Genetic analysis of human absence epilepsy

Idiopathic Mendelian epilepsies have been typically identified as channelopathies. Evidence suggests that mutations in genes encoding GABAA receptors, GABAB receptors or voltage-dependent calcium channels (VDCCs) may underlie childhood absence epilepsy (CAE), an idiopathic generalised epilepsy with complex inheritance. The aims of this project were: i) Ascertainment of a patient resource ii) Investigation of candidate genes by linkage analysis iii) Mutation analysis by direct sequencing iv) Construction of single nucleotide polymorphism (SNP) based haplotypes in candidate genes v) Intra-familial association analysis using SNP based haplotypes DNA and clinical data were obtained from: 53 nuclear CAE pedigrees; 29 families including individuals with CAE and a broader „absence‟ epilepsy phenotype; 217 parent-child trios; a North American family in which absence epilepsy segregates with episodic ataxia type 2 (EA2) Sixteen calcium channel genes and seven GABAA and two GABAB receptor subunit genes were excluded by linkage analysis. Significant linkage was demonstrated for CACNG3 on chromosome 16p12-p13.1 for both CAE and the broader absence phenotype. Positive linkage was also obtained at the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Non-parametric linkage analysis was significant at both the 16p and 15q loci. Two-locus analysis supported a digenic effect from these two loci. Sequencing of CACNG3 revealed 34 sequence variants, none clearly causal, although bioinformatic analysis provided supportive functional evidence. Association analysis showed significant transmission disequilibrium both for individual single nucleotide polymorphisms (SNPs) and SNP based haplotypes spanning CACNG3. This work has provided genetic evidence that CACNG3 and at least one of the three GABAA receptor genes are susceptibility loci for absence epilepsy. Linkage analysis performed in the family with absence epilepsy and EA2 was suggestive that the VDCC CACNA1A was the causative gene. This was subsequently confirmed by sequence analysis in collaboration with the Institute of Neurology, UCL. This is the first reported family in which a CACNA1A mutation that impairs calcium channel function cosegregates with typical absence seizures and 3Hz spike-wave discharges on EEG

Molecular Dynamics simulations of concentrated aqueous electrolyte solutions

Transport properties of concentrated electrolytes have been analyzed using classical molecular dynamics simulations with the algorithms and parameters typical of simulations describing complex electrokinetic phenomena. The electrical conductivity and transport numbers of electrolytes containing monovalent (KCl), divalent (MgCl$_2$), a mixture of both (KCl + MgCl$_2$), and trivalent (LaCl$_3$) cations have been obtained from simulations of the electrolytes in electric fields of different magnitude. The results obtained for different simulation parameters have been discussed and compared with experimental measurements of our own and from the literature. The electroosmotic flow of water molecules induced by the ionic current in the different cases has been calculated and interpreted with the help of the hydration properties extracted from the simulations

Phylogenetic relationships of African Caecilians (Amphibia: Gymnophiona): insights from mitochondrial rRNA gene sequences

Africa (excluding the Seychelles) has a diverse caecilian fauna, including the endemic family Scolecomorphidae and six endemic genera of the more cosmopolitan Caeciliidae. Previous molecular phylogenetic studies have not included any caecilians from the African mainland. Partial 12S and 16S mitochondrial gene sequences were obtained for two species of the endemic African Scolecomorphidae and five species and four genera of African Caeciliids, aligned against previously reported sequences for 16 caecilian species, and analysed using parsimony, maximum likelihood, Bayesian and distance methods. Results are in agreement with traditional taxonomy in providing support for the monophyly of the African Caeciliid genera Boulengerula and Schistometopum and for the Scolecomorphidae. They disagree in indicating that the Caeciliidae is paraphyletic with respect to the Scolecomorphidae. Although more data from morphology and/or molecules will be required to resolve details of the interrelationships of the African caecilian genera, the data provide strong support for at least two origins of caecilians in which the eye is reduced and covered with bone, and do not support the hypotheses that the caecilian assemblages of Africa, and of East and of West Africa are monophyletic

Large-scale analysis of orthologs and paralogs under covarion-like and constant-but-different models of amino acid evolution.

Functional divergence between homologous proteins is expected to affect amino acid sequences in two main ways, which can be considered as proxies of biochemical divergence: a "covarion-like" pattern of correlated changes in evolutionary rates, and switches in conserved residues ("conserved but different"). Although these patterns have been used in case studies, a large-scale analysis is needed to estimate their frequency and distribution. We use a phylogenomic framework of animal genes to answer three questions: 1) What is the prevalence of such patterns? 2) Can we link such patterns at the amino acid level with selection inferred at the codon level? 3) Are patterns different between paralogs and orthologs? We find that covarion-like patterns are more frequently detected than "constant but different," but that only the latter are correlated with signal for positive selection. Finally, there is no obvious difference in patterns between orthologs and paralogs

When is enough...enough? Effective sampling protocols for estimating the survival rates of seabirds with mark-recapture techniques

Capsule: Lower intensity mark-recapture studies, such as those undertaken by citizen scientists, provide an opportunity to improve the spatial representation of survival estimates for birds. Colonial nesting birds are particularly suited to this because, for many species, large numbers of breeding birds and chicks can be located relatively easily. The minimum level of recapture effort required to accurately estimate true survival rates and detect temporal variation largely depended on the respective ringing effort. Therefore, mark-recapture studies should consider both aspects of the field study when setting or adjusting minimum effort guidelines. Furthermore, achieving reliable estimation with short time-series required more intensive survey designs, highlighting the importance of longevity when planning these studies. Aims: To provide minimum guidelines of field effort that can be used to manage smaller projects that monitor survival rates, such as those reliant on citizen scientists. Methods: We conducted a sensitivity analysis that evaluated the statistical power associated with using different mark-recapture survey designs to estimate a fixed ‘true’ survival rate and detect sources of temporal variation and individual heterogeneity within the population. Results: Isolating temporal variation with a good degree (90%) of certainty required the highest levels of survey effort. Based on the assessed survey designs, we recommend studies that have a ten-year trajectory and a recapture rate of 0.6, aim to mark at least 200 new adults per year. The recommended number of marked individuals will decrease if it is possible to achieve higher rates of recapture. Lower rates of juvenile survival and delayed reproduction mean that seabird mark-recapture survey designs that target both chicks and adults offer only marginal improvements in resolving the survival rates of adults, when compared to designs targeting adults only. However, collecting juvenile mark-recapture data provide access to age-specific vital rates that are also valuable for assessing the population dynamics of seabirds. Conclusion: The addition of chicks is unlikely to improve the resolution of adult survival rates markedly, although for species with low natal dispersal and earlier ages of maturity, these data may allow the estimation of other vital rates, such as juvenile survival rates and age of maturity. Implementing minimum effort guidelines potentially enables the effective management of smaller mark-recapture studies, thus minimising the risk that studies fail to achieve the data conditions necessary for robust estimation of survival rates

Design and placement considerations for propeller-type t-zero choppers

The author discusses factors to do with placement and running speeds of propeller-type t-zero choppers, as implemented at ISIS (on chopper spectrometers) and at LANSCE (on a reflectometer, chopper spectrometer and small-angle scattering instrument). In all cases, the purpose is to block the burst of high-energy neutrons that emanates from the source when the proton beam strikes the target, and still be fully open when the thermal neutrons of interest pass through the space occupied by the t-zero chopper. In general, roughly 30 cm of high-strength high-Ni alloy (like nimonic or inconel) is placed in the beam, and for background purposes, it is desirable to place the chopper as far upstream as possible

Use of cumulative mortality data in patients with acute myocardial infarction for early detection of variation in clinical practice: observational study

OBJECTIVES: Use of cumulative mortality adjusted for case mix in patients with acute myocardial infarction for early detection of variation in clinical practice. DESIGN: Observational study. SETTING: 20 hospitals across the former Yorkshire region. PARTICIPANTS: All 2153 consecutive patients with confirmed acute myocardial infarction identified during three months. MAIN OUTCOME MEASURES: Variable life­adjusted displays showing cumulative differences between observed and expected mortality of patients; expected mortality calculated from risk model based on admission characteristics of age, heart rate, and systolic blood pressure. RESULTS: The performance of two individual hospitals over three months was examined as an example. One, the smallest district hospital in the region, had a series of 30 consecutive patients but had five more deaths than predicted. The variable life­adjusted display showed minimal variation from that predicted for the first 15 patients followed by a run of unexpectedly high mortality. The second example was the main tertiary referral centre for the region, which admitted 188 consecutive patients. The display showed a period of apparently poor performance followed by substantial improvement, where the plot rose steadily from a cumulative net lives saved of - 4 to 7. These variations in patient outcome are unlikely to have been revealed during conventional audit practice. CONCLUSIONS: Variable life­adjusted display has been integrated into surgical care as a graphical display of risk­adjusted survival for individual surgeons or centres. In combination with a simple risk model, it may have a role in monitoring performance and outcome in patients with acute myocardial infarction

Quantum dot emission from site-controlled ngan/gan micropyramid arrays

InxGa1−xN quantum dots have been fabricated by the selective growth of GaN micropyramid arrays topped with InGaN/GaN quantum wells. The spatially, spectrally, and time-resolved emission properties of these structures were measured using cathodoluminescence hyperspectral imaging and low-temperature microphotoluminescence spectroscopy. The presence of InGaN quantum dots was confirmed directly by the observation of sharp peaks in the emission spectrum at the pyramid apices. These luminescence peaks exhibit decay lifetimes of approximately 0.5 ns, with linewidths down to 650 me

Neutron depolarization studies of Pd-Ni-Fe-P alloy

Bulk metallic glasses based on the quaternary alloy Pd-Ni-Fe-P exhibit interesting phase behavior depending on temperature and applied magnetic field. Previous work has suggested that a range of magnetic phases including paramagnetic, superparamagnetic, ferromagnetic and spin glass can be observed in this system. We have applied one dimensional neutron depolarization to explore the correlation of magnetic moments in Pd40Ni22.5Fe17.5P20 alloy as a function of temperature and applied magnetic field. The results provided evidence for correlation lengths of ~ 200 Å. The nature of the correlations and the formation mechanism of the induced ferromagnetic phase are discusse

Selectome: a database of positive selection.

Genome wide scans have shown that positive selection is relatively frequent at the molecular level. It is of special interest to identify which protein sites and which phylogenetic branches are affected. We present Selectome, a database which provides the results of a rigorous branch-site specific likelihood test for positive selection. The Web interface presents test results mapped both onto phylogenetic trees and onto protein alignments. It allows rapid access to results by keyword, gene name, or taxonomy based queries. Selectome is freely available at http://bioinfo.unil.ch/selectome/