Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p= 1.3x10(-08), and rs842647 p= 5.26x10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappa B) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain similar to 40% of the heritability of coeliac disease

PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism

Vascular malformations are considered monogenic disorders that result in dysregulated vessel growth. Cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex required to dampen MEKK3 activity. Environmental factors explain differences in CCM natural history between individuals, but why single CCMs often exhibit sudden, rapid growth culminating in stroke or seizure is unknown. Here we demonstrate that CCM growth requires increased PI3K-mTOR signalling and loss of CCM function. We identify PIK3CA gain of function (GOF) and CCM loss of function (LOF) somatic mutations in the same cells in a majority of human CCMs. Using mouse models, we show that CCM growth requires both PI3K GOF and CCM LOF in endothelial cells, and that both CCM LOF and increased expression of the transcription factor KLF4, a downstream MEKK3 effector, augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor Rapamycin effectively blocks CCM formation in mouse models. We establish a three-hit mechanism analogous to cancer in which aggressive vascular malformations arise through the loss of vascular "suppressor genes" that constrain vessel growth and gain of a vascular "oncogene" that stimulates excess vessel growth. These findings suggest that aggressive CCMs may be treated using clinically approved mTORC1 inhibitors

Photocatalytic behaviour of nanocarbon–TiO2 composites and immobilization into hollow fibres

Nanocarbon–TiO2 composites were prepared by the liquid phase deposition method using TiO2 and three different nanocarbon materials: carbon nanotubes, fullerenes and graphene oxide. The photocatalytic efficiency of these composites was studied for the degradation of diphenhydramine pharmaceutical and methyl orange azo-dye compounds. The results suggest different synergistic effects between the carbon phase and the TiO2 particles depending on the nature and content of the nanocarbon material employed. Among all the materials tested, the titania composite containing 4 wt.% of graphene oxide exhibited the highest photocatalytic activity under both near-UV/Vis and visible light irradiation, outperforming the synthesized bare TiO2 and the benchmark Evonik P25 TiO2 photocatalyst. The high efficiency of the composite containing graphene oxide was attributed to the optimal assembly between the TiO2 nanoparticles and graphene oxide sheets, making the material to act simultaneously as electron acceptor and donor, thus suppressing charge recombination. Aiming at technological applications, this photocatalyst was immobilized into hollow fibres, showing significant catalytic activity and stability in continuous operation.Financial support for this work was provided by projects PTDC/AAC-AMB/122312/2010 and PEst-C/EQB/LA0020/2011 financed by FEDER through COMPETE and by FCT - Fundação para a Ciência e a Tecnologia, and by the European Commission (Clean Water - Grant Agreement No. 227017). SMT and LMPM acknowledge financial support from SFRH/BPD/74239/2010 and SFRH/BPD/88964/2012, respectively