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

Theory and practice of optimal mutation rate control in Hamming spaces of DNA sequences

We investigate the problem of optimal control of mutation by asexual self-replicating organisms represented by points in a metric space. We introduce the notion of a relatively monotonic fitness landscape and consider a generalisation of Fisher's geometric model of adaptation for such spaces. Using a Hamming space as a prime example, we derive the probability of adaptation as a function of reproduction parameters (e.g. mutation size or rate). Optimal control rules for the parameters are derived explicitly for some relatively monotonic landscapes, and then a general information-based heuristic is introduced. We then evaluate our theoretical control functions against optimal mutation functions evolved from a random population of functions using a meta genetic algorithm. Our experimental results show a close match between theory and experiment. We demonstrate this result both in artificial fitness landscapes, defined by a Hamming distance, and a natural landscape, where fitness is defined by a DNA-protein affinity. We discuss how a control of mutation rate could occur and evolve in natural organisms. We also outline future directions of this work

Community-Acquired Pneumonia in Sub-Saharan Africa

Community-acquired pneumonia (CAP) in sub-Saharan Africa is a common cause of adult hospitalization and is associated with significant mortality. Human immunodeficiency virus (HIV) prevalence in the region leads to differences in CAP epidemiology compared with most high-income settings: patients are younger, and coinfection with tuberculosis and opportunistic infections is common and difficult to diagnose. Resource limitations affect the availability of medical expertise as well as radiological and laboratory diagnostic services. These factors impact on key aspects of health care, including pathways of investigation, severity assessment, and the selection of empirical antimicrobial therapy. This review summarizes recent data from sub-Saharan Africa describing the burden, etiology, risk factors, and outcome of CAP. We describe the rational and context-appropriate approach to CAP diagnosis and management, including supportive therapy. Priorities for future research to inform strategies for CAP prevention and initial management are suggested

Critical mutation rate has an exponential dependence on population size for eukaryotic-length genomes with crossover

The critical mutation rate (CMR) determines the shift between survival-of-the-fittest and survival of individuals with greater mutational robustness (“flattest”). We identify an inverse relationship between CMR and sequence length in an in silico system with a two-peak fitness landscape; CMR decreases to no more than five orders of magnitude above estimates of eukaryotic per base mutation rate. We confirm the CMR reduces exponentially at low population sizes, irrespective of peak radius and distance, and increases with the number of genetic crossovers. We also identify an inverse relationship between CMR and the number of genes, confirming that, for a similar number of genes to that for the plant Arabidopsis thaliana (25,000), the CMR is close to its known wild-type mutation rate; mutation rates for additional organisms were also found to be within one order of magnitude of the CMR. This is the first time such a simulation model has been assigned input and produced output within range for a given biological organism. The decrease in CMR with population size previously observed is maintained; there is potential for the model to influence understanding of populations undergoing bottleneck, stress, and conservation strategy for populations near extinction

Environmental pleiotropy and demographic history direct adaptation under antibiotic selection

Evolutionary rescue following environmental change requires mutations permitting population growth in the new environment. If change is severe enough to prevent most of the population reproducing, rescue becomes reliant on mutations already present. If change is sustained, the fitness effects in both environments, and how they are associated—termed ‘environmental pleiotropy’—may determine which alleles are ultimately favoured. A population’s demographic history—its size over time—influences the variation present. Although demographic history is known to affect the probability of evolutionary rescue, how it interacts with environmental pleiotropy during severe and sustained environmental change remains unexplored. Here, we demonstrate how these factors interact during antibiotic resistance evolution, a key example of evolutionary rescue fuelled by pre-existing mutations with pleiotropic fitness effects. We combine published data with novel simulations to characterise environmental pleiotropy and its effects on resistance evolution under different demographic histories. Comparisons among resistance alleles typically revealed no correlation for fitness—i.e., neutral pleiotropy—above and below the sensitive strain’s minimum inhibitory concentration. Resistance allele frequency following experimental evolution showed opposing correlations with their fitness effects in the presence and absence of antibiotic. Simulations demonstrated that effects of environmental pleiotropy on allele frequencies depended on demographic history. At the population level, the major influence of environmental pleiotropy was on mean fitness, rather than the probability of evolutionary rescue or diversity. Our work suggests that determining both environmental pleiotropy and demographic history is critical for predicting resistance evolution, and we discuss the practicalities of this during in vivo evolution

Chondromyxoid fibroma management: a single institution experience of 22 cases

Background: Several different strategies have been reported for the treatment of chondromyxoid fibromas, all with variable outcomes and high recurrence rates. Methods: We report on 22 consecutive cases of chondromyxoid fibromas treated by intralesional curettage, four of which had adjuvant cementation at our institution between 2003 and 2010. We assessed the functional outcome using the Musculoskeletal Tumour Society (MSTS) scoring system. Results: Nine males and 16 females with a mean age of 36.5 years (range 11 to 73) and a mean follow-up of 60.7 months were included in the study. Local recurrence occurred in two patients (9%) within the first 2 years following the index procedure. This was treated by re-curettage only of the residual defect. Two postoperative complications occurred: a superficial wound infection in one patient and a transient deep peroneal nerve neurapraxia in the other. The mean postoperative MSTS score was 96.7%. Conclusions: Intralesional curettage and cementation is as an effective treatment strategy for chondromyxoid fibromas, providing satisfactory functional results with a low recurrence rate. Careful case selection with stringent clinical and radiographic follow-up is recommended

Constraining the Kpi vector form factor by tau---> K pi nu_tau and K_l3 decay data

A subtracted dispersive representation of the $K\pi$ vector form factor, $F_+^{K\pi}$, is used to fit the Belle spectrum of \tauKpi decays incorporating constraints from results on $K_{l3}$ decays. Through the use of three subtractions, the slope and curvature of $F_+^{K\pi}$ are obtained directly from the data yielding $\lambda_+'=(25.49 \pm 0.31) \times 10^{-3}$ and $\lambda_+"= (12.22 \pm 0.14) \times 10^{-4}$. The phase-space integrals relevant for $K_{l3}$ analyses are calculated. Additionally, from the pole position on the second Riemann sheet the mass and width of the $K^*(892)^\pm$ are found to be $m_{K^*(892)^\pm}= 892.0\pm 0.5$ MeV and $\Gamma_{K^*(892)^\pm}= 46.5 \pm 1.1$ MeV. Finally, we study the $P$-wave isospin-1/2 $K\pi$ phase-shift and its threshold parameters.Comment: Talk presented at 15th International QCD Conference, Montpellier, France. Submitted to Nuc. Phys. (Proc. Suppl.), 4 pages, 1 figur

Strong Decays of Strange Quarkonia

In this paper we evaluate strong decay amplitudes and partial widths of strange mesons (strangeonia and kaonia) in the 3P0 decay model. We give numerical results for all energetically allowed open-flavor two-body decay modes of all nsbar and ssbar strange mesons in the 1S, 2S, 3S, 1P, 2P, 1D and 1F multiplets, comprising strong decays of a total of 43 resonances into 525 two-body modes, with 891 numerically evaluated amplitudes. This set of resonances includes all strange qqbar states with allowed strong decays expected in the quark model up to ca. 2.2 GeV. We use standard nonrelativistic quark model SHO wavefunctions to evaluate these amplitudes, and quote numerical results for all amplitudes present in each decay mode. We also discuss the status of the associated experimental candidates, and note which states and decay modes would be especially interesting for future experimental study at hadronic, e+e- and photoproduction facilities. These results should also be useful in distinguishing conventional quark model mesons from exotica such as glueballs and hybrids through their strong decays.Comment: 69 pages, 5 figures, 39 table