Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

The ergodic hierarchy, randomness and Hamiltonian chaos

Various processes are often classified as both deterministic and random or chaotic. The main difficulty in analysing the randomness of such processes is the apparent tension between the notions of randomness and determinism: what type of randomness could exist in a deterministic process? Ergodic theory seems to offer a particularly promising theoretical tool for tackling this problem by positing a hierarchy, the so-called ‘ergodic hierarchy’ (EH), which is commonly assumed to provide a hierarchy of increasing degrees of randomness. However, that notion of randomness requires clarification. The mathematical definition of EH does not make explicit appeal to randomness; nor does the usual way of presenting EH involve a specification of the notion of randomness that is supposed to underlie the hierarchy. In this paper we argue that EH is best understood as a hierarchy of random behaviour if randomness is explicated in terms of unpredictability. We then show that, contrary to common wisdom, EH is useful in characterising the behaviour of Hamiltonian dynamical systems.     

The effects of manganese and barium on the cardiac pacemaker current,i f,in rabbit sino-atrial node myocytes

Summary The isolation of ionic fluxes contributing to electric currents through cell membranes often requires block of other undesired components which can be achieved, among others, by divalent cations. Mn²⁺ and Ba²⁺ are often used, for example, to block Ca and K currents. Here we have investigated the effects of these two cations on the properties of the hyperpolarization-activated pacemaker current i_f, in rabbit sino-atrial node myocytes, as obtained by voltage clamp analysis. We find that 2 mM Mn²⁺ shifts the i_f activation curve by 3.2±0.3 mV towards more positive values. However, when 1 mM Ba²⁺ is also added, the positive shift is more than halved (1.3±0.2 mV). We find, too, that in the absence of blocking cations the ACh-induced i_f inhibition is slightly higher than in their presence. These results indicate that the alteration of i_f kinetic properties by Ba²⁺ plus Mn²⁺-containing solutions is minimal.     

Period multupling-evidence for nonlinear behaviour of the canine heart

Although there has recently been considerable interest in applying the theory of nonlinear dynamics to the analysis of complex systems, as yet applications of the theory to biological systems in vivo have been very limited. We report here evidence of nonlinear behaviour in the electrocardiogram and arterial blood pressure traces of the noradrenaline-treated dog. Noradrenaline produces variations in these traces that repeat themselves with regular periods of integral numbers of heart-beats (period multupling), an effect that resembles the 'period-doubling' and other 'bifurcative' behaviour observed when the driving frequency of a nonlinear oscillator is increased above a critical value. The simplest type of periodic variation that we report is the so-called 'electrical alternans', which has long been known as one response of cardiac electrical activity to certain stresses and disease states.     

Combining multiple forecasts given multiple objectives

This paper is concerned with expanding the decision support capabilities of computerized forecasting systems. The expansion allows for the systematic combination of multiple forecasts and the explicit consideration of multiple objectives in the forecast selection process. The methodology used is multiple objective linear programming. Selecting an individual forecast based upon a single objective may not make the best use of available information for a variety of reasons. Combined forecasts may provide a better fit with respect to a single objective than any individual forecast. Even if an individual forecast does provide a good fit with respect to a single objective, a combined forecast may provide a better fit with respect to multiple objectives. An example is used to illustrate the expanded decision support system, its outputs and their properties.