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81.
Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit
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Hoffmann K Muller JS Stricker S Megarbane A Rajab A Lindner TH Cohen M Chouery E Adaimy L Ghanem I Delague V Boltshauser E Talim B Horvath R Robinson PN Lochmüller H Hübner C Mundlos S 《American journal of human genetics》2006,79(2):303-312
Escobar syndrome is a form of arthrogryposis multiplex congenita and features joint contractures, pterygia, and respiratory distress. Similar findings occur in newborns exposed to nicotinergic acetylcholine receptor (AChR) antibodies from myasthenic mothers. We performed linkage studies in families with Escobar syndrome and identified eight mutations within the gamma -subunit gene (CHRNG) of the AChR. Our functional studies show that gamma -subunit mutations prevent the correct localization of the fetal AChR in human embryonic kidney-cell membranes and that the expression pattern in prenatal mice corresponds to the human clinical phenotype. AChRs have five subunits. Two alpha, one beta, and one delta subunit are always present. By switching gamma to epsilon subunits in late fetal development, fetal AChRs are gradually replaced by adult AChRs. Fetal and adult AChRs are essential for neuromuscular signal transduction. In addition, the fetal AChRs seem to be the guide for the primary encounter of axon and muscle. Because of this important function in organogenesis, human mutations in the gamma subunit were thought to be lethal, as they are in gamma -knockout mice. In contrast, many mutations in other subunits have been found to be viable but cause postnatally persisting or beginning myasthenic syndromes. We conclude that Escobar syndrome is an inherited fetal myasthenic disease that also affects neuromuscular organogenesis. Because gamma expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR auto-antibodies crossed the placenta and caused the transient inactivation of the AChR pathway. 相似文献
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Andreas Schmid Zoltan Sutto Nathalie Schmid Lisa Novak Pedro Ivonnet Gabor Horvath Gregory Conner Nevis Fregien Matthias Salathe 《The Journal of biological chemistry》2010,285(39):29998-30007
Human airway cilia contain soluble adenylyl cyclase (sAC) that produces cAMP upon HCO3−/CO2 stimulation to increase ciliary beat frequency (CBF). Because apical HCO3− exchange depends on cystic fibrosis transmembrane conductance regulator (CFTR), malfunctioning CFTR might impair sAC-mediated CBF regulation in cells from patients with cystic fibrosis (CF). By Western blot, sAC isoforms are equally expressed in normal and CF airway epithelial cells, but CBF decreased more in CF than normal cells upon increased apical HCO3−/CO2 exposure in part because of greater intracellular acidification from unbalanced CO2 influx (estimated by 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) fluorescence). Importantly, ciliated cell-specific cAMP production (estimated by FRET fluorescence ratio changes of tagged cAMP-dependent protein kinase (PKA) subunits expressed under a ciliated cell-specific promoter) in response to increased apical HCO3−/CO2 perfusion was higher in normal compared with CF cells. Inhibition of bicarbonate influx via CFTR (CFTRinh172) and inhibition of sAC (KH7) and PKA activation (H89) led to larger CBF declines in normal cells, now comparable with changes seen in CF cells. These inhibitors also reduced FRET changes in normal cells to the level of CF cells with the expected exception of H89, which does not prevent dissociation of the fluorescently tagged PKA subunits. Basolateral permeabilization and subsequent perfusion with HCO3−/CO2 rescued CBF and FRET changes in CF cells to the level of normal cells. These results suggest that CBF regulation by sAC-produced cAMP could be impaired in CF, thereby possibly contributing to mucociliary dysfunction in this disease, at least during disease exacerbations when airway acidification is common. 相似文献
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Espinosa A Zhou W Ek M Hedlund M Brauner S Popovic K Horvath L Wallerskog T Oukka M Nyberg F Kuchroo VK Wahren-Herlenius M 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(10):6277-6285
Patients affected by Sj?gren's syndrome and systemic lupus erythematosus (SLE) carry autoantibodies to an intracellular protein denoted Ro52. Although the serologic presence of Ro52 autoantibodies is used clinically for diagnostic purposes, the function of the protein or why it is targeted as an autoantigen in several rheumatic conditions has not been elucidated. In this study, we show that the expression of Ro52 is significantly increased in PBMC of patients with Sj?gren's syndrome and SLE, and demonstrate that Ro52 is a RING-dependent E3 ligase involved in ubiquitination. Overexpression of Ro52, but not of Ro52 lacking the RING domain, in a mouse B cell line lead to decreased growth in steady state and increased cell death after activation via the CD40 pathway. The role of Ro52 in activation-mediated cell death was further confirmed as a reduction in Ro52 expression restored cell viability. These findings suggest that the increased expression of the Ro52 autoantigen in patients may be directly involved in the reduced cellular proliferation and increased apoptotic cell death observed in Sj?gren's syndrome and SLE, and may thus contribute to the autoantigenic load and induction of autoimmune B and T cell responses observed in rheumatic patients. 相似文献
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Arpad Horvath 《The International Journal of Life Cycle Assessment》2006,11(4):229-239
Goal, Scope and Background This study provides a life cycle inventory of air emissions (CO2, NOx, PM10, and CO) associated with the transportation of
goods by road, rail, and air in the U.S. It includes the manufacturing, use, maintenance, and end-of-life of vehicles, the
construction, operation, maintenance, and end-of-life of transportation infrastructure, as well as oil exploration, fuel refining,
and fuel distribution.
Methods The comparison is performed using hybrid life cycle assessment (LCA), a combination of process-based LCA and economic input-output
analysis-based LCA (EIO-LCA). All these components are added by means of a common functional unit of grams of air pollutant
per ton-mile of freight activity.
Results and Discussion Results show that the vehicle use phase is responsible for approximately 70% of total emissions of CO2 for all three modes.
This confirms that tailpipe emissions underestimate total emissions of freight transportation as infrastructure, pre-combustion,
as well as vehicle manufacturing and end-of-life account for a sizeable share of total emissions. Differences between tailpipe
emissions and total system wide emissions can range from only 4% for road transportation's CO emissions to an almost ten-fold
difference for air transportation's PM10 emissions.
Conclusion Rail freight has the lowest associated air emissions, followed by road and air transportation. Depending on the pollutant,
rail is 50-94% less polluting than road. Air transportation is rated the least efficient in terms of air emissions, partly
due to the fact that it carries low weight cargo. It emits 35 times more CO2 than rail and 18 times more than road transportation
on a ton-mile basis. It is important to consider infrastructure, vehicle manufacturing, and pre-combustion processes, whose
life-cycle share is likely to increase as new tailpipe emission standards are enforced.
Recommendation and Outlook Emission factors, fuel efficiency, and equipment utilization contribute the most to uncertainty in the results. Further studies
are necessary to address all variables that influence these parameters, such as road grade, vehicle speed, and vehicle weight.
A focus on regional variation, end-of-life processes, fuel refining processes, terminals, as well as more accurate infrastructure
allocation between freight and passenger transportation would strengthen the model. 相似文献
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