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PubMed1998

Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach.

This paper provides an overview of the compensatory mechanisms which come into action during experimental and human parkinsonism. The intrinsic properties of the dopaminergic neurones of the substantia nigra pars compacta (SNc) which degenerate during Parkinson's disease are described in detail. It is generally considered that the nigrostriatal pathway is principally responsible for the compensatory preservation of dopaminergic function. It is also becoming clear that the morphological characteristics of dopaminergic neurones and the dual character, synaptic and asynaptic, of striatal dopaminergic innervation engender two modes of transmission, wiring and volume, and that both these modes play a role in the preservation of dopaminergic function. The plasticity of the dopamine neurones, extrinsic or intrinsic to the striatum, can thus be regarded as another compensatory mechanism. Recent anatomical and electrophysiological studies have shown that the SNc receives both glutamatergic and cholinergic inputs. The dynamic role this innervation plays in compensatory mechanisms in the course of the disease is explained and discussed. Recent developments in the field of compensatory mechanisms speak for the urgence to develop a valid chronic model of Parkinson's disease, integrating all the clinical features, even resting tremor, and illustrating the gradual evolution of nigral degeneration observed in human Parkinson's disease. Only a dynamic approach to the physiopathological study of compensatory mechanisms in the basal ganglia will be capable of elucidating these complex questions.

Adaptation, Physiological↗
PubMed2026

A genome-wide in vivo screen reveals fitness pathways required for streptococcal infective endocarditis.

Infective endocarditis (IE) is a life-threatening disease most often caused by blood-borne bacteria that infect previously damaged cardiac tissue. Despite the importance of this disease, the genetic basis for IE-associated fitness remains poorly defined. Here, we present the first genome-wide in vivo analysis of bacterial fitness in a vertebrate model of IE. We identified 146 genes in Streptococcus sanguinis required for IE fitness, the majority of which had not previously been linked to endocarditis. These determinants cluster into conserved metabolic, cell envelope, transport, and regulatory pathways, representing a vast reservoir of potential targets for novel antimicrobial intervention. A subset of these genes was examined in Streptococcus mutans; all were found to be essential for IE fitness in this distantly related oral species as well, suggesting broad conservation. Using experimental evolution, we further show that disruption of key fitness pathways triggers reproducible compensatory "bypass" mechanisms. Together, these findings provide a comprehensive, genome-wide map of the bacterial niche-requirements for streptococcal infective endocarditis.

Animals↗
PubMedDate not supplied

Evolution from obesity to diabetes.

The relationship between obesity and Type 2 diabetes mellitus is so closely related that it is worth questioning the possibility of obesity being more than just one diabetes risk factor among others but a factor which participates causally to the development of Type 2 Diabetes on a genetic background. In this review, the evolution of normal glucose tolerance towards impaired glucose tolerance corresponds to the development of compensatory metabolic changes. These compensatory mechanisms are hyperinsulinaemia and postprandial hyperglycaemia which prevents a defect in glucose uptake and especially glucose storage. These compensatory responses are overcome with time and diabetes develops in spite of the hyperinsulinaemia and the hyperglycaemia. The capacity for glucose storage is decreased and cannot be overcome at this stage by increases of both glucose and insulinemic responses. Inhibition of glycogen synthase activity by an increased muscle glycogen concentration is probably more powerful than its stimulation by insulin and glucose and the capacity for glucose storage remains decreased. Finally with time insulin secretion gradually decreases as a consequence of chronic hyperglycaemia and results in full pancreatic decompensation. At this stage hepatic glucose production is increased. The most important factor in the evolution from obesity to diabetes reside in the permanence of the increase in lipid oxidation and mainly in the duration of obesity. An important consequence of permanently high lipid oxidation is the chronic resistance to glucose uptake, initially compensated for by increased plasma insulin and glucose concentrations. A vicious circle starts after insulin resistance to glucose uptake appears, followed by hyperglycaemia blocking the glucose storage system and by the lack of storing capacity leading to a rise in glycaemia. In conclusion, all these metabolic phenomena are appearing in a sequential way, progressively adapting to the deteriorating situation, through the stages of normal glucose tolerance, impaired glucose tolerance, hyperinsulinaemic and finally hypoinsulinemic diabetes.

Blood Glucose↗
PubMed1976

[Comparative analysis of blood coagulation and various indicators of microcirculation in patients with coronary arteriosclerosis and hypertension in the age aspect].

In patients with hypertensive disease and coronary atherosclerosis the blood-clotting potential increases on account of a rise in the level of procoagulants and inhibition of fibrinolysis. Age-specific differences in the characteristics of the coagulation and fibrinolytic system of the blood are levelled out parallel with the development of atherosclerosis and progressive evolution of hypertensive disease. In patients of advanced age a tendency toward a compensatory increased activity of erythrocytic anticoagulation factors is noted, finding its expression in a drop of the procoagulants level, and increase of anticoagulants and in a rising fibrinolytic activity. Changes in the state of the conjunctival microcirculation and the retinal hemodynamics correlate with the intensity of the pathological process and shifts in the blood coagulation system.

Adaptation, Physiological↗
PubMed1988

Complete sequences of the rRNA genes of Drosophila melanogaster.

In this, the first of three papers, we present the sequence of the ribosomal RNA (rRNA) genes of Drosophila melanogaster. The gene regions of D. melanogaster rDNA encode four individual rRNAs: 18S (1,995 nt), 5.8S (123 nt), 2S (30 nt), and 28S (3,945 nt). The ribosomal DNA (rDNA) repeat of D. melanogaster is AT rich (65.9% overall), with the spacers being particularly AT rich. Analysis of DNA simplicity reveals that, in contrast to the intergenic spacer (IGS) and the external transcribed spacer (ETS), most of the rRNA gene regions have been refractory to the action of slippage-like events, with the exception of the 28S rRNA gene expansion segments. It would seem that the 28S rRNA can accommodate the products of slippage-like events without loss of activity. In the following two papers we analyze the effects of sequence divergence on the evolution of (1) the 28S gene "expansion segments" and (2) the 28S and 18S rRNA secondary structures among eukaryotic species, respectively. Our detailed analyses reveal, in addition to unequal crossing-over, (1) the involvement of slippage and biased mutation in the evolution of the rDNA multigene family and (2) the molecular coevolution of both expansion segments and the nucleotides involved with compensatory changes required to maintain secondary structures of RNA.

Animals↗
PubMed1997

Genome size, secondary simplification, and the evolution of the brain in salamanders.

Compared to other vertebrates, even including lampreys and hagfishes in some respects, salamanders exhibit a relatively simple organization of brain and sense organs which is illustrated here using the visual system as an example. The greatest simplicity is found in the bolitoglossine salamanders, yet all bolitoglossines possess highly projectile tongues and rely on vision for survival; furthermore, some species are agile and acrobatic. The unusual features of the visual system of salamanders include small numbers of large neurons, a low degree of morphological differentiation among neurons, a small proportion of myelinated axons in the optic nerve, and an optic tectum consisting essentially of a periventricular cellular layer and a superficial fiber layer. Similar features are found throughout the central nervous system of salamanders and in the lateral line, auditory and olfactory systems as well. Phylogenetic analysis shows that the most parsimonious interpretation of these data is that the simple organization of the brain and sense organs of salamanders was derived secondarily from a more complex ancestral state. We hypothesize that increased genome size has led to simplification of the nervous system in salamanders. Increased genome size appears to have had profound effects on neural development in salamanders, leading to paedomorphosis, the retention of juvenile or even embryonic characteristics into adulthood. In particular, large genome size is associated with large cell size and reduced rates of cell proliferation, migration and differentiation. Secondary simplification has constrained the function of the salamanders' visual system, primarily by increasing cell size and decreasing cell numbers. However, it also has provided an opportunity for the evolution of compensating mechanisms, which have helped to restore or even enhance visual function. Most apparent among the compensatory mechanisms of bolitoglossine salamanders is the presence of well developed ipsilateral retinotectal projections, which apparently enhance depth perception. It is difficult to explain the unusual history of the nervous system in salamanders solely in terms of natural selection and adaptation. Increasing genome size through selfish replication appears to have played a major role in the evolution of salamander brains by imposing functional constraints as well as creating opportunities for overcoming them.

Animals↗
PubMed1986

Population consequences of mutagenesis and antimutagenesis.

Although the progress in basic understanding of mutagenesis and in techniques for precise measurement of mutation rates in test systems has been enormous, there has been very little progress in applying this information to estimates of germline mutation in humans, and even less in translating such estimates into quantitative assessments of the impact on future generations. This doesn't mean that new information about the mutation process, and antimutagens in particular, is not useful. Lowering the human mutation rate would be good, even if we can't say how good. Some simple population kinetics of a change of mutation are discussed, and it is shown that future environmental changes can be ignored if we assume that the impact of a disease on human welfare is changed by the environment in the same proportion as its effect on fitness. Since the human mutation rate appears to be much higher in males than in females, it would be especially important to find ways of reducing the male rate. The role of transposable elements in determining human spontaneous mutation rates is unknown, but unless data from experimental organisms are grossly misleading, this role may be substantial. It is sometimes argued that such responses as error-prone repair systems may be an evolutionary strategy to allow the population to try a larger repertoire of mutations in times of environmental change. They may also be a survival strategy. I suggest that, although such an evolutionary strategy may possibly be adopted in asexual organisms with a very high reproductive rate, it is very unlikely in Mendelian species with limited reproduction such as most higher animals. The amount of existing variability in a large population is so great relative to that which arises in a few generations by mutation that segregation and recombination of existing alleles would appear to be a better way of coping with changing environment. As the human age of reproduction has increased in the recent evolutionary past, it is possible that the compensatory adjustment of mutation rates has not been fast enough to keep up. Perhaps evolution of mutation rates is more determined by selection to reduce somatic mutation than by selection to reduce germinal mutation. Regardless of the answer to the question of the optimum mutation rate for long-time evolution, in my view, the optimum mutation rate from the standpoint of human welfare for the foreseeable future is zero.

Animals↗
PubMed1996

The broad spectrum of preclinical radiobiology: British contributions.

British radiobiologists have often been at the forefront in taking clinical questions into the laboratory and in taking the results back into the clinic, i.e., what is nowadays labeled as Translational Research. They have published widely and have been very active in lectures, workshops, and discussions, forming an important component of the international communication web, both within the basic science aspects and in the translation from science to medicine, and back again. Major contributions have been made at the cellular and subcellular level, and at the level of multicellular structures, both normal and malignant. The common features of the response of cells to single doses in well-defined conditions have been used to interpret the much greater complexity of tissue and tumor responses treated with repeated small doses in a fractionated course, both of photons and other radiations, with and without chemical modifiers. The many contributions to the field of cell kinetics have provided the tools with which an understanding has been gained of the latency and evolution of radiation damage in different tissues. The prolonged interest in microenvironmental gradients and compensatory responses to injury have provided a framework for designing better radiotherapy schedules, and considerable spin-off to other branches of cancer therapy.

History, 20th Century↗
PubMed1999

[The diagnostic significance of immunogenetic markers in vertebrogenic neurological syndromes].

A total of 116 patients presenting with different neurological syndromes of vertebral osteochondrosis were examined. More common in patients with reflex neurological manifestations of osteochondrosis compared with controls (n = 51) was a complete HLA phenotype (heterozygosity) determining better evolutional and biological resistance to injuring factors and ability to produce adequate adaptive and compensatory reactions. The diagnosing of incomplete phenotype in other groups indicated homozygosity of genes and suggested a high risk for development of the disorder. Criteria have been established for a relative risk of development of the disease for all six vertebrogenic neurological syndromes.

Biomarkers↗
PubMed1986

[Morphologic characteristics of the liver in the postcholecystectomy syndrome].

Liver biopsies of 152 patients with post-cholecystectomy syndrome are studied. Liver alterations observed in these patients are subdivided into morphological syndromes (portal and periportal hepatitis, liver fibrosis and cirrhosis) and their evolution is investigated. Changes of intrahepatic bile ducts are studied and their adaptive-compensatory character is shown. Compensatory processes in the liver parenchyma are also investigated. Patho- and morphogenesis of alterations observed is discussed.

Adult↗
PubMed2001

RNA sequence evolution with secondary structure constraints: comparison of substitution rate models using maximum-likelihood methods.

We test models for the evolution of helical regions of RNA sequences, where the base pairing constraint leads to correlated compensatory substitutions occurring on either side of the pair. These models are of three types: 6-state models include only the four Watson-Crick pairs plus GU and UG; 7-state models include a single mismatch state that combines all of the 10 possible mismatches; 16-state models treat all mismatch states separately. We analyzed a set of eubacterial ribosomal RNA sequences with a well-established phylogenetic tree structure. For each model, the maximum-likelihood values of the parameters were obtained. The models were compared using the Akaike information criterion, the likelihood-ratio test, and Cox's test. With a high significance level, models that permit a nonzero rate of double substitutions performed better than those that assume zero double substitution rate. Some models assume symmetry between GC and CG, between AU and UA, and between GU and UG. Models that relaxed this symmetry assumption performed slightly better, but the tests did not all agree on the significance level. The most general time-reversible model significantly outperformed any of the simplifications. We consider the relative merits of all these models for molecular phylogenetics.

Base Pairing↗
PubMed1994

Kinetics of elemental content changes of bone tissue of mice during evolution under hypokinetic stress.

Concentration of 13 elements in bone tissue of mice held in tightly spaced cages for 3 wk, which caused an acute stress reaction, was determined by means of neutron activation analysis. Functionally different bone tissues of mice skeletons--the femur, accomplishing both supporting and dynamic functions; the parietal bone, being practically immovable; and the ectopic bone, newly formed under kidney capsule in the place of syngeneic bone marrow implantation--were analyzed. Similar dynamics of the elemental composition of investigated bones was found: the progressive demineralization owing to the loss of Ca, P, Mg, and Fe is accompanied by the compensatory inclusion of Sr in the bone tissues. In the ectopic bone, it was not as high. During evolution under hypokinetic stress, the microelement concentrations (Zn, Cr, Rb, Ru, Br, Co, Sb) change significantly. Results obtained form the evidence for some system character of osteoporosis at limited mobility.

Animals↗
PubMed1995

[The adaptive-compensatory reactions in adjusting to space flights].

In this paper an evolutionary approach is used to substantiate the steps of life evolution on Earth towards overcoming the gravitational forces with the formation of metabolic cycles controlling the energetic of anti-G processes. The step of an adaptation to hypogravity was similar to return of surface animals to an aquatic environment. The impossibility of coming back to land was the "price" of adaptation to the aquatic environment. This phenomenon was used by the author as a logical model of human adaptation to a weightless environment. The concept of adaptation is examined from two points of view: adaptation and compensation. The scheme contains 4 steps of adaptation to space mission environments: Step I-preadaptation (phase of primary reactions); Step II-compensation of body structures not being in line with the conditions of a novel environment; Step III-the formation of parameters of an organism corresponding to the norm of adaptation to weightlessness; Step IV-the return of cosmonauts to Earth under hypergravity conditions. In compliance with these steps we consider the tasks of supporting space missions to facilitate body readaptation after return to Earth, i.e., to decrease the "price" of adaptation.

Adaptation, Physiological↗
PubMed1997

Effectiveness of correlation analysis in identifying protein residues undergoing correlated evolution.

Various methods for detecting correlation between sites were evaluated by ascertaining their ability to discriminate positively correlated sites from background correlation at randomly evolved sites. A model for generating pairwise correlations of different degrees is also described. An assortment of physicochemical vectors and similarity and difference matrices were used to discriminate correlated change. There was little difference in effectiveness between the different matrices, but there were significant differences between the matrices and the physicochemical vectors. It is shown that all methods investigated exhibit significant inability to screen out background correlation, particularly in the presence of phylogenetic relatedness between the sequences. Methods using the matrices are unable to distinguish positively correlated from negatively correlated, or compensatory, replacements.

Amino Acid Sequence↗
PubMed1999

Contour tracking using a knowledge-based snake algorithm to construct three-dimensional pharyngeal bolus movement.

Videofluorography (VFG) using a barium-mixed bolus is in wide clinical use for assessing patients with swallowing disorders. VFG is usually done with both lateral (LA) and anterior-posterior (AP) views, most commonly in two separate sittings. A real-time, three-dimensional (3-D) representation of the evolution of a pharyngeal bolus and its volumetric information can potentially help clinicians analyze and visualize the kinematics of swallowing, dysphagia, and compensatory therapeutic strategies. Active contour models, also known as "Snakes," have been used to solve various image analysis and computer vision problems. We applied a Snake algorithm to automate in part the contour tracking and reconstruction of VFG images to visualize and quantitatively analyze the 3-D evolution of a pharyngeal bolus. To improve the accuracy of the Snake search, we provided the additional "knowledge" of the pharyngeal image itself, which served as an extra constraint to push the Snake curve toward the desired contour. VFG of pharyngeal bolus transport in a normal subject was recorded by using barium-mixed boluses (viscosity: 185 centipoise, density: 2.84 g/cc) with volumes of 5, 10, and 20 ml. The resulting LA and AP video images were digitally captured and matched frame by frame. The knowledge-based Snake search algorithm was used to generate Snake points to satisfy both internal (i.e., smoothness) and external (i.e., boundary fitting) constraints. Using these Snake points, we traced the 3-D bolus movement at each time instant, assuming elliptic geometry in the cross-section of the pharyngeal bolus. By concentrating the 3-D images for each time instant, we developed a 3-D movie representing pharyngeal bolus movement. The efficiency, reproducibility, and accuracy of this algorithm in tracing pharyngeal bolus boundaries and estimating front/tail velocities were assessed and found satisfactory. We conclude that 3-D pharyngeal bolus movement can be traced both accurately and efficiently by using a knowledge-based Snake search algorithm.

Algorithms↗
PubMed1990

Site-directed mutagenesis of arginine 179 of thymidylate synthase. A nonessential substrate-binding residue.

X-ray structural studies have shown that Arg-179 of thymidylate synthase is complexed to bound inorganic phosphate or to the 5'-phosphate of the bound substrate dUMP. The importance of Arg-179 to the structure/function of thymidylate synthase is also indicated by its complete conservation among the 17 thymidylate synthases thus far sequenced. In the present work, Arg-179 has been replaced by Thr, Ala, Lys, and Glu using site-directed mutagenesis with a mixture of four synthetic oligonucleotides as primers. The mutant proteins complement thymidylate synthase-deficient Escherichia coli and show high enzyme activity. Each of these mutants has been purified to homogeneity, partially sequenced to verify the mutation, and has had its steady state kinetic parameters determined. The most significant effect of all mutations is localized to a decrease in the net rate of association of thymidylate synthase with dUMP; the Lys mutant also shows an apparent increase in the dissociation constant of the folate cofactor of the reaction. The high activity in the mutant enzymes is explained by "plasticity" of the enzyme and compensatory actions of the other Arg residues. Why the Arg-179 residue has been conserved during evolution remains an open question.

Amino Acid Sequence↗
PubMed1996

Compensatory nearly neutral mutations: selection without adaptation.

One implication of Kacser's analysis of complex metabolic systems is that mutations with small effects exist as a consequence of the typically small flux control coefficient relating enzyme activity to the rate of a metabolic process. Although a slightly detrimental mutation is somewhat less likely to become fixed by chance than a slightly favorable mutation, mutations that are slightly detrimental might be expected to be more numerous than favorable mutations owing to the previous incorporation of favorable mutations by a long history of natural selection. The result is that, as Ohta has pointed out, a significant fraction of mutations that are fixed in evolution are slightly detrimental. In the long run, the fixation of detrimental mutations in a gene increases the opportunity for the occurrence of a compensatory favorable mutation, either in the same gene or in an interacting gene. On a suitably long timescale, therefore, every gene incorporates favorable mutations that compensate for detrimental mutations previously fixed. This form of evolution is driven primarily by natural selection, but it results in no change or permanent improvement in enzymatic function.

Adaptation, Physiological↗
PubMed1985

Direction-selective single units in the nucleus lentiformis mesencephali of the pigeon (Columba livia).

The receptive field properties of single units within the nucleus lentiformis mesencephali (LM) of the pigeon were studied using electrophysiological methods. Previous studies have suggested that the avian LM may be homologous to the nucleus of the optic tract (NOT) in mammals. Single units in the pigeon LM are similar to mammalian NOT units in that they are direction-selective, mostly for horizontal directions, velocity-selective, have large visual receptive fields and respond preferentially to large stimuli with many visual contrasts. In contrast to most reports of NOT units of mammals, more than half of pigeon LM units prefer high velocities (greater than 10 degrees/s), a large proportion (0.37) prefer non-horizontal directions, and receptive fields that are retinotopically arranged within the LM. The response properties of pigeon LM units are compared to the response properties of units within the accessory optic nucleus (the nucleus of the basal optic root or nBOR). In the avian brain, nBOR neurons respond at low velocities (0.5-5 degrees/s) and respond predominantly to vertical stimulus movement whereas LM units respond over a broader range of velocities (0.2-80 degrees/s) and respond predominantly to horizontal movements. Thus, the LM and nBOR may play different roles in the control of compensatory eye movements.

Animals↗