John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

Distinguishable brain activation networks for short- and long-term motor skill learning

Abstract: The acquisition of a new motor skill is characterized first by a short-term, fast learning stage in which performance improves rapidly, and subsequently by a long-term, slower learning stage in which additional performance gains are incremental. Previous functional imaging studies have suggested that distinct brain networks mediate these two stages of learning, but direct comparisons using the same task have not been performed. Here we used a task in which subjects learn to track a continuous 8-s sequence demanding variable isometric force development between the fingers and thumb of the dominant, right hand. Learning-associated changes in brain activation were characterized using functional MRI (fMRI) during short-term learning of a novel sequence, during short-term learning after prior, brief exposure to the sequence, and over long-term (3 wk) training in the task. Short-term learning was associated with decreases in activity in the dorsolateral prefrontal, anterior cingulate, posterior parietal, primary motor, and cerebellar cortex, and with increased activation in the right cerebellar dentate nucleus, the left putamen, and left thalamus. Prefrontal, parietal, and cerebellar cortical changes were not apparent with short-term learning after prior exposure to the sequence. With long-term learning, increases in activity were found in the left primary somatosensory and motor cortex and in the right putamen. Our observations extend previous work suggesting that distinguishable networks are recruited during the different phases of motor learning. While short-term motor skill learning seems associated primarily with activation in a cortical network specific for the learned movements, long-term learning involves increased activation of a bihemispheric cortical-subcortical network in a pattern suggesting "plastic" development of new representations for both motor output and somatosensory afferent information.

Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function

Abstract: The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was upregulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor 1A. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G0-G1 by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy. (Cancer Res 2005; 65(19): 8690-7)

Molecular cloning of ICAM-3, a third ligand for LFA-1, constitutively expressed on resting leukocytes

Abstract: The co-ordinated function of effector and accessory cells in the immune system is assisted by adhesion molecules on the cell surface that stabilize interactions between different cell types. Leukocyte function-associated antigen 1 (LFA-1) is expressed on the surface of all white blood cells and is a receptor for intercellular adhesion molecules (ICAM) 1 and 2 (ref. 3) which are members of the immunoglobulin superfamily. The interaction of LFA-1 with ICAMs 1 and 2 provides essential accessory adhesion signals in many immune interactions, including those between T and B lymphocytes and cytotoxic T cells and their targets. In addition, both ICAMs are expressed at low levels on resting vascular endothelium; ICAM-1 is strongly upregulated by cytokine stimulation and plays a key role in the arrest of leukocytes in blood vessels at sites of inflammation and injury. Recent work has indicated that resting leukocytes express a third ligand, ICAM-3, for LFA-1 (refs 11, 12). ICAM-3 is potentially the most important ligand for LFA-1 in the initiation of the immune response because the expression of ICAM-1 on resting leukocytes is low. We report the expression cloning of a complementary DNA, pICAM-3, encoding a protein constitutively expressed on all leukocytes, which binds LFA-1. ICAM-3 is closely related to ICAM-1, consists of five immunoglobulin domains, and binds LFA-1 through its two N-terminal domains.

High frequencies of alpha-thalassaemia are the result of natural selection by malaria.

Abstract: The frequency of alpha+-thalassaemia, but not other unlinked DNA polymorphisms, exhibits an altitude- and latitude-dependent correlation with malaria endemicity throughout Melanesia, supporting the hypothesis that protection against this parasitic disease is the major factor responsible for the high frequencies of haemoglobinopathies in many parts of the world.