Glacial geomorphology of the High Gredos Massif: Gredos and Pinar valleys (Iberian Central System, Spain)

We present a detailed geomorphological map of the landform assemblages originated by the two major paleoglaciers of the Sierra de Gredos mountain range in the Spanish Iberian Central System. Based on previous works, our map focused on the features formed by Gredos and Pinar paleoglaciers during the last glaciation and subsequent glacial events. Based on a remote sensing analysis and exhaustive field surveys, we identified with great accuracy the local distribution of glacial, periglacial, mass movement, structural, fluvial, and lacustrine features. We recognized three main glacial geomorphological formations representing: (i) the maximum glacial extension reached (peripheral deposits); (ii) the culmination of glacial conditions (principal moraines) and (iii) the local glacial withdrawal (internal deposits). Our map offers a renewed spatial framework on which to conduct higher-resolution glacial chronologies, especially of Late Glacial and Holocene glacial activity, providing key information for performing future paleoclimatic reconstructions of the northern hemisphere mid-latitudes

Assessment of MMP-9, TIMP-1, and COX-2 in normal tissue and in advanced symptomatic and asymptomatic carotid plaques

<p>Abstract</p> <p>Background</p> <p>Mature carotid plaques are complex structures, and their histological classification is challenging. The carotid plaques of asymptomatic and symptomatic patients could exhibit identical histological components.</p> <p>Objectives</p> <p>To investigate whether matrix metalloproteinase 9 (MMP-9), tissue inhibitor of MMP (TIMP), and cyclooxygenase-2 (COX-2) have different expression levels in advanced symptomatic carotid plaques, asymptomatic carotid plaques, and normal tissue.</p> <p>Methods</p> <p>Thirty patients admitted for carotid endarterectomy were selected. Each patient was assigned preoperatively to one of two groups: group I consisted of symptomatic patients (n = 16, 12 males, mean age 66.7 ± 6.8 years), and group II consisted of asymptomatic patients (n = 14, 8 males, mean age 67.6 ± 6.81 years). Nine normal carotid arteries were used as control. Tissue specimens were analyzed for fibromuscular, lipid and calcium contents. The expressions of MMP-9, TIMP-1 and COX-2 in each plaque were quantified.</p> <p>Results</p> <p>Fifty-eight percent of all carotid plaques were classified as Type VI according to the American Heart Association Committee on Vascular Lesions. The control carotid arteries all were classified as Type III. The median percentage of fibromuscular tissue was significantly greater in group II compared to group I (<it>p </it>< 0.05). The median percentage of lipid tissue had a tendency to be greater in group I than in group II (<it>p </it>= 0.057). The percentages of calcification were similar among the two groups. MMP-9 protein expression levels were significantly higher in group II and in the control group when compared with group I (p < 0.001). TIMP-1 expression levels were significantly higher in the control group and in group II when compared to group I, with statistical difference between control group and group I (p = 0.010). COX-2 expression levels did not differ among groups. There was no statistical correlation between MMP-9, COX-2, and TIMP-1 levels and fibrous tissue.</p> <p>Conclusions</p> <p>MMP-9 and TIMP-1 are present in all stages of atherosclerotic plaque progression, from normal tissue to advanced lesions. When sections of a plaque are analyzed without preselection, MMP-9 concentration is higher in normal tissues and asymptomatic surgical specimens than in symptomatic specimens, and TIMP-1 concentration is higher in normal tissue than in symptomatic specimens.</p

The Calderuelas hydro-laccolith (Sierra de Guadarrama National Park), a remarkable periglacial landform

En este trabajo se describe el hallazgo de un hidrolacolito en la Sierra de Guadarrama (Sistema Central). Su estudio se ha realizado mediante la caracterización morfológica y de la estructura interna, a través del empleo de Modelos Digitales del Terreno (MDT) obtenidos de datos LiDAR y varios perfiles geoeléctricos. Los resultados permiten establecer la génesis de esta estructura, de origen periglaciar, y la influencia de los procesos de ladera en su evolución. Los ciclos hielo-deshielo y las condiciones hidrogeológicas del entorno son los factores que controlan la evolución que presenta a lo largo del tiempo esta morfología. Estas estructuras muestran una extraordinaria sensibilidad ambiental, por lo que su monitorización resulta de gran interés para garantizar su preservación futuraThis research describes the finding of a hydro-laccolith in the Sierra de Guadarrama (Central System). The study, based on the combination of Digital Terrain Models (DTM) and geoelectric data, allowed the characterization of the surface morphology and internal structure. The results allow establishing the genesis of this periglacial- related structure and the role played by slope processes in its evolution. Freeze-thawing cycles and hydrogeological conditions are responsible factors that control its evolution over time. Such type of structures show an extraordinary environmental sensitivity, thus their monitoring is of great interest to guarantee their further preservatio

El hidrolacolito de las Calderuelas (Parque Nacional de la Sierra de Guadarrama), una morfología periglaciar singular

En este trabajo se describe el hallazgo de un hidrolacolito en la Sierra de Guadarrama (Sistema Central). Su estudio se ha realizado mediante la caracterización morfológica y de la estructura interna, a través del empleo de Modelos Digitales del Terreno (MDT) obtenidos de datos LiDAR y varios perfiles geoeléctricos. Los resultados permiten establecer la génesis de esta estructura, de origen periglaciar, y la influencia de los procesos de ladera en su evolución. Los ciclos hielo-deshielo y las condiciones hidrogeológicas del entorno son los factores que controlan la evolución que presenta a lo largo del tiempo esta morfología. Estas estructuras muestran una extraordinaria sensibilidad ambiental, por lo que su monitorización resulta de gran interés para garantizar su preservación futura

Improved methodical approach for quantitative BRET analysis of G protein coupled receptor dimerization

G Protein Coupled Receptors (GPCR) can form dimers or higher ordered oligomers, the process of which can remarkably influence the physiological and pharmacological function of these receptors. Quantitative Bioluminescence Resonance Energy Transfer (qBRET) measurements are the gold standards to prove the direct physical interaction between the protomers of presumed GPCR dimers. For the correct interpretation of these experiments, the expression of the energy donor Renilla luciferase labeled receptor has to be maintained constant, which is hard to achieve in expression systems. To analyze the effects of non-constant donor expression on qBRET curves, we performed Monte Carlo simulations. Our results show that the decrease of donor expression can lead to saturation qBRET curves even if the interaction between donor and acceptor labeled receptors is non-specific leading to false interpretation of the dimerization state. We suggest here a new approach to the analysis of qBRET data, when the BRET ratio is plotted as a function of the acceptor labeled receptor expression at various donor receptor expression levels. With this method, we were able to distinguish between dimerization and non-specific interaction when the results of classical qBRET experiments were ambiguous. The simulation results were confirmed experimentally using rapamycin inducible heterodimerization system. We used this new method to investigate the dimerization of various GPCRs, and our data have confirmed the homodimerization of V2 vasopressin and CaSR calcium sensing receptors, whereas our data argue against the heterodimerization of these receptors with other studied GPCRs, including type I and II angiotensin, β2 adrenergic and CB1 cannabinoid receptors

Videodensitometric analysis of advanced carotid plaque: correlation with MMP-9 and TIMP-1 expression

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of MMP (TIMP) promote derangement of the extracellular matrix, which is ultimately reflected in plaque images seen on ultrasound. Videodensitometry can identify structural disturbances in plaques.</p> <p>Objectives</p> <p>To establish the correlations between values determined using videodensitometry in B-mode ultrasound images of advanced carotid plaques and the total expression of MMP-9 and TIMP-1 in these removed plaques.</p> <p>Methods</p> <p>Thirty patients underwent ultrasonic tissue characterization of carotid plaques before surgery, using mean gray level (MGL), energy, entropy and homogeneity. Each patient was assigned preoperatively to one of 2 groups: group I, symptomatic patients (n = 16; 12 males; mean age 66.7 ± 6.8 years), and group II, asymptomatic patients (n = 14; 8 males; mean age 67.6 ± 6.81 years). Tissue specimens were analyzed for MMP-9 and TIMP-1 expression. Nine carotid arteries were used as normal tissue controls.</p> <p>Results</p> <p>MMP-9 expression levels were elevated in group II and in normal tissues compared to group I (p < 0.001). TIMP-1 levels were higher in group II than in group I, and significantly higher in normal tissues than in group I (p = 0.039). The MGL was higher in group II compared to group I (p = 0.038). Energy had greater values in group II compared to group I (<it>p </it>= 0.02). There were no differences between patient groups in homogeneity and entropy. Energy positively correlated with MMP-9 and TIMP-1 expression (p = 0.012 and p = 0.031 respectively). Homogeneity positively correlated with MMP-9 and TIMP-1 expression (p = 0.034 and p = 0.047 respectively). There were no correlations between protein expression and MGL or entropy.</p> <p>Conclusions</p> <p>Videodensitometric computer analysis of ultrasound scanning images can be used to identify stable carotid plaques, which have higher total expression levels of MMP-9 and TIMP-1 than unstable plaques.</p

The Prados del Cervunal morainic complex: Evidence of a MIS 2 glaciation in the Iberian Central System synchronous to the global LGM

© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND licenseThe area of Prados del Cervunal (PC) is an intra-morainic topographic depression located at 1800 m asl in the divide or interfluve between Garganta de Gredos and Garganta del Pinar valleys (Central Gredos; Iberian Central System, ICS). Both valleys, along with the adjacent Hoya Nevada, were occupied by glaciers during the Upper Pleistocene, leading to the development of the Prados del Cervunal moraine complexes studied in this work. Using cartographic methods and morphostratigraphic analysis, the three main glacial formations established in the Regional Chrono-Evolutionary Pattern for the ICS, Peripheral Deposits (PD), Principal Moraine (PM) and Internal Deposits (ID), have been identified and mapped in this area. The chronology of these formations has been implemented by Cosmic Ray Exposure (CRE) techniques using 10Be (new data) and 26Cl (previous data, recalculated in this work) in samples from morainic boulders. With these data, the following chrono-evolutionary sequence has been established: (stage 1) local-Maximum Ice Extent (MIE), dated in 25.0 ± 1.4 ka and corresponding to the maximum age obtained in these paleoglaciers; (stage 2) period of oscillations around the MIE, corresponding to the development of the PD Formation between ∼25 ka and ∼21 ka; (stage 3) period of readvance and stabilisation, dated after ∼21 ka (average age obtained for the PD moraines attached to PM moraines) and previous to ∼18 (minimum age obtained for a main crest of the PM formation); and (stage 4) onset of deglaciation dated around to ∼18 ka (average of ages obtained for the first main crest of the ID formation). During the stages of maximum ice expansion, these three glaciers formed an Ice field whose tongues were interconnected on the PC flat by an ice transfluence system (stages 1 and 2, Plateau Glacier Period). In later stages, the ice masses were partitioned, giving rise to valley glaciers and large moraines forming morainic complexes like those of PC (stages 2, 3 and 4, Valley Glaciers Period). The local MIE and onset of deglaciation stages in this area show a good fit with the ages stablished to global level for the global Last Glacial Maximum (LGM) and the onset of the Last Glacial Termination (Termination I). They also show good correlation at local (with other areas of the ICS), peninsular (with other Iberian mountains) and continental (some areas of the Alps and mountains of Central Europe) level. Finally, this evolutionary sequence and its correlations allowed us to adjust and validate some units of the Regional Chrono-Evolutionary Pattern model and propose the Gredos-Pinar-Cabeza Nevada glacial system as benchmark for the glaciation of Marine Isotope Stage (MIS) 2 in the Iberian Peninsula.This work was supported by the Spanish Ministry of Science and Innovation (project PID2020-117685 GB-I00), Castilla-La Mancha University (UCLM, project 2023-GRIN-34112), ANID FONDECYT postdoctoral #3220537, ANID BASAL CHIC #FB210018 and ANID FONDECYT Regular #1220550. The ASTER AMS national facility (CEREGE, Aix-en-Provence) is supported by the INSU/CNRS, and IRD. The authors acknowledge the help and assistance received from the Sierra de Gredos Regional Park (Environmental Department of the Junta de Castilla y León, JCyL) and to the “Guarderia” (Staff of surveillance and control) of the Gredos Regional Reserve for their remarkable help in the fieldworks.Peer reviewe

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System

INTRODUCTION Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. METHODS The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. RESULTS AND CONCLUSIONS Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe