Pleistocene glacial fluctuations and chronology in the Pas Mountains (Cantabrian Mountains)

RESUMEN. En este trabajo se muestra la evolución de los glaciares de las Montañas de Pas, en la Cordillera Cantábrica Oriental. Se han realizado una cartografía geomorfológica, análisis morfoestratigráfico, prospección eléctrica y sísmica y dataciones en turberas intramorrénicas y till. El complejo morrénico externo (F-I) muestra una edad para la máxima extensión glaciar anterior a 29.1509-28.570 cal a BP. En todo el macizo se ha detectado un segundo avance y equilibrio glaciar (F-II), con sus frentes en posiciones cercanas a la fase anterior. Por último, dos fases (F-III y F-IV) se caracterizaron por la presencia de glaciares muy pequeños, alojados en los circos. La última fase de equilibrio glaciar se ha atribuido a las fases tardías del Pleistoceno, coetáneas o anteriores al Tardiglaciar. Las dataciones realizadas en las Montañas Pasiegas son acordes con dataciones previas realizadas en otros macizos de la Cordillera Cantábrica y confirma la existencia de un máximo glaciar local anterior al LGM Europeo.ABSTRACT. This paper analyses the glacial evolution of the Pas Mountains, in the Eastern Cantabrian Mountains, the glacial landforms and deposits by geomorphological mapping, electric and seismic surveys, and dating intramorainic peat bog and till deposits. The external morainic complex (S-I) shows a glacial extension maximum before 29.150-28.570 cal a BP. A second glacial advance and equilibrium (S-II) have been studied in the entire massif, with glaciers reaching similar positions to the previous phase. Finally, two phases (S-III and S-IV) with very small glaciers developed in the cirque. The last equilibrium glacial phase has been attributed to Late Pleistocene cold phases, previous to Tardiglacial ones. Dating in the Pas Mountains are in agreement with previous dating in the Cantabrian Range and bears out the existence of a glacial maximum, previous to the European LGM

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 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

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

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed

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

Surface NMR survey on Hansbreen Glacier, Hornsund, SW Spitsbergen (Norway)

Glaciers are widely spread on polar and sub-polar regions but also on middle latitude mountains, where cold-dry type glaciers, polythermal glaciers and temperate-wet glaciers are respectively present. Polythermal glaciers have a cold-ice layer (temperature below the pressure melting point) overriding a temperate-ice layer. Nineteen magneticc resonance soundings were done following a 3 Kmprofile on Hansbreen front. Resistivity on the glacier surface, magnetic susceptibility of rocks, electromagnetic noise and total earth's magnetic field measurements confirm that the MRS survey took place in the best conditions. MRS data show different signals amplitudes at the Larmor frequency according to the loop dimension. In a very high electrical resistive context (greater than 2 Mega Ohms meter for glacier ice) the surveyed depth is directly related to the loop area. For small loops (30msquare loop) amplitudes around 50 nV are common as well as some decay time (T*2) above 300 ms. Enlarging the loop size (60 m square loop) it is possible to observe a decrease of the signal amplitude at the Larmor frequency (E0 less than 20 nV) but also the time decay (100 ms greater than =T*2 greater than 40 ms). Increasing loop sizes (90 and 120msquare loops), a slight increase in amplitude at the Larmor frequency, close to 30 nV, is observed with very high time decays (T*2 greater than 500 ms). Ground Penetrating Radar surveys were carried out in Hansbreen at the same location as theMRSsurveyed zone. Available GPR data show a water content of 2,5% on the cold-ice layer (the first 35 m depth) and 2% of water content on the temperate- ice layer but a 4%of water content can also be detected. Both geophysical methods are not convergent because some water content on ice has too short relaxation times being undetectable with conventionalMRSdevices. In that sense the low T*2 time decays data from large MRS loops elucidates that at the temperate-ice layer water flows by seepage through veins and microfractures at a very low rate toward the glacier bottom and a large amount of free water is close to the cold/temperate transition surface. In the cold-ice layer large T*2 time decays are common because water flows through fissures or karstic like conduits. In summary, combining the MRS and GPR techniques gives glaciologists a powerful toolkit to elucidate water flow-paths on glaciers, supercooled meltwater content and subglacial water or aquifers