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

Exploring Consumers’ Attitudes of Smart TV Related Privacy Risks

A number of privacy risks are inherent in the Smart TV ecosystem. It is likely that many consumers are unaware of these privacy risks. Alternatively, they might be aware but consider the privacy risks acceptable. In order to explore this, we carried out an online survey with 200 participants to determine whether consumers were aware of Smart TV related privacy risks. The responses revealed a meagre level of awareness. We also explored consumers’ attitudes towards specific Smart TV related privacy risks. We isolated a number of factors that influenced rankings and used these to develop awareness-raising messages. We tested these messages in an online survey with 155 participants. The main finding was that participants were generally unwilling to disconnect their Smart TVs from the Internet because they valued the Smart TV’s Internet functionality more than their privacy. We subsequently evaluated the awareness-raising messages in a second survey with 169 participants, framing the question differently. We asked participants to choose between five different Smart TV Internet connection options, two of which retained functionality but entailed expending time and/or effort to preserve privacy

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

LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells

Information on protein-protein interactions (PPIs) is of critical importance for studying complex biological systems and developing therapeutic strategies. Here, we present a double-readout bioluminescence-based two-hybrid technology, termed LuTHy, which provides two quantitative scores in one experimental procedure when testing binary interactions. PPIs are first monitored in cells by quantification of bioluminescence resonance energy transfer (BRET) and, following cell lysis, are again quantitatively assessed by luminescence-based co-precipitation (LuC). The double-readout procedure detects interactions with higher sensitivity than traditional single-readout methods and is broadly applicable, for example, for detecting the effects of small molecules or disease-causing mutations on PPIs. Applying LuTHy in a focused screen, we identified 42 interactions for the presynaptic chaperone CSPα, causative to adult-onset neuronal ceroid lipofuscinosis (ANCL), a progressive neurodegenerative disease. Nearly 50% of PPIs were found to be affected when studying the effect of the disease-causing missense mutations L115R and ∆L116 in CSPα with LuTHy. Our study presents a robust, sensitive research tool with high utility for investigating the molecular mechanisms by which disease-associated mutations impair protein activity in biological systems

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

A Participatory Approach to Redesigning Games for Educational Purposes

Even though games designed for educational purposes can be motivating, they usually shelter dated pedagogies, passive learning procedures, and often overlook learners' creativity. In an effort to reinforce the active participation of learners in games, this paper presents a participatory process in which students and teachers are involved in game design. The proposed process concerns redesigning existing commercial games into educational ones and includes establishing the learning goals, identifying appropriate commercial games, adapting the rules and context, crafting and playtesting the game. Using language learning as one application of this process, the paper presents how three well-known tabletop games were redesigned in a foreign language classroom with elementary and intermediate English language learners. The benefits that underlie the process concern students' active participation, boosting their problem-solving skills, and engaging them in creative learning

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

Observations and Hypotheses Related to Low to Middle Free Tropospheric Aerosol, Water Vapor and Altocumulus Cloud Layers within Convective Weather Regimes: A SEAC4RS Case Study

The NASA Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) project included goals related to aerosol particle life cycle in convective regimes. Using the University of Wisconsin High Spectral Resolution Lidar system at Huntsville, Alabama, USA, and the NASA DC-8 research aircraft, we investigate the altitude dependence of aerosol, water vapor and Altocumulus (Ac) properties in the free troposphere from a canonical 12 August 2013 convective storm case as a segue to a presentation of a mission-wide analysis. It stands to reason that any moisture detrainment from convection must have an associated aerosol layer. Modes of covariability between aerosol, water vapor and Ac are examined relative to the boundary layer entrainment zone, 0 ∘C level, and anvil, a region known to contain Ac clouds and a complex aerosol layering structure (Reid et al., 2017). Multiple aerosol layers in regions warmer than 0 ∘C were observed within the planetary boundary layer entrainment zone. At 0 ∘C there is a proclivity for aerosol and water vapor detrainment from storms, in association with melting level Ac shelves. Finally, at temperatures colder than 0 ∘C, weak aerosol layers were identified above Cumulus congestus tops (∼0 and ∼-20 role= presentation style= box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; \u3e∼−20 ∘C). Stronger aerosol signals return in association with anvil outflow. In situ data suggest that detraining particles undergo aqueous-phase or heterogeneous chemical or microphysical transformations, while at the same time larger particles are being scavenged at higher altitudes leading to enhanced nucleation. We conclude by discussing hypotheses regarding links to aerosol emissions and potential indirect effects on Ac clouds