Stress-strain behaviour of the sediments in the tertiary basins associated with the Alentejo? Plasencia fault in the province of Caceres (Spain)

An analysis of the geotechnical information obtained from a large number of field tests (pressuremeter) and laboratory tests (identification, state, and mechanics) on the clay deposits in the small tertiary basins associated with the Alentejo?Plasencia fault in the province of Caceres (Spain) has made it possible to classify them and predict their response to different levels of stress and strain. This geotechnical classification process must consider an appropriate model of constitution. The present article is based on the use of the Hardening Soil Model to facilitate predictions of the stress?strain behaviour of these tertiary clay deposits

Interpretation of the pressuremeter test using numerical models based on deformation tensor equations

The pressuremeter test in boreholes has proven itself as a useful tool in geotechnical explorations, especially comparing its results with those obtained from a mathematical model ruled by a soil representative constitutive equation. The numerical model shown in this paper is aimed to be the reference framework for the interpretation of this test. The model analyses variables such as: the type of response, the initial state, the drainage regime and the constitutive equations. It is a model of finite elements able to work with a mesh without deformation or one adapted to it

Computer Cognitive Rehabilitation in Older People: gradior Program

In the process of aging, there is a cognitive decline due to age. Cognitive impairment is one of the most common symptoms of neurodegenerative diseases such as dementia. Throughout decades, different types of cognitive interventions and approaches have been developed with the main objective of improving or maintaining the cognitive capacities of the elderly. Such is the case of computer cognitive rehabilitation that has been shown to be an effective form of stimulation capable of improving cognitive functioning in the older people. This document describes the computerized cognitive rehabilitation program gradior 4.5 (latest version), specifying its different components, application methodology and its most relevant aspects. The experience developed during the more than 20 years of existence of the program with thousands of patients coming from different devices and the different studies of efficacy and usability developed, in order to satisfy the needs, capacities, limitations and preferences of the users, have given place to this new improved version that makes it a flexible, dynamic, simple, useful and easy to use tool

Computer Cognitive Rehabilitation in Older People: gradior Program

In the process of aging, there is a cognitive decline due to age. Cognitive impairment is one of the most common symptoms of neurodegenerative diseases such as dementia. Throughout decades, different types of cognitive interventions and approaches have been developed with the main objective of improving or maintaining the cognitive capacities of the elderly. Such is the case of computer cognitive rehabilitation that has been shown to be an effective form of stimulation capable of improving cognitive functioning in the older people. This document describes the computerized cognitive rehabilitation program gradior 4.5 (latest version), specifying its different components, application methodology and its most relevant aspects. The experience developed during the more than 20 years of existence of the program with thousands of patients coming from different devices and the different studies of efficacy and usability developed, in order to satisfy the needs, capacities, limitations and preferences of the users, have given place to this new improved version that makes it a flexible, dynamic, simple, useful and easy to use tool.En el proceso de envejecimiento, se produce un declive cognitivo debido a la edad. El deterioro cognitivo es uno de los síntomas más comunes de enfermedades neurodegenerativas como la demencia. A lo largo de décadas se han desarrollado diferentes tipos de intervenciones cognitivas y enfoques con el objetivo principal de mejorar o mantener las capacidades cognitivas de las personas mayores. Tal es el caso de la rehabilitación cognitiva por ordenador, que se ha mostrado como una forma eficaz de estimulación capaz de mejorar el funcionamiento cognitivo en personas mayores. El presente documento describe el programa de rehabilitación cognitiva por ordenador gradior 4.5 (última versión), especificando sus diferentes componentes, metodología de aplicación y sus aspectos más relevantes. La experiencia desarrollada durante los más de 20 años de existencia del programa con miles de pacientes provenientes de diferentes dispositivos y los diferentes estudios de eficacia y usabilidad desarrollados, con el fin de satisfacer las necesidades, capacidades, limitaciones y preferencias de los usuarios, han dado lugar a esta nueva versión mejorada que la convierte en una herramienta flexible, dinámica, sencilla, útil y fácil de usar

Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.This work was partially supported by grants from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02256). CORSA was funded by the Austrian Research Promotion Agency (FFG) BRIDGE grant (no. 829675, to Andrea Gsur), the “Herzfelder’sche Familienstiftung” (grant to Andrea Gsur). Czech Republic CCS was funded by GACR grants (18–09709S, 19–10543S and 20–03997S), ProgresQ28/1.LF and UNCE/MED/006 grants. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). A.K. is a recipient of a Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017) from the Department of Biotechnology (DBT), Government of India (GOI). V.M. received funding from the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds–a way to build Europe–grants PI14-00613, PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE. K.H. was supported by European Union Horizon 2020 grant No. 856620. We thank the CERCA Programme, Generalitat de Catalunya for institutional support

A method to establish marine bio-regions in the pelagic ecosystem based on phytoplanktonic communities. Aplication to the southern Spanish coast

Bioregions in the pelagic ecosystem are frequently established on the basis of remotely sensed properties of the sea surface, such as sea surface temperature or sea surface chlorophyll concentration. Those works dealing with the regionalization of the marine ecosystem by means of the use of properties of the water column are less frequent, and even less those that obtain the data from periodic in situ monitoring programs, which are scarce. In this work we use time series of micro, nano and pico-phytoplanktonic abundances in the upper 100 m of the continental shelves of the Gulf of Cadiz and the Alboran Sea from the projects STOCA and RADMED (southern coast of Spain, Western Mediterranean). The use of times series allows us to estimate the median phytoplanktonic abundances of several phytoplanktonic groups along the water column. These statistics differ substantially from those abundances obtained for one particular campaign, reflecting the large seasonal and inter-annual variability of phytoplanktonic communities. These median profiles, estimated for the four seasons of the year and for several phytoplanktonic groups characterize each of the locations sampled in the aforementioned monitoring programs and are used for establishing the similarity between them. Then, these locations are grouped using a cluster analysis. Using some simulations from numerical experiments we determine which metrics and methods of analysis are the more suitable ones for the regionalization of the area of study. A bootstrap method is also used to determine which differences among bioregions can be considered as statistically significant. Despite the existence of a fast current that connects the Gulf of Cadiz and the Alboran Sea, our results show that the outer part of the Gulf of Cadiz shelf, and that of the Alboran Sea, can be considered as two differentiated bioregions. The latter region shows a higher productivity with a higher abundance of large cells such as diatoms, and the dominance of Synechococcus bacteria over Prochlorococcus ones

Polymorphisms within the TNFSF4 and MAPKAPK2 Loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspBIOmics consortium

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.This study was supported by grants PI20/01845, PI12/02688, and ISCIII-FEDER PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), the Collaborative Research Center/Transregio 124 FungiNet, the Fundacao para a Ciencia e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/03628/2017, and CEECIND/04058/2018), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507, and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003)

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA

Background Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. Methods We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. Results LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. Conclusions Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

Meniere’s disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case–control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661–2.627); p = 1.39 × 10−09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10−11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S