Structure of the human histamine H1 receptor complex with doxepin

The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp?428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys?191(5.39) and/or Lys?179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.     

Quantum teleportation over 143 kilometres using active feed-forward

The quantum internet is predicted to be the next-generation information processing platform, promising secure communication and an exponential speed-up in distributed computation. The distribution of single qubits over large distances via quantum teleportation is a key ingredient for realizing such a global platform. By using quantum teleportation, unknown quantum states can be transferred over arbitrary distances to a party whose location is unknown. Since the first experimental demonstrations of quantum teleportation of independent external qubits, an internal qubit and squeezed states, researchers have progressively extended the communication distance. Usually this occurs without active feed-forward of the classical Bell-state measurement result, which is an essential ingredient in future applications such as communication between quantum computers. The benchmark for a global quantum internet is quantum teleportation of independent qubits over a free-space link whose attenuation corresponds to the path between a satellite and a ground station. Here we report such an experiment, using active feed-forward in real time. The experiment uses two free-space optical links, quantum and classical, over 143?kilometres between the two Canary Islands of La Palma and Tenerife. To achieve this, we combine advanced techniques involving a frequency-uncorrelated polarization-entangled photon pair source, ultra-low-noise single-photon detectors and entanglement-assisted clock synchronization. The average teleported state fidelity is well beyond the classical limit of two-thirds. Furthermore, we confirm the quality of the quantum teleportation procedure without feed-forward by complete quantum process tomography. Our experiment verifies the maturity and applicability of such technologies in real-world scenarios, in particular for future satellite-based quantum teleportation.     

Russian Nuclear Rocket Engine Design for Mars Exploration

This paper is to promote investigation into the nuclear rocket engine (NRE) propulsion option that is considered as a key technology for manned Mars exploration. Russian NRE developed since the 1950s in the former Soviet Union to a full-cale prototype by the 1990s is viewed as advantageous and the most suit-able starting point concept for manned Mars mission application study. The main features of Russian het-erogeneous core NRE design are described and the most valuable experimental performance results are summarized. These results have demonstrated the significant specific impulse performance advantage of the NRE over conventional liquid rocket engine (LRE) propulsion technologies. Based on past experience, the recent developments in the field of high-temperature nuclear fuels, and the latest conceptual studies, the developed NRE concept is suggested to be upgraded to the nuclear power and propulsion system (NPPS), more suitable for future manned Mars missions. Although the NRE still needs development for space appli-cation, the problems are solvable with additional effort and funding.     

Reactive oxygen species produced by NADPH oxidase regulate plant cell growth

Cell expansion is a central process in plant morphogenesis, and the elongation of roots and root hairs is essential for uptake of minerals and water from the soil. Ca2+ influx from the extracellular store is required for (and sets the rates of) cell elongation in roots. Arabidopsis thaliana rhd2 mutants are defective in Ca2+ uptake and consequently cell expansion is compromised--rhd2 mutants have short root hairs and stunted roots. To determine the regulation of Ca2+ acquisition in growing root cells we show here that RHD2 is an NADPH oxidase, a protein that transfers electrons from NADPH to an electron acceptor leading to the formation of reactive oxygen species (ROS). We show that ROS accumulate in growing wild-type (WT) root hairs but their levels are markedly decreased in rhd2 mutants. Blocking the activity of the NADPH oxidase with diphenylene iodonium (DPI) inhibits ROS formation and phenocopies Rhd2-. Treatment of rhd2 roots with ROS partly suppresses the mutant phenotype and stimulates the activity of plasma membrane hyperpolarization-activated Ca2+ channels, the predominant root Ca2+ acquisition system. This indicates that NADPH oxidases control development by making ROS that regulate plant cell expansion through the activation of Ca2+ channels.     

A Realistic Look at Putnam's Argument Against Realism

Putnam's ``model-theoretic' argument against metaphysical realism presupposes that an ideal scientific theory is expressible in a first order language. The central aim of this paper is to show that Putnam's ``first orderization' of science, although unchallenged by numerous critics, makes his argument unsound even for adequate theories, never mind an ideal one. To this end, I will argue that quantitative theories, which dominate the natural sciences, can be adequately interpreted and evaluated only with the help of so-called theories of measurement whose epistemological and methodological purpose is to justify systematic assignments of quantitative values to objects in the world. And, in order to fulfill this purpose, theories of measurement must have an essentially higher order logical structure. As a result, Putnam's argument fails because much of science turns out to rest on essentially higher order theoretical assumptions about the world.     

Deformation and rupture of the oceanic crust may control growth of Hawaiian volcanoes

Hawaiian volcanoes are formed by the eruption of large quantities of basaltic magma related to hot-spot activity below the Pacific Plate. Despite the apparent simplicity of the parent process--emission of magma onto the oceanic crust--the resulting edifices display some topographic complexity. Certain features, such as rift zones and large flank slides, are common to all Hawaiian volcanoes, indicating similarities in their genesis; however, the underlying mechanism controlling this process remains unknown. Here we use seismological investigations and finite-element mechanical modelling to show that the load exerted by large Hawaiian volcanoes can be sufficient to rupture the oceanic crust. This intense deformation, combined with the accelerated subsidence of the oceanic crust and the weakness of the volcanic edifice/oceanic crust interface, may control the surface morphology of Hawaiian volcanoes, especially the existence of their giant flank instabilities. Further studies are needed to determine whether such processes occur in other active intraplate volcanoes.     

Metric unidimensional scaling and global optimization

For the problem of metric unidimensional scaling, the number of local minima is estimated. For locating the globally optimal solution we develop an approach, called the smoothing technique. Although not guaranteed inevitably to locate the global optimum, the smoothing technique did so in all computational experiments where the global optimum was known.