Structural and functional conservation of key domains in InsP3 and ryanodine receptors

Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6??) and without (3.0??) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-β and IBC-α, identifies two discrete interfaces (α and β) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the α-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the β-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-β or B domain), to gate the pore.     

Active terahertz metamaterial devices

The development of artificially structured electromagnetic materials, termed metamaterials, has led to the realization of phenomena that cannot be obtained with natural materials. This is especially important for the technologically relevant terahertz (1 THz = 10(12) Hz) frequency regime; many materials inherently do not respond to THz radiation, and the tools that are necessary to construct devices operating within this range-sources, lenses, switches, modulators and detectors-largely do not exist. Considerable efforts are underway to fill this 'THz gap' in view of the useful potential applications of THz radiation. Moderate progress has been made in THz generation and detection; THz quantum cascade lasers are a recent example. However, techniques to control and manipulate THz waves are lagging behind. Here we demonstrate an active metamaterial device capable of efficient real-time control and manipulation of THz radiation. The device consists of an array of gold electric resonator elements (the metamaterial) fabricated on a semiconductor substrate. The metamaterial array and substrate together effectively form a Schottky diode, which enables modulation of THz transmission by 50 per cent, an order of magnitude improvement over existing devices.     

Evaluating volatility and interval forecasts

A widely used approach to evaluating volatility forecasts uses a regression framework which measures the bias and variance of the forecast. We show that the associated test for bias is inappropriate before introducing a more suitable procedure which is based on the test for bias in a conditional mean forecast. Although volatility has been the most common measure of the variability in a financial time series, in many situations confidence interval forecasts are required. We consider the evaluation of interval forecasts and present a regression‐based procedure which uses quantile regression to assess quantile estimator bias and variance. We use exchange rate data to illustrate the proposal by evaluating seven quantile estimators, one of which is a new non‐parametric autoregressive conditional heteroscedasticity quantile estimator. The empirical analysis shows that the new evaluation procedure provides useful insight into the quality of quantile estimators. Copyright © 1999 John Wiley & Sons, Ltd.     

Cadmium is a mutagen that acts by inhibiting mismatch repair

Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.     

Minimum information about a microarray experiment (MIAME)-toward standards for microarray data.

Microarray analysis has become a widely used tool for the generation of gene expression data on a genomic scale. Although many significant results have been derived from microarray studies, one limitation has been the lack of standards for presenting and exchanging such data. Here we present a proposal, the Minimum Information About a Microarray Experiment (MIAME), that describes the minimum information required to ensure that microarray data can be easily interpreted and that results derived from its analysis can be independently verified. The ultimate goal of this work is to establish a standard for recording and reporting microarray-based gene expression data, which will in turn facilitate the establishment of databases and public repositories and enable the development of data analysis tools. With respect to MIAME, we concentrate on defining the content and structure of the necessary information rather than the technical format for capturing it.     

Organization and sequences of the variable, joining and constant region genes of the human T-cell receptor alpha-chain

An essential property of the immune system is its ability to generate great diversity in antibody and T-cell immune responses. The genetic and molecular mechanisms responsible for the generation of antibody diversity have been investigated during the past several years. The gene for the variable (V) region, which determines antigen specificity, is assembled when one member of each of the dispersed clusters of V gene segments, diversity (D) elements (for heavy chains only) and joining (J) segments are fused by DNA rearrangement. The cloning of the beta-chain of the T-cell antigen receptor revealed that the organization of the beta-chain locus, which is similar to that of immunoglobulin genes, is also composed of noncontiguous segments of V, D, J and constant (C) region genes. The structure of the alpha-chain seems to consist of a V and a C domain connected by a J segment. We report here that the human T-cell receptor alpha-chain gene consists of a number of noncontiguous V and J gene segments and a C region gene. The V region gene segment is interrupted by a single intron, whereas the C region contains four exons. The J segments, situated 5' of the C region gene, are dispersed over a distance of at least 35 kilobases (kb). Signal sequences, which are presumably involved in DNA recombination, are found next to the V and J gene segments.     

The use of museum specimens to reconstruct the genetic variability and relationships of extinct populations

In this review, we discuss the use of DNA from museum specimens to address conservation genetic questions. We provide four examples from our previous studies of the northern hairy-nosed wombat, African wild dog, Ethiopian wolf and red wolf. These species were genetically surveyed using two molecular approaches: first, analysis of short sequences in the mitochondrial genome using species-specific primers, and second, analysis of hypervariable microsatellite loci. The studies demonstrate that museum-derived DNA adds an important dimension to the genetic study of extant populations. Inaccessible populations can be studied, and both the loss of genetic variation and its distribution over space and time can be better understood. Finally, analysis of additional museum material provides definitive evidence for a hybrid origin of the red wolf.     

Estimating private information usage amongst analysts: evidence from UK earnings forecasts

This paper introduces a methodology for estimating the likelihood of private information usage amongst earnings analysts. This is achieved by assuming that one group of analysts generate forecasts based on the underlying dynamics of earnings, while all other analysts are assumed to issue forecasts based on the prevailing consensus forecast. Given this behavioural dichotomy, we are able to derive (and estimate) a structural econometric model of forecast behaviour, which has implications regarding the determinants of analysts' private information endowments and forecast accuracy over the forecast horizon. Copyright © 2010 John Wiley & Sons, Ltd.     

Using CAViaR Models with Implied Volatility for Value‐at‐Risk Estimation

This paper proposes value‐at risk (VaR) estimation methods that are a synthesis of conditional autoregressive value at risk (CAViaR) time series models and implied volatility. The appeal of this proposal is that it merges information from the historical time series and the different information supplied by the market's expectation of risk. Forecast‐combining methods, with weights estimated using quantile regression, are considered. We also investigate plugging implied volatility into the CAViaR models—a procedure that has not been considered in the VaR area so far. Results for daily index returns indicate that the newly proposed methods are comparable or superior to individual methods, such as the standard CAViaR models and quantiles constructed from implied volatility and the empirical distribution of standardised residuals. We find that the implied volatility has more explanatory power as the focus moves further out into the left tail of the conditional distribution of S&P 500 daily returns. Copyright © 2012 John Wiley & Sons, Ltd.