Oncogenic protein tyrosine kinases

Platelet-derived growth factor receptors (PDGFRs) and their ligands, platelet-derived growth factors (PDGFs) play critical roles in mesenchymal cell migration and proliferation. In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue. In adults, PDGFR/PDGF is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases, and especially malignancy. Constitutive activation of the PDGFRalpha or PDGFRbeta receptor tyrosine kinases is seen in myeloid malignancies as a consequence of fusion to diverse partner genes, and activating mutations of PDGFRalpha are seen in gastrointestinal tumours (GISTs). Autocrine signalling as a consequence of PDGF-B overexpression is clearly implicated in the pathogenesis of dermatofibrosarcoma protruberans (DFSP) and overexpression of PDGFRs and/or their ligands has been described in many solid tumours. PDGFR signalling is inhibited by imatinib mesylate, and this compound has clear clinical activity in patients with myeloid malignancies, GIST and DFSP.     

Rapid evolution drives ecological dynamics in a predator-prey system

Ecological and evolutionary dynamics can occur on similar timescales. However, theoretical predictions of how rapid evolution can affect ecological dynamics are inconclusive and often depend on untested model assumptions. Here we report that rapid prey evolution in response to oscillating predator density affects predator-prey (rotifer-algal) cycles in laboratory microcosms. Our experiments tested explicit predictions from a model for our system that allows prey evolution. We verified the predicted existence of an evolutionary tradeoff between algal competitive ability and defence against consumption, and examined its effects on cycle dynamics by manipulating the evolutionary potential of the prey population. Single-clone algal cultures (lacking genetic variability) produced short cycle periods and typical quarter-period phase lags between prey and predator densities, whereas multi-clonal (genetically variable) algal cultures produced long cycles with prey and predator densities nearly out of phase, exactly as predicted. These results confirm that prey evolution can substantially alter predator-prey dynamics, and therefore that attempts to understand population oscillations in nature cannot neglect potential effects from ongoing rapid evolution.     

Biological activity in the deep subsurface and the origin of heavy oil

At temperatures up to about 80 degrees C, petroleum in subsurface reservoirs is often biologically degraded, over geological timescales, by microorganisms that destroy hydrocarbons and other components to produce altered, denser 'heavy oils'. This temperature threshold for hydrocarbon biodegradation might represent the maximum temperature boundary for life in the deep nutrient-depleted Earth. Most of the world's oil was biodegraded under anaerobic conditions, with methane, a valuable commodity, often being a major by-product, which suggests alternative approaches to recovering the world's vast heavy oil resource that otherwise will remain largely unproduced.     

Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice

The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages. Here we have identified the mnd2 mutation as the missense mutation Ser276Cys in the protease domain of the nuclear-encoded mitochondrial serine protease Omi (also known as HtrA2 or Prss25). Protease activity of Omi is greatly reduced in tissues of mnd2 mice but is restored in mice rescued by a bacterial artificial chromosome transgene containing the wild-type Omi gene. Deletion of the PDZ domain partially restores protease activity to the inactive recombinant Omi protein carrying the Ser276Cys mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. The neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease.     

Proton-sensing G-protein-coupled receptors

Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.     

Evidence of two temperate episodes in late Pleistocene deposits at Marsworth, UK

In the British Quaternary, two post-Cromerian interglacials, the Hoxnian and the Ipswichian, are recognized. Evidence of additional interglacials in this interval is widely accepted in the oceanic record of Quaternary events, and the possibility that at least one additional interglacial of this age is represented in Britain has been discussed. However, in the absence of datable interglacial deposits which are seen to overlie one another, the issue has remained controversial. We describe here deposits at Marsworth, UK (Fig. 1) where there is evidence of two temperate episodes, and of intervening periglacial conditions. Stratigraphical superposition is established beyond any reasonable doubt. The later deposit relates to the temperate woodland stage of the Ipswichian Interglacial. Dating of the earlier temperate material by the 230Th/234U disequilibrium method indicates an interglacial episode not previously established in the British Quaternary.