Targeting the Progression of Parkinson’s Disease

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease

Quantum lump dynamics on the two-sphere

It is well known that the low-energy classical dynamics of solitons of Bogomol'nyi type is well approximated by geodesic motion in M_n, the moduli space of static n-solitons. There is an obvious quantization of this dynamics wherein the wavefunction evolves according to the Hamiltonian H_0 equal to (half) the Laplacian on M_n. Born-Oppenheimer reduction of analogous mechanical systems suggests, however, that this simple Hamiltonian should receive corrections including k, the scalar curvature of M_n, and C, the n-soliton Casimir energy, which are usually difficult to compute, and whose effect on the energy spectrum is unknown. This paper analyzes the spectra of H_0 and two corrections to it suggested by work of Moss and Shiiki, namely H_1=H_0+k/4 and H_2=H_1+C, in the simple but nontrivial case of a single CP^1 lump moving on the two-sphere. Here M_1=TSO(3), a noncompact kaehler 6-manifold invariant under an SO(3)xSO(3) action, whose geometry is well understood. The symmetry gives rise to two conserved angular momenta, spin and isospin. A hidden isometry of M_1 is found which implies that all three energy spectra are symmetric under spin-isospin interchange. The Casimir energy is found exactly on the zero section of TSO(3), and approximated numerically on the rest of M_1. The lowest 19 eigenvalues of H_i are found for i=0,1,2, and their spin-isospin and parity compared. The curvature corrections in H_1 lead to a qualitatively unchanged low-level spectrum while the Casimir energy in H_2 leads to significant changes. The scaling behaviour of the spectra under changes in the radii of the domain and target spheres is analyzed, and it is found that the disparity between the spectra of H_1 and H_2 is reduced when the target sphere is made smaller.Comment: 35 pages, 3 figure

The 3D Structure of N132D in the LMC: A Late-Stage Young Supernova Remnant

We have used the Wide Field Spectrograph (WiFeS) on the 2.3m telescope at Siding Spring Observatory to map the [O III] 5007{\AA} dynamics of the young oxygen-rich supernova remnant N132D in the Large Magellanic Cloud. From the resultant data cube, we have been able to reconstruct the full 3D structure of the system of [O III] filaments. The majority of the ejecta form a ring of ~12pc in diameter inclined at an angle of 25 degrees to the line of sight. We conclude that SNR N132D is approaching the end of the reverse shock phase before entering the fully thermalized Sedov phase of evolution. We speculate that the ring of oxygen-rich material comes from ejecta in the equatorial plane of a bipolar explosion, and that the overall shape of the SNR is strongly influenced by the pre-supernova mass loss from the progenitor star. We find tantalizing evidence of a polar jet associated with a very fast oxygen-rich knot, and clear evidence that the central star has interacted with one or more dense clouds in the surrounding ISM.Comment: Accepted for Publication in Astrophysics & Space Science, 18pp, 8 figure

Effectiveness of activity trackers with and without incentives to increase physical activity (TRIPPA): a randomised controlled trial

Background Despite the increasing popularity of activity trackers, little evidence exists that they can improve health outcomes. We aimed to investigate whether use of activity trackers, alone or in combination with cash incentives or charitable donations, lead to increases in physical activity and improvements in health outcomes. Methods In this randomised controlled trial, employees from 13 organisations in Singapore were randomly assigned (1:1:1:1) with a computer generated assignment schedule to control (no tracker or incentives), Fitbit Zip activity tracker, tracker plus charity incentives, or tracker plus cash incentives. Participants had to be English speaking, full-time employees, aged 21–65 years, able to walk at least ten steps continuously, and non-pregnant. Incentives were tied to weekly steps, and the primary outcome, moderate-to-vigorous physical activity (MVPA) bout min per week, was measured via a sealed accelerometer and assessed on an intention-to-treat basis at 6 months (end of intervention) and 12 months (after a 6 month post-intervention follow-up period). Other outcome measures included steps, participants meeting 70 000 steps per week target, and health-related outcomes including weight, blood pressure, and quality-of-life measures. This trial is registered at ClinicalTrials.gov, number NCT01855776. Findings Between June 13, 2013, and Aug 15, 2014, 800 participants were recruited and randomly assigned to the control (n=201), Fitbit (n=203), charity (n=199), and cash (n=197) groups. At 6 months, compared with control, the cash group logged an additional 29 MVPA bout min per week (95% CI 10–47; p=0·0024) and the charity group an additional 21 MVPA bout min per week (2–39; p=0·0310); the difference between Fitbit only and control was not significant (16 MVPA bout min per week [–2 to 35; p=0·0854]). Increases in MVPA bout min per week in the cash and charity groups were not significantly greater than that of the Fitbit group. At 12 months, the Fitbit group logged an additional 37 MVPA bout min per week (19–56; p=0·0001) and the charity group an additional 32 MVPA bout min per week (12–51; p=0·0013) compared with control; the difference between cash and control was not significant (15 MVPA bout min per week [–5 to 34; p=0·1363]). A decrease in physical activity of −23 MVPA bout min per week (95% CI −42 to −4; p=0·0184) was seen when comparing the cash group with the Fitbit group. There were no improvements in any health outcomes (weight, blood pressure, etc) at either assessment. Interpretation The cash incentive was most effective at increasing MVPA bout min per week at 6 months, but this effect was not sustained 6 months after the incentives were discontinued. At 12 months, the activity tracker with or without charity incentives were effective at stemming the reduction in MVPA bout min per week seen in the control group, but we identified no evidence of improvements in health outcomes, either with or without incentives, calling into question the value of these devices for health promotion. Although other incentive strategies might generate greater increases in step activity and improvements in health outcomes, incentives would probably need to be in place long term to avoid any potential decrease in physical activity resulting from discontinuation. Funding Ministry of Health, Singapore

Binding Energy of Charged Excitons in ZnSe-based Quantum Wells

Excitons and charged excitons (trions) are investigated in ZnSe-based quantum well structures with (Zn,Be,Mg)Se and (Zn,Mg)(S,Se) barriers by means of magneto-optical spectroscopy. Binding energies of negatively () and positively (X+) charged excitons are measured as functions of quantum well width, free carrier density and in external magnetic fields up to 47 T. The binding energy of shows a strong increase from 1.4 to 8.9 meV with decreasing quantum well width from 190 to 29 A. The binding energies of X+ are about 25% smaller than the binding energy in the same structures. The magnetic field behavior of and X+ binding energies differ qualitatively. With growing magnetic field strength, increases its binding energy by 35-150%, while for X+ it decreases by 25%. Zeeman spin splittings and oscillator strengths of excitons and trions are measured and discussed

Improved numerical stability of stationary black hole evolution calculations

We experiment with modifications of the BSSN form of the Einstein field equations (a reformulation of the ADM equations) and demonstrate how these modifications affect the stability of numerical black hole evolution calculations. We use excision to evolve both non-rotating and rotating Kerr-Schild black holes in octant and equatorial symmetry, and without any symmetry assumptions, and obtain accurate and stable simulations for specific angular momenta J/M of up to about 0.9M.Comment: 13 pages, 11 figures, 1 typo in Eq. (20) correcte

The Parallel Magnetoconductance of Interacting Electrons in a Two Dimensional Disordered System

The transport properties of interacting electrons for which the spin degree of freedom is taken into account are numerically studied for small two dimensional diffusive clusters. On-site electron-electron interactions tend to delocalize the electrons, while long-range interactions enhance localization. On careful examination of the transport properties, we reach the conclusion that it does not show a two dimensional metal insulator transition driven by interactions. A parallel magnetic field leads to enhanced resistivity, which saturates once the electrons become fully spin polarized. The strength of the magnetic field for which the resistivity saturates decreases as electron density goes down. Thus, the numerical calculations capture some of the features seen in recent experimental measurements of parallel magnetoconductance.Comment: 10 pages, 6 figure

Nonlinear σ\sigma model for disordered superconductors

We suggest a novel nonlinear $\sigma$-model for the description of disordered superconductors. The main distinction from existing models lies in the fact that the saddle point equation is solved non-perturbatively in the superconducting pairing field. It allows one to use the model both in the vicinity of the metal-superconductor transition and well below its critical temperature with full account for the self-consistency conditions. We show that the model reproduces a set of known results in different limiting cases, and apply it for a self-consistent description of the proximity effect at the superconductor-metal interface.Comment: Revised version, 8 pages, 1 fig., revtex; final version, as published, contains a few corrections in the summar

Vibrio parahaemolyticus, enterotoxigenic Escherichia coli, enterohemorrhagic Escherichia coli and Vibrio cholerae

This review highlighted the following: (i) pathogenic mechanism of the thermostable direct hemolysin produced by Vibrio parahaemolyticus, especially on its cardiotoxicity, (ii) heat-labile and heat-stable enterotoxins produced by enterotoxigenic Escherichia coli, especially structure–activity relationship of heat-stable enterotoxin, (iii) RNA N-glycosidase activity of Vero toxins (VT1 and VT2) produced by enterohemorrhagic Escherichia coli O157:H7, (iv) discovery of Vibrio cholerae O139, (v) isolation of new variant of Vibrio cholerae O1 El Tor that carries classical ctxB, and production of high concentration of cholera toxin by these strains, and (vi) conversion of viable but nonculturable (VBNC) Vibrio cholerae to culturable state by co-culture with eukaryotic cells

Treasurehunt: Transients and variability discovered with HST in the JWST North Ecliptic Pole time-domain field

The James Webb Space Telescope (JWST) North Ecliptic Pole (NEP) Time-domain Field (TDF) is a >14' diameter field optimized for multiwavelength time-domain science with JWST. It has been observed across the electromagnetic spectrum both from the ground and from space, including with the Hubble Space Telescope (HST). As part of HST observations over three cycles (the "TREASUREHUNT" program), deep images were obtained with the Wide Field Camera on the Advanced Camera for Surveys in F435W and F606W that cover almost the entire JWST NEP TDF. Many of the individual pointings of these programs partially overlap, allowing an initial assessment of the potential of this field for time-domain science with HST and JWST. The cumulative area of overlapping pointings is ∼88 arcmin2, with time intervals between individual epochs that range between 1 day and 4+ yr. To a depth of mAB ≃ 29.5 mag (F606W), we present the discovery of 12 transients and 190 variable candidates. For the variable candidates, we demonstrate that Gaussian statistics are applicable and estimate that ∼80 are false positives. The majority of the transients will be supernovae, although at least two are likely quasars. Most variable candidates are active galactic nuclei (AGNs), where we find 0.42% of the general z ≲ 6 field galaxy population to vary at the ∼3σ level. Based on a 5 yr time frame, this translates into a random supernova areal density of up to ∼0.07 transients arcmin−2 (∼245 deg−2) per epoch and a variable AGN areal density of ∼1.25 variables arcmin−2 (∼4500 deg−2) to these depths