In the field of dysmorphology, achondroplasia is a well-known disorder. Sinus pericranii (SP), however, is not. The latter condition is a rare vascular malformation characterized by abnormal ...connections between the intracranial and the extracranial venous drainage pathways. The etiology of SP remains unclear, and yet, these defects can be present at birth, develop spontaneously later, or evolve following head trauma. Here, we report on a 2-year-old male with achondroplasia, SP, and craniocervical junction stenosis. The latter two defects required surgical correction. SP is an underappreciated malformation that we propose may be induced by increased intracranial pressure. This case appears to be the first report of this condition in achondroplasia.
Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in ...multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects’ fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/− mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/− mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/− mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the ...majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.
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To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.
We assembled a cohort of ...23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs.
The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p<0.0001).
We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.
The Swift Gamma-Ray Burst Explorer performed its first autonomous, X-ray follow-up to a newly detected GRB on 2005 January 17, within 193 s of the burst trigger by the Swift Burst Alert Telescope. ...While the burst was still in progress, the X-Ray Telescope (XRT) obtained a position and an image for an uncataloged X-ray source simultaneously with the gamma-ray observation. The XRT observed flux during the prompt emission was 1.1 x 10 super(-8) ergs cm super(-2) s super(-1) in the 0.5-10 keV energy band. The emission in the X-ray band decreased by 3 orders of magnitude within 700 s, following the prompt emission. This is found to be consistent with the gamma-ray decay when extrapolated into the XRT energy band. During the following 6.3 hr, the XRT observed the afterglow in an automated sequence for an additional 947 s, until the burst became fully obscured by the Earth limb. A faint, extremely slowly decaying afterglow, a = -0.21, was detected. Finally, a break in the light curve occurred and the flux decayed with a < -1.2. The X-ray position triggered many follow-up observations: no optical afterglow could be confirmed, although a candidate was identified 3" from the XRT position.
The present investigation was designed to gain a better understanding of the psychosocial factors that predict reasons for drinking alcohol and how these drinking motives differentially relate to ...alcohol consumption. Four distinct reasons for drinking alcohol scales were established through factor analysis: drink to cope, drink to be sociable, drink to enhance social confidence, and drink for enjoyment. Multiple regression analyses showed that 1) each reason for drinking was predicted by a somewhat different set of demographic and psychosocial variables, and 2) the reasons for drinking, in turn, differentially predicted multiple indicators of quantity and frequency of alcohol consumption. Theoretical implications of the study results and suggestions for future research are discussed.
Two motives for alcohol consumption have been emphasized in the etiological and the reasons-for-drinking literature: (a) people drink alcohol to cope with stress, and (b) people drink alcohol because ...of social influences. There is support for both of these hypotheses, but the results are usually modest and most authors agree that more complex theories of alcohol consumption are needed. This study examined the interactional effects of reasons for drinking alcohol and situational factors on alcohol consumption. Standardized telephone interviews were conducted with 781 randomly selected Michigan drinkers. Hierarchical multiple regression analyses indicated that gender, friends' alcohol consumption, coping, and social motives for drinking were significant predictors of study participants' alcohol consumption. As predicted, there was a significant interaction between drinking to cope with stress and perceived stress, and there was also a significant interaction between drinking for social reasons and friends' alcohol consumption. Similarities and differences in the results for women, men, Blacks, and Whites are described.
AXIOM: advanced X-ray imaging of the magnetosphere Branduardi-Raymont, Graziella; Sembay, Steve F.; Eastwood, Jonathan P. ...
Experimental astronomy,
04/2012, Letnik:
33, Številka:
2-3
Journal Article
Recenzirano
Odprti dostop
Planetary plasma and magnetic field environments can be studied in two complementary ways—by in situ measurements, or by remote sensing. While the former provide precise information about plasma ...behaviour, instabilities and dynamics on local scales, the latter offers the global view necessary to understand the overall interaction of the magnetospheric plasma with the solar wind. Some parts of the Earth’s magnetosphere have been remotely sensed, but the majority remains unexplored by this type of measurements. Here we propose a novel and more elegant approach employing remote X-ray imaging techniques, which are now possible thanks to the relatively recent discovery of solar wind charge exchange X-ray emissions in the vicinity of the Earth’s magnetosphere. In this article we describe how an appropriately designed and located X-ray telescope, supported by simultaneous in situ measurements of the solar wind, can be used to image the dayside magnetosphere, magnetosheath and bow shock, with a temporal and spatial resolution sufficient to address several key outstanding questions concerning how the solar wind interacts with the Earth’s magnetosphere on a global level. Global images of the dayside magnetospheric boundaries require vantage points well outside the magnetosphere. Our studies have led us to propose ‘AXIOM: Advanced X-ray Imaging of the Magnetosphere’, a concept mission using a Vega launcher with a LISA Pathfinder-type Propulsion Module to place the spacecraft in a Lissajous orbit around the Earth–Moon L1 point. The model payload consists of an X-ray Wide Field Imager, capable of both imaging and spectroscopy, and an in situ plasma and magnetic field measurement package. This package comprises a Proton-Alpha Sensor, designed to measure the bulk properties of the solar wind, an Ion Composition Analyser, to characterise the minor ion populations in the solar wind that cause charge exchange emission, and a Magnetometer, designed to measure the strength and direction of the solar wind magnetic field. We also show simulations that demonstrate how the proposed X-ray telescope design is capable of imaging the predicted emission from the dayside magnetosphere with the sensitivity and cadence required to achieve the science goals of the mission.
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