Deleterious synonymous mutations hitchhike to high frequency in HIV-1 env evolution

Intrapatient HIV-1 evolution is dominated by selection on the protein level in the arms race with the adaptive immune system. When cytotoxic CD8+ T-cells or neutralizing antibodies target a new epitope, the virus often escapes via nonsynonymous mutations that impair recognition. Synonymous mutations do not affect this interplay and are often assumed to be neutral. We analyze longitudinal intrapatient data from the C2-V5 part of the envelope gene (env) and observe that synonymous derived alleles rarely fix even though they often reach high frequencies in the viral population. We find that synonymous mutations that disrupt base pairs in RNA stems flanking the variable loops of gp120 are more likely to be lost than other synonymous changes, hinting at a direct fitness effect of these stem-loop structures in the HIV-1 RNA. Computational modeling indicates that these synonymous mutations have a (Malthusian) selection coefficient of the order of -0.002 and that they are brought up to high frequency by hitchhiking on neighboring beneficial nonsynonymous alleles. The patterns of fixation of nonsynonymous mutations estimated from the longitudinal data and comparisons with computer models suggest that escape mutations in C2-V5 are only transiently beneficial, either because the immune system is catching up or because of competition between equivalent escapes

FFPopSim: An efficient forward simulation package for the evolution of large populations

The analysis of the evolutionary dynamics of a population with many polymorphic loci is challenging since a large number of possible genotypes needs to be tracked. In the absence of analytical solutions, forward computer simulations are an important tool in multi-locus population genetics. The run time of standard algorithms to simulate sexual populations increases as 8^L with the number L of loci, or with the square of the population size N. We have developed algorithms that allow to simulate large populations with a run-time that scales as 3^L. The algorithm is based on an analog of the Fast-Fourier Transform (FFT) and allows for arbitrary fitness functions (i.e. any epistasis) and genetic maps. The algorithm is implemented as a collection of C++ classes and a Python interface.Comment: available from: http://code.google.com/p/ffpopsi

Using argumentation theory to identify the challenges of shared decision-making when the doctor and the patient have a difference of opinion

This paper aims to identify the challenges in the implementation of shared decision-making (SDM) when the doctor and the patient have a difference of opinion. It analyses the preconditions of the resolution of this difference of opinion by using an analytical and normative framework known in the field of argumentation theory as the ideal model of critical discussion. This analysis highlights the communication skills and attitudes that both doctors and patients must apply in a dispute resolution-oriented communication. Questions arise over the methods of empowerment of doctors and patients in these skills and attitudes as the preconditions of SDM. Overall, the paper highlights aspects in which research is needed to design appropriate programmes of training, education and support in order to equip doctors and patients with the means to successfully engage in shared decision-making

A multidisciplinary approach to evaluate the effectiveness of natural attenuation at a contaminated site

This study evaluates the natural attenuation of chlorinated hydrocarbons as remediation action in a contaminated site downtown the city of Parma (Italy). To achieve this goal, a combination of new investigation methods (bio-molecular analysis, compound specific isotope analysis, phytoscreening) has been proposed. The approach (named circular multi step) allows to: fully understand the phenomena that occur at the study site, design new investigation activities, and manage best practices. Consequently, each step of the approach improves the conceptual and numerical models with new knowledge. The activities carried out at the study site allowed to detect a contamination of perchloroethylene in a large part of the city of Parma and, of main importance, underneath a kindergarten. The results of the study did not show significant natural attenuation of chlorinated hydrocarbons and that the detected contamination could refer to the same unknown contaminant source. Furthermore, the innovative phytoscreening technique was applied to assess the presence of chlorinated hydrocarbons at the ground level. The plume spread was estimated through numerical modeling starting from potential contaminant sources. This study enhances the knowledge of groundwater flow and contamination in Parma and allows authorities to design new investigation/reclamation activities through management actions

Erosive Wear Behavior of High-Chromium Cast Iron: Combined Effect of Erodent Powders and Destabilization Heat Treatments

High-chromium cast irons are frequently used in high-demanding applications, where low production costs and wear performance are key factors. The excellent abrasive resistance of these alloys results from the overall microstructural features, i.e., type, morphology, and distribution of hard primary and secondary carbides, along with the matrix constituents. Such a microstructure is the result of the chemical composition and solidification process, even though it could be further tuned by heat treatments. These latter are usually performed to destabilize the austenite and to induce the precipitation of secondary carbides. The present study investigates the combined effect of destabilization heat treatment route and erodent powder type on the erosive wear behavior of two commercial hypereutectic white cast irons. The as-received and the heat-treated materials were analyzed through optical and scanning electron microscopy, hardness tests, and X-ray diffraction to determine the relationship between microstructural variations and applied heat treatment. The erosive resistance was evaluated per the ASTM G76 standard in a purpose-built air blast test rig. Experiments were performed considering a raw meal powder, commonly used in cement factories, and Al2O3 as erodent powders. The adopted heat treatments were effective in increasing the overall hardness of the material, but this was not directly related to the erosion resistance. By contrast, the relative hardness ratio, i.e., erodent/target hardness, affects the erosion rate and different behaviors in relation to the softer/harder erodent particles were found

Milking procedures and milk ejection in Italian Brown cows

The aim of the study was to describe, on the basis of field data, the traits of milk flow curves of Italian Brown cows and to investigate some sources of variation. A total of 1,450 milk flow curves of the whole udder were collected in 81 Italian Brown dairy herds in Lombardy, Italy, using electronic mobile milk flow meters. Parity order and days in milk affected most milk flow traits. Milk flow curves showed some defects dependent on milking management practices: very long machine-on time, long duration of overmilking phase, high percentage of stripping and moderate percentage of bimodality

Parity Violation in Neutron Capture Reactions

In the last decade, the scattering of polarized neutrons on compound nucleus resonances proved to be a powerful experimental technique for probing nuclear parity violation. Longitudinal analyzing powers in neutron transmission measurements on p-wave resonances in nuclei such as $^{139}$La and $^{232}$Th were found to be as large as 10%. Here we examine the possibilities of carrying out a parallel program to measure asymmetries in the $(n,\gamma$) reaction on these same compound nuclear resonances. Symmetry-violating $(n,\gamma$) studies can also show asymmetries as large as 10%, and have the advantage over transmission experiments of allowing parity-odd asymmetries in several different gamma-decay branches from the same resonance. Thus, studies of parity violation in the $(n,\gamma)$ reaction using high efficiency germanium detectors at the Los Alamos Lujan facility, for example, could determine the parity-odd nucleon-nucleon matrix elements in complex nuclei with high accuracy. Additionally, simultaneous studies of the E1 and $V_{PNC}$ matrix elements invol ved in these decays could be used to help constrain the statistical theory of parity non-conservation in compound nuclei.Comment: 10 pages, 1 figur