Fusion to snowdrop lectin magnifies the oral activity of insecticidal omega-Hexatoxin-Hv1a peptide by enabling its delivery to the central nervous system

Background: The spider-venom peptide v-hexatoxin-Hv1a (Hv1a) targets insect voltage-gated calcium channels, acting directly at sites within the central nervous system. It is potently insecticidal when injected into a wide variety of insect pests, but it has limited oral toxicity. We examined the ability of snowdrop lectin (GNA), which is capable of traversing the insect gut epithelium, to act as a ‘‘carrier’’ in order to enhance the oral activity of Hv1a. Methodology/Principal Findings: A synthetic Hv1a/GNA fusion protein was produced by recombinant expression in the yeast Pichia pastoris. When injected into Mamestra brassicae larvae, the insecticidal activity of the Hv1a/GNA fusion protein was similar to that of recombinant Hv1a. However, when proteins were delivered orally via droplet feeding assays, Hv1a/ GNA, but not Hv1a alone, caused a significant reduction in growth and survival of fifth stadium Mamestra brassicae (cabbage moth) larvae. Feeding second stadium larvae on leaf discs coated with Hv1a/GNA (0.1–0.2% w/v) caused $80% larval mortality within 10 days, whereas leaf discs coated with GNA (0.2% w/v) showed no acute effects. Intact Hv1a/GNA fusion protein was delivered to insect haemolymph following ingestion, as shown by Western blotting. Immunoblotting of nerve chords dissected from larvae following injection of GNA or Hv1a/GNA showed high levels of bound proteins. When insects were injected with, or fed on, fluorescently labelled GNA or HV1a/GNA, fluorescence was detected specifically associated with the central nerve chord. Conclusions/Significance: In addition to mediating transport of Hv1a across the gut epithelium in lepidopteran larvae, GNA is also capable of delivering Hv1a to sites of action within the insect central nervous system. We propose that fusion to GNA provides a general mechanism for dramatically enhancing the oral activity of insecticidal peptides and proteins

Factors associated with changes of state of foot conformation and lameness in a flock of sheep

The aim of this research was to investigate transitions between foot conformation, lameness and footrot in sheep. Data came from one lowland flock of approximately 700 ewes studied for 18 months. Multilevel multistate analyses of transitions between good and poor foot conformation states in ewes, and lame and non-lame states in ewes and lambs were conducted. Key results were that the longer sheep had feet in good conformation, the more likely they were to stay in this state; similarly, the longer a ewe was not lame the more likely she was not to become lame. Ewes with poor foot conformation were more likely to become lame (OR: 1.83 (1.24-2.67)) and to be > 4 years (OR: 1.50(1.09-2.05)). Ewes with footrot were less likely to move to good foot conformation (OR: 0.48 (0.31-0.75)) and were more likely to become lame (OR: 3.81(2.60-5.59)). Ewes lame for > 4 days and not treated with parenteral antibacterials had a higher risk of developing (OR: 2.00 (1.08-3.61)), or remaining in (OR: 0.49 (0.29-0.95)) poor foot conformation compared with ewes never lame. Treatment of ewes lame with footrot with parenteral antibacterials increased the probability of transition from a lame to a non-lame state (OR: 1.46 (1.05-2.02)) and these ewes, even if lame for > 4 days, were not more likely to develop poor foot conformation. The risk of a ewe becoming lame increased when at least one of her offspring was lame (OR: 2.03 (1.42-2.92)) and when the prevalence of lameness in the group was ≥ 5% (OR: 1.42 (1.06-1.92)). Lambs were at increased risk of becoming lame when they were male (OR: 1.42 (1.01-2.01)), single (OR: 1.86 (1.34-2.59)) or had a lame dam or sibling (OR: 3.10 (1.81-5.32)). There were no explanatory variables associated with lambs recovering from lameness. We conclude that poor foot conformation in ewes increases the susceptibility of ewes to become lame and that this can arise from untreated footrot. Treatment of ewes lame with footrot with parenteral antibacterials leads to recovery from lameness and prevents or resolves poor foot conformation which then reduces the susceptibility to further lameness with footrot

Four-jet Signal at LEP2 and Supersymmetry

ALEPH has reported a significant excess of four-jet events in the LEP runs above the Z^0 resonance, which however has not been confirmed by the other LEP collaborations. We assume here that this excess corresponds to a physics signal and try to interpret it in the context of supersymmetric models with R-parity violation. Associated production of a left and right selectron can explain all the distinctive features of the ALEPH data: the value of the cross section, the di-jet mass difference, the absence of bottom quarks in the final state, and the di-jet charge content. Our proposed scenario makes definite predictions which can be tested at future LEP runs at higher energies.Comment: 15 pages, LateX, 5 figures. A few typos were corrected. A reference was adde

Hierarchical Neutrino Mass Matrices, CP violation and Leptogenesis

In this work we study examples of hierarchical neutrino mass matrices inspired by family symmetries, compatible with experiments on neutrino oscillations, and for which there is a connection among the low energy CP violation phase associated to neutrino oscillations, the phases appearing in the amplitude of neutrinoless double beta decay, and the phases relevant for leptogenesis. In particular, we determine the predictions from a texture based on an underlying SU(3) family symmetry together with a GUT symmetry, and a strong hierarchy for the masses of the heavy right handed Majorana masses. We also give some examples of inverted hierarchies of neutrino masses, which may be motivated in the context of U(1) family symmetries.Comment: 34 pages. Replaced with published version -typos, corrections and references adde

The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain

OnlinePublChronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis-associated CPP remain underdeveloped. Here, we examined the role of the voltage-gated sodium (NaV) channel NaV1.7 in (i) the sensitivity of vagina-innervating sensory afferents and investigated whether (ii) NaV1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis-associated CPP. The mechanical responsiveness of vagina-innervating sensory afferents was assessed with ex vivo single-unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV1.7 with OD1 sensitised vagina-innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina-innervating pelvic afferents to mechanical stimuli. The highly selective NaV1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV1.7-dependent manner. Moreover, in vivo intra-vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechano-sensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV1.7 plays a crucial role in endometriosis-induced vaginal hyperalgesia. Importantly, NaV1.7 inhibition selectively alleviated endometriosis-associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV1.7 could improve the quality of life of women with endometriosis.Joel Castro, Jessica Maddern, Chun Yuen Chow, Poanna Tran, Irina Vetter, Glenn F. King, Stuart M. Brierle

Current-Density Functional Theory of the Response of Solids

The response of an extended periodic system to a homogeneous field (of wave-vector $q=0$) cannot be obtained from a $q=0$ time-dependent density functional theory (TDDFT) calculation, because the Runge-Gross theorem does not apply. Time-dependent {\em current}-density functional theory is needed and demonstrates that one key ingredient missing from TDDFT is the macroscopic current. In the low-frequency limit, in certain cases, density polarization functional theory is recovered and a formally exact expression for the polarization functional is given.Comment: 5 pages, accepted in PR

Minimal Scenarios for Leptogenesis and CP Violation

The relation between leptogenesis and CP violation at low energies is analyzed in detail in the framework of the minimal seesaw mechanism. Working, without loss of generality, in a weak basis where both the charged lepton and the right-handed Majorana mass matrices are diagonal and real, we consider a convenient generic parametrization of the Dirac neutrino Yukawa coupling matrix and identify the necessary condition which has to be satisfied in order to establish a direct link between leptogenesis and CP violation at low energies. In the context of the LMA solution of the solar neutrino problem, we present minimal scenarios which allow for the full determination of the cosmological baryon asymmetry and the strength of CP violation in neutrino oscillations. Some specific realizations of these minimal scenarios are considered. The question of the relative sign between the baryon asymmetry and CP violation at low energies is also discussed.Comment: 36 pages, 5 figures; minor corrections and references updated. Final version to appear in Phys. Rev.

Wedgebox analysis of four-lepton events from neutralino pair production at the LHC

`Wedgebox' plots constructed by plotting the di-electron invariant mass versus the di-muon invariant mass from pp -> e^+e^- mu^+ mu^- + missing energy signature LHC events. Data sets of such events are obtained across the MSSM input parameter space in event-generator simulations, including cuts designed to remove SM backgrounds. Their study reveals several general features: (1)Regions in the MSSM input parameter space where a sufficient number of events are expected so as to be able to construct a clear wedgebox plot are delineated. (2)The presence of box shapes on a wedgebox plot either indicates the presence of heavy Higgs bosons decays or restricts the location to a quite small region of low \mu and M_2 values \lsim 200 GeV, a region denoted as the `lower island'. In this region, wedgebox plots can be quite complicated and change in pattern rather quickly as one moves around in the (\mu, M_2) plane. (3)Direct neutralino pair production from an intermediate Z^{0*} may only produce a wedge-shape since only \widetilde{\chi}_2^0\widetilde{\chi}_3^0 decays can contribute significantly. (4)A double-wedge or wedge-protruding-from-a-box pattern on a wedgebox plot, which results from combining a variety of MSSM production processes, yields three distinct observed endpoints, almost always attributable to \widetilde{\chi}_{2,3,4}^0 \to \widetilde{\chi}_1^0 \ell^+\ell^- decays, which can be utilized to determine a great deal of information about the neutralino and slepton mass spectra and related MSSM input parameters. Wedge and double-wedge patterns are seen in wedgebox plots in another region of higher \mu and M_2 values, denoted as the`upper island.' Here the pattern is simpler and more stable as one moves across the (\mu, M_2) input parameter space.Comment: 28 pages (LaTeX), 8 figures (encapsulated postscript

Resonant leptogenesis in a predictive SO(10) grand unified model

An SO(10) grand unified model considered previously by the authors featuring lopsided down quark and charged lepton mass matrices is successfully predictive and requires that the lightest two right-handed Majorana neutrinons be nearly degenerate in order to obtain the LMA solar neutrino solution. Here we use this model to test its predictions for baryogenesis through resonant-enhanced leptogenesis. With the conventional type I seesaw mechanism, the best predictions for baryogenesis appear to fall a factor of three short of the observed value. However, with a proposed type III seesaw mechanism leading to three pairs of massive pseudo-Dirac neutrinos, resonant leptogenesis is decoupled from the neutrino mass and mixing issues with successful baryogenesis easily obtained.Comment: 22 pages including 1 figure; published version with reference adde

SU(4)_c x SU(2)_L x SU(2)_R model from 5D SUSY SU(4)_c x SU(4)_{L+R}

We investigate supersymmetric $SU(4)_c\times SU(4)_{L+R}$ theory in 5 dimensions whose compactification on a $S^{(1)}/Z_2$ orbifold yields N=1 supersymmetric $SU(4)_c\times SU(2)_L\times SU(2)_R$ supplemented by a \tl{U}(1) gauge symmetry. We discuss how the $\mu$ problem is resolved, a realistic Yukawa sector achieved, and a stable proton realized. Neutrino masses and oscillations are also briefly discussed.Comment: Version to appear in Physical Review