A recurrent F8 mutation in Irish haemophilia A patients: evidence for a founder effect.

Haemophilia A is a mutationally heterogeneous disorder with approximately 1,000 unique mutations of the Factor VIII (F8) gene recorded to date [1]. With the exception of the intron 22 inversion mutation, which occurs in ~45% of individuals with clinically severe disease, recurrent mutations causing haemophilia A are rare. This reflects a high rate of spontaneous mutation within the F8 gene generally resulting in private mutations within individual kindreds. We have identified a recurrent F8 gene mutation in Irish haemophilia A patients and have used haplotype analysis to investigate its origins.

Clinical traits of LRRK2-associated parkinson's disease in ireland: a link between familial and idiopathic PD

The role of genetics in parkinsonism has been confirmed over the last decade with the identification of genetic variation in seven genes, which are causative in familial forms of the disorder. A number of pathogenic mutations have been identified in the latest gene LRRK2, with a Gly2019Ser amino acid substitution identified in two siblings and one patient with idiopathic Parkinson's disease from Ireland. The clinical features resemble the idiopathic variant with a tremor predominant clinical picture shared by the siblings, slow progression of symptoms, and no observation of cognitive disturbance in all. The family and the sporadic individual were apparently not related and originated from different regions of Ireland, although haplotype analysis does suggest they share a common founder. The influence of the G2019S substitution on protein function and disease phenotype has yet to be fully resolved, but its elucidation will undoubtedly further our understanding of the mechanisms underlying Parkinson's disease.

Cortactin underpins CD44-promoted invasion and adhesion of breast cancer cells to bone marrow endothelial cells

Using a validated tetracycline (tet)-regulated MCF7-founder (MCF7F) expression system to modulate expression of CD44 standard form (CD44s), we report the functional importance of CD44s and that of a novel transcriptional target of hyaluronan (HA)/CD44s signaling, EMS1/cortactin, in underpinning breast cancer metastasis. In functional experiments, tet-regulated induction of CD44s potentiated the migration and invasion of MCF7F cells through HA-supplemented Matrigel. EMS1/cortactin was identified by expression profiling as a novel transcriptional target of HA/CD44 signaling, an association validated by quantitative PCR and immunoblotting experiments in a range of breast cancer cell lines. The mechanistic basis underpinning CD44-promoted transcription of EMS1/cortactin was shown to be dependent upon a NFB mechanism, since pharmacological inhibition of IKinase-2 or suppression of p65 Rel A expression attenuated CD44-induced increases in cortactin mRNA transcript levels. Overexpression of a c-myc tagged murine cortactin construct in the weakly invasive, CD44-deficient MCF7F and T47D cells potentiated their invasion. Furthermore, the functional importance of cortactin to CD44s-promoted metastasis was demonstrated by selective suppression of cortactin in CD44-expressing MCF7F-B5 and MDA-MB-231 breast cancer cells using RNAi, which was shown to result in attenuated CD44-promoted invasion and CD44-promoted adhesion to bone marrow endothelial cells (BMECs).

Non-shivering thermogenesis in common spiny mice Acomys cahirinus from adjacent habitats: response to seasonal acclimatization and salinity acclimation

1. We compared resting metabolic rate (RMR) and non-shivering thermogenesis (NST) values between founder and F1-populations of winter-acclimatized Acomys cahirinus that originated from north- and south-facing slopes (NFS and SFS) of the same valley, representing mesic and xeric habitats. 2. NST was measured by the increase in oxygen consumption (VO2) and body temperature (T-b) after a noradrenaline (NA) injection (VO2 NA, TbNA). 3. Body mass and TbNA values were higher in SFS F1-mice, while RMR and VO2 NA values were higher in NFS F1-mice. Differences were not apparent in founders. 4. Results are consistent with NFS and SFS mice being considered as

Voodoo Institution or Entrepreneurial University? Spin-off Companies, the Entrepreneurial System and Regional Development in the UK

University spin-off companies occupy a prominent position in both government and university policies and aspirations for the commercialization of university research for economic benefit at regional and national levels. However, most university spin-off companies start small and remain small, reflecting founder aspirations, capabilities, and resource endowments. Based on detailed analysis of university spin-offs in Northern Ireland, it is concluded that these companies are technology lifestyle businesses not dynamic high-growth potential start-ups, and it is suggested that the prominence given to spin-offs in the analysis of technology transfer and in discussions of the economic impacts of universities is misplaced.

Eochaid ua Flainn is Eochaid ua Flannucáin: Súil Úr ar an bhFianaise

The evidence for two poets on record in the tenth century is reconsidered. The argument is made that they can be identified as one person, the poet Eochaid ua Flannucáin, a member of the religious community of Armagh and founder of a dynasty which governed the centre of the Irish church for over 150 years.

Characterisation of a C1qtnf5 Ser163Arg Knock-In Mouse Model of Late-Onset Retinal Macular Degeneration

A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD) in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse

Islamist Versus Islamist: Rising Challenge in Gaza

Islam's diversity is a direct result of centuries of schism and factionalism, and presents a challenge to the original spirit of unity as envisaged by its founder, the Prophet Mohammed. Rivalry within Islam undermines the precedent notion of unity through communal belonging (tawhid and ummah). Yet in the twenty-first century this diversity is ignored, and political Islam is represented as being more of a monolith than a spectrum of ideas and aspirations. Generally, the materialization of new Islamist groups is a challenge to those who hold that unity is all. In the Gaza Strip, specifically, the dominant Islamist actor, Hamas, is facing internal challenges from other Islamist elements. These rival Islamists are also influenced by events across their border in post-revolutionary Egypt where a plethora of new Islamist actors are vying for political space and power. This article deals with Hamas's Islamist rivals, and the effects they have had on Hamas's governance of the Gaza Strip, and political and religious legitimacy within it. It will focus on ideological and violent disputes between the Islamist elements in Gaza, and the means by which Hamas and its security elements have tackled newly emerging rivals.

Brutus

This article discusses the eponymous legendary founder of Britain, Brutus, a descendent of the Trojan Aeneas and first king of Britain. It tracks the emergence of Brutus in historiography and literature from the seventh to the sixteenth centuries, from the Historia Brittonum, via the Brut tradition and Geoffrey of Monmouth’s Historia Regum Britannia, to the poem Sir Gawain and the Green Knight, Caxton’s Chronicles of England, Milton’s The History of Britain and Spenser’s The Fairie Queene.

GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

BACKGROUND: In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease.

METHODS: We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively.

RESULTS: Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples.

CONCLUSIONS: These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.