"Boom" and "Bust" cycles in virus growth suggest multiple selective forces in influenza a evolution

<p>Abstract</p> <p>Background</p> <p>Influenza A virus evolution in humans is driven at least in part by mutations allowing the virus to escape antibody neutralization. Little is known about the evolution of influenza in birds, a major reservoir of influenza A.</p> <p>Methods</p> <p>Neutralizing polyclonal antiserum was raised in chicken against reassortant influenza virus, CalX, bearing the hemagglutinin (HA) and neuraminidase (NA) of A/California/7/2004 [H3N2]. CalX was serially passaged in the presence of anti-CalX polyclonal IgY to derive viruses capable of growth in the presence of antibody.</p> <p>Results</p> <p>Polyclonal chicken antibody neutralized both HA activity and infection by CalX, but had no effect on a strain bearing an earlier human H3 and an irrelevant neuraminidase (A/Memphis/71-Bellamy/42 [H3N1]). Surprisingly, most of the antibody-resistant viruses were still at least partially sensitive to neutralization of HA activity and viral infection. Although mutant HA genes bearing changes that might affect antibody neutralization were identified, the vast majority of HA sequences obtained were identical to wild type, and no individual mutant sequence was found in more than one passage, suggesting that those mutations that were observed did not confer sufficient selective advantage to come to dominate the population. Different passages yielded infectious foci of varying size and plaques of varying size and morphology. Yields of infectious virus and relative frequency of different morphologies changed markedly from passage to passage. Sequences of bulk, uncloned PCR products from antibody-resistant passages indicated changes in the PB2 and PA proteins with respect to the wild type virus.</p> <p>Conclusions</p> <p>Each antibody-selected passage consisted of a variety of different cocirculating populations, rather than pure populations of virus able to escape antibody by changes in antibody epitopes. The ability to escape antibody is apparently due to changes in genes encoding the viral polymerase complex, probably resulting in more robust viral replication, allowing the few virus particles not completely neutralized by antibody to rapidly produce large numbers of progeny. Our data suggest that the relative success of an individual variant may depend on both its own gain and loss of fitness, as well as that of its cocirculating variants.</p

Time-dependent calculation of ionization in Potassium at mid-infrared wavelengths

We study the dynamics of the Potassium atom in the mid-infrared, high intensity, short laser pulse regime. We ascertain numerical convergence by comparing the results obtained by the direct expansion of the time-dependent Schroedinger equation onto B-Splines, to those obtained by the eigenbasis expansion method. We present ionization curves in the 12-, 13-, and 14-photon ionization range for Potassium. The ionization curve of a scaled system, namely Hydrogen starting from the 2s, is compared to the 12-photon results. In the 13-photon regime, a dynamic resonance is found and analyzed in some detail. The results for all wavelengths and intensities, including Hydrogen, display a clear plateau in the peak-heights of the low energy part of the Above Threshold Ionization (ATI) spectrum, which scales with the ponderomotive energy Up, and extends to 2.8 +- 0.5 Up.Comment: 15 two-column pages with 15 figures, 3 tables. Accepted for publication in Phys. Rev A. Improved figures, language and punctuation, and made minor corrections. We also added a comparison to the ADK theor

Theory and applications of atomic and ionic polarizabilities

Atomic polarization phenomena impinge upon a number of areas and processes in physics. The dielectric constant and refractive index of any gas are examples of macroscopic properties that are largely determined by the dipole polarizability. When it comes to microscopic phenomena, the existence of alkaline-earth anions and the recently discovered ability of positrons to bind to many atoms are predominantly due to the polarization interaction. An imperfect knowledge of atomic polarizabilities is presently looming as the largest source of uncertainty in the new generation of optical frequency standards. Accurate polarizabilities for the group I and II atoms and ions of the periodic table have recently become available by a variety of techniques. These include refined many-body perturbation theory and coupled-cluster calculations sometimes combined with precise experimental data for selected transitions, microwave spectroscopy of Rydberg atoms and ions, refractive index measurements in microwave cavities, ab initio calculations of atomic structures using explicitly correlated wave functions, interferometry with atom beams, and velocity changes of laser cooled atoms induced by an electric field. This review examines existing theoretical methods of determining atomic and ionic polarizabilities, and discusses their relevance to various applications with particular emphasis on cold-atom physics and the metrology of atomic frequency standards.Comment: Review paper, 44 page

Beyond the caveman: Rethinking masculinity in relation to men’s help-seeking

publication-status: Publishedtypes: ArticleStatistically, men make less use of health-care services than women. This has been interpreted as the result of the ‘hegemonic’ masculine code in which ‘real’ men are understood to be physically fit, uninterested in their health and self-reliant. However, less attention has been paid to understanding how hegemonic masculinity intersects with the wider western socio-cultural contexts of men’s help-seeking, particularly the valorization of health as a form of social achievement. This article presents the results of interviews with 14 higher socio-economic status (SES) men to uncover their ‘interpretive repertoires’ in relation to health and illness, help-seeking and masculinity. Although many interviewees drew on the stereotype of the ‘Neanderthal Man’ who avoids the doctors to explain help-seeking by men ‘in general’, they constructed their own experiences of help-seeking in terms of being responsible, problem-solving and in control. It is argued that the framing of help-seeking in terms of ‘taking action’ chimes with an increasingly pro-active ‘expert patient’ approach within western health-care. This conceptual reconstruction of the dominant masculine code in relation to helpseeking, from ‘Neanderthal Man’ to ‘Action Man’, may lead to greater gender equality in terms of accessing health-care. However, it has the potential to exacerbate social inequalities between men from different SES groups

Convergent close-coupling method for positron scattering from noble gases

We present the convergent close-coupling formulation for positron scattering from noble gases (Ne, Ar, Kr and Xe) within the single-center approximation. Target functions are described in a model of six p-electrons above an inert Hartree–Fock core with only one-electron excitations from the outer p6 shell allowed. Target states have been obtained using a Sturmian (Laguerre) basis in order to model coupling to ionization and positronium (Ps) formation channels. Such an approach is unable to yield explicit Ps-formation cross sections, but is valid below this threshold and above the ionization threshold. The present calculations are found to show good agreement with recent measurements

Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors:Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis

[Image: see text] Trypanosoma bruceiN-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT

Transfer of immunoglobulins through the mammary endothelium and epithelium and in the local lymph node of cows during the initial response after intramammary challenge with E. coli endotoxin

<p>Abstract</p> <p>Background</p> <p>The first hours after antigen stimulation, interactions occur influencing the outcome of the immunological reaction. Immunoglobulins originate in blood and/or are locally synthesized. The transfer of Ig isotypes (Igs) in the udder has been studied previously but without the possibility to distinguish between the endothelium and the epithelium. The purpose of this study was to map the Ig transfer through each barrier, separately, and Ig transfer in the local lymph nodes of the bovine udder during the initial innate immune response.</p> <p>Methods</p> <p>The content of IgG1, IgG2, IgM, IgA and albumin (BSA) was examined in peripheral/afferent mammary lymph and lymph leaving the supramammary lymph nodes, and in blood and milk before (0 h) and during 4 hours after intramammary challenge with <it>Esherichia coli </it>endotoxin in 5 cows.</p> <p>Results</p> <p>Igs increased most rapidly in afferent lymph resulting in higher concentrations than in efferent lymph at postinfusion hour (PIH) 2, contrary to before challenge. Ig concentrations in milk were lower than in lymph; except for IgA at 0 h; and they increased more slowly. <it>Afferent lymph:serum </it>and <it>efferent lymph:serum </it>concentration ratios (CR) of Igs were similar to those of BSA but slightly lower. <it>Milk:afferent lymph </it>(M:A) CRs of each Ig, except for IgG2, showed strikingly different pattern than those of BSA. The M:A CR of IgG1, IgM and IgA were higher than that of BSA before challenge and the CR of IgA and IgG1 remained higher also thereafter. At PIH 2 there was a drop in Ig CRs, except for IgG2, in contrast to the BSA CR which gradually increased. The M:A CR of IgM and Ig A <it>decreased </it>from 0 h to PIH 4, in spite of increasing permeability.</p> <p>Conclusion</p> <p>The transfer of Igs through the <it>endothelium </it>appeared to be merely a result of diffusion although their large molecular size may hamper the diffusion. The transfer through the <it>epithelium </it>and the Ig concentrations in milk seemed more influenced by selective mechanisms and local sources, respectively. Our observations indicate a selective mechanism in the transfer of IgG1 through the epithelium also in lactating glands, not previously shown; a local synthesis of IgA and possibly of IgM, released primarily into milk, not into tissue fluid; that IgG2 transfer through both barriers is a result of passive diffusion only and that the content of efferent lymph is strongly influenced by IgG1, IgM and IgA in the mammary tissue, brought to the lymph node by afferent lymph.</p