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The characterization of the karst conduit network is an essential task to understand the complex flow system within karst aquifers. However, this task is challenging and often associated with uncertainty. Equivalent porous media approaches for modeling flow in karst aquifers fall short of capturing the hydraulic effect of individual karst features, while process‐oriented karst evolution models imply major computational efforts. In this study, we apply the Stochastic Karst Simulator (SKS) developed by Borghi et al. (2012) to generate karst conduit networks at a regional scale of a highly karstified carbonate aquifer located in the Eastern Mediterranean region and extensively used for water supply. The SKS generates conduit network geometries reasonably quick, using a mathematical proxy that mimics conduit evolution. The conduit simulation is based on a conceptual model of the genesis of the aquifer, consisting of different karstification phases. The stochastic approach of the algorithm enables us to generate an ensemble of conduit network realizations and to represent the uncertainties of these simulations in a Karst Probability Map. With only soft input information to constrain conduit evolution, multiple equivalent realizations yield similar resulting network geometries, indicating a robust approach. The presented methodology is numerically efficient, and its input can be easily adjusted. Subsequently, the resulting stochastic spatial distribution of conductivities can be employed for the parametrization of regional karst groundwater models. Key Points: We statistically generate multiple sets of karst conduit network geometries using input data based on soft informationThe resulting Karst Probability Map accounts for uncertainty in the spatial distribution of the karst conduit networkOur approach can assist in the integration of soft information into the parametrization of karst groundwater models [ABSTRACT FROM AUTHOR]

Groundwater resources are crucial to safe drinking supplies in sub‐Saharan Africa, and will be increasingly relied upon in a context of climate change. The need to better understand groundwater calls for innovative approaches to make the best out of the existing information. A methodology to map groundwater potential based on an ensemble of machine learning classifiers is presented. A large borehole database (n = 1848) was integrated into a Geographic Information Systems (GIS) environment and used to train, validate and test 12 machine learning algorithms. Each classifier predicts a binary target (positive or negative borehole) based on the minimum flow rate required for communal domestic supplies. Classification is based on a number of explanatory variables, including landforms, lineaments, soil, vegetation, geology and slope, among others. Correlations between the target and explanatory variables were then generalized to develop groundwater potential maps. Most algorithms attained success rates between 80% and 96% in terms of test score, which suggests that the outcomes provide an accurate picture of field conditions. Statistical learners were observed to perform better than most other algorithms, excepting random forests and support vector machines. Furthermore, it is concluded that the ensemble approach provides added value by incorporating a measure of uncertainty to the results. This technique may be used to rapidly map groundwater potential for rural supply or humanitarian emergencies in areas where there is sufficient historical data but where comprehensive field work is unfeasible. Article impact statement: This paper presents a novel method based on machine learning classifiers to map groundwater potential in remote regions. [ABSTRACT FROM AUTHOR]

A new methodology is presented for the conditioning of categorical multiple-point statistics (MPS) simulations to dynamic data with an iterative ensemble smoother (ES-MDA). The methodology relies on a novel multiresolution parameterization of the categorical MPS simulation. The ensemble of latent parameters is initially defined on the basis of the coarsest-resolution simulations of an ensemble of multiresolution MPS simulations. Because this ensemble is non-multi-Gaussian, additional steps prior to the computation of the first update are proposed. In particular, the parameters are updated at predefined locations at the coarsest scale and integrated as hard data to generate a new multiresolution MPS simulation. The performance of the methodology was assessed on a synthetic groundwater flow problem inspired from a real situation. The results illustrate that the method converges towards a set of final categorical realizations that are consistent with the initial categorical ensemble. The convergence is reliable in the sense that it is fully controlled by the integration of the ES-MDA update into the new conditional multiresolution MPS simulations. Thanks to a massively reduced number of parameters compared to the size of the categorical simulation, the identification of the geological structures during the data assimilation is particularly efficient for this example. The comparison between the estimated uncertainty and a reference estimate obtained with a Monte Carlo method shows that the uncertainty is not severely reduced during the assimilation as is often the case. The connectivity is successfully reproduced during the iterative procedure despite the rather large distance between the observation points. [ABSTRACT FROM AUTHOR]

At the heart of any water distribution system lies more than pipes, pumps, valves, and tanks. It's the people who operate these assets. In many utilities, staff have worked in the same department for decades, yet many feel like they don't have a voice or their opinion doesn't matter. How can a department change this mentality? [ABSTRACT FROM AUTHOR]

Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA-G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5′-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA-G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications. [ABSTRACT FROM AUTHOR]

Solving inverse problems in a complex, geologically realistic, and discrete model space and from a sparse set of observations is a very challenging task. Extensive exploration by Markov chain Monte Carlo (McMC) methods often results in considerable computational efforts. Most optimization methods, on the other hand, are limited to linear (continuous) model spaces and the minimization of an objective function, what often proves to be insufficient. To overcome these problems, we propose a new ensemble-based exploration scheme for geostatistical prior models generated by a multiple-point statistics (MPS) tool. The principle of our method is to expand an existing set of models by using posterior facies information for conditioning new MPS realizations. The algorithm is independent of the physical parametrization. It is tested on a simple synthetic inverse problem. When compared to two existing McMC methods (iterative spatial resampling (ISR) and Interrupted Markov chain Monte Carlo (IMcMC)), the required number of forward model runs was divided by a factor of 8-12. [ABSTRACT FROM AUTHOR]

Focuses on the proposal of a new methodology to forecast the number of samples required to reach an acceptable uncertainty level in terms of overall volumes of polluted soil and costs of remediation. Importance of sampling scheme design in the management of polluted sites; Estimation on the volume of soil requiring remediation and excavation; Application of the technique on a former smelting work site.

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha ( IFN α) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFN α sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho- STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFN α after priming and challenged with IFN α, with a subsequent decrease of phospho- STAT1 and interferon-stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho- STAT1 after ex vivo IFN α stimulation. Finally, we identified baseline phospho- STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFN α sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate clinically the treatment of gingival recession associated with non-carious cervical lesions (NCCLs) by resin modified glass ionomer cement (RMGI) or microfilled resin composite (MRC) and coronally positioned flap (CPF) at 6 months following surgery. Methods: Fifty-nine patients were assigned to one of three treatments: root exposure without NCCL treated with CPF (group 1); root exposure with NCCL treated with RMGI restoration plus CPF (group 2); or root exposure with NCCL treated with MRC restoration plus CPF (group 3). Clinical measurements that were assessed at baseline and at 3 and 6 months after surgery included plaque index (PI), bleeding on probing (BOP); probing depth (PD), recession reduction (RR), clinical attachment level gain (CALG), keratinized tissue height (KTH), keratinized tissue thickness (KTT), percentage of root coverage (RC), and percentage of restored root coverage (RRC). Results: Intra- and intergroup analyses demonstrated no significant differences in PI, BOP, PD, RR, CALG, KTH, or KTT (P>0.05) among the groups at any time. At 6 months, the mean RC was 80.83% ± 21.08% for group 1; the mean RRCs were 71.99% ± 18.69% and 74.18% ± 15.02% for groups 2 and 3, respectively. There were no statistically significant differences in RRC between groups 2 and 3. Conclusion: All treatments showed root coverage improvement without damage to periodontal tissues, supporting the use of CPF for treatment of root surfaces restored with RMGI or MRC as being effective over the 6-month period. [ABSTRACT FROM AUTHOR]

Background: Periodontal disease is a complex pathological process involving a wide spectrum of immunological reactions. The aim of the study was to evaluate the influence of surgical periodontal treatments on peripheral blood lymphocyte subpopulations. Methods: The study was performed in 40 generally healthy individuals diagnosed with generalized chronic periodontitis and a control group of 36 persons without periodontitis. Peripheral blood lymphocyte subpopulations were examined in both groups. Periodontal treatment was performed, using four different surgical procedures, in the study group. Peripheral blood lymphocyte subpopulations were re-evaluated again after 6 months. Results: Periodontal treatment resulted in a significant improvement of all measured clinical parameters, regardless of the surgical procedure. When evaluated in the study group as a whole, percentages of all but CD8+ T lymphocyte subpopulations were significantly different from the control group at baseline. Values in both groups after treatment were similar. Correlation analysis suggests a connection between the presence of CD25+ cells and selected clinical parameters of periodontal disease (probing depth and clinical attachment loss). Conclusions: Statistically significant differences in the percentages of selected lymphocyte subpopulations in the peripheral blood of patients and healthy controls were found. The results suggest a correlation between selected clinical periodontal parameters and percentage of activated cells expressing the interleukin (IL)-2 receptor. Periodontal treatment resulted in significant improvement in the measured clinical and immunological parameters. It seems that the type of surgical treatment has little effect on the normalization of quantitative disturbances of the examined peripheral blood lymphocytes. [ABSTRACT FROM AUTHOR]

To assess the contribution of accumulated winter precipitation and glacial meltwater to the recharge of deep ground water flow systems in fracture crystalline rocks, measurements of environmental isotope ratios, hydrochemical composition, and in situ parameters of ground water were performed in a deep tunnel. The measurements demonstrate the significance of these ground water recharge components for deep ground water flow systems in fractured granites of a high alpine catchment in the Central Alps, Switzerland. Hydrochemical and in situ parameters, as well as δ⊃18O in ground water samples collected in the tunnel, show only small temporal variations. The precipitation record of δ⊃18O shows seasonal variations of ∼14‰ and a decrease of 0.23∼ ± 0.03‰ per 100 m elevation gain. δ⊃2H and δ⊃18O in precipitation are well correlated and plot close to the meteoric water line, as well as δ⊃2H and δ⊃18O in ground water samples, reflecting the meteoric origin of the latter. The depletion of ⊃18O in ground water compared to ⊃18O content in precipitation during the ground water recharge period indicates significant contributions from accumulated depleted winter precipitation to ground water recharge. The hydrochemical composition of the encountered ground water, Na-Ca-HCO3-SO4(-F), reflects an evolution of the ground water along the flowpath through the granite body. Observed tritium concentrations in ground water range from 2.6 to 16.6 TU, with the lowest values associated with a local negative temperature anomaly and anomalous depleted ⊃18O in ground water. This demonstrates the effect of local ground water recharge from meltwater of submodem glacial ice. Such localized recharge from glaciated areas occurs along preferential flowpaths within the granite body that are mainly controlled by observed hydraulic active shear fractures and cataclastic faults. [ABSTRACT FROM AUTHOR]

Three zinc metallopeptidases are implicated in the regulation of fluid homeostasis and vascular tone and represent interesting targets for the treatment of chronic heart failure. We have previously reported the synthesis of a triple inhibitor able to simultaneously inhibit neprilysin (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and endothelin-converting enzyme (ECE-1, EC 3.4.24.71) with nanomolar potency towards NEP and ACE and a lesser affinity for ECE. Here, we report the optimization and biological activities of analogs derived from lead compound 1 (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3- (1H-indol-3-yl)-propionic acid by a structural approach. Among several inhibitors, compound 21, (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid was selected by taking into account its good molecular adaptation with the recently published structures of the three vasopeptidases. This optimization procedure led to an improved pharmacologic activity when compared with 1. [ABSTRACT FROM AUTHOR]

Piezoelectric AlN films crystallised in a hexagonal wurtzite structure with the c-axis oriented perpendicular to the surface were deposited on silicon substrates by dc reactive magnetron sputtering. The evolution of the crystallographic and electrical properties of these films with a nitrogen concentration between 10 and 100% in the Ar–N2 gas mixture was studied using X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDXS) and four-point probe methods. It was found that the electrical properties are correlated to the film structure and to the deposition parameters. The AlN films having a high electrical resistivity (>1014 Ω cm at room temperature) also exhibit a high crystallographic orientation, as determined from the XRD peak intensity. An optimum for the nitrogen concentration is identified in the range 60–80% of N2 in the gas mixture. The Arrhenius plots of electrical resistance give an activation energy of 2.2 eV between 200 °C and 450 °C. This energy is attributed to oxygen impurities. EDXS analysis reveals that oxygen is the only element present in the deposited films, along with Al and N. [ABSTRACT FROM AUTHOR]

We characterized a new signaling pathway leading to the activation of cAMP-responsive element-binding protein (CREB) in several cell lines affected by mitochondrial dysfunction. In vitro kinase assays, inhibitors of several kinase pathways and overexpression of a dominant-negative mutant for calcium/calmodulin kinase IV (CaMKIV), which blocks the activation of CREB, showed that CaMKIV is activated by a mitochondrial activity impairment. A high calcium concentration leading to the disruption of the protein interaction with protein phosphatase 2A explains CaMKIV activation in these conditions. Transcriptionally active phosphorylated CREB was also found in a p0 143B human osteosarcoma cell tine and in a MERRF cybrid cell tine mutated for tRNALYS (A8344G). We also showed that phosphorylated CREB is involved in the proliferation defect induced by a mitochondrial dysfunction. Indeed, cell proliferation inhibition can be prevented by CaMKIV inhibition and CREB dominant-negative mutants. Finally, our data suggest that phosphorylated CREB recruits p53 tumor suppressor protein, modifies its transcriptional activity and increases the expression of p21Waf1/Cip1, a p53-regulated cyclin-dependent kinase inhibitor. [ABSTRACT FROM AUTHOR]

Concentrations of heavy metals, including mercury, have been shown to be altered in the brain and body fluids of Alzheimer’s disease (AD) patients. To explore potential pathophysiological mechanisms we used an in vitro model system (SHSY5Y neuroblastoma cells) and investigated the effects of inorganic mercury (HgCl2) on oxidative stress, cell cytotoxicity, β-amyloid production, and tau phosphorylation. We demonstrated that exposure of cells to 50 μg/L (180 nM) HgCl2 for 30 min induces a 30% reduction in cellular glutathione (GSH) levels (n = 13, p < 0.001). Preincubation of cells for 30 min with 1 μM melatonin or premixing melatonin and HgCl2 appeared to protect cells from the mercury-induced GSH loss. Similarly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assays revealed that 50 μg/L HgCl2 for 24 h produced a 50% inhibition of MTT reduction (n = 9, p < 0.001). Again, melatonin preincubation protected cells from the deleterious effects of mercury, resulting in MTT reduction equaling control levels. The release of β-amyloid peptide (Aβ) 1-40 and 1-42 into cell culture supernatants after exposure to HgCl2 was shown to be different: Aβ 1-40 showed maximal (15.3 ng/ml) release after 4 h, whereas Aβ 1-42 showed maximal (9.3 ng/ml) release after 6 h of exposure to mercury compared with untreated controls (n = 9, p < 0.001). Preincubation of cells with melatonin resulted in an attenuation of Aβ 1-40 and Aβ 1-42 release. Tau phosphorylation was significantly increased in the presence of mercury (n = 9, p < 0.001), whereas melatonin preincubation reduced the phosphorylation to control values. These results indicate that mercury may play a role in pathophysiological mechanisms of AD. [ABSTRACT FROM AUTHOR]

The article discusses the move by art experts to conduct a study on comprehensive cultural project with a view to lying the basis for the future ecomuseum. The research entitled "Inventory of Popular Arts and Traditions of Marie-Galante" attempts to involve a population in the recognition and development of its own culture to define a type of development corresponding to its aspirations. Moreover, Marie-Galante has defined new development models based on the specific needs of the island's inhabitants while improving the preservation of the natural resources. In 1976, the Inventory of Popular Arts and Traditions was established which highlights the local cultural heritage and provide the population with information on its past and present.

The aim was to identify differentially expressed genes in mtDNA-depleted cells that could play a role in two interesting features of these cells such as mitobiogenesis and the generation of a mitochondrial potential. The functional characterization led us to identify mtCLIC, a mitochondrial chloride channel, as a protein that participates in generating a mitochondrial membrane potential in these cells. [ABSTRACT FROM AUTHOR]

Abstract Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases. [ABSTRACT FROM AUTHOR]