Geochemical Anomalies in Soils and Surface Waters in an Area Adjacent to a Long-Used Controlled Municipal Landfill

Municipal landfills, even when controlled, are potential sources of soil and water pollution in surrounding areas, due to the migration of pollutants through water and air. This research assesses geochemical anomalies of heavy elements and rare earth elements in soils and surface waters in an adjacent area to a controlled municipal landfill near Madrid (Central Spain), under long-term operation. Twenty soil and eighteen water samples were collected in 2017 and 2018 and analyzed for this purpose. Spatial distribution and concentrations of heavy elements (Ag, Cd, Cu, Mn, Ni, Pb, Tl, and Zn) and rare Earth elements (La, Ce, and Gd) are heterogeneous and significantly higher than soil background levels, but below the legal limits to consider intervention. Accumulation of heavy and rare Earth elements in soil nearest the landfill is attributed to occur via wind and wind-driven rain transport, while their accumulation in sediments is attributed to water transport through the creeks. Surface waters show large contamination by organic and inorganic compounds and influence geochemical anomalies in sediments. The water quality is below allowable concentrations for drinking water. The combined evaluation of the soil and water samples performed in the present work is proposed as a pilot study that may be applicable to similar surrounding landfill areas worldwideThe work has been partially financed by the Faculty of Sciences of the Autonomous University of Madrid

Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer

Partial suppression of mitochondrial oxidative phosphorylation and the concurrent activation of aerobic glycolysis is a hallmark of proliferating cancer cells. Overexpression of the ATPase inhibitory factor 1 (IF1), an in vivo inhibitor of the mitochondrial ATP synthase, is observed in most prevalent human carcinomas favoring metabolic rewiring to an enhanced glycolysis and cancer progression. Consistently, a high expression of IF1 in hepatocarcinomas and in carcinomas of the lung, bladder, and stomach and in gliomas is a biomarker of bad patient prognosis. In contrast to these findings, we have previously reported that a high expression level of IF1 in breast carcinomas is indicative of less chance to develop metastatic disease. This finding is especially relevant in the bad prognosis group of patients bearing triple-negative breast carcinomas. To investigate the molecular mechanisms that underlie the differential behavior of IF1 in breast cancer progression, we have developed the triple-negative BT549 breast cancer cell line that overexpresses IF1 stably. When compared to controls, IF1-cells partially shut down respiration and enhance aerobic glycolysis. Transcriptomic analysis suggested that migration and invasion were specifically inhibited in IF1-overexpressing breast cancer cells. Analysis of gene expression by qPCR and western blotting indicate that IF1 overexpression supports the maintenance of components of the extracellular matrix (ECM) and E-cadherin concurrently with the downregulation of components and signaling pathways involved in epithelial to mesenchymal transition. The overexpression of IF1 in breast cancer cells has no effect in the rates of cellular proliferation and in the cell death response to staurosporine and hydrogen peroxide. However, the overexpression of IF1 significantly diminishes the ability of the cells to grow in soft agar and to migrate and invade when compared to control cells. Overall, the results indicate that IF1 overexpression despite favoring a metabolic phenotype prone to cancer progression in the specific case of breast cancer cells also promotes the maintenance of the ECM impeding metastatic disease. These findings hence provide a mechanistic explanation to the better prognosis of breast cancer patients bearing tumors with high expression level of IF1.CN-T and IM-R were supported by pre-doctoral FPI-MEC and JAE-CSIC fellowships, respectively. This work was supported by grants from the Ministerio de Economía y Competitividad (SAF2013-41945-R; SAF2016-75916-R), Comunidad Madrid (S2011/BMD-2402), and Fundación Ramón Areces 2015, Spain.Peer reviewedPeer Reviewe

Dibujo y pintura digital: herramientas de software libre para la creación artística

La aparición de iniciativas de software libre está constituyendo actualmente una auténtica revolución, no sólo a nivel tecnológico sino también de carácter social, influyendo tanto al ámbito profesional como al educativo. Cada día más profesionales se interesan por estas innovadoras propuestas y cada vez más facultades apuestan por incluirlas en sus contenidos, ofreciendo con ello al alumno poderosas herramientas de trabajo sin implicar coste económico alguno. Tras la experiencia inicial en el Proyecto de Innovación Educativa sobre El uso del software libre en la Teoría y Práctica artística, se ha pretendido profundizar, con éste proyecto de innovación, en las herramientas digitales que complementan y expanden las posibilidades expresivas del dibujo y la pintura, concentrando la investigación en este ámbito

Selective expression of the neurexin substrate for presenilin in the adult forebrain causes deficits in associative memory and presynaptic plasticity

Presenilins (PS) form the active subunit of the gamma-secretase complex, which mediates the proteolytic clearance of a broad variety of type-I plasma membrane proteins. Loss-of-function mutations in PSEN1/2 genes are the leading cause of familial Alzheimer's disease (fAD). However, the PS/gamma-secretase substrates relevant for the neuronal deficits associated with a loss of PS function are not completely known. The members of the neurexin (Nrxn) family of presynaptic plasma membrane proteins are candidates to mediate aspects of the synaptic and memory deficits associated with a loss of PS function. Previous work has shown that fAD-linked PS mutants or inactivation of PS by genetic and pharmacological approaches failed to clear Nrxn C-terminal frag-ments (NrxnCTF), leading to its abnormal accumulation at presynaptic terminals. Here, we generated transgenic mice that selectively recreate the presynaptic accumulation of NrxnCTF in adult forebrain neurons, leaving unaltered the function of PS/gamma-secretase complex towards other substrates. Behavioral characterization identified selective impairments in NrxnCTF mice, including decreased fear-conditioning memory. Electro-physiological recordings in medial prefrontal cortex-basolateral amygdala (mPFC-BLA) of behaving mice showed normal synaptic transmission and uncovered specific defects in synaptic facilitation. These data functionally link the accumulation of NrxnCTF with defects in associative memory and short-term synaptic plasticity, pointing at impaired clearance of NrxnCTF as a new mediator in ADMinisterio de Ciencia, Innovación y Universidades (RTI2018-101886-B-100)Junta de Andalucía (PY18-823)Junta de Andalucía (P11- CVI-7599)Ministerio de Economía, Industria y Competitividad (BES-2016-076579)Garantía Juvenil contract from Universidad de Sevill

Filósofas: presencia y asusencia del pensamiento femenino en los estudios de Filosofía

Memoria ID-192. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2018-2019

The yeast prefoldin-like URI-orthologue Bud27 associates with the RSC nucleosome remodeler and modulates transcription

Bud27, the yeast orthologue of human URI/RMP, is a member of the prefoldin-like family of ATPindependent molecular chaperones. It has recently been shown to mediate the assembly of the three RNA polymerases in an Rpb5-dependent manner. In this work, we present evidence of Bud27 modulating RNA pol II transcription elongation. We show that Bud27 associates with RNA pol II phosphorylated forms (CTD-Ser5P and CTD-Ser2P), and that its absence affects RNA pol II occupancy of transcribed genes. We also reveal that Bud27 associatesin vivo with the Sth1 component of the chromatin remodeling complex RSC and mediates its association with RNA pol II. Our data suggest that Bud27, in addition of contributing to Rpb5 folding within the RNA polymerases, also participates in the correct assembly of other chromatin-associated protein complexes, such as RSC, thereby modulating their activit

Use of hospital care services by chronic patients according to their characteristics and risk levels by adjusted morbidity groups

Abstract Background In-hospital care of chronic patients is based on their characteristics and risk levels. Adjusted morbidity groups (AMG) is a population stratification tool which is currently being used in Primary Care but not in Hospitals. The objectives of this study were to describe the use of hospital services by chronic patients according to their risk levels assigned by AMG and to analyze influencing variables. Material and methods In this cross-sectional study, patients aged ≥18 years from a healthcare service area classified as chronically ill by the AMG classification system who used their referral hospital services from June 2015 to June 2016 were included. Predisposing and needs factors were collected. Univariate, bivariate and multiple linear regressions were performed. Results Of the 9,443 chronic patients identified (52.1% of the population in the selected area), 4,143 (43.9%) used hospital care services. Their mean age was 62.1 years (standard deviation (SD) = 18.4); 61.8% were female; 9% were high risk; 30% were medium risk, and 61% were low risk. The mean number of hospital service contacts was 5.0 (SD = 6.2), with 3.8 (SD = 4.3) visits to outpatient clinic, 0.7 (SD = 1.2) visits to emergency departments, 0.3 (SD = 2.8) visits to day hospital, and 0.2 (SD = 0.5) hospitalizations. The factors associated with greater service use were predisposing factors such as age (coefficient B (CB) = 0.03; 95% confidence interval (CI) = 0.01–0.05) and Spanish origin (CB = 3.9; 95% CI = 3.2–4.6). Among the needs factors were palliative care (CB = 4.8; 95% CI = 2.8–6.7), primary caregiver status (CB = 2.3; 95% CI = 0.7–3.9), a high risk level (CB = 2.9; 95% CI = 2.1–3.6), multimorbidity (CB = 0.8, 95% CI = 0.4–1.3), chronic obstructive pulmonary disease (COPD) (CB = 1.5, 95% CI = 0.8–2.3), depression (CB = 0.8, 95% CI = 0.3–1.3), active cancer (CB = 4.4, 95% CI = 3.7–5.1), and polymedication (CB = 1.1, 95% CI = 0.5–1.7). Conclusions The use of hospital services by chronic patients was high and increased with the risk level assigned by the AMG. The most frequent type of contact was outpatient consultation. Use was increased with predisposing factors such as age and geographic origin and by needs factors such as multimorbidity, risk level and severe diseases requiring follow-up, home care, and palliative care

TTBK1 and CK1 inhibitors restore TDP-43 pathology and avoid disease propagation in lymphoblast from Alzheimer’s disease patients

IntroductionTDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.MethodologyWe have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.ResultsTDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.ConclusionTTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease

Adalimumab reduces photoreceptor cell death in a mouse model of retinal degeneration

Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNFα ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNFα gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNFα blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the diseaseThis work was supported by the European Regional Development Fund, Institute of Health Carlos III, PI12/0481, SAF2013-41059-R and SAF2013-41945 from the Spanish Ministry of Economy and Competitiveness (MEC). CIBERER is an initiative of the Institute of Health Carlos III from the MEC. Regina Rodrigo has a research-contract SNS Miguel Servet (CP09/118) from Institute of Health Carlos II

Antagonistic pleiotropy in the bifunctional surface protein FadL (OmpP1) during adaptation of Haemophilus influenzae to chronic lung infection associated with Chronic Obstructive Pulmonary Disease

Tracking bacterial evolution during chronic infection provides insights into how host selection pressures shape bacterial genomes. The human-restricted opportunistic pathogen nontypeable Haemophilus influenzae (NTHi) infects the lower airways of patients suffering chronic obstructive pulmonary disease (COPD) and contributes to disease progression. To identify bacterial genetic variation associated with bacterial adaptation to the COPD lung, we sequenced the genomes of 92 isolates collected from the sputum of 13 COPD patients over 1 to 9years. Individuals were colonized by distinct clonal types (CTs) over time, but the same CT was often reisolated at a later time or found in different patients. Although genomes from the same CT were nearly identical, intra-CT variation due to mutation and recombination occurred. Recurrent mutations in several genes were likely involved in COPD lung adaptation. Notably, nearly a third of CTs were polymorphic for null alleles of ompP1 (also called fadL), which encodes a bifunctional membrane protein that both binds the human carcinoembryonic antigen-related cell adhesion molecule 1 (hCEACAM1) receptor and imports long-chain fatty acids (LCFAs). Our computational studies provide plausible three-dimensional models for FadL's interaction with hCEACAM1 and LCFA binding. We show that recurrent fadL mutations are likely a case of antagonistic pleiotropy, since loss of FadL reduces NTHi's ability to infect epithelia but also increases its resistance to bactericidal LCFAs enriched within the COPD lung. Supporting this interpretation, truncated fadL alleles are common in publicly available NTHi genomes isolated from the lower airway tract but rare in others. These results shed light on molecular mechanisms of bacterial pathoadaptation and guide future research toward developing novel COPD therapeutics.IMPORTANCE Nontypeable Haemophilus influenzae is an important pathogen in patients with chronic obstructive pulmonary disease (COPD). To elucidate the bacterial pathways undergoing in vivo evolutionary adaptation, we compared bacterial genomes collected over time from 13 COPD patients and identified recurrent genetic changes arising in independent bacterial lineages colonizing different patients. Besides finding changes in phase-variable genes, we found recurrent loss-of-function mutations in the ompP1 (fadL) gene. We show that loss of OmpP1/FadL function reduces this bacterium's ability to infect cells via the hCEACAM1 epithelial receptor but also increases its resistance to bactericidal fatty acids enriched within the COPD lung, suggesting a case of antagonistic pleiotropy that restricts DeltafadL strains' niche. These results show how H. influenzae adapts to host-generated inflammatory mediators in the COPD airways