Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms

Quantifying the Adaptive Potential of an Antibiotic Resistance Enzyme

For a quantitative understanding of the process of adaptation, we need to understand its “raw material,” that is, the frequency and fitness effects of beneficial mutations. At present, most empirical evidence suggests an exponential distribution of fitness effects of beneficial mutations, as predicted for Gumbel-domain distributions by extreme value theory. Here, we study the distribution of mutation effects on cefotaxime (Ctx) resistance and fitness of 48 unique beneficial mutations in the bacterial enzyme TEM-1 β-lactamase, which were obtained by screening the products of random mutagenesis for increased Ctx resistance. Our contributions are threefold. First, based on the frequency of unique mutations among more than 300 sequenced isolates and correcting for mutation bias, we conservatively estimate that the total number of first-step mutations that increase Ctx resistance in this enzyme is 87 [95% CI 75–189], or 3.4% of all 2,583 possible base-pair substitutions. Of the 48 mutations, 10 are synonymous and the majority of the 38 non-synonymous mutations occur in the pocket surrounding the catalytic site. Second, we estimate the effects of the mutations on Ctx resistance by determining survival at various Ctx concentrations, and we derive their fitness effects by modeling reproduction and survival as a branching process. Third, we find that the distribution of both measures follows a Fréchet-type distribution characterized by a broad tail of a few exceptionally fit mutants. Such distributions have fundamental evolutionary implications, including an increased predictability of evolution, and may provide a partial explanation for recent observations of striking parallel evolution of antibiotic resistance

Activity and Interactions of Liposomal Antibiotics in Presence of Polyanions and Sputum of Patients with Cystic Fibrosis

BACKGROUND:To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA). METHODOLOGY:Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated. RESULTS:The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations--DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold. CONCLUSIONS:Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections

Corrosion behaviour of Mg alloys cladding from nuclear reactors fuel in alkaline solutions

International audienceThe reprocessing of spent fuel from the French UNGG (Graphite Gas Natural Uranium) nuclear power plants generates cladding wastes such are Mg-Mn alloys. A storage strategy is to encapsulate these wastes into cement matrix. The main issue is hydrogen evolution as the main consequence of the corrosion of Mg alloys, regardless of concrete radiolysis. In fact Mg acts as an anode in most of galvanic corrosion systems and the hydrogen can be produced either by water reduction or by Anodic Hydrogen Evolution (AHE). In the last case, an increase in the rate of hydrogen production with increasing applied potential is observed. This phenomenon called "Neg-ative Different Effect" (NDE) is in contradiction with the conventional Tafel equation. The corrosion of magnesium may produce Mg$^+$ cations which react quickly with water to produce hydrogen and stable Mg$^{2+}$ cations. The interstitial solution in concrete pores is characterized by a very high pH. To reproduce the pH solution around 13, 0.1M NaOH solutions were prepared and used as electrolytes from electrochemical experiments. Stainless steel, platinum and graphite were used as cathode to investigate basic galvanic coupling as it can be encountered in the real wastes. The purpose of this work was to investigate the galvanic corrosion of Mg alloys in the high pH solutions. The study of Mg corrosion behaviour was carried out using elec-trochemical measurement: ZRA mode. The analysis of the surface and the corrosion products were performed by Raman spectroscopy. The first results showed a galvan-ic corrosion rate more important with stainless steel rather than with graphite

Les données expérimentales relatives au mécanisme de la division cellulaire

SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Influence d'une couche passive sur la cinétique de réduction d'un couple électrochimique

National audienceEn France, le traitement recyclage des combustibles nucléaires usés est basé sur le procédé PUREX (Plutonium and Uranium Refining by Extraction) pour séparer l’uranium et le plutonium des produits de fission.En amont de PUREX, de l’acide nitrique est utilisé pour dissoudre le combustible. Ainsi de nombreux équipements de l’usine sont en contact avec cet acide. Pour ces équipements, des matériaux passifs ont été judicieusement choisis (aciers inoxydables austénitiques et zirconium) pour leur bonne tenue à la corrosion par l’acide nitrique.Dans le cadre de la maitrise de la durée de vie de ces équipements sur le long terme, un effort est réalisé au sein du LECNA pour modéliser la tenue à la corrosion de ces matériaux en milieu acide nitriqu