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Cardio‐facio‐cutaneous (CFC) syndrome is a developmental disorder caused by constitutively active ERK signaling manifesting mainly from BRAF mutations. Little is known about the role of elevated ERK signaling in CFC syndrome during early development. Here, we show that both SMAD1 and ERK signaling pathways may contribute to the developmental defects in CFC syndrome. Induced pluripotent stem cells (iPSCs) derived from dermal fibroblasts of a CFC syndrome patient (CFC‐iPSCs) revealed early developmental defects in embryoid body (EB) development, β‐catenin localization, and neuronal differentiation. Both SMAD1 and ERK signalings were significantly activated in CFC‐iPSCs during EB formation. Most of the β‐catenin was dissociated from the membrane and preferentially localized into the nucleus in CFC‐EBs. Furthermore, activation of SMAD1 signaling recapitulated early developmental defects in wild‐type iPSCs. Intriguingly, inhibition of SMAD1 signaling in CFC‐iPSCs rescued aberrant EB morphology, impaired neuronal differentiation, and altered β‐catenin localization. These results suggest that SMAD1 signaling may be a key pathway contributing the pathogenesis of CFC syndrome during early development. StemCells2015;33:1447–1455

Clusterin, a protein associated with multiple functions, is expressed in a wide variety of mammalian tissues. Although clusterin is known to be involved in neurodegenerative diseases, ageing, and tumorigenesis, a detailed analysis of the consequences of gain- or loss-of-function approaches has yet to be performed to understand the underlying mechanisms of clusterin functions. Since clusterin levels change in neurological diseases, it is likely that clusterin contributes to cell death and degeneration in general. Zebrafish was investigated as a model system to study human diseases. During development, zebrafish clusterinwas expressed in the notochord and nervous system. Embryonic overexpression of clusterinby mRNA microinjection did not affect axis formation, whereas its knock-down by anti-sense morpholino treatment resulted in neuronal cell death. To analyze the function of clusterinin neurodegeneration, a transgenic zebrafish was investigated, in which nitroreductase expression is regulated under the control of a neuron-specific huCpromoter which is active between the stages of early neuronal precursors and mature neurons. Nitroreductase turns metronidazole into a cytotoxic agent that induces cell death within 12 h. After metronidazole treatment, transgenic zebrafish showed neuron-specific cell death. Interestingly, we also observed a dramatic induction of clusterinexpression in the brain and spinal cord in these fish, suggesting a direct or indirect role of clusterinin neuronal cell death and thus, more generally, in neurodegeneration.

Tuned liquid column damper (TLCD) is used to reduce wind induced building acceleration by tuning its natural frequency to that of a building. After building construction, its natural frequency may differ from the original one. Thus, TLCD installed at a building should have the shifted natural frequency without its serious structural modification. Conventional TLCD changes its natural frequency by only regulating liquid height, which destroys U shape of TLCD. This study proposes new concept of TLCD which yields wide range of natural frequency with very simple modification maintaining original shape. Vertical columns of TLCD are divided into several individual cell type small columns. The liquid in individual cell type columns cannot move by air pressure if their tops are sealed. By taking appropriate number of cell type columns in sealed condition, sectional area ratio of vertical and horizontal columns is changed, which can provide new natural frequency same to shifted natural frequency of a building. TLCD's with multi cells are analytically evaluated and experimentally verified using shaking table test according to the number of sealed cell type small columns.