9 research outputs found
Timing of deposition, orogenesis and glaciation within the Dalradian rocks of Scotland: constraints from U-Pb zircon ages
The stratigraphical and structural continuity of the Late Proterozoic Dalradian rocks of the Scottish Highlands is re-examined in the light of new U-Pb zircon ages on the tuffs belonging to the Tayvallich Volcanic Formation (601 ñ 4 Ma), and on the late Grampian 'Newer Gabbros' (470 ñ 9 Ma) of Insch and Morven-Cabrach in Aberdeenshire. These age data, together with the existing 590 ñ 2 Ma age for the Ben Vuirich Granite, provide key radiometric constraints on the evolution of the Dalradian block, and the implications arising from these ages are critically assessed. Three main conclusions are drawn. (1) The entire Caledonian orogeny, although short-lived, is unlikely to have affected sediments of Arenig age and a break probably occurs between those Dalradian sediments of late Proterozoic (<600 Ma) age and the Ordovician rocks of the Highland Border Complex. (2) A period of crustal thickening probably affected some Dalradian rocks prior to 590 Ma. Such an event is indicated by both the polymetamorphic histories of the lower parts of the Dalradian pile and the contact metamorphic assemblages within the aureole of the Ben Vuirich Granite, which are incompatible with sedimentary thicknesses. (3) Age constraints on global Late Proterozoic glacial activity also suggest that the Dalradian stratigraphy is broken into discrete smaller units. Models involving continuous deposition of Dalradian sediments from pre-750 Ma to 470 Ma are rejected
Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM
Epithermal precious and base metal mineralisation and related magmatism of the Northern Altiplano, Bolivian
Incl. many plates and colour map at backAvailable from British Library Document Supply Centre- DSC:DX75801/87 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo
Géodynamique andine : résumés étendus = Andean geodynamics : extended abstracts = Geodinamica andina : resumenes expandidos
Mineral exploration in the Pitlochry to Glen Clova area, Tayside region, Scotland
Reconnaissance drainage sampling of the area between Pitlochry and Glen Clova in the Highlands
of Scotland was undertaken in 1987 and 1988. 309 stream sediment and 347 panned concentrate
samples were collected and analysed for a variety of major and trace elements.
Four areas were identified with potential for economic gold mineralisation, Glen Clova, Glen Uig,
east of Dunkeld and Bridge of Cally. Detailed sampling and follow-up investigations in Glen Clova
identified a gold-bearing fault zone in the Burn of Fleurs. Levels up to 7 ppm Au were detected in
clay fault gouge and the fault can be traced by geophysical methods for 1.6 km. Features with a
similar trend, such as the orientation of stream courses, can be identified extending for a further 10
km to the southeast. Recommendations for further work to investigate this and other prospective
areas are presented.
The potential of the area for base metal deposits is probably low and the few suphide-bearing veins
are of little economic significance when compared to the stratabound deposits in the Middle
Dalradian. The economic potential of the Highland Boundary fault zone was, however, unexplored
Evaluation of MYBPC3 trans-splicing and gene replacement as therapeutic options in human iPSC-derived cardiomyocytes
Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ∼50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features. We evaluated RNA trans-splicing and gene replacement after transducing hiPSC-CMs with adeno-associated virus. trans-splicing with 5′ or 3′ pre-trans-splicing molecules represented ∼1% of total MYBPC3 transcripts in healthy hiPSC-CMs. In contrast, gene replacement with the full-length MYBPC3 cDNA resulted in ∼2.5-fold higher MYBPC3 mRNA levels in HCM and control hiPSC-CMs. This restored the cMyBP-C level to 81% of the control level, suppressed hypertrophy, and partially restored gene expression to control level in HCM cells. This study provides evidence for (1) the feasibility of trans-splicing, although with low efficiency, and (2) efficient gene replacement in hiPSC-CMs with a MYBPC3 mutation