Parkin Is Protective against Proteotoxic Stress in a Transgenic Zebrafish Model

Mutations in the gene encoding the E3 ubiquitin ligase parkin (PARK2) are responsible for the majority of autosomal recessive parkinsonism. Similarly to other knockout mouse models of PD-associated genes, parkin knockout mice do not show a substantial neuropathological or behavioral phenotype, while loss of parkin in Drosophila melanogaster leads to a severe phenotype, including reduced lifespan, apoptotic flight muscle degeneration and male sterility. In order to study the function of parkin in more detail and to address possible differences in its role in different species, we chose Danio rerio as a different vertebrate model system.We first cloned zebrafish parkin to compare its biochemical and functional aspects with that of human parkin. By using an antisense knockdown strategy we generated a zebrafish model of parkin deficiency (knockdown efficiency between 50% and 60%) and found that the transient knockdown of parkin does not cause morphological or behavioral alterations. Specifically, we did not observe a loss of dopaminergic neurons in parkin-deficient zebrafish. In addition, we established transgenic zebrafish lines stably expressing parkin by using a Gal4/UAS-based bidirectional expression system. While parkin-deficient zebrafish are more vulnerable to proteotoxicity, increased parkin expression protected transgenic zebrafish from cell death induced by proteotoxic stress.Similarly to human parkin, zebrafish parkin is a stress-responsive protein which protects cells from stress-induced cell death. Our transgenic zebrafish model is a novel tool to characterize the protective capacity of parkin in vivo

The value of remote marine aerosol measurements for constraining radiative forcing uncertainty

Aerosol measurements over the Southern Ocean are used to constrain aerosol-cloud interaction radiative forcing (RFaci) uncertainty in a global climate model. Forcing uncertainty is quantified using 1 million climate model variants that sample the uncertainty in nearly 30 model parameters. Measurements of cloud condensation nuclei and other aerosol properties from an Antarctic circumnavigation expedition strongly constrain natural aerosol emissions: default sea spray emissions need to be increased by around a factor of 3 to be consistent with measurements. Forcing uncertainty is reduced by around 7% using this set of several hundred measurements, which is comparable to the 8% reduction achieved using a diverse and extensive set of over 9000 predominantly Northern Hemisphere measurements. When Southern Ocean and Northern Hemisphere measurements are combined, uncertainty in RFaci is reduced by 21 %, and the strongest 20% of forcing values are ruled out as implausible. In this combined constraint, observationally plausible RFaci is around 0.17Wm-2 weaker (less negative) with 95% credible values ranging from-2:51 to-1:17Wm-2 (standard deviation of-2:18 to-1:46Wm-2). The Southern Ocean and Northern Hemisphere measurement datasets are complementary because they constrain different processes. These results highlight the value of remote marine aerosol measurements. © 2020 Laser Institute of America. All rights reserved

Ship-based measurements of ice nuclei concentrations over the Arctic, Atlantic, Pacific and Southern oceans

Ambient concentrations of ice-forming particles measured during ship expeditions are collected and summarised with the aim of determining the spatial distribution and variability in ice nuclei in oceanic regions. The presented data from literature and previously unpublished data from over 23 months of ship-based measurements stretch from the Arctic to the Southern Ocean and include a circumnavigation of Antarctica. In comparison to continental observations, ship-based measurements of ambient ice nuclei show 1 to 2 orders of magnitude lower mean concentrations. To quantify the geographical variability in oceanic areas, the concentration range of potential ice nuclei in different climate zones is analysed by meridionally dividing the expedition tracks into tropical, temperate and polar climate zones. We find that concentrations of ice nuclei in these meridional zones follow temperature spectra with similar slopes but vary in absolute concentration. Typically, the frequency with which specific concentrations of ice nuclei are observed at a certain temperature follows a log-normal distribution. A consequence of the log-normal distribution is that the mean concentration is higher than the most frequently measured concentration. Finally, the potential contribution of ship exhaust to the measured ice nuclei concentration on board research vessels is analysed as function of temperature. We find a sharp onset of the influence at approximately 36 C but none at warmer temperatures that could bias ship-based measurements. © Author(s) 2020. This work is distributed under the Creative Commons Attribution 4.0 License

LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-κB to the nucleus

Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling; however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here, we show that the NF-κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-κB to the nucleus. TNF treatment induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF-mediated NF-κB activation, both serving as a signaling platform, as well as a transport mode for activated NF-κB to the nuclear

Characteristics and sources of fluorescent aerosols in the central Arctic Ocean

The Arctic is sensitive to cloud radiative forcing. Due to the limited number of aerosols present throughout much of the year, cloud formation is susceptible to the presence of cloud condensation nuclei and ice nucleating particles (INPs). Primary biological aerosol particles (PBAP) contribute to INPs and can impact cloud phase, lifetime, and radiative properties. We present yearlong observations of hyperfluorescent aerosols (HFA), tracers for PBAP, conducted with a Wideband Integrated Bioaerosol Sensor, New Electronics Option during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition (October 2019–September 2020) in the central Arctic. We investigate the influence of potential anthropogenic and natural sources on the characteristics of the HFA and relate our measurements to INP observations during MOSAiC. Anthropogenic sources influenced HFA during the Arctic haze period. But surprisingly, we also found sporadic “bursts” of HFA with the characteristics of PBAP during this time, albeit with unclear origin. The characteristics of HFA between May and August 2020 and in October 2019 indicate a strong contribution of PBAP to HFA. Notably from May to August, PBAP coincided with the presence of INPs nucleating at elevated temperatures, that is, &amp;gt;−9°C, suggesting that HFA contributed to the “warm INP” concentration. The air mass residence time and area between May and August and in October were dominated by the open ocean and sea ice, pointing toward PBAP sources from within the Arctic Ocean. As the central Arctic changes drastically due to climate warming with expected implications on aerosol–cloud interactions, we recommend targeted observations of PBAP that reveal their nature (e.g., bacteria, diatoms, fungal spores) in the atmosphere and in relevant surface sources, such as the sea ice, snow on sea ice, melt ponds, leads, and open water, to gain further insights into the relevant source processes and how they might change in the future.</jats:p

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62

NEMO is a ubiquitin-binding protein which regulates canonical NF-kappa B pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-kappa B-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including alpha-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at alpha-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62. Selective autophagy helps to degrade aggregated proteins accumulating in neurodegenerative diseases. Here, the authors show that NEMO, a ubiquitin binding protein previously linked to innate immune signaling, is recruited to misfolded proteins and promotes their autophagic clearance by forming condensates with the autophagy receptor p62

Characteristics and sources of fluorescent aerosols in the central Arctic Ocean

The Arctic is sensitive to cloud radiative forcing. Due to the limited number of aerosols present throughout much of the year, cloud formation is susceptible to the presence of cloud condensation nuclei and ice nucleating particles (INPs). Primary biological aerosol particles (PBAP) contribute to INPs and can impact cloud phase, lifetime, and radiative properties. We present yearlong observations of hyperfluorescent aerosols (HFA), tracers for PBAP, conducted with a Wideband Integrated Bioaerosol Sensor, New Electronics Option during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition (October 2019–September 2020) in the central Arctic. We investigate the influence of potential anthropogenic and natural sources on the characteristics of the HFA and relate our measurements to INP observations during MOSAiC. Anthropogenic sources influenced HFA during the Arctic haze period. But surprisingly, we also found sporadic “bursts” of HFA with the characteristics of PBAP during this time, albeit with unclear origin. The characteristics of HFA between May and August 2020 and in October 2019 indicate a strong contribution of PBAP to HFA. Notably from May to August, PBAP coincided with the presence of INPs nucleating at elevated temperatures, that is, >−9°C, suggesting that HFA contributed to the “warm INP” concentration. The air mass residence time and area between May and August and in October were dominated by the open ocean and sea ice, pointing toward PBAP sources from within the Arctic Ocean. As the central Arctic changes drastically due to climate warming with expected implications on aerosol–cloud interactions, we recommend targeted observations of PBAP that reveal their nature (e.g., bacteria, diatoms, fungal spores) in the atmosphere and in relevant surface sources, such as the sea ice, snow on sea ice, melt ponds, leads, and open water, to gain further insights into the relevant source processes and how they might change in the future

Exploring the coupled ocean and atmosphere system with a data science approach applied to observations from the Antarctic Circumnavigation Expedition

The Southern Ocean is a critical component of Earth's climate system, but its remoteness makes it challenging to develop a holistic understanding of its processes from the small scale to the large scale. As a result, our knowledge of this vast region remains largely incomplete. The Antarctic Circumnavigation Expedition (ACE, austral summer 2016/2017) surveyed a large number of variables describing the state of the ocean and the atmosphere, the freshwater cycle, atmospheric chemistry, and ocean biogeochemistry and microbiology. This circumpolar cruise included visits to 12 remote islands, the marginal ice zone, and the Antarctic coast. Here, we use 111 of the observed variables to study the latitudinal gradients, seasonality, shorter-term variations, geographic setting of environmental processes, and interactions between them over the duration of 90ĝ€¯d. To reduce the dimensionality and complexity of the dataset and make the relations between variables interpretable we applied an unsupervised machine learning method, the sparse principal component analysis (sPCA), which describes environmental processes through 14 latent variables. To derive a robust statistical perspective on these processes and to estimate the uncertainty in the sPCA decomposition, we have developed a bootstrap approach. Our results provide a proof of concept that sPCA with uncertainty analysis is able to identify temporal patterns from diurnal to seasonal cycles, as well as geographical gradients and "hotspots"of interaction between environmental compartments. While confirming many well known processes, our analysis provides novel insights into the Southern Ocean water cycle (freshwater fluxes), trace gases (interplay between seasonality, sources, and sinks), and microbial communities (nutrient limitation and island mass effects at the largest scale ever reported). More specifically, we identify the important role of the oceanic circulations, frontal zones, and islands in shaping the nutrient availability that controls biological community composition and productivity; the fact that sea ice controls sea water salinity, dampens the wave field, and is associated with increased phytoplankton growth and net community productivity possibly due to iron fertilisation and reduced light limitation; and the clear regional patterns of aerosol characteristics that have emerged, stressing the role of the sea state, atmospheric chemical processing, and source processes near hotspots for the availability of cloud condensation nuclei and hence cloud formation. A set of key variables and their combinations, such as the difference between the air and sea surface temperature, atmospheric pressure, sea surface height, geostrophic currents, upper-ocean layer light intensity, surface wind speed and relative humidity played an important role in our analysis, highlighting the necessity for Earth system models to represent them adequately. In conclusion, our study highlights the use of sPCA to identify key ocean-atmosphere interactions across physical, chemical, and biological processes and their associated spatio-temporal scales. It thereby fills an important gap between simple correlation analyses and complex Earth system models. The sPCA processing code is available as open-access from the following link: https://renkulab.io/gitlab/ACE-ASAID/spca-decomposition (last access: 29 March 2021). As we show here, it can be used for an exploration of environmental data that is less prone to cognitive biases (and confirmation biases in particular) compared to traditional regression analysis that might be affected by the underlying research question

Cloud Condensation Nuclei and Ice-Nucleating Particles over the Southern Ocean: Abundance and Properties during the Antarctic Circum-navigation Expedition

Aerosol particles acting as cloud condensation nuclei (CCN) or ice nucleating parti- cles (INP) play a major role in the formation and glaciation of clouds. Thereby they exert a strong impact on the radiation budget of the Earth. Data on abundance and properties of both particle types are sparse, especially for remote areas of the world, such as the Southern Ocean (SO). In this work, unique results from ship-borne aerosol-particle-related in situ measurements and filter sampling in the summertime SO region are presented. An overview of CCN and INP number concentrations on the Southern Ocean is provided and, using additional analyses on particle chemical composition and air-mass origin, insights regarding possible CCN and INP sources and origins are presented, with the help of a correlation analysis. CCN number concentrations spanned 2 orders of magnitude, e.g. for a supersaturation of 0.3 % values ranged roughly from 3 to 590 cm⁻³. CCN showed variable contributions of organic and inorganic material. No distinct size-dependence of the CCN hygroscopicity parameter was apparent, indicating homogeneous composition across sizes (critical dry diameter on average between 30 nm and 110 nm). The relative contribution of sea spray aerosol (SSA) to the CCN number concentration was on average small (below 35 %). Ambient INP number concentrations were measured in the temperature range from −4 to −27 °C using an immersion freezing method. Concentrations spanned up to 3 orders of magnitude, e.g. at −16 °C from 0.2 to 100 m⁻³. Elevated values (above 10 m⁻³ at −16 °C) were measured when the research vessel was in the vicinity of land (excluding Antarctica). Lower, more constant concentrations were measured on the open ocean. This, along with results of backward-trajectory analyses, hints towards terrestrial and/or coastal INP sources being dominant close to ice-free (non-Antarctic) land. In pristine marine areas INP may originate from both oceanic sources and/or long range transport. A correlation analysis yielded strong correlations between sodium mass concentration and particle number concentration in the coarse mode (larger 1 µm), unsurprisingly indicating a significant contribution of SSA to that mode. CCN number concentration was highly correlated with the number concentrations of Aitken (10 to 100 nm) and accumulation mode particles (100 to 1000 nm). This, together with a lack of correlation between sodium mass and Aitken and accumulation mode number concentrations, underlines the important contribution of non-SSA, probably secondarily formed particles, to the CCN population.:1 Introduction 2 Fundamentals 2.1 Aerosol particle activation 2.1.1 Köhler theory 2.1.2 κ-Köhler theory 2.2 Ice nucleation 2.2.1 Homogeneous Freezing 2.2.2 Heterogeneous Freezing 3 Campaign, instrumentation, and data handling 3.1 Antarctic Circum-navigation Expedition 3.2 In situ aerosol measurements 3.2.1 Aerosol number size distribution 3.2.2 Cloud condensation nuclei 3.3 Off-line aerosol characterisation 3.3.1 High-volume sampling 3.3.2 Low-volume sampling 3.3.3 Ice nucleation droplet array (INDA) 3.3.4 Analysis of chemical composition 3.4 Further resources 3.4.1 In-water organic compound measurements 3.4.2 Wind measurements 3.4.3 Air-mass origin analysis 3.4.4 Fluorescent particles 3.4.5 Correlation analysis 4 Results and Discussion 4.1 Aerosol particles and cloud condensation nuclei 4.1.1 Particle number size distributions 4.1.2 CCN number concentrations 4.1.3 CCN hygroscopicity 4.1.4 Air-mass origin for aerosol particle and CCN measurements 4.2 Ice nucleating particles 4.2.1 INP abundance 4.2.2 Air-mass origin for INP measurements 4.3 Chemical composition of sampled aerosol particles 4.4 Correlation analysis 5 Summary and ConclusionsAerosolpartikel, die als Wolkennukleations- oder Eiskeime fungieren, spielen eine Schlüsselrolle in den Entstehungs- und Vereisungsprozessen von Wolken. Mit ihren wolkenrelevanten Eigenschaften haben diese beiden Arten von Aerosolpartikeln einen starken Einfluss auf den Strahlungshaushalt der Erde. Messungen ihrer Häufigkeit und Eigenschaften sind selten, inbesondere in den entlegenen Regionen der Erde wie beispielsweise dem Südlichen Ozean. In dieser Arbeit werden die Ergebnisse von in situ und filterbasierten Partikelmessungen einer Forschungsfahrt auf dem Südlichen Ozean in den Sommermonaten der Südhalbkugel gezeigt. Ein erstmaliger Überblick über die Anzahlkonzentrationen der Wolkennukleations- und Eiskeime über dem Südlichen Ozean wird gegeben. Unter Berücksichtigung weiterer Messergebnisse zur chemischen Zusammensetzung der Partikel und Betrachtungen zur Herkunft der Luftmassen werden Rückschlüsse auf die Herkunft und Quellen der gesammelten, wolkenrelevanten Aerosolpartikel gezogen, auch mit Hilfe einer Korrelationsanalyse. Die Anzahlkonzentration der Wolkennukleationskeime schwankte innerhalb von zwei Größenordnungen, beispielsweise zwischen 3 und 590 cm⁻³ bei 0.3 % Übersättigung. Die chemische Zusammensetzung der Wolkennukleationskeime variierte dabei stark, zwischen organischem und inorganischem Material. Der Hygroskopizitätsparameter zeigte keine Größenabhängigkeit, was für eine intern gemischte Population von Wolkennukleationskeimen spricht (kritische Partikeldurchmesser lagen im Mittel zwischen 30 und 110 nm). Der prozentuale Anteil von Seesalzpartikeln zur Anzahlkonzentration der Wolkennukleationskeime war im Mittel gering (kleiner 35 %). Die Anzahlkonzentration der Eiskeime wurden im Temperaturbereich −4 bis −27 °C mittels einer filterbasierten Immersionsgefriermethode bestimmt. Die Anzahlkonzentrationen schwankten dabei im Bereich von bis zu drei Größenordnungen, beispielsweise zwischen 0.2 und 100 m⁻³ bei einer Temperatur von −16 °C. In Küstennähe, mit Ausnahme von Antarktika, wurden erhöhte Anzahlkonzen- trationen (über 10 m⁻³ bei −16 °C) gemessen. Niedrigere, weniger variable Anzahlkonzentrationen wurden hingegen auf offener See gemessen. Diese Beobachtungen, zusammen mit den Ergebnissen zur Luftmassenherkunft, sprechen für eine Dominanz von terrestrischen und/oder küstennahen Quellen der Eiskeime in der Nähe von eisfreiem (nicht-Antarktischem) Festland. Dabei können in den unbe- rührten, marinen Regionen die Eiskeime aus dem Meer selbst und/oder Ferntransport stammen. Eine Korrelationsanalyse zeigte einen starken Zusammenhang zwischen der Massenkonzentration von Natrium und der Anzahlkonzentration an groben Aerosolpartikeln (größer 1 µm). Daraus folgt ein signifikanter Anteil an Seesalzpartikeln in dieser Partikelgröße. Die Anzahlkonzentration der Wolkennukleationskeime korrelierte stark mit den Anzahlkonzentrationen der Aitken- (10 bis 100 nm) bzw. Akkumulationskerne (100 bis 1000 nm). Diese Beobachtung, zusammen mit dem Fehlen einer Korrelation zwischen Natriummasse und Aitken- oder Akkumulationskernanzahl, unterstreicht die Relevanz von Partikeln die nicht Seesalz sind (vermutlich sekundär geformten Aerosolpartikel) für die Population der Wolkennukleationskeime.:1 Introduction 2 Fundamentals 2.1 Aerosol particle activation 2.1.1 Köhler theory 2.1.2 κ-Köhler theory 2.2 Ice nucleation 2.2.1 Homogeneous Freezing 2.2.2 Heterogeneous Freezing 3 Campaign, instrumentation, and data handling 3.1 Antarctic Circum-navigation Expedition 3.2 In situ aerosol measurements 3.2.1 Aerosol number size distribution 3.2.2 Cloud condensation nuclei 3.3 Off-line aerosol characterisation 3.3.1 High-volume sampling 3.3.2 Low-volume sampling 3.3.3 Ice nucleation droplet array (INDA) 3.3.4 Analysis of chemical composition 3.4 Further resources 3.4.1 In-water organic compound measurements 3.4.2 Wind measurements 3.4.3 Air-mass origin analysis 3.4.4 Fluorescent particles 3.4.5 Correlation analysis 4 Results and Discussion 4.1 Aerosol particles and cloud condensation nuclei 4.1.1 Particle number size distributions 4.1.2 CCN number concentrations 4.1.3 CCN hygroscopicity 4.1.4 Air-mass origin for aerosol particle and CCN measurements 4.2 Ice nucleating particles 4.2.1 INP abundance 4.2.2 Air-mass origin for INP measurements 4.3 Chemical composition of sampled aerosol particles 4.4 Correlation analysis 5 Summary and Conclusion