The EAHAD blood coagulation factor VII variant database

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7 ). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus‐specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross‐species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity

Implementing an apparent-horizon finder in three dimensions

Locating apparent horizons is not only important for a complete understanding of numerically generated spacetimes, but it may also be a crucial component of the technique for evolving black-hole spacetimes accurately. A scheme proposed by Libson et al., based on expanding the location of the apparent horizon in terms of symmetric trace-free tensors, seems very promising for use with three-dimensional numerical data sets. In this paper, we generalize this scheme and perform a number of code tests to fully calibrate its behavior in black-hole spacetimes similar to those we expect to encounter in solving the binary black-hole coalescence problem. An important aspect of the generalization is that we can compute the symmetric trace-free tensor expansion to any order. This enables us to determine how far we must carry the expansion to achieve results of a desired accuracy. To accomplish this generalization, we describe a new and very convenient set of recurrence relations which apply to symmetric trace-free tensors.Comment: 14 pages (RevTeX 3.0 with 3 figures

The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients

Disease-causing alterations within the F8 gene were identified in 177 hemophilia A families of Portuguese origin. The spectrum of non-inversion F8 mutations in 101 families included 67 different alterations, namely: 36 missense, 8 nonsense and 4 splice site mutations, as well as 19 insertions/deletions. Thirty-four of these mutations are novel. Molecular modeling allowed prediction of the conformational changes introduced by selected amino acid substitutions and their correlation with the patients' phenotypes. The relatively frequent, population-specific, missense mutations together with de novo alterations can lead to significant differences in the spectrum of F8 mutations among different populationsThis study was partially supported by Fundação para a Ciência e a Tecnologia: research grant PBIC/C/SAU/1588/92 and Programa de Financiamento Plurianual do CIGM

The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers

Haemophilia published by John Wiley & Sons Ltd Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity

Primary and successive events in the Madden–Julian Oscillation

Conventional analyses of the MJO tend to produce a repeating cycle, such that any particular feature cannot be unambiguously attributed to the current or previous event. We take advantage of the sporadic nature of the MJO and classify each observed Madden-Julian (MJ) event as either primary, with no immediately preceding MJ event, or successive, which does immediately follow a preceding event. 40% of MJ events are primary events. Precursor features of the primary events can be unambiguously attributed to that event. A suppressed convective anomaly grows and decays in situ over the Indian Ocean, prior to the start of most primary MJ events. An associated mid-tropospheric temperature anomaly destabilises the atmosphere, leading to the generation of the active MJ event. Hence, primary MJ events appear to be thermodynamically triggered by a previous dry period, although stochastic forcing may also be important. Other theories predict that boundary-layer convergence, humidity, propagation of dynamical structures around the Equator, sea surface temperatures, and lateral forcing by extratropical transients may all be important in triggering an event. Although precursor signals from these mechanisms are diagnosed from reanalysis and satellite observational data in the successive MJ events, they are all absent in the primary MJ events. Hence, it appears that these apparent precursor signals are part of the MJO once it is established, but do not play a role in the spontaneous generation of the MJO. The most frequent starting location of the primary events is the Indian Ocean, but over half of them start elsewhere, from the maritime continent to the western Pacific

Contributions of regional transport and local sources to ozone exceedances in Houston and Dallas: Comparison of results from a photochemical grid model to aircraft and surface measurements

[1] During the 2000 Texas Air Quality Study (TexAQS) and 2006 Texas Air Quality Study (TexAQS II) field experiments, aircraft measured ozone concentrations upwind, across, and downwind of the Houston and Dallas urban areas. Background ozone transported into Houston contributed, on average, approximately 50% and 66% of the total ozone on 8-h ozone exceedance days investigated by aircraft flights during TexAQS and TexAQS II, respectively. Analysis of a flight over Dallas on one exceedance day showed that transported ozone constituted 72% of the total ozone concentration. The aircraft measurements show that these two major metropolitan areas can be brought close to exceeding the 1997 8-h National Ambient Air Quality Standard for ozone of 0.08 ppm solely by the ozone contribution of regional transport before additional contribution from local sources. Large local contributions were also observed, particularly in Houston. Transport contributions to Dallas area ozone were quantified using the Comprehensive Air Quality Model with Extensions (CAMx) photochemical grid model and source apportionment methods. Model-predicted ozone concentrations were compared to ozone measurements from the aircraft and the surface monitoring network, and showed agreement on the importance of regional transport and local ozone formation. These results emphasize the benefits of regional control strategies, and suggest that local controls alone may not be sufficient to ensure attainment of the 8-h ozone standard in Houston and Dallas

Observed Changes in the Lifetime and Amplitude of the Madden–Julian Oscillation Associated with Interannual ENSO Sea Surface Temperature Anomalies

The Madden-Julian Oscillation (MJO) is analysed using the reanalysis zonal wind and satellite outgoing longwave radiation-based indices of Wheeler and Hendon for the 1974-2005 period. The average life time of MJO events varies with season, being 36 days for events whose central date occurs in December, and 48 days for events in September. The life time of the MJO in the equinoctial seasons (March-May and October-December) is also dependent on the state of the El Nino-Southern Oscillation (ENSO). During October-December it is only 32 days under El Nino conditions, increasing to 48 days under La Nina conditions, with similar values in northern spring. This difference is due to faster eastward propagation of the MJO convective anomalies through the Maritime Continent and western Pacific during El Nino, consistent with theoretical arguments concerning equatorial wave speeds. The analysis is extended back to 1950 by using an alternative definition of the MJO based on just the zonal wind component of the Wheeler and Hendon indices. A rupture in the amplitude of the MJO is found in 1975, at the same time as the well known rupture in the ENSO time series, that has been associated with the Pacific Decadal Oscillation. The mean amplitude of the MJO is 16% larger in the post-rupture period (1976-2005) compared to the pre-rupture period (1950-1975). Before the 1975 rupture, the amplitude of the MJO is a maximum (minimum) under El Nino (La Nina) conditions during northern winter, and a minimum (maximum) under El Nino (La Nina) conditions during northern summer. After the rupture, this relationship disappears. When the MJO-ENSO relationship is analysed using all year round data, or a shorter data set, as in some previous studies, no relationship is found

Detection of missense mutations by single-strand conformational polymorphism (SSCP) analysis in five dysfunctional variants of coagulation factor VII

Five unrelated subjects with dysfunctional coagulation factor VII (FVII) were studied In order to Identify missense mutations affecting function. Exons 2 to 8 and the Intron-exon Junctions of their FVIl genes were amplified from peripheral white blood cell DNA by PCR and screened by SSCP analysis. DNA fragments showing aberrant mobility were sequenced. The following mutations were Identified: In case 1 (FVII: C <1%, FVIl:Ag 18%) a heterozygous A to G transltion at nucleotlde 8915 In exon 6 results In the amlno acid substitution Lys-137 to Glu near the C-termlnus of the FVlla llght chaln; In case 2 (FVII: C 7%, FVll:Ag 47%) a heterozygous A to G transltion at nucleotide 7834 In exon 5 results in the substitution of Gin-100 by Arg in the second EGF-like domain; In case 3 (FVll:C 20%, FVIl:Ag 76%) a homozygous G to A transition at nucleotide position 6055 in exon 4 was detected resulting in substitution of Arg-79 by Gin in the first EGF-like domain; in case 5 (FVIl:C 10%, FVIl:Ag 52%) a heterozygous C to T transition at nucleotide position 6054 in exon 4 also results in the substitution of Arg79, but in this case it is replaced by Trp; case 4 (FVll:C <1%, FVIl:Ag 100%) was homozygous for a previously reported mutation (G to A) at nucleotide position 10715 in exon 8, substituting Gin for Arg at position 304 in the protease domain. Cases 1,2 and 5 evidently have additional undetected mutation