Few and Far Between: How HIV May Be Evading Antibody Avidity

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Towards precision distances and 3D dust maps using broadband Period--Magnitude relations of RR Lyrae stars

We determine the period-magnitude relations of RR Lyrae stars in 13 photometric bandpasses from 0.4 to 12 {\mu}m using timeseries observations of 134 stars. The Bayesian formalism, extended from our previous work to include the effects of line-of-sight dust extinction, allows for the simultaneous inference of the posterior distribution of the mean absolute magnitude, slope of the period-magnitude power-law, and intrinsic scatter about a perfect power-law for each bandpass. In addition, the distance modulus and line-of-sight dust extinction to each RR Lyrae star in the calibration sample is determined, yielding a sample median fractional distance error of 0.66%. The intrinsic scatter in all bands appears to be larger than the photometric errors, except in WISE W1 (3.4 {\mu}m) and W2 (4.6 {\mu}m) where the photometric error ($\sigma \approx 0.05$ mag) is to be comparable or larger than the intrinsic scatter. Additional observations at these wavelengths could improve the inferred distances to these sources further. As an application of the methodology, we infer the distance to the RRc-type star RZCep at low Galactic latitude ($b = 5.5^\circ$) to be $\mu=8.0397\pm0.0123$ mag ($405.4\pm2.3$ pc) with colour excess $E(B-V)=0.2461\pm0.0089$ mag. This distance, equivalent to a parallax of $2467\pm14$ microarcsec, is consistent with the published HST parallax measurement but with an uncertainty that is 13 times smaller than the HST measurement. If our measurements (and methodology) hold up to scrutiny, the distances to these stars have been determined to an accuracy comparable to those expected with Gaia. As RR Lyrae are one of the primary components of the cosmic distance ladder, the achievement of sub-1% distance errors within a formalism that accounts for dust extinction may be considered a strong buttressing of the path to eventual 1% uncertainties in Hubble's constant.Comment: 21 pages, 29 figures, 2 tables, abstract abridged for arXiv. Comments solicited on referee report (received June 9, 2014) linked: https://gist.github.com/profjsb/c6c4e2f3a20ea02f1762 . Public archive of code used to generate results and figures: https://github.com/ckleinastro/period_luminosity_relation_fittin

Probing the distance and morphology of the Large Magellanic Cloud with RR Lyrae stars

We present a Bayesian analysis of the distances to 15,040 Large Magellanic Cloud (LMC) RR Lyrae stars using $V$- and $I$-band light curves from the Optical Gravitational Lensing Experiment, in combination with new $z$-band observations from the Dark Energy Camera. Our median individual RR Lyrae distance statistical error is 1.89 kpc (fractional distance error of 3.76 per cent). We present three-dimensional contour plots of the number density of LMC RR Lyrae stars and measure a distance to the core LMC RR Lyrae centre of ${50.2482\pm0.0546 {\rm(statistical)} \pm0.4628 {\rm(systematic)} {\rm kpc}}$, equivalently ${\mu_{\rm LMC}=18.5056\pm0.0024 {\rm(statistical)} \pm0.02 {\rm(systematic)}}$. This finding is statistically consistent with and four times more precise than the canonical value determined by a recent meta-analysis of 233 separate LMC distance determinations. We also measure a maximum tilt angle of $11.84^{\circ}\pm0.80^{\circ}$ at a position angle of $62^\circ$, and report highly precise constraints on the $V$, $I$, and $z$ RR Lyrae period--magnitude relations. The full dataset of observed mean-flux magnitudes, derived colour excess ${E(V-I)}$ values, and fitted distances for the 15,040 RR Lyrae stars produced through this work is made available through the publication's associated online data.Comment: 7 pages, 8 figure

A dimeric form of the HIV-1 antibody 2G12 elicits potent antibody-dependent cellular cytotoxicity

Objective: Increasing data support a role for antibody-dependent cellular cytotoxicity (ADCC) in controlling HIV-1 infection. We recently isolated a naturally occurring dimeric form of the anti-HIV-1 antibody 2G12 and found it to be significantly more potent than 2G12 monomer in neutralizing primary virus strains. However, given the unusual structure of dimeric 2G12 with two Fc regions, it was not clear whether 2G12 dimer could bind to the CD16 Fc receptor on ADCC effector cells or trigger ADCC. Here we compared the in-vitro ADCC activities of 2G12 monomer and dimer and investigated the effects of including ADCC-enhancing mutations in both forms of 2G12. Methods: An in-vitro ADCC assay using target cells stably expressing gp160 was developed to evaluate the activities of 2G12 monomer and dimer with and without ADCC-enhancing mutations that increase the CD16-binding affinity of the 2G12 Fc region. Results: Both 2G12 monomer and 2G12 dimer elicited ADCC, although the dimer showed increased potency [lower half-maximal concentration (EC50)] in triggering ADCC, thus confirming its ability to bind CD16 and trigger ADCC. The ADCC-enhancing mutations improved the ADCC activity of 2G12 monomer more than 2G12 dimer such that their EC50 values were nearly equal. However, no increase in nonspecific ADCC activity was observed using 2G12 IgGs with these mutations. Conclusion: Given the likelihood that ADCC plays a role in protecting against initial infection and/or controlling chronic infection, these data suggest 2G12 dimers and/or addition of ADCC-enhancing mutations could augment the prophylactic and/or therapeutic potential of 2G12

A Bayesian Approach to Calibrating Period-Luminosity Relations of RR Lyrae Stars in the Mid-Infrared

A Bayesian approach to calibrating period-luminosity (PL) relations has substantial benefits over generic least-squares fits. In particular, the Bayesian approach takes into account the full prior distribution of the model parameters, such as the a priori distances, and refits these parameters as part of the process of settling on the most highly-constrained final fit. Additionally, the Bayesian approach can naturally ingest data from multiple wavebands and simultaneously fit the parameters of PL relations for each waveband in a procedure that constrains the parameter posterior distributions so as to minimize the scatter of the final fits appropriately in all wavebands. Here we describe the generalized approach to Bayesian model fitting and then specialize to a detailed description of applying Bayesian linear model fitting to the mid-infrared PL relations of RR Lyrae variable stars. For this example application we quantify the improvement afforded by using a Bayesian model fit. We also compare distances previously predicted in our example application to recently published parallax distances measured with the Hubble Space Telescope and find their agreement to be a vindication of our methodology. Our intent with this article is to spread awareness of the benefits and applicability of this Bayesian approach and encourage future PL relation investigations to consider employing this powerful analysis method.Comment: 6 pages, 1 figure. Accepted for publication in Astrophysics & Space Science. Following a presentation at the conference The Fundamental Cosmic Distance Scale: State of the Art and the Gaia Perspective, Naples, May 201

Design and characterization of structured protein linkers with differing flexibilities

Engineered fusion proteins containing two or more functional polypeptides joined by a peptide or protein linker are important for many fields of biological research. The separation distance between functional units can impact epitope access and the ability to bind with avidity; thus the availability of a variety of linkers with different lengths and degrees of rigidity would be valuable for protein design efforts. Here, we report a series of designed structured protein linkers incorporating naturally occurring protein domains and compare their properties to commonly used Gly_4Ser repeat linkers. When incorporated into the hinge region of an immunoglobulin G (IgG) molecule, flexible Gly_4Ser repeats did not result in detectable extensions of the IgG antigen-binding domains, in contrast to linkers including more rigid domains such as β2-microglobulin, Zn-α2-glycoprotein and tetratricopeptide repeats. This study adds an additional set of linkers with varying lengths and rigidities to the available linker repertoire, which may be useful for the construction of antibodies with enhanced binding properties or other fusion proteins

Mid-infrared Period-Luminosity Relations of RR Lyrae Stars Derived from the WISE Preliminary Data Release

Interstellar dust presents a significant challenge to extending parallax-determined distances of optically observed pulsational variables to larger volumes. Distance ladder work at mid-infrared wavebands, where dust effects are negligible and metallicity correlations are minimized, have been largely focused on few-epoch Cepheid studies. Here we present the first determination of mid-infrared period-luminosity (PL) relations of RR Lyrae stars from phase-resolved imaging using the preliminary data release of the Wide-Field Infrared Survey Explorer (WISE). We present a novel statistical framework to predict posterior distances of 76 well-observed RR Lyrae that uses the optically constructed prior distance moduli while simultaneously imposing a power-law PL relation to WISE-determined mean magnitudes. We find that the absolute magnitude in the bluest WISE filter is M_W1 = (-0.421+-0.014) - (1.681+-0.147)*log(P/0.50118 day), with no evidence for a correlation with metallicity. Combining the results from the three bluest WISE filters, we find that a typical star in our sample has a distance measurement uncertainty of 0.97% (statistical) plus 1.17% (systematic). We do not fundamentalize the periods of RRc stars to improve their fit to the relations. Taking the Hipparcos-derived mean V-band magnitudes, we use the distance posteriors to determine a new optical metallicity-luminosity relation which we present in Section 5. The results of this analysis will soon be tested by HST parallax measurements and, eventually, with the Gaia astrometric mission.Comment: 33 pages, 12 figures, 2 tables. Accepted for publication in ApJ, June 27th, 201

Intra-Spike Crosslinking Overcomes Antibody Evasion by HIV-1

Antibodies developed during HIV-1 infection lose efficacy as the viral spike mutates. We postulated that anti-HIV-1 antibodies primarily bind monovalently because HIV’s low spike density impedes bivalent binding through inter-spike crosslinking, and the spike structure prohibits bivalent binding through intra-spike crosslinking. Monovalent binding reduces avidity and potency, thus expanding the range of mutations permitting antibody evasion. To test this idea, we engineered antibody-based molecules capable of bivalent binding through intra-spike crosslinking. We used DNA as a “molecular ruler” to measure intra-epitope distances on virion-bound spikes and construct intra-spike crosslinking molecules. Optimal bivalent reagents exhibited up to 2.5 orders of magnitude increased potency (>100-fold average increases across virus panels) and identified conformational states of virion-bound spikes. The demonstration that intra-spike crosslinking lowers the concentration of antibodies required for neutralization supports the hypothesis that low spike densities facilitate antibody evasion and the use of molecules capable of intra-spike crosslinking for therapy or passive protection