TLR4 and TLR7/8 adjuvant combinations generate different vaccine antigen-specific immune outcomes in minipigs when administered via the ID or IN routes

The induction of high levels of systemic and mucosal humoral immunity is a key goal for many prophylactic vaccines. However, adjuvant strategies developed in mice have often performed poorly in the clinic. Due to their closer similarity to humans, minipigs may provide a more accurate picture of adjuvant performance. Based on their complementary signalling pathways, we assessed humoral immune responses to model antigens after co-administration with the toll-like receptor 4 (TLR4) stimulator glucopyranosyl lipid adjuvant (GLA-AF) or the TLR7/8 agonist resiquimod (R848) (alone and in combination) via the intradermal (ID), intranasal (IN) or combined routes in the Gottingen minipig animal model. Surprisingly, we discovered that while GLA-AF additively enhanced the adjuvant effect of R848 when injected ID, it abrogated the adjuvant activity of R848 after IN inoculation. We then performed a route comparison study using a CN54 gp140 HIV Envelope model antigen adjuvanted with R848 + GLA-AF (ID) or R848 alone (IN). Animals receiving priming inoculations via one route were then boosted by the alternate route. Although differences were observed in the priming phase (IN or ID), responses converged upon boosting by the alternative route with no observable impact resultant from the order of administration (ID/IN vs IN/ID). Specific IgG responses were measured at a distal mucosal site (vaginal), although there was no evidence of mucosal linkage as these closely reflected serum antibody levels. These data indicate that the complex in vivo cross-talk between innate pathways are likely tissue specific and cannot be predicted by simple in vitro models

Discrete partitioning of HIV-1 Env forms revealed by viral capture

BACKGROUND: The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. Although functional Env complexes are thought to require trimerization of cleaved gp41/gp120 heterodimers, variable processing can result in the potential incorporation of non-functional uncleaved proteins (gp160), non-trimeric arrangements of gp41/gp120 heterodimers, and gp120 depleted gp41 stumps. The potential distribution of functional and non-functional Env forms across replication-competent viral populations may have important implications for neutralizing and non-neutralizing antibody functions. This study applied an immuno-bead viral capture assay (VCA) to interrogate the potential distribution (heterologous vs homologous) of functional and non-functional forms of virion associated Env. RESULTS: The VCA revealed a significant association between depletion of infectious virions and virion Env incorporation, but not between infectivity and p24-gag. Three distinct subpopulations of virions were identified within pools of genetically homogenous viral particles. Critically, a significant subpopulation of infectious virions were exclusively captured by neutralizing antibodies (nAbs) indicative of a homologous distribution of functional trimeric Env forms. A second infectious subpopulation bound both neutralizing and non-neutralizing antibodies (nnAbs) representative of a heterologous distribution of Env forms, while a third non-infectious subpopulation was predominantly bound by nnAbs recognizing gp41 stumps. CONCLUSIONS: The observation that a distinct and significant subpopulation of infectious virions is exclusively captured by neutralizing antibodies has important implications for understanding antibody binding and neutralization, as well as other antibody effector functions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12977-015-0207-z) contains supplementary material, which is available to authorized users

Trimaximal neutrino mixing from vacuum alignment in A4 and S4 models

Recent T2K results indicate a sizeable reactor angle theta_13 which would rule out exact tri-bimaximal lepton mixing. We study the vacuum alignment of the Altarelli-Feruglio A4 family symmetry model including additional flavons in the 1' and 1" representations and show that it leads to trimaximal mixing in which the second column of the lepton mixing matrix consists of the column vector (1,1,1)^T/sqrt{3}, with a potentially large reactor angle. In order to limit the reactor angle and control the higher order corrections, we propose a renormalisable S4 model in which the 1' and 1" flavons of A4 are unified into a doublet of S4 which is spontaneously broken to A4 by a flavon which enters the neutrino sector at higher order. We study the vacuum alignment in the S4 model and show that it predicts accurate trimaximal mixing with approximate tri-bimaximal mixing, leading to a new mixing sum rule testable in future neutrino experiments. Both A4 and S4 models preserve form dominance and hence predict zero leptogenesis, up to renormalisation group corrections.Comment: 24 pages, 2 figures, version to be published in JHE

Constrained analytical interrelations in neutrino mixing

Hermitian squared mass matrices of charged leptons and light neutrinos in the flavor basis are studied under general additive lowest order perturbations away from the tribimaximal (TBM) limit in which a weak basis with mass diagonal charged leptons is chosen. Simple analytical expressions are found for the three measurable TBM-deviants in terms of perturbation parameters appearing in the neutrino and charged lepton eigenstates in the flavor basis. Taking unnatural cancellations to be absent and charged lepton perturbation parameters to be small, interrelations are derived among masses, mixing angles and the amount of CP-violation.Comment: To be published in the Springer Proceedings in the Physics Series under the heading of the XXI DAE-BRNS Symposium (Guwahati, India

Ultraviolet Completion of Flavour Models

Effective Flavour Models do not address questions related to the nature of the fundamental renormalisable theory at high energies. We study the ultraviolet completion of Flavour Models, which in general has the advantage of improving the predictivity of the effective models. In order to illustrate the important features we provide minimal completions for two known A4 models. We discuss the phenomenological implications of the explicit completions, such as lepton flavour violating contributions that arise through the exchange of messenger fields.Comment: 18 pages, 8 figure

Decaying Dark Matter in the Supersymmetric Standard Model with Freeze-in and Seesaw mechanims

Inspired by the decaying dark matter (DM) which can explain cosmic ray anomalies naturally, we consider the supersymmetric Standard Model with three right-handed neutrinos (RHNs) and R-parity, and introduce a TeV-scale DM sector with two fields \phi_{1,2} and a $Z_3$ discrete symmetry. The DM sector only interacts with the RHNs via a very heavy field exchange and then we can explain the cosmic ray anomalies. With the second right-handed neutrino N_2 dominant seesaw mechanism at the low scale around 10^4 GeV, we show that \phi_{1,2} can obtain the vacuum expectation values around the TeV scale, and then the lightest state from \phi_{1,2} is the decay DM with lifetime around \sim 10^{26}s. In particular, the DM very long lifetime is related to the tiny neutrino masses, and the dominant DM decay channels to \mu and \tau are related to the approximate \mu-\tau symmetry. Furthermore, the correct DM relic density can be obtained via the freeze-in mechanism, the small-scale problem for power spectrum can be solved due to the decays of the R-parity odd meta-stable states in the DM sector, and the baryon asymmetry can be generated via the soft leptogensis.Comment: 24 pages,3 figure

Isolation of two insecticidal toxins from venom of the Australian theraphosid spider Coremiocnemis tropix

© 2016 Elsevier Ltd Sheep flystrike is caused by parasitic flies laying eggs on soiled wool or open wounds, after which the hatched maggots feed on the sheep flesh and often cause large lesions. It is a significant economic problem for the livestock industry as infestations are difficult to control due to ongoing cycles of larval development into flies followed by further egg laying. We therefore screened venom fractions from the Australian theraphosid spider Coremiocnemis tropix to identify toxins active against the sheep blowfly Lucilia cuprina, which is the primary cause of flystrike in Australia. This screen led to isolation of two insecticidal peptides, Ct1a and Ct1b, that are lethal to blowflies within 24 h of injection. The primary structure of these peptides was determined using a combination of Edman degradation and sequencing of a C. tropix venom-gland transcriptome. Ct1a and Ct1b contain 39 and 38 amino acid residues, respectively, including six cysteine residues that form three disulfide bonds. Recombinant production in bacteria (Escherichia coli) resulted in low yields of Ct1a whereas solid-phase peptide synthesis using native chemical ligation produced sufficient quantities of Ct1a for functional analyses. Synthetic Ct1a had no effect on voltage-gated sodium channels from the American cockroach Periplanata americana or the German cockroach Blattella germanica, but it was lethal to sheep blowflies with an LD50 of 1687 pmol/g

An SO(10) Grand Unified Theory of Flavor

We present a supersymmetric SO(10) grand unified theory (GUT) of flavor based on an $S_4$ family symmetry. It makes use of our recent proposal to use SO(10) with type II seesaw mechanism for neutrino masses combined with a simple ansatz that the dominant Yukawa matrix (the {\bf 10}-Higgs coupling to matter) has rank one. In this paper, we show how the rank one model can arise within some plausible assumptions as an effective field theory from vectorlike {\bf 16} dimensional matter fields with masses above the GUT scale. In order to obtain the desired fermion flavor texture we use $S_4$ flavon multiplets which acquire vevs in the ground state of the theory. By supplementing the $S_4$ theory with an additional discrete symmetry, we find that the flavon vacuum field alignments take a discrete set of values provided some of the higher dimensional couplings are small. Choosing a particular set of these vacuum alignments appears to lead to an unified understanding of observed quark-lepton flavor: (i) the lepton mixing matrix that is dominantly tri-bi-maximal with small corrections related to quark mixings; (ii) quark lepton mass relations at GUT scale: $m_b\simeq m_{\tau}$ and $m_\mu\simeq 3 m_s$ and (iii) the solar to atmospheric neutrino mass ratio $m_\odot/m_{\rm atm}\simeq \theta_{\rm Cabibbo}$ in agreement with observations. The model predicts the neutrino mixing parameter, $U_{e3} \simeq \theta_{\rm Cabibbo}/(3\sqrt2) \sim 0.05$, which should be observable in planned long baseline experiments.Comment: Final version of the paper as it will appear in JHEP

Investigating the history of volatiles in the solar system using synchrotron infrared micro-spectroscopy

keywords: Synchrotron infrared micro-spectroscopy, CM chondrite meteorite, Murchison, Aqueous alteration, Asteroids adsurl: https://ui.adsabs.harvard.edu/abs/2018InPhT..94..244K adsnote: Provided by the SAO/NASA Astrophysics Data Syste

Evaluation of chemical strategies for improving the stability and oral toxicity of insecticidal peptides

© 2018 by the authors. Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide !-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability