Identification of low-frequency variants associated with gout and serum uric acid levels

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.     

Forecasting time series with increasing seasonal variation

Four options for modeling and forecasting time series data containing increasing seasonal variation are discussed, including data transformations, double seasonal difference models and two kinds of transfer function-type ARIMA models employing seasonal dummy variables. An explanation is given for the typical ARIMA model identification analysis failing to identify double seasonal difference models for this kind of data. A logical process of selecting one option for a particular case is outlined, focusing on issues of linear versus non-linear increasing seasonal variation, and the level of stochastic versus deterministic behavior in a time series. Example models for the various options are presented for six time series, with point forecast and interval forecast comparisons. Interval forecasts from data-transformation models are found to generally be too wide and sometimes illogical in the dependence of their width on the point forecast level. Suspicion that maximum likelihood estimation of ARIMA models leads to excessive indications of unit roots in seasonal moving-average operators is reported.     

Aristotle’s Difficult Relationship With Modern Economic Theory

This paper reviews Aristotle’s problematic relationship with modern economic theory. It argues that in terms of value and income distribution theory, Aristotle should probably be seen as a precursor to neither classical nor neoclassical economic thought. Indeed, there are strong arguments to be made that Aristotle’s views are completely at odds with all modern economic theory, since, among other things, he was not necessarily concerned with flexible market prices, opposed the use of money to acquire more money, and did not think that the unintended consequences of human activity were generally beneficial. The paper argues however, that this interpretation goes too far. The Benthamite neoclassical theory of choice can be seen as a dumbing down of Aristotle’s theory, applicable to animals, not humans. Adam Smith and Karl Marx were deeply influenced by Aristotle’s work and both started their main economic works with Aristotle: Smith ultimately rejecting, and Marx ultimately developing Aristotle’s views of the use of money to acquire more money. Possibilities for the future development of a new Aristotelian Economics are explored.     

Meteoritic dust from the atmospheric disintegration of a large meteoroid

Much of the mass of most meteoroids entering the Earth's atmosphere is consumed in the process of ablation. Larger meteoroids (> 10 cm), which in some cases reach the ground as meteorites, typically have survival fractions near 1-25 per cent of their initial mass. The fate of the remaining ablated material is unclear, but theory suggests that much of it should recondense through coagulation as nanometre-sized particles. No direct measurements of such meteoric 'smoke' have hitherto been made. Here we report the disintegration of one of the largest meteoroids to have entered the Earth's atmosphere during the past decade, and show that the dominant contribution to the mass of the residual atmospheric aerosol was in the form of micrometre-sized particles. This result is contrary to the usual view that most of the material in large meteoroids is efficiently converted to particles of much smaller size through ablation. Assuming that our observations are of a typical event, we suggest that large meteoroids provide the dominant source of micrometre-sized meteoritic dust at the Earth's surface over long timescales.     

Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.     

Dynamic properties of neurons in cortical area MT in alert and anaesthetized macaque monkeys.

In order to see the world with high spatial acuity, an animal must sample the visual image with many detectors that restrict their analyses to extremely small regions of space. The visual cortex must then integrate the information from these localized receptive fields to obtain a more global picture of the surrounding environment. We studied this process in single neurons within the middle temporal visual area (MT) of macaques using stimuli that produced conflicting local and global information about stimulus motion. Neuronal responses in alert animals initially reflected predominantly the ambiguous local motion features, but gradually converged to an unambiguous global representation. When the same animals were anaesthetized, the integration of local motion signals was markedly impaired even though neuronal responses remained vigorous and directional tuning characteristics were intact. Our results suggest that anaesthesia preferentially affects the visual processing responsible for integrating local signals into a global visual representation.     

Lethargus is a Caenorhabditis elegans sleep-like state

There are fundamental similarities between sleep in mammals and quiescence in the arthropod Drosophila melanogaster, suggesting that sleep-like states are evolutionarily ancient. The nematode Caenorhabditis elegans also has a quiescent behavioural state during a period called lethargus, which occurs before each of the four moults. Like sleep, lethargus maintains a constant temporal relationship with the expression of the C. elegans Period homologue LIN-42 (ref. 5). Here we show that quiescence associated with lethargus has the additional sleep-like properties of reversibility, reduced responsiveness and homeostasis. We identify the cGMP-dependent protein kinase (PKG) gene egl-4 as a regulator of sleep-like behaviour, and show that egl-4 functions in sensory neurons to promote the C. elegans sleep-like state. Conserved effects on sleep-like behaviour of homologous genes in C. elegans and Drosophila suggest a common genetic regulation of sleep-like states in arthropods and nematodes. Our results indicate that C. elegans is a suitable model system for the study of sleep regulation. The association of this C. elegans sleep-like state with developmental changes that occur with larval moults suggests that sleep may have evolved to allow for developmental changes.     

Temporal dynamics of a neural solution to the aperture problem in visual area MT of macaque brain

A critical step in the interpretation of the visual world is the integration of the various local motion signals generated by moving objects. This process is complicated by the fact that local velocity measurements can differ depending on contour orientation and spatial position. Specifically, any local motion detector can measure only the component of motion perpendicular to a contour that extends beyond its field of view. This "aperture problem" is particularly relevant to direction-selective neurons early in the visual pathways, where small receptive fields permit only a limited view of a moving object. Here we show that neurons in the middle temporal visual area (known as MT or V5) of the macaque brain reveal a dynamic solution to the aperture problem. MT neurons initially respond primarily to the component of motion perpendicular to a contour's orientation, but over a period of approximately 60 ms the responses gradually shift to encode the true stimulus direction, regardless of orientation. We also report a behavioural correlate of these neural responses: the initial velocity of pursuit eye movements deviates in a direction perpendicular to local contour orientation, suggesting that the earliest neural responses influence the oculomotor response.