Dihydropyridine Fluorophores Allow for Specific Detection of Human Antibodies in Serum

Antigen recognition by antibodies plays an important role in human biology and in the development of diseases. This interaction provides a basis for multiple diagnostic assays and is a guide for treatments. We have developed dihydropyridine-based fluorophores that form stable complexes with double-stranded DNA and upon recognition of the antibodies to DNA (anti-DNA) provide an optical response. The fluorophores described herein have advantageous optical properties compared to those of the currently available dyes making them valuable for research and clinical diagnostics. By studying a series of novel fluorophores, crucial parameters for the design were established, providing the required sensitivity and specificity in the detection of antibodies. Using these DNA–fluorophore complexes in a direct immunofluorescence assay, antibodies to DNA are specifically detected in 80 patients diagnosed with an autoimmune disease, systemic lupus erythematosus. Positivity indicated by emission change of α-(4′-<i>O</i>-methoxyphenyl)-2-furyl dihydropyridine strongly correlates with other disease biomarkers and autoimmune arthritis

Peptide-oligonucleotide conjugates as nanoscale building blocks for assembly of an artificial three-helix protein mimic

Peptide-based structures can be designed to yield artificial proteins with specific folding patterns and functions. Template-based assembly of peptide units is one design option, but the use of two orthogonal self-assembly principles, oligonucleotide triple helix and a coiled coil protein domain formation have never been realized for de novo protein design. Here, we show the applicability of peptide–oligonucleotide conjugates for self-assembly of higher-ordered protein-like structures. The resulting nano-assemblies were characterized by ultraviolet-melting, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X-ray scattering and transmission electron microscopy. These studies revealed the formation of the desired triple helix and coiled coil domains at low concentrations, while a dimer of trimers was dominating at high concentration. CD spectroscopy showed an extraordinarily high degree of α-helicity for the peptide moieties in the assemblies. The results validate the use of orthogonal self-assembly principles as a paradigm for de novo protein design

Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

peer-reviewedH.D.D., A.J.C., P.J.B. and B.J.H. would like to acknowledge the Dairy Futures Cooperative Research Centre for funding. H.P. and R.F. acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the AgroClustEr ‘Synbreed—Synergistic Plant and Animal Breeding’ (grant 0315527B). H.P., R.F., R.E. and K.-U.G. acknowledge the Arbeitsgemeinschaft Süddeutscher Rinderzüchter, the Arbeitsgemeinschaft Österreichischer Fleckviehzüchter and ZuchtData EDV Dienstleistungen for providing genotype data. A. Bagnato acknowledges the European Union (EU) Collaborative Project LowInputBreeds (grant agreement 222623) for providing Brown Swiss genotypes. Braunvieh Schweiz is acknowledged for providing Brown Swiss phenotypes. H.P. and R.F. acknowledge the German Holstein Association (DHV) and the Confederación de Asociaciones de Frisona Española (CONCAFE) for sharing genotype data. H.P. was financially supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) (grant PA 2789/1-1). D.B. and D.C.P. acknowledge funding from the Research Stimulus Fund (11/S/112) and Science Foundation Ireland (14/IA/2576). M.S. and F.S.S. acknowledge the Canadian Dairy Network (CDN) for providing the Holstein genotypes. P.S. acknowledges funding from the Genome Canada project entitled ‘Whole Genome Selection through Genome Wide Imputation in Beef Cattle’ and acknowledges WestGrid and Compute/Calcul Canada for providing computing resources. J.F.T. was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under awards 2013-68004-20364 and 2015-67015-23183. A. Bagnato, F.P., M.D. and J.W. acknowledge EU Collaborative Project Quantomics (grant 516 agreement 222664) for providing Brown Swiss and Finnish Ayrshire sequences and genotypes. A.C.B. and R.F.V. acknowledge funding from the public–private partnership ‘Breed4Food’ (code BO-22.04-011- 001-ASG-LR) and EU FP7 IRSES SEQSEL (grant 317697). A.C.B. and R.F.V. acknowledge CRV (Arnhem, the Netherlands) for providing data on Dutch and New Zealand Holstein and Jersey bulls.Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Association of copeptin, a surrogate marker for arginine vasopressin secretion, with insulin resistance:Influence of adolescence and psychological stress

In middle-aged and elderly individuals, circulating copeptin concentrations, a surrogate marker for arginine vasopressin (AVP) secretion, associates with insulin resistance (IR). Whether this association is present in adolescents and young adults is unclear. Because psychological stress associates with higher circulating copeptin concentrations and IR, it has been speculated that increased AVP secretion could be a link between psychological stress and IR. We measured plasma copeptin concentrations in 351 14–16-year-old adolescents and 617 20–28-year-old young adults from the Danish site of the European Youth Heart Study, a population-based cardiovascular risk factor study in adolescents and young adults. IR was determined by the homeostatic model assessment method. Among the young adults, we used symptoms of depression, evaluated by means of the Major Depression Inventory (MDI) scale, as a measure of psychological stress. We applied linear regressions to examine associations, expressed as unstandardized regression coefficients (B) with 95% confidence intervals (CIs), between variables of interest, stratified by age group and adjusting for age, sex and Tanner stages. Copeptin and IR were log-transformed. Among the young adults, copeptin associated with IR (B (95%CI) = 0.19 (0.11 to 0.27), P < 0.001). This association was not found among the adolescents (B=-0.01 (-0.12 to 0.09), P = 0.78). MDI score associated with IR (B = 0.010 (0.004 to 0.016), P < 0.001) and copeptin (B=0.010 (0.004 to 0.015); P<0.002) in the young adults. Adjusted for copeptin, the strength of the association between MDI score and IR somewhat diminished (to B=0.008). In conclusion, adolescence and psychological stress appear to influence the association between copeptin and IR