Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown. [Results]: To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity. [Conclusions]: Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations.This study was funded by the CNIC Translational Grant Programme (CNIC-08-2009 to MM and DF), the Spanish Ministerio de Economia y Competitividad (grants BFU2011-23083 to MM, BFU2013-41322-P to JLGS, BFU2012-38111 to AA, and CSD2007-00008 to JLGS and MM), the Comunidad Autónoma de Madrid (grant CELLDD-CM to MM), and the Andalusian Government (grant BIO-396 to JLGS). The CNIC is supported by the Spanish Ministerio de Economia y Competitividad and the Pro-CNIC Foundation.Peer Reviewe

Basement membrane-rich Organoids with functional human blood vessels are permissive niches for human breast cancer metastasis

Metastasic breast cancer is the leading cause of death by malignancy in women worldwide. Tumor metastasis is a multistep process encompassing local invasion of cancer cells at primary tumor site, intravasation into the blood vessel, survival in systemic circulation, and extravasation across the endothelium to metastasize at a secondary site. However, only a small percentage of circulating cancer cells initiate metastatic colonies. This fact, together with the inaccessibility and structural complexity of target tissues has hampered the study of the later steps in cancer metastasis. In addition, most data are derived from in vivo models where critical steps such as intravasation/extravasation of human cancer cells are mediated by murine endothelial cells. Here, we developed a new mouse model to study the molecular and cellular mechanisms underlying late steps of the metastatic cascade. We have shown that a network of functional human blood vessels can be formed by co-implantation of human endothelial cells and mesenchymal cells, embedded within a reconstituted basement membrane-like matrix and inoculated subcutaneously into immunodeficient mice. The ability of circulating cancer cells to colonize these human vascularized organoids was next assessed in an orthotopic model of human breast cancer by bioluminescent imaging, molecular techniques and immunohistological analysis. We demonstrate that disseminated human breast cancer cells efficiently colonize organoids containing a functional microvessel network composed of human endothelial cells, connected to the mouse circulatory system. Human breast cancer cells could be clearly detected at different stages of the metastatic process: initial arrest in the human microvasculature, extravasation, and growth into avascular micrometastases. This new mouse model may help us to map the extravasation process with unprecedented detail, opening the way for the identification of relevant targets for therapeutic intervention

LegioLit: Knappable material lithotheque in the Prehistory Laboratory at the University of León, Spain

This work introduces a comparative collection located in the Prehistory Laboratory at the University of León (Spain) specialised in knappable raw materials, mainly comprising radiolarite and black chert (micro-crypto crystalline quartz), from the western Cantabrian Mountains (north of Iberian Peninsula). A standardised protocol of sample collection and data organisation was developed, which includes the use of several methodologies. First, Geographical Information Systems (GIS) for referencing lithic sources. Second, direct observation of the sample for the macroscopic characterization, both de visu and stereomicroscope. Third, petrographic microscopy for a description of main petrological, and palaeontological features, complemented with the identification of the different minerals that make up the samples by X-ray diffraction (XRD). Forth, X-Ray Fluorescence (XRF), Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) and Thermogravimetry – Differential Scanning Calorimetry (TG-DSC) for geochemical and thermal features of the samples. Finally, the results of these analyses were entered in a database. All this information is contributing towards the creation of a physical reference collection specialised in local Palaeozoic formations (mostly from Devonian to Carboniferous) that outcrop in the western Cantabrian Mountains, a region whose potential resource base was previously not very well known. This collection would allow to compare archaeological lithic remains from different sites inside and outside the Cantabrian Mountains

The Escalada Formation: Characterization of a potential chert supply source in the Cantabrian Mountains (NW Spain) during prehistory.

A study of the chert nodules found in the Escalada Formation (Carboniferous, Ponga region, Cantabrian Zone) was carried out as a means to characterise a number of lithic raw materials found in several prehistoric sites of the Cantabrian Mountains (NW Spain). This study comprises fieldwork aimed at locating the outcrops and obtaining samples. Some selected samples from two localities were used for both petrological (macroscopic and microscopic analyses from thin sections) and geochemical (X-ray fluorescence and powder diffraction) analysis. The macroscopic study shows a rather homogeneus coloration and a conchoidal fracture although two extreme types of cherts with a variety of intermediate forms can be differentiated according to the matrix composition. The microscopic analysis shows a high heterogeneity in carbonate versus silica percentage and gentle differences in some other features such as type of silica, origin of carbonates, occurrence of organic matter and type of skeletal components. The results of several geochemical analysis suggest that there are not geochemical features neither in the major elements nor in the traces that allows us to clearly distinguish between the analysed samples. All these studies allow us to define the main features of these chert nodules and to establish several types and varieties among them. Those varieties with high percentage of silica and with a more homogeneous matrix are the most suitable samples for knapping. These results together with the study of the geological and geographical location of archaeological sites suggest that the nodules from the Escalada Formation likely were lithic material supply sources used in knapping activitiesWhen aiming to demonstrate the use of these materials at archaeological sites the sole macroscopic analysis of the pieces does not suffice; further analyses, such as those involving thin sections, are necessary. The absence of chert from Escalada Formation in some Mesolithic sites in the area was confirmed via these additional analyses

Postcesarean Thromboprophylaxis with Two Different Regimens of Bemiparin

Objectives. To compare the effectiveness of postcesarean thromboprophylaxis with two different regimens of bemiparin. Material and Methods. The study included 646 women with cesarean delivery in our hospital within a 1-year period, randomly assigned to one of two groups for prophylaxis with 3500 IU bemiparin once daily for 5 days or 3500 IU bemiparin once daily for 10 days. Results. There was one case of pulmonary embolism (first day following cesarean). An additional risk factor was present in 98.52% of the women, most frequently emergency cesarean, anemia, or obesity. The only risk factors for thromboembolic disease significantly related to pulmonary thromboembolism were placental abruption and prematurity. There were no differences in thromboembolic events among the two thromboprophylaxis regimens. Conclusions. Cesarean-related thromboembolic events were reduced in our study population due to the thromboprophylactic measures taken. Thromboprophylaxis with 3500 IU bemiparin once daily for 5 days following cesarean was sufficient to avoid thromboembolic events

Influence of two dietary fibers in the oral bioavailability and other pharmacokinetic parameters of ethinyloestradiol

P. 253-257Dietary fibers are widely used in hypoglycaemic, hypolipidemic, slimming diets. It is probable that their ingestion coincides with the oral administration of drugs and a modification of their pharmacokinetics can appear. In the present study, the influence of two soluble fibers (guar gum and psyllium) was evaluated on the pharmacokinetics of ethinyloestradiol (EE) when they were administered together to female rabbits via the oral route. Three groups of rabbits were used. All animals received 1 mg/kg of EE; this compound was administered alone in the control group and with 3.5 g of guar gum or psyllium in the other two groups. When guar gum was administered, there was a decrease in the extent of EE absorbed, but no change was observed in the rate of absorption. When psyllium was administered, the extent of EE absorbed increased slightly and the rate of absorption was slower.S

"Mucientes Chert" in the Northern Iberian Plateau (Spain)

The so-called “Mucientes chert" is a variety that appears in the central area of the Iberian North Plateau, in theDueroBasin. It is widely known in the geological and archaeological literature and its use for knapping was especially important in Prehistory. From a macroscopic point of view it is a nodular chert, with white and very porous cortex, and brown to blackish or beige colour in the inner part.In this work we carried out a more accurate petrographic, mineralogical and chemical characterization of this lithology using SEM, XRD and XRF techniques in samples coming from “Las Canteras” (Mucientes village), a chert outcrop of the “Cuestas” Unit (Vallesian-Aragonian, Miocene Age). Also, we have made a review of its geological occurrence and archaeological distribution areas.  It is intended to sketch the delimitation of the geographical area of occurrence taking into account the geological and archaeological references.

El “Sílex” en la Meseta Norte: sectores central y noroccidental

In this work, a review of the available data on the different types of flint (flint, chert and radiolarites) and of some slates sensu lato utilized for knapping during the Prehistory is carried out in the Northwest quadrant of the Iberian North Plateau, understood as the territory that covers all the hydrographic basin of the river Duero. We have begun with an evaluation of the geological base, by means of field works and analysis of the bibliographical references on these types of rocks and of the geological forma- tions of the ones that can proceed. These have been divided into four source areas: 1) Cantabrian Zone, constituted of sedimentary rocks; 2) “Centroibérica” Zone, formed by metamorphic and igneous rocks; 3) Paleogene and neogene materials that fill the basin of the Duero; and 4) The quaternary river terraces of the Basin of the Duero, whose materials come from the erosion, transportation and sedimentation of diverse rocks from the source area 3 and, in smaller measure, from the source area 1. The fol- lowing section value the data on those raw materials found on archaeological contexts throughout different prehistoric periods. Available studies focus on the following rocks: black chert (laminated and not laminated), radiolarite, “slates”, and the so-called “Mucientes Flint”. Finally, the data obtained in the two previous sections are crossed to outline an image of the management of these lithic resources along the Prehistory, its strategies of exploitation as well as a sketch of its circulation by this region.En este trabajo se realiza una revisión de los datos disponibles sobre los diferentes tipos de sílex (sílex, chert y radiolaritas) y de algunas pizarras sensu lato utilizados para la talla durante la Prehistoria en el cuadrante Noroeste de la Meseta Norte, entendida como el territorio que abarca toda la cuenca hidrográfica del Duero. Se ha comenzado con una evaluación de la base geológica, mediante trabajos de campo y análisis de las referencias bibliográficas sobre estos tipos de rocas y de las formaciones geológicas de las que pueden proceder. Estas últimas han sido divididas en cuatro áreas fuentes: 1) Zona Cantábrica, constituida por rocas sedimentarias; 2) Zona Centroibérica, formada por rocas metamórficas e ígneas; 3) Materiales paleógenos y neógenos que rellenan la cuenca del Duero; y 4) Las terrazas fluviales cuaternarias de la Cuenca del Duero, cuyos materiales proceden de la erosión, transporte y sedimentación de diversas rocas constituyentes del área fuente 3 y, en menor medida, del área fuente 1. En el siguiente apartado se valoran los datos que, sobre esas materias primas, pueden extraerse de los contextos arqueológicos a lo largo de los distintos periodos prehistóricos. Los estudios disponibles se centran en las siguientes rocas: chert negro (laminado y no laminado), radiolarita, “filitas” (pizarra sensu lato) y el denominado “sílex de Mucientes”. Fi- nalmente, se cruzan los datos obtenidos en los dos apartados anteriores para esbozar una imagen de la gestión de estos recursos líticos a lo largo de la Prehistoria que nos permita apuntar sus áreas de aprovisionamiento, sus estrategias de explotación así como un bosquejo de su circulación por esta región

Exploring the Different Degrees of Magnetic Disorder in TbxR1−xCu2 Nanoparticle Alloys

Recently, potential technological interest has been revealed for the production of magnetocaloric alloys using Rare-Earth intermetallics. In this work, three series of TbxR1−xCu2 (R ≡ Gd, La, Y) alloys have been produced in bulk and nanoparticle sizes via arc melting and high energy ball milling. Rietveld refinements of the X-ray and Neutron diffraction patterns indicate that the crystalline structure in all alloys is consistent with TbCu2 orthorhombic Imma bulk crystalline structure. The analyses of the DC-magnetisation (MDC) and AC-susceptibility (χAC) show that three distinct degrees of disorder have been achieved by the combination of both the Tb3+ replacement (dilution) and the nanoscaling. These disordered states are characterised by transitions which are evident to MDC, χAC and specific heat. There exists an evolution from the most ordered Superantiferromagnetic arrangement of the Tb0.5La0.5Cu2 NPs with Néel temperature, TN∼ 27 K, and freezing temperature, Tf∼ 7 K, to the less ordered weakly interacting Superparamagnetism of the Tb0.1Y0.9Cu2 nanoparticles (TN absent, and TB∼ 3 K). The Super Spin Glass Tb0.5Gd0.5Cu2 nanoparticles (TN absent, and Tf∼ 20 K) are considered an intermediate disposition in between those two extremes, according to their enhanced random-bond contribution to frustration.This work has been supported by the Spanish MAT2017-83631-C3-R grant. E.M.J.’s work was supported by “Beca de Colaboración”, BDNS: 311327 granted by Ministerio de Educación, Cultura y Deporte and “Beca Concepción Arenal” BDNS: 406333 granted by the Gobierno de Cantabria and the Universidad de Cantabria. MRF work was supported by FPI (BES-2012-058722)