Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding

Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than translation of the GPCR-binding helix 5. β-Strands 1 - 3 and helix 1 emerge as hubs in the allosteric network that links conformational changes in the GPCR-binding site to disordering of the distal nucleotide-binding site and consequent GDP release. Our approach and insights provide foundations for understanding disease-implicated G protein mutants, illuminating slow events in allosteric networks, and examining unbinding processes with slow off-rates

The Splenic Microvasculature of the Red-Eared Turtle (Chrysemys scripta elegans): A Study Concerning the Question Whether the Circulation is Anatomically Open or Closed

The splenic microvasculature of the turtle Chrysemys scripta elegans was studied by means of scanning electron microscopy of vascular corrosion casts and critical point dried tissue. In addition light- and transmission electron microscopic investigations were carried out. Within the organ the arteries are surrounded by periarterial lymphoid sheaths. The majority of the arterial capillaries, which emerge from these central arteries have open endings within the reticular meshwork of the red pulp. Approximately 10% of the capillaries directly connect with the venous origins. Since these venous capillaries of C. scripta elegans resemble those of nonsinusal mammalian spleens we termed them pulp venules. Several blood cells were seen in passage through the fenestrae of the pulpvenules. The blood cells overcome these wall pores either unimpeded or a striking deformation of the passing cell occurs. In the subcapsular region of the organ radially arranged venous vessels are observed, which drain into a collecting vein

Single-qubit unitary gates by graph scattering

We consider the effects of plane-wave states scattering off finite graphs, as an approach to implementing single-qubit unitary operations within the continuous-time quantum walk framework of universal quantum computation. Four semi-infinite tails are attached at arbitrary points of a given graph, representing the input and output registers of a single qubit. For a range of momentum eigenstates, we enumerate all of the graphs with up to $n=9$ vertices for which the scattering implements a single-qubit gate. As $n$ increases, the number of new unitary operations increases exponentially, and for $n>6$ the majority correspond to rotations about axes distributed roughly uniformly across the Bloch sphere. Rotations by both rational and irrational multiples of $\pi$ are found.Comment: 8 pages, 7 figure

Compounds from fermented noni exudates (fNE) selectively kill human cancer cells

Our recent studies involving fermented noni exudates (fNE) made from noni (Morinda citrifolia) have shown promising anti-cancer activities. Using an in vitro cell culture system, this study examines dozens of compounds isolated from fNE in order to identify specific compounds preferentially toxic to tumor cells. The compounds at concentrations of 20, 5, or 2 μg/ml were added to NL-20 non-tumor lung cells or A549 lung carcinoma cells and incubated for 48 hours. The cytotoxicity of the compounds on the cells was measured using the MTS cell proliferation assay. Several compounds were found selectively effective in killing more A549 tumor cells than NL-20 cells. An antioxidant assay was then performed to investigate if a correlation exists between antioxidant activity and selective cancer cell killing in our samples. We found that samples BGS, C2, BGL, and C1 had the highest amount of antioxidant activity. Of these samples, only C2 showed significant selective A549 cell killing (p\u3c.05 at 2μg/ml). Further testing is necessary to determine the mechanism of action and its possible role in immune activation

Broadcasting graphic war violence: the moral face of Channel 4

Drawing on empirical data from Channel 4 (C4) regarding the broadcasting of violent war imagery, and positioned within Goffman’s notion of the interaction ritual (1959, 1967), this article investigates how C4 negotiate potentially competing commercial, regulatory and moral requirements through processes of discretionary decision-making. Throughout, the article considers the extent to which these negotiations are presented through a series of ‘imaginings’ – of C4 and its audience – which serve to simultaneously guide and legitimate the decisions made. This manifestation of imaginings moves us beyond more blanket explanations of ‘branding’ and instead allows us to see the final programmes as the end product of a series of complex negotiations and interactions between C4 and those multiple external parties significant to the workings of their organization. The insights gleaned from this case study are important beyond the workings of C4 because they help elucidate how all institutions and organizations may view, organize and justify their practices (to both themselves and others) within the perceived constraints in which they operate

Low-energy electron scattering from methanol and ethanol

Measured and calculated differential cross sections for elastic (rotationally unresolved) electron scattering from two primary alcohols, methanol (CH3OH) and ethanol (C2H5OH), are reported. The measurements are obtained using the relative flow method with helium as the standard gas and a thin aperture as the collimating target gas source. The relative flow method is applied without the restriction imposed by the relative flow pressure conditions on helium and the unknown gas. The experimental data were taken at incident electron energies of 1, 2, 5, 10, 15, 20, 30, 50, and 100 eV and for scattering angles of 5°–130°. There are no previous reports of experimental electron scattering differential cross sections for CH3OH and C2H5OH in the literature. The calculated differential cross sections are obtained using two different implementations of the Schwinger multichannel method, one that takes all electrons into account and is adapted for parallel computers, and another that uses pseudopotentials and considers only the valence electrons. Comparison between theory and experiment shows that theory is able to describe low-energy electron scattering from these polyatomic targets quite well