Dynamics of Co-Transcriptional Pre-mRNA Folding Influences the Induction of Dystrophin Exon Skipping by Antisense Oligonucleotides

Antisense oligonucleotides (AONs) mediated exon skipping offers potential therapy for Duchenne muscular dystrophy. However, the identification of effective AON target sites remains unsatisfactory for lack of a precise method to predict their binding accessibility. This study demonstrates the importance of co-transcriptional pre-mRNA folding in determining the accessibility of AON target sites for AON induction of selective exon skipping in DMD. Because transcription and splicing occur in tandem, AONs must bind to their target sites before splicing factors. Furthermore, co-transcriptional pre-mRNA folding forms transient secondary structures, which redistributes accessible binding sites. In our analysis, to approximate transcription elongation, a “window of analysis” that included the entire targeted exon was shifted one nucleotide at a time along the pre-mRNA. Possible co-transcriptional secondary structures were predicted using the sequence in each step of transcriptional analysis. A nucleotide was considered “engaged” if it formed a complementary base pairing in all predicted secondary structures of a particular step. Correlation of frequency and localisation of engaged nucleotides in AON target sites accounted for the performance (efficacy and efficiency) of 94% of 176 previously reported AONs. Four novel insights are inferred: (1) the lowest frequencies of engaged nucleotides are associated with the most efficient AONs; (2) engaged nucleotides at 3′ or 5′ ends of the target site attenuate AON performance more than at other sites; (3) the performance of longer AONs is less attenuated by engaged nucleotides at 3′ or 5′ ends of the target site compared to shorter AONs; (4) engaged nucleotides at 3′ end of a short target site attenuates AON efficiency more than at 5′ end

Pre- and syn-eruptive degassing and crystallisation processes of the 2010 and 2006 eruptions of Merapi volcano, Indonesia

The 2010 eruption of Merapi (VEI 4) was the volcano’s largest since 1872. In contrast to the prolonged and effusive dome-forming eruptions typical of Merapi’s recent activity, the 2010 eruption began explosively, before a new dome was rapidly emplaced. This new dome was subsequently destroyed by explosions, generating pyroclastic density currents (PDCs), predominantly consisting of dark coloured, dense blocks of basaltic andesite dome lava. A shift towards open-vent conditions in the later stages of the eruption culminated in multiple explosions and the generation of PDCs with conspicuous grey scoria and white pumice clasts resulting from sub-plinian convective column collapse. This paper presents geochemical data for melt inclusions and their clinopyroxene hosts extracted from dense dome lava, grey scoria and white pumice generated during the peak of the 2010 eruption. These are compared with clinopyroxene-hosted melt inclusions from scoriaceous dome fragments from the prolonged dome-forming 2006 eruption, to elucidate any relationship between pre-eruptive degassing and crystallisation processes and eruptive style. Secondary ion mass spectrometry analysis of volatiles (H2O, CO2) and light lithophile elements (Li, B, Be) is augmented by electron microprobe analysis of major elements and volatiles (Cl, S, F) in melt inclusions and groundmass glass. Geobarometric analysis shows that the clinopyroxene phenocrysts crystallised at depths of up to 20 km, with the greatest calculated depths associated with phenocrysts from the white pumice. Based on their volatile contents, melt inclusions have re-equilibrated during shallower storage and/or ascent, at depths of ~0.6–9.7 km, where the Merapi magma system is interpreted to be highly interconnected and not formed of discrete magma reservoirs. Melt inclusions enriched in Li show uniform “buffered” Cl concentrations, indicating the presence of an exsolved brine phase. Boron-enriched inclusions also support the presence of a brine phase, which helped to stabilise B in the melt. Calculations based on S concentrations in melt inclusions and groundmass glass require a degassing melt volume of 0.36 km3 in order to produce the mass of SO2 emitted during the 2010 eruption. This volume is approximately an order of magnitude higher than the erupted magma (DRE) volume. The transition between the contrasting eruptive styles in 2010 and 2006 is linked to changes in magmatic flux and changes in degassing style, with the explosive activity in 2010 driven by an influx of deep magma, which overwhelmed the shallower magma system and ascended rapidly, accompanied by closed-system degassing

Relocation of hypocenters from DOMERAPI and BMKG networks: a preliminary result from DOMERAPI project

International audienc

Textural history of recent basaltic-andesites and plutonic inclusions from Merapi volcano

Mt. Merapi in Central Java is one of the most active stratovolcanoes on Earth and is underlain by a multistage plumbing system. Crystal size distribution analyses (CSD) were carried out on recent Merapi basaltic-andesites and co-eruptive magmatic and plutonic inclusions to characterise the crystallisation processes that operate during storage and ascent and to obtain information on respective time scales. The basaltic-andesites exhibit log-linear, kinked-upwards CSD curves for plagioclase and clinopyroxene that can be separated into two main textural populations. Large plagioclase phenocrysts (≥1.6 mm) make up one population, but correspond to crystals with variable geochemical composition and reflect a period of crystal growth at deep to mid-crustal levels. This population was subsequently influenced by crystal accumulation and the onset of crustal assimilation, including the incorporation of high-Ca skarn-derived xenocrysts. Textural re-equilibration is required for these crystals to form a single population in CSD. A second episode of crystal growth at shallower levels is represented by chemically homogenous plagioclase crystals <1.6 mm in size. Crustal assimilation is indicated by, for example, oxygen isotopes and based on the CSD data, crystallisation combined with contamination is likely semi-continuous in these upper crustal storage chambers. The CSD data observed in the basaltic-andesite samples are remarkably consistent and require a large-volume steady state magmatic system beneath Merapi in which late textural equilibration plays a significant role. Plagioclase CSDs of co-eruptive magmatic and plutonic inclusions may contain a third crystal population (<1 mm) not found in the lavas. This third population has probably formed from enhanced degassing of portions of basaltic-andesite magma at shallow crustal levels which resulted in increased crystallinity and basaltic-andesite mush inclusions. A suite of coarse plutonic inclusions is also present that reflects crystallisation and accumulation of crystals in the deep Merapi plumbing system, as deduced from CSD patterns and mineral assemblages