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991.
H Seifarth CL Schlett M Nakano F Otsuka M Károlyi G Liew P Maurovich-Horvat H Alkadhi R Virmani U Hoffmann 《Atherosclerosis》2012,224(1):90-96
ObjectiveThe purpose of this study was to identify histologic characteristics of advanced coronary atherosclerotic plaques that are related with the detection of the napkin-ring sign (NRS) in coronary CT angiography (CCTA).MethodsCCTA was performed in 7 human donor hearts. Histological slicing and stainings were performed in 1 mm increments of each major coronary artery. Histology was co-registered with the CT-data and classified according to the modified AHA classification.ResultsAdvanced plaques (types IV–VI) were present in 139 (23%) of 611 cross sections. Of these 33 (24%) demonstrated an NRS in CCTA. NRS plaques were associated with greater non-core plaque area (median 10.2 vs. 6.4 mm2, p < 0.01) and larger vessel area (median 17.1 vs. 13.0 mm2, p < 0.01). The area of the necrotic/lipid core was larger in plaques with NRS (median 1.1 vs. 0.5 mm2, p = 0.05). Angiogenesis tended to be more frequent in plaques with NRS (48% vs. 30%) whereas micro-calcifications tended to be more frequent in plaques without NRS (27% vs. 46%) (p = 0.06 and 0.07 respectively). In a multivariate analysis, necrotic/lipid core area (OR = 1.9), non-core plaque area (OR = 1.6), and total vessel area (OR = 0.9) independently predicted the appearance of the NRS in coronary CT angiography.ConclusionDelineation of NRS in CCTA is independently linked to the size of the necrotic/lipid core, the size of the non-core plaque and to the vessel area as measured in histology of advanced coronary atherosclerotic plaques. 相似文献
992.
993.
994.
Fraysse B Weinberger F Bardswell SC Cuello F Vignier N Geertz B Starbatty J Krämer E Coirault C Eschenhagen T Kentish JC Avkiran M Carrier L 《Journal of molecular and cellular cardiology》2012,52(6):1299-1307
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from gene mutations to the HCM phenotype remain incompletely understood, partially because current mouse models of HCM do not faithfully reflect the human situation and early hypertrophy confounds the interpretation of functional alterations. The goal of this study was to evaluate whether myofilament Ca(2+) sensitization and diastolic dysfunction are associated or precede the development of left ventricular hypertrophy (LVH) in HCM. We evaluated the function of skinned and intact cardiac myocytes, as well as the intact heart in a recently developed Mybpc3-targeted knock-in mouse model carrying a point mutation frequently associated with HCM. Compared to wild-type, 10-week old homozygous knock-in mice exhibited i) higher myofilament Ca(2+) sensitivity in skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster Ca(2+) transient decay in intact myocytes, and iii) LVH, reduced fractional shortening, lower E/A and E'/A', and higher E/E' ratios by echocardiography and Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit LVH or systolic dysfunction, but exhibited higher myofilament Ca(2+) sensitivity, faster Ca(2+) transient decay, and diastolic dysfunction. These data demonstrate that myofilament Ca(2+) sensitization and diastolic dysfunction are early phenotypic consequences of Mybpc3 mutations independent of LVH. The accelerated Ca(2+) transients point to compensatory mechanisms directed towards normalization of relaxation. We propose that HCM is a model for diastolic heart failure and this mouse model could be valuable in studying mechanisms and treatment modalities. 相似文献
995.
White R Mensan R Bourrillon R Cretin C Higham TF Clark AE Sisk ML Tartar E Gardère P Goldberg P Pelegrin J Valladas H Tisnérat-Laborde N de Sanoit J Chambellan D Chiotti L 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(22):8450-8455
We report here on the 2007 discovery, in perfect archaeological context, of part of the engraved and ocre-stained undersurface of the collapsed rockshelter ceiling from Abri Castanet, Dordogne, France. The decorated surface of the 1.5-t roof-collapse block was in direct contact with the exposed archaeological surface onto which it fell. Because there was no sedimentation between the engraved surface and the archaeological layer upon which it collapsed, it is clear that the Early Aurignacian occupants of the shelter were the authors of the ceiling imagery. This discovery contributes an important dimension to our understanding of the earliest graphic representation in southwestern France, almost all of which was discovered before modern methods of archaeological excavation and analysis. Comparison of the dates for the Castanet ceiling and those directly obtained from the Chauvet paintings reveal that the "vulvar" representations from southwestern France are as old or older than the very different wall images from Chauvet. 相似文献
996.
Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy 总被引:1,自引:0,他引:1
Rahmeh R Damian M Cottet M Orcel H Mendre C Durroux T Sharma KS Durand G Pucci B Trinquet E Zwier JM Deupi X Bron P Banères JL Mouillac B Granier S 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(17):6733-6738
G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin-biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs. 相似文献
997.
Koštál V Šimek P Zahradníčková H Cimlová J Štětina T 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(9):3270-3274
Among vertebrates, only a few species of amphibians and reptiles tolerate the formation of ice crystals in their body fluids. Freeze tolerance is much more widespread in invertebrates, especially in overwintering insects. Evolutionary adaptations for freeze tolerance are considered to be highly complex. Here we show that surprisingly simple laboratory manipulations can change the chill susceptible insect to the freeze tolerant one. Larvae of Drosophila melanogaster, a fruit fly of tropical origin with a weak innate capacity to tolerate mild chilling, can survive when approximately 50% of their body water freezes. To achieve this goal, synergy of two fundamental prerequisites is required: (i) shutdown of larval development by exposing larvae to low temperatures (dormancy) and (ii) incorporating the free amino acid proline in tissues by feeding larvae a proline-augmented diet (cryopreservation). 相似文献
998.
NB Eloy N Gonzalez J Van Leene K Maleux H Vanhaeren L De Milde S Dhondt L Vercruysse E Witters R Mercier L Cromer GT Beemster H Remaut MC Van Montagu G De Jaeger PC Ferreira D Inzé 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(34):13853-13858
The anaphase-promoting complex/cyclosome (APC/C) is a large multiprotein E3 ubiquitin ligase involved in ubiquitin-dependent proteolysis of key cell cycle regulatory proteins, including the destruction of mitotic cyclins at the metaphase-to-anaphase transition. Despite its importance, the role of the APC/C in plant cells and the regulation of its activity during cell division remain poorly understood. Here, we describe the identification of a plant-specific negative regulator of the APC/C complex, designated SAMBA. In Arabidopsis thaliana, SAMBA is expressed during embryogenesis and early plant development and plays a key role in organ size control. Samba mutants produced larger seeds, leaves, and roots, which resulted from enlarged root and shoot apical meristems, and, additionally, they had a reduced fertility attributable to a hampered male gametogenesis. Inactivation of SAMBA stabilized A2-type cyclins during early development. Our data suggest that SAMBA regulates cell proliferation during early development by targeting CYCLIN A2 for APC/C-mediated proteolysis. 相似文献
999.
Kolano A Brunet S Silk AD Cleveland DW Verlhac MH 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(27):E1858-E1867
It is well established that chromosome segregation in female meiosis I (MI) is error-prone. The acentrosomal meiotic spindle poles do not have centrioles and are not anchored to the cortex via astral microtubules. By Cre recombinase-mediated removal in oocytes of the microtubule binding site of nuclear mitotic apparatus protein (NuMA), which is implicated in anchoring microtubules at poles, we determine that without functional NuMA, microtubules lose connection to MI spindle poles, resulting in highly disorganized early spindle assembly. Subsequently, very long spindles form with hyperfocused poles. The kinetochores of homologs make attachments to microtubules in these spindles but with reduced tension between them and accompanied by alignment defects. Despite this, the spindle assembly checkpoint is normally silenced and the advance to anaphase I and first polar body extrusion takes place without delay. Females without functional NuMA in oocytes are sterile, producing aneuploid eggs with altered chromosome number. These findings establish that in mammalian MI, the spindle assembly checkpoint is unable to sustain meiotic arrest in the presence of one or few misaligned and/or misattached kinetochores with reduced interkinetochore tension, thereby offering an explanation for why MI in mammals is so error-prone. 相似文献
1000.
Rune T. Kidmose Nick S. Laursen József Dobó Troels R. Kjaer Sofia Sirotkina Laure Yatime Lars Sottrup-Jensen Steffen Thiel Péter Gál Gregers R. Andersen 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(38):15425-15430
An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation. 相似文献