Fluctuations of fitness distributions and the rate of Muller's ratchet

The accumulation of deleterious mutations is driven by rare fluctuations which lead to the loss of all mutation free individuals, a process known as Muller's ratchet. Even though Muller's ratchet is a paradigmatic process in population genetics, a quantitative understanding of its rate is still lacking. The difficulty lies in the nontrivial nature of fluctuations in the fitness distribution which control the rate of extinction of the fittest genotype. We address this problem using the simple but classic model of mutation selection balance with deleterious mutations all having the same effect on fitness. We show analytically how fluctuations among the fittest individuals propagate to individuals of lower fitness and have a dramatically amplified effects on the bulk of the population at a later time. If a reduction in the size of the fittest class reduces the mean fitness only after a delay, selection opposing this reduction is also delayed. This delayed restoring force speeds up Muller's ratchet. We show how the delayed response can be accounted for using a path integral formulation of the stochastic dynamics and provide an expression for the rate of the ratchet that is accurate across a broad range of parameters.Comment: Genetics 201

Co-trimoxazole prophylaxis in HIV : the evidence

BibliographyHuman immunodeficiency virus (HIV) damages the body’s immune system, making secondary (or opportunistic) infections more common. Treatment and prevention of such infections is integral to the management of patients with HIV infection. Co-trimoxazole is a prophylactic treatment that has a wide range of action against common bacteria, parasites, fungi and yeasts. As part of a minimum care package, UNAIDS/ WHO recommends co-trimoxazole prophylaxis for HIVinfected adults with symptomatic disease (WHO stage II, III or IV), or asymptomatic individuals with CD4 counts ≤500 cells/μl, and for all HIV-positive pregnant women after the first trimester.1 Co-trimoxazole is also recommended for use in children with proven HIV infection and infants exposed to HIV (from 4 - 6 weeks of age until infection with HIV is ruled out).2 The object of this report is to summarise the effects of co-trimoxazole prophylaxis on morbidity and mortality among HIV-infected individuals

Sharp transition towards shared vocabularies in multi-agent systems

What processes can explain how very large populations are able to converge on the use of a particular word or grammatical construction without global coordination? Answering this question helps to understand why new language constructs usually propagate along an S-shaped curve with a rather sudden transition towards global agreement. It also helps to analyze and design new technologies that support or orchestrate self-organizing communication systems, such as recent social tagging systems for the web. The article introduces and studies a microscopic model of communicating autonomous agents performing language games without any central control. We show that the system undergoes a disorder/order transition, going trough a sharp symmetry breaking process to reach a shared set of conventions. Before the transition, the system builds up non-trivial scale-invariant correlations, for instance in the distribution of competing synonyms, which display a Zipf-like law. These correlations make the system ready for the transition towards shared conventions, which, observed on the time-scale of collective behaviors, becomes sharper and sharper with system size. This surprising result not only explains why human language can scale up to very large populations but also suggests ways to optimize artificial semiotic dynamics.Comment: 12 pages, 4 figure

Calibration of optimal execution of financial transactions in the presence of transient market impact

Trading large volumes of a financial asset in order driven markets requires the use of algorithmic execution dividing the volume in many transactions in order to minimize costs due to market impact. A proper design of an optimal execution strategy strongly depends on a careful modeling of market impact, i.e. how the price reacts to trades. In this paper we consider a recently introduced market impact model (Bouchaud et al., 2004), which has the property of describing both the volume and the temporal dependence of price change due to trading. We show how this model can be used to describe price impact also in aggregated trade time or in real time. We then solve analytically and calibrate with real data the optimal execution problem both for risk neutral and for risk averse investors and we derive an efficient frontier of optimal execution. When we include spread costs the problem must be solved numerically and we show that the introduction of such costs regularizes the solution.Comment: 31 pages, 8 figure

A variational method based on weighted graph states

In a recent article [Phys. Rev. Lett. 97 (2006), 107206], we have presented a class of states which is suitable as a variational set to find ground states in spin systems of arbitrary spatial dimension and with long-range entanglement. Here, we continue the exposition of our technique, extend from spin 1/2 to higher spins and use the boson Hubbard model as a non-trivial example to demonstrate our scheme.Comment: 36 pages, 13 figure

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Colonyzer: automated quantification of micro-organism growth characteristics on solid agar

<p>Abstract</p> <p>Background</p> <p>High-throughput screens comparing growth rates of arrays of distinct micro-organism cultures on solid agar are useful, rapid methods of quantifying genetic interactions. Growth rate is an informative phenotype which can be estimated by measuring cell densities at one or more times after inoculation. Precise estimates can be made by inoculating cultures onto agar and capturing cell density frequently by plate-scanning or photography, especially throughout the exponential growth phase, and summarising growth with a simple dynamic model (e.g. the logistic growth model). In order to parametrize such a model, a robust image analysis tool capable of capturing a wide range of cell densities from plate photographs is required.</p> <p>Results</p> <p>Colonyzer is a collection of image analysis algorithms for automatic quantification of the size, granularity, colour and location of micro-organism cultures grown on solid agar. Colonyzer is uniquely sensitive to extremely low cell densities photographed after dilute liquid culture inoculation (spotting) due to image segmentation using a mixed Gaussian model for plate-wide thresholding based on pixel intensity. Colonyzer is robust to slight experimental imperfections and corrects for lighting gradients which would otherwise introduce spatial bias to cell density estimates without the need for imaging dummy plates. Colonyzer is general enough to quantify cultures growing in any rectangular array format, either growing after pinning with a dense inoculum or growing with the irregular morphology characteristic of spotted cultures. Colonyzer was developed using the open source packages: Python, RPy and the Python Imaging Library and its source code and documentation are available on SourceForge under GNU General Public License. Colonyzer is adaptable to suit specific requirements: e.g. automatic detection of cultures at irregular locations on streaked plates for robotic picking, or decreasing analysis time by disabling components such as lighting correction or colour measures.</p> <p>Conclusion</p> <p>Colonyzer can automatically quantify culture growth from large batches of captured images of microbial cultures grown during genome-wide scans over the wide range of cell densities observable after highly dilute liquid spot inoculation, as well as after more concentrated pinning inoculation. Colonyzer is open-source, allowing users to assess it, adapt it to particular research requirements and to contribute to its development.</p

Classical kinetic energy, quantum fluctuation terms and kinetic-energy functionals

We employ a recently formulated dequantization procedure to obtain an exact expression for the kinetic energy which is applicable to all kinetic-energy functionals. We express the kinetic energy of an N-electron system as the sum of an N-electron classical kinetic energy and an N-electron purely quantum kinetic energy arising from the quantum fluctuations that turn the classical momentum into the quantum momentum. This leads to an interesting analogy with Nelson's stochastic approach to quantum mechanics, which we use to conceptually clarify the physical nature of part of the kinetic-energy functional in terms of statistical fluctuations and in direct correspondence with Fisher Information Theory. We show that the N-electron purely quantum kinetic energy can be written as the sum of the (one-electron) Weizsacker term and an (N-1)-electron kinetic correlation term. We further show that the Weizsacker term results from local fluctuations while the kinetic correlation term results from the nonlocal fluctuations. For one-electron orbitals (where kinetic correlation is neglected) we obtain an exact (albeit impractical) expression for the noninteracting kinetic energy as the sum of the classical kinetic energy and the Weizsacker term. The classical kinetic energy is seen to be explicitly dependent on the electron phase and this has implications for the development of accurate orbital-free kinetic-energy functionals. Also, there is a direct connection between the classical kinetic energy and the angular momentum and, across a row of the periodic table, the classical kinetic energy component of the noninteracting kinetic energy generally increases as Z increases.Comment: 10 pages, 1 figure. To appear in Theor Chem Ac