Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1a. Mel-18 negatively regulated the HIF-1a expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1a expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1a protein level. Mel-18 modulated the HIF-1a transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1a/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1a expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1a and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

This study analyzes the relationship between Environmental, Social and Governance (ESG) scores and bond returns using the corporate bond data in Korea during the period of 2010 to 2015. We find that ESG scores include valuable information about the downside risk of firms. This effect is particularly salient for the firms with high information asymmetry such as small firms. Interestingly, of the three ESG criteria, only environmental scores show a significant impact on bond returns when interacted with the firm size, suggesting that high environmental scores lower the cost of debt financing for small firms. Finally, ESG is complementary to credit ratings in assessing credit quality as credit ratings cannot explain away ESG effects in predicting future bond returns. This result suggests that credit rating agencies should either integrate ESG scores into their current rating process or produce separate ESG scores which bond investors integrate with the existing credit ratings by themselves.

A strong correlation between chronic periodontitis and systemic diseases (e.g., cardiovascular disease, metabolic disorders) has been suggested for several decades. However, the evidence supporting this correlation is restricted primarily to epidemiologic studies, with only a few experimental outcomes confirming such a correlation and providing information about the underlying molecular mechanisms. To reveal a correlation between periodontitis and systemic diseases as well as a relevant molecular pathway, we investigated the effects of Porphyromonas gingivalis and Fusobacterium nucleatum, which play roles in chronic periodontitis progression, on Raw264.7 and THP-1 macrophages. Infection with P. gingivalis or F. nucleatum significantly induced the expression of fatty acid binding protein 4 (FABP4), one of the most important adipokines that play a role in the progression of systemic diseases such as atherosclerosis and type 2 diabetes. Periodontal pathogen–induced FABP4 expression in macrophages promoted lipid uptake by these cells, as demonstrated by the diminished lipid accumulation in cells treated with an FABP4 inhibitor, BMS309403, or with knockdown of FABP4 expression. This periodontal pathogen–induced FABP4 expression was dependent on the JNK pathway, and JNK inhibition reduced lipid uptake by reducing FABP4 expression. Serum levels of antibodies against P. gingivalis correlated with serum FABP4 levels in humans, whereas no association occurred between F. nucleatum antibody titers and FABP4 levels. To our knowledge, this report is the first to experimentally demonstrate that periodontal pathogens stimulate lipid uptake in macrophages by modulating FABP4 expression. These findings strongly support the hypothesis that periodontitis may affect the progression of various systemic diseases.

Crashworthiness is an issue that should be considered when designing a passenger vehicle to ensure the occupants' safety in a vehicle accident. Many governments and insurance companies around the world suggest conditions relating to passenger safety in designing vehicles, and regulations that include the conditions have been utilized. The suggested regulations reflect the crashworthiness of structures in order to consider passenger safety. Therefore, these conditions should be used as objective functions or constraints when optimizing a vehicle structure. However, it is difficult to apply gradient-based optimization methods to crash optimization problems because of the large non-linearities of the problems which should be considered in the time domain. The non-linearities and oscillation of the responses make it difficult to calculate the sensitivity information. Therefore, a design method regarding the crash optimization problem needs to be developed. A crash problem should consider the crashworthiness of the vehicle. That is, a design problem should be solved regarding the crash energy conveyed from the outside and injuries to the human body. In the present research, a crashworthiness design optimization method using equivalent static loads that considers the strain energy and injuries of the human body is proposed. The equivalent static loads method for non-linear static response structural optimization (ESLSO) is modified to handle responses imposed on the strain energy and the head injury criterion (HIC) responses. The proposed ESLSO is verified through three practical examples. Design optimization of a crash box and a knee bolster are carried out to maximize absorbed impact energy, and size optimization of a frontal structure of a simplified vehicle is performed to reduce head injury. In verifying the proposed method, traditional optimization methods such as the response surface method are used. The excellence and usefulness of the proposed crashworthiness optimization method are proved by successfully applying it to a crash problem and improving the crashworthiness of the vehicle.

Composites consisting of a quasicrystalline, icosahedral phase (I-phase) and ductile α-Mg can be fabricated by controlling the alloy composition in the Mg–Zn–Y alloy system. The I-phase in Mg–Zn–Y alloys shows a variation in structural order from a well-ordered icosahedral phase to a 1/1 rhombohedral approximant phase. The structural change in the icosahedral phase can be explained by microdomain formation due to compositional change during solidification. The characteristic of strong bonding between icosahedral particles and the α-Mg matrix indicates that the structural change from I-phase to crystalline phase is not discontinuous, but gradual. The interface layer of α-Mg with several nm thickness preserves an orientational relationship with the I-phase, although the remaining α-Mg shows a different orientation due to plastic deformation during deformation (rolling process). Such a strong interface can provide an excellent combination of high strength and formability in Mg-based alloys, enabling application as lightweight structural parts.