Correlating Bedrock Folds to Higher Rates of Arsenic Detection in Groundwater, Southeast Wisconsin, USA.

Arsenic in private drinking water wells is a significant problem across much of eastern Wisconsin, USA. The release mechanism and stratigraphic distribution of sulfide and iron (hydr)oxide sources of arsenic in bedrock aquifers are well understood for northeastern Wisconsin. However, recent geologic mapping has identified numerous small bedrock folds to the south, and the impact of these geologic structures on local groundwater flow and well contamination has been little studied. This paper examines the hydrologic and structural effects of the Beaver Dam anticline, southeast Wisconsin, on arsenic in groundwater in the region. Multivariate logistic regression shows wells near the Beaver Dam anticline are statistically more likely to detect arsenic in groundwater compared to wells farther away. Structural and hydrologic changes related to folding are interpreted to be the cause. Core drilled near the fold axis is heavily fractured, and many fractures are filled with sulfides. Elevated hydraulic conductivity estimates are also recorded near the fold axis, which may reflect a higher concentration of vertical fractures. These structural and hydrologic changes may have led to systematic changes in the distribution and concentration of arsenic-bearing mineral hosts, resulting in the observed detection pattern. For areas with similar underlying geology, this approach may improve prediction of arsenic risk down to the local level.

Human altruism, evolution and moral philosophy.

This paper has two central aims. The first is to explore philosophical complications that arise when we move from (i) explaining the evolutionary origins of genetically influenced traits associated with human cooperation and altruism, to (ii) explaining present manifestations of human thought, feeling and behaviour involving cooperation and altruism. While the former need only appeal to causal factors accessible to scientific inquiry, the latter must engage also with a distinctive form of explanation, i.e. reason-giving explanation, which in turn raises important philosophical questions, the answers to which will affect the nature of the ultimate explanations of our moral beliefs and related actions. On one possibility I will explore, this explanatory project cannot avoid engaging with first-order ethical theory. The second aim is to apply lessons from these explanatory complications to the critique of 'evolutionary debunking arguments', which seek to debunk morality, or at least objective construals of it (i.e. moral realism), by appeal to allegedly scientific debunking explanations of our moral beliefs that would defeat our justification for them. The explanatory complications brought out in the first half raise difficulties for such debunking arguments. If we avoid begging central philosophical questions then such debunking arguments pose little threat of saddling us with moral scepticism or subjectivism, though they do pose an important challenge for those developing a moral realist view.

Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain.

Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.

Negotiation: a necessary art for dental practice.

This brief paper explains why the art of negotiation has become far more important for general dental practitioners. It explains that negotiations take place with patients, with practice staff, and with funding agencies such as Primary Care Trusts. It sets out the principles for successful negotiation and gives two examples of how they can be applied. It concludes that negotiation is a skill that can be learned and that it will be a key skill as the profession faces future challenges.

Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides.

Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.

Ethical pluralism without complementarity.

Grinnell, Bishop, and McCullough (2002) have proposed extending Bohr's notion of complementarity from the realm of quantum physics to that of bioethics, arguing that many ethical disputes cannot in principle be resolved. On this view, we should give up the aim of reaching all-things-considered moral verdicts on a variety of disputed questions, settling instead for a holism of irreducibly complementary perspectives. I discuss a number of difficulties with this proposal, and argue that the desire for inclusiveness that motivates it is properly captured through a different approach to ethical pluralism already familiar in moral philosophy, which does allow for resolution.

(S)-N-[1-(4-cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons.

(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.

Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition.

The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.

Surplus embryos, nonreproductive cloning, and the intend/foresee distinction.

There is, as some public figures have asserted, a real moral difference between creating embryos expressly for medical research and conducting research on embryos that are left over from infertility treatments. To create an embryo intending all along to destroy it is worse. But in the end, it isn't so much worse that we should ban all nonreproductive cloning.