Modulation of the immune response by nematode secreted acetylcholinesterase revealed by heterologous expression in Trypanosoma musculi

Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host

Nonzero |Ue3| from charged lepton corrections and the atmospheric neutrino mixing angle

After the successful determination of the reactor neutrino mixing angle \theta_13 ~ 0.16 \neq 0, a new feature suggested by the current neutrino oscillation data is a sizeable deviation of the atmospheric neutrino mixing angle \theta_23 from \pi/4. Using the fact that the neutrino mixing matrix U = U_e^\dagger U_\nu, where U_e and U_\nu result from the diagonalisation of the charged lepton and neutrino mass matrices, and assuming that U_\nu has a i) bimaximal (BM), ii) tri-bimaximal (TBM) form, or else iii) corresponds to the conservation of the lepton charge L' = L_e - L_\mu - L_\tau (LC), we investigate quantitatively what are the minimal forms of U_e, in terms of angles and phases it contains, that can provide the requisite corrections to U_\nu so that \theta_13, \theta_23 and the solar neutrino mixing angle \theta_12 have values compatible with the current data. Two possible orderings of the 12 and the 23 rotations in U_e, "standard" and "inverse", are considered. The results we obtain depend strongly on the type of ordering. In the case of "standard" ordering, in particular, the Dirac CP violation phase \delta, present in U, is predicted to have a value in a narrow interval around i) \delta ~ \pi in the BM (or LC) case, ii) \delta ~ 3\pi/2 or \pi/2 in the TBM case, the CP conserving values \delta = 0, \pi, 2\pi being excluded in the TBM case at more than 4\sigma

Generalised CP and Δ(6n2)\Delta (6n^2) Family Symmetry in Semi-Direct Models of Leptons

We perform a detailed analysis of $\Delta (6n^2)$ family symmetry combined with a generalised CP symmetry in the lepton sector, breaking to different remnant symmetries $G_{\nu}$ in the neutrino and $G_{l}$ in the charged lepton sector, together with different remnant CP symmetries in each sector. We discuss the resulting mass and mixing predictions for $G_{\nu}=Z_2$ with $G_{l}=K_4,Z_p,p>2$ and $G_{\nu}=K_4$ with $G_{l}=Z_2$. All cases correspond to the preserved symmetry smaller than the full Klein symmetry, as in the semi-direct approach, leading to predictions which depend on a single undetermined real parameter, which mainly determines the reactor angle. We focus on five phenomenologically allowed cases for which we present the resulting predictions for the PMNS parameters as a function of $n$, as well as the predictions for neutrinoless double beta decay.Comment: 65 pages, 19 figures, and the predictions for neutrinoless double beta decay are update