Subversion of actin dynamics by EspM effectors of attaching and effacing bacterial pathogens

Rho GTPases are common targets of bacterial toxins and type III secretion system effectors. IpgB1 and IpgB2 of Shigella and Map of enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli were recently grouped together on the basis that they share a conserved WxxxE motif. In this study, we characterized six WxxxE effectors from attaching and effacing pathogens: TrcA and EspM1 of EPEC strain B171, EspM1 and EspM2 of EHEC strain Sakai and EspM2 and EspM3 of Citrobacter rodentium. We show that EspM2 triggers formation of global parallel stress fibres, TrcA and EspM1 induce formation of localized parallel stress fibres and EspM3 triggers formation of localized radial stress fibres. Using EspM2 and EspM3 as model effectors, we report that while substituting the conserved Trp with Ala abolished activity, conservative Trp to Tyr or Glu to Asp substitutions did not affect stress-fibre formation. We show, using dominant negative constructs and chemical inhibitors, that the activity of EspM2 and EspM3 is RhoA and ROCK-dependent. Using Rhotekin pull-downs, we have shown that EspM2 and EspM3 activate RhoA; translocation of EspM2 and EspM3 triggered phosphorylation of cofilin. These results suggest that the EspM effectors modulate actin dynamics by activating the RhoA signalling pathway

A Farewell to Liouvillians

We examine the Liouvillian approach to the quantum Hall plateau transition, as introduced recently by Sinova, Meden, and Girvin [Phys. Rev. B {\bf 62}, 2008 (2000)] and developed by Moore, Sinova and Zee [Phys. Rev. Lett. {\bf 87}, 046801 (2001)]. We show that, despite appearances to the contrary, the Liouvillian approach is not specific to the quantum mechanics of particles moving in a single Landau level: we formulate it for a general disordered single-particle Hamiltonian. We next examine the relationship between Liouvillian perturbation theory and conventional calculations of disorder-averaged products of Green functions and show that each term in Liouvillian perturbation theory corresponds to a specific contribution to the two-particle Green function. As a consequence, any Liouvillian approximation scheme may be re-expressed in the language of Green functions. We illustrate these ideas by applying Liouvillian methods, including their extension to $N_L > 1$ Liouvillian flavors, to random matrix ensembles, using numerical calculations for small integer $N_L$ and an analytic analysis for large $N_L$. We find that behavior at $N_L > 1$ is different in qualitative ways from that at $N_L=1$. In particular, the $N_L = \infty$ limit expressed using Green functions generates a pathological approximation, in which two-particle correlation functions fail to factorize correctly at large separations of their energy, and exhibit spurious singularities inside the band of random matrix energy levels. We also consider the large $N_L$ treatment of the quantum Hall plateau transition, showing that the same undesirable features are present there, too

Atenolol versus losartan in children and young adults with Marfan's syndrome

BACKGROUND : Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS : We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS : From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [+/- SD] age, 11.5 +/- 6.5 years in the atenolol group and 11.0 +/- 6.2 years in the losartan group), who had an aorticroot z score greater than 3.0. The baseline-adjusted rate of change (+/- SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139 +/- 0.013 and -0.107 +/- 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS : Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period

Dimensional Crossover of Localisation and Delocalisation in a Quantum Hall Bar

The 2-- to 1--dimensional crossover of the localisation length of electrons confined to a disordered quantum wire of finite width $L_y$ is studied in a model of electrons moving in the potential of uncorrelated impurities. An analytical formula for the localisation length is derived, describing the dimensional crossover as function of width $L_y$, conductance $g$ and perpendicular magnetic field $B$ . On the basis of these results, the scaling analysis of the quantum Hall effect in high Landau levels, and the delocalisation transition in a quantum Hall wire are reconsidered.Comment: 12 pages, 7 figure

Measurement of the Running of the Electromagnetic Coupling at Large Momentum-Transfer at LEP

The evolution of the electromagnetic coupling, alpha, in the momentum-transfer range 1800GeV^2 < -Q^2 < 21600GeV^2 is studied with about 40000 Bhabha-scattering events collected with the L3 detector at LEP at centre-of-mass energies 189-209GeV. The running of alpha is parametrised as: alpha(Q^2) = alpha_0/(1-C Delta alpha(Q^2)), where alpha_0=\alpha(Q^2=0) is the fine-structure constant and C=1 corresponds to the evolution expected in QED. A fit to the differential cross section of the e+e- ->e+e- process for scattering angles in the range |cos theta|<0.9 excludes the hypothesis of a constant value of alpha, C=0, and validates the QED prediction with the result: C = 1.05 +/- 0.07 +/- 0.14, where the first uncertainty is statistical and the second systematic

On complex-valued 2D eikonals. Part four: continuation past a caustic

Theories of monochromatic high-frequency electromagnetic fields have been designed by Felsen, Kravtsov, Ludwig and others with a view to portraying features that are ignored by geometrical optics. These theories have recourse to eikonals that encode information on both phase and amplitude -- in other words, are complex-valued. The following mathematical principle is ultimately behind the scenes: any geometric optical eikonal, which conventional rays engender in some light region, can be consistently continued in the shadow region beyond the relevant caustic, provided an alternative eikonal, endowed with a non-zero imaginary part, comes on stage. In the present paper we explore such a principle in dimension $2.$ We investigate a partial differential system that governs the real and the imaginary parts of complex-valued two-dimensional eikonals, and an initial value problem germane to it. In physical terms, the problem in hand amounts to detecting waves that rise beside, but on the dark side of, a given caustic. In mathematical terms, such a problem shows two main peculiarities: on the one hand, degeneracy near the initial curve; on the other hand, ill-posedness in the sense of Hadamard. We benefit from using a number of technical devices: hodograph transforms, artificial viscosity, and a suitable discretization. Approximate differentiation and a parody of the quasi-reversibility method are also involved. We offer an algorithm that restrains instability and produces effective approximate solutions.Comment: 48 pages, 15 figure

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog