Variabilidad transcripcional y enfermedades comunes. Hacia una herramienta diagnóstica

Las enfermedades comunes, como la diabetes o las enfermedades cardiovasculares, tienen un importante componente genético. El conocimiento de las variantes génicas que las causan es esencial para el diseño de futuras herramientas diagnósticas. Mientras que las mutaciones localizadas en las regiones codificantes tienen una elevada penetrancia y no pueden explicar la genética de las enfermedades comunes, las variantes en las regiones reguladoras tienen una serie de propiedades que las hacen ideales para hacerlo. En primer lugar, presentan una penetrancia baja. Además, poseen una mayor capacidad de interaccionar con los cambios ambientales. La existencia de un gran número de polimorfismos en las regiones reguladoras hace necesario implementar estrategias lo más económicas posibles para su identificación y caracterización. La selección de genes candidatos, seguida de análisis bioinformáticos, es una de ellas. Pero el análisis sería incompleto sin la realización de ensayos funcionales cuyos métodos se describen en este capítulo. Los más habituales son el retardo en gel y los ensayos con genes reporteros, una de cuyas principales limitaciones es la imposibilidad de llevarlos a cabo en gran escala. Por esta razón se están diseñando nuevas aproximaciones con este objetivo. La combinación de todos ellos ya ha producido resultados interesantes. Es de esperar que en los próximos años se produzca un desarrollo que permita la aplicación a gran escala y que permita desarrollar algoritmos que sirvan como pruebas para diagnosticar el riesgo de padecer las enfermedades más comunes

EEG activity represents the correctness of perceptual decisions trial-by-trial

Performance monitoring is an executive function, which we depend on for detecting and evaluating the consequences of our behavior. Although event related potentials (ERPs) have revealed the existence of differences after correct and incorrect decisions, it is not known whether there is a trial-by-trial representation of the accuracy of the decision. We recorded the electroencephalographic activity (EEG) while participants performed a perceptual discrimination task, with two levels of difficulty, in which they received immediate feedback. Receiver Operating Characteristic (ROC) analyses were used to reveal two components that convey trial-by-trial representations of the correctness of the decisions. Firstly, the performance monitoring-related negativity (PM-N), a negative deflection whose amplitude is higher (more negative) after incorrect trials. Secondly, the performance monitoring-related positivity (PM-P), a positive deflection whose amplitude is higher after incorrect trials. During the time periods corresponding to these components, trials can be accurately categorized as correct or incorrect by looking at the EEG activity; this categorization is more accurate when based on the PM-P. We further show that the difficulty of the discrimination task has a different effect on each component: after easy trials the latency of the PM-N is shorter and the amplitude of the PM-P is higher than after difficult trials. Consistent with previous interpretations of performance-related ERPs, these results suggest a functional differentiation between these components. The PM-N could be related to an automatic error detection system, responsible for fast behavioral corrections of ongoing actions, while the PM-P could reflect the difference between expected and actual outcomes and be related to long-term changes in the decision process

Electronic versus steric control in palladium complexes of carboranyl phosphine-iminophosphorane ligands

[Abstract] A new family of carboranyl phosphine-iminophosphorane ligands was prepared and characterized. The new ligands present a carboranyl group directly attached to the iminophosphorane nitrogen atom through a cage carbon atom (C-carboranyl derivatives L1–L3) or through the B3 boron atom (B-carboranyl derivatives L4 and L5), and the phosphine group on a side chain derived from the diphosphine dppm, i.e. with a two-atom spacer between the P and N donor atoms. The non-carboranyl analogue L6, with a biphenyl group on the nitrogen atom, was also synthesized for comparison. These potential (P, N) ligands were used to obtain palladium complexes (Pd1–Pd6) and, thus, study how the different inductive effect of the carboranyl substituents can modify the coordinating ability of the nitrogen atom. The structural analysis of the complexes revealed two different coordination modes for the ligands: the (P, N) chelate coordination and the unexpected P-terminal coordination, which is not observed for non-carboranyl phosphine-iminophosphoranes. These unexpected structural differences led us to perform DFT calculations on the ligands and metal complexes. The calculations show that the final coordination modes depend on the balance between the electronic and steric properties of the particular carboranyl group.This work was supported by Xunta de Galicia (Spain) (grant no. 10PXIB209285PR)Xunta de Galicia; 10PXIB209285P

Enhancing Survival, Engraftment, and Osteogenic Potential of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. MSC-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in MSC-based regenerative techniques

IR characterization of Ln2−xSrxCoO4 (x≥1; Ln=La, Nd) oxides

[Abstract] We have recorded the FTIR spectra of powder samples of Ln2−xSrxCoO4 (Ln=La, Nd) at room temperature. We have identified the infrared active modes (3A2u+4Eu), and analyzed how they change as a function of Ln and the Sr doping. We correlate the obtained results with structural data obtained from powder X-ray diffraction studies and with the electronic properties displayed by these samples

Impact of Old Pb Mining and Metallurgical Production in Soils from the Linares Mining District (Spain)

[EN] Mineral processing and metallurgy production centers may leave a far-reaching fingerprint of soil contamination. This scenario is particularly relevant in the mining district of Linares (Southern Spain), where former industrial sites are now dedicated to other land uses. Within this context, we selected five sectors of concern in Linares region, which are currently used as agricultural and residential areas. The study began with an edaphic characterization, including grain-size fractioning and soil chemical analyses, which were complemented by mineralogical and sequential extraction information. Anomalous soil concentrations of As, Cd, Cu, Pb, and Zn were found, with higher values than the admissible regional guideline limits. Moreover, chemical speciation indicated that in general, Pb, Zn, and Cd were highly available and bound mainly to the carbonate fraction. In addition, health risk assessment evidenced potential threats by Pb and As. Regarding remediation approaches, we observed that, in soils affected by mining and ore dressing activities, the clay and silt size fractions contained the highest pollution load, making them suitable for a size classification treatment. By contrast, in areas affected by metallurgical activity, pollutants were prone to be evenly distributed among all grain sizes, thereby complicating the implementation of such remediation strategies

Mesenchymal stem cells secretome : The cornerstone of cell-free regenerative medicine

Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.Supported by Spanish Ministerio de Economía y competitividad, No. RTI2018-097324; Predoctoral program in Biomedicine from the University of Cantabria and the Instituto de Investigación Valdecilla (IDIVAL), No. PREVAL 19/02 and PREVAL 20/01

Cytotoxicity analysis of oxazine 4-perchlorate fluorescence nerve potential clinical biomarker for guided surgery

Biological tissue discrimination is relevant in guided surgery. Nerve identification is critical to avoid potentially severe collateral damage. Fluorescence imaging by oxazine 4-perchlorate (O4P) has been recently proposed. In this work, the cytotoxicity of O4P on U87 human-derived glioma cells has been investigated as a function of concentration and operating room irradiation modes. A custom-built optical irradiation device was employed for controlled optical dosimetry. DNA damage and O4P intracellular localization was also investigated by immunofluorescence and confocal microscopy. The results show that concentration below 100 µM can be considered safe. These results contribute to the assessment of the feasibility of O4P as a nerve biomarker.Spanish Ministry of Science, Research and Universities, cofunded by FEDER funds (PGC2018-101464-BI00); San Cándido Foundation

Peculiarities in the electrical and magnetic properties of cobalt perovskites Ln1−xMxCoO3 (Ln3+: La3+, M2+: Ca2+, Sr2+, Ba2+; Ln3+: Nd3+, M2+: Sr2+)

This is the accepted manuscript of the following article: Señarís-Rodríguez, M. et al. (1999). Peculiarities in the electrical and magnetic properties of cobalt perovskites Ln1−xMxCoO3 (Ln3+: La3+, M2+: Ca2+, Sr2+, Ba2+; Ln3+: Nd3+, M2+: Sr2+). International Journal Of Inorganic Materials, 1(3-4), 281-287. doi: 10.1016/s1466-6049(99)00042-2We refer here to the electrical and magnetic properties of the Ln1−xMxCoO3 systems (Ln3+: La3+, M2+: Ca2+, Sr2+, Ba2+; Ln3+: Nd3+, M2+: Sr2+), paying special attention to those ferromagnetic compounds that display M–I transitions as temperature rises: La1−xMxCoO3 (M2+: Ca2+, Sr2+, Ba2+) in the compositional interval x=0.2–0.3, and Nd1−xSrxCoO3, with x=0.40. The magneto-transport properties of such materials are peculiar and interesting: they show diodic behavior and large relaxation effects — these latter being specially important in the Nd compound — they display magnetoresistive effects specially at the M–I transition temperatures, and they age with time. All these results are discussed on the basis of the inhomogeneous electronic structure of these doped cobalt perovskites and taking into account the influence of the lanthanide ion on their magnetic and electrical propertiesWe thank the Spanish DGICYT for financial support under project MAT98-0416-C03-02S

Nanoparticle-mediated selective Sfrp-1 silencing enhances bone density in osteoporotic mice

Osteoporosis (OP) is characterized by a loss in bone mass and mineral density. The stimulation of the canonical Wnt/?-catenin pathway has been reported to promote bone formation, this pathway is controlled by several regulators as secreted frizzled-related protein-1 (Sfrp-1), antagonist of the pathway. Thus, Sfrp-1 silencing therapies could be suitable for enhancing bone growth. However, the systemic stimulation of Wnt/?-catenin has been correlated with side effects. This work hypothesizes the administration of lipid-polymer NPs (LPNPs) functionalized with a MSC specific aptamer (Apt) and carrying a SFRP1 silencing GapmeR, could favor bone formation in OP with minimal undesired effects. Suitable SFRP1 GapmeR-loaded Apt-LPNPs (Apt-LPNPs-SFRP1) were administered in osteoporotic mice and their biodistribution, toxicity and bone induction capacity were evaluated. The aptamer functionalization of the NPs modified their biodistribution profile showing a four-fold increase in the bone accumulation and a ten-fold decrease in the hepatic accumulation compared to naked LPNPs. Moreover, the histological evaluation revealed evident changes in bone structure observing a more compact trabecular bone and a cortical bone thickness increase in the Apt-LPNPs-SFRP1 treated mice with no toxic effects. Therefore, these LPNPs showed suitable properties and biodistribution profiles leading to an enhancement on the bone density of osteoporotic mice.Funding: This work is part of the project RTI2018-097324-B-100 funded by MCIN/AEI/10.13039/501100011033 and by ERDF “A way of making Europe”. Patricia García-García thanks the University of La Laguna for her research grant (M-ULL)