bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation
Authors: Sanders David W. , Jumper Chanelle C. , Ackerman Paul J. , Bracha Dan , Donlic Anita , Kim Hahn , Kenney Devin , Castello-Serrano Ivan , Suzuki Saori , Tamura Tomokazu , Tavares Alexander H. , Saeed Mohsan , Holehouse Alex S. , Ploss Alexander , Levental Ilya , Douam Florian , Padera Robert F. , Levy Bruce D. , Brangwynne Clifford P. 
Published: December 2020

SummaryMany enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ∼6000 drugs and >30 spike variants. Together with cell biological and biophysical approaches, the screen reveals an essential role for membrane cholesterol in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins, and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.HighlightsCell-cell fusion at ACE2-spike clusters cause pathological syncytia in COVID-19Drug screen reveals critical role for membrane lipid composition in fusionSpike’s unusual membrane-proximal cysteines and aromatics are essential for fusionCholesterol tunes relative infectivity of SARS-CoV-2 viral particles
DeepCellState: an autoencoder-based framework for predicting cell type-specific transcriptional states induced by drug treatment
Authors: Umarov Ramzan , Li Yu , Arner Erik 
Published: December 2020

AbstractDrug treatment induces cell type-specific transcriptional programs, and as the number of combinations of drugs and cell types grows, the cost for exhaustive screens measuring the transcriptional drug response becomes intractable. We developed DeepCellState, a deep learning autoencoder-based framework, for predicting the induced transcriptional state in a cell type after drug treatment, based on the drug response in another cell type. Training the method on a large collection of transcriptional drug perturbation profiles, prediction accuracy improves significantly over baseline and alternative deep learning approaches when applying the method to two cell types, with improved accuracy when generalizing the framework to additional cell types. Treatments with drugs or whole drug families not seen during training are predicted with similar accuracy, and the same framework can be used for predicting the results from other interventions, such as gene knock-downs. Finally, analysis of the trained model shows that the internal representation is able to learn regulatory relationships between genes in a fully data-driven manner.
Structure-guided microbial targeting of antistaphylococcal prodrugs
Authors: Miller Justin J. , Shah Ishaan T. , Hatten Jayda , Barekatain Yasaman , Mueller Elizabeth A. , Moustafa Ahmed M. , Edwards Rachel L. , Dowd Cynthia S. , Planet Paul J. , Muller Florian L. , Jez Joseph M. , Odom John Audrey R. 
Published: December 2020

AbstractCarboxy ester prodrugs have been widely employed as a means to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can successfully mask problematic chemical features that prevent cellular uptake and can be used to target delivery of compounds to specific tissues. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, curbing their potential therapeutic applications. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes due to a paucity of information about the selectivity of microbial esterases. Here we identify the bacterial esterases, GloB and FrmB, that are required for carboxy ester prodrug activation inStaphylococcus aureus.Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, which revealed several promoieties likely to be serum esterase-resistant while still being microbially labile. These studies lay the groundwork for structure-guided design of anti-staphyloccal promoieties and expand the range of molecules to target staphyloccal pathogens.
IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function inDrosophila
Authors: Werner Sascha , Zitouni Sihem , Okenve-Ramos Pilar , Mendonça Susana , Sporbert Anje , Spalthoff Christian , Göpfert Martin C. , Jana Swadhin Chandra , Bettencourt-Dias Mónica 
Published: December 2020

AbstractCilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, theDrosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, theDrosophilaguanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, which is evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases.
Cell-derived hexameric β-amyloid: a novel insight into composition, self-assembly and nucleating properties
Authors: Vadukul Devkee M. , Vrancx Céline , Burguet Pierre , Contino Sabrina , Suelves Nuria , Serpell Louise C , Quinton Loïc , Kienlen-Campard Pascal 
Published: December 2020

AbstractA key hallmark of Alzheimer’s disease (AD) is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein (APP), the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its nucleating properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.
Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches
Authors: Su Chun , Pahl Matthew C. , Grant Struan F. A. , Wells Andrew D. 
Published: December 2020

AbstractPromoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full scale Hi-C. 3D promoter ‘interactome’ maps are crucial for understanding how epigenomic features like histone modifications and open chromatin, or genetic variants identified in genome wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed. Here, we performed a head-to-head comparison between promoter capture C (PCC) and promoter capture Hi-C (PCHiC) with the respective 4 cutters DpnII and MboI versus 6 cutter HindIII datasets from the same five cell types. While PCHiC generally produces a higher signal to noise ratio for significant interactions in comparison to PCC, we show that DpnII/MboI detects more proximal interactions and shows little overlap with the HindIII detection range. Promoter-interacting genomic regions mapped by 4-cutters are more enriched for regulatory features and disease-associated genetic variation than 6-cutters maps, suggesting that high-resolution maps better capture gene regulatory architectures than do lower resolution approaches.
Network control and balanced scorecard as inscriptions in purchaser–provider arrangements: insights from a hybrid government agency
Authors: Zawawi Nur Haiza Muhammad , Hoque Zahirul 
Published: December 2020

PurposeThis article examines the power of management control mechanisms as “inscriptions” for bringing the interests of organisations within a purchaser–provider network into alignment.Design/methodology/approachThe study contributes to accounting and accountability literature in hybrid organisations by applying actor-network theory to a case study organisation. This enables an analysis of how a government agency, operating as a social service provider to the community, developed and used management control mechanisms in its intra-organisational units to ensure its operations were aligned with the expectations of inter-organisational networks in a purchaser–provider context. Data were collected using open-ended interviews and by examining internal accounting and management reports, government archival records and newspaper articles.FindingsAnalysis of the results demonstrates that inter-organisational network control was internalised within the provider organisation because of the ability of the controls to function as inscriptions that influenced organisational actions. The authors conclude that the network control travelled across boundaries over time and was assimilated by the provider organisation to become its internal management control mechanisms.Research limitations/implicationsA single case study of a government service provider agency may limit the generalisation of the findings to other hybrid entities or networks. The significant practical essence of this study lies in the diversity within the results that offer a rich representation of the impact of purchaser–provider arrangements on internal organisational systems within a hybrid public sector setting.Originality/valueThe outcomes enhance knowledge of how a hybrid government agency developed, mobilised and institutionalised its management control mechanisms to ensure the activities of one party are consistent with the other parties' expectations within a network.
Fake it or make it: employee well-being in emotional work settings
Authors: Mehta Poonam 
Published: December 2020

PurposeThe objective of the present study is to measure the well-being of employees who are engaged in frontline roles and actively engrossed in frequent regulation and management of emotions while performing interpersonal interactions. The study has conceptualised the comprehensive model to measure employee well-being with three work-related dimensions, namely work engagement, burnout and job satisfaction in emotional work settings.Design/methodology/approachThe study has been conducted on employees of the civil aviation industry in North India working on various frontline profiles. Data have been collected from 600 employees through a pretested questionnaire, and structural equation modelling (SEM) has been performed to test the hypothesis.FindingsThe findings of the study have revealed that all three dimensions, namely work engagement, burnout and job satisfaction are statistically significant measures of employee well-being in emotional work settings. Also, the study has determined that employees are highly satisfied and engaged at work despite having a feeling of burnout.Research limitations/implicationsThe study has enriched the literature by presenting and analysing a comprehensive model of employee well-being in emotional work settings of the civil aviation industry.Practical implicationsThe study will aid the various service industries in the framing of the intervention and training programs, which would help in promoting the well-being of employees who are specifically engaged in emotional work.Social implicationsThe study is very substantial in offering various parameters over which national well-being policies for individuals can be framed.Originality/valuePriorly, very few studies have attempted to recognise the role of the aforementioned variables in emotional work settings in a comprehensive manner. Further, the study has emphasised the unrecognised role of job satisfaction and work engagement where burnout is prevailing due to the presence of high emotional job demands.
Managing business model innovation: an innovative approach towards designing a digital ecosystem and multi-sided platform
Authors: Hoch Nino Bernd , Brad Stelian 
Published: December 2020

PurposeThis study aims to increase understanding regarding the transformation of traditional business models, integrating digital technologies. The significance of digitisation within business models has increased dramatically in recent years. Because of this, new knowledge on how to transform traditional business models into digital business models in a systematic way is needed. Digital technologies, embedded in previously non-digital goods, force companies to rethink their business models.Design/methodology/approachA design science research methodology was chosen for this study. A literature review and semi-structured interviews served as the theoretical foundation to integrate behavioural science into the design science process. From the design science perspective, an artefact is introduced to provide an architectural framework to manage business model innovation in a systematic way. The artefact's application is demonstrated through a case study conducted at a real company and evaluated afterwards by means of structured interviews with experts.FindingsThe authors propose a highly useable and valuable conceptual framework for systematic business model innovation. However, one limitation of the research is that it was conducted among construction professionals in Germany, and so the result might not hold true for other firms or industry branches.Research limitations/implicationsThe research was conducted among construction professionals in Germany, and this acts as a limitation, as the result might not hold true for other firms or industry branches.Originality/valueThe purpose of this study is to provide managers with a framework for business model innovation, helping them systematically integrate digital technologies to create customer-added value. The proposed framework presents an innovative conceptual analysis of systematic business model innovation, which has not been addressed in prior studies.
Who is counted as in-work poor? Testing five different definitions when measuring in-work poverty in Sweden 1987–2017
Authors: Jansson Birgitta , Broström Lovisa 
Published: December 2020

PurposeThere is ongoing debate amongst in-work poverty researchers as to how to answer the question “who is counted as in-work poor?” and how to define the minimum size of work that should be used to determine a “working threshold”. The purpose of this paper aims to contribute to this debate by testing five different definitions of a “working threshold” and discussing their implications when testing the different measurement outcomes.Design/methodology/approachThe authors use data from Statistics Sweden (SCB), including the total population registered as living in Sweden for each year from 1987 to 2017. All calculations are on a yearly basis and in fixed prices (2017). The data set used is based on linked administrative data retrieved from Statistics Sweden and the software used is SAS 9.4.FindingsResults show how in-work poverty trends differ by measurement approach. The two definitions with the lowest income thresholds are found to include a very heterogenic group of individuals. The development of in-work poverty in Sweden over 30 years show decreasing in-work poverty during the first decade followed by an increase to almost the same levels at the end of the period. In-work poverty in Sweden has transformed from being female-dominated in 1987 and the typical person in in-work poverty 2017 is a male immigrant, aged 26–55 years.Practical implicationsThis methodological discussion might lead to a new definition of who is a worker amongst the in-work poor, which could consequently affect who is counted as being in in-work poverty and lead to new social policy measures.Originality/valueThis is, to the authors' knowledge, the first time different definitions of work requirement used to define in-work poverty have been tested on a data set including the total population and over a period of 30 years.
Taxi within a grab? A gender-invariant model of mobile taxi adoption
Authors: Ooi Keng-Boon , Foo Fang-Ee , Tan Garry Wei-Han , Hew Jun-Jie , Leong Lai-Ying 
Published: December 2020

PurposeThe paper intends to examine mobile taxi (m-taxi) adoption, so as to close the gap in the current literature and clarify the behaviour of users by synthesising technological factors that are related to the characteristics of m-taxi applications with non-technological factors that are associated with the psychological characteristics of customers. The moderating effects of gender were also tested.Design/methodology/approachA self-administered questionnaire was adopted for data collection with 415 useable responses. The theoretical lens was tested via partial least squares-structural equation modelling. Additionally, state-of-the-art techniques such as permutation and multigroup analysis were applied.FindingsResults indicate that social pressure, technology anxiety, effort expectancy, performance expectancy, and service and system quality are not significantly related to behavioural intention. Also, findings show no significant differences among gender in this study, which suggests that the model is invariant across gender groups.Originality/valueThis study provides a novel insight by taking a broader perspective of ride-hailing terminology by considering both taxis and private vehicles.
Crisis determination and financial contagion: an analysis of the Hong Kong and Tokyo stock markets using an MSBVAR approach
Authors: Troug Haytem , Murray Matt 
Published: December 2020

PurposeThe purpose of this paper then, is to add to the existing literature on financial contagion. While a vast amount of the debate has been made using data from the late 1990s, this paper differentiates itself by analysing more current data, centred around the most recent global financial crisis, with specific focus on the stock markets of Hong Kong and Tokyo.Design/methodology/approachEmploying Pearson and Spearman correlation measures, the dynamic relationship of the two markets is determined over tranquil and crisis periods, as specified by an Markov-Switching Bayesian Vector AutoRegression (MSBVAR) model.FindingsThe authors find evidence in support of the existence of financial contagion (defined as an increase in correlation during a crisis period) for all frequencies of data analysed. This contagion is greatest when examining lower-frequency data. Additionally, there is also weaker evidence in some data sub-samples to support “herding” behaviour, whereby higher market correlations persist, following a crisis period.Research limitations/implicationsThe intention of this paper was not to analyse the cause or transmission mechanism of contagion between financial markets. Therefore future studies could extend the methodology used in this paper by including exogenous macroeconomic factors in the MSBVAR model.Originality/valueThe results of this paper serve to explain why the debate of the persistence and in fact existence of financial contagion remains alive. The authors have shown that the frequency of a time series dataset has a significant impact on the level of observed correlation and thus observation of financial contagion.
International capital flows with safe assets accumulation
Authors: Hung Ly Dai 
Published: December 2020

PurposeThe author studies the role of safe assets accumulation in shaping the pattern of international capital flows.Design/methodology/approachThe author combines a theoretical model and the empirical analysis. The model is a two-country open economy, while the evidence is based on a fixed-effect regression on a panel of 19 countries of the eurozone.FindingsIn an open two-country economy, a positive productivity shock raises both mean and variance of wealth accumulation rate, then, leading to a greater holding of safe assets for risk-sharing motivation. Upon financial integration, the shock can induce the outflows of net total capital. The evidence of 19 eurozone countries confirms the theory and also uncovers that the safe assets (bonds) are the dominant driver of cross-border capital flows within the eurozone.Research limitations/implicationsThe model can be extended to account for the impact of safe assets on the economic growth, then, analyzes the role of safe assets within financial globalization. Taking into account the impact of safe assets on the open-economy economic growth can be the next step to approach the issue.Practical implicationsThe paper also provides important policy implication. Since a higher productivity level can raise the outflows of net total capital through the accumulation of foreign safe assets, an economy needs to increase its supply of safe asset along with upgrading its domestic productivity level. This combination is important for the long-run capital accumulation and economic growth of an economy with an increasing path of the productivity level.Originality/valueThe paper seeks a balance between theory and evidence on international capital flows. Moreover, the paper bridges the gap between the literature on international capital flows and the literature on safe assets. And the paper also focuses on the economies of the eurozone.