Deposition of complement factors (opsonisation) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonisation of superparamagnetic iron oxide nanoworms (SPIO NWs) with the third complement protein (C3) was dependent on the biomolecule corona. Here we show that natural antibodies play a critical role in C3 opsonisation of SPIO NWs and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonisation on immunoglobulin binding is predominantly universal and is observed regardless of the complement activation pathway. Few surface-bound immunoglobulin molecules trigger complement activation and opsonisation. While the total amount of nanoparticle-absorbed protein does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonisation, and may determine individual complement responses to nanomedicines.

Background: We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human

A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding QTLs for gene expression and the trait of interest, has been applied in the current study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules, and identify biological functions that contribute to the predisposition to consume varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes), and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, and glial-neuronal communication. Our results illustrate that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. While no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes.

These findings may be useful for policy decisions about appropriate screening intervals and for use in statistical models that estimate the costs and benefits of mammography by age and screening interval.