The transcription factor Sox9 was first discovered in patients with campomelic dysplasia, a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis. Since then, its role as a cell fate determiner during embryonic development has been well characterized; Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs. However, recent data has shown that ectoderm- and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools, suggesting its role in cell maintenance and specification during adult life. The versatility of Sox9 may be explained by a combination of post-transcriptional modifications, binding partners, and the tissue type in which it is expressed. Considering its importance during both development and adult life, it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases, including fibrosis and cancer. This review provides a summary of the various roles of Sox9 in cell fate specification, stem cell biology, and related human diseases. Ultimately, understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.

Osteogenic differentiation from mesenchymal progenitor cells (MPCs) are initiated and regulated by a cascade of signaling events. Either Wnt/β-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER) signaling by estradiol (E2) or exogenously expressed ERα in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERα-mediated synergy can be effectively blocked by ERα antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERα significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on β-catenin/Tcf reporter activity. However, ERα expression is up-regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERβ expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERα expression and down-regulating ERβ expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis.

This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Abstract Background/Aims: Osteosarcoma (OS) is the most common primary bone malignancy in children and young adults. Molecular mechanisms underlying the pathogenesis of OS remain to be fully understood. Several members of the E-F hand calcium-binding S100 protein family are differentially expressed in human cancers. We previously showed that S100A6 is highly expressed in OS tumors. In this study, we investigated the role of S100A4 in regulating OS proliferation and osteogenic differentiation. Methods/Results: Endogenous S100 expression was examined by semi-quantitative PCR in human OS lines. Adenoviral vector-mediated overexpression and RNAi knockdown of S100A4 were used to assess S100A4's effects on cell proliferation, migration and invasion and osteogenic differentiation. Apoptosis was assessed by using anti-caspase-3 immunostaining and flow cytometry with annexin V staining. Early osteogenic marker alkaline phosphatase (ALP) and late markers osteocalcin (OCN) and osteopontin (OPN) were assessed to determine the status of osteogenic differentiation. We found that S100A4 was elevated in metastatic MG63.2 cells. S100A4 knockdown inhibited cell proliferation, prolonged cell doubling time, and induced significant apoptosis. Silencing S100A4 expression in OS cells delayed cell wounding closure and diminished the numbers of migrated OS cells in transwell invasion assay. Furthermore, silencing S100A4 expression stimulated ALP

Borderline Personality Disorder (BPD) is a major mental illness with a lifetime prevalence of approximately 1-3%, characterized by a persistent pattern of instability in relationships, mood, impulse regulation, and sense of self. This results in impulsive self-damaging behavior, high suicide rates, and severe functional impairment. BPD has a complex, multifactorial etiology, resulting from an interaction among genetic and environmental substrates, and has moderate to high heritability based on twin and family studies. However, our understanding of the genetic architecture of BPD is very limited. This is a critical obstacle since genetics can pave the way for identifying new treatment targets and developing preventive and disease-modifying pharmacological treatments which are currently lacking. We review genetic studies in BPD, with a focus on limitations and challenges and future directions. Genetic research in BPD is still in its very early stages compared to other major psychiatric disorders. Most early genetic studies in BPD were non-replicated association studies in small samples, focused on single candidate genes. More recently, there has been one genome-wide linkage study and a genome-wide association study (GWAS) of subclinical BPD traits and a first GWAS in a relatively modest sample of patients fulfilling full diagnostic criteria for the disorder. Although there are adequate animal models for some of the core dimensions of BPD, there is a lack of translational research including data from animal models in BPD. Research in more pioneering fields, such as imaging genetics, deep sequencing and epigenetics, holds promise for elucidating the pathophysiology of BPD and identifying new treatment targets.

The effects of the heat flux on the thermal decomposition of the commercial flame-retardant ethylenepropylene-diene monomer rubber in a cone calorimeter with a piloted ignition were quantitatively investigated. Correlation analysis of the heat flux and various characteristic parameters, including the ignition time, the thermal thickness, the mass loss rate (MLR), the heat release rate (HRR) and the effective heat of combustion, was conducted. It was found that the transformed ignition time (1/t ig ) 0.55 and 1/t ig , the peak and average MLR, the first and second peak HRR, the HRR in the quasi-steady stage and the average HRR all increased linearly with the heat flux. The thermal thickness (d P ) decreased with the heat flux and was proportional to q= _ q 00 . The specimens under the heat fluxes B35 kW m -2 behaved as thermally thin solids, while the thermal decomposition behavior of the specimens under the heat fluxes [35 kW m -2 may be characterized employing the thermally thick heating model. The flammability properties including the critical heat flux, the minimum heat flux, the ignition temperature, the heat of gasification and the heat of combustion, which were calculated theoretically based upon the correlations of the ignition time data, the MLR data and the HRR data with the heat flux, were in accordance with the experimental measured values.

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The effects of external radiation heat flux on the combustion characteristics of pure transformer insulating paperboard (PTIP) and oil‐impregnated transformer insulating paperboard (OITIP) were investigated experimentally. The experiments were conducted with the cone calorimeter using five external radiation heat fluxes that ranged from 25 to 80 kW/m2. The results showed that the ignition time decreased with the external radiation heat flux, and the ignition time of PTIP was much longer than that of OITIP. Both the PTIP and OITIP are thermal thick materials, and the critical radiation heat flux of the PTIP was larger than that of the OITIP. For the PTIP, the peak of the heat release rate (HRR) and toxic gas productions had no significant difference, while those of the OITIP increased with the external radiation heat flux. The HRR peak of the PTIP was larger than that of the OITIP with the external radiation heat fluxes of 25, 35, 50, and 65 kW/m2. When the radiation heat flux increased to 80 kW/m2, the HRR peak of the OITIP became higher. From the perspective of the CO production rate, the hazard of PTIP fires was more severe than that of OITIP fires under the external radiation heat fluxes of 25 and 35 kW/m2. The CO production rate of the PITP was lower than that of the OITP with the high external radiation heat fluxes of 50, 65 and 80 kW/m2. © 2017 American Institute of Chemical Engineers Process Process Saf Prog 37:362–368, 2018