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"Sharp, Alan"
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The Consequences of the Peace
The Versailles Settlement, at the time of its creation a vital part of the Paris Peace Conference, suffers today from a poor reputation: despite its lofty aim to settle the world's affairs at a stroke, it is widely considered to have paved the way for a second major global conflict within a generation. Woodrow Wilson's controversial principle of self-determination amplified political complexities in the Balkans, and the war and its settlement bear significant responsibility for boundaries and related conflicts in today's Middle East. After almost a century, the settlement still casts a long shadow.This revised and updated edition ofThe Consequences of the Peacesets the ramifications of the Paris Peace treaties-for good or ill-within a long-term context. Alan Sharp presents new materials in order to argue that the responsibility for Europe's continuing interwar instability cannot be wholly attributed to the peacemakers of 1919-23. Marking the centenary of World War I and the approaching centenary of the Peace Conference itself, this book is a clear and concise guide to the global legacy of the Versailles Settlement.
eBook
A huntingtin-associated protein enriched in brain with implications for pathology
HUNTINGTON's disease (HD) is an autosomal dominant neuro-degenerative disorder caused by an expanding polyglutamine repeat in the IT 15 or huntingtin gene
1
. Although this gene is widely expressed
2–9
and is required for normal development
10–12
, the pathology of HD is restricted to the brain, for reasons that remain poorly understood. The huntingtin gene product is expressed at similar levels in patients and controls, and the genetics of the disorder
13,14
suggest that the expansion of the polyglutamine repeat induces a toxic gain of function, perhaps through interactions with other cellular proteins
15–18
. Here we report the identification of a protein (huntingtin-associated protein (HAP)-l) that binds to huntingtin. This binding is enhanced by an expanded polyglutamine repeat, the length of which is also known to correlate with the age of disease onset
19–21
. The HAP-1 protein is enriched in the brain, suggesting a possible basis for the selective brain pathology of HD.
Journal Article
Anglo-French Relations in the Twentieth Century
Anglo-French Relations in the Twentieth Century is a collection of studies on the key episodes of the difficult and often discordant Anglo-French exchange over the past century. The authors critically re-evaluate: * the role of Spain in Anglo-French relations up to 1918 * the missed opportunity of the 1920s with the failure of France and Britain to find sufficient common ground and co-operation * the short-lived Anglo-French alliance and the Second World War * the degree of Anglo-French Imperial co-operation * the Suez Crisis * British and French policies on European Integration.
eBook
Lymphocyte Apoptosis: Mediation by Increased Type 3 Inositol 1,4,5- Trisphosphate Receptor
B and T lymphocytes undergoing apoptosis in response to anti-immunoglobulin M antibodies and dexamethasone, respectively, were found to have increased amounts of messenger RNA for the inositol 1,4,5-trisphosphate receptor (IP$_3$R) and increased amounts of IP$_3$R protein. Immunohistochemical analysis revealed that the augmented receptor population was localized to the plasma membrane. Type 3 IP$_3$R (IP$_3$R3) was selectively increased during apoptosis, with no enhancement of type 1 IP$_3$R (IP$_3$R1). Expression of IP$_3$R3 antisense constructs in S49 T cells blocked dexamethasone-induced apoptosis, whereas IP$_3$R3 sense, IP$_3$R1 sense, or IP$_3$R1 antisense control constructs did not block cell death. Thus, the increases in IP$_3$R3 may be causally related to apoptosis.
Journal Article
Expansion of Polyglutamine Repeat in Huntingtin Leads to Abnormal Protein Interactions Involving Calmodulin
Huntington's disease (HD) is an inherited neurodegenerative disorder associated with expansion of a CAG repeat in the IT15 gene. The IT15 gene is translated to a protein product termed huntingtin that contains a polyglutamine (polyGln) tract. Recent investigations indicate that the cause of HD is expansion of the polyGln tract. However, the function of huntingtin and how the expanded polyGln tract causes HD is not known. We investigate potential protein-protein interactions of huntingtin using affinity resins. Huntingtin from brain extracts is retained on calmodulin (CAM)-Sepharose in a calcium-dependent fashion. We purify rat huntingtin to apparent homogeneity using a combination of DEAE-cellulose column chromatography, ammonium sulfate precipitation, and preparative SDS/PAGE. Purified rat huntingtin does not interact with CAM directly as revealed by 125I-CAM overlay. Huntingtin forms a large CAM-containing complex of over 1,000 kDa in the presence of calcium, which partially disassociates in the absence of calcium. Furthermore, an increased amount of mutant huntingtin from HD patient brains is retained on CAM-Sepharose compared to normal huntingtin from control patient brains, and the mutant allele is preferentially retained on CAM-Sepharose in the absence of calcium. These results suggest that huntingtin interacts with other proteins including CAM and that the expansion of polyGln alters this interaction.
Journal Article
Huntingtin-Associated Protein (HAP1): Discrete Neuronal Localizations in the Brain Resemble those of Neuronal Nitric Oxide Synthase
Huntington disease stems from a mutation of the protein huntingtin and is characterized by selective loss of discrete neuronal populations in the brain. Despite a massive loss of neurons in the corpus striatum, NO-generating neurons are intact. We recently identified a brain-specific protein that associates with huntingtin and is designated huntingtin-associated protein (HAP1). We now describe selective neuronal localizations of HAP1. In situ hybridization studies reveal a resemblance of HAP1 and neuronal nitric oxide synthase (nNOS) mRNA localizations with dramatic enrichment of both in the pedunculopontine nuclei, the accessory olfactory bulb, and the supraoptic nucleus of the hypothalamus. Both nNOS and HAP1 are enriched in subcellular fractions containing synaptic vesicles. Immunocytochemical studies indicate colocalizations of HAP1 and nNOS in some neurons. The possible relationship of HAP1 and nNOS in the brain is reminiscent of the relationship of dystrophin and nNOS in skeletal muscle and suggests a role of NO in Huntington disease, analogous to its postulated role in Duchenne muscular dystrophy.
Journal Article
Localization of inositol trisphosphate receptor subtype 3 to insulin and somatostatin secretory granules and regulation of expression in islets and insulinoma cells
Calcium ions play a central role in stimulus-secretion coupling in pancreatic beta cells, and an elevation of cytosolic Ca(2+) levels is necessary for insulin secretion. Inositol 1,4,5-trisphosphate mobilizes intracellular Ca(2+) stores in the beta cell by binding to specific receptors that are ligand-activated Ca(2+) channels. The inositol trisphosphate receptors comprise a family of structurally related proteins with distinct but overlapping tissue distributions. Previous studies indicated that the predominant inositol trisphosphate receptor subtype expressed in rat pancreatic islets was the protein designated IP3R-3. We have confirmed the expression of IP3R-3 in pancreatic islets by immunohistocytochemistry and localized this protein to the secretory granules of insulin-secreting beta cells and somatostatin-secreting delta cells by immunogold electron microscopy. Secretory granules contain high levels of Ca(2+), and the presence of IP3R-3 in the granule provides a mechanism for mobilizing granule Ca(2+) stores in response to glucose and/or hormones. The release of Ca(2+) from granule stores would increase the Ca(2+) concentration in the surrounding cytoplasm and promote rapid exocytosis of granules, especially those granules in close proximity to the plasma membrane. The levels of IP3R-3 were increased in pancreatic islets of diabetic rats and rats that had been refed after a period of fasting. They were also increased in rat insulinoma RINm5F cells cultured in 25 mM glucose compared with cells cultured in 5 mM glucose. The localization of IP3R-3 to secretory granules of insulin-secreting 13 cells and somatostatin-secreting delta cells suggests that granule Ca(2+) stores actively participate in the secretory process and that their release is regulated by inositol 1,4,5-trisphosphate. The regulation of IP3R-3 levels by glucose, diabetes, and refeeding may allow the beta cell to adjust the insulin secretory response to changing physiological conditions.
Journal Article
