Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

Probing Evolutionary Repeatability: Neutral and Double Changes and the Predictability of Evolutionary Adaptation

The question of how organisms adapt is among the most fundamental in evolutionary biology. Two recent studies investigated the evolution of Escherichia coli in response to challenge with the antibiotic cefotaxime. Studying five mutations in the beta-lactamase gene that together confer significant antibiotic resistance, the authors showed a complex fitness landscape that greatly constrained the identity and order of intermediates leading from the initial wildtype genotype to the final resistant genotype. Out of 18 billion possible orders of single mutations leading from non-resistant to fully-resistant form, they found that only 27 (1.5x10(-7)%) pathways were characterized by consistently increasing resistance, thus only a tiny fraction of possible paths are accessible by positive selection. I further explore these data in several ways.Allowing neutral changes (those that do not affect resistance) increases the number of accessible pathways considerably, from 27 to 629. Allowing multiple simultaneous mutations also greatly increases the number of accessible pathways. Allowing a single case of double mutation to occur along a pathway increases the number of pathways from 27 to 259, and allowing arbitrarily many pairs of simultaneous changes increases the number of possible pathways by more than 100 fold, to 4800. I introduce the metric 'repeatability,' the probability that two random trials will proceed via the exact same pathway. In general, I find that while the total number of accessible pathways is dramatically affected by allowing neutral or double mutations, the overall evolutionary repeatability is generally much less affected.These results probe the conceivable pathways available to evolution. Even when many of the assumptions of the analysis of Weinreich et al. (2006) are relaxed, I find that evolution to more highly cefotaxime resistant beta-lactamase proteins is still highly repeatable

Current whole-body MRI applications in the neurofibromatoses

ObjectivesThe Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials.MethodsA systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy.ResultsWB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility.ConclusionsWB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI

Solid phase extraction for removal of matrix effects in lipophilic marine toxin analysis by liquid chromatography-tandem mass spectrometry

The potential of solid phase extraction (SPE) clean-up has been assessed to reduce matrix effects (signal suppression or enhancement) in the liquid chromatography-tandem mass spectrometry (LC¿MS/MS) analysis of lipophilic marine toxins. A large array of ion-exchange, silica-based, and mixed-function SPE sorbents was tested. Polymeric sorbents were found to retain most of the toxins. Optimization experiments were carried out to maximize recoveries and the effectiveness of the clean-up. In LC¿MS/MS analysis, the observed matrix effects can depend on the chromatographic conditions used, therefore, two different HPLC methods were tested, using either an acidic or an alkaline mobile phase. The recovery of the optimized SPE protocol was around 90% for all toxins studied and no break-through was observed. The matrix effects were determined by comparing signal response from toxins spiked in crude and SPE-cleaned extracts with those derived from toxins prepared in methanol. In crude extracts, all toxins suffered from matrix effects, although in varying amounts. The most serious effects were observed for okadaic acid (OA) and pectenotoxin-2 (PTX2) in the positive electrospray ionization mode (ESI+). SPE clean-up on polymeric sorbents in combination with the alkaline LC method resulted in a substantial reduction of matrix effects to less than 15% (apparent recovery between 85 and 115%) for OA, yessotoxin (YTX) in ESI¿ and azaspiracid-1 (AZA1), PTX2, 13-desmethyl spirolides C (SPX1), and gymnodimine (GYM) in ESI+. In combination with the acidic LC method, the matrix effects after SPE were also reduced but nevertheless approximately 30% of the matrix effects remained for PTX2, SPX1, and GYM in ESI+. It was concluded that SPE of methanolic shellfish extracts can be very useful for reduction of matrix effects. However, the type of LC and MS methods used is also of great importance. SPE on polymeric sorbents in combination with LC under alkaline conditions was found the most effective method

Clinical Interactions in Electronic Medical Records Towards the Development of a Token-Economy Model

The use of electronic medical records (EMRs) plays a crucial role in the successful implementation of the Universal Healthcare Law which promises quality and affordable healthcare to all Filipinos. Consequently, the current adoption of EMRs should be studied from the perspective of the healthcare provider. As most studies look into use of EMRs by doctors or patients, there are very few that extend studies to look at possible interaction of doctor and patient in the same EMR environment. Understanding this interaction paves the way for possible incentives that will increase the use and adoption of the EMR. This study uses process mining to understand simulated doctor-patient interaction, with the goal of developing interaction features and a token economy framework to increase EMR adoption. Results from the process mining showed that current EMR interaction remains low, and highlighted the need for interaction features to promote preventive healthcare. Moreover, process mining from the simulated logs showed that consistency and time are important factors in encouraging usage. Activity category, relative frequency of activity, relative case frequency of activity and average time spent on activity are features that may serve as the foundation for a token economy framework for EMRs

Chemical Evaluation of African Palm Weevil, Rhychophorus phoenicis, Larvae as a Food Source

The chemical properties of the African palm weevil, Rhychophorus phoenicis (F.) (Coleoptera: Curculionidae), larvae were evaluated using standard methodology. The chloroform-methanol extract yielded 37.12% on a dry basis. The oil was liquid at room temperature with a flash point of 36.0 °C. Analysis of the physical constants indicated values of 192.25 Wijs and 427.70 mg KOH/g as iodine and saponification, respectively. Fatty acid analysis of the extracted oil showed the presence of unsaturated fatty acids at low levels. Palmitic acid and stearic acid constituted 35.3 and 60.5% of the oil, respectively. The usual behaviour of the oil at room temperature, irrespective of the level of unsaturation of its constituent fatty acid was noted. The total protein content of the defatted palm weevil larva (dry basis) was estimated at 66.3%. The amino acid values compared favourably to FAO reference protein, except for tryptophan, which was limiting. All the other essential amino acids were adequate. Mineral analysis revealed high levels of potassium (1025 mg/100 g) and phosphorus (685 mg/100 g). The dried and defatted palm weevil lava represents a very good source of protein, and a good complement of essential amino acids

Experimental delayed-choice entanglement swapping

Motivated by the question, which kind of physical interactions and processes are needed for the production of quantum entanglement, Peres has put forward the radical idea of delayed-choice entanglement swapping. There, entanglement can be "produced a posteriori, after the entangled particles have been measured and may no longer exist". In this work we report the first realization of Peres' gedanken experiment. Using four photons, we can actively delay the choice of measurement-implemented via a high-speed tunable bipartite state analyzer and a quantum random number generator-on two of the photons into the time-like future of the registration of the other two photons. This effectively projects the two already registered photons onto one definite of two mutually exclusive quantum states in which either the photons are entangled (quantum correlations) or separable (classical correlations). This can also be viewed as "quantum steering into the past"

Exact exchange-correlation potential of a ionic Hubbard model with a free surface

We use Lanczos exact diagonalization to compute the exact exchange-correlation (xc) potential of a Hubbard chain with large binding energy ("the bulk") followed by a chain with zero binding energy ("the vacuum"). Several results of density functional theory in the continuum (sometimes controversial) are verified in the lattice. In particular we show explicitly that the fundamental gap is given by the gap in the Kohn-Sham spectrum plus a contribution due to the jump of the xc-potential when a particle is added. The presence of a staggered potential and a nearest-neighbor interaction V allows to simulate a ionic solid. We show that in the ionic regime in the small hopping amplitude limit the xc-contribution to the gap equals V, while in the Mott regime it is determined by the Hubbard U interaction. In addition we show that correlations generates a new potential barrier at the surface