Enhanced nasopharyngeal infection and shedding associated with an epidemic lineage of emm3 group A Streptococcus

Background: A group A Streptococcus (GAS) lineage of genotype emm3, sequence type 15 (ST15) was associated with a six month upsurge in invasive GAS disease in the UK. The epidemic lineage (Lineage C) had lost two typical emm3 prophages, Φ315.1 and Φ315.2 associated with the superantigen ssa, but gained a different prophage (ΦUK-M3.1) associated with a different superantigen, speC and a DNAse spd1. Methods and Results: The presence of speC and spd1 in Lineage C ST15 strains enhanced both in vitro mitogenic and DNAse activities over non-Lineage C ST15 strains. Invasive disease models in Galleria mellonella and SPEC-sensitive transgenic mice, revealed no difference in overall invasiveness of Lineage C ST15 strains compared to non-Lineage C ST15 strains, consistent with clinical and epidemiological analysis. Lineage C strains did however markedly prolong murine nasal infection with enhanced nasal and airborne shedding compared to non-Lineage C strains. Deletion of speC or spd1 in two Lineage C strains identified a possible role for spd1 in airborne shedding from the murine nasopharynx. Conclusions: Nasopharyngeal infection and shedding of Lineage C strains was enhanced compared to nonLineage C strains and this was, in part, mediated by the gain of the DNase spd1 through prophage acquisition

On massive gravitons in 2+1 dimensions

The Fierz-Pauli (FP) free field theory for massive spin 2 particles can be extended, in a spacetime of (1+2) dimensions (3D), to a generally covariant parity-preserving interacting field theory, in at least two ways. One is "new massive gravity" (NMG), with an action that involves curvature-squared terms. Another is 3D "bigravity", which involves non-linear couplings of the FP tensor field to 3D Einstein-Hilbert gravity. We review the proof of the linearized equivalence of both "massive 3D gravity" theories to FP theory, and we comment on their similarities and differences.Comment: 6 pages, to appear in the proceedings of the Spanish Relativity Meeting ERE2009, Bilbao; minor changes, reference adde

Afshar's Experiment does not show a Violation of Complementarity

A recent experiment performed by S. Afshar [first reported by M. Chown, New Scientist {\bf 183}, 30 (2004)] is analyzed. It was claimed that this experiment could be interpreted as a demonstration of a violation of the principle of complementarity in quantum mechanics. Instead, it is shown here that it can be understood in terms of classical wave optics and the standard interpretation of quantum mechanics. Its performance is quantified and it is concluded that the experiment is suboptimal in the sense that it does not fully exhaust the limits imposed by quantum mechanics.Comment: 6 pages, 6 figure

AP-4-mediated axonal transport controls endocannabinoid production in neurons

Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown. The adaptor protein complex AP-4 mediates anterograde axonal transport and is essential for axon health. AP-4-deficient patients suffer from a severe neurodevelopmental and neurodegenerative disorder. Here we identify DAGLB (diacylglycerol lipase-beta), a key enzyme for generation of the endocannabinoid 2-AG (2-arachidonoylglycerol), as a cargo of AP-4 vesicles. During normal development, DAGLB is targeted to the axon, where 2-AG signalling drives axonal growth. We show that DAGLB accumulates at the trans-Golgi network of AP-4-deficient cells, that axonal DAGLB levels are reduced in neurons from a patient with AP-4 deficiency, and that 2-AG levels are reduced in the brains of AP-4 knockout mice. Importantly, we demonstrate that neurite growth defects of AP-4-deficient neurons are rescued by inhibition of MGLL (monoacylglycerol lipase), the enzyme responsible for 2-AG hydrolysis. Our study supports a new model for AP-4 deficiency syndrome in which axon growth defects arise through spatial dysregulation of endocannabinoid signalling.Special thanks to the MPIB Imaging Facility for outstanding technical support, in particular to Giovanni Cardone for his advice and assistance with the implementation of image analysis pipelines, as well as feedback on the manuscript, and to Martin Spitaler for his expert technical advice for imaging experiments

Towards the Formalization of Fractional Calculus in Higher-Order Logic

Fractional calculus is a generalization of classical theories of integration and differentiation to arbitrary order (i.e., real or complex numbers). In the last two decades, this new mathematical modeling approach has been widely used to analyze a wide class of physical systems in various fields of science and engineering. In this paper, we describe an ongoing project which aims at formalizing the basic theories of fractional calculus in the HOL Light theorem prover. Mainly, we present the motivation and application of such formalization efforts, a roadmap to achieve our goals, current status of the project and future milestones.Comment: 9 page

Characterization of an engineered human purine nucleoside phosphorylase fused to an anti-her2/neu single chain Fv for use in ADEPT

Abstract Background Antibody Directed Enzyme Prodrug Therapy (ADEPT) can be used to generate cytotoxic agents at the tumor site. To date non-human enzymes have mainly been utilized in ADEPT. However, these non-human enzymes are immunogenic limiting the number of times that ADEPT can be administered. To overcome the problem of immunogenicity, a fully human enzyme, capable of converting a non-toxic prodrug to cytotoxic drug was developed and joined to a human tumor specific scFv yielding a fully human targeting agent. Methods A double mutant of human purine nucleoside phosphorylase (hDM) was developed which unlike the human enzyme can cleave adenosine-based prodrugs. For tumor-specific targeting, hDM was fused to the human anti-HER2/neu single chain Fv (scFv), C6 MH3B1. Enzymatic activity of hDM with its natural substrates and prodrugs was determined using spectrophotomeric approaches. A cell proliferation assay was used to assess the cytotoxicity generated following conversion of prodrug to drug as a result of enzymatic activity of hDM. Affinity of the targeting scFv, C6 MH3B1 fused to hDM to Her2/neu was confirmed using affinity chromatography, surface plasmon resonance, and flow-cytometry. Results In vitro hDM-C6 MH3B1 binds specifically to HER2/neu expressing tumor cells and localizes hDM to tumor cells, where the enzymatic activity of hDM-C6 MH3B1, but not the wild type enzyme, results in phosphorolysis of the prodrug, 2-fluoro-2'-deoxyadenosine to the cytotoxic drug 2-fluoroadenine (F-Ade) causing inhibition of tumor cell proliferation. Significantly, the toxic small drug diffuses through the cell membrane of HER2/neu expressing cells as well as cells that lack the expression of HER2/neu, causing a bystander effect. F-Ade is toxic to cells irrespective of their growth rate; therefore, both the slowly dividing tumor cells and the non-dividing neighboring stromal cells that support tumor growth should be killed. Analysis of potential novel MHCII binding peptides resulting from fusion of hDM to C6 MH3B1 and the two mutations in hDM, and of the structure of hDM compared to the wild-type enzyme suggests that hDM-C6 MH3B1 should exhibit minimal immunogenicity in humans. Conclusion hDM-C6 MH3B1 constitutes a novel human based protein that addresses some of the limitations of ADEPT that currently preclude its successful use in the clinic

Covariant coarse-graining of inhomogeneous dust flow in General Relativity

A new definition of coarse-grained quantities describing the dust flow in General Relativity is proposed. It assigns the coarse--grained expansion, shear and vorticity to finite-size comoving domains of fluid in a covariant, coordinate-independent manner. The coarse--grained quantities are all quasi-local functionals, depending only on the geometry of the boundary of the considered domain. They can be thought of as relativistic generalizations of simple volume averages of local quantities in a flat space. The procedure is based on the isometric embedding theorem for S^2 surfaces and thus requires the boundary of the domain in question to have spherical topology and positive scalar curvature. We prove that in the limit of infinitesimally small volume the proposed quantities reproduce the local expansion, shear and vorticity. In case of irrotational flow we derive the time evolution for the coarse-grained quantities and show that its structure is very similar to the evolution equation for their local counterparts. Additional terms appearing in it may serve as a measure of the backreacton of small-scale inhomogeneities of the flow on the large-scale motion of the fluid inside the domain and therefore the result may be interesting in the context of the cosmological backreaction problem. We also consider the application of the proposed coarse-graining procedure to a number of known exact solutions of Einstein equations with dust and show that it yields reasonable results.Comment: 17 pages, 5 figures. Version accepted in Classical and Quantum Gravity

On Non-Linear Actions for Massive Gravity

In this work we present a systematic construction of the potentially ghost-free non-linear massive gravity actions. The most general action can be regarded as a 2-parameter deformation of a minimal massive action. Further extensions vanish in 4 dimensions. The general mass term is constructed in terms of a "deformed" determinant from which this property can clearly be seen. In addition, our formulation identifies non-dynamical terms that appear in previous constructions and which do not contribute to the equations of motion. We elaborate on the formal structure of these theories as well as some of their implications.Comment: v3: 22 pages, minor comments added, version to appear in JHE