An ensemble approach to assess hydrological models’ contribution to uncertainties in the analysis of climate change impact on water resources

Over the recent years, several research efforts investigated the impact of climate change on water resources for different regions of the world. The projection of future river flows is affected by different sources of uncertainty in the hydro-climatic modelling chain. One of the aims of the QBic3 5 project (Que´bec-Bavarian International Collaboration on Climate Change) is to assess the contribution to uncertainty of hydrological models by using an ensemble of hydrological models presenting a diversity of structural complexity (i.e. lumped, semi distributed and distributed models). The study investigates two humid, mid-latitude catchments with natural flow conditions; one located in 10 Southern Que´bec (Canada) and one in Southern Bavaria (Germany). Daily flow is simulated with four different hydrological models, forced by outputs from regional climate models driven by a given number of GCMs’ members over a reference (1971–2000) and a future (2041–2070) periods. The results show that the choice of the hydrological model does strongly affect the climate change response of selected hydrological indicators, especially those related to low flows. Indicators related to high flows seem less sensitive on the choice of the hydrological model. Therefore, the computationally less demanding models (usually simple, lumped and conceptual) give a significant level of trust for high and overall mean flows

On the need for bias correction in regional climate scenarios to assess climate change impacts on river runoff

In climate change impact research, the assessment of future river runoff as well as the catchment scale water balance is impeded by different sources of modeling uncertainty. Some research has already been done in order to quantify the uncertainty of climate 5 projections originating from the climate models and the downscaling techniques as well as from the internal variability evaluated from climate model member ensembles. Yet, the use of hydrological models adds another layer of incertitude. Within the QBic3 project (Qu´ebec-Bavaria International Collaboration on Climate Change) the relative contributions to the overall uncertainty from the whole model chain (from global climate 10 models to water management models) are investigated using an ensemble of multiple climate and hydrological models. Although there are many options to downscale global climate projections to the regional scale, recent impact studies tend to use Regional Climate Models (RCMs). One reason for that is that the physical coherence between atmospheric and land-surface 15 variables is preserved. The coherence between temperature and precipitation is of particular interest in hydrology. However, the regional climate model outputs often are biased compared to the observed climatology of a given region. Therefore, biases in those outputs are often corrected to reproduce historic runoff conditions from hydrological models using them, even if those corrections alter the relationship between temperature and precipitation. So, as bias correction may affect the consistency between RCM output variables, the use of correction techniques and even the use of (biased) climate model data itself is sometimes disputed among scientists. For those reasons, the effect of bias correction on simulated runoff regimes and the relative change in selected runoff indicators is explored. If it affects the conclusion of climate change analysis in 25 hydrology, we should consider it as a source of uncertainty. If not, the application of bias correction methods is either unnecessary in hydro-climatic projections, or safe to use as it does not alter the change signal of river runoff. The results of the present paper highlight the analysis of daily runoff simulated with four different hydrological models in two natural-flow catchments, driven by different regional climate models for a reference and a future period. As expected, bias correction of climate model outputs is important for the reproduction of the runoff regime of the 5 past regardless of the hydrological model used. Then again, its impact on the relative change of flow indicators between reference and future period is weak for most indicators with the exception of the timing of the spring flood peak. Still, our results indicate that the impact of bias correction on runoff indicators increases with bias in the climate simulations

Tuning the Clock: Uranium and Thorium Chronometers Applied to CS 31082-001

We obtain age estimates for the progenitor(s) of the extremely metal-poor ([Fe/H = -2.9) halo star CS 31082-001, based on the recently reported first observation of a Uranium abundance in this (or any other) star. Age estimates are derived by application of the classical r-process model with updated nuclear physics inputs. The [U/Th] ratio yields an age of 13+-4 Gyr or 8+-4 Gyr, based on the use of the ETFSI-Q or the new HFBCS-1 nuclear mass models, respectively. Implications for Thorium chronometers are discussed.Comment: 5 pages incl. 1 figure, a shorter 3 page version will be published in the proceedings of the "Astrophysical Ages and Timescales" conference held in Hilo, Hawaii, Feb 5-9, 200

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models

: Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of in vitro and in vivo evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis in vitro, as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients' autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting

Current Clinical Trials in Pemphigus and Pemphigoid

Autoimmune bullous dermatoses (AIBDs) are a group of rare chronic inflammatory skin diseases, which clinically manifest as blisters and erosions of the skin and/or mucosa. Immunologically, AIBDs are characterized and caused by autoantibodies targeting adhesion molecules in the skin and mucosa. According to the histological location of the blistering, AIBDs are classified into the following two main subtypes: pemphigus (intraepidermal blistering) and pemphigoid (subepidermal blistering). Most AIBDs were potentially life-threatening diseases before the advent of immunosuppressive drugs, especially systemic steroid therapies, which suppress pathogenic immunological activity. Although there have been recent advancements in the understanding of the pathogenesis of AIBDs, glucocorticosteroids and/or adjuvant immunosuppressive drugs are still needed to control disease activity. However, the long-term use of systemic immunosuppression is associated with major adverse events, including death. Based on the growing understanding of AIBD pathogenesis, novel treatment targets have emerged, some of which are currently being evaluated in clinical trials. Within this article, we review the current clinical trials involving pemphigus and pemphigoid and discuss the rationale that lead to these trials. Overall, we aim to foster insights into translational research in AIBDs to improve patient care

Risk factors and sequelae of epidermolysis bullosa acquisita: A propensity-matched global study in 1,344 patients

Identification of risk factors and sequelae of any given disease is of key importance. For common diseases, primary prevention and disease management are based on this knowledge. For orphan diseases, identification of risk factors and sequelae has been challenging. With the advent of large databases, e.g., TriNetX, this can now be addressed. We used TriNetX to identify risk factors and sequelae of epidermolysis bullosa acquisita (EBA), a severe and orphan autoimmune disease. To date, there is only enigmatic information on EBA comorbidity. We recruited 1,344 EBA patients in the Global Collaborative Network of TriNetX. Using the “explore outcomes” function we identified 55 diagnoses with a different prevalence between EBA and no-EBA patients. We next performed propensity-matched, retrospective cohort studies in which we determined the risk of EBA development following any of the identified 55 diseases. Here, 31/55 diseases were identified as risk factors for subsequent EBA. Importantly, the highest risk for EBA were other chronic inflammatory diseases (CID), especially lupus erythematosus and lichen planus. Lastly, we determined the risk to develop any of the identified diseases after EBA diagnosis. Here, 38/55 diseases were identified as sequelae. Notably, EBA patients showed an increased risk for metabolic and cardiovascular disease, and thrombosis. Furthermore, the risk for CIDs, especially lupus erythematosus and lichen planus, was elevated. These insights into risk factors and sequelae of EBA are not only of clinical relevance, e.g., optimizing cardiovascular disease risk, but in addition, point to shared pathogenetic pathways between EBA and other inflammatory diseases

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases

Identification of Quantitative Trait Loci in Experimental Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. Several lines of evidence underscore the contribution of autoantibodies against type VII collagen (COL7) to the pathogenesis of EBA. Furthermore, EBA susceptibility is associated with the MHC haplotype in patients (HLA-DR2) and in immunization-induced EBA in mice (H2s). The latter study indicated an additional contribution of non-MHC genes to disease susceptibility. To identify non-MHC genes controlling EBA susceptibility, we intercrossed EBA-susceptible MRL/MpJ with EBA-resistant NZM2410/J and BXD2/TyJ as well as Cast mice. Mice of the fourth generation of this four-way autoimmune-prone advanced intercross line were immunized with a fragment of murine COL7 to induce EBA. Anti-COL7 autoantibodies were detected in 84% of mice, whereas deposition of complement at the dermal–epidermal junction (DEJ) was observed in 50% of the animals; 33% of immunized mice presented with overt clinical EBA. Onset of clinical disease was associated with several quantitative trait loci (QTLs) located on chromosomes 9, 12, 14, and 19, whereas maximum disease severity was linked to QTLs on chromosomes 1, 15, and 19. This more detailed insight into the pathogenesis of EBA may eventually lead to new treatment strategies for EBA and other autoantibody-mediated diseases