by an upfield shift of the bithiazole proton resonances consistent with partial intercalation of this group between base pairs. The effect of temperature and ionic strength on the binding of both free bleomycin and the Zn(II) complex has been studied. Consistent with earlier studies on polynucleotides, the rate of exchange between the free drug and the drug-oligonucleotide complex is rapid on the 1H NMR chemical shift time scale. Binding of the oligonucleotide induced changes in resonances assigned to protons in the metal-binding region of Zn(II)-bleomycin. Intermolecular nuclear Overhauser effect enhancements between bleomycin and the oligonucleotide have not been detected.     

Correlated sequence-signatures as markers of protein-protein interaction

As protein-protein interaction is intrinsic to most cellular processes, the ability to predict which proteins in the cell interact can aid significantly in identifying the function of newly discovered proteins, and in understanding the molecular networks they participate in. Here we demonstrate that characteristic pairs of sequence-signatures can be learned from a database of experimentally determined interacting proteins, where one protein contains the one sequence-signature and its interacting partner contains the other sequence-signature. The sequence-signatures that recur in concert in various pairs of interacting proteins are termed correlated sequence-signatures, and it is proposed that they can be used for predicting putative pairs of interacting partners in the cell. We demonstrate the potential of this approach on a comprehensive database of experimentally determined pairs of interacting proteins in the yeast Saccharomyces cerevisiae. The proteins in this database have been characterized by their sequence-signatures, as defined by the InterPro classification. A statistical analysis performed on all possible combinations of sequence-signature pairs has identified those pairs that are over-represented in the database of yeast interacting proteins. It is demonstrated how the use of the correlated sequence-signatures as identifiers of interacting proteins can reduce significantly the search space, and enable directed experimental interaction screens.     

Mouse models for studying pacemaker channel function and sinus node arrhythmia

Pacemaker activity of the heart is generated by a small group of cells forming the sinoatrial node (SAN). Cells of the SAN are spontaneously active and generate action potentials with remarkable regularity and stability under all physiological conditions. The exact molecular mechanisms underlying pacemaker potentials in the SAN have not yet been fully elucidated. Several voltage-dependent ion channels as well as intracellular calcium cycling processes are thought to contribute to the pacemaker activity. Hyperpolarization-activated cation channels, which generate the I_f current, have biophysical properties which seem ideally suited for the initiation of spontaneous electrical activity. This review describes recent work on several transgenic mice lacking different cardiac HCN channel subtypes. The role of I_f for normal pacemaking and sinus node arrhythmia as revealed by these genetic models will be discussed. In addition, a new mouse line is described which enables gene targeting in a temporally-controlled manner selectively in SAN cells. Elucidating the function of HCN and other ion channels in well-controlled mouse models should ultimately lead to a better understanding of the mechanisms underlying human sinoatrial arrhythmias.     

The interaction between subunits in the tubulin dimer.

Limited proteolysis and chemical cross-linking techniques have been used to study the interaction between alpha- and beta-tubulin subunits. Trypsin digestion of tubulin dimer resulted in the cleavage of the alpha-subunit into two fragments, whereas chymotrypsin cleaved the beta-subunit into two distinct fragments. All of these fragments have been mapped on the tubulin subunits by further proteolysis with formic acid. Cross-linking of trypsin- and chymotrypsin-cleaved subunits has been performed with two different cross-linker agents of different cross-linking distance. The addition of formaldehyde resulted in the cross-linking of the alpha-tubulin N-terminal fragment with beta-tubulin C-terminal domain. The same result was obtained when methyl 4-mercaptobutyrimidate was used.     

A specific area of the compound eye in the cricket Gryllus bimaculatus sends photic information to the circadian pacemaker in the contralateral optic lobe

The circadian locomotor rhythm of the cricket Gryllus bimaculatus is primarily regulated by a pair of interacting optic lobe circadian pacemaker systems. The interaction involves phase-dependent modulation of the free-running period and phase-dependent suppression of activity. Since photic information has been shown to be involved in the interaction, we examined the regional difference in photoreception for the interaction within cricket compound eyes. The activity rhythm of animals receiving partial reduction of one compound eye combined with severance of the contralateral optic nerve split into entrained and free-running components under a 13-h light to 13-h dark cycle. All the animals operated on showed a phase-dependent suppression of activity, and most animals showed a phase-dependent modulation of the period of the free-running component. However, removal of the dorsocaudal area of the compound eye resulted in a severe reduction of the amplitude of the phase-dependent-period modulation. These results suggest that the dorsocaudal portion of the compound eye is a specific region receiving photic signals that are transmitted to the circadian pacemaker in the contralateral optic lobe and that the phase-dependent suppression of activity is caused by a mechanism separate from that for the period modulation.     

The development of the conduction system in the mouse embryo heart: III. The development of sinus muscle and sinoatrial node

The origin and development of the sinus musculature, and the sinoatrial node (SAN), were studied in mouse embryo heart from the 8th day postcoitum (dpc) to the neonate. In the medial wall of the right common cardinal vein (RCCV), the muscle cells clearly derive from the splanchnic epithelium, whereas in the dorsolateral wall of the sinus horns, the loose mesenchymal cells appear to transform into the early sinus muscle. The early sinus muscle is particularly voluminous around the right venous valve (RVV). The 9-dpc heart shows regular contractions, but a morphologically definable SAN is not seen until 11 dpc, located in the medioanterior wall of the RCCV. There is indication that the loose mesenchymal cells play a role in the development of the nodal fibers. The SAN and the atrioventricular conduction system (AVCS) develop simultaneously in the 11-to 12-dpc mouse embryo heart. In the medioanterior wall of the left common cardinal vein (LCCV), a transient node-like structure was found. This, however, integrates into the left atrial wall in the 13-dpc and older embryos. Growth and early differentiation of the sinus muscle proceed distally during embryonic life to the point where it is indistinguishable from the atrial musculature.     

Theoretical studies on the interaction of proteins and nucleic acids. I. The binding of beta-pleated sheets to A- and B-DNA

A theoretical investigation of the interaction between a beta-ribbon consisting of two glycine hexapeptides and DNA in its A and B conformations is presented. A refined semi-empirical energy formula and a sophisticated energy minimization technique are used to optimize the complex, taking into account the DNA-beta-ribbon interaction, the full flexibility of the oligopeptide chains and of the positions of the DNA screening counterions. A considerable flexibility of the beta-ribbon is demonstrated, which allows the polypeptide fragment to interact comfortably with both forms of DNA considered and with different base-pair sequences. The results are discussed in connection with the general problem of DNA-protein recognition.