5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with noncardiovascular death in CKD populations are lacking. The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n ¼ 2185 CKD patients). After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG þ rs2283368 CC/CT þ rs2320762 GG). Among the patients with the three SNPs genotyped (n ¼ 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA þ rs2283368 TT þ rs2320762 GT/TT). All the other combinations [n ¼ 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher fhazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]g and lower [HR 6 × 10- (95% CI 3.3 × 10--1.1 × 10-)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Sedimentary heterogeneity and petrophysical characterization of Barremian tsunami and barrier island/inlet deposits: The Aliaga outcrop as a reservoir analogue (Galve sub-basin, eastern Spain)

In this study, we examined two sandstones bodies of the Camarillas Fm. The porosity and permeability models of each sandstone body, the tsunami deposit at the bottom and the barrier island – tidal inlet deposit at the top, supplied two independent reservoir models reflecting different sedimentary processes. Through study cases from outcrop data, we show that the dissolution of CO2 reached 40% of the total injected where the injection point was in thin zones (1–3 m-thick). The study cases presented here represent nearly one grid block (grid cell) of classic reservoir models, but are very complex in terms of petrophysical distribution. Geological model uncertainty is low (outcrop data), and facies are well correlated to petrophysics. Both deposits stored 50–60% of injected CO2 by residual and dissolution trapping over 7.5 years. The injection rate per day (maximum 200 sm3/day for the tsunami reservoir and 400 sm3/day for the barrier island − tidal inlet (b.i/inlet) reservoir) and the total amount of injected CO2 (108,000–116,000 sm3, ∼200 ton in 1.2–1.7 years) were very low in comparison with an in industrial project; however, results of this study have an important impact on the assessment and estimation of dissolved CO2 in aqueous phase, and could be used in studies on upscaling methods

Facies and petrophysical modelling of a thick lower cretaceous tsunami deposit in E Spain: Up-scaling from sample to outcrop scales

The tsunami deposit (up to 3 m thick) of the Cretaceous Camarillas Formation in the Galve sub-basin (eastern Spain) is characterized by a large lateral extent (35 km(2)) and facies uniformity, consisting in fine to coarse subarkosic-arkosic sandstones. At the scale of outcrop observation, different lithofacies were distinguished and related to sedimentation processes. Sand facies distribution conditioned the fades heterogeneity at both mesoscopic or outcrop scales (10(-1)-10(1) m scale) and sample scale (10(-3)-10(-2) m). The sample features were up-scaled to that of a facies model using probability functions and variograms as well as to outcrop-scale data (geometry and size) of facies distribution, and it showed a good correlation with the facies distribution at the outcrop. Porosity is strongly correlated to permeability and the pairs of porosity and permeability values fall into the global hydraulic element (GHEs) 5, so that they can be up-scaled into reservoir models in terms of hydraulic properties. From data analysis, no apparent link between sand sorting and porosity and permeability values was observed. The petrophysical models, which were independent of facies models, were up-scaled taking into account the porosity and permeability values from sample data and the statistical analysis of their distribution along the outcrop. The permeability model was carried out as a function of porosity by applying a linear relation, which simplified the modelling process and discarded permeability uncertainties linked to fades distribution in the deposit In spite of different source data, the petrophysical models show a distribution of lower and higher values that resembles the facies model. Consequently, our modelling results clearly suggest the link of facies type and their grain size distributions with the petrophysical properties into the deposit. Consistency between fades and petrophysical models and outcrop-scale observations make it possible to extrapolate to other deposits related to similar sedimentary processes

One-pot synthesis of compact DNA silica particles for gene delivery and extraordinary DNA preservation

Repairing genetic defects using exogenous DNA is a major challenge the science is currently facing. This requires the design of vectors that can effectively encapsulate, protect and target nucleic acids to specific cells safely and precisely. Here we have designed silica-based physiologically responsive particles to encapsulate, store, and transfer DNA. Unlike existing vectors (e.g., viral or lipidic particles), these DNA@SiO2 systems are very stable at room temperature. We also demonstrate how they protect the encapsulated DNA from exposure to different biological and physicochemical stresses, including DNase, denaturation temperatures (>100 °C), or reactive oxygen species (ROS). Remarkably, upon cellular uptake, these vectors dissolve safely unpacking the DNA and transfecting the cells.The versatility of the design is such that it can encapsulate genes without gene/size restrictions, in single or multiple layers of silica, so different genes can be expressed sequentially. This allows the time-controlled transcription of several genes, mimicking viral gene expression cascades, or even “fine-tuning” gene expression in transfected cells on demand. In addition, the method is easily scalable, reproducible, and inexpensive, enabling large-scale production and batch-quality testing, all of which are important for the personalized therapeutics industry. The high stability of these DNA vectors allows for easy and low-cost transport from the point of production to virtually any destination, making them unique as gene delivery tools

Outcrop scale reservoir characterisation and flow modelling of CO2 injection in the tsunami and the barrier island—Tidal inlet reservoirs of the Camarillas Fm. (Galve sub-basin, Teruel, NE Spain)

In this study, we examined two sandstones bodies of the Camarillas Fm. The porosity and permeability models of each sandstone body, the tsunami deposit at the bottom and the barrier island – tidal inlet deposit at the top, supplied two independent reservoir models reflecting different sedimentary processes. Through study cases from outcrop data, we show that the dissolution of CO2 reached 40% of the total injected where the injection point was in thin zones (1–3 m-thick). The study cases presented here represent nearly one grid block (grid cell) of classic reservoir models, but are very complex in terms of petrophysical distribution. Geological model uncertainty is low (outcrop data), and facies are well correlated to petrophysics. Both deposits stored 50–60% of injected CO2 by residual and dissolution trapping over 7.5 years. The injection rate per day (maximum 200sm3/day for the tsunami reservoir and 400 sm3/day for the barrier island − tidal inlet (b.i/inlet) reservoir) and the total amount of injected CO2 (108,000–116,000 sm3, ∼200 ton in 1.2–1.7 years) were very low in comparison with an in industrial project; however, results of this study have an important impact on the assessment and estimation of dissolved CO2 in aqueous phase, and could be used in studies on upscaling methods

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases