The Human Cytomegalovirus Fc Receptor gp68 Binds the Fc CH2-CH3 Interface of Immunoglobulin G

Recognition of immunoglobulin G (IgG) by surface receptors for the Fc domain of immunoglobulin G (Fc{gamma}), Fc{gamma}Rs, can trigger both humoral and cellular immune responses. Two human cytomegalovirus (HCMV)-encoded type I transmembrane receptors with Fc{gamma}-binding properties (vFc{gamma}Rs), gp34 and gp68, have been identified on the surface of HCMV-infected cells and are assumed to confer protection against IgG-mediated immunity. Here we show that Fc{gamma} recognition by both vFc{gamma}Rs occurs independently of N-linked glycosylation of Fc{gamma}, in contrast with the properties of host Fc{gamma}Rs. To gain further insight into the interaction with Fc{gamma}, truncation mutants of the vFc{gamma}R gp68 ectodomain were probed for Fc{gamma} binding, resulting in localization of the Fc{gamma} binding site on gp68 to residues 71 to 289, a region including an immunoglobulin-like domain. Gel filtration and biosensor binding experiments revealed that, unlike host Fc{gamma}Rs but similar to the herpes simplex virus type 1 (HSV-1) Fc receptor gE-gI, gp68 binds to the CH2-CH3 interdomain interface of the Fc{gamma} dimer with a nanomolar affinity and a 2:1 stoichiometry. Unlike gE-gI, which binds Fc{gamma} at the slightly basic pH of the extracellular milieu but not at the acidic pH of endosomes, the gp68/Fc{gamma} complex is stable at pH values from 5.6 to pH 8.1. These data indicate that the mechanistic details of Fc binding by HCMV gp68 differ from those of host Fc{gamma}Rs and from that of HSV-1 gE-gI, suggesting distinct functional and recognition properties

Non-Abelian Dark Sectors and Their Collider Signatures

Motivated by the recent proliferation of observed astrophysical anomalies, Arkani-Hamed et al. have proposed a model in which dark matter is charged under a non-abelian "dark" gauge symmetry that is broken at ~ 1 GeV. In this paper, we present a survey of concrete models realizing such a scenario, followed by a largely model-independent study of collider phenomenology relevant to the Tevatron and the LHC. We address some model building issues that are easily surmounted to accommodate the astrophysics. While SUSY is not necessary, we argue that it is theoretically well-motivated because the GeV scale is automatically generated. Specifically, we propose a novel mechanism by which mixed D-terms in the dark sector induce either SUSY breaking or a super-Higgs mechanism precisely at a GeV. Furthermore, we elaborate on the original proposal of Arkani-Hamed et al. in which the dark matter acts as a messenger of gauge mediation to the dark sector. In our collider analysis we present cross-sections for dominant production channels and lifetime estimates for primary decay modes. We find that dark gauge bosons can be produced at the Tevatron and the LHC, either through a process analogous to prompt photon production or through a rare Z decay channel. Dark gauge bosons will decay back to the SM via "lepton jets" which typically contain >2 and as many as 8 leptons, significantly improving their discovery potential. Since SUSY decays from the MSSM will eventually cascade down to these lepton jets, the discovery potential for direct electroweak-ino production may also be improved. Exploiting the unique kinematics, we find that it is possible to reconstruct the mass of the MSSM LSP. We also present decay channels with displaced vertices and multiple leptons with partially correlated impact parameters.Comment: 44 pages, 25 figures, version published in JHE

Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention

The Chicken Yolk Sac IgY Receptor, a Mammalian Mannose Receptor Family Member, Transcytoses IgY across Polarized Epithelial Cells

In mammals the transfer of passive immunity from mother to young is mediated by the MHC-related receptor FcRn, which transports maternal IgG across epithelial cell barriers. In birds, maternal IgY in egg yolk is transferred across the yolk sac to passively immunize chicks during gestation and early independent life. The chicken yolk sac IgY receptor (FcRY) is the ortholog of the mammalian phospholipase A2 receptor, a mannose receptor family member, rather than an FcRn or MHC homolog. FcRn and FcRY both exhibit ligand binding at the acidic pH of endosomes and ligand release at the slightly basic pH of blood. Here we show that FcRY expressed in polarized mammalian epithelial cells functioned in endocytosis, bidirectional transcytosis, and recycling of chicken FcY/IgY. Confocal immunofluorescence studies demonstrated that IgY binding and endocytosis occurred at acidic but not basic pH, mimicking pH-dependent uptake of IgG by FcRn. Colocalization studies showed FcRY-mediated internalization via clathrin-coated pits and transport involving early and recycling endosomes. Disruption of microtubules partially inhibited apical-to-basolateral and basolateral-to-apical transcytosis, but not recycling, suggesting the use of different trafficking machinery. Our results represent the first cell biological evidence of functional equivalence between FcRY and FcRn and provide an intriguing example of how evolution can give rise to systems in which similar biological requirements in different species are satisfied utilizing distinct protein folds

Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540

Face Mask Use and Control of Respiratory Virus Transmission in Households

Mask use is associated with low adherence, but adherent mask users are significantly protected against seasonal disease

Staphylococcus aureus Surface Protein SdrE Binds Complement Regulator Factor H as an Immune Evasion Tactic

Similar to other highly successful invasive bacterial pathogens, Staphylococcus aureus recruits the complement regulatory protein factor H (fH) to its surface to inhibit the alternative pathway of complement. Here, we report the identification of the surface-associated protein SdrE as a fH-binding protein using purified fH overlay of S. aureus fractionated cell wall proteins and fH cross-linking to S. aureus followed by mass spectrometry. Studies using recombinant SdrE revealed that rSdrE bound significant fH whether from serum or as a purified form, in both a time- and dose-dependent manner. Furthermore, rSdrE-bound fH exhibited cofactor functionality for factor I (fI)-mediated cleavage of C3b to iC3b which correlated positively with increasing amounts of fH. Expression of SdrE on the surface of the surrogate bacterium Lactococcus lactis enhanced recruitment of fH which resulted in increased iC3b generation. Moreover, surface expression of SdrE led to a reduction in C3-fragment deposition, less C5a generation, and reduced killing by polymorphonuclear cells. Thus, we report the first identification of a S. aureus protein associated with the staphylococcal surface that binds factor H as an immune evasion mechanism

Revealing the Appetite of the Marine Aquarium Fish Trade: The Volume and Biodiversity of Fish Imported into the United States

The aquarium trade and other wildlife consumers are at a crossroads forced by threats from global climate change and other anthropogenic stressors that have weakened coastal ecosystems. While the wildlife trade may put additional stress on coral reefs, it brings income into impoverished parts of the world and may stimulate interest in marine conservation. To better understand the influence of the trade, we must first be able to quantify coral reef fauna moving through it. Herein, we discuss the lack of a data system for monitoring the wildlife aquarium trade and analyze problems that arise when trying to monitor the trade using a system not specifically designed for this purpose. To do this, we examined an entire year of import records of marine tropical fish entering the United States in detail, and discuss the relationship between trade volume, biodiversity and introduction of non-native marine fishes. Our analyses showed that biodiversity levels are higher than previous estimates. Additionally, more than half of government importation forms have numerical or other reporting discrepancies resulting in the overestimation of trade volumes by 27%. While some commonly imported species have been introduced into the coastal waters of the USA (as expected), we also found that some uncommon species in the trade have also been introduced. This is the first study of aquarium trade imports to compare commercial invoices to government forms and provides a means to, routinely and in real time, examine the biodiversity of the trade in coral reef wildlife species

The structural plasticity of white matter networks following anterior temporal lobe resection

Anterior temporal lobe resection is an effective treatment for refractory temporal lobe epilepsy. The structural consequences of such surgery in the white matter, and how these relate to language function after surgery remain unknown. We carried out a longitudinal study with diffusion tensor imaging in 26 left and 20 right temporal lobe epilepsy patients before and a mean of 4.5 months after anterior temporal lobe resection. The whole-brain analysis technique tract-based spatial statistics was used to compare pre- and postoperative data in the left and right temporal lobe epilepsy groups separately. We observed widespread, significant, mean 7%, decreases in fractional anisotropy in white matter networks connected to the area of resection, following both left and right temporal lobe resections. However, we also observed a widespread, mean 8%, increase in fractional anisotropy after left anterior temporal lobe resection in the ipsilateral external capsule and posterior limb of the internal capsule, and corona radiata. These findings were confirmed on analysis of the native clusters and hand drawn regions of interest. Postoperative tractography seeded from this area suggests that this cluster is part of the ventro-medial language network. The mean pre- and postoperative fractional anisotropy and parallel diffusivity in this cluster were significantly correlated with postoperative verbal fluency and naming test scores. In addition, the percentage change in parallel diffusivity in this cluster was correlated with the percentage change in verbal fluency after anterior temporal lobe resection, such that the bigger the increase in parallel diffusivity, the smaller the fall in language proficiency after surgery. We suggest that the findings of increased fractional anisotropy in this ventro-medial language network represent structural reorganization in response to the anterior temporal lobe resection, which may damage the more susceptible dorso-lateral language pathway. These findings have important implications for our understanding of brain injury and rehabilitation, and may also prove useful in the prediction and minimization of postoperative language deficits