Search

Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by deficiency of the ubiquitously expressed SMN protein. Here, we present a retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavorable imbalance between endothelial injury and repair, as indicated by increased circulating endothelial cell counts and decreased endothelial progenitor cell counts in blood circulation. The cellular markers of endothelial injury were associated with disease severity and improved following SMN restoration treatment in cultured endothelial cells from patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarker findings indicate microvasculopathy as a fundamental feature of SMA. Our findings provide mechanistic insights into previously described SMA microvascular complications, and highlight the functional role of SMN in the periphery, including the vascular system, where deficiency of SMN can be addressed by systemic SMN-restoring treatment., Introduction Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused, in approximately 95% of patients, by homozygous deletion of the survival motor neuron 1 gene (SMN1) (1). The [...]

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter (64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO-(64)Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM(-1) s(-1), and an r 2 relaxivity of 83.9 mM(-1) s(-1) (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages.

Bowditch characterized relative hyperbolicity in terms of group actions on fine hyperbolic graphs with finitely many edge orbits and finite edge stabilizers. In this paper, we define generalized fine actions on hyperbolic graphs, in which the peripheral subgroups are allowed to stabilize finite subgraphs rather than stabilizing a point. Generalized fine actions are useful for studying groups that act relatively geometrically on a CAT(0) cube complex, which were recently defined by the first two authors. Specifically, we show that any group acting relatively geometrically on a CAT(0) cube complex admits a generalized fine action on the one-skeleton of the cube complex. For generalized fine actions, we prove a criterion for relative quasiconvexity of subgroups that cocompactly stabilize quasiconvex subgraphs, generalizing a result of Martínez-Pedroza and Wise in the setting of fine hyperbolic graphs. As an application, we obtain a characterization of boundary separation in generalized fine graphs and use it to prove that Bowditch boundary points in relatively geometric actions are always separated by a hyperplane stabilizer. [ABSTRACT FROM AUTHOR]

Organizational programs and policies are important facilitators of employees' career development. However, organizations face a developmental paradox: Their career-aiding programs and policies might increase the employability of their employees, who might then leave the company. Guided by organizational support theory, we propose a theory-driven reciprocation view that explains why organization-sponsored career development practices might actually strengthen the current employment relationship. We argued that by offering career aids and resources, an organization can promote its employees' perceptions of organizational support. These perceptions evoke reciprocation, manifested in strengthened organizational attachment that enhances job performance and lowers turnover. In a meta-analysis of over 1,000 articles, we found that employer-sponsored career development practices were related to employees' job performance and turnover via the mechanisms of perceived organizational support and organizational attachment. Further, this relationship was even stronger when career development practices signaled greater care by being available (vs. used), institutionally embedded (vs. relational), and career focused (vs. job focused). [ABSTRACT FROM AUTHOR]