Biallelic GINS2 variant p.(Arg114Leu) causes Meier-Gorlin syndrome with craniosynostosis

Contains fulltext : 284813.pdf (Publisher’s version ) (Open Access)INTRODUCTION: Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS). OBJECTIVE: Identification of novel genes associated with MGORS. METHODS: Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, in silico structural protein analysis and modelling in budding yeast. RESULTS: A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in GINS2 was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with CDC45-related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia. CONCLUSION: GINS2 is a new disease-associated gene, expanding the genetic aetiology of MGORS

HOx observations over West Africa during AMMA: impact of isoprene and NOx

Aircraft OH and HO2 measurements made over West Africa during the AMMA field campaign in summer 2006 have been investigated using a box model constrained to observations of long-lived species and physical parameters. "Good" agreement was found for HO2 (modelled to observed gradient of 1.23 ± 0.11). However, the model significantly overpredicts OH concentrations. The reasons for this are not clear, but may reflect instrumental instabilities affecting the OH measurements. Within the model, HOx concentrations in West Africa are controlled by relatively simple photochemistry, with production dominated by ozone photolysis and reaction of O(1D) with water vapour, and loss processes dominated by HO2 + HO2 and HO2 + RO2. Isoprene chemistry was found to influence forested regions. In contrast to several recent field studies in very low NOx and high isoprene environments, we do not observe any dependence of model success for HO2 on isoprene and attribute this to efficient recycling of HOx through RO2 + NO reactions under the moderate NOx concentrations (5–300 ppt NO in the boundary layer, median 76 ppt) encountered during AMMA. This suggests that some of the problems with understanding the impact of isoprene on atmospheric composition may be limited to the extreme low range of NOx concentrations

Effect of oxygen concentration on the kinetics of oxygen loss and thermal donor formation in silicon at temperatures between 350°c and 500°c

We have measured thermal donor and interstitial oxygen concentrations during isothermal anneals in samples containing different initial concentrations of interstitial oxygen. The rate of donor formation is a strong function of oxygen concentration at all temperatures and depends on [Oi]3.5 at 450°C, similar to that found in previous studies. However the donor introduction rate tends asymptotically to a dependency on [Oi]2 at lower temperatures. At these same temperatures, the loss of interstitial oxygen from solution is described by a model of stable O2 dimer formation. These results show that O2 dimer formation is the rate limiting step in both oxygen loss and donor formation. If thermal donor defects contain more than two oxygen atoms then it is implied that oxygen dimers diffuse more rapidly than isolated oxygen atoms. © (1993) Trans Tech Publications, Switzerland

Transitioning to resilience and sustainability in urban communities

Adapting to the challenges of rapid urban growth and societal change will require mechanisms for efficient transitioning to an embedded resilience. This has become central to the exploration of methods for achieving truly sustainable urban growth. However, while transitioning and resilience are useful descriptors, they can be abstract or conflicting ideals and their meanings obscured by a lack of concrete examples, both being barriers to many planning objectives. In this paper, we hold a lens over key issues in transitioning to resilience in urban areas by outlining emerging challenges that may offer directions towards operationalising how cities might transition to a more resilient future, while ensuring that communities are at the center of the process. The emerging and challenging areas – geospatial ICT, green infrastructure planning, novel design using collaborative responses, climate planning, limiting urban sprawl and short-circuit economic approaches – are explored as viable facets for devising and sustaining urban transition strategies. We conclude with a discussion on the need for developing a synergistic approach in practice to facilitate transition.European Research CouncilFP7 Grant Agreement 282834 / TURAS ProjectSB. 15/05/201