Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells

The insulin/IGF-1 (insulin-like growth factor 1)-activated protein kinase Akt (also known as protein kinase B) phosphorylates Ser(487) in the ‘ST loop’ (serine/threonine-rich loop) within the C-terminal domain of AMPK-α1 (AMP-activated protein kinase-α1), leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr(172). Surprisingly, the equivalent site on AMPK-α2, Ser(491), is not an Akt target and is modified instead by autophosphorylation. Stimulation of HEK (human embryonic kidney)-293 cells with IGF-1 caused reduced subsequent Thr(172) phosphorylation and activation of AMPK-α1 in response to the activator A769662 and the Ca(2+) ionophore A23187, effects we show to be dependent on Akt activation and Ser(487) phosphorylation. Consistent with this, in three PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt is thus hyperactivated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr(172) phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the αC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyperactivation of Akt in tumour cells is to restrain activation of the LKB1 (liver kinase B1)–AMPK pathway, which would otherwise inhibit cell growth and proliferation

Measurement of the rate of nu_e + d --> p + p + e^- interactions produced by 8B solar neutrinos at the Sudbury Neutrino Observatory

Solar neutrinos from the decay of $^8$B have been detected at the Sudbury Neutrino Observatory (SNO) via the charged current (CC) reaction on deuterium and by the elastic scattering (ES) of electrons. The CC reaction is sensitive exclusively to nu_e's, while the ES reaction also has a small sensitivity to nu_mu's and nu_tau's. The flux of nu_e's from ^8B decay measured by the CC reaction rate is \phi^CC(nu_e) = 1.75 +/- 0.07 (stat)+0.12/-0.11 (sys.) +/- 0.05(theor) x 10^6 /cm^2 s. Assuming no flavor transformation, the flux inferred from the ES reaction rate is \phi^ES(nu_x) = 2.39+/-0.34 (stat.)+0.16}/-0.14 (sys) x 10^6 /cm^2 s. Comparison of \phi^CC(nu_e) to the Super-Kamiokande Collaboration's precision value of \phi^ES(\nu_x) yields a 3.3 sigma difference, providing evidence that there is a non-electron flavor active neutrino component in the solar flux. The total flux of active ^8B neutrinos is thus determined to be 5.44 +/-0.99 x 10^6/cm^2 s, in close agreement with the predictions of solar models.Comment: 6 pages (LaTex), 3 figures, submitted to Phys. Rev. Letter

First Neutrino Observations from the Sudbury Neutrino Observatory

The first neutrino observations from the Sudbury Neutrino Observatory are presented from preliminary analyses. Based on energy, direction and location, the data in the region of interest appear to be dominated by 8B solar neutrinos, detected by the charged current reaction on deuterium and elastic scattering from electrons, with very little background. Measurements of radioactive backgrounds indicate that the measurement of all active neutrino types via the neutral current reaction on deuterium will be possible with small systematic uncertainties. Quantitative results for the fluxes observed with these reactions will be provided when further calibrations have been completed.Comment: Latex, 7 pages, 10 figures, Invited paper at Neutrino 2000 Conference, Sudbury, Canada, June 16-21, 2000 to be published in the Proceeding

Measurement of the νe\nu_e and Total 8^{8}B Solar Neutrino Fluxes with the Sudbury Neutrino Observatory Phase I Data Set

This article provides the complete description of results from the Phase I data set of the Sudbury Neutrino Observatory (SNO). The Phase I data set is based on a 0.65 kt-year exposure of heavy water to the solar $^8$B neutrino flux. Included here are details of the SNO physics and detector model, evaluations of systematic uncertainties, and estimates of backgrounds. Also discussed are SNO's approach to statistical extraction of the signals from the three neutrino reactions (charged current, neutral current, and elastic scattering) and the results of a search for a day-night asymmetry in the $\nu_e$ flux. Under the assumption that the $^8$B spectrum is undistorted, the measurements from this phase yield a solar $\nu_e$ flux of $\phi(\nu_e) = 1.76^{+0.05}_{-0.05}{(stat.)}^{+0.09}_{-0.09} {(syst.)} \times 10^{6}$ cm$^{-2}$ s$^{-1}$, and a non-$\nu_e$ component $\phi(\nu_{\mu\tau}) = 3.41^{+0.45}_{-0.45}{(stat.)}^{+0.48}_{-0.45} {(syst.)} \times 10^{6}$ cm$^{-2}$ s$^{-1}$. The sum of these components provides a total flux in excellent agreement with the predictions of Standard Solar Models. The day-night asymmetry in the $\nu_e$ flux is found to be $A_{e} = 7.0 \pm 4.9 \mathrm{(stat.)^{+1.3}_{-1.2}}$, when the asymmetry in the total flux is constrained to be zero.Comment: Complete (archival) version of SNO Phase I results. 78 pages, 46 figures, 34 table

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bahaism in Persia

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Managing projects in organizations : How to make the best use of time, techniques, and people

San Franciscoxix, 247 p.; 23 c

Framing decisions: decision-making that accounts for irrationality, people and constraints

The economic crisis of 2008-2009 was a transformational event: it demonstrated that smart people aren''t as smart as they and the public think. The crisis arose because a lot of highly educated people in high-impact positions- political power brokers, business leaders, and large segments of the general public-made a lot of bad decisions despite unprecedented access to data, highly sophisticated decision support systems, methodological advances in the decision sciences, and guidance from highly experienced experts. How could we get things so wrong? The answer, says J. Davidson Frame in Framin