Search

The processes that control genome stability are essential for the development of the Central Nervous System (CNS) and the prevention of neurological disease. Here we investigated whether activation of a DNA damage response by dysfunctional telomeres affects neurogenesis. More specifically, we analyzed ATR-dependent DNA damage response by depletion of POT1a in neural progenitors. These experiments revealed that POT1a inactivation leads to a partially penetrant lethality, and surviving mice displayed ataxia due to loss of neuronal progenitor cells, and died by 3 weeks of age. Inactivation of p53 was sufficient to completely suppress the lethality associated with POT1a depletion and rescued the neuronal defects characterizing POT1a depleted animals. In contrast, activation of ATM by the depletion of the shelterin protein TRF2 resulted in a fully penetrant lethality that could not be rescued by p53 inactivation (Lobanova et al.). This data reveals that activation of distinct types of DNA damage response pathway give rise to different types of neuropathology. Moreover, our data provides an explanation for the heterogeneity of the neurological defects observed in patients affected by telomere biological disorders.

This chapter analyses the policy implications of the climate change challenge. Are current emission reduction pledges made in Copenhagen/Cancun enough to stabilise the climate and limit global average temperature increase to 2 oC? If not, what will the consequences be? What alternative growth pathways could stabilise the global average atmospheric concentration of greenhouse gases (GHG) at 450 ppm, the level which has a 50% chance of keeping the temperature rise to 2 oC? What policies are needed, and what will be the costs and benefits to the economy? How can the world adapt to the warming that is already occurring? To shed light on these questions, this chapter first looks at trends to 2050 in GHG concentration and emissions (including from land use), temperature and precipitation under the Environmental Outlook Baseline scenario of “business-as-usual” (i.e. no new action). It then takes stock of the state of climate policy today. Most countries use a mix of policy instruments, including carbon pricing (carbon taxes, cap-and-trade emissions trading, fossil fuel subsidy reform), other energy efficiency policies, information-based approaches and innovation policies to foster clean technology. The chapter then looks at what further action is needed by comparing different mitigation scenarios against the Baseline. These include various scenarios to stabilise GHG concentrations at 450 ppm and 550 ppm using different technology options, e.g. carbon capture and storage, phasing out nuclear power, and increasing the use of biofuels; linking carbon markets; and various emissions permit allocation rules. The chapter concludes by outlining how limiting global warming will require transformative policies to reconcile short-term action with long-term climate objectives, balancing their costs and benefits. Timely adaptation policies to limit damage by the already changing climate will also be essential.

Humic substances (HS) are the major components of the mixture of materials that comprise soil organic matter, and these substances, which are by far the most abundant organic materials in the environment, are themselves complicated mixtures of biologically transformed organic debris. However, it is likely that many of the solubilization properties of the mixtures arise from the presence of nonhumic components that are intimately associated with the HS and that cannot be separated effectively from these components. Separation and fractionation techniques are improving, and most of the instruments needed to advance awareness of the composition and aspects of structures are now in place. There is a need, however, to review the operational definitions that now apply and to put in place a classification system that will take into account origins and some compositional characteristics. The broad based definition of humin is especially unsatisfactory. This umbrella term covers a mixture of materials that are insoluble in aqueous systems and that contain nonhumic components such as long chain hydrocarbons, esters, acids, and even relatively polar structures of microbial origin, such as polysaccharides and glomalin, that can be associated with the nonpolar moieties and with soil minerals, as well as plant components that are highly resistant to decomposition. Advances in the humic sciences in recent times have been impressive, and the questioning of 'ingrained' theories and concepts is opening vistas through which we are seeing new concepts of size, shape, and association; the remarkable developments in nuclear magnetic resonance are also allowing better interpretations of compositions and of aspects of structures. From these advances will emerge a more fundamental understanding of HS functions in such important roles as the stabilization of soil aggregates, the binding of anthropogenic organic chemicals, and the sequestration of C from atmospheric CO2. The latter function is especially important at this time because we need to know why some soils sequester more C than others and why the qualities (or composition and structure) of HS in some soils are different from those in others.

Prolactin fragments inhibit blood vessel formation, whereas anti-prolactin antibodies induce angiogenesis in the cornea. Endothelial cells from brain capillaries and the umbilical vein produce prolactin, and this study was undertaken to determine whether retinal capillary endothelial cells could be a source for prolactin in the eye.Primary cultures of rat retinal endothelial cells were investigated for the expression of prolactin mRNA by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis and by in situ hybridization. The prolactin protein was analyzed by immunocytochemistry, enzyme-linked immunoabsorbent assay, Western blot analysis, and the Nb2-cell bioassay. The effect of prolactin and the 16-kDa prolactin fragment on retinal endothelial cell proliferation was investigated, and the expression of the cloned prolactin receptor was analyzed by RT-PCR and Southern blot analysis.Retinal endothelial cells expressed prolactin mRNA and full-length 23-kDa prolactin. Prolactin was observed in the cytoplasm of cells and in their conditioned medium at levels 300 times those described in endothelial cells from other vessels and species. Exogenous 16-kDa prolactin inhibited rat retinal endothelial cell proliferation, whereas 23-kDa prolactin was inactive. No evidence was obtained for the expression of the cloned prolactin receptor in these cells, but the prolactin receptor was amplified in whole rat retina.Endothelial cells from the microcirculation of rat retina produce and release prolactin. That the cloned prolactin receptor was not expressed in these cells argues against direct autocrine effects of prolactin. Possible paracrine effects are suggested by the expression of the prolactin receptor in retinal tissue.