Hydrogeophysics and remote sensing for the design of hydrogeological conceptual models in hard rocks - Sardón catchment (Spain)

Hard rock aquifers are highly heterogeneous and hydrogeologically complex. To contribute to the design of hydrogeological conceptual models of hard rock aquifers, we propose a multi-techniques methodology based on a downward approach that combines remote sensing (RS), non-invasive hydrogeophysics and hydrogeological field data acquisition. The proposed methodology is particularly suitable for data scarce areas. It was applied in the pilot research area of Sardón catchment (80 km2) located west of Salamanca (Spain). The area was selected because of hard-rock hydrogeology, semi-arid climate and scarcity of groundwater resources. The proposed methodology consisted of three main steps. First, we detected the main hydrogeological features at the catchment scale by processing: (i) a high resolution digital terrain model to map lineaments and to outline fault zones; and (ii) high-resolution, multispectral satellite QuickBird and WorldView-2 images to map the outcropping granite. Second, we characterized at the local scale the hydrogeological features identified at step one with: i) ground penetrating radar (GPR) to assess groundwater table depth complementing the available monitoring network data; ii) 2D electric resistivity tomography (ERT) and frequency domain electromagnetic (FDEM) to retrieve the hydrostratigraphy along selected survey transects; iii) magnetic resonance soundings (MRS) to retrieve the hydrostratigraphy and aquifer parameters at the selected survey sites. In the third step, we drilled 5 boreholes (25 to 48 m deep) and performed slug tests to verify the hydrogeophysical interpretation and to calibrate the MRS parameters. Finally, we compiled and integrated all acquired data to define the geometry and parameters of the Sardón aquifer at the catchment scale. In line with a general conceptual model of hard rock aquifers, we identified two main hydrostratigraphic layers: a saprolite layer and a fissured layer. Both layers were intersected and drained by fault zones that control the hydrogeology of the catchment. The spatial discontinuities of the saprolite layer were well defined by RS techniques while subsurface geometry and aquifer parameters by hydrogeophysics. The GPR method was able to detect shallow water table at depth between 1 and 3 m b.g.s. The hydrostratigraphy and parameterization of the fissured layer remained uncertain because ERT and FDEM geophysical methods were quantitatively not conclusive while MRS detectability was restricted by low volumetric water content. The proposed multi-technique methodology integrating cost efficient RS, hydrogeophysics and hydrogeological field investigations allowed us to characterize geometrically and parametrically the Sardón hard rock aquifer system, facilitating the design of hydrogeological conceptual model of the area

Halofuginone inhibits the establishment and progression of melanoma bone metastases

Transforming growth factor (TGF-β) derived from bone fuels melanoma bone metastases by inducing tumor secretion of pro-metastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we demonstrate for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable to those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiographys. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis

GLI2-Mediated Melanoma Invasion and Metastasis

Background The transforming growth factor-β (TGF-β) pathway, which has both tumor suppressor and pro-oncogenic activities, is often constitutively active in melanoma and is a marker of poor prognosis. Recently, we identified GLI2, a mediator of the hedgehog pathway, as a transcriptional target of TGF-β signaling. Methods We used real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine GLI2 expression in human melanoma cell lines and subsequently classified them as GLI2high or as GLI2low according to their relative GLI2 mRNA and protein expression levels. GLI2 expression was reduced in a GLI2high cell line with lentiviral expression of short hairpin RNA targeting GLI2. We assessed the role of GLI2 in melanoma cell invasiveness in Matrigel assays. We measured secretion of matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography and expression of E-cadherin by western blotting and RT-PCR. The role of GLI2 in development of bone metastases was determined following intracardiac injection of melanoma cells in immunocompromised mice (n = 5-13). Human melanoma samples (n = 79) at various stages of disease progression were analyzed for GLI2 and E-cadherin expression by immunohistochemistry, in situ hybridization, or RT-PCR. All statistical tests were two-sided. Results Among melanoma cell lines, increased GLI2 expression was associated with loss of E-cadherin expression and with increased capacity to invade Matrigel and to form bone metastases in mice (mean osteolytic tumor area: GLI2high vs GLI2low, 2.81 vs 0.93 mm2, difference = 1.88 mm2, 95% confidence interval [CI] = 1.16 to 2.60, P < .001). Reduction of GLI2 expression in melanoma cells that had expressed high levels of GLI2 substantially inhibited both basal and TGF-β-induced cell migration, invasion (mean number of Matrigel invading cells: shGLI2 vs shCtrl (control), 52.6 vs 100, difference = 47.4, 95% CI = 37.0 to 57.8, P = .024; for shGLI2 + TGF-β vs shCtrl + TGF-β, 31.0 vs 161.9, difference = −130.9, 95% CI = −96.2 to −165.5, P = .002), and MMP secretion in vitro and the development of experimental bone metastases in mice. Within human melanoma lesions, GLI2 expression was heterogeneous, associated with tumor regions in which E-cadherin was lost and increased in the most aggressive tumors. Conclusion GLI2 was directly involved in driving melanoma invasion and metastasis in this preclinical stud

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Search for Branons at LEP

We search, in the context of extra-dimension scenarios, for the possible existence of brane fluctuations, called branons. Events with a single photon or a single Z-boson and missing energy and momentum collected with the L3 detector in e^+ e^- collisions at centre-of-mass energies sqrt{s}=189-209$ GeV are analysed. No excess over the Standard Model expectations is found and a lower limit at 95% confidence level of 103 GeV is derived for the mass of branons, for a scenario with small brane tensions. Alternatively, under the assumption of a light branon, brane tensions below 180 GeV are excluded

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Association of social vulnerability factors with power outage burden in Washington state: 2018–2021

Major power outages have risen over the last two decades, largely due to more extreme weather conditions. However, there is a lack of knowledge on the distribution of power out-ages and its relationship to social vulnerability and co-occurring hazards. We examined the associations between localized outages and social vulnerability factors (demographic characteristics), controlling for environmental factors (weather), in Washington State between 2018–2021. We additionally analyzed the validity of PowerOutage.us data compared to federal datasets. The population included 27 counties served by 14 electric utilities. We developed a continuous measure of daily outage burden using PowerOutage.us data and operationalized social vulnerability using four factors: poverty level, unemployment, disability , and limited English proficiency. We applied zero-altered lognormal generalized additive mixed-effects models to characterize the relationship between social vulnerability and daily power outage burden, controlling for daily minimum temperature, maximum wind speed, and precipitation, from 2018 to 2021 in Washington State. We found that social vulnerability factors have non-linear relationships with outages. Wind and precipitation are consistent drivers of outage occurrence and duration. There are seasonal effects that vary by county-utility area. Both PowerOutage.us and federal datasets have missing and inaccurate outage data. This is the first study evaluating differential exposure to localized outages as related to social vulnerability that has accounted for weather and temporal correlation. There is a lack of transparency into power outage distribution for those most vulnerable to climate impacts, despite known contributions by electric utilities to climate change. For effective public health surveillance of power outages and transparency, outage data should be made available at finer spatial resolution and temporal scales and/or utilities should be required to report differential exposure to power outages for socially vulnerable populations

Comparison of code-oriented site classification in the Saguenay region, Québec

Local geological and geotechnical conditions can have significant effects on the incoming seismic waves and their spatial variation. Commonly referred to as site-effects, certain conditions can significantly amplify the intensity of the seismic shaking and make it more destructive. Site effects are accounted for in national building codes by the selection of amplification factors as functions of soil category, seismic intensity and frequency. The soil type is categorized by considering representative shearwave velocity, the number of blows in the standard penetration test, and/or undrained shear strength in the top 30 meters. Although soil categorizations based on these geotechnical parameters are more or less similar across earthquake-prone countries, there are some differences, which may result in over- or underestimation of the potential site effects. The SaguenayLac-Saint-Jean region (SLSJ) is located in a moderate seismicity zone in Eastern Canada; the last major earthquake in this region occurred in 1988 with a moment magnitude of 5.9. The presence of important deposits of sensitive clays in SLSJ combined with the strong impedance contrast between the unconsolidated deposits and the underlying crystalline bedrock can play an important role in the soil dynamic response. Different soil classification criteria and respective amplification factors are compared: the 2015 National Earthquake Hazards Reduction Program (NEHRP), Eurocode 8, and the 2015 National Building Code of Canada (NBCC). The advantages and disadvantages of each classification approach are discussed