Influence of lateral and top boundary conditions on regional air quality prediction: A multiscale study coupling regional and global chemical transport models

The sensitivity of regional air quality model to various lateral and top boundary conditions is studied at 2 scales: a 60 km domain covering the whole USA and a 12 km domain over northeastern USA. Three global models (MOZART-NCAR, MOZART-GFDL and RAQMS) are used to drive the STEM-2K3 regional model with time-varied lateral and top boundary conditions (BCs). The regional simulations with different global BCs are examined using ICARTT aircraft measurements performed in the summer of 2004, and the simulations are shown to be sensitive to the boundary conditions from the global models, especially for relatively long-lived species, like CO and O3. Differences in the mean CO concentrations from three different global-model boundary conditions are as large as 40 ppbv, and the effects of the BCs on CO are shown to be important throughout the troposphere, even near surface. Top boundary conditions show strong effect on O3 predictions above 4 km. Over certain model grids, the model’s sensitivity to BCs is found to depend not only on the distance from the domain’s top and lateral boundaries, downwind/upwind situation, but also on regional emissions and species properties. The near-surface prediction over polluted area is usually not as sensitive to the variation of BCs, but to the magnitude of their background concentrations. We also test the sensitivity of model to temporal and spatial variations of the BCs by comparing the simulations with time-varied BCs to the corresponding simulations with time-mean and profile BCs. Removing the time variation of BCs leads to a significant bias on the variation prediction and sometime causes the bias in predicted mean values. The effect of model resolution on the BC sensitivity is also studied

Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.

International audienceAutism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD

p62 filaments capture and present ubiquitinated cargos for autophagy

The removal of misfolded, ubiquitinated proteins is an essential part of the protein quality control. The ubiquitin‐proteasome system (UPS) and autophagy are two interconnected pathways that mediate the degradation of such proteins. During autophagy, ubiquitinated proteins are clustered in a p62‐dependent manner and are subsequently engulfed by autophagosomes. However, the nature of the protein substrates targeted for autophagy is unclear. Here, we developed a reconstituted system using purified components and show that p62 and ubiquitinated proteins spontaneously coalesce into larger clusters. Efficient cluster formation requires substrates modified with at least two ubiquitin chains longer than three moieties and is based on p62 filaments cross‐linked by the substrates. The reaction is inhibited by free ubiquitin, K48‐, and K63‐linked ubiquitin chains, as well as by the autophagosomal marker LC3B, suggesting a tight cross talk with general proteostasis and autophagosome formation. Our study provides mechanistic insights on how substrates are channeled into autophagy.© 2018 The Author