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PubMed1982

Experimental chemical diabetes and pregnancy in the rat. Evolution of glucose tolerance and insulin response.

The effect of pregnancy on the course of experimental chemical diabetes (CD) has been studied in the rat. Glucose tolerance tests (0.5 g/kg i.v.) have been performed serially in the virgin state (2 mo), late pregnancy (20.5 day of gestation), and 1 and 2 mo after delivery, in control and in CD female rats. During gestation in the controls basal plasma glucose is decreased, and plasma glucose levels after glucose load, and also lower than levels found in the virgin state. Glucose tolerance is not significantly affected. Nevertheless, glucose-induced insulin secretion in pregnant animals is increased compared with the virgin state. Glucose tolerance remains unchanged 1 and 2 mo postpartum, but insulin response to glucose becomes significantly lower than in the virgin state. In the pregnant CD rats basal plasma glucose is decreased, but plasma glucose levels after glucose load are similar to values found in the virgin state, thus suggesting decreased glucose tolerance. Glucose-induced insulin secretion is increased compared with the virgin state. Glucose tolerance remains deteriorated 1 and 2 mo postpartum, but insulin secretion is no longer significantly different. These findings indicate that in CD female rats glucose tolerance is and remains deteriorated by pregnancy, while in normal female rats it is and remains unchanged. Thus, despite increased insulin response to glucose during late gestation in the CD rats, the diabetogenicity of pregnancy is confirmed with this experimental model.

Animals↗
PubMed1990

Evolution of the tryptophan synthetase of fungi. Analysis of experimentally fused Escherichia coli tryptophan synthetase alpha and beta chains.

During evolution of fungi, the separate tryptophan synthetase alpha and beta polypeptides of bacteria appear to have been fused in the order alpha-beta rather than the beta-alpha order that would be predicted from the order of the corresponding structural genes in all bacteria. We have fused the tryptophan synthetase polypeptides of Escherichia coli in both orders, alpha-beta and beta-alpha, with and without a short connecting (con) sequence, to explore possible explanations for the domain arrangement in fungi. We find that proteins composed of any of the four fused polypeptides, beta-alpha, beta-con-alpha, alpha-beta, and alpha-con-beta, are highly active enzymatically. However, only the alpha-beta and alpha-con-beta proteins are as active as the wild type enzyme. All four fusion proteins appear to be less soluble in vivo than the wild type enzyme; this abnormal characteristic is minimal for the alpha-con-beta enzyme. The alpha and beta domains of the four fusion polypeptides were not appreciably more heat labile than the wild type polypeptides. Competition experiments with mutant tryptophan synthetase alpha protein, and the fusion proteins suggest that in each fusion protein the joined alpha and beta domains have a functional tunnel connecting their alpha and beta active sites. Three tryptophan synthetase beta'-alpha fusion proteins were examined in which the carboxyl-terminal segment of the wild type beta polypeptide was deleted and replaced by a shorter, unnatural sequence. The resulting deletion fusion proteins were enzymatically inactive and were found predominantly in the cell debris. Evaluation of our findings in relation to the three-dimensional structure of the tryptophan synthetase enzyme complex of Salmonella typhimurium (5) and the results of mutational analyses with E. coli suggest that tryptophan synthetase may have evolved via an alpha-beta rather than a beta-alpha fusion because in beta-alpha fusions the amino-terminal helix of the alpha chain cannot assume the conformation required for optimal enzymatic activity.

Amino Acid Sequence↗
PubMed2001

Evolution of embryology: a synthesis of classical, experimental, and molecular perspectives.

Embryology as a modern science began at the beginning of the 19th century and continued as the classic period until the 1940s. During this period, a body of basic knowledge was established which, generally, described the events of development. From 1940 to 1970 experimental or causal embryology predominated; explanations of secondary causes were demonstrated for development. The decade of the 1970s was a decade of transition that led to the current revolution in molecular biology that began in the 1980s. Molecular biology and its new branch, molecular genetics, shook up the heretofore serene, but already limited, field of embryology. Today the discipline of embryology is being built on the analysis of the results of genetic expression. Embryology is now concerned with understanding development from the viewpoint of the activation and transcription of DNA sequences, which will allow us to approach the first causes or underlying genetic and epigenetic mechanisms of development. As a result, embryology and genetics have fused into a wider biological subdiscipline, developmental biology. Will this be enough to define the full scope of our knowledge of embryonic development? What is certainly evident is that the molecular period of embryology will help achieve a better understanding of the schemata constructed by classic and experimental embryologists. Furthermore, to the degree that the molecular analysis of whatever phenomenon of development requires additional foundational knowledge, classic and experimental embryology will not have exhausted all their possibilities.

Embryology↗
PubMed2001

The probability that beneficial mutations are lost in populations with periodic bottlenecks.

Population bottlenecks affect the dynamics of evolution, increasing the probability that beneficial mutations will be lost. Recent protocols for the experimental study of evolution involve repeated bottlenecks-when fresh media are inoculated during serial transfer or when chemostat tubes are changed. Unlike population reductions caused by stochastic environmental factors, these bottlenecks occur at known, regular intervals and with a fixed dilution ratio. We derive the ultimate probability of extinction for a beneficial mutation in a periodically bottlenecked population, using both discrete and continuous approaches. We show that both approaches yield the same approximation for extinction probability. From this, we derive an approximate expression for an effective population size.

Biological Evolution↗
PubMed2026

Enhancing detection of polygenic adaptation: a comparative study of machine learning and statistical approaches using simulated evolve-and-resequence data.

BACKGROUND: Detecting signals of polygenic adaptation remains a significant challenge in population genomics, as traditional methods often struggle to identify the associated subtle, multi-locus allele-frequency shifts. Here, we introduced and tested several novel approaches combining machine learning techniques with traditional statistical tests to detect polygenic adaptation patterns in time-series of allele frequency changes from whole genome data. We implemented a Naive Bayesian Classifier (NBC) and One-Class Support Vector Machines (OCSVM), and compared their performance against the classical Fisher's Exact Test (FET). Furthermore, we combined machine learning and statistical models (OCSVM-FET and NBC-FET), resulting in 5 competing approaches. The framework is mainly designed and validated for evolve-and-resequence (EaR) experimental designs, where defined selection pressures and temporal sampling are feasible, but might be applicable for certain natural experiments as well. RESULTS: Using a simulated dataset based on empirical C. riparius Pool-Seq data, we evaluated methods across evolutionary scenarios varying in generation, selection strength, and number of loci under selection. Our results demonstrate that the combined OCSVM-FET approach consistently outperformed competing methods, achieving the lowest false positive rate, highest area under the curve, and high accuracy. The performance peak aligned with what we term the 'late dynamic phase' of adaptation - the period after initial selection has occurred but before fixation - highlighting the method's sensitivity to ongoing selective processes. CONCLUSIONS: Furthermore, we emphasize the critical role of parameter tuning, balancing biological assumptions with methodological rigor. While broader applicability remains an important direction for future work, the present benchmarking is intentionally scoped to EaR experimental contexts.

Machine Learning↗
PubMed2003

Evolution of microglial and astroglial response during experimental intracerebral haemorrhage in the rat.

Intracerebral haemorrhage is a strong stimulus for both microglial and astroglial activations. There are some important pathophysiological features during haemorrhage that do not occur in ischaemic or traumatic brain injuries, and may influence the dynamics and intensity of glial activation. Studies on the evolution of glial reaction may have practical importance to the introduction of new therapeutic methods for influencing the inflammatory reaction during haemorrhage. Microglial and astroglial responses to experimental intracerebral haematoma were studied in 50 adult rats for 5 minutes after injection of 100 microl autologous arterial blood into the striatum. The survival period varied from 1 to 21 days. Microglial-macrophage lineage cells were immunocytochemically stained with antibodies OX42, OX6 and ED1. The astrocytic population was studied by means of anti-GFAP staining. Changes in cellular morphology and intensity of staining were time-dependent reactions in both microglial and astroglial cells. Strong activation of microglial-macrophage lineage cells revealed with OX6-and OX42-immunoreactivity started during the first postoperative day. The complete pattern of activation for ED1-immunoreactivity was observed from the third postoperative day. At this stage, numerous phagocytic macrophages started to appear in the perihaematoma region. Morphological changes were most intensive during the second postoperative week. The astroglial (anti-GFAP) reaction was observed after the third postoperative day and proceeded less dynamically. The glial reaction gradually stopped but not completely during the period of observation. The early occurrence of glial activation, pattern of morphological changes and characteristic sequence of antigens expression indicate a very intense type of glial reaction. Evolution of glial response to haemorrhage reveals characteristic features. In our opinion, the initial phase of glial activation, comprising 72 hours after the occurrence of haemorrhage, is potentially the most promising period for influencing the extent of glial reaction with therapeutic agents.

Animals↗
PubMed1998

Translational selection and molecular evolution.

An interplay among experimental studies of protein synthesis, evolutionary theory, and comparisons of DNA sequence data has shed light on the roles of natural selection and genetic drift in 'silent' DNA evolution.

Animals↗
PubMed1999

Dynamical evolution of sand ripples under water.

We have performed an experimental study on the evolution of sand ripples formed under the action of an oscillatory flow. An annular sand-water cell was used in order to investigate a wide range of parameters. The sand ripples follow an irreversible condensation mechanism from small to large wavelength until a final state is reached. The wavelength and the shape of these stable sand patterns are mainly governed by the fluid displacement and the static angle of the granular media. A strong hysteresis affects the evolution of steep ripples. When the acceleration of the sand bed reaches a critical value, the final pattern is modified by the superficial fluidization of the sand layer.

Journal Article↗
PubMed2025

Pervasive fitness trade-offs revealed by rapid adaptation to shifting population densities in large experimental populations of Drosophila melanogaster.

Trade-offs are an inherent feature of organismal biology that are expected play a fundamental role in the evolution of natural populations. Efforts to quantify trade-offs are largely confined to phenotypic measurements and the identification of negative genetic-correlations among fitness-relevant traits. Here, we use time-series genomic data collected during experimental evolution in large, genetically diverse populations of Drosophila melanogaster to directly measure the manifestation of trade-offs in response to fluctuating selection on ecological timescales. Specifically, we first conducted a lab-based selection experiment to quantify a genome-wide signal of antagonistic pleiotropy elicited in response to shifting population densities and associated with reproduction and stress tolerance selection. In doing so, we identified a putative role of two cosmopolitan inversions in these trade-offs. We then conducted an independent experiment to show that a simple manipulation of increasing population density under controlled lab-based conditions identified loci that are relevant to selection during population expansion and collapse in a complex, semi-natural setting. In concert, our results reveal how adaptation in complex, natural environments can be coarse-grained in such a manner to drive repeatable and predictable patterns of genomic variation, and further add credence to models positing a role of generic fitness trade-offs in the maintenance of variation in natural populations.

Drosophila melanogaster↗
PubMed2006

Universal properties of two-port scattering, impedance, and admittance matrices of wave-chaotic systems.

Statistical fluctuations in the eigenvalues of the scattering, impedance, and admittance matrices of two-port wave-chaotic systems are studied experimentally using a chaotic microwave cavity. These fluctuations are universal in that their properties are dependent only upon the degree of loss in the cavity. We remove the direct processes introduced by the nonideally coupled driving ports through a matrix normalization process that involves the radiation-impedance matrix of the two driving ports. We find good agreement between the experimentally obtained marginal probability density functions (PDFs) of the eigenvalues of the normalized impedance, admittance, and scattering matrix and those from random matrix theory (RMT). We also experimentally study the evolution of the joint PDF of the eigenphases of the normalized scattering matrix as a function of loss. Experimental agreement with the theory by Brouwer and Beenakker for the joint PDF of the magnitude of the eigenvalues of the normalized scattering matrix is also shown.

Journal Article↗
PubMed2006

Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis.

BACKGROUND: Carcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution. METHODS: A comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues. RESULTS: We identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer. CONCLUSION: The results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution.

Amino Acid Sequence↗
PubMedDate not supplied

Macroevolution is more than repeated rounds of microevolution.

Arguments over macroevolution versus microevolution have waxed and waned through most of the twentieth century. Initially, paleontologists and other evolutionary biologists advanced a variety of non-Darwinian evolutionary processes as explanations for patterns found in the fossil record, emphasizing macroevolution as a source of morphologic novelty. Later, paleontologists, from Simpson to Gould, Stanley, and others, accepted the primacy of natural selection but argued that rapid speciation produced a discontinuity between micro- and macroevolution. This second phase emphasizes the sorting of innovations between species. Other discontinuities appear in the persistence of trends (differential success of species within clades), including species sorting, in the differential success between clades and in the origination and establishment of evolutionary novelties. These discontinuities impose a hierarchical structure to evolution and discredit any smooth extrapolation from allelic substitution to large-scale evolutionary patterns. Recent developments in comparative developmental biology suggest a need to reconsider the possibility that some macroevolutionary discontinuites may be associated with the origination of evolutionary innovation. The attractiveness of macroevolution reflects the exhaustive documentation of large-scale patterns which reveal a richness to evolution unexplained by microevolution. If the goal of evolutionary biology is to understand the history of life, rather than simply document experimental analysis of evolution, studies from paleontology, phylogenetics, developmental biology, and other fields demand the deeper view provided by macroevolution.

Biological Evolution↗
PubMed2000

Further evidence for a role of nitric oxide in experimental allergic encephalomyelitis: aminoguanidine treatment modifies its clinical evolution.

The role of nitric oxide (NO) in inflammatory/demyelinating diseases is undergoing extensive investigation as a potential target for therapeutic intervention. However, interference with NO production has resulted in contrasting effects on the development of experimental allergic encephalomyelitis (EAE), the most widely used experimental model for multiple sclerosis (MS). Purpose of this paper was both the analysis of the individual clinical evolution of EAE induced in Lewis female rats by active immunisation and the evaluation of the effect of treatment with aminoguanidine, a selective inhibitor for the inducible isoform of nitric oxide synthase (iNOS). In our experimental model, relapse occurred in 66% of animals. Aminoguanidine treatment, started 3 days before immunisation, guaranteed a complete recovery from the acute phase and a delayed, milder relapse. Moreover, 79 days after immunisation inflammatory cellular infiltrates in the spinal cord were reduced. These data further support the involvement of NO in EAE evolution.

Acute Disease↗
PubMed1980

A theory of modular evolution for bacteriophages.

The modular theory of virus evolution has clear experimental support among the temperate bacteriophages of the enteric bacteria. However, there is also similar genetic and DNA heteroduplex evidence for such evolution among other families of bacteriophages: the virulent bacteriophages of the enterics comprise several families: the T-even group, the T3-T7 group (which has many members among different species of bacteria, including bacteria as widely divergent as E. coli and Caulobacter crescentus. It nicely explains the diffusion of very similar homologous bacteriophages into hosts whose own DNAs have diverged very greatly from each other in nucleotide sequence. It also accounts for the rigorous maintenance of regulatory schemes while units of function (including regions coding for proteins) diverge more rapidly. It should also be noted that the considerations that make modular evolution seem advantageous for bacteriophages apply equally well to viruses of higher organisms. Furthermore, the kinds of heteroduplex similarity observed among animal viruses are reminiscent of what is found for bacteriophages. Viruses found in widely divergent hosts show much greater similarity than would be expected; quite possibly animal viruses also evolve as a population of interchangeable modules.

Bacteriophage lambda↗
PubMed2000

The evolution of RNA viruses: A population genetics view.

RNA viruses are excellent experimental models for studying evolution under the theoretical framework of population genetics. For a proper justification of this thesis we have introduced some properties of RNA viruses that are relevant for studying evolution. On the other hand, population genetics is a reductionistic theory of evolution. It does not consider or make simplistic assumptions on the transformation laws within and between genotypic and phenotypic spaces. However, such laws are minimized in the case of RNA viruses because the phenotypic space maps onto the genotypic space in a much more linear way than on higher DNA-based organisms. Under experimental conditions, we have tested the role of deleterious and beneficial mutations in the degree of adaptation of vesicular stomatitis virus (VSV), a nonsegmented virus of negative strand. We also have studied how effective population size, initial genetic variability in populations, and environmental heterogeneity shapes the impact of mutations in the evolution of vesicular stomatitis virus. Finally, in an integrative attempt, we discuss pros and cons of the quasispecies theory compared with classic population genetics models for haploid organisms to explain the evolution of RNA viruses.

Biological Evolution↗
PubMed2004

Comparative study of macro- and microsurgical extrahepatic cholestasis in the rat.

The long-term (5-week) evolution of two experimental models of extrahepatic cholestasis, i.e., macrosurgical by bile duct ligation (n = 20) and microsurgical by biliary tract resection (n = 13), is studied. All cholestatic animals showed jaundice, choluria, and portosystemic collateral circulation. Macrosurgical cholestasis causes greater hepatosplenomegaly, hilar biliary pseudocysts, and ascites. Microsurgical extrahepatic cholestasis occurs with a lower degree of hepatosplenomegaly as well as with serum increase (P < 0.001) of gamma-GT and alkaline phosphatase. The bile ductular proliferation in the four hepatic lobes is very intense (P < 0.001) in both experimental models. The differences between both experimental models may be considered secondary to the increase of the predisposition to infection in rats with bile duct ligation, that complicates their evolution. The microsurgical cholestasis model could be useful in studying cholestasis secondary to biliary atresia.

Alkaline Phosphatase↗
PubMed1979

[The primary structure of the hemoglobin of the greylag goose (Answer anser) and the unequal evolution of the beta-chains (an experimental approach to a biochemical analysis of behaviour (author's transl)].

The primary structures of the alpha- and beta-chains from greylag goose (Anser anser) hemoglobin are given. The sequence was deduced automatically in the sequenator. They differ from chicken alpha-chains in the exchange of 30, from beta-chains in the exchange of only 8 amino acid residues, respectively. The contact points of inositol pentaphosphate with the beta-chains are identical in chicken and greylag goose. Unequal evolution of the beta-chains was found, which is published here for the first time. By comparing the sequences of chicken and greylag goose and considering paleontological data, we found the mutation rate of the alpha-chains to be normal, i.e. 6 million years/mutation. This corresponds to the values for other species. The mutation rate of beta-chains is reduced and was calculated at 25 million years/mutation. This is possibly due to a specific function of beta-chains. This paper is the basis of our attempt to explain on a molecular basis the ability of bar-headed goose (Anser indicus) to fly and breathe at high altitudes.

Altitude↗