25-year development of the theory of functional systems at P K Anokhin Institute of Normal Physiology and the Department of Normal Physiology of I M Sechenov Moscow Medical Academy

New trends in the development of the theory of functional systems proposed by P.K. Anokhin in the scientific complex P.K. Anokhin Institute--Department of Normal Physiology during the last twenty five years are regarded. It has been shown that the functional systems represent an objective reality. Holographic and informational properties of the functional systems and general principles of their interrelations in the whole organism i.e. hierarchic domination, multiparametric and successive interaction have been disclosed. Some notions about "systemo-quanta" of vital activity as discrete units of dynamic activity of functional systems have been formulated. Further developments in the systemogenesis of behavioral acts also are presented. New ideas about pacemaker mechanism of dominant biological motivations, the role of oligopeptides in the system organization of behavioral acts have been formulated. The role of early genes in formation of behavioral reactions of animals and in the mechanisms of emotional stress is shown. The role of some oligopeptides in the mechanisms of resistance to emotional stress is stated. Some devices modeling the properties of functional systems and able to assess different organism's functional systems have been developed. Practical application of the theory of functional systems is also shown in the paper.     

Self-organizing proto-replicators and the origin of life

Standard theories suggest that the first informational replicator involved RNA molecules (or a more primitive analogue) and that a preliminary step for the development of such replicating systems may have been the emergence of subunits capable of forming chains and interchain pairings. Following these hypotheses, this discussion describes various abstract simulations designed to investigate the structures resulting from such interactions for generalised subunits. Three classes of pairing strategy were considered for a range of subunit concentrations. The resulting dynamic self-organization of the systems produced high levels of structural complexity (some at low subunit concentrations and in the presence of disruptive subunits) and a significantly increased percentage of complementary base pairing (particularly in the more substantial structures). These properties of the systems, which did not require pre-existing replicators, templates or functional catalysts, were shown to be sensitive to the form of pairing strategy, subunit concentrations and various conditions that could theoretically be altered by products of the systems. Though no systems behaved as a replicator, some possessed collections of properties from which a replicating system might theoretically be constructed without requiring the introduction of additional classes of properties. The implications of such systems were considered with respect to the origin of life.     

Acceptor of action results as a structural functional basis of dynamic stereotype activities of the brain

The system mechanisms of brain dynamic stereotypes formation are considered. The brain dynamic stereotypes are shown to be formed on the structures of acceptor of action results by dominating motivations and reinforcements. Acceptors of action results are widely spread in brain structures. They are presented in functional systems which form behavioral acts of animals with spreading neural excitations in collaterals of axons of pyramidal tract. Reinforcing excitations form specific architectonic of acceptors of action results, which include brain structures corresponding to modalities of parameters of reinforcements. Dominating motivations, which predict future events, excite molecular engrams of action results which were formed by previous reinforcements.     

Correlation between the functional status of brain structures and the degree of coherence of their potentials during food-getting behavior in the dog

By means of the cited formula, integral indices of potential coherence of the following pairs of brain structures were calculated: hippocampus--frontal cortex, amygdala--frontal cortex, hippocampus--amygdala. In food-procuring behavior of dogs, the values of these indices increase simultaneously with the increase of the level of functional state of the brain structures. The values become higher under the action of a signal with a greater informational significance for alimentary need satisfaction than under the action of a signal with lesser informational significance.     

Inverted micellar structures in bilayer membranes. Formation rates and half-lives.

Two sorts of inverted micellar structures have previously been proposed to explain morphological and 31P-NMR observations of bilayer systems. These structures only form in systems with components that can adopt the inverse hexagonal (HII) phase. LIP (lipidic particles) are intrabilayer structures, whereas IMI (inverted micellar intermediates) are structures that form between apposed bilayers. Here, we calculate the formation rates and half-lives of these structures to determine which (or if either) of these proposed structures is a likely explanation of the data. Calculations for the egg phosphatidylethanolamine and the Ca+-cardiolipin systems show that IMI form orders of magnitude faster than LIP, which should form slowly, if at all. This result is probably true in general, and indicates that "lipidic particle" electron micrograph images probably represent interbilayer structures, as some have previously proposed. It is shown here that IMI are likely intermediates in the lamellar----HII phase transitions and in the process of membrane fusion in some systems. The calculated formation rates, half-lives, and vesicle-vesicle fusion rates are in agreement with this observation.     

A novel member of the protein disulfide oxidoreductase family from Aeropyrum pernix K1: structure, function and electrostatics

The formation of disulfide bonds between cysteine residues is a rate-limiting step in protein folding. To control this oxidative process, different organisms have developed different systems. In bacteria, disulfide bond formation is assisted by the Dsb protein family; in eukarya, disulfide bond formation and rearrangement are catalyzed by PDI. In thermophilic organisms, a potential key role in disulfide bond formation has recently been ascribed to a new cytosolic Protein Disulphide Oxidoreductase family whose members have a molecular mass of about 26 kDa and are characterized by two thioredoxin folds comprising a CXXC active site motif each. Here we report on the functional and structural characterization of ApPDO, a new member of this family, which was isolated from the archaeon Aeropyrum pernix K1. Functional studies have revealed that ApPDO can catalyze the reduction, oxidation and isomerization of disulfide bridges. Structural studies have shown that this protein has two CXXC active sites with fairly similar geometrical parameters typical of a stable conformation. Finally, a theoretical calculation of the cysteine pK(a) values has suggested that the two active sites have similar functional properties and each of them can impart activity to the enzyme. Our results are evidence of functional similarity between the members of the Protein Disulphide Oxidoreductase family and the eukaryotic enzyme PDI. However, as the different three-dimensional features of these two biological systems strongly suggest significantly different mechanisms of action, further experimental studies will be needed to make clear how different three-dimensional structures can result in systems with similar functional behavior.     

A computational model of action selection in the basal ganglia. II. Analysis and simulation of behaviour

 In a companion paper a new functional architecture was proposed for the basal ganglia based on the premise that these brain structures play a central role in behavioural action selection. The current paper quantitatively describes the properties of the model using analysis and simulation. The decomposition of the basal ganglia into selection and control pathways is supported in several ways. First, several elegant features are exposed – capacity scaling, enhanced selectivity and synergistic dopamine modulation – which might be expected to exist in a well designed action selection mechanism. The discovery of these features also lends support to the computational premise of selection that underpins our model. Second, good matches between model globus pallidus external segment output and globus pallidus internal segment and substantia nigra reticulata area output, and neurophysiological data, have been found which are indicative of common architectural features in the model and biological basal ganglia. Third, the behaviour of the model as a signal selection mechanism has parallels with some kinds of action selection observed in animals under various levels of dopaminergic modulation. Received: 16 July 2000 / Accepted in revised form: 30 October 2000     

Information transfer from peptide nucleic acids to RNA by template-directed syntheses.

Peptide nucleic acids (PNAs) are uncharged analogs of DNA and RNA in which the ribose-phosphate backbone is substituted by a backbone held together by amide bonds. PNAs are interesting as models of alternative genetic systems because they form potentially informational base paired helical structures. A PNA C10 oligomer has been shown to act as template for efficient formation of oligoguanylates from activated guanosine ribonucleotides. In a previous paper we used heterosequences of DNA as templates in sequence-dependent polymerization of PNA dimers. In this paper we show that information can be transferred from PNA to RNA. We describe the reactions of activated mononucleotides on heterosequences of PNA. Adenylic, cytidylic and guanylic acids were incorporated into the products opposite their complement on PNA, although less efficiently than on DNA templates.     

In silico evolution of functional modules in biochemical networks

Understanding the large reaction networks found in biological systems is a daunting task. One approach is to divide a network into more manageable smaller modules, thus simplifying the problem. This is a common strategy used in engineering. However, the process of identifying biological modules is still in its infancy and very little is understood about the range and capabilities of motif structures found in biological modules. In order to delineate these modules, a library of functional motifs has been generated via in silico evolution techniques. On the basis of their functional forms, networks were evolved from four broad areas: oscillators, bistable switches, homeostatic systems and frequency filters. Some of these motifs were constructed from simple mass action kinetics, others were based on Michaelis-Menten kinetics as found in protein/protein networks and the remainder were based on Hill equations as found in gene/protein interaction networks. The purpose of the study is to explore the capabilities of different network architectures and the rich variety of functional forms that can be generated. Ultimately, the library may be used to delineate functional motifs in real biological networks.     

Fragments of Functional Proteins: Role in Endocrine Regulation

Systematic analysis of structures, localization, formation and biological activities of endogenous peptides derived from functional proteins, such as hemoglobin, myelin basic protein, immunoglobulins, etc., allowed establishing the basic features of that group of compounds. The sets of these peptides in mammalian tissues, or tissue-specific peptide pools are: (i) tissue specific; (ii) stable at normal conditions; (iii) conservative in the same tissues of different mammalian species; (iv) dependent on the general state of homeostasis of tissue or the whole organism. Formation of such peptides has features of both conformation and site specificity and also involves the action of carboxy- and amino-peptidases. As a result, the families of structurally related families of peptides are generated. The fragments of functional proteins exhibit a wide range of the biological effects, characteristic both for hormones and parahormones, from hormone-releasing to growth-regulatory activity. At the same time, the molecular mechanisms of action of the majority of such peptides are unknown. On the basis of the data obtained the components of tissue-specific peptide pools are considered to form a novel regulatory system, complementary to other peptidergic systems such as hormonal, nervous, immune, etc. The biological role of the fragments of functional proteins in vivo and the patterns of interaction with other regulatory systems are suggested.     

Passive competition between pairs of self-ordering proto-replicators and the effect of primitive membranes

Self-ordering proto-replicators provide an abstract, simulation based investigation of a possible intermediary step in the development of informational replicators. They involve the dynamic self-ordering of generalised subunits of at least two types into coherent and mobile structures, and do not require the pre-existence of templates, replicators or functional catalysts. The following discussion naturally extends this approach to include pairs of such systems linked via a probabilistic, inter-system movement of structures. Initially for two specific forms of self-ordering proto-replicator, various types of probabilistic movement were studied, both with and without a simple model of a primitive membrane. Then for a specific probabilistic movement, which was again considered with and without membranes, different pairings of twelve forms of self-ordering proto-replicators were studied. The results show that the systems exhibited a form of passive competition for subunits and that this produced a new level of multi-system self-ordering that depended upon the relative self-ordering capabilities of the individual systems. This effect was also found to be significantly more pronounced for those systems that included the primitive membranes. The implications for the origins of life were then considered.     

Propofol, a general anesthetic, promotes the formation of fluid phase domains in model membranes

The molecular site of anesthetic action remains an area of intense research interest. It is not clear whether general anesthetics act through direct binding to proteins or by perturbing the membrane properties of excitable tissues. Several studies indicate that anesthetics affect the properties of either membrane lipids or proteins. However, gaps remain in our understanding of the molecular mechanism of anesthetic action. Recent developments in membrane biology have led to the concept of small-scale domain structures in lipid and lipid--protein coupled systems. The role of such domain structures in anesthetic action has not been studied in detail. In the present study, we investigated the effect of anesthetics on lipid domain structures in model membranes using the fluorescent spectral properties of Laurdan (6-dodecanoyl-2-dimethylamino naphthalene). Propofol, a general anesthetic, promoted the formation of fluid domains in model membranes of dipalmitoyl phosphatidyl choline (DPPC) or mixtures of lipids of varying acyl chains (DPPC:DMPC dimyristoyl phosphatidyl choline 1:1). The estimated size of these domains is 20--50 A. Based on these studies, we speculate that the mechanism of anesthetic action may involve effects on protein--lipid coupled systems through alterations in small-scale lipid domain structures.     

Adaptation as a manifestation of informational connections in living systems

The problem of adaptation of living systems in terms of the concept of informational communications is considered. The informational communication means the qualitative evaluation of information and determines correspondence of living systems to concrete conditions of life during interaction of these living systems to the source of the information. The system of the wholeorganism regulatory chemical communication is the main functional basis for the informational communication. Due to it, the transformation of the information signal in biological systems is performed, which results in their adequate response according to this information. The existence of living systems and their adaptation are determined by peculiarities of functioning of elements of their regulatory systems according to the character of the informational communication.     

An experimental basis for carcinogenic effects of ultraviolet radiation

Several hypotheses to explain ultraviolet carcinogenesis have been advanced. One such theory contended that cholesterol was directly involved in actinic carcinogenesis. Although the hypothesis, in its original form, was generally abandoned by the scientific community, it has been revived and modified from time to time as structures and functions of steroid hormones become more clearly understood. In essence it suggests that carcinogenic substances, structurally related to steroid hormones might result from photochemical conversion of cholesterol. Although some compounds with such properties have been isolated under controlled chemical conditions, until recently the failure to find such compounds in biological systems had cast serious doubt upon the validity of this hypothesis. It has now been demonstrated that cholesterol-derived oxidation products are formed in human skin upon exposure to ultraviolet light. One of the products formed is known to possess carcinogenic properties when administered to experimental animals. Furthermore, it has been reported by other investigators that the control mechanism for cholesterol synthesis is absent in liver tumors. Whether this biochemical lesion plays a causal role in the etiology of this disease is unknown but altered cholesterol metabolism has also been implicated in actinically induced skin cancer. It has been demonstrated in this laboratory that skin sterol synthesis is inhibited by light. The principal site of action of light on sterol synthesis appears to be prior to the formation of acetyl coenzyme A in the biosynthetic pathway. Sterol-derived photoproducts produce similar effects as light upon sterol synthesis. These observations suggest more than just a coincidental role of light upon sterols and sterol metabolism in the etiology of skin cancer. Lunar Science Institute Contribution.     

The functional state of children from 9 to 10 years of age under the conditions of intense informational load and physical working capacity

Three-way ANOVA has shown that the functional state (FS) of children from 9 to 10 years of age (n = 91) under intense informational load is significantly influenced by the aerobic and anaerobic components of physical working capacity and their interaction. It has been found that 4 to 21% of the total variation of the studied FS indices are related to the bioenergetic resources of the body. It has been shown that the high levels of development of the aerobic and anaerobic glycolytic capacities are associated with the optimal changes in the FS under the conditions of intense informational load. At the same time, the interaction of the aerobic and anaerobic glycolytic components of physical working capacity exerts the most significant influence on the productivity and “psychophysiological cost” of intellectual activity. The high anaerobic glycolytic and anaerobic alactate capacities proved to have opposite functional effects. The former contribute to a decrease in excessive autonomic reactivity under the conditions of intense work and diminution of trait anxiety; the latter, on the contrary, determine hypermobilization of the system of autonomic support of activity. The results suggest that a combined use of rational proportions of physical loads of the aerobic, anaerobic glycolytic, and anaerobic alactate types will provide efficient control of children’s FS under the conditions of intense intellectual activity.     

Redox regulation of cellular processes: A biophysical model and experiment

A model for the redox regulation of the functional state of the cell has been constructed on the basis of representation of electron transfer processes by equivalent electric circuits. The mechanism of action of redox-active molecules on biosystems has been discussed in terms of circuit theory. A method for determining the parameters of cellular redox sensors has been proposed. It has been established that the concentration and redox potential of compounds entering the cell are the main regulatory parameters of redox signals for the cell. It has been experimentally shown that the calcium response to hydrogen peroxide in rat C6 glioma cells and human FL amnion cells depends on the redox-buffer capacity of cells.     

The informational concept of searching for periodicity in symbol sequences

Method of informational decomposition has been developed, allowing one to reveal hidden periodicity in any symbol sequences. The informational decomposition is calculated without conversion of a symbol sequence into the numerical one, which facilitates finding periodicities in a symbol sequence. The method permits introducing an analog of the autocorrelation function of a symbol sequence. The method developed by us has been applied to reveal hidden periodicities in nucleotide and amino acid sequences, as well as in different poetical texts. Hidden periodicity has been detected in various genes, testifying to their quantum structure. The functional and structural role of hidden periodicity is discussed.