Noble gases confirm plume-related mantle degassing beneath Southern Africa.

Southern Africa is characterised by unusually elevated topography and abnormal heat flow. This can be explained by thermal perturbation of the mantle, but the origin of this is unclear. Geophysics has not detected a thermal anomaly in the upper mantle and there is no geochemical evidence of an asthenosphere mantle contribution to the Cenozoic volcanic record of the region. Here we show that natural CO2 seeps along the Ntlakwe-Bongwan fault within KwaZulu-Natal, South Africa, have C-He isotope systematics that support an origin from degassing mantle melts. Neon isotopes indicate that the melts originate from a deep mantle source that is similar to the mantle plume beneath Réunion, rather than the convecting upper mantle or sub-continental lithosphere. This confirms the existence of the Quathlamba mantle plume and importantly provides the first evidence in support of upwelling deep mantle beneath Southern Africa, helping to explain the regions elevation and abnormal heat flow.

Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype.

The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.

Localization of α7 nicotinic acetylcholine receptor mRNA and protein within the cholinergic anti-inflammatory pathway.

Electrical stimulation of the vagus nerve attenuates tumor necrosis factor (TNF) synthesis by macrophages and reduces the systemic inflammatory response. Current evidence suggests that the α7 nicotinic acetylcholine receptor present in the celiac/superior mesenteric ganglia is a key component in vagus nerve signaling to the spleen; however, there is currently no direct anatomical evidence that the α7 receptor is present in the murine celiac/superior mesenteric ganglia. Our study addresses this deficiency by providing anatomical evidence that the α7 receptor is expressed within the celiac/superior mesenteric ganglia and splenic nerve fibers using immunohistochemistry and quantitative polymerase chain reaction (qPCR). α7 receptor mRNA is highly expressed in the celiac/superior mesenteric ganglia and at low levels in the spleen compared to the brain. Double-labeling for α7 and tyrosine hydroxylase shows that α7 receptor protein is present on noradrenergic neurons within the ganglia and prejunctionally on noradrenergic nerve fibers within the spleen. The α7 receptor in the ganglia provides a possible location for the action of α7-selective agonists, while prejunctional α7 receptor expressed on splenic nerves may induce an increase in norepinephrine release in a positive feedback system enhanced by lymphocyte-derived acetylcholine.

Astroglia up-regulate transcription and secretion of 'readthrough' acetylcholinesterase following oxidative stress.

Novel and diverse functions of glial cells are currently the focus of much attention [A. Volterra and J. Meldolesi (2005) Nature Rev. 6, 626-640]. Here we present evidence that rat astroglia release acetylcholinesterase (AChE) as part of their response to hypoxic damage. Exposure of astroglia to tert-butyl hydroperoxide, and hence oxidative stress, subsequently leads to a switching in mRNA from the classical membrane-bound T-AChE to a preferential increase in the splice variant for a soluble form, R-AChE, This change in expression is reflected in increased perinuclear and reduced cytoplasmic AChE staining of the insulted glial cells, with a concomitant and marked increase in extracellular secretion that peaks at 1 h post-treatment. An analogous increase in R-AChE, over a similar time scale, occurs in response to psychological stress [D. Kaufer et al. (1998) Nature 93, 373-377], as well as to head injury and stroke [E. Shohami et al. (1999) J. Neurotrauma 6, 365-76]. The data presented here suggest that glial cells may be key chemical intermediaries in such situations and, perhaps more generally in pathological conditions involving oxidative stress, such as neurodegeneration.