NFATc1 affects mouse splenic B cell function by controlling the calcineurin–NFAT signaling network

Mouse B cells lacking NFATc1 exhibit defective proliferation, survival, isotype class switching, cytokine production, and T cell help

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing–remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-β inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-β on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis

How do individual species and Plant Functional Type responses to environmental change differ in Dynamic Vegetation Models? - A forest stand analysis

Originally dedicated to simulate vegetation at the global scale, dynamic (global) vegetation models (D(G)VMs) classify vegetation into Plant Functional Types (PFTs) to represent the largest set of plant species. PFTs are clusters of species that share common morphological and physiological traits. However, PFT classification becomes surely too coarse to reflect the large diversity in plant species responses to climate and environmental changes, a critical point for biodiversity questions. Thus, some efforts focus now on applying DVMs at the species level refining the definition of morphophysiological parameters from initial PFT traits to specific traits collected or found in trait databases. What are the effects of using species-specific parameters? Do dynamic vegetation models better reproduce historical forest growth and mortality observed in monitored stands? How will individual species respond to future climate compared to PFTs? To study these questions, we used two process-based dynamic vegetation models CARAIB (Dury et al., 2011) as well as LPJ-GUESS (Smith et al., 2001), and compared their outputs. CARAIB has been previously adapted to model a set of 40 European tree species, differentiated by their specific traits, proper climatic requirements and tolerances. LPJ-GUESS features a detailed representation of climate sensitive tree species dynamics, resource competition and canopy structure (Hickler et al., 2012). The respective tree species are distinguished by taking differences in phenology, allometry and bioclimatic limits into account. Model simulations were performed in accordance with the experimental protocol of the COST Action PROFOUND (“Towards robust projections of European forests under climate change”) for several European forest stands selected in the project. We particularly focused on Fagus sylvatica stand in Sorø (Denmark), Picea abies stand in Solling (Germany) and Pinus sylvestris (and Picea abies) stands in Hyytiala (Finland). The experiments include site-specific soil characteristics, management practices (planting, thinning and harvest) and climate conditions. For the historical period (from planting year to 2014), besides local observations, simulations were also run with the original (0.5-degree spatial resolution) and locally bias-corrected (LBC) ISIMIP2B outputs of global climate models for testing the reliance of DVM results to the spatial resolution of climatic inputs. For the future period (2005-2100), vegetation models were driven by the ISIMIP2B climates under different Representative Concentration Pathways. The simulations at the PFT level were performed following the same protocol replacing the locally present species by their representative PFTs. The carbon and water fluxes obtained from the different experiments carried out with the two DVMs were compared with eddy-covariance data from each site.PROFOUND (Towards robust projections of European forests under climate change

An R package facilitating sensitivity analysis, calibration and forward simulations with the LPJ-GUESS dynamic vegetation model

Dynamic global vegetation models (DGVMs) are of crucial importance for understanding and predicting vegetation, carbon, nitrogen and water dynamics of ecosystems in response to climate change. Their complexity, however, creates challenges for model analysis and data integration. A solution is to interface DGVMs with established statistical computing environments. Here we introduce rLPJGUESS, an R-package that couples the widely used DGVM LPJ-GUESS with the R environment for statistical computing, making existing R-packages and functions readily available to perform complex analyses with this model. We demonstrate the advantages of this framework by using rLPJGUESS to perform several otherwise laborious tasks: first, a set of single simulations, followed by global and local sensitivity analyses, a Bayesian calibration with a Markov-Chain Monte Carlo (MCMC) algorithm, and a predictive simulation with multiple climate scenarios. Our example highlights the opportunities of interfacing existing models in earth and environmental sciences with state-of-the-art computing environments such as R

Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium