Interplay between Exonic Splicing Enhancers, mRNA Processing, and mRNA Surveillance in the Dystrophic Mdx Mouse

BACKGROUND: Pre-mRNA splicing, the removal of introns from RNA, takes place within the spliceosome, a macromolecular complex composed of five small nuclear RNAs and a large number of associated proteins. Spliceosome assembly is modulated by the 5′ and 3′ splice site consensus sequences situated at the ends of each intron, as well as by exonic and intronic splicing enhancers/silencers recognized by SR and hnRNP proteins. Nonsense mutations introducing a premature termination codon (PTC) often result in the activation of cellular quality control systems that reduce mRNA levels or alter the mRNA splicing pattern. The mdx mouse, a commonly used genetic model for Duchenne muscular dystrophy (DMD), lacks dystrophin by virtue of a premature termination codon (PTC) in exon 23 that also severely reduces the level of dystrophin mRNA. However, the effect of the mutation on dystrophin RNA processing has not yet been described. METHODOLOGY/PRINCIPAL FINDING: Using combinations of different biochemical and cellular assays, we found that the mdx mutation partially disrupts a multisite exonic splicing enhancer (ESE) that is recognized by a 40 kDa SR protein. In spite of the presence of an inefficient intron 22 3′ splice site containing the rare GAG triplet, the mdx mutation does not activate nonsense-associated altered splicing (NAS), but induces exclusively nonsense-mediated mRNA decay (NMD). Functional binding sites for SR proteins were also identified in exon 22 and 24, and in vitro experiments show that SR proteins can mediate direct association between exon 22, 23, and 24. CONCLUSIONS/SIGNIFICANCE: Our findings highlight the complex crosstalk between trans-acting factors, cis-elements and the RNA surveillance machinery occurring during dystrophin mRNA processing. Moreover, they suggest that dystrophin exon–exon interactions could play an important role in preventing mdx exon 23 skipping, as well as in facilitating the pairing of committed splice sites

Precise determination of the mass of the Higgs boson and tests of compatibility of its couplings with the standard model predictions using proton collisions at 7 and 8 TeV

Peer reviewe

Gold nanomaterials in the management of lung cancer

Lung cancer (LC) is one of the most deadly cancers worldwide, with very low survival rates, mainly due to poor management, which has barely changed in recent years. Nanomedicines, especially gold nanomaterials, with their unique and size-dependent properties offer a potential solution to many challenges in the field. The versatility afforded by the shape, size, charge and surface chemistry of gold nanostructures allows them to be adapted for many applications in the diagnosis, treatment and imaging of LC. In this review, a survey of the most recent advances in the field is presented with an emphasis on the optical properties of gold nanoscale materials and their use in cancer management. Gold nanoparticle toxicology has also been a focus of interest for many years but the studies have also sometimes arrived at contradictory conclusions. To enable extrapolation and facilitate the development of medicines based on gold nanomaterials, it must be assumed that each design will have its own unique characteristics that require evaluation before translation to the clinic. Advances in the understanding and recognition of the molecular signatures of LC have aided the development of personalised medicines. Tailoring the treatment to each case should, ideally increase the survival outcomes as well as reduce medical costs. This review seeks to present the potential of gold nanomaterials in LC management and to provide a unified view, which will be of interest to those in the field as well as researchers considering entering this highly important area of research