The structure of human CD23 and its interactions with IgE and CD21

The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcɛRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response. We have determined the three-dimensional structure of the C-type lectin domain of CD23 in solution by nuclear magnetic resonance spectroscopy. An analysis of concentration-dependent chemical shift perturbations have allowed us to identify the residues engaged in self-association to the trimeric state, whereas ligand-induced changes have defined the binding sites for IgE and CD21. The results further reveal that CD23 can bind both ligands simultaneously. Despite the C-type lectin domain structure, none of the interactions require calcium. We also find that IgE and CD23 can interact to form high molecular mass multimeric complexes. The interactions that we have described provide a solution to the paradox that CD23 is involved in both up- and down-regulation of IgE and provide a structural basis for the development of inhibitors of allergic disease

Exploiting Locally Imposed Anisotropies in (Ga,Mn)As: a Non-volatile Memory Device

Progress in (Ga,Mn)As lithography has recently allowed us to realize structures where unique magnetic anisotropy properties can be imposed locally in various regions of a given device. We make use of this technology to fabricate a device in which we study transport through a constriction separating two regions whose magnetization direction differs by 90 degrees. We find that the resistance of the constriction depends on the flow of the magnetic field lines in the constriction region and demonstrate that such a structure constitutes a non-volatile memory device

Passive phloem loading and long-distance transport in a synthetic tree-on-a-chip

Vascular plants rely on differences of osmotic pressure to export sugars from regions of synthesis (mature leaves) to sugar sinks (roots, fruits). In this process, known as M\"unch pressure flow, the loading of sugars from photosynthetic cells to the export conduit (the phloem) is crucial, as it sets the pressure head necessary to power long-distance transport. Whereas most herbaceous plants use active mechanisms to increase phloem concentration above that of the photosynthetic cells, in most tree species, for which transport distances are largest, loading seems to occur via passive symplastic diffusion from the mesophyll to the phloem. Here, we use a synthetic microfluidic model of a passive loader to explore the nonlinear dynamics that arise during export and determine the ability of passive loading to drive long-distance transport. We first demonstrate that in our device, phloem concentration is set by the balance between the resistances to diffusive loading from the source and convective export through the phloem. Convection-limited export corresponds to classical models of M\"unch transport, where phloem concentration is close to that of the source; in contrast, diffusion-limited export leads to small phloem concentrations and weak scaling of flow rates with the hydraulic resistance. We then show that the effective regime of convection-limited export is predominant in plants with large transport resistances and low xylem pressures. Moreover, hydrostatic pressures developed in our synthetic passive loader can reach botanically relevant values as high as 10 bars. We conclude that passive loading is sufficient to drive long-distance transport in large plants, and that trees are well suited to take full advantage of passive phloem loading strategies

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

On the Theory of Evolution Versus the Concept of Evolution: Three Observations

Here we address three misconceptions stated by Rice et al. in their observations of our article Paz-y-Miño and Espinosa (Evo Edu Outreach 2:655–675, 2009), published in this journal. The five authors titled their note “The Theory of Evolution is Not an Explanation for the Origin of Life.” First, we argue that it is fallacious to believe that because the formulation of the theory of evolution, as conceived in the 1800s, did not include an explanation for the origin of life, nor of the universe, the concept of evolution would not allow us to hypothesize the possible beginnings of life and its connections to the cosmos. Not only Stanley Miller’s experiments of 1953 led scientists to envision a continuum from the inorganic world to the origin and diversification of life, but also Darwin’s own writings of 1871. Second, to dismiss the notion of Rice et al. that evolution does not provide explanations concerning the universe or the cosmos, we identify compelling scientific discussions on the topics: Zaikowski et al. (Evo Edu Outreach 1:65–73, 2008), Krauss (Evo Edu Outreach 3:193–197, 2010), Peretó et al. (Orig Life Evol Biosph 39:395–406, 2009) and Follmann and Brownson (Naturwissenschaften 96:1265–1292, 2009). Third, although we acknowledge that the term Darwinism may not be inclusive of all new discoveries in evolution, and also that creationists and Intelligent Designers hijack the term to portray evolution as ideology, we demonstrate that there is no statistical evidence suggesting that the word Darwinism interferes with public acceptance of evolution, nor does the inclusion of the origin of life or the universe within the concept of evolution. We examine the epistemological and empirical distinction between the theory of evolution and the concept of evolution and conclude that, although the distinction is important, it should not compromise scientific logic

Suicide ideation of individuals in online social networks

Suicide explains the largest number of death tolls among Japanese adolescents in their twenties and thirties. Suicide is also a major cause of death for adolescents in many other countries. Although social isolation has been implicated to influence the tendency to suicidal behavior, the impact of social isolation on suicide in the context of explicit social networks of individuals is scarcely explored. To address this question, we examined a large data set obtained from a social networking service dominant in Japan. The social network is composed of a set of friendship ties between pairs of users created by mutual endorsement. We carried out the logistic regression to identify users' characteristics, both related and unrelated to social networks, which contribute to suicide ideation. We defined suicide ideation of a user as the membership to at least one active user-defined community related to suicide. We found that the number of communities to which a user belongs to, the intransitivity (i.e., paucity of triangles including the user), and the fraction of suicidal neighbors in the social network, contributed the most to suicide ideation in this order. Other characteristics including the age and gender contributed little to suicide ideation. We also found qualitatively the same results for depressive symptoms.Comment: 4 figures, 9 table

The Distances of the Magellanic Clouds

The present status of our knowledge of the distances to the Magellanic Clouds is evaluated from a post-Hipparcos perspective. After a brief summary of the effects of structure, reddening, age and metallicity, the primary distance indicators for the Large Magellanic Cloud are reviewed: The SN 1987A ring, Cepheids, RR Lyraes, Mira variables, and Eclipsing Binaries. Distances derived via these methods are weighted and combined to produce final "best" estimates for the Magellanic Clouds distance moduli.Comment: Invited review article to appear in ``Post Hipparcos Cosmic Candles'', F. Caputo & A. Heck (Eds.), Kluwer Academic Publ., Dordrecht, in pres

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation