Representation of dissolved organic carbon in the JULES land surface model (vn4.4_JULES-DOCM)

Current global models of the carbon (C) cycle consider only vertical gas exchanges between terrestrial or oceanic reservoirs and the atmosphere, thus not considering the lateral transport of carbon from the continents to the oceans. Therefore, those models implicitly consider all of the C which is not respired to the atmosphere to be stored on land and hence overestimate the land C sink capability. A model that represents the whole continuum from atmosphere to land and into the ocean would provide a better understanding of the Earth's C cycle and hence more reliable historical or future projections. A first and critical step in that direction is to include processes representing the production and export of dissolved organic carbon in soils. Here we present an original representation of dissolved organic C (DOC) processes in the Joint UK Land Environment Simulator (JULES-DOCM) that integrates a representation of DOC production in terrestrial ecosystems based on the incomplete decomposition of organic matter, DOC decomposition within the soil column, and DOC export to the river network via leaching. The model performance is evaluated in five specific sites for which observations of soil DOC concentration are available. Results show that the model is able to reproduce the DOC concentration and controlling processes, including leaching to the riverine system, which is fundamental for integrating terrestrial and aquatic ecosystems. Future work should include the fate of exported DOC in the river system as well as DIC and POC export from soil

A New tool for the assessment of severe anthropogenic eutrophication in wetlands under increasing human pressure

It is about time the assessment of trophic state in wetlands is no longer estimated through the regressions and thresholds modelled for deep-stratified lakes where sediment nutrient recycling was purposely neglected. We are in badly need of a system trophic indicator to be used as a reference for biological indicators. The recent use of biological communities (macro-invertebrates, diatoms, etc) for the evaluation of the “ecological state” of a water body implicitly requires the assessment of its “trophic state”

Impacts of global change on Mediterranean forests and their services

The increase in aridity, mainly by decreases in precipitation but also by higher temperatures, is likely the main threat to the diversity and survival of Mediterranean forests. Changes in land use, including the abandonment of extensive crop activities, mainly in mountains and remote areas, and the increases in human settlements and demand for more resources with the resulting fragmentation of the landscape, hinder the establishment of appropriate management tools to protect Mediterranean forests and their provision of services and biodiversity. Experiments and observations indicate that if changes in climate, land use and other components of global change, such as pollution and overexploitation of resources, continue, the resilience of many forests will likely be exceeded, altering their structure and function and changing, mostly decreasing, their capacity to continue to provide their current services. A consistent assessment of the impacts of the changes, however, remains elusive due to the difficulty of obtaining simultaneous and complete data for all scales of the impacts in the same forests, areas and regions. We review the impacts of climate change and other components of global change and their interactions on the terrestrial forests of Mediterranean regions, with special attention to their impacts on ecosystem services. Management tools for counteracting the negative effects of global change on Mediterranean ecosystem- services are finally discussed

Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models.

[EN] BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated invitro, invivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation invitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA invivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells invitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA. LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors.This article is based upon work from the COST Action CA18122 European Cholangiocarcinoma Network supported by COST (European Cooperation in Science and Technology: www.cost.eu)

Effectiveness of a psycho-educational program for improving quality of life of fibromyalgia patients

<p>Abstract</p> <p>Background</p> <p>Most fibromyalgia patients are seen in primary care (PC). However, the effectiveness of the treatments prescribed by general practitioners is usually minimal. The main objective of the present research is to assess the efficacy of structured psycho-educational intervention, combined with relaxation, developed to improve the quality of life of patients suffering fibromyalgia (FM). The second objective is to assess the cost-effectiveness of this multimodal intervention.</p> <p>Method/Design</p> <p><it>Design</it>. Randomized controlled trial with a 12-month follow-up involving two groups, one of which is the intervention group that includes patients receiving a psychoeducational program and the other the control group consisting of patients treated for FM in the usual way.</p> <p><it>Setting</it>. Three urban PC centers in the province of Barcelona (Spain).</p> <p><it>Sample</it>. The total sample comprises 218 patients (over 18 years of age) suffering FM, selected from a database (Rheumatology service-Viladecans Hospital) of patients with this illness. Only those patients introduced in the database between the years 2005 and 2007 were included in the selection. Selected patients will be asked for written informed consent to participate in the study.</p> <p><it>Intervention</it>. Multi-component program including information about the illness, counselling about physical exercise and training in autogenic relaxation. The intervention consists of nine 2-hour sessions delivered during a two-month period. The pharmacological treatment prescribed by the physician was maintained in both groups.</p> <p><it>Main variables</it>. Sociodemographic characteristics, quality of life, use and cost of healthcare and social services.</p> <p><it>Measures</it>. Quality of life is to be measured with the FIQ and the EuroQol-5D, and the use of healthcare services with an adapted version of the Client Service Receipt Inventory (CSRI). These variables will be measured before the beginning of the program (baseline) and 1, 2, 6 and 12 months later.</p> <p>Discussion</p> <p>This research project is an attempt to demonstrate that a psycho-educational program implemented in the context of PC can produce a significant increase in the quality of life for patients with FM, as well as a decrease in the use of healthcare and social services, compared with usual care.</p> <p>Trial registration</p> <p>NCT00550966</p

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

The use of radiocarbon 14 C to constrain carbon dynamics in the soil module of the land surface model ORCHIDEE (SVN r5165)

International audienceDespite the importance of soil as a large component of the terrestrial ecosystem, the soil compartments are not well represented in land surface models (LSMs). Indeed, soils in current LSMs are generally represented based on a very simplified schema that can induce a misrepresentation of the deep dynamics of soil carbon. Here, we present a new version of the Institut Pierre Simon Laplace (IPSL) LSM called ORCHIDEE-SOM (ORganizing Carbon and Hydrology in Dynamic EcosystEms-Soil Organic Matter), incorporating the C-14 dynamics into the soil. ORCHIDEE-SOM first simulates soil carbon dynamics for different layers, down to 2 m depth. Second, concentration of dissolved organic carbon and its transport are modelled. Finally, soil organic carbon decomposition is considered taking into account the priming effect. After implementing C-14 in the soil module of the model, we evaluated model outputs against observations of soil organic carbon and modern C-14 fraction ((FC)-C-14) for different sites with different characteristics. The model managed to reproduce the soil organic carbon stocks and the (FC)-C-14 along the vertical profiles for the sites examined. However, an overestimation of the total carbon stock was noted, primarily on the surface layer. Due to C-14, it is possible to probe carbon age in the soil, which was found to be underestimated. Thereafter, two different tests on this new version have been established. The first was to increase carbon residence time of the passive pool and decrease the flux from the slow pool to the passive pool. The second was to establish an equation of diffusion, initially constant throughout the profile, making it vary exponentially as a function of depth. The first modifications did not improve the capacity of the model to reproduce observations, whereas the second test improved both estimation of surface soil carbon stock as well as soil carbon age. This demonstrates that we should focus more on vertical variation in soil parameters as a function of depth, in order to upgrade the representation of the global carbon cycle in LSMs, thereby helping to improve predictions of the of soil organic carbon to environmental changes