International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Solvent-Driven Conformational Exchange for Amide-Linked Bichromophoric BODIPY Derivatives

The fluorescence lifetime and quantum yield are seen to depend in an unexpected manner on the nature of the solvent for a pair of tripartite molecules composed of two identical boron dipyrromethene (BODIPY) residues attached to a 1,10-phenanthroline core. A key feature of these molecular architectures concerns the presence of an amide linkage that connects the BODIPY dye to the heterocyclic platform. The secondary amide derivative is more sensitive to environmental change than is the corresponding tertiary amide. In general, increasing solvent polarity, as measured by the static dielectric constant, above a critical threshold tends to reduce fluorescence but certain hydrogen bond accepting solvents exhibit anomolous behaviour. Fluorescence quenching is believed to arise from light-induced charge transfer between the two BODIPY dyes, but thermodynamic arguments alone do not explain the experimental findings. Molecular modelling is used to argue that the conformation changes in strongly polar media in such a way as to facilitate improved rates of light-induced charge transfer. These solvent-induced changes, however, differ remarkably for the two types of amide

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Masking and Demasking Strategies for the BF₂–BODIPYs as a Tool for BODIPY Fluorophores

An efficient and chemoselective route for transforming BF₂–BODIPYs to Et₂B-BODIPYs (masking) was developed using Et₂AlCl. The Et groups can be easily replaced with F atoms using BF₃·Et₂O in moist CH₂Cl₂ to regenerate the BF₂–BODIPYs (demasking). The masking–demasking strategy is very useful for synthesizing functionalized BODIPYs via nucleophilic and reductive reactions. The masking strategy was used to synthesize a BODIPY dimer by McMurry coupling of a formyl Et₂B–BODIPY, while a new BODIPY with an asymmetrically substituted B-center was synthesized using the demasking strategy

Euler solution using cartesian grid with a gridless least-squares boundary treatment

AIAA Journal432246-255AIAJ

Application of whole exome sequencing in elucidating the phenotype and genotype spectrum of junctional epidermolysis bullosa: A preliminary experience of a tertiary care centre in India

•Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogenous group of genetic skin disorders.•We show the utility of WES in understanding the phenotype and genotype spectrum in four Indian JEB families.•Computational modeling studies have been used to understand the probable molecular consequence of a missense mutation on the structure-function relationship of lamininβ3 protein.•This is the first report documenting the phenotype-genotype correlations of JEB patients from India. Junctional epidermolysis bullosa (JEB) is a diverse group of genodermatoses associated with extreme skin fragility. Despite several well-characterized genetic studies, molecular diagnosis of this heterogeneous group is still challenging. Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing (WES) as a fast and efficient diagnostic strategy in several genodermatoses. In view of the scarcity and need of molecular studies for JEB in India, we sought to explore the potential of WES in understanding the mutational spectrum of this rare, in certain subtypes lethal, sub-group of EB. WES was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations. Overall, four unrelated families (6 patients) of JEB with a highly variable clinical presentation including a rare case of LOC syndrome were studied. WES revealed 4 variations in 3 genes (LAMA3, LAMB3 and COL17A1) that are implicated in JEB. None of the variations were recurrent. In addition we proposed the probable molecular consequence of a missense mutation on the structure-function relationship of lamininβ3 protein through computational modeling studies. Being the first report documenting the phenotype-genotype correlations of JEB patients from India, our preliminary experience with WES is clearly encouraging and serves as a nidus for future large-scale molecular studies to actively identify and understand JEB patients in Indian population