The Rules of Human T Cell Fate in vivo.

The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells in vitro, lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate in vivo. We combined data from in vivo stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans in vivo to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naïve and memory, CD4+ and CD8+ T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naïve and memory T cell dynamics and was also able to predict the independent dataset

Explicit kinetic heterogeneity: mechanistic models for interpretation of labeling data of heterogeneous cell populations

Estimation of division and death rates of lymphocytes in different conditions is vital for quantitative understanding of the immune system. Deuterium, in the form of deuterated glucose or heavy water, can be used to measure rates of proliferation and death of lymphocytes in vivo. Inferring these rates from labeling and delabeling curves has been subject to considerable debate with different groups suggesting different mathematical models for that purpose. We show that the three models that are most commonly used are in fact mathematically identical and differ only in their interpretation of the estimated parameters. By extending these previous models, we here propose a more mechanistic approach for the analysis of data from deuterium labeling experiments. We construct a model of "kinetic heterogeneity" in which the total cell population consists of many sub-populations with different rates of cell turnover. In this model, for a given distribution of the rates of turnover, the predicted fraction of labeled DNA accumulated and lost can be calculated. Our model reproduces several previously made experimental observations, such as a negative correlation between the length of the labeling period and the rate at which labeled DNA is lost after label cessation. We demonstrate the reliability of the new explicit kinetic heterogeneity model by applying it to artificially generated datasets, and illustrate its usefulness by fitting experimental data. In contrast to previous models, the explicit kinetic heterogeneity model 1) provides a mechanistic way of interpreting labeling data; 2) allows for a non-exponential loss of labeled cells during delabeling, and 3) can be used to describe data with variable labeling length

Childhood and the politics of scale: Descaling children's geographies?

This is the post-print version of the final published paper that is available from the link below. Copyright @ 2008 SAGE Publications.The past decade has witnessed a resurgence of interest in the geographies of children's lives, and particularly in engaging the voices and activities of young people in geographical research. Much of this growing body of scholarship is characterized by a very parochial locus of interest — the neighbourhood, playground, shopping mall or journey to school. In this paper I explore some of the roots of children's geographies' preoccupation with the micro-scale and argue that it limits the relevance of research, both politically and to other areas of geography. In order to widen the scope of children's geographies, some scholars have engaged with developments in the theorization of scale. I present these arguments but also point to their limitations. As an alternative, I propose that the notion of a flat ontology might help overcome some difficulties around scalar thinking, and provide a useful means of conceptualizing sociospatiality in material and non-hierarchical terms. Bringing together flat ontology and work in children's geographies on embodied subjectivity, I argue that it is important to examine the nature and limits of children's spaces of perception and action. While these spaces are not simply `local', they seldom afford children opportunities to comment on, or intervene in, the events, processes and decisions that shape their own lives. The implications for the substance and method of children's geographies and for geographical work on scale are considered

A Policy Maker’s Guide to Designing Payments for Ecosystem Services

Over the past five years, there has been increasing interest around the globe in payment schemes for the provision of ecosystem services, such as water purification, carbon sequestration, flood control, etc. Written for an Asian Development Bank project in China, this report provides a user-friendly guide to designing payments for the provision of ecosystem services. Part I explains the different types of ecosystem services, different ways of assessing their value, and why they are traditionally under-protected by law and policy. This is followed by an analysis of when payments for services are a preferable approach to other policy instruments. Part II explains the design issues underlying payments for services. These include identification of the service as well as potential buyers and sellers, the level of service needed, payment timing, payment type, and risk allocation. Part II contains a detailed analysis of the different types of payment mechanisms, ranging from general subsidy and certification to mitigation and offset payments. Part III explores the challenges to designing a payment scheme. These include the ability to monitor service provision, secure property rights, perverse incentives, supporting institutions, and poverty alleviation

Dynamics and stability of the Godel universe

We use covariant techniques to describe the properties of the Godel universe and then consider its linear response to a variety of perturbations. Against matter aggregations, we find that the stability of the Godel model depends primarily upon the presence of gradients in the centrifugal energy, and secondarily on the equation of state of the fluid. The latter dictates the behaviour of the model when dealing with homogeneous perturbations. The vorticity of the perturbed Godel model is found to evolve as in almost-FRW spacetimes, with some additional directional effects due to shape distortions. We also consider gravitational-wave perturbations by investigating the evolution of the magnetic Weyl component. This tensor obeys a simple plane-wave equation, which argues for the neutral stability of the Godel model against linear gravity-wave distortions. The implications of the background rotation for scalar-field Godel cosmologies are also discussed.Comment: Revised version, to match paper published in Class. Quantum Gra