bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia induces a transcriptional early primitive streak signature in pluripotent cells enhancing spontaneous elongation and lineage representation in gastruloids
Authors: López-Anguita Natalia , Gassaloglu Seher Ipek , Stötzel Maximilian , Typou Marina , Virta Iiris , Hetzel Sara , Buschow René , Koksal Burak , Atilla Derya , Maitschke-Rajasekharan Ronald , Chen Rui , Mattei Alexandra L. , Bedzhov Ivan , Meierhofer David , Meissner Alexander , Veenvliet Jesse V. , Bulut-Karslioglu Aydan 
Published: July 2021

ABSTRACTThe cellular microenvironment together with intrinsic regulators shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, components of the hypoxia response and how their interplay impacts stem cell transcriptional networks and lineage choices remain poorly understood. Here we investigated the molecular effects of acute and prolonged hypoxia on distinct embryonic and extraembryonic stem cell types as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem (ES) cells. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. Importantly, hypoxia also modulates T levels in conventional gastruloids and enhances representation of endodermal and neural markers. Mechanistically, we identify Hif1α as a central factor that mediates the transcriptional response to hypoxia in balance with epigenetic and metabolic rewiring. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development
Maturation, developmental site, and pathology dictate murine neutrophil function
Authors: Mackey John B. G. , McFarlane Amanda J. , Jamieson Thomas , Jackstadt Rene , Raffo-Iraolagoitia Ximena L. , Secklehner Judith , Cortes-Lavaud Xabier , Fercoq Frédéric , Clarke William , Hedley Ann , Gilroy Kathryn , Lilla Sergio , Vuononvirta Juho , Graham Gerard J. , De Filippo Katia , Murphy Daniel J. , Steele Colin W. , Norman Jim C. , Bird Thomas G. , Mann Derek A. , Morton Jennifer P. , Zanivan Sara , Sansom Owen J. , Carlin Leo M. 
Published: July 2021

AbstractNeutrophils have been implicated in poor outcomes in cancer and severe inflammation. We found that neutrophils expressing intermediate levels of Ly6G (Ly6GInt) were present in mouse cancer models and more abundant in those with high rates of spontaneous metastasis. Maturation, age, tissue localization and functional capacity all drive neutrophil heterogeneity. Recent studies have proposed various markers to distinguish between these heterogeneous sub-populations; however, these markers are limited to specific models of inflammation and cancer. Here, we identify and define Ly6G expression level as a robust and reliable marker to distinguish neutrophils at different stages of maturation. Ly6GIntneutrophils were bona fide ‘immature neutrophils’ with reduced immune regulatory and adhesion capacity. Whereas the bone marrow is a more recognised site of granulopoiesis, the spleen also produces neutrophils in homeostasis and cancer. Strikingly, neutrophils matured faster in the spleen than in the bone marrow with unique transcriptional profiles. We propose that developmental origin is critical in neutrophil identity and postulate that neutrophils that develop in the spleen supplement the bone marrow by providing an intermediate more mature reserve before emergency haematopoiesis.
microRNA-mediated regulation of microRNA machinery controls cell fate decisions
Authors: Liu Qiuying , Novak Mariah K. , Pepin Rachel , Eich Taylor , Hu Wenqian 
Published: July 2021

AbstractmicroRNAs associate with Argonaute proteins, forming the microRNA-induced silencing complex (miRISC), to repress target gene expression post-transcriptionally. Although microRNAs are critical regulators in mammalian cell differentiation, our understanding of how microRNA machinery, such as the miRISC, are regulated during development is still limited. We previously showed that repressing the production of one Argonaute protein, Ago2, by Trim71 is important for mouse embryonic stem cells (mESC) self-renewal (Liu et al., 2021). Here we show that among the four Argonaute proteins in mammals, Ago2 is the major developmentally regulated Argonaute protein in mESCs. Moreover, in pluripotency, besides the Trim71-mediated regulation of Ago2 (Liu et al., 2021), microRNA-182/microRNA-183 also repress Ago2. Specific inhibition of this microRNA-mediated repression results in stemness defects and accelerated differentiation through the let-7 microRNA pathway. These results reveal a microRNA-mediated regulatory circuit on microRNA machinery that is critical to maintaining pluripotency.
Single Cell Variability of CRISPR-Cas Interference and Adaptation
Authors: McKenzie Rebecca E. , Keizer Emma M. , Vink Jochem N.A. , van Lopik Jasper , Büke Ferhat , Kalkman Vera , Fleck Christian , Tans Sander J. , Brouns Stan J.J. 
Published: July 2021

AbstractCRISPR-Cas defence is a combination of adaptation to new invaders by spacer acquisition, and interference by targeted nuclease activity. While these processes have been studied on a population level, the individual cellular variability has remained unknown. Here, using a microfluidic device combined with time-lapse microscopy, we monitor invader clearance in a population of Escherichia coli across multiple generations. We observed that CRISPR interference is fast with a narrow distribution of clearance times. In contrast, for invaders with escaping PAM mutations we show large cell-to-cell variability of clearance times, which originates from primed CRISPR adaptation. Faster growth and cell division, as well as higher levels of Cascade, increase the chance of clearance by interference. In contrast, faster growth is associated with decreased chances of clearance by priming. A mathematical model explains the experimental findings, and identifies Cascade binding to the mutated invader DNA, rather than spacer integration, as the main source of priming heterogeneity. The highly stochastic nature of primed CRISPR adaptation implies that only subpopulations of bacteria are able to respond to invading threats in a timely manner. We conjecture that CRISPR-Cas dynamics and heterogeneity at the cellular level are crucial to understanding the strategy of bacteria in their competition with other species and phages.
Transcriptome wide association study of coronary artery disease identifies novel susceptibility genes
Authors: Li Ling , Chen Zhifen , von Scheidt Moritz , Steiner Andrea , Güldener Ulrich , Koplev Simon , Ma Angela , Hao Ke , Pan Calvin , Lusis Aldons J. , Pang Shichao , Kessler Thorsten , Ermel Raili , Sukhavasi Katyayani , Ruusalepp Arno , Gagneur Julien , Erdmann Jeanette , Kovacic Jason C. , Björkegren Johan L.M. , Schunkert Heribert 
Published: July 2021

AbstractTranscriptome-wide association studies (TWAS) explore genetic variants affecting gene expression for association with a trait. Here we studied coronary artery disease (CAD) using this approach by first determining genotype-regulated expression levels in nine CAD relevant tissues by EpiXcan in two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these data we next imputed gene expression in respective nine tissues from individual level genotype data on 37,997 CAD cases and 42,854 controls for a subsequent gene-trait association analysis. Transcriptome-wide significant association (P < 3.85e-6) was observed for 114 genes, which by genetic means were differentially expressed predominately in arterial, liver, and fat tissues. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel (CAND1, EGFLAM, EZR, FAM114A1, FOCAD, GAS8, HOMER3, KPTN, MGP, NLRC4, RGS19, SDCCAG3, STX4, TSPAN11, TXNRD3, UFL1, WASF1, and WWP2). Gene set analyses showed that TWAS genes were strongly enriched in CAD-related pathways and risk traits. Associations with CAD or related traits were also observed for damaging mutations in 67 of these TWAS genes (11 novel) in whole-exome sequencing data of UK Biobank. Association studies in human genotype data of UK Biobank and expression-trait association statistics of atherosclerosis mouse models suggested that newly identified genes predominantly affect lipid metabolism, a classic risk factor for CAD. Finally, CRISPR/Cas9-based gene knockdown of RGS19 and KPTN in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Taken together, our TWAS approach was able to i) prioritize genes at known GWAS risk loci and ii) identify novel genes which are associated with CAD.
Evolutionary conservation of centriole rotational asymmetry in the human centrosome
Authors: Gaudin Noémie , Gil Paula Martin , Boumendjel Meriem , Ershov Dmitry , Pioche-Durieu Catherine , Bouix Manon , Delobelle Quentin , Maniscalco Lucia , Ngan Phan Thanh Bich , Heyer Vincent , Reina-San-Martin Bernardo , Azimzadeh Juliette 
Published: July 2021

AbstractCentrioles are formed by microtubule triplets in a nine-fold symmetric arrangement. In flagellated protists and in animal multiciliated cells, accessory structures tethered to specific triplets render the centrioles rotationally asymmetric, a property that is key to cytoskeletal and cellular organization in these contexts. In contrast, centrioles within the centrosome of animal cells display no conspicuous rotational asymmetry. Here, we uncover rotationally asymmetric molecular features in human centrioles. Using ultrastructure expansion microscopy, we show that LRRCC1, the ortholog of a protein originally characterized in flagellate green algae, associates preferentially to two consecutive triplets in the distal lumen of human centrioles. LRRCC1 partially co-localizes and affects the recruitment of another distal component, C2CD3, which also has an asymmetric localization pattern in the centriole lumen. Together, LRRCC1 and C2CD3 delineate a structure reminiscent of a filamentous density observed by electron microscopy in flagellates, termed the ‘acorn’. Functionally, the depletion of LRRCC1 in human cells induced defects in centriole structure, ciliary assembly and ciliary signaling, supporting that LRRCC1 cooperates with C2CD3 to organizing the distal region of centrioles. Since a mutation in the LRRCC1 gene has been identified in Joubert syndrome patients, this finding is relevant in the context of human ciliopathies. Taken together, our results demonstrate that rotational asymmetry is an ancient property of centrioles that is broadly conserved in human cells. Our work also reveals that asymmetrically localized proteins are key for primary ciliogenesis and ciliary signaling in human cells.
E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis
Authors: Shi Yuhua , Yang Yang , Xu Weilv , Xu Wei , Fu Xinyu , Lv Qian , Xia Jie , Shi Fushan 
Published: July 2021

AbstractGasdermin D (GSDMD) participates in activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.
Lung Epithelial Regulation of BCL2 Related Protein A1 (BCL2A1) by Coronaviruses (SARS-CoV) and Type I Interferon Signaling
Authors: Ramana Chilakamarti V. 
Published: July 2021

AbstractHighly pathogenic respiratory viruses such as 1918 influenza (HIN1) and coronavirus (SARS-CoV-2) induce significant lung injury with diffuse alveolar damage, capillary leak, and extensive cell death resulting in acute respiratory distress syndrome (ARDS). Direct effects of the virus, as well as host immune response such as proinflammatory cytokine production, contribute to programmed cell death or apoptosis. Alveolar lung epithelial type II (AT2) cells play a major role in the clearance of respiratory viruses, secretion of surfactant proteins and antimicrobial substances into the bronchoalveolar fluid as well as repair of lung injury. Gene expression in AT2 cells is regulated in a tissue and cell-specific manner and in a temporal fashion. The availability of tissue and cell-specific RNA datasets in Human Protein Atlas led to the identification of localized expression patterns of BCL-2 family members such as BCL2 related protein A1 (BCL2A1) in AT2 cells and immune cells of the lung. BCL2A1 expression was regulated by multiple stimuli including Toll-like receptor (TLR) ligands, interferons (IFNs), inflammatory cytokines, and inhibited by the steroid dexamethasone. In this study, regulation of BCL2A1 gene expression in human lung epithelial cells by several respiratory viruses and type I interferon signaling was investigated. SARS-CoV-2 infection significantly induced BCL2A1 expression in human lung epithelial cells within 24 hours that required the expression of Angiotensin-converting enzyme 2 (ACE2). BCL2A1 mRNA induction by SARS-CoV-2 was correlated with the induced expression of IFN-β and IFN-regulated transcription factor mRNA. BCL2A1 was induced by IFN-β treatment or by infection with influenza virus lacking the non-structural protein1(NS1) in NHBE cells. Furthermore, bioinformatics revealed that a subset of BCL-2 family members involved in the control of apoptosis and transcription such as BCL2A1, BCL2L14, BCL3, and BCL6 were regulated in the lung epithelial cells by coronaviruses and in the lung tissue samples of COVID-19 patients. Transcriptomic data also suggested that these genes were differentially regulated by the steroid drug dexamethasone.
Cdc14 activates autophagy to regulate spindle pole body dynamics during meiosis
Authors: Feng Wenzhi , Argüello-Miranda Orlando , Qian Suhong , Wang Fei 
Published: July 2021

SummaryAutophagy, a conserved eukaryotic lysosomal degradation pathway that responds to environmental and cellular cues, is regulated by multiple signaling pathways that oversee cell survival, growth, and proliferation. In budding yeast, autophagy plays an essential role in meiotic exit, although the molecular mechanisms underlying its regulation and cargo selection remain unknown. In this study, we found that autophagy is maintained during meiosis and is upregulated at anaphase I and anaphase II. In addition, we found that cells with higher levels of autophagy during meiosis I and II completed meiosis faster, and that genetically activated autophagy machinery increased sporulation efficiency. Strikingly, our data revealed that Cdc14, a highly conserved phosphatase that counteracts Cdc28 (CDK1), is a meiosis-specific autophagy regulator. At anaphase I and anaphase II, Cdc14 was activated and released from the nucleolus into the cytoplasm, where it dephosphorylated Atg13 to stimulate Atg1 kinase activity and thus autophagy. Importantly, the meiosis-specific spindle pole body (SPB, the yeast centrosome) component (Spo74) was sensitized to autophagy-mediated degradation at anaphase II, upon its dephosphorylation by Cdc14. Together, our findings reveal a meiosis-tailored mechanism of Cdc14 that spatiotemporally guides meiotic autophagy activity to control SPB dynamics.
Combination of Antiviral Drugs to Inhibit SARS-CoV-2 Polymerase and Exonuclease as Potential COVID-19 Therapeutics
Authors: Wang Xuanting , Sacramento Carolina Q. , Jockusch Steffen , Chaves Otávio Augusto , Tao Chuanjuan , Fintelman-Rodrigues Natalia , Chien Minchen , Temerozo Jairo R. , Li Xiaoxu , Kumar Shiv , Xie Wei , Patel Dinshaw J. , Meyer Cindy , Garzia Aitor , Tuschl Thomas , Bozza Patrícia T. , Russo James J. , Souza Thiago Moreno L. , Ju Jingyue 
Published: July 2021

AbstractSARS-CoV-2 has an exonuclease-based proofreader, which removes nucleotide inhibitors such as Remdesivir that are incorporated into the viral RNA during replication, reducing the efficacy of these drugs for treating COVID-19. Combinations of inhibitors of both the viral RNA-dependent RNA polymerase and the exonuclease could overcome this deficiency. Here we report the identification of hepatitis C virus NS5A inhibitors Pibrentasvir and Ombitasvir as SARS-CoV-2 exonuclease inhibitors. In the presence of Pibrentasvir, RNAs terminated with the active forms of the prodrugs Sofosbuvir, Remdesivir, Favipiravir, Molnupiravir and AT-527 were largely protected from excision by the exonuclease, while in the absence of Pibrentasvir, there was rapid excision. Due to its unique structure, Tenofovir-terminated RNA was highly resistant to exonuclease excision even in the absence of Pibrentasvir. Viral cell culture studies also demonstrate significant synergy using this combination strategy. This study supports the use of combination drugs that inhibit both the SARS-CoV-2 polymerase and exonuclease for effective COVID-19 treatment.
Vigeo and CSR—The Daughter of Globalization
Authors: Yemen Gerry , Kamin Ronald G. , Wicks Andrew C. 
Published: July 2021

The Vigeo case is used in Darden’s Global EMBA “Business Ethics” course. The case raises the issue of how we determine what constitutes a socially responsible business, and how to apply that idea in a global context. It therefore could also be used effectively in courses in marketing, finance, or global economies and markets.With a global leadership and sustainability perspective, this field-based case uses Vigeo, a European leader among environmental, social, and governance (ESG) rating agencies headquartered in Paris, to set the stage for an analysis of what it means to be a socially responsible business. It allows for an exploration of decision-making and moral overtones that are often difficult to resolve. The material also lets students explore the idea of global values-are there such things, and if so, what are they? The case opens with a summary of issues that include how CEO Nicole Notat plans to grow the company in 2012. She had to take a strategic view of where the SRI market was going and be prepared. The board had asked Notat to think more strategically about China. Would Vigeo adapt existing services and products to the Chinese market? Would entering an emerging market such as China mean rethinking the business model from the ground up? How would either strategy fit with the company’s overall mission?This case is also available in French. Contact DBP to obtain the French version.
What drives the growth of start-up firms? A tool for mapping the state-of-the-art of the empirical literature
Authors: Pugliese Roberto , Bortoluzzi Guido , Balzano Marco 
Published: July 2021

PurposeThis study aims to enrich the current theoretical debate on the growth of start-up firms by extensively investigating the ongoing empirical studies in this research stream. Moreover, this study identifies drivers whose support roles are confirmed in the literature and recommends further research opportunities.Design/methodology/approachIn this study, we analysed the results of 316 empirical studies on start-up firms and growth and also identified and categorised 66 growth drivers. We presented these drivers in three-dimensional charts: 1) the frequency of using each driver in the 316 studies, 2) the consistency of each driver as measured by the number of studies supporting its statistical significance and 3) the net effect (positive or negative) of each driver on growth.FindingsOur analysis compares extant studies on growth drivers and shows some under-explored growth factors of start-up firms.Practical implicationsBoth start-up managers and policymakers can benefit from this study. This study provided managers with a fine-grained tool on the main growth drivers and can guide policymakers in supporting policies for start-up firms.Originality/valueThis study provides a rich, fine-grained and coherent picture of several potential growth drivers of start-up firms. Moreover, we extended our analysis to various potential drivers more than previous studies on this topic, thereby providing fruitful insights into the critical growth factors for start-up firms.
Design for safety in construction in Nigeria: a qualitative inquiry of the critical opportunities
Authors: Umeokafor Nnedinma , Okoro Chioma , Diugwu Ikechukwu , Umar Tariq 
Published: July 2021

PurposeThe purpose of this paper is to investigate the critical opportunities for design for safety (DFS), the potential statutory (and non-statutory) health and safety (H&S) responsibilities of designers including DFS and its workability in developing countries.Design/methodology/approachInterviews were conducted among 28 multi-designers including Architects, Civil Engineers and Builders and the data was analysed thematically.FindingsThe study revealed that the likelihood of designers, clients, etc. inclining to change because of the infancy stage of H&S in developing countries, making it “fallow” for H&S was a barrier. The opportunities for DFS include the willingness of designers to develop DFS skills and knowledge, which results in a welcoming attitude towards DFS. Further, the success recorded by professional bodies on other regulatory matters and designers' greater inclination to comply with DFS when professional bodies are involved in the regulatory process of DFS remain key opportunities for DFS.Practical implicationsFor statutory-backed DFS to achieve the objective at the optimum level, the role of professional bodies in the regulatory and sensitisation processes, geographic differences in DFS legislation enforcement, nuanced and strategic design and enforcement of any legislation that will support DFS should be taken into consideration.Social implicationsA grassroots collaborative approach to developing and implementing DFS in the country and the exploitation of the zeal of designers to have DFS-related knowledge, is recommended.Originality/valueTo the knowledge of the authors, this is the first study that examines the opportunities for DFS in developing countries when it is (or not) supported by statute and the need to advance the understanding of DFS in developing countries through qualitative enquiry.