Fibrillin-rich microfibrils are extracellular assemblies that impart structural properties to the connective tissue. To elucidate the contribution of fibrillin-rich microfibrils to organogenesis, we have examined the vascular phenotype of a newly created strain of mice that completely lacks fibrillin-1 and the consequences of combined deficiency of fibrillins 1 and 2 on tissue formation. The results demonstrated that fibrillins 1 and 2 perform partially overlapping functions during aortic development. Elastogenesis is a complex biological process that involves the organized deposition and self-assembly of several macromolecules into microfibrils and elastic fibers (1). Elastic fibers are made of an amorphous core of cross-linked elastin and other molecules and microfibrils; the latter are heterogeneous in composition and can also form macroaggregates devoid of elastin (2, 3). Fibrillins 1 and 2 are the main structural components of extracellular microfibrils and the defective gene products in Marfan syndrome (MFS) 3 and congenital contractural arachnodactyly (CCA), respectively (4, 5). MFS is a pleiotropic disorder of the connective tissue with wide variation in clinical severity (6). Cardiovascular manifestations in the form of aortic dilatation, dissection, and rupture contribute significantly to morbidity and mortality in affected individuals. CCA, on the other hand, is a rare condition akin to MFS but with major manifestations confined to the musculoskeletal system (6). Fibrillins are large cysteine-rich glycoproteins (ϳ350 kDa) composed primarily of multiple repeated domains homologous to the calcium binding epidermal growth factor module and of distinct 8-cysteine modules (2, 3, 5). Fibrillins polymerize into a characteristic beadson-a-string microfibril structure, which gives rise to the microfibril lattice by lateral association of the individual microfibril polymers and probable association of other structural components. Fibrillins can form homo-or heteropolymeric microfibrils and can interact with integrins, growth factors, several other matrix components, and latent transforming growth factor -binding proteins.Differential expression of elastic fiber components, dynamic cell-matrix interactions, and microfibril-mediated modulation of signaling molecules account for the diverse architectures and functions of elastic networks during the development and growth of individual organ systems (5). The process of aortic media formation is an illustrative example of the interplay between resident cells and elastic fiber components that ultimately results in the highly organized and functionally competent tissue (7,8). At about mid-gestation, vascular smooth muscle cells (VSMC) deposit fibrillins and tropoelastin molecules into the surrounding matrix and begin to organize them into elastic fibers. The latter process extends into early neonatal life accompanied by the gradual growth of elastic fibers into mature elastic lamellae that separate parallel layers of quiescent VSMC. The resulting organization of th...
Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803–814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE‐SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age‐group‐related differences for the subsequent memory contrast, and the FADE‐SAME score additionally exhibited age‐group‐related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single‐value scores of memory‐related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.
Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19–24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.
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