Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith-Magenis microdeletion

Recombination between repeated sequences at various loci of the human genome are known to give rise to DNA rearrangements associated with many genetic disorders. Perhaps the most extensively characterized genomic region prone to rearrangement is 17p12, which is associated with the peripheral neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP) and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2). Homologous recombination between 24-kb flanking repeats, termed CMT1A-REPs, results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal duplication product is associated with CMT1A (ref. 2). Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2) (ref. 3,4). Most patients (>90%) carry deletions of the same genetic markers and define a common deletion. We report seven unrelated patients with de novo duplications of the same region deleted in SMS. A unique junction fragment, of the same apparent size, was identified in each patient by pulsed field gel electrophoresis (PFGE). Further molecular analyses suggest that the de novo17p11.2 duplication is preferentially paternal in origin, arises from unequal crossing over due to homologous recombination between flanking repeat gene clusters and probably represents the reciprocal recombination product of the SMS deletion. The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is milder than that associated with deficiency of this genomic region. This mechanism of reciprocal deletion and duplication via homologous recombination may not only pertain to the 17p11.2 region, but may also be common to other regions of the genome where interstitial microdeletion syndromes have been defined.     

Sequential inactivation of Rho GTPases and Lim kinase by Pseudomonas aeruginosa toxins ExoS and ExoT leads to endothelial monolayer breakdown

Pseudomonas aeruginosa is a major human opportunistic pathogen and one of the most important causal agents of bacteremia. For non-blood-borne infection, bacterial dissemination requires the crossing of the vascular endothelium, the main barrier between blood and the surrounding tissues. Here, we investigated the effects of P. aeruginosa type 3 secretion effectors, namely ExoS, ExoT, and ExoY, on regulators of actin cytoskeleton dynamics in primary endothelial cells. ExoS and ExoT similarly affected the Lim kinase-cofilin pathway, thereby promoting actin filament severing. Cofilin activation was also observed in a mouse model of P. aeruginosa-induced acute pneumonia. Rho, Rac, and Cdc42 GTPases were sequentially inactivated, leading to inhibition of membrane ruffling, filopodia, and stress fiber collapse, and focal adhesion disruption. At the end of the process, ExoS and ExoT produced a dramatic retraction in all primary endothelial cell types tested and thus a rupture of the endothelial monolayer. ExoY alone had no effect in this context. Cell retraction could be counteracted by overexpression of actin cytoskeleton regulators. In addition, our data suggest that moesin is neither a direct exotoxin target nor an important player in this process. We conclude that any action leading to inhibition of actin filament breakdown will improve the barrier function of the endothelium during P. aeruginosa infection.     

Fibrinolytic system in the dog with experimental renal (goldblatt) hypertension

Résumé Nous avons constaté, au cours de l'hypertension arterielle produite chez le chien d'après la technique deGoldblatt, l'inhibition de la fibrinolyse des euglobulines, l'augmentation considérable de fibrinogène et de plasminogène. L'intervention chirurgicale de contrôle produisit seulement une augmentation moindre de fibrinogène, sans inhibition de la fibrinolyse.

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Supported in part by a grant from the Polish Academy of Sciences, Department II and VI.     

Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome

We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment.     

Release of plasminogen activator from normal and neoplastic endometrium

Summary In the medium of endometrial carcinoma cultures, anti-urokinase-reacting plasminogen activator was released in contrast to cultures of normal or hyperplastic endometrium.This investigation was supported by grants from Malmö General Hospital, the Council for Tobacco Research, USA and the Swedish Medical Research Council (B79-17X-04523-05B).     

Ontogeny of the sex steroid and prolactin receptors in the male rat adrenal gland

Summary Cytosolic estrogen and androgen receptors and membrane prolactin-binding sites in the male adrenal glands showed a definite pattern during sexual development. The level of sexual steroid receptors paralleled adrenal growth, whereas prolactin binding reached its maximum value in mature rats.Lüthy, I. A., Predoctoral Fellow from the Consejo Nacional de Investigaciones Cientificas y Técnicas and Calandra, R. S., Research Career Awardee from the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.Acknowledgments. We would like to thank Mrs D. Bas and Mrs D. B. Destéfano for the skillful technical assistance and the secretarial work, respectively. This work was partially supported by the Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina (CONICET), and the Comisión Nacional de Energía Atómica.     

Alteration of mitochondrial bioenergetics due to intravenous injection of a perfluorocarbon emulsion

Wistar albino rats were intravenously injected with 1 ml of an oxyphoretic emulsion of perfluorobutylfurane and killed 3, 7 or 30 days later. Mitochondria isolated from the liver and kidneys of treated rats showed a small decrease in the transmembrane electrical potential and a substantial depression of the rates of both ATP synthesis and ADP-stimulated respiration. These alterations in mitochondrial oxidative phosphorylation appear to be induced by perfluorocarbon and/or tensioactive molecules interacting with hydrophobic cell structures.     

Phase transformation and crystal growth behavior of 8mol% (SmO1.5, GdO1.5, and YO1.5) stabilized ZrO2 powders

Nanocrystalline powders of ZrO2–8mol%SmO1.5(8SmSZ), ZrO2–8mol%GdO1.5 (8GdSZ), and ZrO2–8mol%YO1.5 (8YSZ) were prepared by a simple reverse-coprecipitation technique. Differential thermal analysis/thermogravimetry (DTA/TG), Fourier transform infra-red spectroscopy (FTIR), X-ray diffraction (XRD), Raman spectroscopy, and high-resolution transmission electron microscopy (HRTEM) were used to study the phase transformation and crystal growth behavior. The DTA results showed that the ZrO2 freeze-dried precipitates crystallized at 529, 465, and 467°C in the case of 8SmSZ, 8GdSZ, and 8YSZ, respectively. The XRD and Raman results confirmed the presence of tetragonal ZrO2 when the dried precipitates were calcined in the temperature range from 600 to 1000°C for 2 h. The crystallite size increased with increasing calcination temperature. The activation energies were calculated as 12.39, 12.45, and 16.59 kJ/mol for 8SmSZ, 8GdSZ, and 8YSZ respectively.