Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2

Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors

And in the Darkness Bind Them: Equatorial Rings, B[e] Supergiants, and the Waists of Bipolar Nebulae

We report the discovery of two new circumstellar ring nebulae in the western Carina Nebula. The brighter object, SBW1, resembles a lidless staring eye and encircles a B1.5 Iab supergiant. Its size is identical to the inner ring around SN1987A, but SBW1's low N abundance indicates that the star didn't pass through a RSG phase. The fainter object, SBW2, is a more distorted ring, is N-rich, and has a central star that seems to be invisible. We discuss these two new nebulae in context with rings around SN1987A, Sher25, HD168625, RY Scuti, WeBo1, SuWt2, and others. The ring bearers fall into two groups: Five rings surround hot supergiants, and all except for the one known binary are carbon copies of the ring around SN1987A. We propose a link between these rings and B[e] supergiants, where the rings derive from the same material in an earlier B[e] phase. The remaining four rings surround evolved intermediate-mass stars; all members of this ring fellowship are close binaries, hinting that binary interactions govern the forging of such rings. We estimate that there may be several thousand more dark rings in the Galaxy, but we are scarcely aware of their existence due to selection effects. The lower-mass objects might be the equatorial density enhancements often invoked to bind the waists of bipolar PNe.Comment: AJ accepted, 27 page

A dusty pinwheel nebula around the massive star WR 104

Wolf-Rayet (WR) stars are luminous massive blue stars thought to be immediate precursors to the supernova terminating their brief lives. The existence of dust shells around such stars has been enigmatic since their discovery some 30 years ago; the intense radiation field from the star should be inimical to dust survival. Although dust-creation models, including those involving interacting stellar winds from a companion star, have been put forward, high-resolution observations are required to understand this phenomena. Here we present resolved images of the dust outflow around Wolf-Rayet WR 104, obtained with novel imaging techniques, revealing detail on scales corresponding to about 40 AU at the star. Our maps show that the dust forms a spatially confined stream following precisely a linear (or Archimedian) spiral trajectory. Images taken at two separate epochs show a clear rotation with a period of 220 +/- 30 days. Taken together, these findings prove that a binary star is responsible for the creation of the circumstellar dust, while the spiral plume makes WR 104 the prototype of a new class of circumstellar nebulae unique to interacting wind systems.Comment: 7 pages, 2 figures, Appearing in Nature (1999 April 08

Bouncing Universes with Varying Constants

We investigate the behaviour of exact closed bouncing Friedmann universes in theories with varying constants. We show that the simplest BSBM varying-alpha theory leads to a bouncing universe. The value of alpha increases monotonically, remaining approximately constant during most of each cycle, but increasing significantly around each bounce. When dissipation is introduced we show that in each new cycle the universe expands for longer and to a larger size. We find a similar effect for closed bouncing universes in Brans-Dicke theory, where $G$ also varies monotonically in time from cycle to cycle. Similar behaviour occurs also in varying speed of light theories

Space-based research in fundamental physics and quantum technologies

Space-based experiments today can uniquely address important questions related to the fundamental laws of Nature. In particular, high-accuracy physics experiments in space can test relativistic gravity and probe the physics beyond the Standard Model; they can perform direct detection of gravitational waves and are naturally suited for precision investigations in cosmology and astroparticle physics. In addition, atomic physics has recently shown substantial progress in the development of optical clocks and atom interferometers. If placed in space, these instruments could turn into powerful high-resolution quantum sensors greatly benefiting fundamental physics. We discuss the current status of space-based research in fundamental physics, its discovery potential, and its importance for modern science. We offer a set of recommendations to be considered by the upcoming National Academy of Sciences' Decadal Survey in Astronomy and Astrophysics. In our opinion, the Decadal Survey should include space-based research in fundamental physics as one of its focus areas. We recommend establishing an Astronomy and Astrophysics Advisory Committee's interagency ``Fundamental Physics Task Force'' to assess the status of both ground- and space-based efforts in the field, to identify the most important objectives, and to suggest the best ways to organize the work of several federal agencies involved. We also recommend establishing a new NASA-led interagency program in fundamental physics that will consolidate new technologies, prepare key instruments for future space missions, and build a strong scientific and engineering community. Our goal is to expand NASA's science objectives in space by including ``laboratory research in fundamental physics'' as an element in agency's ongoing space research efforts.Comment: a white paper, revtex, 27 pages, updated bibliograph

A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial

Medical Research Council, UK Department for International Development, and Wellcome Trust

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table

Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2

Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors

Evolution of the Scale Factor with a Variable Cosmological Term

Evolution of the scale factor a(t) in Friedmann models (those with zero pressure and a constant cosmological term Lambda) is well understood, and elegantly summarized in the review of Felten and Isaacman [Rev. Mod. Phys. 58, 689 (1986)]. Developments in particle physics and inflationary theory, however, increasingly indicate that Lambda ought to be treated as a dynamical quantity. We revisit the evolution of the scale factor with a variable Lambda-term, and also generalize the treatment to include nonzero pressure. New solutions are obtained and evaluated using a variety of observational criteria. Existing arguments for the inevitability of a big bang (ie., an initial state with a=0) are substantially weakened, and can be evaded in some cases with Lambda_0 (the present value of Lambda) well below current experimental limits.Comment: 29 pages, 12 figures (not included), LaTeX, uses Phys Rev D style files (revtex.cls, revtex.sty, aps.sty, aps10.sty, prabib.sty). To appear in Phys Rev

A Changing Wind Collision

We report on the first detection of a global change in the X-ray emitting properties of a wind–wind collision, thanks to XMM-Newton observations of the massive Small Magellenic Cloud (SMC) system HD 5980. While its light curve had remained unchanged between 2000 and 2005, the X-ray flux has now increased by a factor of ~2.5, and slightly hardened. The new observations also extend the observational coverage over the entire orbit, pinpointing the light-curve shape. It has not varied much despite the large overall brightening, and a tight correlation of fluxes with orbital separation is found without any hysteresis effect. Moreover, the absence of eclipses and of absorption effects related to orientation suggests a large size for the X-ray emitting region. Simple analytical models of the wind–wind collision, considering the varying wind properties of the eruptive component in HD 5980, are able to reproduce the recent hardening and the flux-separation relationship, at least qualitatively, but they predict a hardening at apastron and little change in mean flux, contrary to observations. The brightness change could then possibly be related to a recently theorized phenomenon linked to the varying strength of thin-shell instabilities in shocked wind regions