Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials

Background: This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. Methods: Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). Findings: All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. Interpretation: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. Fund: BioMarin Pharmaceutical Inc. Keywords: Enzyme replacement therapy, Antidrug antibody, Circulating immune complex, Hypersensitivity, Phenylalanin

Evaluation of Concussion Incidence and Modulating Factors in the 2013-2017 Australian Football League

The increasing awareness and popularization of concussions in the research realm over the last few years have begun to shed more light on the detrimental effects associated with repetitive head trauma. While the majority of the current literature focuses on the National Football League (NFL) and National Hockey League (NHL), several other high-impact sports have been implementing concussion management protocols to protect their players. The Australian Football League (AFL) is a prime example of a major contact sport that has undertaken recent changes to its concussion assessment and management modalities. We recognize the benefit of reporting potential changes in concussion rates over the 2013-2017 AFL seasons. We were interested in some of the factors not yet evaluated before, which may contribute to the overall concussion incidence such as “style-of-play” factors” (home/away, win/loss, points scored, time of season). We hope the results of this analysis shed light on the mechanisms by which concussion rates can be mitigated across major contact sports

Anisotropic splitting of intersubband spin plasmons in quantum wells with bulk and structural inversion asymmetry

In semiconductor heterostructures, bulk and structural inversion asymmetry and spin-orbit coupling induce a k-dependent spin splitting of valence and conduction subbands, which can be viewed as being caused by momentum-dependent crystal magnetic fields. This paper studies the influence of these effective magnetic fields on the intersubband spin dynamics in an asymmetric n-type GaAs/AlGaAs quantum well. We calculate the dispersions of intersubband spin plasmons using linear response theory. The so-called D'yakonov-Perel' decoherence mechanism is inactive for collective intersubband excitations, i.e., crystal magnetic fields do not lead to decoherence of spin plasmons. Instead, we predict that the main signature of bulk and structural inversion asymmetry in intersubband spin dynamics is a three-fold, anisotropic splitting of the spin plasmon dispersion. The importance of many-body effects is pointed out, and conditions for experimental observation with inelastic light scattering are discussed.Comment: 8 pages, 6 figure

SPIRITS 16tn in NGC 3556: A heavily obscured and low-luminosity supernova at 8.8 Mpc

We present the discovery by the SPitzer InfraRed Intensive Transients Survey (SPIRITS) of a likely supernova (SN) in NGC 3556 at only 8.8 Mpc, which, despite its proximity, was not detected by optical searches. A luminous infrared (IR) transient at $M_{[4.5]} = -16.7$ mag (Vega), SPIRITS 16tn is coincident with a dust lane in the inclined, star-forming disk of the host. Using IR, optical, and radio observations, we attempt to determine the nature of this event. We estimate $A_V \approx$ 8 - 9 mag of extinction, placing it among the three most highly obscured IR-discovered SNe to date. The [4.5] light curve declined at a rate of 0.013 mag day$^{-1}$, and the $[3.6] - [4.5]$ color grew redder from 0.7 to $\gtrsim$ 1.0 mag by 184.7 days post discovery. Optical/IR spectroscopy shows a red continuum, but no clearly discernible features, preventing a definitive spectroscopic classification. Deep radio observations constrain the radio luminosity of SPIRITS 16tn to $L_{\nu} \lesssim 10^{24}$ erg s$^{-1}$ Hz$^{-1}$ between 3 - 15 GHz, excluding many varieties of radio core-collapse SNe. A type Ia SN is ruled out by the observed red IR color, and lack of features normally attributed to Fe-peak elements in the optical and IR spectra. SPIRITS 16tn was fainter at [4.5] than typical stripped-envelope SNe by $\approx$ 1 mag. Comparison of the spectral energy distribution to SNe II suggests SPIRITS 16tn was both highly obscured, and intrinsically dim, possibly akin to the low-luminosity SN 2005cs. We infer the presence of an IR dust echo powered by a peak luminosity of the transient of $5 \times 10^{40}$ erg s$^{-1} < L_{\mathrm{peak}} < 4\times10^{43}$ erg s$^{-1}$, consistent with the observed range for SNe II. This discovery illustrates the power of IR surveys to overcome the compounding effects of visible extinction and optically sub-luminous events in completing the inventory of nearby SNe.Comment: 25 pages, 10 figures, submitted to Ap

LoCuSS: The Sunyaev-Zel'dovich Effect and Weak Lensing Mass Scaling Relation

We present the first weak-lensing-based scaling relation between galaxy cluster mass, M_wl, and integrated Compton parameter Y_sph. Observations of 18 galaxy clusters at z~0.2 were obtained with the Subaru 8.2-m telescope and the Sunyaev-Zel'dovich Array. The M_wl-Y_sph scaling relations, measured at Delta=500, 1000, and 2500 rho_c, are consistent in slope and normalization with previous results derived under the assumption of hydrostatic equilibrium (HSE). We find an intrinsic scatter in M_wl at fixed Y_sph of 20%, larger than both previous measurements of M_HSE-Y_sph scatter as well as the scatter in true mass at fixed Y_sph found in simulations. Moreover, the scatter in our lensing-based scaling relations is morphology dependent, with 30-40% larger M_wl for undisturbed compared to disturbed clusters at the same Y_sph at r_500. Further examination suggests that the segregation may be explained by the inability of our spherical lens models to faithfully describe the three-dimensional structure of the clusters, in particular, the structure along the line-of-sight. We find that the ellipticity of the brightest cluster galaxy, a proxy for halo orientation, correlates well with the offset in mass from the mean scaling relation, which supports this picture. This provides empirical evidence that line-of-sight projection effects are an important systematic uncertainty in lensing-based scaling relations.Comment: Accepted versio

Convergent evolution of conserved mitochondrial pathways underlies repeated adaptation to extreme environments

Extreme environments test the limits of life; yet, some organisms thrive in harsh conditions. Extremophile lineages inspire questions about how organisms can tolerate physiochemical stressors and whether the repeated colonization of extreme environments is facilitated by predictable and repeatable evolutionary innovations. We identified the mechanistic basis underlying convergent evolution of tolerance to hydrogen sulfide (H2S)-a toxicant that impairs mitochondrial function-across evolutionarily independent lineages of a fish (Poecilia mexicana, Poeciliidae) from H2S-rich springs. Using comparative biochemical and physiological analyses, we found that mitochondrial function is maintained in the presence of H2S in sulfide spring P. mexicana but not ancestral lineages from nonsulfidic habitats due to convergent adaptations in the primary toxicity target and a major detoxification enzyme. Genome-wide local ancestry analyses indicated that convergent evolution of increased H2S tolerance in different populations is likely caused by a combination of selection on standing genetic variation and de novo mutations. On a macroevolutionary scale, H2S tolerance in 10 independent lineages of sulfide spring fishes across multiple genera of Poeciliidae is correlated with the convergent modification and expression changes in genes associated with H2S toxicity and detoxification. Our results demonstrate that the modification of highly conserved physiological pathways associated with essential mitochondrial processes mediates tolerance to physiochemical stress. In addition, the same pathways, genes, and-in some instances-codons are implicated in H2S adaptation in lineages that span 40 million years of evolution

LoCuSS: A Comparison of Sunyaev-Zel'dovich Effect and Gravitational Lensing Measurements of Galaxy Clusters

We present the first measurement of the relationship between the Sunyaev-Zel'dovich effect signal and the mass of galaxy clusters that uses gravitational lensing to measure cluster mass, based on 14 X-ray luminous clusters at z~0.2 from the Local Cluster Substructure Survey. We measure the integrated Compton y-parameter, Y, and total projected mass of the clusters (M_GL) within a projected clustercentric radius of 350 kpc, corresponding to mean overdensities of 4000-8000 relative to the critical density. We find self-similar scaling between M_GL and Y, with a scatter in mass at fixed Y of 32%. This scatter exceeds that predicted from numerical cluster simulations, however, it is smaller than comparable measurements of the scatter in mass at fixed T_X. We also find no evidence of segregation in Y between disturbed and undisturbed clusters, as had been seen with T_X on the same physical scales. We compare our scaling relation to the Bonamente et al. relation based on mass measurements that assume hydrostatic equilibrium, finding no evidence for a hydrostatic mass bias in cluster cores (M_GL = 0.98+/-0.13 M_HSE), consistent with both predictions from numerical simulations and lensing/X-ray-based measurements of mass-observable scaling relations at larger radii. Overall our results suggest that the Sunyaev-Zel'dovich effect may be less sensitive than X-ray observations to the details of cluster physics in cluster cores.Comment: Minor changes to match published version: 2009 ApJL 701:114-11

Joint analysis of X-ray and Sunyaev Zel'dovich observations of galaxy clusters using an analytic model of the intra-cluster medium

We perform a joint analysis of X-ray and Sunyaev Zel'dovich (SZ) effect data using an analytic model that describes the gas properties of galaxy clusters. The joint analysis allows the measurement of the cluster gas mass fraction profile and Hubble constant independent of cosmological parameters. Weak cosmological priors are used to calculate the overdensity radius within which the gas mass fractions are reported. Such an analysis can provide direct constraints on the evolution of the cluster gas mass fraction with redshift. We validate the model and the joint analysis on high signal-to-noise data from the Chandra X-ray Observatory and the Sunyaev-Zel'dovich Array for two clusters, Abell 2631 and Abell 2204.Comment: ApJ in pres

RGS12 Interacts with the SNARE-binding Region of the Ca v 2.2 Calcium Channel

Activation of GABAB receptors in chick dorsal root ganglion (DRG) neurons inhibits the Cav2.2 calcium channel in both a voltage-dependent and voltage-independent manner. The voltage-independent inhibition requires activation of a tyrosine kinase that phosphorylates the alpha1 subunit of the channel and thereby recruits RGS12, a member of the "regulator of G protein signaling" (RGS) proteins. Here we report that RGS12 binds to the SNARE-binding or "synprint" region (amino acids 726-985) in loop II-III of the calcium channel alpha1 subunit. A recombinant protein encompassing the N-terminal PTB domain of RGS12 binds to the synprint region in protein overlay and surface plasmon resonance binding assays; this interaction is dependent on tyrosine phosphorylation and yet is within a sequence that differs from the canonical NPXY motif targeted by other PTB domains. In electrophysiological experiments, microinjection of DRG neurons with synprint-derived peptides containing the tyrosine residue Tyr-804 altered the rate of desensitization of neurotransmitter-mediated inhibition of the Cav2.2 calcium channel, whereas peptides centered about a second tyrosine residue, Tyr-815, were without effect. RGS12 from a DRG neuron lysate was precipitated using synprint peptides containing phosphorylated Tyr-804. The high degree of conservation of Tyr-804 in the SNARE-binding region of Cav2.1 and Cav2.2 calcium channels suggests that this region, in addition to the binding of SNARE proteins, is also important for determining the time course of the modulation of calcium current via tyrosine phosphorylation