Biomedical subjects
Publications and source records attributed to F Taddei.
Genomic sequences provide evidence for a common origin of life and its evolution via selection of genetic variants created by mutation and recombination. Two classes of genes are known to accelerate mutation and/or recombination rates in bacterial populations: stress-inducible wild-type genes, usually part of the SOS regulon, and genes whose functional loss, or downregulation, increases the rate of genetic variability (mutator and/or hyper-rec mutants).
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Conjugational crosses trigger SOS induction in Escherichia coli F(-) cells mated with Salmonella enterica serovar Typhimurium Hfr donors. Using an epigenetic indicator of SOS induction, we showed that a strong SOS response occurring in a subpopulation of mated mismatch repair-deficient cells totally abolishes genetic barriers between these two genera.
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Genomic sequence data provide evidence for a common origin of life and for its evolution by genetic variation via mutation and recombination. This paper discusses the fundamental dialectic paradigm of evolution--stability versus variability--at the crossroads of molecular genetics, population genetics, ecology, and the emerging science of experimental evolution. Experimental evolution of molecules, viruses, and bacteria can be used not only to test some basic evolutionary hypotheses but also to create new organisms for applications in biotechnology, agriculture, and medicine.
Selection of mutator alleles, increasing the mutation rate up to 10, 000-fold, has been observed during in vitro experimental evolution. This spread is ascribed to the hitchhiking of mutator alleles with favorable mutations, as demonstrated by a theoretical model using selective parameters corresponding to such experiments. Observations of unexpectedly high frequencies of mutators in natural isolates suggest that the same phenomenon could occur in the wild. But it remains questionable whether realistic in natura parameter values could also result in selection of mutators. In particular, the main parameters of adaptation, the size of the adapting population and the height and steepness of the adaptive peak characterizing adaptation, are very variable in nature. By simulation approach, we studied the effect of these parameters on the selection of mutators in asexual populations, assuming additive fitness. We show that the larger the population size, the more likely the fixation of mutator alleles. At a large population size, at least four adaptive mutations are needed for mutator fixation; moreover, under stronger selection stronger mutators are selected. We propose a model based on multiple mutations to illustrate how second-order selection can optimize population fitness when few favorable mutations are required for adaptation.
The objective of this study was to describe the normal blood flow velocity waveforms in the main branches of the right and left pulmonary arteries in the human fetus and to establish reference ranges for different Doppler parameters during the second half of pregnancy. Cross-sectional data were collected from 86 healthy human singleton fetuses between 18 and 38 weeks of gestation. With advancing gestation a significant increase (p < 0.001) in the peak systolic velocity, time averaged velocity and time velocity integral was observed. The pulsatility index decreased significantly (p < 0.05) in the same period, suggesting a decrease in the pulmonary arterial vascular resistance. The acceleration time (AT) and the ratio of AT to ejection time (AT/ET), described in postnatal cardiology as having an inverse correlation with mean arterial pressure, increased significantly (p < 0.001). This is possibly the result of decreased pulmonary arterial pressure. The data show that Doppler examination of blood flow in the main stem of both the right and the left pulmonary arteries of the fetus is feasible, and increases insight into the lung perfusion of the human fetus. The observed changes throughout gestation are in accordance with animal experiments showing an increase in perfusion as well as a decrease in the vascular resistance and pressure.
The advent of fetal echocardiography combined with Doppler technology gave the clinicians the possibility to evaluate and clarify the main aspects of fetal and postnatal circulatory physiology. From the end of cardiogenesis to the end of gestation the developmental changes of the fetal myocardial structure, ventricular function and circulatory physiology have all been studied. Also the physiological features of the transitional circulation in the first postnatal period, as well as the developmental changes in the morphology and function of the neonatal ventricles can be assessed by Doppler echocardiography. This review is divided in two parts. In the first one we will briefly discuss the contractile properties of the fetal myocardium, the cardiac performance and dynamics of the fetal circulation; in the second one we will consider the physiological aspects of the transitional circulation, the structural features of the immature neonatal myocardium, as well as the developmental changes of the myocardial mechanics as shown by Doppler ultrasound.
Oxidized guanine (8-oxo-7,8-dihydroguanine; 8-oxo-G) is a potent mutagen because of its ambiguous pairing with cytosine and adenine. The Escherichia coli MutT protein specifically hydrolyzes both 8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) and 8-oxo-guanosine triphosphate (8-oxo-rGTP), which are otherwise incorporated in DNA and RNA opposite template A. In vivo, this cleaning of the nucleotide pools decreases both DNA replication and transcription errors. The effect of mutT mutation on transcription fidelity was shown to depend on oxidative metabolism. Such control of transcriptional fidelity by the ubiquitous MutT function has implications for evolution of RNA-based life, phenotypic expression, adaptive mutagenesis, and functional maintenance of nondividing cells.
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Speciation involves the establishment of genetic barriers between closely related organisms. The extent of genetic recombination is a key determinant and a measure of genetic isolation. The results reported here reveal that genetic barriers can be established, eliminated, or modified by manipulating two systems which control genetic recombination, SOS and mismatch repair. The extent of genetic isolation between enterobacteria is a simple mathematical function of DNA sequence divergence. The function does not depend on hybrid DNA stability, but rather on the number of blocks of sequences identical in the two mating partners and sufficiently large to allow the initiation of recombination. Further, there is no obvious discontinuity in the function that could be used to define a level of divergence for distinguishing species.
Because most newly arising mutations are neutral or deleterious, it has been argued that the mutation rate has evolved to be as low as possible, limited only by the cost of error-avoidance and error-correction mechanisms. But up to one per cent of natural bacterial isolates are 'mutator' clones that have high mutation rates. We consider here whether high mutation rates might play an important role in adaptive evolution. Models of large, asexual, clonal populations adapting to a new environment show that strong mutator genes (such as those that increase mutation rates by 1,000-fold) can accelerate adaptation, even if the mutator gene remains at a very low frequency (for example, 10[-5]). Less potent mutators (10 to 100-fold increase) can become fixed in a fraction of finite populations. The parameters of the model have been set to values typical for Escherichia coli cultures, which behave in a manner similar to the model in long-term adaptation experiments.
Besides an immediate cellular adaptation to stress, organisms can resist such challenges through changes in their genetic material. These changes can be due to mutation or acquisition of pre-evolved functions via horizontal transfer. In this chapter we will review evidence from bacterial genetics that suggests that the frequency of such events can increase in response to stress by activating mutagenic response (e.g. the SOS response) and by inhibiting antimutagenic activities (e.g. mismatch repair system, MRS). Natural selection, by favoring adaptations, can also select for the mechanism(s) that has/have generated the adaptive changes by hitchhiking. These mutator mechanisms can sometimes respond very specifically, though blindly, to the challenge of the environment. Such stress-induced increases in mutation rates enhance genetic polymorphism, which is the structural component of the barrier to genetic exchange. Since SOS and MRS are the enzymatic controls of this barrier, the modulation of these systems can lead to a burst of speciation.
Bacteria live in unstructured and structured environments, experiencing feast and famine lifestyles. Bacterial colonies can be viewed as model structured environments. SOS induction and mutagenesis have been observed in aging Escherichia coli colonies, in the absence of exogenous sources of DNA damage. This cAMP-dependent mutagenesis occurring in Resting Organisms in a Structured Environment (ROSE) is unaffected by a umuC mutation and therefore differs from both targeted UV mutagenesis and recA730 (SOS constitutive) untargeted mutagenesis. As a recB mutation has only a minor effect on ROSE mutagenesis it also differs from both adaptive reversion of the lacI33 allele and from iSDR (inducible Stable DNA Replication) mutagenesis. Besides its recA and lexA dependence, ROSE mutagenesis is also uvrB and polA dependent. These genetic requirements are reminiscent of the untargeted mutagenesis in lambda phage observed when unirradiated lambda infects UV-irradiated E. coli. These mutations, which are not observed in aging liquid cultures, accumulate linearly with the age of the colonies. ROSE mutagenesis might offer a good model for bacterial mutagenesis in structured environments such as biofilms and for mutagenesis of quiescent eukaryotic cells.
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UNLABELLED: A Methodical Study: AIM OF THE STUDY: To analyse the feasibility of colour and spectral Doppler assessment of blood flow in the fetal right (RPA) and left (LPA) main pulmonary arteries in relation to fetal position and to gestational age. STUDY DESIGN: The fetal position was a priori divided into 3 types, depending on whether the fetal heart was visualised apically (Type 1), from the right side (Type 2) or from the left side (Type 3). Three groups A (19-25 weeks gestation), B (26-32) and C (33-39) including 33 consecutive pregnancies each, were examined to document the fetal position as well as the rate of the successful Doppler examinations of the RPA and/or LPA. RESULTS: The fetal position Type 2 was most common throughout gestation (in group A = 42%, B = 36%, C = 51%) followed by the type 3 and then type 1. The rate of successful Doppler records from the RPA and LPA depended on the fetal position: In Type 2 RPA in 98%; in Type 3, LPA in 100%; but the apical approach was not effective (< 40%). Depending on gestational age, the success rates for a Doppler examination of at least one vessel were high (> 85%), whereas successful examination of both vessels was unlikely (12%). CONCLUSIONS: In the second half of pregnancy, independent of fetal position, Doppler examination of at least one pulmonary artery is successful in most cases, whereas the assessment of both vessels is rather difficult.
Barriers to chromosomal gene transfer between bacterial species control their genetic isolation. These barriers, such as different microhabitats, the host ranges of genetic exchange vectors and restriction-modification systems, limit gene exchange, but the major limitation is genomic sequence divergence. The mismatch-repair system inhibits interspecies recombination, the inducible SOS system stimulates interspecies recombination, while natural selection determines the effective recombination frequencies.
The objective of this study was to describe blood flow velocity waveforms of fetal peripheral pulmonary arteries in normally grown and growth-retarded fetuses. Doppler studies were performed in 182 normally grown fetuses (gestational age 18-40 weeks) and in 61 growth-retarded fetuses (gestational age 24-36 weeks) that were free from structural and chromosomal abnormalities and whose umbilical and middle cerebral artery Doppler findings suggested uteroplacental insufficiency as the most likely etiology of the growth defect. The pulsatility index was used to quantify the velocity waveforms. Successful recordings were obtained in 90.1% of the normally grown and 93.4% of the growth-retarded fetuses. In normally grown fetuses the pulsatility index values significantly decreased with advancing gestation. In growth-retarded fetuses the pulsatility index values were significantly elevated compared to those of normal fetuses. A significant relationship was observed between the severity of hypoxia and pulsatility index values from the peripheral pulmonary arteries in 29 fetuses in which Doppler recordings were obtained immediately before cordocentesis. In conclusion, these data show that in normal fetuses the Doppler-measured impedance to flow in the peripheral pulmonary circulation decreases with advancing gestation. Impedance to flow in the lungs is elevated in the presence of growth retardation and this increase is related to the severity of fetal hypoxia.