Energetic landscape of alpha-lytic protease optimizes longevity through kinetic stability.

During the evolution of proteins the pressure to optimize biological activity is moderated by a need for efficient folding. For most proteins, this is accomplished through spontaneous folding to a thermodynamically stable and active native state. However, in the extracellular bacterial alpha-lytic protease (alphaLP) these two processes have become decoupled. The native state of alphaLP is thermodynamically unstable, and when denatured, requires millennia (t1/2 approximately 1,800 years) to refold. Folding is made possible by an attached folding catalyst, the pro-region, which is degraded on completion of folding, leaving alphaLP trapped in its native state by a large kinetic unfolding barrier (t1/2 approximately 1.2 years). alphaLP faces two very different folding landscapes: one in the presence of the pro-region controlling folding, and one in its absence restricting unfolding. Here we demonstrate that this separation of folding and unfolding pathways has removed constraints placed on the folding of thermodynamically stable proteins, and allowed the evolution of a native state having markedly reduced dynamic fluctuations. This, in turn, has led to a significant extension of the functional lifetime of alphaLP by the optimal suppression of proteolytic sensitivity.     

The unique features of follicular T cell subsets

The germinal center (GC) reaction is critical for humoral immunity, but also contributes adversely to a variety of autoimmune diseases. While the major protective function of GCs is mediated by plasma cells and memory B cells, follicular helper T (TFH) cells represent a specialized T cell subset that provides essential help to the antigen-specific B cells in the form of membrane-bound ligands and secreted factors such as IL-21. Recent studies have revealed that TFH cells are capable of considerable functional diversity as well as possessing the ability to form memory cells. The molecular basis of this plasticity and heterogeneity is only now emerging. It has also become apparent that several other populations of follicular T cells exist, including natural killer T cells and regulatory T cells. In this review we will discuss the function of follicular T cells and interaction of these populations within the GC response.     

Multi-model ensembles in climate science: Mathematical structures and expert judgements

Projections of future climate change cannot rely on a single model. It has become common to rely on multiple simulations generated by Multi-Model Ensembles (MMEs), especially to quantify the uncertainty about what would constitute an adequate model structure. But, as Parker points out (2018), one of the remaining philosophically interesting questions is: “How can ensemble studies be designed so that they probe uncertainty in desired ways?” This paper offers two interpretations of what General Circulation Models (GCMs) are and how MMEs made of GCMs should be designed. In the first interpretation, models are combinations of modules and parameterisations; an MME is obtained by “plugging and playing” with interchangeable modules and parameterisations. In the second interpretation, models are aggregations of expert judgements that result from a history of epistemic decisions made by scientists about the choice of representations; an MME is a sampling of expert judgements from modelling teams. We argue that, while the two interpretations involve distinct domains from philosophy of science and social epistemology, they both could be used in a complementary manner in order to explore ways of designing better MMEs.     

Constructing and evaluating core inflation measures from component‐level inflation data

This paper undertakes a comprehensive examination of 10 measures of core inflation and evaluates which measure produces the best forecast of headline inflation out‐of‐sample. We use the Personal Consumption Expenditure Price Index as our measure of inflation. We use two sets of components (17 and 50) of the Personal Consumption Expenditure Price Index to construct these core inflation measures and evaluate these measures at the three time horizons (6, 12 and 24 months) most relevant for monetary policy decisions. The best measure of core inflation for both sets of components and over all time horizons uses weights based on the first principal component of the disaggregated (component‐level) prices. Interestingly, the results vary by the number of components used; when more components are used the weights based on the persistence of each component is statistically equivalent to the weights generated by the first principal component. However, those forecasts using the persistence of 50 components are statistically worse than those generated using the first principal component of 17 components. The statistical superiority of the principal component method is due to the fact that it extracts (in the first principal component) the common source of variation in the component level prices that accurately describes trend inflation over the next 6–24 months.