Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.     

The long and winding road from correlation to causation

Follow-up studies of a Crohn's disease risk locus encompassing IRGM have revealed unexpected complexity. A new study shows that a synonymous variant in the IRGM coding region alters a binding site for miR-196 and modulates IRGM-dependent autophagy, adding to the list of possible mechanisms by which this locus influences disease risk.     

The twins and the bucket: How Einstein made gravity rather than motion relative in general relativity

In publications in 1914 and 1918, Einstein claimed that his new theory of gravity in some sense relativizes the rotation of a body with respect to the distant stars (a stripped-down version of Newton's rotating bucket experiment) and the acceleration of the traveler with respect to the stay-at-home in the twin paradox. What he showed was that phenomena seen as inertial effects in a space-time coordinate system in which the non-accelerating body is at rest can be seen as a combination of inertial and gravitational effects in a (suitably chosen) space-time coordinate system in which the accelerating body is at rest. Two different relativity principles play a role in these accounts: (a) the relativity of non-uniform motion, in the weak sense that the laws of physics are the same in the two space-time coordinate systems involved; (b) what Einstein in 1920 called the relativity of the gravitational field, the notion that there is a unified inertio-gravitational field that splits differently into inertial and gravitational components in different coordinate systems. I provide a detailed reconstruction of Einstein's rather sketchy accounts of the twins and the bucket and examine the role of these two relativity principles. I argue that we can hold on to (b) but that (a) is either false or trivial.     

A mixture likelihood approach for generalized linear models

A mixture model approach is developed that simultaneously estimates the posterior membership probabilities of observations to a number of unobservable groups or latent classes, and the parameters of a generalized linear model which relates the observations, distributed according to some member of the exponential family, to a set of specified covariates within each Class. We demonstrate how this approach handles many of the existing latent class regression procedures as special cases, as well as a host of other parametric specifications in the exponential family heretofore not mentioned in the latent class literature. As such we generalize the McCullagh and Nelder approach to a latent class framework. The parameters are estimated using maximum likelihood, and an EM algorithm for estimation is provided. A Monte Carlo study of the performance of the algorithm for several distributions is provided, and the model is illustrated in two empirical applications.     

From forecasting to ‘la prospective’ a new way of looking at futures

Although‘La Prospective’is not well known in the Anglo-Saxon forecasting literature, it has been for many years widely used in France and other Latin countries with considerable success. Lately, because of the inaccuracy of forecasting and the large forecasting errors that have been experienced, it is suggested that the Prospective approach can be used as a way of dealing with these problems. The main characteristics of‘La Prospective’are that it does not look at the future as a continuation of the past but rather as the outcome of the wishes of various actors and the constraints imposed on them by the environment. Its purpose is to assist in creating alternative futures and then select some alternative that allows for maximum freedom of action.     

Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.     

The timing of the last deglaciation in North Atlantic climate records

To determine the mechanisms governing the last deglaciation and the sequence of events that lead to deglaciation, it is important to obtain a temporal framework that applies to both continental and marine climate records. Radiocarbon dating has been widely used to derive calendar dates for marine sediments, but it rests on the assumption that the 'apparent age' of surface water (the age of surface water relative to the atmosphere) has remained constant over time. Here we present new evidence for variation in the apparent age of surface water (or reservoir age) in the North Atlantic ocean north of 40 degrees N over the past 20,000 years. In two cores we found apparent surface-water ages to be larger than those of today by 1,230 +/- 600 and 1,940 +/- 750 years at the end of the Heinrich 1 surge event (15,000 years BP) and by 820 +/- 430 to 1,010 +/- 340 years at the end of the Younger Dryas cold episode. During the warm B?lling-Aller?d period, between these two periods of large reservoir ages, apparent surface-water ages were comparable to present values. Our results allow us to reconcile the chronologies from ice cores and the North Atlantic marine records over the entire deglaciation period. Moreover, the data imply that marine carbon dates from the North Atlantic north of 40 degrees N will need to be corrected for these highly variable effects.     

Disruption of fragmented parent bodies as the origin of asteroid families

Asteroid families are groups of small bodies that share certain orbit and spectral properties. More than 20 families have now been identified, each believed to have resulted from the collisional break-up of a large parent body in a regime where gravity controls the outcome of the collision more than the material strength of the rock. The size and velocity distributions of the family members provide important constraints for testing our understanding of the break-up process, but erosion and dynamical diffusion of the orbits over time can erase the original signature of the collision. The recently identified young Karin family provides a unique opportunity to study a collisional outcome almost unaffected by orbit evolution. Here we report numerical simulations modelling classes of collisions that reproduce the main characteristics of the Karin family. The sensitivity of the outcome of the collision to the internal structure of the parent body allows us to show that the family must have originated from the break-up of a pre-fragmented parent body, and that all large family members formed by the gravitational reaccumulation of smaller bodies. We argue that most of the identified asteroid families are likely to have had a similar history.