Down regulation of the high-affinity IgE receptor associated with successful treatment of chronic idiopathic urticaria with omalizumab

Chronic idiopathic urticaria is a condition that is often controllable with antihistamine therapy. However, some patients have disease burden that is difficult to manage, non-responsive to antihistamines and often requires immunosuppressive medications such as corticosteroids or cyclosporine. We present here a study that demonstrates the effectiveness of omalizumab in treating this condition and the temporal relationship between improvement and down regulation of the high affinity IgE receptor (FcεRI). For this, blood samples were obtained from a symptomatic patient before each treatment and processed for flow cytometric analysis of FcεRI levels on the surface of blood basophils. Down regulation of FcεRI was observed in association with significant clinical improvement and discontinuation of immunosuppressive medications

Classical skyrmions in SU(N)/SO(N) cosets

We construct the skyrmion solutions appearing in the coset spaces SU(N)/SO(N) for N > 2 and compute their classical mass. For N = 3, the third homotopy group pi_3(SU(3)/SO(3)) = Z_4 implies the existence of two distinct solutions: the skyrmion of winding number two has spherical symmetry and is found to be the lightest non-trivial field configuration; the skyrmion and antiskyrmion of winding number plus and minus one are slightly heavier and of toroidal shape. For N >= 4, there is only one skyrmion since the third homotopy group is Z_2. It is found to have spherical symmetry and is significantly lighter than the N = 3 solutions.Comment: 14 pages, 3 figures; v2: discussion improve

Scanning-probe spectroscopy of semiconductor donor molecules

Semiconductor devices continue to press into the nanoscale regime, and new applications have emerged for which the quantum properties of dopant atoms act as the functional part of the device, underscoring the necessity to probe the quantum structure of small numbers of dopant atoms in semiconductors[1-3]. Although dopant properties are well-understood with respect to bulk semiconductors, new questions arise in nanosystems. For example, the quantum energy levels of dopants will be affected by the proximity of nanometer-scale electrodes. Moreover, because shallow donors and acceptors are analogous to hydrogen atoms, experiments on small numbers of dopants have the potential to be a testing ground for fundamental questions of atomic and molecular physics, such as the maximum negative ionization of a molecule with a given number of positive ions[4,5]. Electron tunneling spectroscopy through isolated dopants has been observed in transport studies[6,7]. In addition, Geim and coworkers identified resonances due to two closely spaced donors, effectively forming donor molecules[8]. Here we present capacitance spectroscopy measurements of silicon donors in a gallium-arsenide heterostructure using a scanning probe technique[9,10]. In contrast to the work of Geim et al., our data show discernible peaks attributed to successive electrons entering the molecules. Hence this work represents the first addition spectrum measurement of dopant molecules. More generally, to the best of our knowledge, this study is the first example of single-electron capacitance spectroscopy performed directly with a scanning probe tip[9].Comment: In press, Nature Physics. Original manuscript posted here; 16 pages, 3 figures, 5 supplementary figure

Cleavage of Kininogen and Subsequent Bradykinin Release by the Complement Component: Mannose-Binding Lectin-Associated Serine Protease (MASP)-1

Bradykinin (BK), generated from high-molecular-weight kininogen (HK) is the major mediator of swelling attacks in hereditary angioedema (HAE), a disease associated with C1-inhibitor deficiency. Plasma kallikrein, activated by factor XIIa, is responsible for most of HK cleavage. However other proteases, which activate during episodes of angioedema, might also contribute to BK production. The lectin pathway of the complement system activates after infection and oxidative stress on endothelial cells generating active serine proteases: MASP-1 and MASP-2. Our aim was to study whether activated MASPs are able to digest HK to release BK. Initially we were trying to find potential new substrates of MASP-1 in human plasma by differential gel electrophoresis, and we identified kininogen cleavage products by this proteomic approach. As a control, MASP-2 was included in the study in addition to MASP-1 and kallikrein. The proteolytic cleavage of HK by MASPs was followed by SDS-PAGE, and BK release was detected by HPLC. We showed that MASP-1 was able to cleave HK resulting in BK production. MASP-2 could also cleave HK but could not release BK. The cleavage pattern of MASPs is similar but not strictly identical to that of kallikrein. The catalytic efficiency of HK cleavage by a recombinant version of MASP-1 and MASP-2 was about 4.0×102 and 2.7×102 M−1s−1, respectively. C1-inhibitor, the major inhibitor of factor XIIa and kallikrein, also prevented the cleavage of HK by MASPs. In all, a new factor XII- and kallikrein-independent mechanism of bradykinin production by MASP-1 was demonstrated, which may contribute to the pro-inflammatory effect of the lectin pathway of complement and to the elevated bradykinin levels in HAE patients

Omalizumab efficacy in cases of chronic spontaneous urticaria is not explained by the inhibition of sera activity in effector cells

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb's mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation

The S-Matrix in Twistor Space

The simplicity and hidden symmetries of (Super) Yang-Mills and (Super)Gravity scattering amplitudes suggest the existence of a "weak-weak" dual formulation in which these structures are made manifest at the expense of manifest locality. We suggest that this dual description lives in (2,2) signature and is naturally formulated in twistor space. We recast the BCFW recursion relations in an on-shell form that begs to be transformed into twistor space. Our twistor transformation is inspired by Witten's, but differs in treating twistor and dual twistor variables more equally. In these variables the three and four-point amplitudes are amazingly simple; the BCFW relations are represented by diagrammatic rules that precisely define the "twistor diagrams" of Andrew Hodges. The "Hodges diagrams" for Yang-Mills theory are disks and not trees; they reveal striking connections between amplitudes and suggest a new form for them in momentum space. We also obtain a twistorial formulation of gravity. All tree amplitudes can be combined into an "S-Matrix" functional which is the natural holographic observable in asymptotically flat space; the BCFW formula turns into a quadratic equation for this "S-Matrix", providing a holographic description of N=4 SYM and N=8 Supergravity at tree level. We explore loop amplitudes in (2,2) signature and twistor space, beginning with a discussion of IR behavior. We find that the natural pole prescription renders the amplitudes well-defined and free of IR divergences. Loop amplitudes vanish for generic momenta, and in twistor space are even simpler than their tree-level counterparts! This further supports the idea that there exists a sharply defined object corresponding to the S-Matrix in (2,2) signature, computed by a dual theory naturally living in twistor space.Comment: V1: 46 pages + 23 figures. Less telegraphic abstract in the body of the paper. V2: 49 pages + 24 figures. Largely expanded set of references included. Some diagrammatic clarifications added, minor typo fixe

Quantifying the Spatial Ecology of Wide-Ranging Marine Species in the Gulf of California: Implications for Marine Conservation Planning

There is growing interest in systematic establishment of marine protected area (MPA) networks and representative conservation sites. This movement toward networks of no-take zones requires that reserves are deliberately and adequately spaced for connectivity. Here, we test the network functionality of an ecoregional assessment configuration of marine conservation areas by evaluating the habitat protection and connectivity offered to wide-ranging fauna in the Gulf of California (GOC, Mexico). We first use expert opinion to identify representative species of wide-ranging fauna of the GOC. These include leopard grouper, hammerhead sharks, California brown pelicans and green sea turtles. Analyzing habitat models with both structural and functional connectivity indexes, our results indicate that the configuration includes large proportions of biologically important habitat for the four species considered (25–40%), particularly, the best quality habitats (46–57%). Our results also show that connectivity levels offered by the conservation area design for these four species may be similar to connectivity levels offered by the entire Gulf of California, thus indicating that connectivity offered by the areas may resemble natural connectivity. The selected focal species comprise different life histories among marine or marine-related vertebrates and are associated with those habitats holding the most biodiversity values (i.e. coastal habitats); our results thus suggest that the proposed configuration may function as a network for connectivity and may adequately represent the marine megafauna in the GOC, including the potential connectivity among habitat patches. This work highlights the range of approaches that can be used to quantify habitat protection and connectivity for wide-ranging marine species in marine reserve networks

Peripheral vasoconstriction influences thenar oxygen saturation as measured by near-infrared spectroscopy

Purpose: Near-infrared spectroscopy has been used as a noninvasive monitoring tool for tissue oxygen saturation (StO2) in acutely ill patients. This study aimed to investigate whether local vasoconstriction induced by body surface cooling significantly influences thenar StO2 as measured by InSpectra model 650. Methods: Eight healthy individuals (age 26 ± 6 years) participated in the study. Using a cooling blanket, we aimed to cool the entire body surface to induce vasoconstriction in the skin without any changes in central temperature. Thenar StO2 was noninvasively measured during a 3-min vascular occlusion test using InSpectra model 650 with a 15-mm probe. Measurements were analyzed for resting StO2 values, rate of StO2 desaturation (RdecStO2, %/min), and rate of StO2 recovery (RincStO2, %/s) before, during, and after skin cooling. Measurements also included heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), capillary refill time (CRT), forearm-to-fingertip skintemperature gradient (Tskin-diff), perfusion index (PI), and tissue hemoglobin index (THI). Results: In all subjects MAP, CO, SV, and core temperature did not change during the procedure. Skin cooling resulted in a significant decrease in StO2 from 82% (80-87) to 72% (70-77) (P\0.05) and in RincStO2 from 3.0%/s (2.8-3.3) to 1.7%/s (1.1-2.0) (P\0.05). Similar changes in CRT, Tskin-diff, and PI were also observed: from 2.5 s (2.0-3.0) to 8.5 s (7.2-11.0) (P\0.05), from 1.0 (-1.6-1.8) to 3.1 (P\0.05), and from 10.0% (9.1-11.7) to 2.5

Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape

We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase I hypersensitivity analysis followed by sequencing (DNase-seq) experiment with accuracy comparable to that of chromatin immunoprecipitation followed by sequencing (ChIP-seq). We applied PIQ to analyze DNase-seq data from mouse embryonic stem cells differentiating into prepancreatic and intestinal endoderm. We identified 120 and experimentally validated eight 'pioneer' TF families that dynamically open chromatin. Four pioneer TF families only opened chromatin in one direction from their motifs. Furthermore, we identified 'settler' TFs whose genomic binding is principally governed by proximity to open chromatin. Our results support a model of hierarchical TF binding in which directional and nondirectional pioneer activity shapes the chromatin landscape for population by settler TFs.National Institutes of Health (U.S.) (Common Fund 5UL1DE019581)National Institutes of Health (U.S.) (Common Fund RL1DE019021)National Institutes of Health (U.S.) (Common Fund 5TL1EB008540)National Institutes of Health (U.S.) (Grant 1U01HG007037)National Institutes of Health (U.S.) (Grant 5P01NS055923