Monovinyl sulfone beta-cyclodextrin. A flexible drug carrier system

Cyclodextrins have been conjugated to target various receptors and have also been functionalized with carbohydrates for targeting specific organs. However, this approach is based on a rigid design that implies the ad hoc synthesis of each cyclodextrin-targeting agent conjugate. We hypothesized that: 1) a modular design that decouples the carrier function from the targeting function leads to a flexible system, 2) combining the reactivity of the vinyl sulfone group toward biomolecules that act as targeting agents with the ability of cyclodextrin to form complexes with a wide range of drugs may yield a versatile system that allows the targeting of different organs with different drugs, and 3) the higher reactivity of histidine residues toward the vinyl sulfone group can be exploited to couple the cyclodextrin to the targeting system with a degree of regioselectivity. As a proof of concept, we synthesized a monovinyl sulfone beta-cyclodextrin (module responsible for the payload), which, after coupling to recombinant antibody fragments raised against Trypanosoma brucei (module responsible for targeting) and loading with nitrofurazone (module responsible for therapeutic action) resulted in an effective delivery system that targets the surface of the parasites and shows trypanocidal activity

Effects of intermediate scales on renormalization group running of fermion observables in an SO(10) model

In the context of non-supersymmetric SO(10) models, we analyze the renormalization group equations for the fermions (including neutrinos) from the GUT energy scale down to the electroweak energy scale, explicitly taking into account the effects of an intermediate energy scale induced by a Pati--Salam gauge group. To determine the renormalization group running, we use a numerical minimization procedure based on a nested sampling algorithm that randomly generates the values of 19 model parameters at the GUT scale, evolves them, and finally constructs the values of the physical observables and compares them to the existing experimental data at the electroweak scale. We show that the evolved fermion masses and mixings present sizable deviations from the values obtained without including the effects of the intermediate scale.Comment: Comments: 20 pages, 3 figures. Final version published in JHE

Sfrp3 modulates stromal-epithelial crosstalk during mammary gland development by regulating Wnt levels

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal–epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal–epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development

On "New Massive" 4D Gravity

We construct a four-dimensional (4D) gauge theory that propagates, unitarily, the five polarization modes of a massive spin-2 particle. These modes are described by a "dual" graviton gauge potential and the Lagrangian is 4th-order in derivatives. As the construction mimics that of 3D "new massive gravity", we call this 4D model (linearized) "new massive dual gravity". We analyse its massless limit, and discuss similarities to the Eddington-Schroedinger model.Comment: 17 pages, v2 : version published in JHE

On the importance of the 1-loop finite corrections to seesaw neutrino masses

In the standard seesaw mechanism, finite corrections to the neutrino mass matrix arise from 1-loop self-energy diagrams mediated by a heavy neutrino. We study in detail these corrections and demonstrate that they can be very significant, exceeding in several cases the tree-level result. We consider the normal and inverted hierarchy spectra for light neutrinos and compute the finite corrections to the different elements of the neutrino mass matrix. Special attention is paid to their dependence with the parameters of the seesaw model. Among the cases in which the corrections can be large, we identify the fine-tuned models considered previously in the literature, where a strong cancellation between the different parameters is required to achieve compatibility with the experimental data. As a particular example, we also analyze how these corrections modify the tribimaximal mixing pattern and find that the deviations may be sizable, in particular for $\theta_{13}$. Finally, we emphasize that due to their large size, the finite corrections to neutrino masses have to be taken into account if one wants to properly scan the parameter space of seesaw models.Comment: 24 pages, 11 figure

Minimal models with light sterile neutrinos

We study the constraints imposed by neutrino oscillation experiments on the minimal extensions of the Standard Model (SM) with $n_R$ gauge singlet fermions ("right-handed neutrinos"), that can account for neutrino masses. We consider the most general coupling to SM fields of the new fields, in particular those that break lepton number and we do not assume any a priori hierarchy in the mass parameters. We proceed to analyze these models starting from the lowest level of complexity, defined by the number of extra fermionic degrees of freedom. The simplest choice that has enough free parameters in principle (i.e. two mass differences and two angles) to explain the confirmed solar and atmospheric oscillations corresponds to $n_R=1$. This minimal choice is shown to be excluded by data. The next-to-minimal choice corresponds to $n_R=2$. We perform a systematic study of the full parameter space in the limit of degenerate Majorana masses by requiring that at least two neutrino mass differences correspond to those established by solar and atmospheric oscillations. We identify several types of spectra that can fit long-baseline reactor and accelerator neutrino oscillation data, but fail in explaining solar and/or atmospheric data. The only two solutions that survive are the expected seesaw and quasi-Dirac regions, for which we set lower and upper bounds respectively on the Majorana mass scale. Solar data from neutral current measurements provide essential information to constrain the quasi-Dirac region. The possibility to accommodate the LSND/MiniBoone and reactor anomalies, and the implications for neutrinoless double-beta decay and tritium beta decay are briefly discussed.Comment: 32 pages, 15 figures. Misprints and a small error corrected, references added. Conclusions unchange

Non-unitary Leptonic Mixing and Leptogenesis

We investigate the relation between non-unitarity of the leptonic mixing matrix and leptogenesis. We discuss how all parameters of the canonical type-I seesaw mechanism can, in principle, be reconstructed from the neutrino mass matrix and the deviation of the effective low-energy leptonic mixing matrix from unitary. When the mass M' of the lightest right-handed neutrino is much lighter than the masses of the others, we show that its decay asymmetries within flavour-dependent leptogenesis can be expressed in terms of two contributions, one depending on the unique dimension five (d=5) operator generating neutrino masses and one depending on the dimension six (d=6) operator associated with non-unitarity. In low-energy seesaw scenarios where small lepton number violation explains the smallness of neutrino masses, the lepton number conserving d=6 operator contribution generically dominates over the d=5 operator contribution which results in a strong enhancement of the flavour-dependent decay asymmetries without any resonance effects. To calculate the produced final baryon asymmetry, the flavour equilibration effects directly related to non-unitarity have to be taken into account. In a simple realization of this non-unitarity driven leptogenesis, the lower bound on M' is found to be about 10^8 GeV at the onset of the strong washout regime, more than one order of magnitude below the bound in "standard" thermal leptogenesis.Comment: 19 pages, REVTeX4, 2 eps and 2 axodraw figure

Beyond the standard seesaw: neutrino masses from Kahler operators and broken supersymmetry

We investigate supersymmetric scenarios in which neutrino masses are generated by effective d=6 operators in the Kahler potential, rather than by the standard d=5 superpotential operator. First, we discuss some general features of such effective operators, also including SUSY-breaking insertions, and compute the relevant renormalization group equations. Contributions to neutrino masses arise at low energy both at the tree level and through finite threshold corrections. In the second part we present simple explicit realizations in which those Kahler operators arise by integrating out heavy SU(2)_W triplets, as in the type II seesaw. Distinct scenarios emerge, depending on the mechanism and the scale of SUSY-breaking mediation. In particular, we propose an appealing and economical picture in which the heavy seesaw mediators are also messengers of SUSY breaking. In this case, strong correlations exist among neutrino parameters, sparticle and Higgs masses, as well as lepton flavour violating processes. Hence, this scenario can be tested at high-energy colliders, such as the LHC, and at lower energy experiments that measure neutrino parameters or search for rare lepton decays.Comment: LaTeX, 34 pages; some corrections in Section