Cigarette smoking and risk of acoustic neuromas and pituitary tumours in the Million Women Study

BACKGROUND: The relationship between cigarette smoking and incidence of acoustic neuromas and pituitary tumours is uncertain. METHODS: We examined the relation between smoking and risk of acoustic neuromas and pituitary tumours in a prospective study of 1.2 million middle-aged women in the United Kingdom. RESULTS: Over 10.2 million person years of follow-up, 177 women were diagnosed with acoustic neuromas and 174 with pituitary tumours. Current smokers at recruitment were at significantly reduced risk of incident acoustic neuroma compared with never smokers (adjusted relative risk (RR)=0.41, 95% confidence interval (CI)=0.24-0.70, P=0.001). Past smokers did not have significantly different risk of acoustic neuroma than never smokers (RR=0.87, 95% CI=0.62-1.22, P=0.4). Smoking was not associated with incidence of pituitary tumours (RR in current vs never smokers=0.91, 95% CI=0.60-1.40, P=0.7). CONCLUSION: Women who smoke are at a significantly reduced risk of acoustic neuromas, but not of pituitary tumours, compared with never smokers. Acoustic neuromas are much rarer than the cancers that are increased among smokers

A genome-wide study of Hardy–Weinberg equilibrium with next generation sequence data

Statistical tests for Hardy–Weinberg equilibrium have been an important tool for detecting genotyping errors in the past, and remain important in the quality control of next generation sequence data. In this paper, we analyze complete chromosomes of the 1000 genomes project by using exact test procedures for autosomal and X-chromosomal variants. We find that the rate of disequilibrium largely exceeds what might be expected by chance alone for all chromosomes. Observed disequilibrium is, in about 60% of the cases, due to heterozygote excess. We suggest that most excess disequilibrium can be explained by sequencing problems, and hypothesize mechanisms that can explain exceptional heterozygosities. We report higher rates of disequilibrium for the MHC region on chromosome 6, regions flanking centromeres and p-arms of acrocentric chromosomes. We also detected long-range haplotypes and areas with incidental high disequilibrium. We report disequilibrium to be related to read depth, with variants having extreme read depths being more likely to be out of equilibrium. Disequilibrium rates were found to be 11 times higher in segmental duplications and simple tandem repeat regions. The variants with significant disequilibrium are seen to be concentrated in these areas. For next generation sequence data, Hardy–Weinberg disequilibrium seems to be a major indicator for copy number variation.Peer ReviewedPostprint (published version

Heterogeneous nuclear ribonucleoproteins R and Q accumulate in pathological inclusions in FTLD-FUS

Frontotemporal lobar degeneration (FTLD) is pathologically subdivided based on the presence of particular pathological proteins that are identified in inclusion bodies observed post-mortem. The FTLD-FUS subgroup is defined by the presence of the fused in sarcoma protein (FUS) in pathological inclusions. FUS is a heterogeneous nuclear ribonucleoprotein (hnRNP) protein and a member of the FET (FUS, EWS, TAF15) protein family. It shuttles between the nucleus and cytoplasm, and has been implicated in many cellular functions including translation, splicing, and RNA transport. EWS, TAF15 and the nuclear import receptor transportin have been shown to co-accumulate with FUS in neuronal inclusions specifically in FTLD-FUS, with transportin-positive inclusions most frequently observed. Here, we report the identification of hnRNP R and hnRNP Q in neuronal cytoplasmic and intranuclear inclusions in the frontal cortex and hippocampus of FTLD-FUS patients, as frequently as transportin. hnRNP R and hnRNP Q were not found in the characteristic pathological inclusions observed in FTLD-TDP (subtypes A-C). Additionally, we studied the expression of hnRNP R in the frontal and temporal cortices from patients with FTLD and found significantly increased expression of the heterogeneous nuclear ribonucleoprotein R in several FTLD disease groups. Our identification of the frequent presence of hnRNP R and hnRNP Q in FTLD-FUS inclusions suggests a potential role for these hnRNPs in FTLD-FUS pathogenesis and supports the role of dysfunctional RNA metabolism in FTLD

Stability of cluster solutions in a cooperative consumer chain model

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ Springer-Verlag Berlin Heidelberg 2012.We study a cooperative consumer chain model which consists of one producer and two consumers. It is an extension of the Schnakenberg model suggested in Gierer and Meinhardt [Kybernetik (Berlin), 12:30-39, 1972] and Schnakenberg (J Theor Biol, 81:389-400, 1979) for which there is only one producer and one consumer. In this consumer chain model there is a middle component which plays a hybrid role: it acts both as consumer and as producer. It is assumed that the producer diffuses much faster than the first consumer and the first consumer much faster than the second consumer. The system also serves as a model for a sequence of irreversible autocatalytic reactions in a container which is in contact with a well-stirred reservoir. In the small diffusion limit we construct cluster solutions in an interval which have the following properties: The spatial profile of the third component is a spike. The profile for the middle component is that of two partial spikes connected by a thin transition layer. The first component in leading order is given by a Green's function. In this profile multiple scales are involved: The spikes for the middle component are on the small scale, the spike for the third on the very small scale, the width of the transition layer for the middle component is between the small and the very small scale. The first component acts on the large scale. To the best of our knowledge, this type of spiky pattern has never before been studied rigorously. It is shown that, if the feedrates are small enough, there exist two such patterns which differ by their amplitudes.We also study the stability properties of these cluster solutions. We use a rigorous analysis to investigate the linearized operator around cluster solutions which is based on nonlocal eigenvalue problems and rigorous asymptotic analysis. The following result is established: If the time-relaxation constants are small enough, one cluster solution is stable and the other one is unstable. The instability arises through large eigenvalues of order O(1). Further, there are small eigenvalues of order o(1) which do not cause any instabilities. Our approach requires some new ideas: (i) The analysis of the large eigenvalues of order O(1) leads to a novel system of nonlocal eigenvalue problems with inhomogeneous Robin boundary conditions whose stability properties have been investigated rigorously. (ii) The analysis of the small eigenvalues of order o(1) needs a careful study of the interaction of two small length scales and is based on a suitable inner/outer expansion with rigorous error analysis. It is found that the order of these small eigenvalues is given by the smallest diffusion constant ε22.RGC of Hong Kon

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Existence and Stability of a Spike in the Central Component for a Consumer Chain Model

We study a three-component consumer chain model which is based on Schnakenberg type kinetics. In this model there is one consumer feeding on the producer and a second consumer feeding on the first consumer. This means that the first consumer (central component) plays a hybrid role: it acts both as consumer and producer. The model is an extension of the Schnakenberg model suggested in \cite{gm,schn1} for which there is only one producer and one consumer. It is assumed that both the producer and second consumer diffuse much faster than the central component. We construct single spike solutions on an interval for which the profile of the first consumer is that of a spike. The profiles of the producer and the second consumer only vary on a much larger spatial scale due to faster diffusion of these components. It is shown that there exist two different single spike solutions if the feed rates are small enough: a large-amplitude and a small-amplitude spike. We study the stability properties of these solutions in terms of the system parameters. We use a rigorous analysis for the linearized operator around single spike solutions based on nonlocal eigenvalue problems. The following result is established: If the time-relaxation constants for both producer and second consumer vanish, the large-amplitude spike solution is stable and the small-amplitude spike solution is unstable. We also derive results on the stability of solutions when these two time-relaxation constants are small. We show a new effect: if the time-relaxation constant of the second consumer is very small, the large-amplitude spike solution becomes unstable. To the best of our knowledge this phenomenon has not been observed before for the stability of spike patterns. It seems that this behavior is not possible for two-component reaction-diffusion systems but that at least three components are required. Our main motivation to study this system is mathematical since the novel interaction of a spike in the central component with two other components results in new types of conditions for the existence and stability of a spike. This model is realistic if several assumptions are made: (i) cooperation of consumers is prevalent in the system, (ii) the producer and the second consumer diffuse much faster than the first consumer, and (iii) there is practically an unlimited pool of producer. The first assumption has been proven to be correct in many types of consumer groups or populations, the second assumption occurs if the central component has a much smaller mobility than the other two, the third assumption is realistic if the consumers do not feel the impact of the limited amount of producer due to its large quantity. This chain model plays a role in population biology, where consumer and producer are often called predator and prey. This system can also be used as a model for a sequence of irreversible autocatalytic reactions in a container which is in contact with a well-stirred reservoir