The Role of NEDD4 E3 Ubiquitin–Protein Ligases in Parkinson’s Disease

Parkinson’s disease (PD) is a debilitating neurodegenerative disease that causes a great clinical burden. However, its exact molecular pathologies are not fully understood. Whilst there are a number of avenues for research into slowing, halting, or reversing PD, one central idea is to enhance the clearance of the proposed aetiological protein, oligomeric α-synuclein. Oligomeric α-synuclein is the main constituent protein in Lewy bodies and neurites and is considered neurotoxic. Multiple E3 ubiquitin-protein ligases, including the NEDD4 (neural precursor cell expressed developmentally downregulated protein 4) family, parkin, SIAH (mammalian homologues of Drosophila seven in absentia), CHIP (carboxy-terminus of Hsc70 interacting protein), and SCFFXBL5 SCF ubiquitin ligase assembled by the S-phase kinase-associated protein (SKP1), cullin-1 (Cul1), a zinc-binding RING finger protein, and the F-box domain/Leucine-rich repeat protein 5-containing protein FBXL5), have been shown to be able to ubiquitinate α-synuclein, influencing its subsequent degradation via the proteasome or lysosome. Here, we explore the link between NEDD4 ligases and PD, which is not only via α-synuclein but further strengthened by several additional substrates and interaction partners. Some members of the NEDD4 family of ligases are thought to crosstalk even with PD-related genes and proteins found to be mutated in familial forms of PD. Mutations in NEDD4 family genes have not been observed in PD patients, most likely because of their essential survival function during development. Following further in vivo studies, it has been thought that NEDD4 ligases may be viable therapeutic targets in PD. NEDD4 family members could clear toxic proteins, enhancing cell survival and slowing disease progression, or might diminish beneficial proteins, reducing cell survival and accelerating disease progression. Here, we review studies to date on the expression and function of NEDD4 ubiquitin ligases in the brain and their possible impact on PD pathology.</jats:p

A Time Series Analysis of Air Pollution and Preterm Birth in Pennsylvania, 1997–2001

Preterm delivery can lead to serious infant health outcomes, including death and lifelong disability. Small increases in preterm delivery risk in relation to spatial gradients of air pollution have been reported, but previous studies may have controlled inadequately for individual factors. Using a time-series analysis, which eliminates potential confounding by individual risk factors that do not change over short periods of time, we investigated the effect of ambient outdoor particulate matter with diameter ≤10 μm (PM(10)) and sulfur dioxide on risk for preterm delivery. Daily counts of preterm births were obtained from birth records in four Pennsylvania counties from 1997 through 2001. We observed increased risk for preterm delivery with exposure to average PM(10) and SO(2) in the 6 weeks before birth [respectively, relative risk (RR) = 1.07; 95% confidence interval (CI), 0.98–1.18 per 50 μg/m(3) increase; RR = 1.15; 95% CI, 1.00–1. 32 per 15 ppb increase], adjusting for long-term preterm delivery trends, co-pollutants, and offsetting by the number of gestations at risk. We also examined lags up to 7 days before the birth and found an acute effect of exposure to PM(10) 2 days and 5 days before birth (respectively, RR = 1.10; 95% CI, 1.00–1.21; RR = 1.07; 95% CI, 0.98–1.18) and SO(2) 3 days before birth (RR = 1.07; 95% CI, 0.99–1.15), adjusting for covariates, including temperature, dew point temperature, and day of the week. The results from this time-series analysis, which provides evidence of an increase in preterm birth risk with exposure to PM(10) and SO(2), are consistent with prior investigations of spatial contrasts

Creating an "enabling environment" for taking insecticide treated nets to national scale: the Tanzanian experience

INTRODUCTION: Malaria is the largest cause of health services attendance, hospital admissions and child deaths in Tanzania. At the Abuja Summit in April 2000 Tanzania committed itself to protect 60% of its population at high risk of malaria by 2005. The country is, therefore, determined to ensure that sustainable malaria control using insecticide-treated nets is carried out on a national scale. CASE DESCRIPTION: Tanzania has been involved for two decades in the research process for developing insecticide-treated nets as a malaria control tool, from testing insecticides and net types, to assessing their efficacy and effectiveness, and exploring new ways of distribution. Since 2000, the emphasis has changed from a project approach to that of a concerted multi-stakeholder action for taking insecticide-treated nets to national scale (NATNETS). This means creating conditions that make insecticide-treated nets accessible and affordable to all those at risk of malaria in the country. This paper describes Tanzania's experience in (1) creating an enabling environment for insecticide-treated nets scale-up, (2) promoting the development of a commercial sector for insecticide-treated nets, and (3) targeting pregnant women with highly subsidized insecticide-treated nets through a national voucher scheme. As a result, nearly 2 million insecticide-treated nets and 2.2 million re-treatment kits were distributed in 2004. CONCLUSION: National upscaling of insecticide-treated nets is possible when the programme is well designed, coordinated and supported by committed stakeholders; the Abuja target of protecting 60% of those at high risk is feasible, even for large endemic countries

Dynamic Environmental Photosynthetic Imaging Reveals Emergent Phenotypes.

Understanding and improving the productivity and robustness of plant photosynthesis requires high-throughput phenotyping under environmental conditions that are relevant to the field. Here we demonstrate the dynamic environmental photosynthesis imager (DEPI), an experimental platform for integrated, continuous, and high-throughput measurements of photosynthetic parameters during plant growth under reproducible yet dynamic environmental conditions. Using parallel imagers obviates the need to move plants or sensors, reducing artifacts and allowing simultaneous measurement on large numbers of plants. As a result, DEPI can reveal phenotypes that are not evident under standard laboratory conditions but emerge under progressively more dynamic illumination. We show examples in mutants of Arabidopsis of such "emergent phenotypes" that are highly transient and heterogeneous, appearing in different leaves under different conditions and depending in complex ways on both environmental conditions and plant developmental age. These emergent phenotypes appear to be caused by a range of phenomena, suggesting that such previously unseen processes are critical for plant responses to dynamic environments

Traffic-related pollution and asthma prevalence in children. Quantification of associations with nitrogen dioxide.

Ambient nitrogen dioxide is a widely available measure of traffic-related air pollution and is inconsistently associated with the prevalence of asthma symptoms in children. The use of this relationship to evaluate the health impact of policies affecting traffic management and traffic emissions is limited by the lack of a concentration-response function based on systematic review and meta-analysis of relevant studies. Using systematic methods, we identified papers containing quantitative estimates for nitrogen dioxide and the 12 month period prevalence of asthma symptoms in children in which the exposure contrast was within-community and dominated by traffic pollution. One estimate was selected from each study according to an a priori algorithm. Odds ratios were standardised to 10 μg/m(3) and summary estimates were obtained using random- and fixed-effects estimates. Eighteen studies were identified. Concentrations of nitrogen dioxide were estimated for the home address (12) and/or school (8) using a range of methods; land use regression (6), study monitors (6), dispersion modelling (4) and interpolation (2). Fourteen studies showed positive associations but only two associations were statistically significant at the 5 % level. There was moderate heterogeneity (I(2) = 32.8 %) and the random-effects estimate for the odds ratio was 1.06 (95 % CI 1.00 to 1.11). There was no evidence of small study bias. Individual studies tended to have only weak positive associations between nitrogen dioxide and asthma prevalence but the summary estimate bordered on statistical significance at the 5 % level. Although small, the potential impact on asthma prevalence could be considerable because of the high level of baseline prevalence in many cities. Whether the association is causal or indicates the effects of a correlated pollutant or other confounders, the estimate obtained by the meta-analysis would be appropriate for estimating impacts of traffic pollution on asthma prevalence

Loop lessons from Wilson loops in N=4 supersymmetric Yang-Mills theory

N=4 supersymmetric Yang-Mills theory exhibits a rather surprising duality of Wilson-loop vacuum expectation values and scattering amplitudes. In this paper, we investigate this correspondence at the diagram level. We find that one-loop triangles, one-loop boxes, and two-loop diagonal boxes can be cast as simple one- and two- parametric integrals over a single propagator in configuration space. We observe that the two-loop Wilson-loop "hard-diagram" corresponds to a four-loop hexagon Feynman diagram. Guided by the diagrammatic correspondence of the configuration-space propagator and loop Feynman diagrams, we derive Feynman parameterizations of complicated planar and non-planar Feynman diagrams which simplify their evaluation. For illustration, we compute numerically a four-loop hexagon scalar Feynman diagram.Comment: 20 pages, many figures. Two references added. Published versio

Physics of Neutron Star Kicks

It is no longer necessary to `sell' the idea of pulsar kicks, the notion that neutron stars receive a large velocity (a few hundred to a thousand km s$^{-1}$) at birth. However, the origin of the kicks remains mysterious. We review the physics of different kick mechanisms, including hydrodynamically driven, neutrino and magnetically driven kicks.Comment: 8 pages including 1 figure. To be published in "Stellar Astrophysics" (Pacific Rim Conference Proceedings), (Kluwer Pub.

Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study

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A Tale of Two Current Sheets

I outline a new model of particle acceleration in the current sheet separating the closed from the open field lines in the force-free model of pulsar magnetospheres, based on reconnection at the light cylinder and "auroral" acceleration occurring in the return current channel that connects the light cylinder to the neutron star surface. I discuss recent studies of Pulsar Wind Nebulae, which find that pair outflow rates in excess of those predicted by existing theories of pair creation occur, and use those results to point out that dissipation of the magnetic field in a pulsar's wind upstream of the termination shock is restored to life as a viable model for the solution of the "$\sigma$" problem as a consequence of the lower wind 4-velocity implied by the larger mass loading.Comment: 17 pages, 6 figures, Invited Review, Proceedings of the "ICREA Workshop on The High-Energy Emission from Pulsars and their Systems", Sant Cugat, Spain, April 12-16, 201