Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment

Palaeoecology and palaeoenvironment of Mississippian coastal lakes and marshes during the early terrestrialisation of tetrapods

The Ballagan Formation of northern Britain provides an exceptional record of Early Mississippian ecosystems that developed as tetrapods emerged onto land. In this paper, we study two 500-metre sections of the formation near Berwick-upon-Tweed, which are characterised by abundant ferroan dolostone beds. Five lithofacies are identified: cemented siltstone and sandstone, homogeneous dolomicrite, mixed dolomite and siltstone, mixed calcite and dolomite, and dolomite with evaporite minerals. Cemented sediments have non-planar to planar subhedral dolomite crystals, up to 40 μm in size, whereas other facies predominantly comprise dolomicrite or planar euhedral dolomite rhombs 15 μm in size, with patches of larger rhombs indicating partial recrystallisation. The macro- and microfossil content of the dolostones is dominated by sarcopterygian (rhizodont) and actinopterygian fish, bivalves, Serpula, ostracods and Chondrites trace fossils; with rarer Spirorbis, chondrichthyans (Ageleodus, hybodonts and ?ctenacanths, xenacanths), non-gyracanth acanthodians, gastropods, eurypterids, brachiopods, plant debris, wood, lycopsid roots, charcoal, megaspores, phycosiphoniform burrows, Zoophycos? and Rhizocorallium. The oxygen and carbon isotope composition of dolomites range from –3.6‰ to –1.7‰ (for δ18O) and –2.6‰ to +1.6‰ (for δ13C) respectively indicating dolomite growth in mixed salinity waters. Frequent marine storm-surge events transported marine waters and animals into floodplain lakes, where evaporation, interstitial sulphate-reducing bacteria, iron reduction and methanogenesis allowed dolomite growth in the shallow sub-surface. Secondary pedogenic modification (by roots, brecciation, desiccation, and soil forming processes) is common and represents lake evaporation with, in some cases, saline marsh development. The dolostone facies are part of a complex environmental mosaic of sub-aerial dry floodplain, wet marshy floodplains, rivers, and lakes ranging in salinity from freshwater to hypersaline. Marine influence is strongest at the base of the formation and decreases over time, as the floodplain became drier, and forested areas became more established. Coastal lakes were an important habitat for animals recovering from the end-Devonian Hangenberg Crisis and may have acted as a pathway for euryhaline fishes, molluscs and arthropods to access freshwater environments

Phylogenetic and environmental context of a Tournaisian tetrapod fauna

The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods (Perittodus?apsconditus, Koilops?herma, Ossirarus?kierani, Diploradus?austiumensis and Aytonerpeton?microps) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere.</p

Phylogenetic and environmental context of a Tournaisian tetrapod fauna

The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods (Perittodus?apsconditus, Koilops?herma, Ossirarus?kierani, Diploradus?austiumensis and Aytonerpeton?microps) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere.</p

Conceptual Uncertainty and Reasoning Tools

Abstract. Problems of conceptual uncertainty have been dealt with in theories of formal logic. Such theories try to accommodate vagueness in two main ways. One is fuzzy logic that introduces degrees of truth. The other way of accommodating formal logic to vagueness is super valuations and its descendants. This paper studies a more inclusive class of reasoning support than formal logic. In the present approach, conceptual uncertainty, including vagueness is represented as higher order uncertainty. A taxonomy of epistemic and conceptual uncertainty is provided. Finally, implications of conceptual uncertainty for reasoning support systems are analyzed.