bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19
Authors: Mirabelli Carmen , Wotring Jesse W. , Zhang Charles J. , McCarty Sean M. , Fursmidt Reid , Frum Tristan , Kadambi Namrata S. , Amin Anya T. , O’Meara Teresa R. , Pretto Carla D. , Spence Jason R. , Huang Jessie , Alysandratos Konstantinos D. , Kotton Darrell N. , Handelman Samuel K. , Wobus Christiane E. , Weatherwax Kevin J. , Mashour George A. , O’Meara Matthew J. , Sexton Jonathan Z. 
Published: May 2020

ABSTRACTThe global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10-15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds within vitroantiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infectionin vitro.Notably, we discovered that lactoferrin, a glycoprotein classically found in secretory fluids, including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.IMPORTANCESince its emergence in China in December 2019, SARS-CoV-2 has caused a global pandemic. Repurposing of FDA-approved drugs is a promising strategy for identifying rapidly deployable treatments for COVID-19. Herein, we developed a pipeline for quantitative high-throughput image-based screening of SARS-CoV-2 infection in human cells that led to the identification of several FDA-approved drugs and clinical candidates within vitroantiviral activity.
The linear ubiquitin chain assembly complex LUBAC generates heterotypic ubiquitin chains
Authors: Carvajal Alan Rodriguez , Diaz Carlos Gomez , Vogel Antonia , Sonn-Segev Adar , Schodl Katrin , Deszcz Luiza , Orban-Nemeth Zsuzsanna , Sakamoto Shinji , Mechtler Karl , Kukura Philipp , Clausen Tim , Haselbach David , Ikeda Fumiyo 
Published: May 2020

AbstractThe linear ubiquitin chain assembly complex (LUBAC) is the only known ubiquitin ligase that generates linear/Met1-linked ubiquitin chains. One of the LUBAC components, HOIL-1L, was recently shown to catalyse oxyester bond formation between the C-terminus of ubiquitin and some substrates. However, oxyester bond formation in the context of LUBAC has not been directly observed. We present the first 3D reconstruction of LUBAC obtained by electron microscopy and report its generation of heterotypic ubiquitin chains containing linear linkages with oxyester-linked branches. We found that addition of the oxyester-bound branches depends on HOIL-1L catalytic activity. We suggest a coordinated ubiquitin relay mechanism between the HOIP and HOIL-1L ligases supported by cross-linking mass spectrometry data, which show proximity between the catalytic RBR domains. Mutations in the linear ubiquitin chain-binding NZF domain of HOIL-1L reduces chain branching confirming its role in the process. In cells, these heterotypic chains were induced by TNF. In conclusion, we demonstrate that LUBAC assembles heterotypic ubiquitin chains with linear and oxyester-linked branches by the concerted action of HOIP and HOIL-1L.
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Authors: Douangamath Alice , Fearon Daren , Gehrtz Paul , Krojer Tobias , Lukacik Petra , Owen C. David , Resnick Efrat , Strain-Damerell Claire , Aimon Anthony , Ábrányi-Balogh Péter , Brandaõ-Neto José , Carbery Anna , Davison Gemma , Dias Alexandre , Downes Thomas D , Dunnett Louise , Fairhead Michael , Firth James D. , Jones S. Paul , Keely Aaron , Keserü György M. , Klein Hanna F , Martin Mathew P. , Noble Martin E. M. , O’Brien Peter , Powell Ailsa , Reddi Rambabu , Skyner Rachael , Snee Matthew , Waring Michael J. , Wild Conor , London Nir , von Delft Frank , Walsh Martin A. 
Published: May 2020

SummaryCOVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments was progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Functional microRNA targetome undergoes degeneration-induced shift in the retina
Authors: Chu-Tan Joshua A. , Feng Zhi-Ping , Wooff Yvette , Cioanca Adrian V. , Schumann Ulrike , Aggio-Bruce Riemke , Patel Hardip , Rutar Matt , Hannan Katherine , Panov Konstantin , Provis Jan , Natoli Riccardo 
Published: May 2020

SummaryMicroRNA (miRNA) play a significant role in the pathogenesis of complex neurodegenerative diseases, including age-related macular degeneration, acting as post-transcriptional gene suppressors through their association with argonaute (AGO) protein family members. However, to understand their role in disease, investigation into the regulatory nature of miRNA with their targets is required. To identify the active-miRnome-targetome interactions in the degenerating retina, AGO2 HITS-CLIP was performed using a mouse model of retinal degeneration. Analysis revealed a similar miRnome between healthy and damaged retinas, however, a shift in the active targetome was observed. This shift was also demonstrated by a change in the seed binding regions of miR-124-3p, the most abundant retinal miRNA loaded in AGO2. Following damage, AGO2 was localised to the inner retinal layers indicating a locational miRNA response to retinal damage. This study provides important insight into the alteration of miRNA regulatory activity that occurs as a response to retinal degeneration.
Osteoconductive material of a newly developed resin modified glass ionomer cement containing bioactive glasses for biomedical purposes
Authors: Ana Ika Dewi 
Published: May 2020

AbstractHybridization of resin modified- glass ionomer cement (RMGIC) and bioactive glass (BAG) may result higher mechanical strength and resistance to disintegration, while less contain of polyacrylic acid would lead to bioactivity of the cement. In the present study we investigated the effect of BAG from the CaSiO3-Ca3(PO4)2system addition to the bioactivity of RMGIC. The BAG containing 10, 15, and 20% of P2O5(denoted as CSP10, 15, and 20) were used in the study to modify the powder of RMGIC, with apatite wollastonite (AWG) was chosen for a comparison. The surface bioactivity was assessed using XRD, FT-IR, and SEM analysis after specimen immersion in the simulated body fluid (SBF). Measurement of Ca, P, F, Sr, and Al was conducted for the remaining SBF. Cells studies were done to evaluate cell attachment, proliferation, and differentiation on the RMGIC containing BAG compared to the one without BAG. Results of Sr and Al analysis lead to the conclusion that addition of BAG may not influence stability of the matrix of the cement. It was also confirmed that addition of bioactive glass was positive factor indicating excellent ions exchange in SBF and spontaneous growth of apatite by consuming the Ca and P ions in the surrounding fluid. The ability of osteoblasts differentiation on the four types of bioactive cements were higher than that of RMGIC without BAG. These results might provide novel insights into the development of a new generation of osteoconductive biomedical materials.
Defining a critical enhancer near Nanog using chromatin-focused approaches identifies RNA Pol II recruitment as required for expression
Authors: Agrawal Puja , Blinka Steven , Pulakanti Kirthi , Reimer Michael H. , Rao Sridhar 
Published: May 2020

ABSTRACTTranscriptional enhancers have been defined by their ability to operate independent of distance and orientation in plasmid-based reporter assays of gene expression. Currently, histone marks are used heavily to identify and define enhancers but both methods do not consider the endogenous role of an enhancer in the context of native chromatin. We employed a combination of genomic editing, single cell analyses, and sequencing approaches to investigate aNanog-associatedcis-regulatory element (CRE) which has been reported by others to be either an alternative promoter or a super-enhancer (SE). We first demonstrate both distance and orientation independence in native chromatin, eliminating the issues raised with plasmid-based approaches. We also demonstrate that the dominant SE modulatesNanogglobally and operates by recruiting and/or initiating RNA Polymerase II. Our studies have important implications to how transcriptional enhancers are defined and how they regulate gene expression.AUTHOR SUMMARYDifferent DNA elements help regulate the levels of gene expression. One such element are enhancers, short sequences that interact with genes to modulate levels of expression but can operate over large distances. Previously, these sequences were defined by their ability to regulate expression independent of their distance from a gene and the orientation of the sequence. However, these characteristics were found using techniques that did not recapitulate the native environment. Here, we have shown that an enhancer of one gene is indeed an enhancer by testing its distance and orientation-independence within the native environment. We also show that the mechanisms by which the enhancer is regulating expression is by controlling the levels of RNA Polymerase II at a gene. RNA Polymerase II is the protein that converts the gene sequence to a form usable by a cell, called mRNA. This is interesting because while this has been considered historically the main way enhancers operate, more recent work has focused on other, later regulatory steps involved in controlling mRNA production.
Evaluation of Antibacterial and Antioxidant activity of methanol crude extract ofAspilia africanaleaves: an in vitro approach
Authors: Oluwarinu Adepoju , Omololu-Aso  
Published: May 2020

ABSTRACTAspilia africana(Compositae) is one of such plants considered of great importance in pharmacopeia of traditional medicine. Its leaf is widely used in ethnomedicinal practices in tropical Africa because of its ability to stop bleeding and promote rapid healing of wounds. This study was carried out on the leaf part to determine its antimicrobial and antioxidant potentials of its leaf methanol extract. The methanolic extract of the leaf was subjected to preliminary phytochemical screening and it indicated the presence of saponins, tannin, resin, phlobatannins, and phenols. Thein-vitroantibacterial test of the methanol crude extract using agar well diffusion method showed broad-spectrum activity with minimum bactericidal concentration of 30, 75 mg/mL forKlebsiella pneumonia, and Bacillus subtilisrespectively.In-vitroantioxidant activities using 2, 2–diphenyl-1-picrylhydrazyl assay indicate that the methanol leaves extract had higher activity than of 92.23 µg/mL compared to standard drugs (Ascorbic acid 1.07mg/mL) and IC50at 4.66. This study concluded thatAspilia africanamethanol crude extract exhibits dosage-dependent antioxidant potential and could be further explored if it’s are in pure form.
Engineering multiple levels of specificity in an RNA viral vector
Authors: Gao Xiaojing J. , Chong Lucy S. , Ince Michaela H. , Kim Matthew S. , Elowitz Michael B. 
Published: May 2020

AbstractSynthetic molecular circuits could provide powerful therapeutic capabilities, but delivering them to specific cell types and controlling them remains challenging. An ideal “smart” viral delivery system would enable controlled release of viral vectors from “sender” cells, conditional entry into target cells based on cell-surface proteins, conditional replication specifically in target cells based on their intracellular protein content, and an evolutionarily robust system that allows viral elimination with drugs. Here, combining diverse technologies and components, including pseudotyping, engineered bridge proteins, degrons, and proteases, we demonstrate each of these control modes in a model system based on the rabies virus. This work shows how viral and protein engineering can enable delivery systems with multiple levels of control to maximize therapeutic specificity.
Quantitative live-cell imaging and computational modelling yield novel insight into endogenous WNT/CTNNB1 signaling dynamics
Authors: de Man S.M.A. , Zwanenburg G. , van der Wal T. , Hink M.A. , van Amerongen R. 
Published: May 2020

AbstractWNT/CTNNB1 signaling regulates tissue development and homeostasis in all multicellular animals. Multiple aspects of the underlying molecular mechanism remain poorly understood and critical information on endogenous WNT/CTNNB1 signaling dynamics is missing. Here we combine CRISPR/Cas9-mediated genome editing and quantitative live-cell microscopy to measure diffusion characteristics of fluorescently tagged, endogenous CTNNB1 in human cells with high spatiotemporal resolution under both physiological and oncogenic conditions. State-of-the-art functional imaging reveals that a substantial fraction of CTNNB1 resides in slow-diffusing complexes in the cytoplasm, irrespective of the activation status of the pathway. The identity of this cytoplasmic CTNNB1 complex changes according to the phosphorylation status of CTNNB1 as it undergoes a major reduction in size when WNT/CTNNB1 is (hyper)activated. We also measure the concentration of complexed and free CTNNB1 in both the cytoplasm and the nucleus before and after WNT stimulation, and use these parameters to build a minimal computational model of WNT/CTNNB1 signaling. Using this integrated experimental and computational approach, our work reveals that WNT pathway activation regulates the dynamic distribution of CTNNB1 across different functional pools by modulating three regulatory nodes: the cytoplasmic destruction complex, nucleocytoplasmic shuttling and nuclear retention.
Developing key performance indicators for hospital facilities management services: a developing country perspective
Authors: Amos Daniel , Au-Yong Cheong Peng , Musa Zairul Nisham 
Published: May 2020

PurposeKey performance indicators (KPIs) help to monitor performance, thereby revealing the gap between planned and executed results relative to organizational objectives. The purpose of this paper is to develop KPIs for performance measurement of facilities management (FM) services in public hospitals.Design/methodology/approachFollowing a comprehensive literature review of KPIs in FM, a set of KPIs were first selected. This was then subjected to content validation by experts. Thereafter a questionnaire survey was conducted to identify participants perception on the level of importance of the proposed KPIs. The main analytical tool used was SPSS factor analysis/principal component extraction.FindingsAdapting an expanded balanced scorecard typology, the paper identifies 17 KPIs, which are useful for performance improvement of FM. The study also introduces new financial dimensions beyond the traditional cost and profit-centered metrics.Research limitations/implicationsThe study was limited to three FM services. Although the results of the Kruskal–Wallis test shows no significant difference in the level of importance on more than 80% of the indicators, larger sample is required in future studies to examine indicator preference for the respective services. An empirical study to test the proposed indicators to measure FM performance could also be a next step.Originality/valueThe paper presents the first step to develop performance indicators, which are of relevance to FM performance measurement and could be utilized to improve performance. The indicators are largely generic and can easily be adapted by other FM service sectors for performance measurement.
The role of product innovation and customer centricity in transforming tacit and explicit knowledge into profitability
Authors: López-Cabarcos M. Ángeles , Srinivasan Suresh , Vázquez-Rodríguez Paula 
Published: May 2020

PurposeBy fusing knowledge-based theory, organizational learning theory and dynamics capability theory, this study aims to explore, on the one hand, the linkage between exploration, sensing and tacit knowledge, and on the other hand, exploitation, seizing and explicit knowledge. Thereby, it argues that not only tacit knowledge but also explicit knowledge contributes to competitive advantage for firms. This study also investigates how knowledge transforms into profitability.Design/methodology/approachThe conceptual model is tested with a study sample of 153 industrial organizations using structural equation modelling.FindingsResults confirm the importance of both tacit and explicit knowledge for achieving sustainable competitive advantages. Furthermore, both tacit and explicit knowledge transform into profitability, both directly and through product innovation and customer centricity which play partial mediating roles.Practical implicationsExplicit knowledge strategies can be easier to manage, implement and institutionalize than tacit knowledge strategies, which require human component and intervention to succeed. Managers should hence first implement explicit knowledge strategies to gain expeditious results. Further, with the advent of digital technologies and algorithms that can extract deep customer insights and organizational experiences which are highly tacit in nature and codifying the same into explicit knowledge, the importance of explicit knowledge is further enlarged.Originality/valueBy fusing three adjacent theories to establish a robust model specification, this study is able to demonstrate the contribution of explicit knowledge in the firm’s competitive advantages.
An artificial intelligence approach to support knowledge management on the selection of creativity and innovation techniques
Authors: Botega Luiz Fernando de Carvalho , da Silva Jonny Carlos 
Published: May 2020

Purpose
Creativity is an important skill for design teams to reach new and useful solutions. Designers often use one or more of creativity and innovation techniques (CITs) to achieve the desired creative potential during new product development (NPD). The selection of adequate CITs requires considerable expertise, given the multiple application contexts and the extensive number of techniques available. The purpose of this study is to present a creativity support system able to manage this amount of information and provide valuable knowledge to improve NPD.

Design/methodology/approach
This study presents a knowledge-based system prototype using artificial intelligence (AI) to support knowledge management on the selection of CITs for design. CITs assertion is modelled through a double inference process using five categories, correlating over 500 different entry scenarios to 24 implemented CITs. The techniques are classified according to: design stage, innovation focus, team relationship, execution method and difficult of use. Prototype outputs explanations on the inference process and chosen techniques information.

Findings
To demonstrate the system scope, two opposite design cases are presented. The system was validated by experts in knowledge management and mechanical engineering design. The validation process demonstrates relevance of the approach and improvement directions for future developments.

Originality/value
Though literature contains toolkits and taxonomy for CITs, no work applies AI to identify design scenarios, select best CITs and instruct about their use. Validators reported to know less than half of the available techniques, showing a clear knowledge gap among design experts.
Co-creative place innovation in an arctic town
Authors: Lindberg Malin , Wikberg Nilsson Åsa , Segerstedt Eugenia , Hidman Erik , Nilsson Kristina L. , Karlberg Helena , Balogh Johanna 
Published: May 2020

PurposeThe purpose of this paper is to shed light on co-creative approaches for place innovation in an Arctic town, based on the relocation of Kiruna’s city center in northern Sweden. Three cases of co-creative innovation processes in Kiruna are investigated and compared: an R&D project about local perceptions and visions of attractive urban environments; an R&D project about norm-creative design principles for inclusive and attractive urban design; and an R&D project about cross-industrial synergies for city center attractiveness.Design/methodology/approachThe study’s research design encompasses a comparative and participatory approach. The comparative approach implies investigation and comparison of three cases of co-creative innovation processes in Kiruna. The participatory approach implies joint development of new knowledge by researchers and local actors. The data consists of participatory observations of workshops and qualitative interviews with local actors.FindingsThe study reveals that the studied processes have harnessed the city center relocation as an opportunity to make Kiruna more attractive to residents and visitors, by using the co-creative approaches of Living Lab, Now-Wow-How and Norm-creative design. These approaches have enabled experts and local actors to jointly identify excluding patterns and norms in the relocation process and to envision inclusive and attractive (re-)configurations and (re-)conceptualizations of the future Kiruna.Research limitations/implicationsThe results add to the academic strand of inclusive urban transformation, by providing insights into co-creative approaches for re-imagining an Arctic town in times of industrial and social change. New insights are provided regarding how the geographical, industrial and cultural identity of an Arctic town can be harnessed to envision new configuration, content and communication that is attractive and accessible for a diversity of residents and visitors.Practical implicationsThe results highlight the potential to harness Arctic and rural characteristics in the promotion of urban attractiveness and public well-being, especially when combined with co-creative identification and transformation of excluding norms and patterns.Originality/valueThe results provide new insights into how co-creative approaches may facilitate innovative and inclusive renewal of towns and cities in the Arctic and beyond.