Phenotypic switching of populations of cells in a stochastic environment

In biology phenotypic switching is a common bet-hedging strategy in the face of uncertain environmental conditions. Existing mathematical models often focus on periodically changing environments to determine the optimal phenotypic response. We focus on the case in which the environment switches randomly between discrete states. Starting from an individual-based model we derive stochastic differential equations to describe the dynamics, and obtain analytical expressions for the mean instantaneous growth rates based on the theory of piecewise deterministic Markov processes. We show that optimal phenotypic responses are non-trivial for slow and intermediate environmental processes, and systematically compare the cases of periodic and random environments. The best response to random switching is more likely to be heterogeneity than in the case of deterministic periodic environments, net growth rates tend to be higher under stochastic environmental dynamics. The combined system of environment and population of cells can be interpreted as host-pathogen interaction, in which the host tries to choose environmental switching so as to minimise growth of the pathogen, and in which the pathogen employs a phenotypic switching optimised to increase its growth rate. We discuss the existence of Nash-like mutual best-response scenarios for such host-pathogen games.Comment: 17 pages, 6 figure

The export competitiveness of the newly industrialised east Asian economies: How real is the Chinese threat in electronics?

This paper examines the export performance of China in electronics compared to the east Asian NIEs exporting to the USA, the European Union, and Japan between 1988 and 2001 using a dynamic version of shift-share analysis to overcome some of the inherent drawbacks of the widely-used static shift-share methodology. Our findings suggest that China has now emerged as a serious contender in the export market for electronic goods, but this position has not been a dominant one. For electronics as a whole, the principal gainers after 1995 appear to be newcomers China and Malaysia at the expense of the older Tigers, like Singapore and Hong Kong. To some extent this represents a natural process of ‘catch-up’. Moreover, no single NIE has dominated all categories of electronic exports. In the east Asian region, the less developed members of ASEAN would appear to be most at risk in the immediate future since they compete head on with China in lower-end manufacturing and are in danger of being ‘leapfrogged’ in the value-added chain. The more advanced NIEs are in a better position since they have time to increase value-added before China catches up and may benefit more from the opportunities China offers in terms of production and service complementarities

Intrinsic noise in systems with switching environments

We study individual-based dynamics in finite populations, subject to randomly switching environmental conditions. These are inspired by models in which genes transition between on and off states, regulating underlying protein dynamics. Similarly switches between environmental states are relevant in bacterial populations and in models of epidemic spread. Existing piecewise-deterministic Markov process (PDMP) approaches focus on the deterministic limit of the population dynamics while retaining the randomness of the switching. Here we go beyond this approximation and explicitly include effects of intrinsic stochasticity at the level of the linear-noise approximation. Specifically we derive the stationary distributions of a number of model systems, in good agreement with simulations. This improves existing approaches which are limited to the regimes of fast and slow switching.Comment: 15 pages, 11 figure

A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

Pluripotent embryonic stem cells are of paramount importance for biomedical research thanks to their innate ability for self-renewal and differentiation into all major cell lines. The fateful decision to exit or remain in the pluripotent state is regulated by complex genetic regulatory network. Latest advances in transcriptomics have made it possible to infer basic topologies of pluripotency governing networks. The inferred network topologies, however, only encode boolean information while remaining silent about the roles of dynamics and molecular noise in gene expression. These features are widely considered essential for functional decision making. Herein we developed a framework for extending the boolean level networks into models accounting for individual genetic switches and promoter architecture which allows mechanistic interrogation of the roles of molecular noise, external signaling, and network topology. We demonstrate the pluripotent state of the network to be a broad attractor which is robust to variations of gene expression. Dynamics of exiting the pluripotent state, on the other hand, is significantly influenced by the molecular noise originating from genetic switching events which makes cells more responsive to extracellular signals. Lastly we show that steady state probability landscape can be significantly remodeled by global gene switching rates alone which can be taken as a proxy for how global epigenetic modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure

The 24 hour lung function time profile of olodaterol once daily versus placebo and tiotropium in patients with moderate to very severe chronic obstructive pulmonary disease

Background: Olodaterol is a once-daily long-acting β2-agonist being investigated for the treatment of chronic obstructive pulmonary disease, with ≥ 24 hour bronchodilator activity. Methods: Two replicate, randomized, double-blind, four-way crossover (6-week treatment periods), active (tiotropium 18 μg via HandiHaler®)- and placebo-controlled trials were conducted to evaluate the 24 hour forced expiratory volume in 1 second (FEV1) profile of olodaterol (5 and 10 μg) once daily (via Respimat®). Patients continued with inhaled corticosteroids and xanthines. Spirometry was performed at baseline and over the entire 24 hour post-dose period at week 6 of each treatment phase. Co-primary end points were change from study baseline (response) in FEV1 area under the curve from 0–12 hours (AUC0–12) and FEV1 AUC from 12–24 hours (AUC12–24); key secondary end point was FEV1 AUC from 0–24 hours response. Results: In study 1222.39, there was a significant difference from placebo in FEV1 AUC0–12 and AUC12–24 responses (P<0.0001) with olodaterol 5 μg (0.185 and 0.131 L) and 10 μg (0.207 and 0.178 L) at 6 weeks; similar results were observed for tiotropium (0.173 and 0.123 L). In study 1222.40, responses were 0.197 and 0.153 L with olodaterol 5 μg, 0.221 and 0.170 L with 10 μg, and 0.221 and 0.164 L with tiotropium versus placebo (P<0.0001). Incidence of adverse events was comparable across treatments. Conclusions: These data confirm the 24 hour lung-function efficacy profile of once-daily olodaterol, with FEV1 responses comparable to tiotropium

Concert or Cacophony? In Search of a New International Order. Report on the Trilateral Practitioners Workshop “Creative Destruction: Toward an Effective International System”, Berlin, July 7-8, 2011

The global order has been in flux since the end of the Cold War. Two fundamental trends are reshaping the international system: Power shifts at the global level are creating a more diverse international order, in which emerging and resurgent players pursue and assert their own interests. While it is not clear whether Western economic, political, and cultural dominance is coming to an end, there is no mistaking the world’s growing pluralism. At the same time, the emerging international concert – or cacophony – is characterized by deepening interdependence. All major (and minor) powers are facing challenges of economic growth, energy security, and environmental sustainability, all of which are intimately interconnected and which no nation can successfully confront on its own. Moreover, the pace at which change is occurring is accelerating, requiring decision makers to move faster at the very time that problems are becoming more complex. This creates a fundamental dilemma as managing this interdependence through multilateral cooperation demands enlightened self-interest when established means of interaction are being undermined. Thus, the interaction of shifting power and increasing interdependence is transforming global politics, pushing it towards an unprecedented configuration of international relations