Computational approach to inquiry based science education

The paper sets out the context for the EU Seventh Framework ‘Pathway to Inquiry Based Science Education’ (IBSE) project. After the context has been outlined, the paper is organised into the following sections: 1. National situation with regard to Science Education in Ireland. 2. Inquiry approaches promoted by Pathway. 3. Adopting IBSE into the Science Education Curriculum. 4. ICT in IBSE. 5. Reflection on IBSE

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.publishedVersio

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The photospheric boundary of Sun-to-Earth coupled models

The least understood component of the Sun-to-Earth coupled system is the solar atmosphere-the visible layers of the Sun that encompass the photosphere, chromosphere, transition region and low corona. Coronal mass ejections (CMEs), principal drivers of space weather, are magnetically driven phenomena that are thought to originate in the low solar corona. Their initiation mechanism, however, is still a topic of great debate. If we are to develop physics-based models with true predictive capability, we must progress beyond simulations of highly idealized magnetic configurations, and develop the techniques necessary to incorporate observations of the vector magnetic field at the solar photosphere into numerical models of the solar corona. As a first step toward this goal, we drive the SAIC coronal model with the complex magnetic fields and flows that result from a sub-photospheric MHD simulation of an emerging active region. In particular, we successfully emerge a twisted Omega-loop into a pre-existing coronal arcade. To date, it is not possible to directly measure the magnetic field in the solar corona. Instead, we must rely on nonpotential extrapolations to generate the twisted, pre-eruptive coronal topologies necessary to initiate data-driven MHD simulations of CMEs. We therefore investigate whether a non-constant-a force-free extrapolation can successfully reproduce the magnetic features of a self-consistent MHD simulation of flux emergence through a stratified model atmosphere. We generate force-free equilibria from simulated photospheric and chromospheric vector magnetograms, and compare these results to the MHD calculation. We then apply these techniques to an IVM (Mees Solar Observatory) vector magnetogram of NOAA active-region 8210, a source of a number of eruptive events on the Sun. (C) 2004 Elsevier Ltd. All rights reserved

The photospheric boundary of Sun-to-Earth coupled models

The least understood component of the Sun-to-Earth coupled system is the solar atmosphere-the visible layers of the Sun that encompass the photosphere, chromosphere, transition region and low corona. Coronal mass ejections (CMEs), principal drivers of space weather, are magnetically driven phenomena that are thought to originate in the low solar corona. Their initiation mechanism, however, is still a topic of great debate. If we are to develop physics-based models with true predictive capability, we must progress beyond simulations of highly idealized magnetic configurations, and develop the techniques necessary to incorporate observations of the vector magnetic field at the solar photosphere into numerical models of the solar corona. As a first step toward this goal, we drive the SAIC coronal model with the complex magnetic fields and flows that result from a sub-photospheric MHD simulation of an emerging active region. In particular, we successfully emerge a twisted Omega-loop into a pre-existing coronal arcade. To date, it is not possible to directly measure the magnetic field in the solar corona. Instead, we must rely on nonpotential extrapolations to generate the twisted, pre-eruptive coronal topologies necessary to initiate data-driven MHD simulations of CMEs. We therefore investigate whether a non-constant-a force-free extrapolation can successfully reproduce the magnetic features of a self-consistent MHD simulation of flux emergence through a stratified model atmosphere. We generate force-free equilibria from simulated photospheric and chromospheric vector magnetograms, and compare these results to the MHD calculation. We then apply these techniques to an IVM (Mees Solar Observatory) vector magnetogram of NOAA active-region 8210, a source of a number of eruptive events on the Sun. (C) 2004 Elsevier Ltd. All rights reserved

Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women

Physical activity reduces risk of colon cancer by 20–30%. Aberrant methylation patterns are common epigenetic alterations in colorectal adenomas, and cancers and play a role in cancer initiation and progression. Alterations identified in normal colon tissue represent apotential ‘field cancerization’ process, where normal colon is primed for carcinogenesis. Here, we investigate methylation patterns in three genes –Ena/VASP-like (EVL), (CDKN2A (p14, ARF)), and Oestrogen Receptor-1 (ESR1)– in normal colon tissue collected at baseline and 12 months from 202 sedentary men and women, 40–75 years, enrolled in a randomized controlled trial testing an exercise intervention vs. control (http://clinicaltrials.gov/show/NCT00668161). Participants were randomized to moderate-to-vigorous intensity exercise, 60 minutes/day, 6 days/week for 12 months, or usual lifestyle. Sigmoid colon biopsies were obtained at baseline and 12-months, DNA extracted, and bisulphite converted. Droplet digital methylation-specific PCR was performed for EVL, p14ARF, and ESR1. Generalized estimating equations modification of linear regression was used to model relationships between intervention effects and gene methylation levels, adjusting for possible confounders. There were no statistically significant differences between methylation patterns at 12-months between exercisers and controls. ESR1 methylation patterns differed by sex: women −10.58% (exercisers) +11.10% (controls); men +5.54% (exercisers), −8.16% (controls) (P=0.05), adjusting for BMI and age. There were no statistically significant changes in methylation patterns in any gene stratified by change in VO2max or minutes/week of exercise. While no statistically significant differences were found in gene methylation patterns comparing exercises vs. controls, 12-month exercise effects on ESR1 methylation differed by sex, warranting further study

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N‑terminal acetylation

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10