Occlusion in the Flow of New Drugs for Cardiovascular Disease.

There is a large misalignment between unmet need and both private and public investment activity in cardiovascular disease. In this paper, we quantify the magnitude of the gap, analyze a range of potential root causes in two main categories (issues of feasibility and valuation), and propose steps toward solutions to close the gap.

Precision medicine in the age of big data: The present and future role of large-scale unbiased sequencing in drug discovery and development.

High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice.

The stability and persistence of mutualisms embedded in community interactions.

In this paper we argue that two-species models of mutualism may be oversimplifications of the real world that lead to erroneous predictions. We present a four-species model of a pollination mutualism embedded in other types of community interactions. Conclusions derived from two-species models about the destabilizing effect of mutualisms are misleading when applied to the present scenario; although the mutualisms are locally destabilizing, the effect is more than canceled by an increased chance of feasibility. The crucial difference is the interaction of the mutualists with other species in a larger web. Furthermore, community persistence (without unrealistic population explosion), arguably a superior ecological criterion, is greatly enhanced by the presence of mutualisms. Therefore, we predict that mutualisms should be common in the real world, a prediction matching empirial findings and in contrast to the predictions from local stability analysis of basic two-species models. This method of stabilizing a mutualism appears superior in some ways to the often-used method of introducing density dependence in the strength of the mutualism, because it permits obligate mutualisms to exist even at low densities, again matching empirical findings. Lastly, this study is an example of how complex model assemblages can behave qualitatively differently from analogous simpler ones.

The evolution of diapause in a coupled host-parasitoid system.

Diapause of part of a population during a breeding opportunity is widespread among insects. We explore the evolution of such diapause in a coupled host-parasitoid system, using a discrete-generation population dynamic model that incorporates diapause. We show that diapause in the host tends to be a stabilizing factor while diapause in the parasitoid does not affect the stability boundaries. We then allow the frequency of diapause in the host and parasitoid to evolve, and find the joint population and evolutionary dynamic equilibrium by numerical methods. At the equilibrium, population dynamics exhibit cycles and host diapause always occurs. Parasitoid diapause often occurs, though this depends on exact parameter values. Thus, intrinsically generated fluctuations in fitness (due to cyclical population dynamics) lead to the evolution of diapause as a bet-hedging mechanism.