Recently, flood risk assessments have been extended to national and continental scales. Most of these assessments assume homogeneous scenarios, i.e. the regional risk estimate is obtained by summing ...up the local estimates, whereas each local damage value has the same probability of exceedance. This homogeneity assumption ignores the spatial variability in the flood generation processes. Here, we develop a multi-site, extreme value statistical model for 379 catchments across Europe, generate synthetic flood time series which consider the spatial correlation between flood peaks in all catchments, and compute corresponding economic damages. We find that the homogeneity assumption overestimates the 200-year flood damage, a benchmark indicator for the insurance industry, by 139%, 188% and 246% for the United Kingdom (UK), Germany and Europe, respectively. Our study demonstrates the importance of considering the spatial dependence patterns, particularly of extremes, in large-scale risk assessments.
Hyper-immunoglobulin E syndrome (HIES) is a compound primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with ...disproportionately milder inflammatory responses, referred to as cold abscesses, and skeletal abnormalities. Although some cases of familial HIES with autosomal dominant or recessive inheritance have been reported, most cases of HIES are sporadic, and their pathogenesis has remained mysterious for a long time. Here we show that dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES. We found that eight out of fifteen unrelated non-familial HIES patients had heterozygous STAT3 mutations, but their parents and siblings did not have the mutant STAT3 alleles, suggesting that these were de novo mutations. Five different mutations were found, all of which were located in the STAT3 DNA-binding domain. The patients' peripheral blood cells showed defective responses to cytokines, including interleukin (IL)-6 and IL-10, and the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3. These results highlight the multiple roles played by STAT3 in humans, and underline the critical involvement of multiple cytokine pathways in the pathogenesis of HIES.
Background & Aims Homozygous loss of function mutations in interleukin-10 ( IL10 ) and interleukin-10 receptors ( IL10R ) cause severe infantile (very early onset) inflammatory bowel disease (IBD). ...Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. Methods We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. Results Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R−mediated signaling in all patients who received the transplant. Conclusions We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.
Meteotsunamis are long waves generated by displacement of a water body due to atmospheric pressure disturbances that have similar spatial and temporal characteristics to landslide tsunamis. NAMI ...DANCE that solves the nonlinear shallow water equations is a widely used numerical model to simulate tsunami waves generated by seismic origin. Several validation studies showed that it is highly capable of representing the generation, propagation and nearshore amplification processes of tsunami waves, including inundation at complex topography and basin resonance. The new module of NAMI DANCE that uses the atmospheric pressure and wind forcing as the other inputs to simulate meteotsunami events is developed. In this paper, the analytical solution for the generation of ocean waves due to the propagating atmospheric pressure disturbance is obtained. The new version of the code called NAMI DANCE SUITE is validated by comparing its results with those from analytical solutions on the flat bathymetry. It is also shown that the governing equations for long wave generation by atmospheric pressure disturbances in narrow bays and channels can be written similar to the 1D case studied for tsunami generation and how it is integrated into the numerical model. The analytical solution of the linear shallow water model is defined, and results are compared with numerical solutions. A rectangular shaped flat bathymetry is used as the test domain to model the generation and propagation of ocean waves and the development of Proudman resonance due to moving atmospheric pressure disturbances. The simulation results with different ratios of pressure speed to ocean wave speed (Froude numbers) considering sub-critical, critical and super-critical conditions are presented. Fairly well agreements between analytical solutions and numerical solutions are obtained. Additionally, basins with triangular (lateral) and stepwise shelf (longitudinal) cross sections on different slopes are tested. The amplitudes of generated waves at different time steps in each simulation are presented with discussions considering the channel characteristics. These simulations present the capability of NAMI DANCE SUITE to model the effects of bathymetric conditions such as shelf slope and local bathymetry on wave amplification due to moving atmospheric pressure disturbances.
In this paper, we show that the application of different entropy methods for world indices. To do this, we use the world indices such as Istanbul Stock Indices (BIST 30), Brazil Index (Bovespa), ...Germany Index (DAX), Britain Index (FTSE100), South Korea (KOSP?), Japan Index (N?kkei 225), United States Index (SP 500), and China Index (SHANGAI) that have been investigated over all of 8 years (2010-2018). We obtain Shannon, Tsallis, R?nyi and at last the approximate entropy. Consequently, we provide computational results for these entropies for weekly and monthly data.
nema
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed ...with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
Biallelic inactivating mutations in
IL21R
causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported ...previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in
IL21R
were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5–7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (
n
= 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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