Acid-Labile Traceless Click Linker for Protein Transduction

Intracellular delivery of active proteins presents an interesting approach in research and therapy. We created a protein transduction shuttle based on a new traceless click linker that combines the advantages of click reactions with implementation of reversible pH-sensitive bonds. The azidomethyl-methylmaleic anhydride (AzMMMan) linker was found compatible with different click chemistries, demonstrated in bioreversible protein modification with dyes, polyethylene glycol, or a transduction carrier. Linkages were stable at physiological pH but reversible at the mild acidic pH of endosomes or lysosomes. We show that pH-reversible attachment of a defined endosome-destabilizing three-arm oligo(ethane amino)amide carrier generates an effective shuttle for protein delivery. The cargo protein nlsEGFP, when coupled via the traceless AzMMMan linker, experiences efficient cellular uptake and endosomal escape into the cytosol, followed by import into the nucleus. In contrast, irreversible linkage to the same shuttle hampers nuclear delivery of nlsEGFP which after uptake remains trapped in the cytosol. Successful intracellular delivery of bioactive ß-galactosidase as a model enzyme was also demonstrated using the pH-controlled shuttle system

A Complete Theory of Grand Unification in Five Dimensions

A fully realistic unified theory is constructed, with SU(5) gauge symmetry and supersymmetry both broken by boundary conditions in a fifth dimension. Despite the local explicit breaking of SU(5) at a boundary of the dimension, the large size of the extra dimension allows precise predictions for gauge coupling unification, alpha_s(M_Z) = 0.118 \pm 0.003, and for Yukawa coupling unification, m_b(M_Z) = 3.3 \pm 0.2 GeV. A complete understanding of the MSSM Higgs sector is given; with explanations for why the Higgs triplets are heavy, why the Higgs doublets are protected from a large tree-level mass, and why the mu and B parameters are naturally generated to be of order the SUSY breaking scale. All sources of d=4,5 proton decay are forbidden, while a new origin for d=6 proton decay is found to be important. Several aspects of flavor follow from an essentially unique choice of matter location in the fifth dimension: only the third generation has an SU(5) mass relation, and the lighter two generations have small mixings with the heaviest generation. The entire superpartner spectrum is predicted in terms of only two free parameters. The squark and slepton masses are determined by their location in the fifth dimension, allowing a significant experimental test of the detailed structure of the extra dimension. Lepton flavor violation is found to be generically large in higher dimensional unified theories with high mediation scales of SUSY breaking. In our theory this forces a common location for all three neutrinos, predicting large neutrino mixing angles. Rates for mu -> e gamma, mu -> e e e, mu -> e conversion and tau -> mu gamma are larger in our theory than in conventional 4D supersymmetric GUTs. Proposed experiments probing mu -> e transitions will probe the entire interesting parameter space of our theory.Comment: 51 pages, late

Enhancing lepton flavour violation in the supersymmetric inverse seesaw beyond the dipole contribution

In minimal supersymmetric models the $Z$-penguin usually provides sub-dominant contributions to charged lepton flavour violating observables. In this study, we consider the supersymmetric inverse seesaw in which the non-minimal particle content allows for dominant contributions of the $Z$-penguin to several lepton flavour violating observables. In particular, and due to the low-scale (TeV) seesaw, the penguin contribution to, for instance, \Br(\mu \to 3e) and $\mu-e$ conversion in nuclei, allows to render some of these observables within future sensitivity reach. Moreover, we show that in this framework, the $Z$-penguin exhibits the same non-decoupling behaviour which had previously been identified in flavour violating Higgs decays in the Minimal Supersymmetric Standard Model.Comment: 29 pages, 9 figures, 4 tables; v2: minor corrections, version to appear in JHE

Asymptotic Limits and Zeros of Chromatic Polynomials and Ground State Entropy of Potts Antiferromagnets

We study the asymptotic limiting function $W({G},q) = \lim_{n \to \infty}P(G,q)^{1/n}$, where $P(G,q)$ is the chromatic polynomial for a graph $G$ with $n$ vertices. We first discuss a subtlety in the definition of $W({G},q)$ resulting from the fact that at certain special points $q_s$, the following limits do not commute: $\lim_{n \to \infty} \lim_{q \to q_s} P(G,q)^{1/n} \ne \lim_{q \to q_s} \lim_{n \to \infty} P(G,q)^{1/n}$. We then present exact calculations of $W({G},q)$ and determine the corresponding analytic structure in the complex $q$ plane for a number of families of graphs ${G}$, including circuits, wheels, biwheels, bipyramids, and (cyclic and twisted) ladders. We study the zeros of the corresponding chromatic polynomials and prove a theorem that for certain families of graphs, all but a finite number of the zeros lie exactly on a unit circle, whose position depends on the family. Using the connection of $P(G,q)$ with the zero-temperature Potts antiferromagnet, we derive a theorem concerning the maximal finite real point of non-analyticity in $W({G},q)$, denoted $q_c$ and apply this theorem to deduce that $q_c(sq)=3$ and $q_c(hc) = (3+\sqrt{5})/2$ for the square and honeycomb lattices. Finally, numerical calculations of $W(hc,q)$ and $W(sq,q)$ are presented and compared with series expansions and bounds.Comment: 33 pages, Latex, 5 postscript figures, published version; includes further comments on large-q serie

Muon to electron conversion in the Littlest Higgs model with T-parity

Little Higgs models provide a natural explanation of the little hierarchy between the electroweak scale and a few TeV scale, where new physics is expected. Under the same inspiring naturalness arguments, this work completes a previous study on lepton flavor-changing processes in the Littlest Higgs model with T-parity exploring the channel that will eventually turn out to be the most sensitive, \mu-e conversion in nuclei. All one-loop contributions are carefully taken into account, results for the most relevant nuclei are provided and a discussion of the influence of the quark mixing is included. The results for the Ti nucleus are in good agreement with earlier work by Blanke et al., where a degenerate mirror quark sector was assumed. The conclusion is that, although this particular model reduces the tension with electroweak precision tests, if the restrictions on the parameter space derived from lepton flavor violation are taken seriously, the degree of fine tuning necessary to meet these constraints also disfavors this model.Comment: 26 pages, 7 figures, 4 tables; discussion improved, results unchanged, one reference added, version to appear in JHE

Density of states for the π\pi-flux state with bipartite real random hopping only: A weak disorder approach

Gade [R. Gade, Nucl. Phys. B \textbf{398}, 499 (1993)] has shown that the local density of states for a particle hopping on a two-dimensional bipartite lattice in the presence of weak disorder and in the absence of time-reversal symmetry(chiral unitary universality class) is anomalous in the vicinity of the band center $\epsilon=0$ whenever the disorder preserves the sublattice symmetry. More precisely, using a nonlinear-sigma-model that encodes the sublattice (chiral) symmetry and the absence of time-reversal symmetry she argues that the disorder average local density of states diverges as $|\epsilon|^{-1}\exp(-c|\ln\epsilon|^\kappa)$ with $c$ some non-universal positive constant and $\kappa=1/2$ a universal exponent. Her analysis has been extended to the case when time-reversal symmetry is present (chiral orthogonal universality class) for which the same exponent $\kappa=1/2$ was predicted. Motrunich \textit{et al.} [O. Motrunich, K. Damle, and D. A. Huse, Phys. Rev. B \textbf{65}, 064206 (2001)] have argued that the exponent $\kappa=1/2$ does not apply to the typical density of states in the chiral orthogonal universality class. They predict that $\kappa=2/3$ instead. We confirm the analysis of Motrunich \textit{et al.} within a field theory for two flavors of Dirac fermions subjected to two types of weak uncorrelated random potentials: a purely imaginary vector potential and a complex valued mass potential. This model is believed to belong to the chiral orthogonal universality class. Our calculation relies in an essential way on the existence of infinitely many local composite operators with negative anomalous scaling dimensions.Comment: 30 pages, final version published in PR

Lepton Flavor Violation in the Two Higgs Doublet Model type III

We consider the Two Higgs Doublet Model (2HDM) of type III which leads to Flavour Changing Neutral Currents (FCNC) at tree level in the leptonic sector. In the framework of this model we can have, in principle, two situations: the case (a) when both doublets acquire a vacuum expectation value different from zero and the case (b) when only one of them is not zero. In addition, we show that we can make two types of rotations for the flavor mixing matrices which generates four types of lagrangians, with the rotation of type I we recover the case (b) from the case (a) in the limit $\tan \beta \to \infty$, and with the rotation of type II we obtain the case (b) from (a) in the limit $\tan \beta \to 0.$Moreover, two of the four possible lagrangians correspond to the models of types I and II plus Flavor Changing (FC) interactions. The analitical expressions of the partial lepton number violating widths $\Gamma (\mu \to eee)$ and $\Gamma (\mu \to e\gamma)$are derived for the cases (a) and (b) and both types of rotations.$$In all cases these widths go asymptotically to zero in the decoupling limit for all Higgses. We present from our analysis upper bounds for the flavour changing transition $\mu \to e,$ and we show that such bounds are sensitive to the VEV structure and the type of rotation utilized.Comment: 7 pages RevTeX4, 4 figures postscript, new section added and some new reference

Tunable Charge Density Wave Transport in a Current-Effect Transistor

The collective charge density wave (CDW) conduction is modulated by a transverse single-particle current in a transistor-like device. Nonequilibrium conditions in this geometry lead to an exponential reduction of the depinning threshold, allowing the CDWs to slide for much lower bias fields. The results are in excellent agreement with a recently proposed dynamical model in which ''wrinkles'' in the CDW wavefronts are ''ironed'' by the transverse current. The experiment might have important implications for other driven periodic media, such as moving vortex lattices or ''striped phases'' in high-Tc superconductors.Comment: 4 pages, 4 figure

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined multifunctional carriers for targeted gene delivery. For this purpose, at first propargyl amine cored PAMAM dendrons with ester ends were synthesized. The chain terminal ester groups were then modified by oligoamines with different secondary amino densities. The oligoamine-modified PAMAM dendrons were well biocompatible, as demonstrated in cytotoxicity assays. Among the different oligoamine-modified dendrons, PAMAM-pentaethylenehexamine (PEHA) dendron polyplexes displayed the best gene transfer ability. Conjugation of PAMAM-PEHA dendron with PEG spacer was conducted via click reaction, which was performed before amidation with PEHA. The resultant PEG-PAMAM-PEHA copolymer was then coupled with EGF ligand. pDNA transfections in HuH-7 hepatocellular carcinoma cells showed a 10-fold higher efficiency with the polyplexes containing conjugated EGF as compared to the ligand-free ones, demonstrating the concept of ligand targeting. Overall gene transfer efficiencies, however, were moderate, suggesting that additional measures for overcoming subsequent intracellular bottlenecks in delivery have to be taken