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PubMedDate not supplied

Regeneration of skeletal and cardiac muscle in mammals: do nonprimate models resemble human pathology?

Most of the available information regarding the regenerative potential and compensatory remodeling of mammalian tissues has been obtained from nonprimate animals, mainly rodent experimental models. The increasing use of transgenic mice for studies of the mechanisms controlling organogenesis and regeneration also requires a clear understanding of their applicability as experimental models for studies of similar processes in humans and other mammals. Application of modern cell biology methods to studies of regenerative processes has provided new insights into similarity and differences in cellular responses to injury in the tissues of different mammalian species. During more than 200-million years of progressive divergent evolution of mammals, cellular mechanisms of tissue regeneration and compensatory remodeling evolved together with increasingly adaptive functional specialization and structural complexity of mammalian tissues and organs. Rodents represent a phylogenetically ancient order of mammals that has conservatively retained a number of morphofunctional characteristics of early representatives of this class, which include enhanced regenerative capacity of tissues. A comparative analysis of regenerative processes in skeletal and cardiac muscle, as well as in several other mammalian tissues, shows that time courses and intensities of regeneration in response to the same type of injury vary even within taxonomically related species (e.g., rat, mouse, and hamster). The warm bloodedness of mammals facilitated the development of more complex mechanisms of metabolic, immune, and neurohumoral regulation, which resulted in a stronger dependence of regenerative processes on vascularization and innervation. For this reason, interspecies modifications of regenerative responses are limited by the capacity of the animal to resorb rapidly the foci of necrosis and to revascularize and reinnervate the volume of the regenerating tissue. These differences, among other factors, result in significantly lower rates of reparative regeneration in mammals possessing larger body sizes than rodents. A review of these data strongly indicates that the phylogenetic age and biological differences between different species should be taken into account before extrapolation of regenerative properties of nonprimate tissues on the regenerative responses in the primates.

Animals↗
PubMed1995

Striatal expression of substance P and methionin-enkephalin in genes in patients with Parkinson's disease.

The striatal expression of substance P (SP) and methionin-enkephalin (met-enk) genes was studied post mortem by in situ hybridization in patients with Parkinson's disease and a group of control subjects. No significant difference in striatal expression of these two neuropeptide messenger RNAs (mRNAs) was found in the patients compared with control subjects. This contrasts with animal models of parkinsonism, where expression of SP mRNA is decreased and met-enk mRNA increased. Possible explanations include: (1) compensatory mechanisms, which may develop during the long term evolution of Parkinson's disease; (2) normalized expression of the two genes resulting from chronic L-DOPA therapy.

Aged↗
PubMed1980

Pyruvate kinase deficiency hemolytic anemia: enzymatic characterization studies in twelve patients.

Erythrocyte pyruvate kinase from twelve patients with hereditary erythrocyte pyruvate kinase (PK) deficiency was investigated according to the recommended methods for the characterization of red cell pyruvate kinase variants. Family members were also studied. Abnormalities were frequently noted in the affinity for the substrate, phosphoenolpyruvate; allosteric activator, fructose-1,6-diphosphate; allosteric inhibitor, ATP; and also in heat stability and electrophoretic pattern. Several different PK variants were identified. Polyacrylamide gel electrophoresis revealed the presence of immature activity bands in the red cells of some patients. These bands presumably represent residuals of isozymes produced during the evolution of erythrocyte PK, and may occur as a compensatory mechanism for the defective isozyme.

Adenosine Triphosphate↗
PubMed1991

Secondary structure constraints on the evolution of Drosophila 28 S ribosomal RNA expansion segments.

Eukaryotic ribosomal RNA genes contain rapidly evolving regions of unknown function termed expansion segments. We present the comparative analysis of the primary and secondary structure of two expansion segments from the large subunit rRNA gene of ten species of Drosophila and the tsetse fly species Glossina morsitans morsitans. At the primary sequence level, most of the differences observed in the sequences obtained are single base substitutions. This is in marked contrast with observations in vertebrate species in which the insertion or deletion of repetitive motifs, probably generated by a DNA-slippage mechanism, is a major factor in the evolution of these regions. The secondary structure of the two regions, supported by multiple compensatory base changes, is highly conserved between the species examined and supports the existence of a general folding pattern for all eukaryotes. Intriguingly, the evolutionary rate of expansion segments is very slow relative to other genic and non-genic regions of the Drosophila genome. These results suggest that the evolution of expansion segments in the rDNA multigene family is a balance between the homogenization of new mutations by unequal crossing over and a combination of selection against some such mutations per se and selection for subsequent compensatory mutations, in order to maintain a particular RNA secondary structure.

Animals↗
PubMed1983

Myocardial hypertrophy and cardiac failure: a complex interrelationship.

The interrelationship between myocardial hypertrophy and myocardial function is a complex one. In patients with essential hypertension, the appearance of left ventricular hypertrophy may be an ominous sign, often presaging the evolution of congestive heart failure. In other settings, such as valvular heart disease, congestive cardiomyopathy, and ischemic heart disease, myocardial hypertrophy serves as a compensatory mechanism in response to excessive loading conditions. This article reviews experimental and clinical data concerning the evolution of hypertrophy and its relationship to myocardial function.

Animals↗
PubMed2025

Sequential antibiotic exposure restores antibiotic susceptibility.

BACKGROUND: The prevalence of antibiotic resistance continues to rise, rendering many valuable antimicrobial drugs ineffective. Pairwise cyclic antibiotic therapy, where treatment is rapidly switched between two antibiotics, has been demonstrated in vitro to limit the evolution of antibiotic resistance. However, what happens when resistance inevitably evolves to one of the drugs? METHODS: In this study, we perform over 450 evolution experiments to test the resilience of four proposed cyclic therapies. We use soft agar gradient evolution and 'flat plates' to identify resistance trade-offs that are resilient to compensatory mitigation. Resensitizations were detected by antimicrobial susceptibility assays, and their mechanistic underpinnings were elucidated via genomic and phenotypic analyses. RESULTS: Resistance evolves readily and collateral sensitivity (CS) (where resistance to drug A leads to hypersensitivity to drug B) does not hinder the evolution of multidrug resistance and does not predict or promote resensitization. However, if resistance to drug B increases susceptibility to A, a phenomenon we term backward CS, resistance to A can be reduced or even reversed. For example, we show that Escherichia coli cells frequently become hypersensitive to β-lactams upon aminoglycoside resistance acquisition, due to conflicting modifications to the proton motive force and efflux pumps. We also find for the first time that polymyxin B resistance can be entirely reversed by exposure to tigecycline, through the acquisition of compensatory mutations that reduce the fitness penalty of tigecycline resistance. CONCLUSIONS: The longevity of drug cycling protocols can be significantly improved by leveraging backwards CS to resensitize cells as antibiotic resistance evolves.

Anti-Bacterial Agents↗
PubMed1993

Diastolic dysfunction in post-cardiac surgical management.

Although an appropriate definition of primary diastolic failure is still not at hand, primary diastolic failure is a distinct pathophysiologic syndrome. It is due to an increased resistance to ventricular filling and results in an inappropriate upward shift of the diastolic P-V relationship, especially during exercise. This leads to exercise intolerance with symptoms of congestion. The causes are known, ie, impaired systolic relaxation, decreased diastolic compliance, and inappropriate tachycardia. Pathophysiologically impaired (incomplete or slowed) systolic relaxation must be distinguished from physiologic, compensatory prolonged contraction (delayed or retarded relaxation). Treatment of diastolic failure is feasible, but necessitates a clear understanding of the etiology, pathogenesis, and pathophysiology of the underlying cardiac disease. Optimal therapy will depend on the type of disease, on the phase during the pathophysiologic evolution of a given disease, and on the coexistence and relative contribution of various compensatory or decompensatory mechanisms. This often requires a comprehensive analysis of hemodynamics, for example, with echo-doppler, completed, whenever necessary, by catheterization.

Cardiac Output, Low↗
PubMed1998

Evolution of osmotic stress signaling via MAP kinase cascades.

Cells respond to changes in osmotic pressure with compensatory molecular adaptations that allow them to re-establish homeostasis of osmotically disturbed aspects of cell structure and function. In addition, some cell types respond to osmotic stress by changing their phenotype or, if their tolerance threshold is exceeded, by initiating programmed cell death. To understand how cells achieve these different types of adaptive response to osmotic stress, it is necessary to identify the key elements of osmosensory signal transduction and to analyze the complex networks that process osmotic stimuli imposed upon cells by their environment. This review highlights mitogen-activated protein kinase (MAPK) cascades as important intracellular signal-transduction pathways activated in response to changes in osmolality. A unifying theme of osmotic stress signaling via MAPKs seems to be regulation of the cell cycle as part of the cellular stress response. This very important physiological capacity may have been conserved throughout evolution as a major function of MAPKs from many different subfamilies. The evidence for this conjecture is discussed, and our current knowledge about osmotic stress signaling pathways in yeast, animals and plants is briefly reviewed.

Animals↗
PubMed1993

Mapping the stability determinants of bacterial tyrosyl transfer RNA synthetases by an experimental evolutionary approach.

The tyrosyl-tRNA synthetases from Bacillus stearothermophilus (Bst-TyrTS) and Escherichia coli (Eco-TyrTS) are 56% identical in amino acid sequence. To map and characterize the set of interactions that makes Bst-TyrTS more stable than Eco-TyrTS, a family of nine hybrid proteins was constructed between the two enzymes. The N-terminal part of each hybrid came from Eco-TyrTS and the C-terminal part from Bst-TyrTS. The stability and activity of these hybrids were estimated by experiments of thermal inactivation and tRNA charging. For all the hybrids, the temperature of half-inactivation in 30 minutes was above 44 degrees C and the rate of charging was at least 40% that of Bst-TyrTS. In general, the temperature of half-inactivation increased and the rate of charging decreased monotonically when the number of residues coming from the more stable and less active Bst-TyrTS increased. As a result, the rate of charging decreased when the temperature of half-inactivation increased. These results show that the sequences and structures of the two enzymes can replace each other locally and still give a stable and active TyrTS, and that the greater stability of Bst-TyrTS is due to cumulative changes of residues scattered along the sequence. They suggest that Bst-TyrTS is more rigid than Eco-TyrTS at low temperature. The existence of a few exceptional hybrids, having stabilities or activities lower than those of the neighbouring hybrids, shows that compensatory changes of residues have occurred between the two sequences during evolution. These exceptions could be explained by the systematic identification of the couples of residues that are in contact in the Bst-TyrTS structure and become heterologous in some hybrids.

Binding Sites↗
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↗