Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblastmediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis 1,2 . Here we report that interferon regulatory factor 8 (IRF8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor κB ligand (RANKL, also called TRANCE, ODF, and OPGL), which is encoded by the Tnfsf11 gene. Mice deficient in IRF8 exhibited severe osteoporosis due to increased numbers of osteoclasts, and enhanced bone destruction following lipopolysaccharide (LPS) administration. Irf8 -/-osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor α (TNFα). IRF8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF8 inhibits osteoclast formation Correspondence should be addressed to M.T. (takami@dent.showa-u.ac.jp). AUTHOR CONTRIBUTIONS B.Z. performed most of the experiments with significant assistance from M.T. X.W. conducted the histological analysis. A.Y., T.K., X.H., and T.T. assisted with the experiments. K.O. provided the Irf8 −/− mice. B.Z. and M.T. designed the project and wrote the manuscript. Y.C. provided recombinant RANKL and contributed to manuscript preparation. L.B.I. oversaw the bone marrow chimera and human cell experiments and contributed to manuscript revision. H.T. oversaw the inflammatory bone destruction experiments and provided critical advice for the experiments. M.T. and R.K. supervised the project. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. [3][4][5] . Numerous studies have focused on these upregulated genes and their roles in osteoclastogenesis. On the other hand, the expression levels of various genes are simultaneously downregulated during osteoclastogenesis 6 . The biological significance of the downregulated expression of these genes following RANK activation, however, has not been fully elucidated. NIH Public AccessTo identify genes that show reduced expression levels in response to RANK signaling, we performed a genome-wide screening of mRNAs from osteoclast precursors and osteoclasts using a DNA microarray technique (data not shown). Among the identified genes, expression of the transcription factor Irf8 [also called interferon consensus sequence binding protein (ICSBP)] was found to be downregulated during the initial phase of osteoclastogenesis triggered by RANKL (data not shown). IRF8 is known to be specifically expressed in immune cells, including monocytes/macrophages, B lymphocytes, and activated T lymphocytes 7-9 . It is a member of the IRF family and has been shown to regulate myeloid cell development by...

Microvascular free tissue transfer has gained world-wide acceptance as a means of reconstructing post-oncologic surgical defects in the head and neck region. Since 1977, the authors have introduced this reconstructive procedure to head and neck reconstruction after cancer ablation, and a total of 2372 free flaps were transferred in 2301 patients during a period of over 23 years. The most frequently used flap was the rectus abdominis flap (784 flaps: 33.1 percent), followed by the jejunum (644 flaps: 27.2 percent) and the forearm flap (384 flaps: 16.2 percent). In the reported series, total and partial flap necrosis accounted for 4.2 percent and 2.5 percent of cases, respectively. There was a significant statistical difference ( p < 0.05) in complete flap survival rate between immediate and secondary reconstruction cases. The authors believe that the above-mentioned three flaps have been a major part of the armamentarium for head and neck reconstruction because of a lower rate of flap necrosis, compared to other flaps.

Adult hippocampal neurogenesis has been implicated in cognitive and emotional processes, and in response to antidepressant treatment. However, little is known about how the adult stem cell lineage contributes to hippocampal structure and function and how this process is modulated by the animal’s experience. Here we perform an indelible lineage analysis and report that neural stem cells can produce expanding and persisting populations of not only neurons, but also stem cells in the adult hippocampus. Furthermore, the ratio of stem cells to neurons depends on experiences of the animal or the location of the stem cell. Surprisingly, social isolation facilitated accumulation of stem cells, but not neurons. These results show that neural stem cells accumulate in the adult hippocampus, and that the stem cell-lineage relationship is under control of anatomic and experiential niches. Our findings suggest that, in the hippocampus, fate specification may act as a form of cellular plasticity for adapting to environmental changes.

We discuss the weak coupling expansion of massless QCD with the Dirac operator which is derived by Neuberger based on the overlap formalism and satisfies the Ginsparg-Wilson relation. The axial U(1) anomaly associated to the chiral transformation proposed by Lüscher is calculated as an application and is shown to have the correct form of the topological charge density for perturbative backgrounds. The coefficient of the anomaly is evaluated as a winding number related to a certain five-dimensional fermion propagator. †