Transcriptional control of the forkhead thyroid transcription factor TTF-2 by thyrotropin, insulin, and insulin-like growth factor I

The hormonal regulation of both thyroglobulin and thyroperoxidase promoter activity in FRTL-5 thyroid cells takes place, at least in part, through a hormone-responsive element to which the thyroid transcription factor TTF-2 binds. The TTF-2 cDNA, encoded by the titf2 locus, has recently been cloned and classified as a member of the forkhead transcription factor family. Here, we demonstrate that TTF-2 mRNA levels become undetectable in FRTL-5 thyroid cells cultured for 4 days in 0.2% serum and in the absent of thyrotropin (TSH) and insulin. Addition of TSH, insulin or insulin-like growth factor I (IGF-I) to the culture medium increases the levels of this transcription factor in a dose- and time-dependent manner and requires ongoing protein synthesis. The TSH effect is greater than that produced by insulin or IGF-I and is similar to the effect produced by the cAMP analog forskolin. The TSH and insulin effects are additive. In all cases, the mRNA levels increase is accompanied by an increase in transcription rate, as demonstrated by run-off assays. These data demonstrate that the TTF-2 mRNA is under tight hormonal control. This is consistent with an important role for TTF-2 as a mediator of the transcriptional activation of thyroid-specific genes (thyroglobulin and thyroperoxidase) by TSH via cAMP and by insulin through the IGF-I receptor

FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1

FOXE1 is a thyroid-specific transcription factor essential for thyroid gland development and maintenance of the differentiated state. Interestingly, a strong association has been recently described between FOXE1 expression and susceptibility to thyroid cancer, but little is known about the mechanisms underlying FOXE1-induced thyroid tumorigenesis. Here, we used a panel of human thyroid cancer-derived cell line s covering the spectrum of thyroid cancer phenotypes to examine FOXE1 expression and to test for correlations between FOXE1 expression, the allele frequency of two SNPs and a length polymorphism in or near the FOXE1 locus associated with cancer susceptibility, and the migration ability of thyroid cancer cell lines. Results showed that FOXE1 expression correlated with differentiation status according to histological sub-type, but not with SNP genotype or cell migration ability. However, loss-and-gain-of-function experiments revealed that FOXE1 modulates cell migration, suggesting a role in epithelial-to-mesenchymal transition (EMT). Our previous genome-wide expression analysis identified Zeb1, a major EMT inducer, as a putative Foxe1 target gene. Indeed, gene silencing of FOXE1 decreased ZEB1 expression, whereas its overexpression increased ZEB1 transcriptional activity. FOXE1 was found to directly interact with the ZEB1 promoter. Lastly, ZEB1 silencing decreased the ability of thyroid tumoral cells to migrate and invade, pointing to its im portance in thyroid tumor mestastases. In conclusion, we have identified ZEB1 as a bona fide target of FOXE1 in thyroid cancer cells, which provides new insights into the role of FOXE1 in regulating cell migration and invasion in thyroid cancerThis work was supported by grants SAF2016-75531-R from Ministerio de Ciencia, Innovación y Universidades (MICIU), Spain, Fondo Europeo de Desarrollo Regional FEDER, B2017/BMD-3724 from Comunidad de Madrid, and GCB14142311CRES from Fundación Española Contra el Cáncer (AECC)

The Interaction between the Forkhead Thyroid Transcription Factor TTF-2 and the Constitutive Factor CTF/NF-1 Is Required for Efficient Hormonal Regulation of the Thyroperoxidase Gene Transcription

The forkhead thyroid-specific transcription factor TTF-2 is the main mediator of thyrotropin and insulin regulation of thyroperoxidase (TPO) gene expression. This function depends on multimerization and specific orientation of its DNA-binding site, suggesting that TTF-2 is part of a complex interaction network within the TPO promoter. This was confirmed by transfection experiments and by protein-DNA interaction studies, which demonstrated that CTF/NF1 proteins bind 10 base pairs upstream of the TTF-2- binding site to enhance its action in hormone-induced expression of the TPO gene. GST pull-down assays showed that TTF-2 physically interacts with CTF/NF1 proteins. In addition, we demonstrate that increasing the distance between both transcription factors binding sites by base pair insertion results in loss of promoter activity and in a drastic decrease on the ability of the promoter to respond to the hormones. CTF/NF1 is a family of transcription factors that contributes to constitutive and cell-type specific gene expression. Originally identified as factors implicated in the replication of adenovirus, this group of proteins (CTF/NF1-A, -B, -C, and - X) is now known to be involved in the regulation of several genes. In contrast to other reports regarding the involvement of these proteins in inducible gene expression, we show here that members of this family of transcription factors are regulated by hormones. With the use of specific CTF/NF1 DNA probes and antibodies we demonstrate that CTF/NF1-C is a thyrotropin-, cAMP-, and insulin-inducible protein. Thus CTF/NF1 proteins do not only mediate hormone-induced gene expression cooperating with TTF-2, but are themselves hormonally regulated. All these findings are clearly of important value in understanding the mechanisms governing the transcription regulation of RNA polymerase II promoters, which often contain binding sites for multiple transcription factors

Solvable Lie algebras are not that hypo

We study a type of left-invariant structure on Lie groups, or equivalently on Lie algebras. We introduce obstructions to the existence of a hypo structure, namely the 5-dimensional geometry of hypersurfaces in manifolds with holonomy SU(3). The choice of a splitting g^*=V_1 + V_2, and the vanishing of certain associated cohomology groups, determine a first obstruction. We also construct necessary conditions for the existence of a hypo structure with a fixed almost-contact form. For non-unimodular Lie algebras, we derive an obstruction to the existence of a hypo structure, with no choice involved. We apply these methods to classify solvable Lie algebras that admit a hypo structure.Comment: 21 pages; v2: presentation improved, typos corrected, notational conflicts eliminated. To appear in Transformation Group

Microstructure and texture analysis of δ-hydride precipitation in Zircaloy-4 materials by electron microscopy and neutron diffraction

This work presents a detailed microstructure and texture study of various hydrided Zircaloy-4 materials by neutron diffraction and microscopy. The results show that the precipitated δ-ZrH1.66 generally follows the δ (111) //α (0001) and δ[]//α[] orientation relationship with the α-Zr matrix. The δ-hydride displays a weak texture that is determined by the texture of the α-Zr matrix, and this dependence essentially originates from the observed orientation correlation between α-Zr and δ-hydride. Neutron diffraction line profile analysis and high-resolution transmission electron microscopy observations reveal a significant number of dislocations present in the δ-hydride, with an estimated average density one order of magnitude higher than that in the α-Zr matrix, which contributes to the accommodation of the substantial misfit strains associated with hydride precipitation in the α-Zr matrix. The present observations provide an insight into the behaviour of δ-hydride precipitation in zirconium alloys and may help with understanding the induced embrittling effect of hydrides.Fil: Wang, Zhiyang. University of Wollongong; Australia. Australian Nuclear Science and Technology Organisation; AustraliaFil: Garbe, Ulf. Australian Nuclear Science and Technology Organisation; AustraliaFil: Li, Huijun. University of Wollongong; AustraliaFil: Wang, Yanbo. University of Sydney; AustraliaFil: Studer, Andrew J.. Australian Nuclear Science and Technology Organisation; AustraliaFil: Sun, Guangai. Institute of Nuclear Physics and Chemistry, CAEP; ChinaFil: Harrison, Robert P.. Australian Nuclear Science and Technology Organisation, Institute of Materials Engineering; AustraliaFil: Liao, Xiaozhou. University of Sydney; AustraliaFil: Vicente Alvarez, Miguel Angel. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Santisteban, Javier Roberto. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kong, Charlie. University of New South Wales; Australi

Mapping the spectral index of Cassiopeia A : evidence for flattening from radio to infrared

Funding: The work of VD is supported by a grant from the NWO graduate programme/GRAPPA-PhD programme. JVHS acknowledges support from the STFC grant ST/R000824/1.Synchrotron radiation from supernova remnants is caused by electrons accelerated through diffusive shock acceleration (DSA). The standard DSA theory predicts an electron spectral index of p = 2, corresponding to a radio spectral index of α = −0.5. An extension of DSA theory predicts that the accelerated particles change the shock structure, resulting in a spectrum that is steeper than p > 2 (α < −0.5) at low energies and flattens with energy. For Cassiopeia A, a synchrotron spectral flattening was previously reported for a small part of the remnant in the mid-infrared regime. Here, we present new measurements for spectral flattening using archival radio (4.72 GHz) and mid-infrared (3.6 μm) data, and we produce a complete spectral index map to investigate the spatial variations within the remnant. We compare this to measurements of the radio spectral index from L-band (1.285 GHz) and C-band (4.64 GHz) maps. Our result shows overall spectral flattening across the remnant (αR-IR ∼ −0.5 to −0.7), to be compared with the radio spectral index of αR = −0.77. The flattest values coincide with the locations of most recent particle acceleration. In addition to overall flattening, we detect a relatively steeper region in the south-east of the remnant (αR-IR ∼ −0.67). We explore whether these locally steeper spectra could be the result of synchrotron cooling, which provides constraints on the local magnetic field strengths and the age of the plasma, suggesting B ≲ 2 mG for an age of 100 yr, and even B ≲ 1 mG using the age of Cas A, in agreement with other estimates.Publisher PDFPeer reviewe

New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: FoxE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FoxE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FoxE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FoxE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility. [Methodology/Principal Finding]:I n order to further investigate downstream FoxE1 targets, we performed a genome-wide expression screening after knocking-down FoxE1 and obtained new insights into FoxE1 transcriptional networks in thyroid follicular cells. After validation, we confirmed Adamts9, Cdh1, Duox2 and S100a4 as upregulated genes and Casp4, Creld2, Dusp5, Etv5, Hsp5a, Nr4a2 and Tm4sf1 as downregulated genes when FoxE1 was silenced. In promoter regions of putative FoxE1-regulated genes and also in the promoters of the classical thyroid genes Nis, Pax8 and Titf1, we performed an in silico search of the FoxE1 binding motif that was in close proximity to the NF1/CTF binding sequence, as previously described for other forkhead factors. Using chromatin immunoprecipitation we detected specific in vivo FoxE1 binding to novel regulatory regions in two relevant thyroid genes, Nis and Duox2. Moreover, we demonstrated simultaneous binding of FoxE1 and NF1/CTF to the Nis upstream enhancer region, as well as a clear functional activation of the Nis promoter by both transcription factors. [Conclusions/Significance]:In search for potential downstream mediators of FoxE1 function in thyroid cells, we identified two novel direct FoxE1 target genes. To our knowledge, this is the first evidence regarding the implication of Nis and Duox2 in executing the transcriptional program triggered by FoxE1. Furthermore, this study points out the important role of FoxE1 in the regulation of a large number of genes in thyroid cells. © 2013 Fernández et al.This work was supported by Grants BFU-2010-16025 from the Dirección General de Proyectos de Investigación; RD06/0020/0060 and RD12/0036/0030 from FIS, Instituto de Salud Carlos III; and S2011/BMD-2328 TIRONET project from the Comunidad de Madrid (Spain). LP Fernández holds a postdoctoral grant of the Juan de la Cierva programme of the Spanish Government.Peer Reviewe

Internal stresses in steel plate generated by shape memory alloy inserts

Neutron strain scanning was employed to investigate the internal stress fields in steel plate coupons with embedded prestrained superelastic NiTi shape memory alloy inserts. Strain fields in steel were evaluated at T = 21 °C and 130 °C on virgin coupons as well as on mechanically and thermally fatigued coupons. Internal stress fields were evaluated by direct calculation of principal stress components from the experimentally measured lattice strains as well as by employing an inverse finite element modeling approach. It is shown that if the NiTi inserts are embedded into the elastic steel matrix following a carefully designed technological procedure, the internal stress fields vary with temperature in a reproducible and predictable way. It is estimated that this mechanism of internal stress generation can be safely applied in the temperature range from −20 °C to 150 °C and is relatively resistant to thermal and mechanical fatigue. The predictability and fatigue endurance of the mechanism are of essential importance for the development of future smart metal matrix composites or smart structures with embedded shape memory alloy components

The impact and cost-effectiveness of combined HIV prevention scenarios among transgender women sex-workers in Lima, Peru: A mathematical modelling study

Background HIV incidence remains high among transgender women in Lima, Peru, most of whom report sex work. On the basis of a stakeholder analysis and health system capacity assessment, we designed a mathematical model to guide HIV programmatic planning among transgender women sex workers (TWSW) in Lima. Methods Using a deterministic compartmental model, we modelled HIV transmission among TWSW, their stable partners, and their clients to estimate the impact and cost-effectiveness of combinations of interventions compared with the standard of care on reducing HIV incidence over a 10-year period. We simulated HIV transmission accounting for differences in sexual positioning in anal intercourse and condom use by partner type and fitted the model to HIV surveillance data using Latin hypercube sampling. The interventions we considered were 15% relative increase in condom use with clients and 10% relative increase with stable partners; increase in antiretroviral treatment (ART) coverage at CD4 count lower than 500 cells per mm3 and greater than or equal to 500 cells per mm3; and 15% pre-exposure prophylaxis (PrEP) coverage using generic and branded formulations. We considered a basic scenario accounting for current limitations in the Peruvian HIV services and an enhanced scenario assuming achievement of the UNAIDS 90-90-90 targets and general improvements in HIV services. The 50 best fits according to log-likelihood were used to give the minimum and maximum values of intervention effect for each combination. We used disability-adjusted life-years (DALYs) to measure the negative health outcomes associated with HIV infection that could be averted through the interventions investigated and calculated incremental cost-effectiveness ratios to compare their cost-effectiveness. Findings Under the basic scenario, combining the four interventions of increasing condom use with clients and stable partners, extending ART to people with CD4 count greater than or equal to 500 cells per mm3, and 15% PrEP coverage with generic drugs would avert 47% (range 27–51) of new infections in TWSW, their clients, and their stable partners over 10 years, with an incremental cost-effectiveness ratio of US$509 per DALY averted. Under the enhanced scenario, this strategy would avert 61$1003 per DALY averted. Under both scenarios, implementation of this strategy approaches or surpasses the 50% incidence reduction goal and would represent a cost-effective use of country resources if generic PrEP drugs are used. The total cost of implementing this strategy under the enhanced scenario would be approximately $1·2 million per year over 10 years, corresponding to 10% of the current Global Fund's yearly contribution in Peru. Interpretation Investments in HIV services among TWSW in Lima would be cost-effective, even under stringent cost-effectiveness criteria when accounting for setting-specific resource constraints. Notable improvements in HIV testing rates, innovative interventions to increase condom use, and reduced PrEP costs will be key to achieving the 50% incidence reduction goal. Modelling studies incorporating stakeholders' perspectives and health system assessments can bring added value to HIV policy making