Intraspecific Epitopic Variation in a Carbohydrate Antigen Exposed on the Surface of Trichostrongylus colubriformis Infective L3 Larvae

The carbohydrate larval antigen, CarLA, is present on the exposed surface of all strongylid nematode infective L3 larvae tested, and antibodies against CarLA can promote rapid immune rejection of incoming Trichostrongylus colubriformis larvae in sheep. A library of ovine recombinant single chain Fv (scFv) antibody fragments, displayed on phage, was prepared from B cell mRNA of field-immune sheep. Phage displaying scFvs that bind to the surface of living exsheathed T. colubriformis L3 larvae were identified, and the majority of worm-binding scFvs recognized CarLA. Characterization of greater than 500 worm surface binding phage resulted in the identification of nine different anti-CarLA scFvs that recognized three distinct T. colubriformis CarLA epitopes based on blocking and additive ELISA. All anti-CarLA scFvs were specific to the T. colubriformis species of nematode. Each of the three scFv epitope classes displayed identical Western blot recognition patterns and recognized the exposed surface of living T. colubriformis exsheathed L3 larvae. Surprisingly, each of the anti-CarLA scFvs was able to bind to only a subset of worms. Double-labelling indirect immunofluorescence revealed that the three classes of anti-CarLA scFvs recognize distinct, non-overlapping, T. colubriformis sub-populations. These results demonstrate that individual T. colubriformis L3 larvae display only one of at least three distinct antigenic forms of CarLA on their surface at any given time, and suggest that antigenic variation within CarLA is likely a mechanism of immune evasion in strongylid nematodes

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress

© 2017 the American Physiological Society. This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P _ 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P \u3c 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (Hb-Sat: 56 ± 13 vs. 71 ± 6%; P = 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P \u3c 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P \u3c 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress. NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress

Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

We describe a computational protocol to aid the design of small molecule and peptide drugs that target protein-protein interactions, particularly for anti-cancer therapy. To achieve this goal, we explore multiple strategies, including finding binding hot spots, incorporating chemical similarity and bioactivity data, and sampling similar binding sites from homologous protein complexes. We demonstrate how to combine existing interdisciplinary resources with examples of semi-automated workflows. Finally, we discuss several major problems, including the occurrence of drug-resistant mutations, drug promiscuity, and the design of dual-effect inhibitors.Fil: Goncearenco, Alexander. National Institutes of Health; Estados UnidosFil: Li, Minghui. Soochow University; China. National Institutes of Health; Estados UnidosFil: Simonetti, Franco Lucio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Shoemaker, Benjamin A. National Institutes of Health; Estados UnidosFil: Panchenko, Anna R. National Institutes of Health; Estados Unido

Initial Data and Coordinates for Multiple Black Hole Systems

We present here an alternative approach to data setting for spacetimes with multiple moving black holes generalizing the Kerr-Schild form for rotating or non-rotating single black holes to multiple moving holes. Because this scheme preserves the Kerr-Schild form near the holes, it selects out the behaviour of null rays near the holes, may simplify horizon tracking, and may prove useful in computational applications. For computational evolution, a discussion of coordinates (lapse function and shift vector) is given which preserves some of the properties of the single-hole Kerr-Schild form

Control sideband generation for dual-recycled laser interferometric gravitational wave detectors

We present a discussion of the problems associated with generation of multiple control sidebands for length sensing and control of dual-recycled, cavity-enhanced Michelson interferometers and the motivation behind more complicated sideband generation methods. We focus on the Mach–Zehnder interferometer as a topological solution to the problem and present results from tests carried out at the Caltech 40 m prototype gravitational wave detector. The consequences for sensing and control for advanced interferometry are discussed, as are the implications for future interferometers such as Advanced LIGO

Very high frequency gravitational wave background in the universe

Astrophysical sources of high frequency gravitational radiation are considered in association with a new interest to very sensitive HFGW receivers required for the laboratory GW Hertz experiment. A special attention is paid to the phenomenon of primordial black holes evaporation. They act like black body to all kinds of radiation, including gravitons, and, therefore, emit an equilibrium spectrum of gravitons during its evaporation. Limit on the density of high frequency gravitons in the Universe is obtained, and possibilities of their detection are briefly discussed.Comment: 14 page

From one cell to the whole froth: a dynamical map

We investigate two and three-dimensional shell-structured-inflatable froths, which can be constructed by a recursion procedure adding successive layers of cells around a germ cell. We prove that any froth can be reduced into a system of concentric shells. There is only a restricted set of local configurations for which the recursive inflation transformation is not applicable. These configurations are inclusions between successive layers and can be treated as vertices and edges decorations of a shell-structure-inflatable skeleton. The recursion procedure is described by a logistic map, which provides a natural classification into Euclidean, hyperbolic and elliptic froths. Froths tiling manifolds with different curvature can be classified simply by distinguishing between those with a bounded or unbounded number of elements per shell, without any a-priori knowledge on their curvature. A new result, associated with maximal orientational entropy, is obtained on topological properties of natural cellular systems. The topological characteristics of all experimentally known tetrahedrally close-packed structures are retrieved.Comment: 20 Pages Tex, 11 Postscript figures, 1 Postscript tabl

Rationality as the Rule of Reason

The demands of rationality are linked both to our subjective normative perspective (given that rationality is a person-level concept) and to objective reasons or favoring relations (given that rationality is non-contingently authoritative for us). In this paper, I propose a new way of reconciling the tension between these two aspects: roughly, what rationality requires of us is having the attitudes that correspond to our take on reasons in the light of our evidence, but only if it is competent. I show how this view can account for structural rationality on the assumption that intentions and beliefs as such involve competent perceptions of downstream reasons, and explore various implications of the account

Properties of Accretion Flows Around Coalescing Supermassive Black Holes

What are the properties of accretion flows in the vicinity of coalescing supermassive black holes (SBHs)? The answer to this question has direct implications for the feasibility of coincident detections of electromagnetic (EM) and gravitational wave (GW) signals from coalescences. Such detections are considered to be the next observational grand challenge that will enable testing general relativity in the strong, nonlinear regime and improve our understanding of evolution and growth of these massive compact objects. In this paper we review the properties of the environment of coalescing binaries in the context of the circumbinary disk and hot, radiatively inefficient accretion flow models and use them to mark the extent of the parameter space spanned by this problem. We report the results from an ongoing, general relativistic, hydrodynamical study of the inspiral and merger of black holes, motivated by the latter scenario. We find that correlated EM+GW oscillations can arise during the inspiral phase followed by the gradual rise and subsequent drop-off in the light curve at the time of coalescence. While there are indications that the latter EM signature is a more robust one, a detection of either signal coincidentally with GWs would be a convincing evidence for an impending SBH binary coalescence. The observability of an EM counterpart in the hot accretion flow scenario depends on the details of a model. In the case of the most massive binaries observable by the Laser Interferometer Space Antenna, upper limits on luminosity imply that they may be identified by EM searches out to z~0.1-1. However, given the radiatively inefficient nature of the gas flow, we speculate that a majority of massive binaries may appear as low luminosity AGN in the local universe.Comment: Revised version accepted to Class. Quantum Grav. for proceedings of 8th LISA Symposium. 15 pages, 3 figures, includes changes suggested in referee report

Are moving punctures equivalent to moving black holes?

When simulating the inspiral and coalescence of a binary black-hole system, special care needs to be taken in handling the singularities. Two main techniques are used in numerical-relativity simulations: A first and more traditional one ``excises'' a spatial neighbourhood of the singularity from the numerical grid on each spacelike hypersurface. A second and more recent one, instead, begins with a ``puncture'' solution and then evolves the full 3-metric, including the singular point. In the continuum limit, excision is justified by the light-cone structure of the Einstein equations and, in practice, can give accurate numerical solutions when suitable discretizations are used. However, because the field variables are non-differentiable at the puncture, there is no proof that the moving-punctures technique is correct, particularly in the discrete case. To investigate this question we use both techniques to evolve a binary system of equal-mass non-spinning black holes. We compare the evolution of two curvature 4-scalars with proper time along the invariantly-defined worldline midway between the two black holes, using Richardson extrapolation to reduce the influence of finite-difference truncation errors. We find that the excision and moving-punctures evolutions produce the same invariants along that worldline, and thus the same spacetimes throughout that worldline's causal past. This provides convincing evidence that moving-punctures are indeed equivalent to moving black holes.Comment: 4 pages, 3 eps color figures; v2 = major revisions to introduction & conclusions based on referee comments, but no change in analysis or result