De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.     

Elaborating a Critical Realist Approach to Soft Systems Methodology

Systemic Practice and Action Research - This paper explores the implications of adopting a critical realist approach to soft systems methodology (SSM) both to address local problematic situations...     

Hyperion's sponge-like appearance

Hyperion is Saturn's largest known irregularly shaped satellite and the only moon observed to undergo chaotic rotation. Previous work has identified Hyperion's surface as distinct from other small icy objects but left the causes unsettled. Here we report high-resolution images that reveal a unique sponge-like appearance at scales of a few kilometres. Mapping shows a high surface density of relatively well-preserved craters two to ten kilometres across. We have also determined Hyperion's size and mass, and calculated the mean density as 544 +/- 50 kg m(-3), which indicates a porosity of >40 per cent. The high porosity may enhance preservation of craters by minimizing the amount of ejecta produced or retained, and accordingly may be the crucial factor in crafting this unusual surface.     

Causal forces: Structuring knowledge for time-series extrapolation

This paper examines a strategy for structuring one type of domain knowledge for use in extrapolation. It does so by representing information about causality and using this domain knowledge to select and combine forecasts. We use five categories to express causal impacts upon trends: growth, decay, supporting, opposing, and regressing. An identification of causal forces aided in the determination of weights for combining extrapolation forecasts. These weights improved average ex ante forecast accuracy when tested on 104 annual economic and demographic time series. Gains in accuracy were greatest when (1) the causal forces were clearly specified and (2) stronger causal effects were expected, as in longer-range forecasts. One rule suggested by this analysis was: ‘Do not extrapolate trends if they are contrary to causal forces.’ We tested this rule by comparing forecasts from a method that implicitly assumes supporting trends (Holt's exponential smoothing) with forecasts from the random walk. Use of the rule improved accuracy for 20 series where the trends were contrary; the MdAPE (Median Absolute Percentage Error) was 18% less for the random walk on 20 one-year ahead forecasts and 40% less for 20 six-year-ahead forecasts. We then applied the rule to four other data sets. Here, the MdAPE for the random walk forecasts was 17% less than Holt's error for 943 short-range forecasts and 43% less for 723 long-range forecasts. Our study suggests that the causal assumptions implicit in traditional extrapolation methods are inappropriate for many applications.     

A nebula of gases from Io surrounding Jupiter

Several planetary missions have reported the presence of substantial numbers of energetic ions and electrons surrounding Jupiter; relativistic electrons are observable up to several astronomical units (au) from the planet. A population of energetic (>30[?]keV) neutral particles also has been reported, but the instrumentation was not able to determine the mass or charge state of the particles, which were subsequently labelled energetic neutral atoms. Although images showing the presence of the trace element sodium were obtained, the source and identity of the neutral atoms---and their overall significance relative to the loss of charged particles from Jupiter's magnetosphere---were unknown. Here we report the discovery by the Cassini spacecraft of a fast (>103[?]km[?]s-1) and hot magnetospheric neutral wind extending more than 0.5[?]au from Jupiter, and the presence of energetic neutral atoms (both hot and cold) that have been accelerated by the electric field in the solar wind. We suggest that these atoms originate in volcanic gases from Io, undergo significant evolution through various electromagnetic interactions, escape Jupiter's magnetosphere and then populate the environment around the planet. Thus a 'nebula' is created that extends outwards over hundreds of jovian radii.