Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

PolyQ (polyglutamine) diseases such as HD (Huntington's disease) or SCA1 (spinocerebellar ataxia type 1) are neurodegenerative disorders caused by abnormally elongated polyQ tracts in human proteins. PolyQ expansions promote misfolding and aggregation of disease-causing proteins, leading to the appearance of nuclear and cytoplasmic inclusion bodies in patient neurons. Several lines of experimental evidence indicate that this process is critical for disease pathogenesis. However, the molecular mechanisms underlying spontaneous polyQ-containing aggregate formation and the perturbation of neuronal processes are still largely unclear. The present chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing HTTex1 (huntingtin exon 1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed

The Continuous Monitoring of Desert Dust using an Infrared-based Dust Detection and Retrieval Method

Airborne dust and sand are significant aerosol sources that can impact the atmospheric and surface radiation budgets. Because airborne dust affects visibility and air quality, it is desirable to monitor the location and concentrations of this aerosol for transportation and public health. Although aerosol retrievals have been derived for many years using visible and near-infrared reflectance measurements from satellites, the detection and quantification of dust from these channels is problematic over bright surfaces, or when dust concentrations are large. In addition, aerosol retrievals from polar orbiting satellites lack the ability to monitor the progression and sources of dust storms. As a complement to current aerosol dust retrieval algorithms, multi-spectral thermal infrared (8-12 micron) data from the Moderate Resolution Imaging Spectroradiometer (MODIS) and the Meteosat-8 Spinning Enhanced Visible and Infrared Imager (SEVIRI) are used in the development of a prototype dust detection method and dust property retrieval that can monitor the progress of Saharan dust fields continuously, both night and day. The dust detection method is incorporated into the processing of CERES (Clouds and the Earth s Radiant Energy System) aerosol retrievals to produce dust property retrievals. Both MODIS (from Terra and Aqua) and SEVERI data are used to develop the method

The pathobiology of perturbed mutant huntingtin protein-protein interactions in Huntington's disease

Mutations are at the root of many human diseases. Still, we largely do not exactly understand how they trigger pathogenesis. One, more recent, hypothesis has been that they comprehensively perturb protein-protein interaction (PPI) networks and significantly alter key biological processes. Under this premise, many rare genetic disorders with Mendelian inheritance, like e.g. Huntington's disease and several spinocerebellar ataxias, are likely to be caused by complex genotype-phenotype relationships involving abnormal PPIs. These altered PPI networks and their effects on cellular pathways are poorly understood at the molecular level. In this review, we focus on PPIs that are perturbed by the expanded pathogenic polyglutamine tract in huntingtin (HTT), the protein which, in its mutated form, leads to the autosomal dominant, neurodegenerative Huntington's disease. One aspect of perturbed mutant HTT interactions is the formation of abnormal protein species such as fibrils or large neuronal inclusions due to homotypic and heterotypic aberrant molecular interactions. This review focuses on abnormal PPIs that are associated with the assembly of mutant HTT aggregates in cells and their potential relevance in disease. Furthermore, the mechanisms and pathobiological processes that may contribute to phenotype development, neuronal dysfunction and toxicity in HD brains are also discussed

Swelling of Transported Smoke from Savanna Fires over the Southeast Atlantic Ocean

We use the recently released Cloud Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) Version 4.1 (V4) lidar data to study the smoke plumes transported from Southern African biomass burning areas. Significant improvements in the CALIPSO V4 Level 1 calibration and V4 Level 2 algorithms lead to a better representation of their optical properties, with the aerosol subtype improvements being particularly relevant to smoke over this area. For the first time, we show evidence of smoke particles increasing in size, evidenced in their particulate color ratios, as they are transported over the South Atlantic Ocean from the source regions over Southern Africa. We hypothesize that this is due to hygroscopic swelling of the smoke particles and is reflected in the higher relative humidity in the middle troposphere for profiles with smoke. This finding may have implications for radiative forcing estimates over this area and is also relevant to the ORACLES field mission

Swelling of Transported Smoke from Savanna fires over the Southeast Atlantic Ocean

We use the recently released Version 4 (V4) lidar data products from CALIPSO to study the smoke plumes transported from Southern African biomass burning areas. The significant improvements in CALIPSO V4 Level 1 calibration and the V4 Level 2 aerosol subtyping algorithms, the latter being particularly relevant to biomass burning smoke over this area, lead to a better representation of their optical properties. For the first time, we show evidence of smoke particles increasing in size, evidenced in their particulate color ratios, as they are transported over the South Atlantic Ocean from the source regions over Southern Africa. This is likely due to hygroscopic swelling of the smoke particles and is reflected in the higher relative humidity in the middle troposphere for profiles with smoke. This finding may have implications for radiative forcing estimates over this area and is relevant to the ORACLES field mission that is currently underway

DULIP: A dual luminescence-based co-immunoprecipitation assay for interactome mapping in mammalian cells

Mapping of protein-protein interactions (PPIs) is critical for understanding protein function and complex biological processes. Here, we present DULIP, a dual luminescence-based co-immunoprecipitation assay, for systematic PPI mapping in mammalian cells. DULIP is a second-generation luminescence-based PPI screening method for the systematic and quantitative analysis of co-immunoprecipitations using two different luciferase tags. Benchmarking studies with positive and negative PPI reference sets revealed that DULIP allows the detection of interactions with high sensitivity and specificity. Furthermore, the analysis of a PPI reference set with known binding affinities demonstrated that both low- and high-affinity interactions can be detected with DULIP assays. Finally, using the well-characterized interaction between Syntaxin-1 and Munc18, we found that DULIP is capable of detecting the effects of point mutations on interaction strength. Taken together, our studies demonstrate that DULIP is a sensitive and reliable method of great utility for systematic interactome research. It can be applied for interaction screening as well as for the validation of PPIs in mammalian cells. Moreover, DULIP permits the specific analysis of mutation-dependent binding patterns

Global statistics of liquid water content and effective number concentration of water clouds over ocean derived from combined CALIPSO and MODIS measurements

This study presents an empirical relation that links the volume extinction coefficients of water clouds, the layer integrated depolarization ratios measured by lidar, and the effective radii of water clouds derived from collocated passive sensor observations. Based on Monte Carlo simulations of CALIPSO lidar observations, this method combines the cloud effective radius reported by MODIS with the lidar depolarization ratios measured by CALIPSO to estimate both the liquid water content and the effective number concentration of water clouds. The method is applied to collocated CALIPSO and MODIS measurements obtained during July and October of 2006, and January 2007. Global statistics of the cloud liquid water content and effective number concentration are presented

NOGAPS-ALPHA model simulations of stratospheric ozone during the SOLVE2 campaign

This paper presents three-dimensional prognostic O₃ simulations with parameterized gas-phase photochemistry from the new NOGAPS-ALPHA middle atmosphere forecast model. We compare 5-day NOGAPS-ALPHA hindcasts of stratospheric O₃ with satellite and DC-8 aircraft measurements for two cases during the SOLVE II campaign: (1) the cold, isolated vortex during 11-16 January 2003; and (2) the rapidly developing stratospheric warming of 17-22 January 2003. In the first case we test three different photochemistry parameterizations. NOGAPS-ALPHA O₃ simulations using the NRL-CHEM2D parameterization give the best agreement with SAGE III and POAM III profile measurements. 5-day NOGAPS-ALPHA hindcasts of polar O₃ initialized with the NASA GEOS4 analyses produce better agreement with observations than do the operational ECMWF O₃ forecasts of case 1. For case 2, both NOGAPS-ALPHA and ECMWF 114-h forecasts of the split vortex structure in lower stratospheric O₃ on 21 January 2003 show comparable skill. Updated ECMWF O₃ forecasts of this event at hour 42 display marked improvement from the 114-h forecast; corresponding updated 42-hour NOGAPS-ALPHA prognostic O₃ fields initialized with the GEOS4 analyses do not improve significantly. When NOGAPS-ALPHA prognostic O₃ is initialized with the higher resolution ECMWF O₃ analyses, the NOGAPS-ALPHA 42-hour lower stratospheric O₃ fields closely match the operational 42-hour ECMWF O₃ forecast of the 21 January event. We find that stratospheric O₃ forecasts at high latitudes in winter can depend on both model initial conditions and the treatment of photochemistry over periods of 1-5 days. Overall, these results show that the new O₃ initialization, photochemistry parameterization, and spectral transport in the NOGAPS-ALPHA NWP model can provide reliable short-range stratospheric O₃ forecasts during Arctic winter