Summary: Bone grafts are the second most common tissue transplanted in the United States, and they are an essential treatment tool in the field of acute and reconstructive traumatic orthopaedic surgery. Available in cancellous, cortical, or bone marrow aspirate form, autogenous bone graft is regarded as the gold standard in the treatment of posttraumatic conditions such as fracture, delayed union, and nonunion. However, drawbacks including donor-site morbidity and limited quantity of graft available for harvest make autograft a less-than-ideal option for certain patient populations. Advancements in allograft and bone graft substitutes in the past decade have created viable alternatives that circumvent some of the weak points of autografts. Allograft is a favorable alternative for its convenience, abundance, and lack of procurement-related patient morbidity. Options include structural, particulate, and demineralized bone matrix form. Commonly used bone graft substitutes include calcium phosphate and calcium sulfate synthetics—these grafts provide their own benefits in structural support and availability. In addition, different growth factors including bone morphogenic proteins can augment the healing process of bony defects treated with grafts. Autograft, allograft, and bone graft substitutes all possess their own varying degrees of osteogenic, osteoconductive, and osteoinductive properties that make them better suited for different procedures. It is the purpose of this review to characterize these properties and present clinical evidence supporting their indications for use in the hopes of better elucidating treatment options for patients requiring bone grafting in an orthopaedic trauma setting.

Longstanding observations suggest that acetylation and/or amino-terminal tail structure of histones H3 and H4 are critical for eukaryotic cells. For Saccharomyces cerevisiae, loss of a single H4-specific histone acetyltransferase (HAT), Esa1p, results in cell cycle defects and death. In contrast, although several yeast HAT complexes preferentially acetylate histone H3, the catalytic subunits of these complexes are not essential for viability. To resolve the apparent paradox between the significance of H3 versus H4 acetylation, we tested the hypothesis that H3 modification is essential, but is accomplished through combined activities of two enzymes. We observed that Sas3p and Gcn5p HAT complexes have overlapping patterns of acetylation. Simultaneous disruption of SAS3, the homolog of the MOZ leukemia gene, and GCN5, the hGCN5/PCAF homolog, is synthetically lethal due to loss of acetyltransferase activity. This key combination of activities is specific for these two HATs because neither is synthetically lethal with mutations of other MYST family or H3-specific acetyltransferases. Further, the combined loss of GCN5 and SAS3 functions results in an extensive, global loss of H3 acetylation and arrest in the G 2 /M phase of the cell cycle. The strikingly similar effect of loss of combined essential H3 HAT activities and the loss of a single essential H4 HAT underscores the fundamental biological significance of each of these chromatin-modifying activities.

Nociceptive neurons in the peripheral nervous system detect noxious stimuli and report the information to the central nervous system. Most nociceptive neurons express the vanilloid receptor, TRPV1, a non-selective cation channel gated by vanilloid ligands such as capsaicin, the pungent essence of chili peppers. Here, we report the synthesis and biological application of two caged vanilloids-biologically inert precursors that, when photolyzed, release bioactive vanilloid ligands. The two caged vanilloids, Nb-VNA and Nv-VNA, are photoreleased with quantum efficiency of 0.13 and 0.041, respectively. Under flash photolysis conditions, photorelease of Nb-VNA and Nv-VNA is 95% complete in ∼40 μs and ∼125 μs, respectively. Through 1-photon excitation with ultraviolet light (360 nm), or 2-photon excitation with red light (720 nm), the caged vanilloids can be photoreleased in situ to activate TRPV1 receptors on nociceptive neurons. The consequent increase in intracellular free Ca 2+ concentration ([Ca 2+ ] i ) can be visualized by laser-scanning confocal imaging of neurons loaded with the fluorescent Ca 2+ indicator, fluo-3. Stimulation results from TRPV1 receptor activation, because the response is blocked by capsazepine, a selective TRPV1 antagonist. In Ca 2+ -free extracellular medium, photoreleased vanilloid can still elevate [Ca 2+ ] i , which suggests that TRPV1 receptors also reside on endomembranes in neurons and can mediate Ca 2+ release from intracellular stores. Notably, whole-cell voltage clamp measurements showed that flash photorelease of vanilloid can activate TRPV1 channels in < 4 msec at 22°C. In combination with 1-or 2-photon excitation, caged vanilloids are a powerful tool for probing morphologically distinct structures of nociceptive sensory neurons with high spatial and temporal precision. Keywords photolysis; photorelease; uncaging; molecular probes In the peripheral nervous system, nociceptive sensory neurons, or nociceptors, detect noxious stimuli and convert these stimuli into action potentials that are transmitted to the central nervous system (1). The vast majority of nociceptive neurons express the vanilloid receptor, TRPV1, 2 which is a ligand-gated non-selective cation channel with high permeability to

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