Role of glucose and CcpA in capsule expression and virulence of Streptococcus suis

Streptococcus suis is one of the most important pathogens in pigs and is also an emerging zoonotic agent. After crossing the epithelial barrier, S. suis causes bacteraemia, resulting in meningitis, endocarditis and bronchopneumonia. Since the host environment seems to be an important regulatory component for virulence, we related expression of virulence determinants of S. suis to glucose availability during growth and to the sugar metabolism regulator catabolite control protein A (CcpA). We found that expression of the virulence-associated genes arcB, representing arcABC operon expression, cps2A, representing capsular locus expression, as well as sly, ofs, sao and epf, differed significantly between exponential and early stationary growth of a highly virulent serotype 2 strain. Deletion of ccpA altered the expression of the surface-associated virulence factors arcB, sao and eno, as well as the two currently proven virulence factors in pigs, ofs and cps2A, in early exponential growth. Global expression analysis using a cDNA expression array revealed 259 differentially expressed genes in early exponential growth, of which 141 were more highly expressed in the CcpA mutant strain 10¿ccpA and 118 were expressed to a lower extent. Interestingly, among the latter genes, 18 could be related to capsule and cell wall synthesis. Correspondingly, electron microscopy characterization of strain 10¿ccpA revealed a markedly reduced thickness of the capsule. This phenotype correlated with enhanced binding to porcine plasma proteins and a reduced resistance to killing by porcine neutrophils. Taken together, our data demonstrate that CcpA has a significant effect on the capsule synthesis and virulence properties of S. suis

G-flux and Spectral Divisors

We propose a construction of G-flux in singular elliptic Calabi-Yau fourfold compactifications of F-theory, which in the local limit allow a spectral cover description. The main tool of construction is the so-called spectral divisor in the resolved Calabi-Yau geometry, which in the local limit reduces to the Higgs bundle spectral cover. We exemplify the workings of this in the case of an E_6 singularity by constructing the resolved geometry, the spectral divisor and in the local limit, the spectral cover. The G-flux constructed with the spectral divisor is shown to be equivalent to the direct construction from suitably quantized linear combinations of holomorphic surfaces in the resolved geometry, and in the local limit reduces to the spectral cover flux.Comment: 30 page

Mechanistic insights into an engineered riboswitch: a switching element which confers riboswitch activity

While many different RNA aptamers have been identified that bind to a plethora of small molecules only very few are capable of acting as engineered riboswitches. Even for aptamers binding the same ligand large differences in their regulatory potential were observed. We address here the molecular basis for these differences by using a set of unrelated neomycin-binding aptamers. UV melting analyses showed that regulating aptamers are thermally stabilized to a significantly higher degree upon ligand binding than inactive ones. Regulating aptamers show high ligand-binding affinity in the low nanomolar range which is necessary but not sufficient for regulation. NMR data showed that a destabilized, open ground state accompanied by extensive structural changes upon ligand binding is important for regulation. In contrast, inactive aptamers are already pre-formed in the absence of the ligand. By a combination of genetic, biochemical and structural analyses, we identified a switching element responsible for destabilizing the ligand free state without compromising the bound form. Our results explain for the first time the molecular mechanism of an engineered riboswitch

Chiral symmetry breaking of magnetic vortices by sample roughness

Finite-element micromagnetic simulations are employed to study the chiral symmetry breaking of magnetic vortices, caused by the surface roughness of thin-film magnetic structures. An asymmetry between vortices with different core polarizations has been experimentally observed for square-shaped platelets. E.g., the threshold fields for vortex core switching were found to differ for core up and down. This asymmetry was however not expected for these symmetrically-shaped structures, where both core polarizations should behave symmetrically. Three-dimensional finite element simulations are employed to show that a small surface roughness can break the symmetry between vortex cores pointing up and down. A relatively small sample roughness is found sufficient to reproduce the experimentally observed asymmetries. It arises from the lack of mirror-symmetry of the rough thin-film structures, which causes vortices with different handedness to exhibit asymmetric dynamics

Safety, tolerability, and impact on allergic inflammation of autologous E.coli autovaccine in the treatment of house dust mite asthma - a prospective open clinical trial

Background: Asthma is increasing worldwide and results from a complex immunological interaction between genetic susceptibility and environmental factors. Autovaccination with E. coli induces a strong TH-1 immune response, thus offering an option for the treatment of allergic diseases. Methods: Prospective open trial on safety, tolerability, and impact on allergic inflammation of an autologous E.coli autovaccine in intermittent or mild persistent house dust mite asthma. Determination of exhaled nitric monoxide (eNO) before and after bronchial mite challenge initially and after nine months of autovaccination. Results: Median eNO increase after autovaccination was significantly smaller (from 27.3 to 33.8 ppb; p=0.334) compared to initial values (from 32.6 to 42.2 ppb; p=0.046) (p=0.034). In nine subjects and a total of 306 injections, we observed 101 episodes of local erythema (33.3%; median of maximal diameter 2.5 cm), 95 episodes of local swelling (31.1%; median of maximal diameter 3 cm), and 27 episodes of local pain (8.8%). Four subjects reported itching at the injection site with a total of 30 episodes (9.8%). We observed no serious adverse events. All organ functions (inclusive electrocardiogramm) and laboratory testing of the blood (clinical chemistry, hematology) and the urine (screening test, B-microglobuline) were within normal limits. Vital signs undulated within the physiological variability. Conclusion: The administration of autologous autovacine for the treatment of house dust mite asthma resulted in a reduction of the eNO increase upon bronchial mite challenge. In nine subjects and 306 injections, only a few mild local reactions and no systemic severe adverse events were observed. EudraCT Nr. 2005-005534-12 ClinicalTrials.gov ID NCT0067720

On Flux Quantization in F-Theory

We study the problem of four-form flux quantization in F-theory compactifications. We prove that for smooth, elliptically fibered Calabi-Yau fourfolds with a Weierstrass representation, the flux is always integrally quantized. This implies that any possible half-integral quantization effects must come from 7-branes, i.e. from singularities of the fourfold. We subsequently analyze the quantization rule on explicit fourfolds with Sp(N) singularities, and connect our findings via Sen's limit to IIB string theory. Via direct computations we find that the four-form is half-integrally quantized whenever the corresponding 7-brane stacks wrap non-spin complex surfaces, in accordance with the perturbative Freed-Witten anomaly. Our calculations on the fourfolds are done via toric techniques, whereas in IIB we rely on Sen's tachyon condensation picture to treat bound states of branes. Finally, we give general formulae for the curvature- and flux-induced D3 tadpoles for general fourfolds with Sp(N) singularities.Comment: 46 page

Lectures on F-theory compactifications and model building

These lecture notes are devoted to formal and phenomenological aspects of F-theory. We begin with a pedagogical introduction to the general concepts of F-theory, covering classic topics such as the connection to Type IIB orientifolds, the geometry of elliptic fibrations and the emergence of gauge groups, matter and Yukawa couplings. As a suitable framework for the construction of compact F-theory vacua we describe a special class of Weierstrass models called Tate models, whose local properties are captured by the spectral cover construction. Armed with this technology we proceed with a survey of F-theory GUT models, aiming at an overview of basic conceptual and phenomenological aspects, in particular in connection with GUT breaking via hypercharge flux.Comment: Invited contribution to the proceedings of the CERN Winter School on Supergravity, Strings and Gauge Theory 2010, to appear in Classical and Quantum Gravity; 63 pages; v2: references added, typos correcte

Unification, KK-thresholds and the top Yukawa coupling in F-theory GUTs

In a class of F-theory SU(5) GUTs the low energy chiral mass spectrum is obtained from rank one fermion mass textures with a hierarchical structure organised by U(1) symmetries embedded in the exceptional E_8 group. In these theories chiral fields reside on matter `curves' and the tree level masses are computed from integrals of overlapping wavefuctions of the particles at the triple intersection points. This calculation requires knowledge of the exact form of the wavefuctions. In this work we propose a way to obtain a reliable estimate of the various quantities which determine the strength of the Yukawa couplings. We use previous analysis of KK threshold effects to determine the (ratios of) heavy mass scales of the theory which are involved in the normalization of the wave functions. We consider similar effects from the chiral spectrum of these models and discuss possible constraints on the emerging matter content. In this approach, we find that the Yukawa couplings can be determined solely from the U(1) charges of the states in the `intersection' and the torsion which is a topological invariant quantity. We apply the results to a viable SU(5) model with minimal spectrum which satisfies all the constraints imposed by our analysis. We use renormalization group analysis to estimate the top and bottom masses and find that they are in agreement with the experimental values.Comment: 28 pages, 2 figure

On Flux Quantization in F-Theory II: Unitary and Symplectic Gauge Groups

We study the quantization of the M-theory G-flux on elliptically fibered Calabi-Yau fourfolds with singularities giving rise to unitary and symplectic gauge groups. We seek and find its relation to the Freed-Witten quantization of worldvolume fluxes on 7-branes in type IIB orientifold compactifications on Calabi-Yau threefolds. By explicitly constructing the appropriate four-cycles on which to calculate the periods of the second Chern class of the fourfolds, we find that there is a half-integral shift in the quantization of G-flux whenever the corresponding dual 7-brane is wrapped on a non-spin submanifold. This correspondence of quantizations holds for all unitary and symplectic gauge groups, except for SU(3), which behaves mysteriously. We also perform our analysis in the case where, in addition to the aforementioned gauge groups, there is also a 'flavor' U(1)-gauge group.Comment: 33 pages, 4 figure

Gauge Fluxes in F-theory and Type IIB Orientifolds

We provide a detailed correspondence between G_4 gauge fluxes in F-theory compactifications with SU(n) and SU(n)x(1) gauge symmetry and their Type IIB orientifold limit. Based on the resolution of the relevant F-theory Tate models we classify the factorisable G_4-fluxes and match them with the set of universal D5-tadpole free U(1)-fluxes in Type IIB. Where available, the global version of the universal spectral cover flux corresponds to Type IIB gauge flux associated with a massive diagonal U(1). In U(1)-restricted Tate models extra massless abelian fluxes exist which are associated with specific linear combinations of Type IIB fluxes. Key to a quantitative match between F-theory and Type IIB is a proper treatment of the conifold singularity encountered in the Sen limit of generic F-theory models. We also shed further light on the brane recombination process relating generic and U(1)-restricted Tate models.Comment: 53 pages, 3 figures; v2: Refs added; v3: minor corrections to match version published in JHE