Congenital heart anomalies in the first trimester: From screening to diagnosis.

Congenital heart defects occur in approximately 1% of liveborn children and represent the most common form of congenital malformation. Due to the small size and complexity of the heart structures, prenatal diagnosis is most often made in the second trimester of pregnancy. Early diagnosis however offers significant advantages regarding the timing of further investigations, prenatal counseling, and access to management options. In the last decade, advances in antenatal imaging have improved the detection of cardiac malformations with increasing emphasis on earlier pregnancy screening and diagnosis. We aim to summarize current "state of the art" imaging of the fetal heart in the first trimester

Stoichiometry of a regulatory splicing complex revealed by single-molecule analyses

Splicing is regulated by complex interactions of numerous RNA-binding proteins. The molecular mechanisms involved remain elusive, in large part because of ignorance regarding the numbers of proteins in regulatory complexes. Polypyrimidine tract-binding protein (PTB), which regulates tissue-specific splicing, represses exon 3 of α-tropomyosin through distant pyrimidine-rich tracts in the flanking introns. Current models for repression involve either PTB-mediated looping or the propagation of complexes between tracts. To test these models, we used single-molecule approaches to count the number of bound PTB molecules both by counting the number of bleaching steps of GFP molecules linked to PTB within complexes and by analysing their total emissions. Both approaches showed that five or six PTB molecules assemble. Given the domain structures, this suggests that the molecules occupy primarily multiple overlapping potential sites in the polypyrimidine tracts, excluding propagation models. As an alternative to direct looping, we propose that repression involves a multistep process in which PTB binding forms small local loops, creating a platform for recruitment of other proteins that bring these loops into close proximity

The splicing landscape is globally reprogrammed during male meiosis

Meiosis requires conserved transcriptional changes, but it is not known whether there is a corresponding set of RNA splicing switches. Here, we used RNAseq of mouse testis to identify changes associated with the progression from mitotic spermatogonia to meiotic spermatocytes. We identified ∼150 splicing switches, most of which affect conserved protein-coding exons. The expression of many key splicing regulators changed in the course of meiosis, including downregulation of polypyrimidine tract binding protein (PTBP1) and heterogeneous nuclear RNP A1, and upregulation of nPTB, Tra2β, muscleblind, CELF proteins, Sam68 and T-STAR. The sequences near the regulated exons were significantly enriched in target sites for PTB, Tra2β and STAR proteins. Reporter minigene experiments investigating representative exons in transfected cells showed that PTB binding sites were critical for splicing of a cassette exon in the Ralgps2 mRNA and a shift in alternative 5′ splice site usage in the Bptf mRNA. We speculate that nPTB might functionally replace PTBP1 during meiosis for some target exons, with changes in the expression of other splicing factors helping to establish meiotic splicing patterns. Our data suggest that there are substantial changes in the determinants and patterns of alternative splicing in the mitotic-to-meiotic transition of the germ cell cycle

Evidence of Hot Carrier Extraction in Metal Halide Perovskite Solar Cells

The presence of hot carriers is presented in the operational properties of an (FA,Cs)Pb(I, Br, Cl)3 solar cell at ambient temperatures and under practical solar concentration. At 100 K, clear evidence of hot carriers is observed in both the high energy tail of the photoluminescence spectra and from the appearance of a non-equilibrium photocurrent at higher fluence in light J-V measurements. At room temperature, however, the presence of hot carriers in the emission at elevated laser fluence are shown to compete with a gradual red shift in the PL peak energy as photo induced halide segregation begins to occur at higher lattice temperature. The effects of thermionic emission of hot carriers and the presence of a non-equilibrium carrier distribution are also shown to be distinct from simple lattice heating. This results in large unsaturated photocurrents at high powers as the Fermi distribution exceeds that of the heterointerface controlling carrier transport and rectification

Atomistic origins of high-performance in hybrid halide perovskite solar cells

The performance of organometallic perovskite solar cells has rapidly surpassed that of both conventional dye-sensitised and organic photovoltaics. High power conversion efficiency can be realised in both mesoporous and thin-film device architectures. We address the origin of this success in the context of the materials chemistry and physics of the bulk perovskite as described by electronic structure calculations. In addition to the basic optoelectronic properties essential for an efficient photovoltaic device (spectrally suitable band gap, high optical absorption, low carrier effective masses), the materials are structurally and compositionally flexible. As we show, hybrid perovskites exhibit spontaneous electric polarisation; we also suggest ways in which this can be tuned through judicious choice of the organic cation. The presence of ferroelectric domains will result in internal junctions that may aid separation of photoexcited electron and hole pairs, and reduction of recombination through segregation of charge carriers. The combination of high dielectric constant and low effective mass promotes both Wannier-Mott exciton separation and effective ionisation of donor and acceptor defects. The photoferroic effect could be exploited in nanostructured films to generate a higher open circuit voltage and may contribute to the current-voltage hysteresis observed in perovskite solar cells.Comment: 6 pages, 5 figure

Histone Deacetylase Activity Modulates Alternative Splicing

There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ∼700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications