The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has devastated the global economy and claimed more than 1.7 million lives, presenting an urgent global health crisis. ...To identify host factors required for infection by SARS-CoV-2 and seasonal coronaviruses, we designed a focused high-coverage CRISPR-Cas9 library targeting 332 members of a recently published SARS-CoV-2 protein interactome. We leveraged the compact nature of this library to systematically screen SARS-CoV-2 at two physiologically relevant temperatures along with three related coronaviruses (human coronavirus 229E HCoV-229E, HCoV-NL63, and HCoV-OC43), allowing us to probe this interactome at a much higher resolution than genome-scale studies. This approach yielded several insights, including potential virus-specific differences in Rab GTPase requirements and glycosylphosphatidylinositol (GPI) anchor biosynthesis, as well as identification of multiple pan-coronavirus factors involved in cholesterol homeostasis. This coronavirus essentiality catalog could inform ongoing drug development efforts aimed at intercepting and treating coronavirus disease 2019 (COVID-19) and help prepare for future coronavirus outbreaks.
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•SARS-CoV-2 host protein interactome CRISPR screens for SARS-CoV-2 and three coronaviruses•Parallel CRISPR screens uncover unique and shared coronavirus host factors•Numbers of interacting host proteins and functional interactors are not proportional•Identified SARS-CoV-2 host factors are expressed in relevant cells in the human airway
Building upon a published SARS-CoV-2 protein interactome, Hoffmann et al. use a custom CRISPR library to determine which of these interacting host proteins are essential for infection by SARS-CoV-2 virus as well as three seasonal coronaviruses. These factors represent potential targets to combat COVID-19 and perhaps future coronavirus outbreaks.
Complementarities play a crucial role in socio-technical transitions as they accelerate technology development or decline. Missing complementary components in contrast may hamper the emergence of new ...technologies or negatively affect sector performance. In this paper, we introduce a conceptual framework to analyze complementarities and to understand their consequences for transitions. Our framework consists of four building blocks: i) different relationships, ii) different components, iii) different purposes and iv) complementarity dynamics. The latter two aspects go beyond existing concepts as they highlight the relative and dynamic nature of complementarities. We illustrate the applicability of the framework with examples from the ongoing energy transition. Finally, we discuss a series of complementarity bottlenecks and potential strategies by firms and policy makers of how to resolve these.
•We highlight the relevance of complementarities and their dynamics for socio-technical transitions.•We introduce a framework to systematically study complementarities.•We direct attention to the distinction of complementarities at the sector and technology level.•We illustrate our framework with examples from photovoltaics, wind power and alternative vehicles.•We present complementarity related bottlenecks and discuss strategies of how to address them.
The basophil activation test (BAT) has become a pervasive test for allergic response through the development of flow cytometry, discovery of activation markers such as CD63 and unique markers ...identifying basophil granulocytes. Basophil activation test measures basophil response to allergen cross‐linking IgE on between 150 and 2000 basophil granulocytes in <0.1 ml fresh blood. Dichotomous activation is assessed as the fraction of reacting basophils. In addition to clinical history, skin prick test, and specific IgE determination, BAT can be a part of the diagnostic evaluation of patients with food‐, insect venom‐, and drug allergy and chronic urticaria. It may be helpful in determining the clinically relevant allergen. Basophil sensitivity may be used to monitor patients on allergen immunotherapy, anti‐IgE treatment or in the natural resolution of allergy. Basophil activation test may use fewer resources and be more reproducible than challenge testing. As it is less stressful for the patient and avoids severe allergic reactions, BAT ought to precede challenge testing. An important next step is to standardize BAT and make it available in diagnostic laboratories. The nature of basophil activation as an ex vivo challenge makes it a multifaceted and promising tool for the allergist. In this EAACI task force position paper, we provide an overview of the practical and technical details as well as the clinical utility of BAT in diagnosis and management of allergic diseases.
In future electricity systems with a high share of intermittent renewable power generation, battery technologies have the potential to support power quality and security. The growing scientific ...literature on batteries reflects the high attention that currently rests on these technologies. This paper reviews the existing literature on lifecycle costs of batteries in stationary applications. The primary result of this review is that, despite the current high degree of variance in technological and economic battery data, a systematic assessment of the underlying uncertainty is lacking. The present paper addresses this disparity with an investigation of the impact of uncertainty in input parameters on lifecycle costs of four battery technologies across six electricity system applications. Based on input data collected from literature and via expert interviews, a probabilistic techno-economic model was built that calculates lifecycle costs and systematically addresses uncertainty in input parameters by applying a Monte Carlo simulation. The main conclusion of this paper is that the present uncertainty in cost and technical parameters of batteries exceeds by far the differences in lifecycle costs across technologies. For most electricity storage applications, the absolute differences in mean lifecycle costs across technologies are negligible compared to the uncertainty ranges of the mean lifecycle costs. Therefore, a competition still exists between the four analyzed battery technologies and so far a leading technology has yet to emerge in any of the investigated applications.
In recent years, increasing levels of resistance to the four FDA-approved anti-influenza virus drugs have been described and vaccine manufacturers have experienced demands that exceed their capacity. ...This situation underlines the urgent need for novel antivirals as well as innovations in vaccine production in preparation for the next influenza epidemic. Here we report the development of a cell-based high-throughput screen which we have used for the identification of compounds that modulate influenza virus growth either negatively or positively. We screened a library of compounds with known biological activity and identified distinct groups of inhibitors and enhancers that target sodium channels or protein kinase C (PKC). We confirmed these results in viral growth assays and find that treatment with a sodium channel opener or PKC inhibitor significantly reduces viral replication. In contrast, inhibition of sodium channels or activation of PKC leads to enhanced virus production in tissue culture. These diametrically opposing effects strongly support a role for PKC activity and the regulation of Na
+ currents in influenza virus replication and both may serve as targets for antiviral drugs. Furthermore, we raise the possibility that compounds that result in increased viral titers may be beneficial for boosting the production of tissue culture-grown influenza vaccines.
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.
This study adds two new perspectives to the long-running debate regarding the linkage between corporate social performance (CSP) and corporate financial performance (CFP): First, we add the aspect of ...issue materiality and suggest research to put more emphasis on the question of how individual CSP issues can be assumed to systematically influence the business environment from a theoretical point of view. Second, we highlight the measurement level of the underlying data screens as an important determinant of the actual effects of CSP on CFP. Focusing on climate change, we developed a set of questions that cover a firm’s carbon emissions and carbon management strategies. These questions were included in a questionnaire sent out annually to the 2,500 largest companies by market cap within the Dow Jones Global Index by an independent Swiss-based asset management firm. Our results show that when using carbon emissions as an outcome-based measurement, corporate environmental performance pays off. Conversely, when using carbon management as a process-based measurement, we find a negative relationship between corporate environmental performance and CFP.
Molecular virology tools are critical for basic studies of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and for developing new therapeutics. Experimental systems that do not rely ...on viruses capable of spread are needed for potential use in lower-containment settings. In this work, we use a yeast-based reverse genetics system to develop spike-deleted SARS-CoV-2 self-replicating RNAs. These noninfectious self-replicating RNAs, or replicons, can be trans-complemented with viral glycoproteins to generate replicon delivery particles for single-cycle delivery into a range of cell types. This SARS-CoV-2 replicon system represents a convenient and versatile platform for antiviral drug screening, neutralization assays, host factor validation, and viral variant characterization.
Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition ...of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
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