The interplay of intrinsic disorder and macromolecular crowding on {\alpha}-synuclein fibril formation

{\alpha}-synuclein ({\alpha}-syn) is an intrinsically disordered protein which is considered to be one of the causes of Parkinson's disease. This protein forms amyloid fibrils when in a highly concentrated solution. The fibril formation of {\alpha}-syn is induced not only by increases in {\alpha}-syn concentration but also by macromolecular crowding. In order to investigate the coupled effect of the intrinsic disorder of {\alpha}-syn and macromolecular crowding, we construct a lattice gas model of {\alpha}-syn in contact with a crowding agent reservoir based on statistical mechanics. The main assumption is that {\alpha}-syn can be expressed as coarse-grained particles with internal states coupled with effective volume; and disordered states are modeled by larger particles with larger internal entropy than other states. Thanks to the simplicity of the model, we can exactly calculate the number of conformations of crowding agents, and this enables us to prove that the original grand canonical ensemble with a crowding agent reservoir is mathematically equivalent to a canonical ensemble without crowding agents. In this expression, the effect of macromolecular crowding is absorbed in the internal entropy of disordered states; it is clearly shown that the crowding effect reduces the internal entropy. Based on Monte Carlo simulation, we provide scenarios of crowding-induced fibril formation. We also discuss the recent controversy over the existence of helically folded tetramers of {\alpha}-syn, and suggest that macromolecular crowding is the key to resolving the controversy.Comment: 11 pages, 14 figure

Method to Predict Crowding Effects by Postprocessing Molecular Dynamics Trajectories: Application to the Flap Dynamics of HIV-1 Protease.

The internal dynamics of proteins inside of cells may be affected by the crowded intracellular environments. Here, we test a novel approach to simulations of crowding, in which simulations in the absence of crowders are postprocessed to predict crowding effects, against the direct approach of simulations in the presence of crowders. The effects of crowding on the flap dynamics of HIV-1 protease predicted by the postprocessing approach are found to agree well with those calculated by the direct approach. The postprocessing approach presents distinct advantages over the direct approach in terms of accuracy and speed and is expected to have broad impact on atomistic simulations of macromolecular crowding

On the theory of equalizing differences Increasing abundances of types of workers may increase their earnings

The theory of equalising differences recognises that wage differentials may be required to equalise the attractiveness of alternative occupations. We examine this theory using the Conley/Wooders 'crowding types'' model. The crowding types model distinguishes between the tastes of a player and his crowding type, those attributes of the player that directly effect the well-being of other players in the same club - a player''s skill, productivity or personality are examples. A club can be interpreted as firm in which the job attributes are the club goods thus, the crowding types model, with its distinction between tastes and crowding types, provides a natural environment in which to study equalising differences. In contrast to results for earlier models, we demonstrate that even when small groups of players are strictly effective in a strong sense, an increase in the abundance of players of one crowding type can increase the core payoffs to players of that crowding type.cooperative game theory

Public spending and Scottish devolution : crowding out, or crowding in?

There has been a developing debate about the performance of the Scottish economy under devolution and the effect of the expansion of the public sector on Scottish growth. Several commentators have expressed concern that the size of the public sector in Scotland is now a drag on growth, while others take a more sanguine view. This debate is well summarised in Marsh and Zuleeg (2006). However, this is a debate in which the evidence is often not well marshalled and there is often more heat than light generated. There is a suspicion that arguments about the effect and role of the public sector often derive more from the ultimate values and political preferences of proponents than from hard analysis and evidence

The Crowding-Out of Work Ethics

This paper analyses optimal contracts in a principal-agent model where the agent is intrinsically motivated at the outset and there is an endogenous relationship between the structure of incentive payments and intrinsic motivation (crowding effects). The analysis shows that crowding effects have implications for the optimal contract and that under some conditions the principal can do better without implementing any economic incentives. Furthermore, it is shown that when high-powered incentives diminish intrinsic motivation (crowding-out) the first-best solution in a principal-agent framework is unattainable.Agency theory; intrinsic motivation; crowding effects

Crowding effects in vehicular traffic

While the impact of crowding on the diffusive transport of molecules within a cell is widely studied in biology, it has thus far been neglected in traffic systems where bulk behavior is the main concern. Here, we study the effects of crowding due to car density and driving fluctuations on the transport of vehicles. Using a microscopic model for traffic, we found that crowding can push car movement from a superballistic down to a subdiffusive state. The transition is also associated with a change in the shape of the probability distribution of positions from negatively-skewed normal to an exponential distribution. Moreover, crowding broadens the distribution of cars' trap times and cluster sizes. At steady state, the subdiffusive state persists only when there is a large variability in car speeds. We further relate our work to prior findings from random walk models of transport in cellular systems.Comment: 23 pages, 11 figures, accepted for publication in PLoS ON

Fiscal Policy Discretion, Private Spending, and Crisis Episodes

In this paper, we assess the impact of fiscal policy discretion on economic activity in the short and medium-term. Using a panel of 132 countries from 1960 to 2008, we find that fiscal policy discretion provides a net stimulus to the economy in the short-run and crowding-in effects are amplified once crisis episodes are controlled for– in particular, banking crises - giving a great scope for fiscal policy stimulus packages. However, crowding-out effects take over in the long-run – especially, in the case of debt crises -, in line with the concerns about long-term debt sustainability.Fiscal policy discretion, GDP growth, private consumption, private investment, crowding-in, crowding-out