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"Hoffmann, H."
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Human host factors required for influenza virus replication
Host factors in flu infectivity
Two genome-wide RNA interference screens published in this issue identify human host factors required for influenza A virus replication in lung epithelia cell lines. König
et al
. identify 295 host genes required for influenza replication. Of those, 219 are required for efficient wild-type virus growth, and 23 are required for viral entry. Karlas
et al
. report the discovery of 287 host genes influencing virus replication. An independent assay confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. These studies should provide a number of potential targets for host factor-directed antivirals for treatment of influenza viral infection.
The small coding capacity of the influenza A virus demands that the virus use the host cellular machinery for many aspects of its life cycle. An integrated systems approach, based on genome-wide RNA interference screening, is now used to identify 295 cellular cofactors required for early-stage influenza virus replication. Knowledge of these host cell requirements provides further targets that could be pursued for antiviral drug development.
Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle
1
. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host–pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-β. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIβ (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
Journal Article
Common human genetic variants of APOE impact murine COVID-19 mortality
Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (
APOE
) gene, homozygous in approximately 3% of the world’s population
1
and associated with Alzheimer’s disease, atherosclerosis and anti-tumour immunity
2
–
5
, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the
APOE2
or
APOE4
variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent
APOE3
allele.
APOE2
and
APOE4
mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that
APOE
genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis,
P
= 2.6 × 10
−7
). Our findings suggest
APOE
genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess
APOE
genotyping as a means of identifying patients at high risk for adverse outcomes.
Mice bearing different variants of
APOE
exhibit different COVID-19 outcomes, with
APOE2
and
APOE4
associated with more severe disease, and this relationship between
APOE
genotype and disease severity is supported by clinical data in humans.
Journal Article
Bröhan 100 : Art Nouveau, Art Deco, Functionalism, Berlin Secession : design and art
\"This lavishly illustrated publication on the Bröhan Museum's collection, established in 1973 by entrepreneur and collector Karl H. Bröhan (1921-2000), surveys the main trends in the history of design between 1890 and 1940. From French Art Nouveau and the British Arts and Crafts movement, the book proceeded to Jugendstil and the German Werkstätten, Viennese Modernism and the international Art Déco movements, then all the way on to the functionalist design of the 1930s. It uses 100 objects or pairs of objects to vividly communicate the history of art and collecting. A special section is devoted to the artists of the Berlin Secession. A must for fans of Jugendstil, Art Déco and functionalist design.\"--Vendor website.
Book
Strategies for managing a portfolio of alliances
Interorganizational relationships are recognized as an increasingly important source of competitive advantage. Hence, goal-oriented management of the alliance portfolio--all the alliances of the focal firm--plays a decisive role in company performance. Consequently, the configuration and development of the alliance portfolio become important strategic issues. In light of that, this article develops theoretical propositions that seek to clarify what determines the configuration and evolution of an alliance portfolio, and then presents the results of a longitudinal study to illustrate the developed theoretical framework. Building on contingency theory and a coevolutionary framework, we were able to identify three distinctive types of portfolio strategies at business level and to illustrate how they interact with the development of the business strategy and the business environment. Encompassing all this, the study illustrates and explains developmental paths and patterns in the evolution of an alliance portfolio. The developmental course typically evolves from adapting to shaping and to exploiting (stabilizing), according to the state of strategic uncertainty and the firm's resource endowment. A sudden increase in exogenous strategic uncertainty, however, can lead to a strategic shift back to an exploration or hybrid strategy.
Journal Article
Hybrid Ambidexterity: How the Environment Shapes Incumbents’ Use of Structural and Contextual Approaches
According to the literature on ambidexterity, organizations can use structural or contextual approaches to simultaneously explore novel opportunities and exploit existing ones. So far, however, we know very little about what induces organizations to focus on structural versus contextual ambidexterity, or how they combine the two approaches to maximize organizational learning. To shed more light on these questions, we investigate how the environment shapes a firm’s use of structural and contextual ambidexterity. Drawing on a comparative, longitudinal case study of the four largest electric utility companies in Germany, we show that firms focused on structural ambidexterity whenever they perceived emerging opportunities in the environment as requiring organizational culture and capabilities fundamentally different from their own. Contextual ambidexterity, on the other hand, became particularly important when opportunities in the environment were both numerous and uncertain, requiring the organization to leverage the distributed attention and expertise of its frontline employees. We show that environments characterized by opportunities that are numerous/uncertain and require novel culture and capabilities lead organizations to invest in initiatives that combine elements of both structural and contextual ambidexterity—an approach we label
hybrid ambidexterity
. Our theory framework synthesizes and complements existing work that has started to investigate the antecedents of structural versus contextual ambidexterity. We challenge the prevailing understanding of contextual and structural ambidexterity as dichotomous categories and reconceptualize them as two ends of a continuum. In addition, we provide initial evidence that firms’ ambidexterity approaches are influenced by managers’ perceptions of capabilities and opportunities.
Journal Article
Direct sulfuric acid formation from the gas-phase oxidation of reduced-sulfur compounds
Sulfuric acid represents a fundamental precursor for new nanometre-sized atmospheric aerosol particles. These particles, after subsequent growth, may influence Earth´s radiative forcing directly, or indirectly through affecting the microphysical and radiative properties of clouds. Currently considered formation routes yielding sulfuric acid in the atmosphere are the gas-phase oxidation of SO
2
initiated by OH radicals and by Criegee intermediates, the latter being of little relevance. Here we report the observation of immediate sulfuric acid production from the OH reaction of emitted organic reduced-sulfur compounds, which was speculated about in the literature for decades. Key intermediates are the methylsulfonyl radical, CH
3
SO
2
, and, even more interestingly, its corresponding peroxy compound, CH
3
SO
2
OO. Results of modelling for pristine marine conditions show that oxidation of reduced-sulfur compounds could be responsible for up to ∼50% of formed gas-phase sulfuric acid in these areas. Our findings provide a more complete understanding of the atmospheric reduced-sulfur oxidation.
Experiments verify that oxidation of organic sulphur compounds, such as DMS, directly yields gas-phase H
2
SO
4
. Simulations reveal that this pathway can be competitive with SO
2
oxidation over oceans in the Southern Hemisphere.
Journal Article
Estimating evaporation with thermal UAV data and two-source energy balance models
Estimating evaporation is important when managing water resources and cultivating crops. Evaporation can be estimated using land surface heat flux models and remotely sensed land surface temperatures (LST), which have recently become obtainable in very high resolution using lightweight thermal cameras and Unmanned Aerial Vehicles (UAVs). In this study a thermal camera was mounted on a UAV and applied into the field of heat fluxes and hydrology by concatenating thermal images into mosaics of LST and using these as input for the two-source energy balance (TSEB) modelling scheme. Thermal images are obtained with a fixed-wing UAV overflying a barley field in western Denmark during the growing season of 2014 and a spatial resolution of 0.20 m is obtained in final LST mosaics. Two models are used: the original TSEB model (TSEB-PT) and a dual-temperature-difference (DTD) model. In contrast to the TSEB-PT model, the DTD model accounts for the bias that is likely present in remotely sensed LST. TSEB-PT and DTD have already been well tested, however only during sunny weather conditions and with satellite images serving as thermal input. The aim of this study is to assess whether a lightweight thermal camera mounted on a UAV is able to provide data of sufficient quality to constitute as model input and thus attain accurate and high spatial and temporal resolution surface energy heat fluxes, with special focus on latent heat flux (evaporation). Furthermore, this study evaluates the performance of the TSEB scheme during cloudy and overcast weather conditions, which is feasible due to the low data retrieval altitude (due to low UAV flying altitude) compared to satellite thermal data that are only available during clear-sky conditions. TSEB-PT and DTD fluxes are compared and validated against eddy covariance measurements and the comparison shows that both TSEB-PT and DTD simulations are in good agreement with eddy covariance measurements, with DTD obtaining the best results. The DTD model provides results comparable to studies estimating evaporation with similar experimental setups, but with LST retrieved from satellites instead of a UAV. Further, systematic irrigation patterns on the barley field provide confidence in the veracity of the spatially distributed evaporation revealed by model output maps. Lastly, this study outlines and discusses the thermal UAV image processing that results in mosaics suited for model input. This study shows that the UAV platform and the lightweight thermal camera provide high spatial and temporal resolution data valid for model input and for other potential applications requiring high-resolution and consistent LST.
Journal Article