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

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

Evolucion tectonotérmica del área metamórfica del SO de Salamanca (Zona Centroibérica O de España)

Los estudios realizados en el sector suroccidental de la provincia de Salamanca en el marco del Proyecto MAGNA, han permitido obtener nuevos datos sobre la estratigrafia, estructura y metamorfismo del potente y monotono conjunto de metasedimentos del Complejo Esquisto-grauvaquico que afloran en el Area. Estos materiales fueron sometidos a une deformaci6n hercinica polifasica cuyas estructuras pueden agruparse en tres fases principales de deformacion, ademas de otras tardias. La primera fase produce un tren de pliegues de longitud de onda kilometrica y de direccion NO-SE. Durante la segunda fase se desarrolla una zona de cizalla subhorizontal, de espesor kilometrico y con sentido de movimiento de bloque de techo hacia el Sureste. aue tiene caracter extensional. La tercera fase oroduce un re.o le-a emiento de las estructuras o r e vias, practicamente coaxial con la primera fase. Esta deformacion esta acompariada de un metamorfismo inicial de presiones intermedias que evoluciona posteriormente a otro de baja presión. El conjunto de los datos permite ser integrado en un modelo de evolución tectonotermal en el que el engrosamiento cortical, al que va asociado el metamorfismo de presiones intermedias, se ve interrumpido por un colapso extensional controlado por la zona de cizalla de segunda fase, responsable del gradiente metamórfico de bajas presiones. [ABSTRACT] A new set of data concerning the stratigraphy, structure and metamorphism of the monotonous Schist and Graywacke Complex, exposed in the southwestern Salamanca province, have been made available as an outgrowh of studies undertaken in the framework of the MAGNA Project. In structural terms, these allow characterization of the Hercynian orogeny as a polyphase event with three main phases of deformation and some late phases of less importance. The first phase was responsible forthe formation of NW-SE striking folds with kilometric wavelengths. A kilometre scale thick, extensional shear zone with downthrown to the SE of the hangingwall characterizes the second phase. The third phase in turn, roughly coaxial with the first one. resulted in a refoldino of the oreviouslv formed structures. This deformation seouence devolooed under initial metamordhic conditions of an iniermediaie pressuie type and evolved subsequently to a lowi pressure regime. The tectonothermal evolution of this area is thus envisaged in response to an initial crustal thickening event. The one associated to the intermediate pressure metamophic regimen, subsequently interrumpted by an extensional collapse of the thickened crust, controlled by the second phase shear zone. This is held responsible for the shift to the lower pressure metamorphic conditions which dominated the second part of the evolution

Detection of optical emission from the supernova remnant G7.7–3.7

The work of VD is supported by a grant from NWO graduate programme/GRAPPA-PhD programme. VD also acknowledges support from the LKBF, subsidy no. 19.2.027. JVHS acknowledges support from STFC grant ST/R000824/1. PZ acknowledges the support from the NWO Veni Fellowship, grant no. 639.041.647 and NSFC grant 11590781. SA thanks the support under the grant 5077 financed by IAASARS/NOA. AdB thanks the support from the Spanish Government Ministerio de Ciencia e Innovación through grants PGC-2018-091, 3741-B-C22, and SEV 2015-0548, from the Canarian Agency for Research, Innovation and Information Society (ACIISI) of the Canary Islands Government, and from the European Regional Development Fund (ERDF), under grant with reference ProID2017010115.We present the first optical study of the supernova remnant (SNR) G7.7–3.7, with the aim of determining its evolutionary phase since it has been suggested to be the remnant of SN 386 AD. We obtained narrow-band images in the filters H α + [N ii], H β, [O iii], [S ii] that revealed faint optical emission in the southern region of the SNR consisting of two filaments elongated in the east–west direction aligned with the X-ray emitting region of the remnant. The filaments were seen in H α + [N ii], [O iii] images and marginally in the [S ii] images, with a non-detection in H β. Long-slit spectroscopy of the three regions along one filament revealed large ratios of [S ii]/H α = (1.6–2.5), consistent with that expected for a shock-heated SNR. The [S ii] doublet ratio observed in two of the regions implies an upper limit for the electron density of the gas, with estimates falling below 400 cm−3 and 600 cm−3 in the respective areas. We discuss potential physical mechanisms that formed the observed optical filaments and we suggest that most likely they resulted by a collision of the SNR with a dense circumstellar shell lying at the southern region of the remnant.Publisher PDFPeer reviewe