Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435-474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome.

Observations and analysis of a 63-year-old reinforced concrete promenade railing exposed to the North Sea

Despite being exposed to the harsh sea-spray environment of the North Sea at Arbroath, Scotland, for over 63 years, many of the reinforced concrete precast beam elements of the 1.5 km long promenade railing are still in very good condition and show little evidence of reinforcement corrosion. In contrast, railing replacements constructed in about 1968 and in 1993 are almost all badly cracked as a result of extensive corrosion of the longitudinal reinforcement. This is despite the newer concrete appearing to be of better quality than the 1943 concrete. Statistics for maximum crack width for each of the three populations, based on measurements made in 2004 and in 2006, are presented. In situ and laboratory measurements show that the 1943 concrete appears to have high permeability but it also shows high electrical resistivity. Chloride penetration measurements show the 1943 and 1993 concretes to have similar chloride profiles and similar chloride concentrations at the reinforcement bars. This is inconsistent with the 1943 beams showing much less reinforcement corrosion than their later replacements and casts doubt on the conventional practice for durability design focusing on reducing concrete permeability through denser concretes or greater cover.

The Fraud Act 2006: some early observations and comparisons with the former law

Provides a detailed analysis of the Fraud Act 2006 provisions on the offence of fraud by false representation (s.2) and the offence of obtaining services dishonestly (s.11) and assesses the extent to which they address problems arising in connection with the former deception offences under the Theft Acts 1968 and 1978. [From Legal Journals Index]

Experiments and observations made at the Plymouth Laboratory

Diagnostic characters in flat fishes. Development of the egg in flat fishes & pipe fishes. A piebald plaice. Growth & distribution of young food-fishes. Notes on rare or interesting specimens.