Differential transcriptional and post-translational transcription factor 7-like regulation among nondiabetic individuals and type 2 diabetic patients.

Human genetic studies have revealed that the T minor allele of single nucleotide polymorphism rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with an increased risk of diabetes by 30%-40%. Molecular and clinical studies are of great importance for understanding how this unique variation in TCF7L2 influences type 2 diabetes (T2D) onset and progression. At the molecular level, some studies have been performed in diabetic mice and pancreatic islets from healthy human donors. Whereas TCF7L2 mRNA levels are up-regulated in islets, protein levels are down-regulated. We performed studies on TCF7L2 splicing, mRNA expression, and protein levels in immortalized human lymphocytes from nondiabetic individuals and T2D patients carrying the C/C or the at-risk T/T genotype. Our results show differential expression of TCF7L2 splice variants between nondiabetic and T2D patients carrying the at-risk genotype, as well as differences in protein levels. Therefore, we investigated the regulation of splice variants, and our results propose that splicing of exon 4 is under control of the serine-arginine-rich factor transformer 2 β (TRA2B). Finally, we studied the endoplasmic reticulum stress pathways, looking for a posttranslational explanation. We saw a shift in the activation of these pathways between nondiabetic individuals and T2D patients carrying the at-risk genotype. These results suggest that, in human immortalized lymphocytes carrying the at-risk T/T genotype, first the differential expression of TCF7L2 splice variants implies a regulation, at least for exon 4, by TRA2B and second, the differential protein levels between both T/T carriers point to a different activation of endoplasmic reticulum stress pathways

Evaluation of an intervention program for the initiation to basketball aimed at teaching the game's rules

The rules of a game determine the technical and tactical skills necessary for the game, such as in basketball. An intervention program was designed that aimed to teach the rules that were considered to be the most important for the initiation to basketball and to teach the players the technical and tactical skills from these rules. The objective of the present study was to develop and assess an intervention program based on the coach's perceptions of the program. The study's sample was a mini-basketball team of 14 players and the team's coach. The program lasted 8 months and had three weekly practice sessions. The instruments utilized for data collection were the daily training reflections, action research cycles, and the audio recordings. The data were analyzed qualitatively. The coding was done by the research team, and after several trial sessions, a Kappa index of K=.78 was achieved, which assured inter-coder reliability. Among the results, it should be highlighted that the rules were the backbone of the program. As the program progressed, the players better understood their use. Likewise, they understood the relationship between the technical and tactical skills and the rules, fostering their involvement in the learning process and their familiarization with the game. In conclusion, the experience of teaching basketball initiation through familiarizing players with the rules was positive due to the cognitive involvement of the players in the learning process.Las reglas condicionan los aspectos técnicos y tácticos del juego, como el baloncesto. Se diseñó un programa de intervención basado en la enseñanza de las reglas consideradas más importantes para la iniciación y, a partir de éstas, el aprendizaje de los medios técnicos y tácticos. El objetivo del presente trabajo se centró en el desarrollo y evaluación del programa de intervención a través de la percepción de la entrenadora. La muestra del estudio fue un equipo de 14 jugadores de minibasket y su entrenadora. El programa duró 8 meses con tres entrenamientos semanales. Los instrumentos utilizados para la recogida de datos han sido los Diarios de entrenamiento, Ciclos de Supervisión y Ciclos de Audio. Los datos fueron analizados cualitativamente. La codificación fue realizada por el equipo de investigación y tras varios entrenamientos se alcanzó un índice Kappa de K=.78, lo que garantizó la fiabilidad inter-codificadores. Entre los resultados, se destaca que las reglas pueden suponer el eje vertebrador de la programación. A medida que avanzó el programa, los jugadores fueron entendiendo su utilidad. Asimismo, comprendieron la relación entre los aspectos técnico-tácticos y las reglas fomentando su implicación en el proceso de aprendizaje y la familiarización con el juego. A modo de conclusión, la experiencia de enseñar la iniciación al baloncesto a través de las reglas ha sido positiva por la implicación cognitiva de los jugadores en el proceso de aprendizaje

The IBaCoP planning system: instance-based configured portfolios

Sequential planning portfolios are very powerful in exploiting the complementary strength of different automated planners. The main challenge of a portfolio planner is to define which base planners to run, to assign the running time for each planner and to decide in what order they should be carried out to optimize a planning metric. Portfolio configurations are usually derived empirically from training benchmarks and remain fixed for an evaluation phase. In this work, we create a per-instance configurable portfolio, which is able to adapt itself to every planning task. The proposed system pre-selects a group of candidate planners using a Pareto-dominance filtering approach and then it decides which planners to include and the time assigned according to predictive models. These models estimate whether a base planner will be able to solve the given problem and, if so, how long it will take. We define different portfolio strategies to combine the knowledge generated by the models. The experimental evaluation shows that the resulting portfolios provide an improvement when compared with non-informed strategies. One of the proposed portfolios was the winner of the Sequential Satisficing Track of the International Planning Competition held in 2014.We thank the authors of the base planners because our work is based largely on their previous effort. This work has been partially supported by the Spanish projects TIN2011-27652-C03-02, TIN2012-38079-C03-02 and TIN2014-55637-C2-1-R

New Splice Site Acceptor Mutation in AIRE Gene in Autoimmune Polyendocrine Syndrome Type 1

Autoimmune polyglandular syndrome type 1 (APS-1, OMIM 240300) is a rare autosomal recessive disorder, characterized by the presence of at least two of three major diseases: hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. We aim to identify the molecular defects and investigate the clinical and mutational characteristics in an index case and other members of a consanguineous family. We identified a novel homozygous mutation in the splice site acceptor (SSA) of intron 5 (c.653-1G>A) in two siblings with different clinical outcomes of APS-1. Coding DNA sequencing revealed that this AIRE mutation potentially compromised the recognition of the constitutive SSA of intron 5, splicing upstream onto a nearby cryptic SSA in intron 5. Surprisingly, the use of an alternative SSA entails the uncovering of a cryptic donor splice site in exon 5. This new transcript generates a truncated protein (p.A214fs67X) containing the first 213 amino acids and followed by 68 aberrant amino acids. The mutation affects the proper splicing, not only at the acceptor but also at the donor splice site, highlighting the complexity of recognizing suitable splicing sites and the importance of sequencing the intron-exon junctions for a more precise molecular diagnosis and correct genetic counseling. As both siblings were carrying the same mutation but exhibited a different APS-1 onset, and one of the brothers was not clinically diagnosed, our finding highlights the possibility to suspect mutations in the AIRE gene in cases of childhood chronic candidiasis and/or hypoparathyroidism otherwise unexplained, especially when the phenotype is associated with other autoimmune diseases

Differential methylation of TCF7L2 promoter in peripheral blood DNA in newly diagnosed, drug-naïve patients with type 2 diabetes

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and age- and Body Mass Index (BMI)- matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D

Binding Potassium to Improve Treatment With Renin-Angiotensin-Aldosterone System Inhibitors: Results From Multiple One-Stage Pairwise and Network Meta-Analyses of Clinical Trials

This manuscript presents findings from the first dichotomous data pooling analysis on clinical trials (CT) regarding the effectiveness of binding potassium. The results emanated from pairwise and network meta-analyses aiming evaluation of response to commercial potassium-binding polymers, that is, to achieve and maintain normal serum potassium (n = 1,722), and the association between this response and an optimal dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) needing individuals affected by heart failure (HF) or resistant hypertension, who may be consuming other hyperkalemia-inducing drugs (HKID) (e.g., b-blockers, heparin, etc.), and frequently are affected by chronic kidney disease (CKD) (n = 1,044): According to the surface under the cumulative ranking area (SUCRA), sodium zirconium cyclosilicate (SZC) (SUCRA >0.78), patiromer (SUCRA >0.58) and sodium polystyrene sulfonate (SPS) (SUCRA 5.1 mEq/L), and, when normokalemia is achieved, patiromer 16.8–25.2 g/day (SUCRA = 0.94) and patiromer 8.4–16.8 g/day (SUCRA = 0.41) can allow to increase the dose of spironolactone up to 50 mg/day in subjects affected by heart failure (HF) or with resistant hypertension needing treatment with other RAASi. The potential of zirconium cyclosilicate should be explored further, as no data exists to assess properly its capacity to optimize dosing of RAASi, contrarily as it occurs with patiromer. More research is also necessary to discern between benefits of binding potassium among all type of hyperkalemic patients, for example, patients with DM who may need treatment for proteinuria, patients with early hypertension, etc.Fil: Lizaraso Soto, Frank. Universidad de Valladolid; EspañaFil: Gutiérrez Abejón, Eduardo. Universidad de Valladolid; EspañaFil: Bustamante Munguira, Juan. Universidad de Valladolid; EspañaFil: Martín García, Débora. Universidad de Valladolid; EspañaFil: Chimeno, María Montserrat. Hospital Virgen de la Concha; EspañaFil: Nava Rebollo, Álvaro. Hospital Virgen de la Concha; EspañaFil: Maurtua Briseño Meiggs, Álvaro. Woodland Medical Practicenhs; Reino UnidoFil: Fernández, Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Universidad Nacional de Cuyo; Argentina. Universidad de Burgos. Departamento de Didácticas Específicas; EspañaFil: Bustamante Munguira, Elena. Universidad de Valladolid; EspañaFil: de Paz, Félix Jesús. Universidad de Valladolid; EspañaFil: Grande Villoria, Jesús. Universidad de Valladolid; España. Universite de Lausanne; SuizaFil: Ochoa Sangrador, Carlos. Sanidad de Castilla y León; EspañaFil: Pascual, Manuel. Universite de Lausanne; SuizaFil: Álvarez, F. Javier. Universidad de Valladolid; EspañaFil: Herrera Gómez, Francisco. Universite de Lausanne; Suiza. Universidad de Valladolid; Españ

Development of anti-membrane type 1-matrix metalloproteinase nanobodies as immunoPET probes for triple negative breast cancer imaging

14 p.-6 fig.1 tab.Triple-negative breast cancer (TNBC) is characterized by aggressiveness and high rates of metastasis. The identification of relevant biomarkers is crucial to improve outcomes for TNBC patients. Membrane type 1-matrix metalloproteinase (MT1-MMP) could be a good candidate because its expression has been reported to correlate with tumor malignancy, progression and metastasis. Moreover, single-domain variable regions (VHHs or Nanobodies) derived from camelid heavy-chain-only antibodies have demonstrated improvements in tissue penetration and blood clearance, important characteristics for cancer imaging. Here, we have developed a nanobody-based PET imaging strategy for TNBC detection that targets MT1-MMP. A llama-derived library was screened against the catalytic domain of MT1-MMP and a panel of specific nanobodies were identified. After a deep characterization, two nanobodies were selected to be labeled with gallium-68 (68Ga). ImmunoPET imaging with both ([68Ga]Ga-NOTA-3TPA14 and [68Ga]Ga-NOTA-3CMP75) in a TNBC mouse model showed precise tumor-targeting capacity in vivo with high signal-to-background ratios. (68Ga)Ga-NOTA-3CMP75 exhibited higher tumor uptake compared to (68Ga)Ga-NOTA-3TPA14. Furthermore, imaging data correlated perfectly with the immunohistochemistry staining results. In conclusion, we found a promising candidate for nanobody-based PET imaging to be further investigated as a diagnostic tool in TNBC.This research was supported by BBVA Foundation grants for Scientific Research Teams: “Imaging of triple-negative breast cancer with specific miniaturized antibodies by ImmunoPET (BREIMPET)” Ref.:PR[17]_BIO_IMG_0114 (2017) and “Radioinmunotheragnostics for metastatic lung cancer with pretargeted clickable Ab Fragments (TherAbnostic)” Ref.: PR[19]_BIO_IMG_0096. (2020).Peer reviewe

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Now, the part of intuition. Research, Art and Creation, 2018

Catálogo de Exposición del Máster en Investigación en Arte y Creación de la UCM. Muestra celebrada del 25 de septiembre al 10 de octubre de 2018 en la Sala de Exposiciones de la Facultad de Bellas Artes. C / Pintor el Greco 2, Ciudad Universitaria. 28040 Madrid. Comisariado de Javier Mañero Rodicio.Exhibition catalog of the Master in Art and Creation Research of the UCM. September 25 to October 10, 2018 in the Exhibition Hall of the Faculty of Fine Arts. C / Pintor El Greco 2, University City. 28040 Madrid. Curated by Javier Mañero Rodicio.Fac. de Bellas ArtesFALSEFacultad de Bellas Artes. Universidad Complutense de Madrid.pu