The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent ...transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization.
Ti and TiN thin films (50–140nm thick) are grown by dc reactive magnetron sputtering PVD in an inverted cylindrical magnetron (ICM) thanks to an original industrial process corresponding to a ...continuous reactive deposition on moving stainless steel wires. Thin films are fully characterized by X-ray Photoelectron Spectroscopy, Transmission Electron Microscopy coupled with Energy Dispersive Spectroscopy and Orientation Phase Mapping. The stoichiometry of TiN is adjusted thanks to N2 flow. At the beginning of poisoned mode, golden stoichiometric TiN thin films are obtained. In the metallic mode, greyish TiNx films are grown whereas at higher N2 flow, TiNxOy films are synthetized with preferential O incorporation instead of N enrichment. Grain orientation maps reveal that Ti and TiN thin films are highly polycrystalline: Ti films have an equiaxis morphology whereas TiN thin films have a tendency to present 〈111〉 columnar grains with 〈001〉 oriented grains at the nucleation step. Finally, a low temperature of growth (of about 350°C and <650°C) is needed in order to prevent chemical diffusion from the stainless steel substrate into the rich-titanium films.
•Ti and TiN thin films are grown by PVD in an inverted cylindrical magnetron on moving stainless steel wires.•Thin films are characterized in terms of color, morphology, chemical composition, and crystalline structure.•TEM orientation maps permit to access to grain orientation and morphology in the thin films at a nanometric resolution.•A low growth temperature is needed in order to prevent chemical diffusion from the substrate into rich-titanium films.
Following the identification of a set of hypoxia-regulated microRNAs (miRNAs), recent studies have highlighted the importance of miR-210 and of its transcriptional regulation by the transcription ...factor hypoxia-inducible factor-1 (HIF-1). We report here that miR-210 is overexpressed at late stages of non-small cell lung cancer. Expression of miR-210 in lung adenocarcinoma A549 cells caused an alteration of cell viability associated with induction of caspase-3/7 activity. miR-210 induced a loss of mitochondrial membrane potential and the apparition of an aberrant mitochondrial phenotype. The expression profiling of cells overexpressing miR-210 revealed a specific signature characterized by enrichment for transcripts related to 'cell death' and 'mitochondrial dysfunction', including several subunits of the electron transport chain (ETC) complexes I and II. The transcript coding for one of these ETC components, SDHD, subunit D of succinate dehydrogenase complex (SDH), was validated as a bona fide miR-210 target. Moreover, SDHD knockdown mimicked miR-210-mediated mitochondrial alterations. Finally, miR-210-dependent targeting of SDHD was able to activate HIF-1, in line with previous studies linking loss-of-function SDH mutations to HIF-1 activation. miR-210 can thus regulate mitochondrial function by targeting key ETC component genes with important consequences on cell metabolism, survival and modulation of HIF-1 activity. These observations help explain contradictory data regarding miR-210 expression and its putative function in solid tumors.
Until recently, Intergovernmental Panel on Climate Change (IPCC) emission factor methodology, based on simple empirical relationships, has been used to estimate carbon (C) and nitrogen (N) fluxes for ...regional and national inventories. However, the 2005 USEPA greenhouse gas inventory includes estimates of N2O emissions from cultivated soils derived from simulations using DAYCENT, a process-based biogeochemical model. DAYCENT simulated major U.S. crops at county-level resolution and IPCC emission factor methodology was used to estimate emissions for the approximately 14% of cropped land not simulated by DAYCENT. The methodology used to combine DAYCENT simulations and IPCC methodology to estimate direct and indirect N(2)O emissions is described in detail. Nitrous oxide emissions from simulations of presettlement native vegetation were subtracted from cropped soil N(2)O to isolate anthropogenic emissions. Meteorological data required to drive DAYCENT were acquired from DAYMET, an algorithm that uses weather station data and accounts for topography to predict daily temperature and precipitation at 1-km2 resolution. Soils data were acquired from the State Soil Geographic Database (STATSGO). Weather data and dominant soil texture class that lie closest to the geographical center of the largest cluster of cropped land in each county were used to drive DAYCENT. Land management information was implemented at the agricultural-economic region level, as defined by the Agricultural Sector Model. Maps of model-simulated county-level crop yields were compared with yields estimated by the USDA for quality control. Combining results from DAYCENT simulations of major crops and IPCC methodology for remaining cropland yielded estimates of approximately 109 and approximately 70 Tg C(O)2 equivalents for direct and indirect, respectively, mean annual anthropogenic N(2)O emissions for 1990-2003.
Transient osteoporosis of the hip (TOH) is usually reported in middle-aged men or during pregnancy as a benign self-limiting condition. Nevertheless, its impact on quality of life in terms of pain ...and disability is considerable. Also, it can lead to insufficiency fractures or, more rarely, evolve into osteonecrosis. This condition is anecdotally described in the pediatric age and very little is known about how it may affect the growing bone. We herein describe a case of TOH in a 10-year-old child treated at our pediatric rheumatology service and summarize the pediatric cases of TOH previously reported in literature. There are two points of interest in our case report, the first one being the unusual complication of TOH with a femoral physis fracture and the second the complete recovery after the off-label therapy with bisphosphonates. We suggest that interventional medical treatment could be considered in selected cases of juvenile TOH, to prevent any possible irreversible damage on the femoral physis. As far as we know, this is the first report of neridronate employment in children affected by TOH.
Atmospheric CO2 enrichment may stimulate plant growth directly through (1) enhanced photosynthesis or indirectly, through (2) reduced plant water consumption and hence slower soil moisture depletion, ...or the combination of both. Herein we describe gas exchange, plant biomass and species responses of five native or semi-native temperate and Mediterranean grasslands and three semi-arid systems to CO2 enrichment, with an emphasis on water relations. Increasing CO2 led to decreased leaf conductance for water vapor, improved plant water status, altered seasonal evapotranspiration dynamics, and in most cases, periodic increases in soil water content. The extent, timing and duration of these responses varied among ecosystems, species and years. Across the grasslands of the Kansas tallgrass prairie, Colorado shortgrass steppe and Swiss calcareous grassland, increases in aboveground biomass from CO2 enrichment were relatively greater in dry years. In contrast, CO2-induced aboveground biomass increases in the Texas C3/C4 grassland and the New Zealand pasture seemed little or only marginally influenced by yearly variation in soil water, while plant growth in the Mojave Desert was stimulated by CO2 in a relatively wet year. Mediterranean grasslands sometimes failed to respond to CO2-related increased late-season water, whereas semiarid Negev grassland assemblages profited. Vegetative and reproductive responses to CO2 were highly varied among species and ecosystems, and did not generally follow any predictable pattern in regard to functional groups. Results suggest that the indirect effects of CO2 on plant and soil water relations may contribute substantially to experimentally induced CO2-effects, and also reflect local humidity conditions. For landscape scale predictions, this analysis calls for a clear distinction between biomass responses due to direct CO2 effects on photosynthesis and those indirect CO2 effects via soil moisture as documented here.
Agricultural soils are responsible for the majority of nitrous oxide (N2O) emissions in the USA. Irrigated cropping, particularly in the western USA, is an important source of N2O emissions. However, ...the impacts of tillage intensity and N fertilizer amount and type have not been extensively studied for irrigated systems. The DAYCENT biogeochemical model was tested using N2O, crop yield, soil N and C, and other data collected from irrigated cropping systems in northeastern Colorado during 2002 to 2006. DAYCENT uses daily weather, soil texture, and land management information to simulate C and N fluxes between the atmosphere, soil, and vegetation. The model properly represented the impacts of tillage intensity and N fertilizer amount on crop yields, soil organic C (SOC), and soil water content. DAYCENT N2O emissions matched the measured data in that simulated emissions increased as N fertilization rates increased and emissions from no-till (NT) tended to be lower on average than conventional-till (CT). However, the model overestimated N2O emissions. Lowering the amount of N2O emitted per unit of N nitrified from 2 to 1% helped improve model fit but the treatments receiving no N fertilizer were still overestimated by more than a factor of 2. Both the model and measurements showed that soil NO3- levels increase with N fertilizer addition and with tillage intensity, but DAYCENT underestimated NO3- levels, particularly for the treatments receiving no N fertilizer. We suggest that DAYCENT could be improved by reducing the background nitrification rate and by accounting for the impact of changes in microbial community structure on denitrification rates.
Disordered urbanization and deforestation are the main activities proposed as causal factors of re-emergence of American cutaneous leishmaniasis caused by Leishmania braziliensis. The purpose of this ...work was to investigate, in the hyperendemic area of Argentina, the distribution of Phlebotomine sand flies at the modified primary vegetation-crop interface, as one of the potential sites where the effects of changing landscape on sand fly populations may be manifested. Twenty samplings were made between June 2004 and August 2005. The traps to catch sand flies were set on two consecutive nights every month (except in 5 mo, where it became every 15 d). The relationship between sand fly abundance and meteorological and landscape variables was analyzed using non-metric multidimensional scaling and Kendall's correlation coefficients. Lutzomyia neivai (Pinto) was the most abundant species, followed by Lutzomyia migonei (França), Lutzomyia cortelezzii (Brèthes), Lutzomyia shannoni (Dyar), and Lutzomyia punctigeniculata (Floch and Abonnenc). Traps located close to modified areas collected the greatest numbers of sand flies, whereas traps located in the least modified area (adjacent to the primary vegetation) collected the fewest. There was a strong negative correlation between the abundance of sand flies and precipitation. This study shows that even small modifications in the landscape led to an increase in sand fly abundance, mainly Lu. neivai, a Leishmania braziliensis vector. This underscores the need for recommendations about the risk of American cutaneous leishmaniasis before any environmental intervention is done in an endemic area, as well as for the monitoring of sand fly population dynamics at the site of intervention, before, during, and after the process.
Many antiepileptic drugs (AEDs) are associated with hematological disorders that range from mild thrombocytopenia or neutropenia to anemia, red cell aplasia, until bone marrow failure. Fortunately, ...potentially fatal hematological disorders such as aplastic anemia are very rare. This review investigates hematological effects associated with classic and newer AEDs: a PubMed search indexed for MEDLINE was undertaken to identify studies in adults, children and animals using the name of all anticonvulsant drugs combined with the terms “hematological disease” and “hematological abnormalities” as key words. The most common hematological alterations occur with older AEDs than newer. Indeed, careful hematological monitoring is needed especially using carbamazepine, phenytoin and valproic acid. The pathogenetic mechanisms are still unknown: they seem to be related to an immunological mechanism, but drugs pharmacokinetics and pharmacodynamics interactions may also play an important role. Further research is needed to assess the real pathogenetic mechanism at the basis of hematological complications caused by AEDs.
A Monte Carlo analysis was combined with an empirically based approach to quantify uncertainties in soil nitrous oxide (N2O) emissions from U.S. croplands estimated with the DAYCENT simulation model. ...Only a subset of croplands was simulated in the Monte Carlo analysis, which was used to infer uncertainties across the larger spatiotemporal domain. Specifically, one simulation representing dominant weather, soil type, and N inputs was performed for each major commodity crop in the 3000 counties occurring within the conterminous United States. We randomly selected 300 counties for the Monte Carlo analysis and randomly drew model inputs from probability distribution functions (100 iterations). A structural uncertainty estimator was developed by deriving a statistical equation from a comparison of DAYCENT‐simulated N2O emissions with measured emissions from experiments in North America. We estimated soil N2O emission of 201 Gg N from major commodity crops in 2007, with a 95% confidence interval (CI) of 133–304 Gg N. This implies a relative CI of 34% below and 51% above the estimate at the national scale, but the CIs tended to be larger at the regional level, particularly in regions with low emissions. Spatial variability in emissions was driven primarily by differences in N inputs from fertilizer and manure, while temporal variability was driven more by N mineralization rates, which are correlated with weather patterns in DAYCENT. A higher portion of total uncertainty was due to model structure compared to model inputs, suggesting that improvements in model algorithms and parameterization are needed to produce results with higher precision and accuracy.
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