Effects of nucleosome stability on remodeler-catalyzed repositioning.

Chromatin remodelers are molecular motors that play essential roles in the regulation of nucleosome positioning and chromatin accessibility. These machines couple the energy obtained from the binding and hydrolysis of ATP to the mechanical work of manipulating chromatin structure through processes that are not completely understood. Here we present a quantitative analysis of nucleosome repositioning by the imitation switch (ISWI) chromatin remodeler and demonstrate that nucleosome stability significantly impacts the observed activity. We show how DNA damage induced changes in the affinity of DNA wrapping within the nucleosome can affect ISWI repositioning activity and demonstrate how assay-dependent limitations can bias studies of nucleosome repositioning. Together, these results also suggest that some of the diversity seen in chromatin remodeler activity can be attributed to the variations in the thermodynamics of interactions between the remodeler, the histones, and the DNA, rather than reflect inherent properties of the remodeler itself.

Safety and efficacy of recombinant human bone morphogenetic protein 2 on cranial defect closure in the pediatric population.

BACKGROUND: Traditional reconstructive options for cranial defects include autogenous bone graft, bone substitutes, and synthetic materials. The established standard for repairing cranial defects is autogenous bone. However, young children do not have abundant donor sites for bone harvest, which leads to challenges in closing calvarial defects. Synthetic materials are not ideal alternatives because they require subsequent retrieval and are prone to infection. Their long-term effects on growth of the skull are also not well studied. Bone morphogenetic protein 2 (BMP-2), are shown to positively affect closure of cranial defects in animal models. We present a study comparing the efficacy and safety of closure of cranial defect with bone graft augmented with recombinant human BMP-2 (rhBMP-2) and compared with a series of patients treated with bone graft alone. METHODS: This study is a retrospective multicenter evaluation of 36 patients spanning 5 years. Twenty-one patients undergoing cranial defect closure augmented with rhBMP-2 were compared with 15 patients who underwent cranial defect closure using cranial bone shavings alone. We measured preoperative and postoperative defect size on volumetric computed tomographic scan reconstructions to compare defect sizes. RESULTS: The rhBMP-2 group had slightly increased proportional closure compared with the control group, 86% versus 76% (P < 0.018), respectively. Two patients in the rhBMP-2 group had postoperative fusion of a suture that was known to be patent at the time of cranial defect closure. No instances of brain edema, herniation, airway compromise, or other adverse effects directly attributable to rhBMP-2 were observed. CONCLUSIONS: Bone morphogenetic protein 2 may increase the amplitude and uptake of cranial bone grafts in cranial defect closure. This study shows that defect sizes of up to 16 cm can be reliably closed using this technique. Postoperative fusion of uninvolved sutures in 2 patients indicates that rhBMP-2 may have unreported adverse effects; consideration of this finding should be weighed against the benefit of improved closure of calvarial defects.