bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood Unit Segments Accurately Represent the Biophysical Properties of Red Blood Cells in Blood Bags but Not Hemolysis
Authors: Islamzada Emel , Matthews Kerryn , Lamoureux Erik , Duffy Simon P. , Scott Mark D. , Ma Hongshen
Published: July 2021

BACKGROUND

The biophysical properties of red blood cells (RBCs) provide potential biomarkers for the quality of donated blood. Blood unit segments provide a simple and nondestructive way to sample RBCs in clinical studies of transfusion efficacy, but it is not known whether RBCs sampled from segments accurately represent the biophysical properties of RBCs in blood bags.

STUDY DESIGN AND METHODS

RBCs were sampled from blood bags and segments every two weeks during 8 weeks of storage at 4 °C. RBC deformability was measured by deformabilitybased sorting using the microfluidic ratchet device in order to derive a rigidity score. Standard hematological parameters, including mean corpuscular volume (MCV), red cell distribution width (RDW), mean cell hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and hemolysis were measured at the same time points.

RESULTS

Deformability of RBCs stored in blood bags was retained over 4 weeks storage but a progressive loss of deformability was observed at weeks 6 and 8. This trend was mirrored in blood unit segments with a strong correlation to the blood bag data. Strong correlations were also observed between blood bag and segment for MCV, MCHC and MCH, but not for hemolysis.

CONCLUSION

RBCs sampled from blood unit segments accurately represents the biophysical properties of RBCs in blood bags, but not hemolysis. Blood unit segments provide a simple and non-destructive sample for measuring RBC biophysical properties in clinical studies.
The impact of rheotaxis and flow on the aggregation of organisms
Authors: Painter Kevin J.
Published: July 2021

Dispersed populations often need to organise into groups. Chemical attractants provide one means of directing individuals into an aggregate, but whether these structures emerge can depend on various factors, such as there being a sufficiently large population or the response to the attractant being sufficiently sensitive. In an aquatic environment, fluid flow may heavily impact on population distribution and many aquatic organisms adopt a rheotaxis response when exposed to a current, orienting and swimming according to the flow field. Consequently, flow-induced transport could be substantially different for the population members and any aggregating signal they secrete. With the aim of investigating how flows and rheotaxis responses impact on an aquatic population’s ability to form and maintain an aggregated profile, we develop and analyse a mathematical model that incorporates these factors. Through a systematic analysis into the effect of introducing rheotactic behaviour under various forms of environmental flow, we demonstrate that each of flow and rheotaxis can act beneficially or detrimentally on the ability to form and maintain a cluster. Synthesising these findings, we test a hypothesis that density-dependent rheotaxis may be optimal for group formation and maintenance, in which individuals increase their rheotactic effort as they approach an aggregated state.
Evaluation of sample preservation and storage methods for metaproteomics analysis of intestinal microbiomes
Authors: Mordant Angie , Kleiner Manuel
Published: July 2021

A critical step in studies of the intestinal microbiome using meta-omics approaches is the preservation of samples before analysis. Preservation is essential for approaches that measure gene expression, such as metaproteomics, which is used to identify and quantify proteins in microbiomes. Intestinal microbiome samples are typically stored by flash freezing and storage at −80°C, but some experimental set-ups do not allow for immediate freezing of samples. In this study, we evaluated methods to preserve fecal microbiome samples for metaproteomics analyses when flash freezing is not possible. We collected fecal samples from C57BL/6 mice and stored them for 1 and 4 weeks using the following methods: flash-freezing in liquid nitrogen, immersion in RNAlater™, immersion in 95% ethanol, immersion in a RNAlater-like buffer, and combinations of these methods. After storage we extracted protein and prepared peptides for LC-MS/MS analysis to identify and quantify peptides and proteins. All samples produced highly similar metaproteomes, except for ethanol-preserved samples that were distinct from all other samples in terms of protein identifications and protein abundance profiles. Flash-freezing and RNAlater™ (or RNAlater-like treatments) produced metaproteomes that differed only slightly, with less than 0.7% of identified proteins differing in abundance. In contrast, ethanol preservation resulted in an average of 9.5% of the identified proteins differing in abundance between ethanol and the other treatments. Our results suggest that preservation at room temperature in RNAlater™, or an RNAlater-like solution, performs as well as freezing for the preservation of intestinal microbiome samples before metaproteomics analyses.

Importance

Metaproteomics is a powerful tool to study the intestinal microbiome. By identifying and quantifying a large number of microbial, dietary, and host proteins in microbiome samples, metaproteomics provides direct evidence of the activities and functions of microbial community members. A critical step for metaproteomic workflows is preserving samples before analysis because protein profiles are susceptible to fast change in response to changes in environmental conditions (air exposure, temperature changes, etc.). This study evaluated the effects of different preservation treatments on the metaproteomes of intestinal microbiome samples.
MIXTURE of human expertise and deep learning—Developing an explainable model for predicting pathological diagnosis and survival in patients with interstitial lung disease
Authors: Uegami Wataru , Bychkov Andrey , Ozasa Mutsumi , Uehara Kazuki , Kataoka Kensuke , Johkoh Takeshi , Kondo Yasuhiro , Sakanashi Hidenori , Fukuoka Junya
Published: July 2021

Interstitial pneumonia is a heterogeneous disease with a progressive course and poor prognosis, at times even worse than those in the main cancer types. Histopathological examination is crucial for its diagnosis and estimation of prognosis. However, the evaluation strongly depends on the experience of pathologists, and the reproducibility of diagnosis is low.

Herein, we propose MIXTURE (huMan-In-the-loop eXplainable artificial intelligence Through the Use of REcurrent training), a method to develop deep learning models for extracting pathologically significant findings based on an expert pathologist’s perspective with a small annotation effort. The procedure of MIXTURE consists of three steps as follows. First, we created feature extractors for tiles from whole slide images using self-supervised learning. The similar looking tiles were clustered based on the output features and then pathologists integrated the pathologically synonymous clusters. Using the integrated clusters as labeled data, deep learning models to classify the tiles into pathological findings were created by transfer-learning the feature extractors. We developed three models for different magnifications.

Using these extracted findings, our model was able to predict the diagnosis of usual interstitial pneumonia, a finding suggestive of progressive disease, with high accuracy (AUC 0.90). This high accuracy could not be achieved without the integration of findings by pathologists. The patients predicted as UIP had significantly poorer prognosis (five-year overall survival [OS]: 55.4%) than those predicted as non-UIP (OS: 95.2%). The Cox proportional hazards model for each microscopic finding and prognosis pointed out dense fibrosis, fibroblastic foci, elastosis, and lymphocyte aggregation as independent risk factors. We suggest that MIXTURE may serve as a model approach to different diseases evaluated by medical imaging, including pathology and radiology, and be the prototype for artificial intelligence that can collaborate with humans.
Single-cell transcriptomic resolution of stem cells and their developmental trajectories in the hippocampus reveals epigenetic control of cell state perseverance
Authors: Salas-Bastos Adrián , Treppner Martin , Herman Josip S. , Koutsogiannis Dimitrios , Binder Harald , Stadler Michael B. , Grün Dominic , Vogel Tanja
Published: July 2021

Despite conceptual research on hippocampus development and the application of single-cell-resolved technologies, the nature and maturation of its diverse progenitor populations are unexplored. The chromatin modifier DOT1L balances progenitor proliferation and differentiation, and conditional loss-of-function mice featured impaired hippocampus development. We applied single-cell RNA sequencing on DOT1L-mutant mice and explored cell trajectories in the E16.5 hippocampus. We resolved in our data five distinct neural stem cell populations with the developmental repertoire to specifically generate the cornu ammonis (CA) 1 field and the dentate gyrus (DG). Within the two developing CA1- and CA3-fields, we identified two distinct maturation states and we thus propose CA1- and CA3-differentiation along the radial axis. In the developing hippocampus, DOT1L is primarily involved in the proper development of CA3 and the DG, and it serves as a state-preserving epigenetic factor that orchestrates the expression of several important transcription factors that impact neuronal differentiation and maturation.

Graphical Abstract

The developing hippocampus contains distinct and spatially separated NSC populations that differ in expression of a specific set of firstly described marker genes.

CA pyramidal neurons mature along the radial axis and pass through distinct maturation states.

DOT1L preserves the dentate granule cell lineage in the developing hippocampus and limits maturation in the CA1- and CA3-fields development.

DOT1L gates cell maturation as upstream regulator of transcription factor expression that confer instrumental roles in hippocampus development.
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

The 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

Neutrophils 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

microRNAs 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

CRISPR-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

Transcriptome-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

Centrioles 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

Gasdermin 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

Highly 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

Autophagy, 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

SARS-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.
Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity
Authors: Klemz Sabrina , Wallach Thomas , Korge Sandra , Rosing Mechthild , Klemz Roman , Maier Bert , Fiorenza Nicholas C. , Kaymak Irem , Fritzsche Anna K. , Herzog Erik D. , Stanewsky Ralf , Kramer Achim
Published: July 2021

In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and Drosophila. Genetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1 DNA occupancy and decreased transcriptional activity, which counteracts the “kamikaze” properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ-mediated inhibition of CLOCK/BMAL1.
A graph neural network model to estimate cell-wise metabolic flux using single-cell RNA-seq data
Authors: Alghamdi Norah , Chang Wennan , Dang Pengtao , Lu Xiaoyu , Wan Changlin , Gampala Silpa , Huang Zhi , Wang Jiashi , Ma Qin , Zang Yong , Fishel Melissa , Cao Sha , Zhang Chi
Published: July 2021

The metabolic heterogeneity and metabolic interplay between cells are known as significant contributors to disease treatment resistance. However, with the lack of a mature high-throughput single-cell metabolomics technology, we are yet to establish systematic understanding of the intra-tissue metabolic heterogeneity and cooperative mechanisms. To mitigate this knowledge gap, we developed a novel computational method, namely, single-cell flux estimation analysis (scFEA), to infer the cell-wise fluxome from single-cell RNA-sequencing (scRNA-seq) data. scFEA is empowered by a systematically reconstructed human metabolic map as a factor graph, a novel probabilistic model to leverage the flux balance constraints on scRNA-seq data, and a novel graph neural network–based optimization solver. The intricate information cascade from transcriptome to metabolome was captured using multilayer neural networks to capitulate the nonlinear dependency between enzymatic gene expressions and reaction rates. We experimentally validated scFEA by generating an scRNA-seq data set with matched metabolomics data on cells of perturbed oxygen and genetic conditions. Application of scFEA on this data set showed the consistency between predicted flux and the observed variation of metabolite abundance in the matched metabolomics data. We also applied scFEA on five publicly available scRNA-seq and spatial transcriptomics data sets and identified context- and cell group–specific metabolic variations. The cell-wise fluxome predicted by scFEA empowers a series of downstream analyses including identification of metabolic modules or cell groups that share common metabolic variations, sensitivity evaluation of enzymes with regards to their impact on the whole metabolic flux, and inference of cell–tissue and cell–cell metabolic communications.
Likelihood-based deconvolution of bulk gene expression data using single-cell references
Authors: Erdmann-Pham Dan D. , Fischer Jonathan , Hong Justin , Song Yun S.
Published: July 2021

Direct comparison of bulk gene expression profiles is complicated by distinct cell type mixtures in each sample that obscure whether observed differences are actually caused by changes in the expression levels themselves or are simply a result of differing cell type compositions. Single-cell technology has made it possible to measure gene expression in individual cells, achieving higher resolution at the expense of increased noise. If carefully incorporated, such single-cell data can be used to deconvolve bulk samples to yield accurate estimates of the true cell type proportions, thus enabling one to disentangle the effects of differential expression and cell type mixtures. Here, we propose a generative model and a likelihood-based inference method that uses asymptotic statistical theory and a novel optimization procedure to perform deconvolution of bulk RNA-seq data to produce accurate cell type proportion estimates. We show the effectiveness of our method, called RNA-Sieve, across a diverse array of scenarios involving real data and discuss extensions made uniquely possible by our probabilistic framework, including a demonstration of well-calibrated confidence intervals.
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

Purpose

This 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/approach

In 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.

Findings

Our analysis compares extant studies on growth drivers and shows some under-explored growth factors of start-up firms.

Practical implications

Both 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/value

This 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

Purpose

The 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/approach

Interviews were conducted among 28 multi-designers including Architects, Civil Engineers and Builders and the data was analysed thematically.

Findings

The 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 implications

For 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 implications

A 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/value

To 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.
Investigating the technical efficiency of Japanese national universities following corporatization: a two-stage data envelopment analysis approach
Authors: Thai Khanh Quoc , Noguchi Masayoshi
Published: July 2021

Purpose

The purpose of this study is to measure the technical efficiency of Japanese national universities over the period 2010–2016. In addition, the authors also sought to identify the determinants of efficiency, especially those amenable to public policy intervention.

Design/methodology/approach

First, the authors ran a global intertemporal data envelopment analysis to understand the trends in efficiency for national universities over the relevant period. Following this, the authors conducted a second-stage regression using a double-bootstrapped truncated regression model to identify the possible determinants of efficiency.

Findings

The authors found no evidence to suggest that technical efficiency of national universities systematically decreased or increased in response to either structural reform or a reduction to government grants. Moreover, the share of government grants, the size of universities and disciplines of study offered by the universities were statistically significant determinants of efficiency.

Practical implications

The study results suggest that efficacious public policy remedies might include inter alia measures to reduce the reliance on public funding, efforts to attract more foreign students, the execution of mergers among small universities and consolidation of inefficient departments.

Originality/value

This research fills an important gap in the scholarly literature with respect to Japanese national universities and identifies possible determinants to efficiency, which are amenable to remedial public policy interventions.
Enhanced optimization assisted interference mitigation with vertical beamforming in 3D MIMO-OFDMA for 5G wireless communication network
Authors: Yadav Ranjeet , Tripathi Ashutosh
Published: July 2021

Purpose

Multiple input multiple-output (MIMO) has emerged as one among the many noteworthy technologies in recent wireless applications because of its powerful ability to improve bandwidth efficiency and performance, i.e. through developing its unique spatial multiplexing capability and spatial diversity gain. For carrying out an enhanced communication in next-generation networks, the MIMO and orthogonal frequency division multiple systems were combined that facilitate the spatial multiplexing on resource blocks (RBs) based on time-frequency. This paper aims to propose a novel approach for maximizing the throughput of cell-edge users and cell-center users.

Design/methodology/approach

In this work, the specified multi-objective function is defined as the single objective function, which is solved by the introduction of a new improved algorithm as well. This optimization problem can be resolved by the fine-tuning of certain parameters such as assigned power for RB, cell-center user, cell-edge user and RB allocation. The fine-tuning of parameters is attained by a new improved Lion algorithm (LA), termed as Lion with new cub generation (LA-NCG) model. Finally, the betterment of the presented approach is validated over the existing models in terms of signal to interference plus noise ratio, throughput and so on.

Findings

On examining the outputs, the adopted LA-NCG model for 4BS was 66.67%, 66.67% and 20% superior to existing joint processing coordinated multiple point-based dual decomposition method (JC-DDM), fractional programming (FP) and LA models. In addition, the throughput of conventional JC-DDM, FP and LA models lie at a range of 10, 45 and 35, respectively, at the 100th iteration. However, the presented LA-NCG scheme accomplishes a higher throughput of 58. Similarly, the throughput of the adopted scheme observed for 8BS was 59.68%, 44.19% and 9.68% superior to existing JC-DDM, FP and LA models. Thus, the enhancement of the adopted LA-NCG model has been validated effectively from the attained outcomes.

Originality/value

This paper adopts the latest optimization algorithm called LA-NCG to establish a novel approach for maximizing the throughput of cell-edge users and cell-center users. This is the first that work uses LA-NCG-based optimization that assists in fine-tuning certain parameters such as assigned power for RB, cell-center user, cell-edge user and RB allocation.
Thermal treatment process of PET bottles filaments using industrial design of experiments
Authors: Lemos Cotrim Syntia , Machado Ageu Araújo , Leal Gislaine Camila Lapasini , Ravagnani Mauro Antonio da Silva Sá , Galdamez Edwin Vladimir Cardoza
Published: July 2021

Purpose

The purpose of this paper is to present the application of Design of Experiments techniques for the analysis of operating parameters of an industrial oven for the heat treatment process of polyethylene terephthalate (PET) bottle filaments.

Design/methodology/approach

The focus is on evaluating new ways of operating the transformation process. The main issue is to raise what are the variables interfering with the performance of the oven. The complete 2k factorial for three factors of control was used to analyze the behavior of these variables and their relationships in the specific response parameter for the process.

Findings

The results presented in this work allow the company to have greater knowledge about the operation of the equipment. The study showed possibilities of 14.8% energy reduction.

Research limitations/implications

The heat treatment activity was characterized as a critical point in the production process, and techniques with empirical approaches, based on statistical techniques, was an opportunity that the company has to improve the execution of activities without major investments for the quality of the final product. The application of statistical quality techniques showed to be very promising.

Originality/value

The fact that the study was conducted using subjective quality performance makes this work different from others presented in the literature, showing the possibility to apply Design of Experiments using main control factors based on the opinion of experienced personnel involved in the process analyzed.
The power of fears in the travel decision – covid-19 against lack of money
Authors: Gajić Tamara , Petrović Marko D. , Blešić Ivana , Radovanović Milan M. , Syromiatnikova Julia A.
Published: July 2021

Purpose

During the pandemic, two types of fear were identified that occur significantly in all groups or profiles of people. The aim of this paper is to determine which of the two types of fears exist in certain psychological groups, and which of the fears strongly influence the decision to travel.

Design/methodology/approach

The VALS 2 method and standardized questionnaire were used for the segmentation of the tourist market or for the determination of the psychographic profiles of the consumers, and three additional questions were joined to it as they were vital for the research of the type of fear and its impact on the decision for traveling. When the reliability of the questionnaire and the validity of the sample were determined, the data were further processed using a computer program package IMB AMOS SPSS 21.00, and then, based on the theoretical suppositions and hypotheses, the SEM structural model was created.

Findings

The paper indicates the existence of established types of fears in humans, when it comes to pandemics and similar crisis situations. People are most afraid of infection during travel, and lack of funds and job loss during the critical period of the pandemic. The research conducted confirms that all groups of people, who are determined by the psychological technique VALS 2, react with a certain dose of fear and make decisions under the pressure of fears.

Research limitations/implications

The research had limitations in terms of contact with people and conducting live surveys. The measures during the pandemic, which were carried out by the state, included social distance and limited movement of people.

Practical implications

The work can contribute to the community, along with similar research. The results of the research will be available, and it will be possible to see the behavior of people during crisis situations, and the impact of fears on making decisions, both travel decisions and decisions related to other areas of life.

Originality/value

The paper provides research results on a large sample of respondents, and can serve as a basis for further research in the field of tourism, psychology and similar fields. It is crucial to consider the type of fears, and the strength of the impact of these fears on the decision to travel, during crisis situations.