Organic nanofibers embedding stimuli-responsive threaded molecular components

While most of the studies on molecular machines have been performed in solution, interfacing these supramolecular systems with solid-state nanostructures and materials is very important in view of their utilization in sensing components working by chemical and photonic actuation. Host polymeric materials, and particularly polymer nanofibers, enable the manipulation of the functional molecules constituting molecular machines, and provide a way to induce and control the supramolecular organization. Here, we present electrospun nanocomposites embedding a self-assembling rotaxane-type system that is responsive to both optical (UV-visible light) and chemical (acid/base) stimuli. The system includes a molecular axle comprised of a dibenzylammonium recognition site and two azobenzene end groups, and a dibenzo[24]crown-8 molecular ring. The dethreading and rethreading of the molecular components in nanofibers induced by exposure to base and acid vapors, as well as the photoisomerization of the azobenzene end groups, occur in a similar manner to what observed in solution. Importantly, however, the nanoscale mechanical function following external chemical stimuli induces a measurable variation of the macroscopic mechanical properties of nanofibers aligned in arrays, whose Young's modulus is significantly enhanced upon dethreading of the axles from the rings. These composite nanosystems show therefore great potential for application in chemical sensors, photonic actuators and environmentally responsive materials.Comment: 39 pages, 16 figure

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer

Mutational heterogeneity in cancer and the search for new cancer genes

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention