Research, #Huh? Improving research awareness in NHS Grampian through a website and more

We would like to thank all of the public, participants and staff who have helped with this work, both in Grampian and across Scotland. Their support and help have been invaluable. We would also like to thank the Chief Scientist Office for funding the creation of the website.Peer reviewe

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Photochemical reaction of arenecarbonitriles in the presence of alkylsilanes, silyl ethers and silyl amines

The irradn. of benzene-1,2,4,5-tetracarbonitrile, and benzene-1,2,4- as well as benzene-1,3,5-tricarbonitrile in the presence of various tetraalkylsilanes, alkoxytrialkylsilanes, hexamethyldisiloxane or heptamethyldisilazane leads to alkylation of the aromatics

Modelling blowdown of pressure vessels containing two-phase hydrocarbons mixtures with the partial phase equilibrium approach

This paper describes the development and validation of a new unsteady model, VBsim, for the simulation of the rapid depressurization or blowdown of pressure vessels containing two-phase (vapour and liquid) hydrocarbons mixtures with non-ideal behaviour. Accounting for non-equilibrium effects between the constituent fluid phases, i.e. temperature differences between phases, the model calculates the time variation of fluid pressure, temperature and composition inside the vessel adopting the equations of state for non-ideal gas. It is based on a split two fluids model (vapour and liquid) and it considers internal heat and mass transfer processes, as well as heat transfer with the vessel wall and the external environment. In order to account for the mass exchanged between the gas and the liquid phase, in conditions away from the thermodynamic equilibrium, an innovative version of the partial phase equilibrium (PPE) approach has been introduced. A validation of the proposed model has been performed by comparing its results with experimental and calculated data from literature showing a good agreement

A new integrated approach to study the thermal and mechanical response of vessels subject to a safe blowdown process

The problems related to the blowdown of pressure vessels containing mixtures of hydrocarbons are well known amongst industries involved in plant design and hydrocarbons extraction. In this paper a new integrate approach to study the rapid two-phase depressurization (blowdown) of a vessel containing a mixture of hydrocarbons is presented. The method presented is based on a new mathematical model developed by some of the authors for the thermo-fluid dynamic characterization of the process (VBsim) and the finite element analysis for the mechanical simulations. Indeed, the pressure and thermal stress levels to which the vessel is exposed during the blowdown can present a number of consequences, such as cracks in the walls that have to be predicted by an accurate simulation of the blowdown process. In addition, from the economic point of view it is important to properly simulate the two-phase vessel blowdown to ensure the selection of the most cost-effective materials to conduct this operation in safe conditions. To demonstrate the effectiveness of the present approach, a vessel blowdown case from literature has been simulated and the most critical points in terms of thermal and mechanical stresses of the vessel wall have been identified. In addition, the FEM model build up can be used also for a complete Design of Experiments (DOE) analysis

Severe keratin 5 and 14 mutations induce down-regulation of junction proteins in keratinocytes

The intermediate filament cytoskeleton is essential for the development and maintenance of normal tissue function. A number of diverse recent observations implicate these filament systems in sensing stress and protecting cells against its worst consequences. Cells expressing severely disruptive keratin mutations, characteristic of Dowling-Meara EBS, were previously reported to show elevated responses to physiological stress, and partial disassembly of cell junctions was reported upon direct mechanical stress to the cells. Gene expression microarray analysis has therefore been used here to examine the broad spectrum of effects of mutant keratins. Many genes associated with keratins and other components of the cytoskeleton showed altered expression levels; in particular, many cell junction components are down-regulated in EBS cells. That this is due to the expression of the mutant keratins, and not to other genetic variables, is supported by observation of the same effects in isogenic cells generated from wild type keratinocytes transfected with the same keratin mutations in the helix boundary motifs of K14 or K5. Whilst the mechanism underlying this is unclear, these findings may help to explain other aspects of EBS-associated pathology, such as faster scratch wound migration, or acantholysis (cell-cell separation) in patients' skin. Constitutive stress combined with constitutively weakened cell junctions may also contribute to a recently reported increased risk of non-melanoma skin cancer in EBS patients

Mutations in the iodotyrosine deiodinase gene and hypothyroidism

DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism. Copyrigh