Gain-of-Function Mutation in Filamin A Potentiates Platelet Integrin αβ Activation

OBJECTIVE: Dominant mutations of the X-linked filamin A () gene are responsible for filaminopathies A, which are rare disorders including brain periventricular nodular heterotopia, congenital intestinal pseudo-obstruction, cardiac valves or skeleton malformations, and often macrothrombocytopenia. APPROACH AND RESULTS: We studied a male patient with periventricular nodular heterotopia and congenital intestinal pseudo-obstruction, his unique X-linked allele carrying a stop codon mutation resulting in a 100-amino acid-long FLNa C-terminal extension (NP_001447.2: ). Platelet counts were normal, with few enlarged platelets. FLNa was detectable in all platelets but at 30% of control levels. Surprisingly, all platelet functions were significantly upregulated, including platelet aggregation and secretion, as induced by ADP, collagen, or von Willebrand factor in the presence of ristocetin, as well as thrombus formation in blood flow on a collagen or on a von Willebrand factor matrix. Most importantly, patient platelets stimulated with ADP exhibited a marked increase in αβ integrin activation and a parallel increase in talin recruitment to β, contrasting with normal Rap1 activation. These results are consistent with the mutant FLNa affecting the last step of αβ activation. Overexpression of mutant FLNa in the HEL megakaryocytic cell line correlated with an increase (compared with wild-type FLNa) in PMA-induced fibrinogen binding to and in talin and kindlin-3 recruitment by αβ. CONCLUSIONS: Altogether, our results are consistent with a less binding of mutant FLNa to β and the facilitated recruitment of talin by β on platelet stimulation, explaining the increased αβ activation and the ensuing gain-of-platelet functions

Convection, Thermal Bifurcation, and the Colors of A stars

Broad-band ultraviolet photometry from the TD-1 satellite and low dispersion spectra from the short wavelength camera of IUE have been used to investigate a long-standing proposal of Bohm-Vitense that the normal main sequence A- and early-F stars may divide into two different temperature sequences: (1) a high temperature branch (and plateau) comprised of slowly rotating convective stars, and (2) a low temperature branch populated by rapidly rotating radiative stars. We find no evidence from either dataset to support such a claim, or to confirm the existence of an "A-star gap" in the B-V color range 0.22 <= B-V <= 0.28 due to the sudden onset of convection. We do observe, nonetheless, a large scatter in the 1800--2000 A colors of the A-F stars, which amounts to ~0.65 mags at a given B-V color index. The scatter is not caused by interstellar or circumstellar reddening. A convincing case can also be made against binarity and intrinsic variability due to pulsations of delta Sct origin. We find no correlation with established chromospheric and coronal proxies of convection, and thus no demonstrable link to the possible onset of convection among the A-F stars. The scatter is not instrumental. Approximately 0.4 mags of the scatter is shown to arise from individual differences in surface gravity as well as a moderate spread (factor of ~3) in heavy metal abundance and UV line blanketing. A dispersion of ~0.25 mags remains, which has no clear and obvious explanation. The most likely cause, we believe, is a residual imprecision in our correction for the spread in metal abundances. However, the existing data do not rule out possible contributions from intrinsic stellar variability or from differential UV line blanketing effects owing to a dispersion in microturbulent velocity.Comment: 40 pages, 14 figures, 1 table, AAS LaTex, to appear in The Astrophysical Journa

Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients

BACKGROUND: Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions. METHODS: Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments. RESULTS: We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1–170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected. CONCLUSION: A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far

Face scanning and spontaneous emotion preference in Cornelia de Lange syndrome and Rubinstein-Taybi syndrome

Background Existing literature suggests differences in face scanning in individuals with different socio-behavioural characteristics. Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RTS) are two genetically defined neurodevelopmental disorders with unique profiles of social behaviour. Methods Here, we examine eye gaze to the eye and mouth regions of neutrally expressive faces, as well as the spontaneous visual preference for happy and disgusted facial expressions compared to neutral faces, in individuals with CdLS versus RTS. Results Results indicate that the amount of time spent looking at the eye and mouth regions of faces was similar in 15 individuals with CdLS and 17 individuals with RTS. Both participant groups also showed a similar pattern of spontaneous visual preference for emotions. Conclusions These results provide insight into two rare, genetically defined neurodevelopmental disorders that have been reported to exhibit contrasting socio-behavioural characteristics and suggest that differences in social behaviour may not be sufficient to predict attention to the eye region of faces. These results also suggest that differences in the social behaviours of these two groups may be cognitively mediated rather than subcortically mediated

Comparing the effectiveness of hyperspectral imaging and Raman spectroscopy:A case study on Armenian manuscripts

Additional file 1. Additional Figures S1–S5 and Tables S1, S2

The field Am and rho Puppis-like stars: Lithium and heavier elements

International audienceWith observations at the Canada-France-Hawaii telescope, photospheric abundances of two evolved field Am stars, tau UMa and HR 178, have been determined for Li, Al, Si, S, Fe, Ni, and Eu by model abundance analysis. Thanks to these new determined abundances and the HIPPARCOS mission, making it possible to better estimate the evolutionary stage of field stars, one can consider the influence of evolution on the abundances of Am stars. No abundance trend for Al, Si, S, and Fe is found during Main Sequence evolution, up to its very last phases. The abundance of Li is, generally, cosmic. Large Li deficiencies may be observed in the very last phases (the ``hook'' region of the H-R diagram) and, too, on the red side of the Am phenomenon region where the rho Puppis-like stars lie

The field Am and

With observations at the Canada-France-Hawaii telescope, photospheric abundances of two evolved field Am stars, τ UM

Spectrum of CREBBP gene dosage anomalies in Rubinstein–Taybi Syndrome patients

International audienc