Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

40Ar/39Ar geochronology of Carboniferous-Permian volcanism in the Midland Valley, Scotland

Twenty-one new 40Ar/39Ar step-heating experiments on mineral separates from intrusive and extrusive Carboniferous and Permian igneous rocks in the Midland Valley of Scotland yielded seventeen concordant experiments with a relative age precision better than 1% (2). These ages resolve inconsistencies between existing K-Ar dates on the same samples and their stratigraphical constraints correlated to recently published timescales. The precise 40Ar/39Ar dates are stratigraphically constrained to stage level and can contribute to Carboniferous timescale tie points at the Tournaisian-Visean boundary, within the Visean and at the Carboniferous–Permian boundary. Situated in the extending Variscan foreland, two distinct phases of extension-related transitional to alkaline volcanism have been resolved in the Dinantian: the Garleton Hills Volcanic Formation in the eastern Midland Valley near the Tournaisian–Visean boundary, 342.1 1.3 and 342.4 1.1 Ma; and the Clyde Plateau Volcanic Formation in the western Midland Valley during the mid Visean, 335 2 to 329.2 1.4 Ma. Alkaline basic sills near Edinburgh, previously thought to be Namurian, appear to be coeval with the Clyde Plateau Volcanic Formation at 331.8 ± 1.3 to 329.3 1.5 Ma. The new ages allow correlation between these short-lived Dinantian magmatic pulses and extensional and magmatic phases in the Northumberland–Solway and Tweed basins to the south. After late Westphalian, end Variscan, compression and a regionally important tholeiitic intrusive phase at c. 301-295 Ma, alkaline magmatism related to post-Variscan extension occurred in the central and western Midland Valley during the latest Carboniferous or Permian from 298.3 ± 1.3 to 292.1 ± 1.1 Ma. This correlates well with post-Varsican extension and magmatism observed across the NW European foreland from 300-280 Ma

Nitrogen leaching and herbage production on intensively managed grass and grass-clover pastures on sandy soil in Finland

v2007o

Adaptive smoothed particle hydrodynamics for high strain hydrodynamics with material strength

10.1007/s00193-005-0002-1Shock Waves15121-2