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This study focuses on a lightweight syntactic foam constituted by an epoxy matrix filled with polydispersed Glass Microballoons (GMs) up to 0.75 volume fraction. We present experimental results on hydrostatic loading which demonstrate the possibility of different failure modes depending on whether the surface of the composite is painted/coated or not. In order to explain this surprising behaviour, we propose a three-dimensional Finite Element (FE) micromechanical model. First, we develop a cubic MultiParticle Unit Cell (MPUC) which includes 100 randomly placed GMs and accounting for their polydispersion, in terms of both size and radius ratio. This model is validated by subjecting it to effective uniaxial stress and comparing its predictions of the elastic moduli with experimental findings and an analytical homogenisation technique. Second, towards modelling failure, we implement a structural criterion proposed by our group, which posits that any GM undergoes brittle failure when its average elastic energy density reaches a critical value. We then utilise our measurements of the effective strength under uniaxial compressive stress to identify different critical values for selected types of GMs. Third, on the basis of the MPUC, we reach our goal by developing a larger FE model, including 300 GMs, which enables the study of the stress diffusion from the external surface through an appropriately thick layer of composite, under macroscopic uniform pressure. This micromechanical model allows us to demonstrate the influence of the paint/coating on the syntactic foam failure mode through a detailed analysis of the collapsed GMs and the matrix stress state. [ABSTRACT FROM AUTHOR]

SKP2 is the substrate recognition subunit of the ubiquitin ligase complex which targets p27 KIP1 for degradation. Induced at the G 1 /S transit of the cell cycle, SKP2 is frequently overexpressed in human cancers and contributes to malignancy. We previously identified SKP2 as a possible MYCN target gene and hence hypothesise that SKP2 is a potential therapeutic target in MYCN amplified disease. A positive correlation was identified between MYCN activity and SKP2 mRNA expression in Tet21N MYCN-regulatable cells and a panel of MYCN amplified and non-amplified neuroblastoma cell lines. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to E-boxes within the SKP2 promoter and induced transcriptional activity which was decreased by the removal of MYCN and E-box mutation. Although SKP2 knockdown inhibited cell growth in both MYCN amplified and non-amplified cells, cell cycle arrest and apoptosis were induced only in non- MYCN amplified neuroblastoma cells. In conclusion these data identify SKP2 as a direct transcriptional target of MYCN and supports SKP2 as a potential therapeutic target in neuroblastoma. [ABSTRACT FROM AUTHOR]

Intellectual disability in Down syndrome (DS) appears to be related to severe proliferation impairment during brain development. Recent evidence shows that it is not only cellular proliferation that is heavily compromised in DS, but also cell fate specification and dendritic maturation. The amyloid precursor protein (APP), a gene that is triplicated in DS, plays a key role in normal brain development by influencing neural precursor cell proliferation, cell fate specification, and neuronal maturation. APP influences these processes via two separate domains, the APP intracellular domain (AICD) and the soluble secreted APP. We recently found that the proliferation impairment of neuronal precursors (NPCs) from the Ts65Dn mouse model for DS was caused by derangement of the Shh pathway due to overexpression of patched1(Ptch1), its inhibitory regulator. Ptch1 overexpression was related to increased levels within the APP/ AICD system. The overall goal of this study was to determine whether APP contributes to neurogenesis impairment in DS by influencing in addition to proliferation, cell fate specification, and neurite development. We found that normalization of APP expression restored the reduced neuronogenesis, the increased astrogliogenesis, and the reduced neurite length of trisomic NPCs, indicating that APP overexpression underpins all aspects of neurogenesis impairment. Moreover, we found that two different domains of APP impair neuronal differentiation and maturation in trisomic NPCs. The APP/AICD system regulates neuronogenesis and neurite length through the Shh pathway, whereas the APP/secretedAPsystem promotes astrogliogenesis through an IL-6-associated signaling cascade. These results provide novel insight into the mechanisms underlying brain development alterations in DS. [ABSTRACT FROM AUTHOR]

CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN protooncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5′-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU. [ABSTRACT FROM AUTHOR]

Increased expression of specific ATP-binding cassette (ABC) transporters is known to mediate the efflux of chemotherapeutic agents from cancer cells. Therefore, establishing how ABC transporter genes are controlled at their transcription level may help provide insight into the role of these multifaceted transporters in the malignant phenotype. We have investigated ABC transporter gene expression in a large neuroblastoma data set of 251 tumor samples. Clustering analysis demonstrated a strong association between differential ABC gene expression patterns in tumor samples and amplification of the MYCN oncogene, suggesting a correlation with MYCN function. Using expression profiling and chromatin immunoprecipitation studies, we show that MYCN oncoprotein coordinately regulates transcription of specific ABC transporter genes, by acting as either an activator or a repressor. Finally, we extend these notions to c-MYC showing that it can also regulate the same set of ABC transporter genes in other tumor cells through similar dynamics. Overall our findings provide insight into MYC-driven molecular mechanisms that contribute to coordinate transcriptional regulation of a large set of ABC transporter genes, thus affecting global drug efflux. [ABSTRACT FROM AUTHOR]