Distinct conformations, aggregation and cellular internalization of different tau strains

The inter-cellular propagation of tau aggregates in several neurodegenerative diseases involves, in part, recurring cycles of extracellular tau uptake, initiation of endogenous tau aggregation, and extracellular release of at least part of this protein complex. However, human brain tau extracts from diverse tauopathies exhibit variant or “strain” specificity in inducing inter-cellular propagation in both cell and animal models. It is unclear if these distinctive properties are affected by disease-specific differences in aggregated tau conformation and structure. We have used a combined structural and cell biological approach to study if two frontotemporal dementia (FTD)-associated pathologic mutations, V337M and N279K, affect the aggregation, conformation and cellular internalization of the tau four-repeat domain (K18) fragment. In both heparin-induced and native-state aggregation experiments, each FTD variant formed soluble and fibrillar aggregates with remarkable morphological and immunological distinctions from the wild type (WT) aggregates. Exogenously-applied oligomers of the FTD tau-K18 variants (V337M and N279K) were significantly more efficiently taken up by SH-SY5Y neuroblastoma cells than WT tau-K18, suggesting mutation-induced changes in cellular internalization. However, shared internalization mechanisms were observed: endocytosed oligomers were distributed in the cytoplasm and nucleus of SH-SY5Y cells and the neurites and soma of human induced pluripotent stem cell-derived neurons where they co-localized with endogenous tau and the nuclear protein nucleolin. Altogether, evidence of conformational and aggregation differences between WT and disease-mutated tau K18 is demonstrated, which may explain their distinct cellular internalization potencies. These findings may account for critical aspects of the molecular pathogenesis of tauopathies involving WT and mutated tau

Generation of entangled states and error protection from adiabatic avoided level crossings

We consider the environment-affected dynamics of $N$ self-interacting particles living in one-dimensional double wells. Two topics are dealt with. First, we consider the production of entangled states of two-level systems. We show that by adiabatically varying the well biases we may dynamically generate maximally entangled states, starting from initially unentangled product states. Entanglement degradation due to a common type of environmental influence is then computed by solving a master equation. However, we also demonstrate that entanglement production is unaffected if the system-environment coupling is of the type that induces ``motional narrowing''. As our second but related topic, we construct a different master equation that seamlessly merges error protection/detection dynamics for quantum information with the environmental couplings responsible for producing the errors in the first place. Adiabatic avoided crossing schemes are used in both topics.Comment: 14 pages, 6 figures. Minor changes. To appear in Phys. Rev.

Maximal Neutrino Mixing from an Attractive Infrared Fixed Point

In the Standard Model (and MSSM), renormalization effects on neutrino mixing are generally very small and the attractive fixed points are at vanishing neutrino mixing. However for multi-higgs extensions of the Standard Model, renormalization effects on neutrino mixing can be large and nontrivial fixed points are possible. Here we examine a simple two-higgs model. For two flavors, maximal mixing is an attractive infrared fixed point. For three flavors, the neutrino mass matrix evolves towards large off-diagonal elements at low energies. The experimentally suggested bimaximal neutrino mixing pattern is one possible attractive infrared fixed point.Comment: 16 page

Football in the community schemes: Exploring the effectiveness of an intervention in promoting healthful behaviour change

This study aims to examine the effectiveness of a Premier League football club’s Football in the Community (FitC) schemes intervention in promoting positive healthful behaviour change in children. Specifically, exploring the effectiveness of this intervention from the perspectives of the participants involved (i.e. the researcher, teachers, children and coaches). A range of data collection techniques were utilized including the principles of ethnography (i.e. immersion, engagement and observations), alongside conducting focus groups with the children. The results allude to the intervention merely ‘keeping active children active’ via (mostly) fun, football sessions. Results highlight the important contribution the ‘coach’ plays in the effectiveness of the intervention. Results relating to working practice (i.e. coaching practice and coach recruitment) are discussed and highlighted as areas to be addressed. FitC schemes appear to require a process of positive organizational change to increase their effectiveness in strategically attending to the health agenda

Constraints on diffuse neutrino background from primordial black holes

We calculated the energy spectra and the fluxes of electron neutrino emitted in the process of evaporation of primordial black holes (PBHs) in the early universe. It was assumed that PBHs are formed by a blue power-law spectrum of primordial density fluctuations. We obtained the bounds on the spectral index of density fluctuations assuming validity of the standard picture of gravitational collapse and using the available data of several experiments with atmospheric and solar neutrinos. The comparison of our results with the previous constraints (which had been obtained using diffuse photon background data) shows that such bounds are quite sensitive to an assumed form of the initial PBH mass function.Comment: 18 pages,(with 7 figures

Results from the Antarctic Muon and Neutrino Detector Array (AMANDA)

We show new results from both the older and newer incarnations of AMANDA (AMANDA-B10 and AMANDA-II, respectively). These results demonstrate that AMANDA is a functioning, multipurpose detector with significant physics and astrophysics reach. They include a new higher-statistics measurement of the atmospheric muon neutrino flux and preliminary results from searches for a variety of sources of ultrahigh energy neutrinos: generic point sources, gamma-ray bursters and diffuse sources producing muons in the detector, and diffuse sources producing electromagnetic or hadronic showers in or near the detector.Comment: Invited talk at the XXth International Conference on Neutrino Physics and Astrophysics (Neutrino 2002), Munich, Germany, May 25-30, 200

Neutrophils use selective autophagy receptor Sqstm1/p62 to target Staphylococcus aureus for degradation in vivo in zebrafish

Macroautophagy/autophagy functions to degrade cellular components and intracellular pathogens. Autophagy receptors, including SQSTM1/p62, target intracellular pathogens. Staphylococcus aureus is a significant pathogen of humans, especially in immunocompromise. S. aureus may use neutrophils as a proliferative niche, but their intracellular fate following phagocytosis has not been analyzed in vivo. In vitro, SQSTM1 can colocalize with intracellular Staphylococcus aureus, but whether SQSTM1 is beneficial or detrimental in host defense against S. aureus in vivo is unknown. Here we determine the fate and location of S. aureus within neutrophils throughout zebrafish infection. We show Lc3 and Sqstm1 recruitment to phagocytosed S. aureus is altered depending on the bacterial location within the neutrophil and that Lc3 marking of bacterial phagosomes within neutrophils may precede bacterial degradation. Finally, we show Sqstm1 is important for controlling cytosolic bacteria, demonstrating for the first time a key role of Sqstm1 in autophagic control of S. aureus in neutrophils

IceCube - the next generation neutrino telescope at the South Pole

IceCube is a large neutrino telescope of the next generation to be constructed in the Antarctic Ice Sheet near the South Pole. We present the conceptual design and the sensitivity of the IceCube detector to predicted fluxes of neutrinos, both atmospheric and extra-terrestrial. A complete simulation of the detector design has been used to study the detector's capability to search for neutrinos from sources such as active galaxies, and gamma-ray bursts.Comment: 8 pages, to be published with the proceedings of the XXth International Conference on Neutrino Physics and Astrophysics, Munich 200

Hard pomeron enhancement of ultrahigh-energy neutrino-nucleon cross-sections

An unknown small-x behavior of nucleon structure functions gives appreciable uncertainties to high-energy neutrino-nucleon cross-sections. We construct structure functions using at small x Regge inspired description by A. Donnachie and P. V. Landshoff with soft and hard pomerons, and employing at larger x the perturbative QCD expressions. The smooth interpolation between two regimes for each Q^2 is provided with the help of simple polynomial functions. To obtain low-x neutrino-nucleon structure functions $F_2^{\nu N, \bar \nu N}(x,Q^2)$ and singlet part of $F_{3}^{\nu N,\bar \nu N}(x,Q^2)$ from Donnachie-Landshoff function $F_2^{ep}(x,Q^2)$, we use the Q^2-dependent ratios R_2(Q^2) and R_3(Q^2) derived from perturbative QCD calculations. Non-singlet part of F_3 at low x, which is very small, is taken as power-law extrapolation of perturbative function at larger x. This procedure gives a full set of smooth neutrino-nucleon structure functions in the whole range of x and Q^2 at interest. Using these structure functions, we have calculated the neutrino-nucleon cross-sections and compared them with some other cross-sections known in literature. Our cross-sections turn out to be the highest among them at the highest energies, which is explained by contribution of the hard pomeron.Comment: Final revised version, accepted by Phys. Rev. D; 18 pages, 7 figure

Sensitivity of the IceCube Detector to Astrophysical Sources of High Energy Muon Neutrinos

We present the results of a Monte-Carlo study of the sensitivity of the planned IceCube detector to predicted fluxes of muon neutrinos at TeV to PeV energies. A complete simulation of the detector and data analysis is used to study the detector's capability to search for muon neutrinos from sources such as active galaxies and gamma-ray bursts. We study the effective area and the angular resolution of the detector as a function of muon energy and angle of incidence. We present detailed calculations of the sensitivity of the detector to both diffuse and pointlike neutrino emissions, including an assessment of the sensitivity to neutrinos detected in coincidence with gamma-ray burst observations. After three years of datataking, IceCube will have been able to detect a point source flux of E^2*dN/dE = 7*10^-9 cm^-2s^-1GeV at a 5-sigma significance, or, in the absence of a signal, place a 90% c.l. limit at a level E^2*dN/dE = 2*10^-9 cm^-2s^-1GeV. A diffuse E-2 flux would be detectable at a minimum strength of E^2*dN/dE = 1*10^-8 cm^-2s^-1sr^-1GeV. A gamma-ray burst model following the formulation of Waxman and Bahcall would result in a 5-sigma effect after the observation of 200 bursts in coincidence with satellite observations of the gamma-rays.Comment: 33 pages, 13 figures, 6 table