A relational theory of biological systems

The relational phenomena exhibited by metabolizing systems may be considered as special cases of those exhibited by a more general class of systems. This class is specified, and some of tis properties developed. An attempt is then made to apply these properties to a theory of metabolism by suitable specialization. A number of biologically significant theorems are obtained which apply directly to the theory of the free-living single cell. Among the results obtained are the following: On the basis of our model, there must always exist a component of the system which cannot be replaced or repaired by the system in the event of its inhibition or destruction. Under certain conditions, a metabolizing system possesses a component the inhibition of which will completely terminate the metabolic activity of the system. Furthermore a number of other diverse phenomena, such as the effects of a deficient environment, encystment phenomena, and even an indication of why a metabolizing system which represents a cell should possess a nucleus, follow in a straightforward fashion from our model.     

A relational theory of biological systems II

The general Theory of Categories is applied to the study of the (M, R)-systems previously defined. A set of axioms is provided which characterize “abstract (M, R)-systems”, defined in terms of the Theory of Categories. It is shown that the replication of the repair components of these systems may be accounted for in a natural way within this framework, thereby obviating the need for anad hoc postulation of a replication mechanism. A time-lag structure is introduced into these abstract (M, R)-systems. In order to apply this structure to a discussion of the “morphology” of these systems, it is necessary to make certain assumptions which relate the morphology to the time lags. By so doing, a system of abstract biology is in effect constructed. In particular, a formulation of a general Principle of Optimal Design is proposed for these systems. It is shown under what conditions the repair mechanism of the system will be localized into a spherical region, suggestive of the nuclear arrangements in cells. The possibility of placing an abstract (M, R)-system into optimal form in more than one way is then investigated, and a necessary and sufficient condition for this occurrence is obtained. Some further implications of the above assumptions are then discussed.     

On the reversibility of environmentally induced alterations in abstract biological systems

The environmentally induced alterations in structure of (M, ℜ) which were described previously (R. Rosen,Bull. Math. Biophysics,23, 165–171, 1961) are examined from the standpoint of determining under what circumstances they can be reversed by further environmental interactions. For simplicity we consider only the case of (M, ℜ)-systems possessing one “metabolic” and one “genetic” component. In the case of environmentally induced alteration of the “metabolic” component alone, a necessary and sufficient condition is given for the reversibility of the alteration. In the case of alteration of the “genetic” component, the situation becomes more complex; several partial results are given, but a full analysis is not available at this time. Some possible biological implications of this analysis are discussed. This research was supported by the United States Air Force through the Air Force Office of Scientific Research of the Air Research and Development Command, under Contract no. AF-49(638)-917 and Grant no. AF-AFOSR-9-63.     

Dynamic structure theory: A structural approach to social and biological systems

The relationships that define the structure of a given ecosystem, social system, or even a physiological function can only exist if certain parameters are confined to a certain range of values. As the values change and exceed this given range the relationships are forced to change, and so produce a new pattern of relationships. The concept of a dynamic structure captures this potential for structural change in relation to a set of parameters. The precise definition of structure and allowable transformation constitutes the definition of a category. The total range of parameters associated with all the relevant structures provides a parameter space which is assumed to be a manifold. Maps with extra structure from the manifold to the category define dynamic structures. The domain of differential dynamic systems is the manifold, and a flow or movement across the manifold is associated with a series of structural transformations in the category. In some cases a structure outruns its parameter range, to be faced with an obstruction—an absence of possible transformations. Ways of studying such “obstructions” are considered along with the related problem of extending a dynamic structure beyond a previously given set of parameters. The cost or resistance of transformations is also studied. The concepts of dynamic structures are illustrated by the structural change of food webs and they are used in a necessarily qualitative fashion to study dominance structures of social orders and finally to speculate on the qualitative nature of evolutionary change of functional aspects of organisms.     

Functional and structural alterations induced by copper in xanthine oxidase

Xanthine oxidase （XO）, a key enzyme in purine metabolism, produces reactive oxygen species causing vascular injuries and chronic heart failure. Here, copper＇s ability to alter XO activity and structure was investigated in vitro after pre-incubation of the enzyme with increasing Cue＋ concentrations for various periods of time. The enzymatic activity was measured by following XO-catalyzed xanthine oxidation to uric acid under steady-state kinetics conditions. Structural alterations were assessed by electronic absorption, fluorescence, and circular dichroism spectroscopy. Results showed that Cu^2＋ either stimulated or inhibited XO activity, depending on metal concentration and preincubation length, the latter also determining the inhibition type. Cu^2＋-xo complex formation was characterized by modifications in XO electronic absorption bands, intrinsic fluorescence, and α-helical and β-sheet content. Apparent dissociation constant values implied high- and low-affinity Cu^2＋ binding sites in the vicinity of the enzyme＇s reactive centers. Data indicated that Cu^2＋ binding to high-affinity sites caused alterations around XO molybdenum and flavin adenine dinucleotide centers, changes in secondary structure, and moderate activity inhibition; binding to low affinity sites caused alterations around all XO reactive centers including FeS, changes in tertiary structure as reflected by alterations in spectral properties, and drastic activity inhibition. Stimulation was attributed to transient stabilization of XO optimal conformation. Results also emphasized the potential role of copper in the regulation of XO activity stemming from its binding properties.     

Conformational changes and activity alterations induced by nickel ion in horseradish peroxidase

Conformational changes induced by the binding of nickel to horseradish peroxidase C (HRPC) were studied by electronic absorption spectroscopy, fluorescence spectroscopy and circular dichroism spectroscopy. Incubation of HRPC with various concentrations of Ni(2+) for 5 minutes resulted in changes in the enzyme absorption spectrum, including variations in the intensities of the Soret, beta and charge transfer (CT1) bands absorption, shift in the Soret, beta and CT1 bands maxima and absorption increase at 275 nm. Increases in the enzyme's intrinsic fluorescence as determined by fluorescence spectroscopy, as well as changes in the alpha-helical content, as determined by circular dichroism spectroscopy, were also found. Correlatively, alterations of the enzymatic activity by Ni(2+) were studied by following the H(2)O(2)-mediated oxidation of o-dianisidine and 2,2'-azinobis(3-ethylbenzothiazolinesulfonic acid) (ABTS) by HRPC. With both reducing substrates, it was found that in the presence of sufficient amount of enzyme, 1-10 mM nickel would enhance the enzymatic activity, while higher Ni(2+) concentrations (20-50 mM) would inhibit it. The enzyme was completely inhibited after 5 minutes incubation in 50 mM Ni(2+). Prolonged incubation would induce complete inhibition at lower Ni(2+) concentrations. Spectrophotometry investigations also showed that inhibitory concentrations of Ni(2+) altered compounds I and II formation, compound II being the first affected. Based on spectrophotometry, fluorescence and circular dichroism spectroscopy, and data on compounds I and II formation, a scheme is suggested for HRPC conformational changes in different Ni(2+) concentrations. HRPC was found to have four potential attachment sites for Ni(2+) which were sequentially occupied in a dose- and time-dependent manner by the metallic ion.     

Blood chemical changes and renal histological alterations induced by gentamicin in rats

Gentamicin is an effective widely used antibiotic, but the risk of nephrotoxicity and oxidative damage limit its long-term use. Hence, the current study aims to elucidate such hazardous effects. To achieve the study aim male Wistar albino rats (Rattus norvegicus) were exposed to gentamicin to investigate the resultant blood chemical changes and renal histological alterations. In comparison with control rats, gentamicin produced outstanding tubular, glomerular and interstitial alterations that included degeneration, necrosis, cytolysis and cortical tubular desquamation together with mesangial hypercellularity, endothelial cell proliferation and blood capillary congestion. Compared with control animals significant blood chemical changes (P < 0.05) including free radicals, ALT, AST, ALP, serum creatinine and serum urea were recorded in gentamicin-injected animals. The findings revealed that exposure to gentamicin can induce significant histological alterations in the kidney as well as remarkable blood chemical changes that might indicate marked renal failure.     

Protein structural changes induced by their uptake at interfaces

For insertion into lipidic media, most hydrosoluble proteins must cross the lipid-water interface and thus undergo conformational transitions. According to their chemical sequences these transitions may be restricted to changes involving only the tertiary structure, while for other proteins this environment modification will induce drastic changes such as the unfolding of large domains. The structural transitions are mainly governed by the presence of hydrophobic domains and/or by the existence of induced amphipathic properties.     

Resveratrol induced structural and biochemical alterations in the tegument of Raillietina echinobothrida

The root tuber of Carex species has been used as an anthelmintic medicine for intestinal helminthic infections in the Northeast region of India. The main compound present in the root tuber of the genus Carex is resveratrol. Therefore, the present study was conducted to evaluate the anthelmintic effects of resveratrol in Raillietina echinobothrida by using motility observation, electron microscopy, histochemical and biochemical analysis. Resveratrol causes complete inactivation and flaccid paralysis of the cestode, followed by death. The treated parasites also exhibited extensive distortion of the surface fine topography and decrease in the activities of major tegumental enzymes compared to that of control parasite. Ultrastructural alterations include changes in cell organelles present in the tegument and sub-tegumental cyton. Extensive alterations in the surface topography of the treated parasites resulted in a decrease in the activities of tegumental enzyme which suggest that, resveratrol may be useful as a therapeutic agent to treat cestode parasites.     

Reactive oxygen species induced structural alterations of substance P

Substance P (SP(1-11)) was exposed to a continuous flux of superoxide (O2-) or hydroxyl radicals ((.)OH) in a hypoxanthine (HX)/xanthine oxidase (86 mU) system in the presence of 1 mM deferoxamine and 40 mM D-mannitol or 50 muM FeCI(3). 6H(2)O and 50 muM EDTA, respectively. O2- caused fragmentation between the Phe(7) and Phe(8), whereas (.)OH induced cleavage also between the Phe(8) and Gly(9). Reactive oxygen species H(2)O(2) and HCIO did not cause fragmentation, but modification of the amino acid side chains and/or aggregation with altered hydrophobicity in reverse phase high performance liquid chromatography compared to native SP(1-11). Furthermore, exposure of SP(1-11) to phorbol myristate acetate preactivated neutrophils resuited in products similar to those observed upon exposure to superoxide or hydroxyl radicals in a cell-free HX/xanthine oxidase system. This study suggests that, in contrast to rigid proteins, fragmentation is relatively easily induced in a small peptide like SP(1-11), perhaps due to strain on the peptide and t-carbon bonds caused by the movable, random coil configuration acquired by SP(1-11) in an aqueous solution. Oxidative modification might modulate paracrine actions of SP(1-11) at site of inflammation.     

A contribution to the theory of biological staining based on the principles for structural organization of biological macromolecules

Biological staining is to a large degree explainable based on the principles governing folding and aggregation of macromolecules in aqueous solution. Most macromolecules are polyions, which, except for heteropolysaccharides, have a large proportion of nonpolar or only slightly polar residues. Because they are amphiphilic, they react in water by a complex set of hydrophobic interactions involving charged residues, nonpolar residues and water molecules. The hydrophobic interactions lead to complex folding systems or micelle-like structures. Dyes are amphiphilic molecules with a tendency to form micelles, but with limitations due to geometric constraints and charge repulsion. Macromolecules and dyes react with each other in aqueous solution following the same principles as for the structural organization of macromolecules, as in protein folding for example. Dye binding requires near contact between nonpolar groups in both the dye and macromolecule, and this is accomplished by choosing a pH at which the dye and macromolecule have opposite net charges. Charge attraction is insufficient for binding in most cases, but it is directive because it determines which macromolecules a given dye ion is able to contact. These considerations apply to the staining of globular (cytoplasmic) proteins and to nucleic acid staining. The staining mechanism is by hydrophobic interactions. Above approximately pH 3.5, DNA may also bind dyes by hydrophobic intercalation between the bases of the double helix; at lower pH the double helix opens and dye binding is as for RNA and globular proteins. Heteroglycans (mucins) have virtually no nonpolar groups, so nonpolar interactions are restricted to the dye molecules. Metachromatic staining of heteroglycans is due to hydrophobic bonding or micelle formation between the monovalent planar dye molecules aided by charge neutralization by the negatively charged heteroglycans. Alternatively, as the charge attraction increases with the number of closely placed charges, acidic heteroglycans may be stained by a polycation such as alcian blue or colloidal iron. For elastic fiber and collagen staining, actual hydrophobic interactions are less important and hydrogen bonding and simple nonpolar interactions play a major role. These macromolecules may therefore be stained using a nonaqueous alcoholic solution.     

A contribution to the theory of biological staining based on the principles for structural organization of biological macromolecules

Biological staining is to a large degree explainable based on the principles governing folding and aggregation of macromolecules in aqueous solution. Most macromolecules are polyions, which, except for heteropolysaccharides, have a large proportion of nonpolar or only slightly polar residues. Because they are amphiphilic, they react in water by a complex set of hydrophobic interactions involving charged residues, nonpolar residues and water molecules. The hydrophobic interactions lead to complex folding systems or micelle-like structures. Dyes are amphiphilic molecules with a tendency to form micelles, but with limitations due to geometric constraints and charge repulsion. Macromolecules and dyes react with each other in aqueous solution following the same principles as for the structural organization of macromolecules, as in protein folding for example. Dye binding requires near contact between nonpolar groups in both the dye and macromolecule, and this is accomplished by choosing a pH at which the dye and macromolecule have opposite net charges. Charge attraction is insufficient for binding in most cases, but it is directive because it determines which macromolecules a given dye ion is able to contact. These considerations apply to the staining of globular (cytoplasmic) proteins and to nucleic acid staining. The staining mechanism is by hydrophobic interactions. Above approximately pH 3.5, DNA may also bind dyes by hydrophobic intercalation between the bases of the double helix; at lower pH the double helix opens and dye binding is as for RNA and globular proteins. Heteroglycans (mucins) have virtually no nonpolar groups, so nonpolar interactions are restricted to the dye molecules. Metachromatic staining of heteroglycans is due to hydrophobic bonding or micelle formation between the monovalent planar dye molecules aided by charge neutralization by the negatively charged heteroglycans. Alternatively, as the charge attraction increases with the number of closely placed charges, acidic heteroglycans may be stained by a polycation such as alcian blue or colloidal iron. For elastic fiber and collagen staining, actual hydrophobic interactions are less important and hydrogen bonding and simple nonpolar interactions play a major role. These macromolecules may therefore be stained using a nonaqueous alcoholic solution.     

Microdissection studies of the structural alterations induced in rat kidneys by experimental postischemic acute renal failure

A unique opportunity presented itself for a morphologic study of experimental unilateral acute renal failure (ARF) in male rats. The ARF had been induced in the rats by temporary occlusion (1h) of the left renal artery. Twenty-nine rats were divided into subsets as follows: 2-3 h, 24 h, 1 week, 2, 4, 8, and 12 weeks following release of occlusion. Microdissection showed a heterogeneous population of abnormally structured proximal tubules in which the regressive lesions of tubular necrosis were combined with the progressive reaction of repair. The lesions demonstrated are reminiscent of those which have been described in ARF in the human and in experimental animals. Many proximal tubules in the 2- to 3-hour subset presented 1-3 disruptive lesions (DLs) while greater numbers of proximal tubules from the 24-hour group presented 1-5 DLs. Many proximal tubules presented no DLs, but nearly all from the 24-hour subset (97-100%) displayed a squamate appearance which paralleled and was caused by acute tubular necrosis. At 1 week, a dilated pars recta was common, but by this time, the squamate pattern had disappeared. Many casts were present. At 2 weeks, many fewer casts were present in proximal tubules and none were seen at 4, 8 or 12 weeks. The nephrons, particularly the proximal tubules, presented a variety of structural alterations at 2, 4, 8 and 12 weeks. Changes of special interest include (1) the presence of swan-necks; (2) a distinctive squamate appearance of the proximal tubules in the animals killed at 24 h; (3) a spiral, curled appearance caused by differential hyperplasia in animals at 4, 8 and 12 weeks, and (4) a tendency for ischemic lesions to involve all layers of the renal cortex.