Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis

Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies

Modification of water retention and rheological properties of fresh state cement-based mortars by guar gum derivatives

International audienceThe present study examines the influence of chemical composition and structure of guar gum derivatives on water retention capacity (WR) and rheological behavior of fresh state cement-based mortars. The investigation was also completed by adsorption isotherms. For this, original guar gum, three HydroxyPropyl Guars (HPG) and two hydrophobically modified HPGs were selected. The effect of the molar substitution (MSHP) and of hydrophobic substitution (DSAC) was investigated. The results highlight that chemical composition of HPGs has a remarkable effect on fresh state properties of mortars. The original guar gum does not impact on neither WR nor rheological behavior. Increasing MSHP leads to an improvement of the WR and the stability of mortars while the hydrophobic units further enhance WR and lead to a decrease in the yield stress and an increase in the resistance to the flow of admixed mortars

Effect of Guar Gum Derivatives on Fresh State Properties of Portland Cement-Based Mortars

International audienceMortars are traditionally made from a mixture of sand, a binder and water. However, modern factory-made mortars are currently, very complex materials. Indeed, to exhibit various properties from the fresh paste to the hardened material, mortar formulations are composed of many mineral and organic admixtures. Among organic admixtures, polysaccharides are widely used in mortar formulation to improve water retention capacity of the freshly-mixed materials. The water retention capacity is an essential property of mortars to enhance cement hydration and its adhesion to a substrate. Moreover, many polysaccharide admixtures, acting as viscosity-enhancing agents, prevent segregation and improve the homogeneity and workability of cement-based system. Indeed, the viscosity of the system strongly increases using polysaccharides. Nevertheless, polysaccharides, as sugars, act on cement hydration. The main drawback is the retarding effect in hydration mechanism and setting-time of the cement.The aim of this study is to focus on the effect of guar gum derivatives on fresh state properties of Portland cement-based mortars, such as water retention, rheological behavior and the hydration delay. This work focuses on the guar gum derivatives since their manufacturing process is low pollutant and they provide very good properties to cement-based mortars. The results highlight that the chemical composition of guar gum derivatives (MS, DS, additional alkyl chain) are the key levers to improve water retention of mortars and to adapt the rheological behavior of the cementitious paste to a specific application

Change of Electronic Structure Induced by Magnetic Transitions in CeBi

The temperature dependence of the electronic structure of CeBi arising from two types of antiferromagnetic transitions based on optical conductivity ($\sigma(\omega)$) was observed. The $\sigma(\omega)$ spectrum continuously and discontinuously changes at 25 and 11 K, respectively. Between these temperatures, two peaks in the spectrum rapidly shift to the opposite energy sides as the temperature changes. Through a comparison with the band calculation as well as with the theoretical $\sigma(\omega)$ spectrum, this peak shift was explained by the energy shift of the Bi $6p$ band due to the mixing effect between the Ce $4f \Gamma_8$ and Bi $6p$ states. The single-layer antiferromagnetic ($+-$) transition from the paramagnetic state was concluded to be of the second order. The marked changes in the $\sigma(\omega)$ spectrum at 11 K, however, indicated the change in the electronic structure was due to a first-order-like magnetic transition from a single-layer to a double-layer ($++--$) antiferromagnetic phase.Comment: 4 pages, to be published in J. Phys. Soc. Jpn. 73 Aug. (2004

Bandstructure and Fermi Surfaces of CeRh3B2

The electronic bandstructure and the Fermi surfaces of ferromagnetic CeRh3B2 are calculated by using FLAPW and LSDA+U method. As assuming several kinds of the ground state to describe the 4f electronic state, we propose a fully orbital- and spin-polarized state |lz=0, sx=1/2> as the ground state, instead of the conventional LS-coupled CEF ground state, generally expected in typical 4f compounds. This is supported by the fact that both the observed magnetic moment and the observed dHvA frequencies are well explained by the calculated electronic structure and the Fermi surfaces. The unconventional ground state is stabilized by the strong 4f-4f direct mixing between the neighbored Ce atoms along the extremely small distance along the c-axis in the hexagonal crystal cell.Comment: 8 pages, 9 figures, submitted to JPSJ (accepted and will appear in the issue of Vol.79, No.4

Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor (TGF ) signaling is essential for testicular aging and regulating testis size

Follistatin-like 3 (FSTL3) is a glycoprotein that binds and inhibits the action of TGFβ ligands such as activin. The roles played by FSTL3 and activin signaling in organ development and homeostasis are not fully understood. The authors show mice deficient in FSTL3 develop markedly enlarged testes that are also delayed in their age-related regression. These FSTL3 knockout mice exhibit increased Sertoli cell numbers, allowing for increased spermatogenesis but otherwise showing normal testicular function. The data show that FSTL3 deletion leads to increased AKT signaling and SIRT1 expression in the testis. This demonstrates a cross-talk between TGFβ ligand and AKT signaling and leads to a potential mechanism for increased cellular survival and antiaging. The findings identify crucial roles for FSTL3 in limiting testis organ size and promoting age-related testicular regression

Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease

Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFβ) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFβ signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-α and IL-1β in ear fluids. We also identified downstream effects on TGFβ signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFβ pathway. The identification and characterization of the Tgif mutant supports the role of TGFβ signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population