bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury
Authors: Cross AR , de Andrea CE , María Villalba-Esparza , Landecho Acha MF , Cerundolo L , Weeratunga P , Etherington R , Denney L , Ogg G , Ho LP , Roberts ISD , Hester J , Klenerman P , Melero I , Sansom SN , Issa F 
Published: June 2021

AbstractSevere lung damage in COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways and genes present across the spectrum of histopathological damage in COVID-19 lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from areas of interest within well preserved post-mortem lung samples from three patients. Despite substantial inter-patient heterogeneity we discovered evidence for a common immune cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines including CXCL9, CXCL10 and CXCL11 which are known to promote the recruitment of CXCR3+ immune cells. The tumour necrosis factor (TNF) superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were found to be consistently upregulated in the areas with severe tissue damage. We used published spatial and single cell SARS-CoV-2 datasets to confirm our findings in the lung tissue from additional cohorts of COVID-19 patients. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.One Sentence SummarySpatial analysis identifies IFNγ response signatures as focal to severe alveolar damage in COVID-19 pneumonitis.
N-glycolylneuraminic acid serum biomarker levels are elevated in breast cancer patients at all stages of disease
Authors: Shewell Lucy K. , Day Christopher J. , Kutasovic Jamie R. , Abrahams Jodie L. , Wang Jing , Poole Jessica , Niland Colleen , Ferguson Kaltin , Saunus Jodi M. , Lakhani Sunil R. , von Itzstein Mark , Paton James C. , Paton Adrienne W. , Jennings Michael P 
Published: June 2021

AbstractBackgroundNormal human tissues do not express glycans terminating with the sialic acid N-glycolylneuraminic acid (Neu5Gc), yet Neu5Gc-containing glycans have been consistently found in human tumor tissues, cells and secretions and have been proposed as a cancer biomarker. We engineered a Neu5Gc-specific lectin called SubB2M, and previously reported elevated Neu5Gc biomarkers in serum from ovarian cancer patients using a Surface Plasmon Resonance (SPR)-based assay. Here we report an optimized SubB2M SPR-based assay and use this new assay to analyse sera from breast cancer patients for Neu5Gc levels.MethodsTo enhance specificity of our SPR-based assay, we included a non-sialic acid binding version of SubB, SubBA12, to control for any non-specific binding to SubB2M, which improved discrimination of cancer-free controls from early-stage ovarian cancer. We analysed 96 serum samples from breast cancer patients at all stages of disease compared to 22 cancer-free controls using our optimized SubB2M-A12-SPR assay. We also analysed a collection of serum samples collected at 6 monthly intervals from breast cancer patients at high risk for disease recurrence or spread.ResultsAnalysis of sera from breast cancer cases revealed significantly elevated levels of Neu5Gc biomarkers at all stages of breast cancer. We show that Neu5Gc serum biomarker levels can discriminate breast cancer patients from cancer-free individuals with 98.96% sensitivity and 100% specificity. Analysis of serum collected prospectively, post-diagnosis, from breast cancer patients at high risk for disease recurrence showed a trend for a decrease in Neu5Gc levels immediately following treatment for those in remission.ConclusionsNeu5Gc serum biomarkers are a promising new tool for early detection and disease monitoring for breast cancer that may complement current imaging- and biopsy-based approaches.
Genetics of tibia bone properties of crossbred commercial laying hens in different housing systems
Authors: Johnsson Martin , Wall Helena , Pinto Fernando A Lopes , Fleming Robert H. , McCormack Heather A. , Benavides-Reyes Cristina , Dominguez-Gasca Nazaret , Sanchez-Rodriguez Estefania , Dunn Ian C. , Rodriguez-Navarro Alejandro B. , Kindmark Andreas , de Koning Dirk-Jan 
Published: June 2021

AbstractOsteoporosis and bone fractures are a severe problem for the welfare of laying hens, with genetics and environment, such as housing system, each making substantial contributions to bone strength. In this work, we performed genetic analyses of bone strength, bone mineral density and bone composition, as well as body weight, in 860 commercial crossbred laying hens from two different companies, kept in either furnished cages or floor pens. We compared bone traits between housing systems and crossbreds, and performed a genome-wide association study of bone properties and body weight.As expected, the two housing systems produced a large difference in bone strength, with layers housed in floor pens having stronger bones. These differences were accompanied by differences in bone geometry, mineralisation and chemical composition. Genome-scans either combining or independently analysing the two housing systems revealed no genome-wide significant loci for bone breaking strength. We detected three loci for body weight that were shared between the housing systems on chromosomes 4, 6 and 27 (either genome-wide significant or suggestive when the housing systems were analysed individually) and these coincide with associations for bone length.In summary, we found substantial differences in bone strength, content and composition between hens kept in floor pens and furnished cages that could be attributed to greater physical activity in pen housing. We found little evidence for large-effect loci for bone strength in commercial crossbred hens, consistent with a highly polygenic architecture for bone strength in the production environment. The lack of consistent genetic associations between housing systems in combination with the differences in bone phenotypes support gene-by-environment interactions with housing system.
Apoptotic Find-me Signals are an Essential Driver of Stem Cell Conversion To The Cardiac Lineage
Authors: Fort Loic , Gama Vivian , Macara Ian G. 
Published: June 2021

AbstractPluripotent stem cells can be driven by manipulation of Wnt signaling through a series of states similar to those that occur during early embryonic development, transitioning from an epithelial phenotype into the cardiogenic mesoderm lineage and ultimately into functional cardiomyocytes 1–4. Strikingly, we observed that induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) undergo widespread apoptosis upon Wnt activation, followed by a synchronous epithelial-mesenchymal transition (EMT). The EMT requires induction of transcription factors SNAI1/SNAI2 downstream of MESP1 expression, and double knock-out of SNAI1/2, or loss of MESP1 in iPSCs blocks EMT and prevents cardiac differentiation. Remarkably, blockade of early apoptosis chemically or by ablation of pro-apoptotic genes also completely prevents the EMT, suppressing even the earliest events in mesoderm conversion, including EOMES, TBX6, and MESP1 induction. Conditioned medium from WNT-activated WT iPSCs overcomes the block to EMT by cells incapable of apoptosis (Apop-), suggesting the involvement of soluble factors from apoptotic cells in mesoderm conversion. Treatment with a purinergic P2Y receptor inhibitor or addition of apyrase demonstrated a requirement for nucleotide triphosphate signaling. ATP was sufficient to induce a partial EMT in Apop- cells treated with WNT activator. We conclude that nucleotides, in addition to acting as chemo-attractants for clearance of apoptotic cells can, unexpectedly, function as essential paracrine signals in mesoderm specification.
CDK9 and PP2A regulate RNA polymerase II transcription termination and coupled RNA maturation
Authors: Tellier Michael , Zaborowska Justyna , Neve Jonathan , Nojima Takayuki , Hester Svenja , Fournier Marjorie , Furger Andre , Murphy Shona 
Published: June 2021

AbstractCDK9 is a kinase critical for the productive transcription of protein-coding genes by RNA polymerase II (pol II). As part of P-TEFb, CDK9 phosphorylates the carboxyl-terminal domain (CTD) of pol II and elongation factors, which allows pol II to elongate past the early elongation checkpoint (EEC) encountered soon after initiation. We show that, in addition to halting pol II at the EEC, loss of CDK9 activity causes premature termination of transcription across the last exon, loss of polyadenylation factors from chromatin, and loss of polyadenylation of nascent transcripts. Inhibition of the phosphatase PP2A abrogates the premature termination and loss of polyadenylation caused by CDK9 inhibition, indicating that this kinase/phosphatase pair regulates transcription elongation and RNA processing at the end of protein-coding genes. We also confirm the splicing factor SF3B1 as a target of CDK9 and show that SF3B1 in complex with polyadenylation factors is lost from chromatin after CDK9 inhibition. These results emphasize the important roles that CDK9 plays in coupling transcription elongation and termination to RNA maturation downstream of the EEC.
Cell adhesions link subcellular actomyosin dynamics to tissue scale force production during vertebrate convergent extension
Authors: Huebner Robert J. , Weng Shinuo , Lee Chanjae , Sarıkaya Sena , Papoulas Ophelia , Cox Rachael M. , Marcotte Edward M. , Wallingford John B. 
Published: June 2021

SummaryAxis extension is a fundamental biological process that shapes multicellular organisms. The design of an animal’s body plan is encoded in the genome and execution of this program is a multiscale mechanical progression involving the coordinated movement of proteins, cells, and whole tissues. Thus, a key challenge to understanding axis extension is connecting events that occur across these various length scales. Here, we use approaches from proteomics, cell biology, and tissue biomechanics to describe how a poorly characterized cell adhesion effector, the Armadillo Repeat protein deleted in Velo-Cardio-Facial syndrome (Arvcf) catenin, controls vertebrate head-to-tail axis extension. We find that Arvcf catenin is required for axis extension within the intact organism but is not required for extension of isolated tissues. We then show that the organism scale phenotype is caused by a modest defect in force production at the tissue scale that becomes apparent when the tissue is challenged by external resistance. Finally, we show that the tissue scale force defect results from dampening of the pulsatile recruitment of cell adhesion and cytoskeletal proteins to cell membranes. These results not only provide a comprehensive understanding of Arvcf function during an essential biological process, but also provide insight into how a modest cellular scale defect in cell adhesion results in an organism scale failure of development.
Evaluating the cost of pharmaceutical purification for a long-duration space exploration medical foundry
Authors: McNulty Matthew J. , Berliner Aaron J. , Negulescu Patrick G. , McKee Liber , Hart Olivia , Yates Kevin , Arkin Adam P. , Nandi Somen , McDonald Karen A. 
Published: June 2021

AbstractThere are medical treatment vulnerabilities in longer-duration space missions present in the current International Space Station crew health care system with risks, arising from spaceflight-accelerated pharmaceutical degradation and resupply lag times. Bioregenerative life support systems may be a way to close this risk gap by leveragingin situresource utilization (ISRU) to perform pharmaceutical synthesis and purification. Recent literature has begun to consider biological ISRU using microbes and plants as the basis for pharmaceutical life support technologies. However, there has not yet been a rigorous analysis of the processing and quality systems required to implement biologically-produced pharmaceuticals for human medical treatment. In this work, we use the equivalent system mass (ESM) metric to evaluate pharmaceutical purification processing strategies for longer-duration space exploration missions. Monoclonal antibodies, representing a diverse therapeutic platform capable of treating multiple space-relevant disease states, were selected as the target products for this analysis. We investigate the ESM resource costs (mass, volume, power, cooling, and crew time) of an affinity-based capture step for monoclonal antibody purification as a test case within a manned Mars mission architecture. We compare six technologies (three biotic capture methods and three abiotic capture methods), optimize scheduling to minimize ESM for each technology, and perform scenario analysis to consider a range of input stream compositions and pharmaceutical demand. We also compare the base case ESM to scenarios of alternative mission configuration, equipment models, and technology reusability. Throughout the analyses, we identify key areas for development of pharmaceutical life support technology and improvement of the ESM framework for assessment of bioregenerative life support technologies.
Targeting activated macrophages intracellular milieu to augment anti-inflammatory drug potency
Authors: Gouveia Virgínia M. , Rizzello Loris , Vidal Bruno , Nunes Claudia , Poma Alessandro , Lopez-Vasquez Ciro , Scarpa Edoardo , Brandner Sebastian , Oliveira António , Fonseca João E. , Reis Salette , Battaglia Giuseppe 
Published: June 2021

AbstractWe present pH-responsive phosphorylcholine polymersomes ability to target activated macrophages via scavenger receptors, enter them via endocytosis, and escape from early endosomes enabling the intra-cellular drug delivery. Using an arthritis experimental model and the gold standard disease modifying anti-rheumatic drug, methotrexate, we prove that polymersomes augments therapeutic efficacy, while minimizing the off-target effect. First, we demonstrate the selective accumulation of polymersomes within the inflamed synovial tissues and cells, including macrophages. Second, we show the beneficial therapeutic effect of methotrexate loaded polymersomes in preventing both joint inflammation and further damage. Hence, we prove the therapeutic potential of polymersomes in enhancing the complete prevention of arthritis progression, which makes it a promising nanotherapy for arthritis treatment as well as other inflammatory disorders.TeaserWe show that the effective targeting and delivery of drugs to the main inflammation actors, the macrophages, enhances arthritis therapy.
ROPIUS0: A deep learning-based protocol for protein structure prediction and model selection and its performance in CASP14
Authors: Margelevičius Mindaugas 
Published: June 2021

AbstractProtein structure prediction has recently been revolutionized when AlphaFold2 [1] predicted protein structures with near-experimental accuracy in the latest CASP14 season of critical assessment of methods of protein structure prediction (CASP). Among numerous implications, this breakthrough has led to a rapidly growing number of high-quality structural models [2]. We present a protocol ROPIUS0 for protein structure prediction and model selection and discuss its benefits in the new era of structure prediction. At the core of the ROPIUS0 protocol is the deep learning module developed for the selection of protein structural models. It is shown that the direct use of predicted inter-residue distances may be sufficient to discriminate between correct and incorrect protein folds, considering only a small fraction of predicted distances. We extensively tested the protocol: In the latest CASP14 prediction season, a ROPIUS0 variant based on model selection ranked 13th in the category of tertiary structure prediction. Its performance is on par with top-performing automated prediction servers when tested on the CASP13 dataset, and it performs similarly on a CAMEO dataset. The results suggest ways to improve searching for structurally similar and homologous proteins without considerably increasing speed. Our new open-source threading tool based on comparing a subset of inter-residue distances demonstrates the effectiveness and application of the deep learning module of the ROPIUS0 protocol.
Does the fundamental indexation portfolio perform better? An Indian investigation
Authors: Kumar Santosh , Tiwari Ranjit 
Published: June 2021

PurposeThis study aims to compare the fundamental indexation (FI) portfoliovis-à-visthe cap-weighted index (CWI). It also explored the return-generating attributes of the FI portfolios.Design/methodology/approachThis study extracted relevant data from the Centre for Monitoring Indian Economy’s Prowess database from March 1996 to March 2017 from a sample of National Stock Exchange (NSE) 500 companies. The FI portfolios were constructed with First_50 and Next_50 stocks using the latest and five years of trailing average aggregations. Further, the regression technique was used to identify the return-generating attributes of FI portfolios.FindingsIt was found that the FI portfolios based on First_50 and Next_50 stocks outperformed the CWI (i.e. NSE_First_50 and NSE_Next_50) in the Indian capital market, and between the two, the FI portfolios based on Next_50 stocks were superior to the FI portfolios based on First_50 stocks. The cross-sectional superiority of FI portfolios is obvious if they are sorted according to four fundamentals, namely, total income, sales, operating cash flows and profit before depreciation interest tax and amortisation. The return-generating process of FI portfolios is well-explained by market premium followed by value premium and investment premium.Practical implicationsThis study may enable portfolio managers and investors to measure FI portfolios’ superiority in the Indian capital market and identify the return-generating attributes of FI portfolios so that the loadings can be switched amongst different priced factors for higher yield. Further, this study extends the FI literature, providing evidence from one of the world’s fastest-growing economies.Originality/valueTo the best of the knowledge, this is amongst the first few studies to explore the performance of FI portfoliosvis-à-visCWIs in India, and to use Fama and French (2015) asset pricing models to understand the return-generating attributes of FI portfolios. It is also novel in the sense that it considers the FI portfolios for a longer duration, predating 1997 and coinciding with the inception of CWIs, namely, NSE_First_50 (inception: 1995) and NSE_Next_50 (inception: 1996), reducing the apprehensions of data-snooping biases.
Non-vegan consumers buying vegan food: the moderating role of conformity
Authors: Martinelli Elisa , De Canio Francesca 
Published: June 2021

PurposeNon-vegan consumers are increasingly shifting their food habits and lifestyles towards vegan food. Thus, in addition to traditional, though poorly studied, ethical motives (i.e. animal, environmental, spiritual, health concerns), other factors may influence the purchase of vegan food. Within this context, the paper investigates the moderating role of conformity in enticing consumers to buy vegan food products, together with the main traditional consumers' concerns influencing their attitude towards vegan food. The study also considers the role of the willingness to pay a premium price as a direct driver of the intention to buy vegan.Design/methodology/approachAn online survey was performed in Italy on a number of major Facebook thematic pages. A dataset based on 250 Italian non-vegans was used to implement a structural equation model.FindingsFindings show that spiritual and animal concerns are direct drivers of non-vegan buyers' attitude towards vegan food. Attitude, then, strongly influences the intention to buy vegan foods. Though less impactful, non-vegans' willingness to pay a premium price is a motive positively influencing their intention to buy vegan food. The positive and significant moderating effect exerted by conformity on the attitude-intention path confirms the amplifying role played by trends and lifestyles on consumers' food buying choices.Originality/valueThis study contributes to the food and consumer behaviour literature in being the first exploring the moderating role played by conformity in inducing non-vegan consumers to buy vegan food. Environmental, animal, spiritual and health concerns are investigated from the non-vegan perspective.
A repurchase intention model of Indonesian herbal tea consumers: integrating perceived enjoyment and health belief
Authors: Astrini Nidya , Bakti I Gede Mahatma Yuda , Rakhmawati Tri , Sumaedi Sik , Yarmen Medi 
Published: June 2021

PurposeThis research seeks to develop a model to predict repurchase intention based on the modified theory of planned behavior (TPB).Design/methodology/approachThis research is quantitative study involving 150 respondents from five major cities in Indonesia. Data were collected using a questionnaire. Data analysis used confirmatory factor analysis–structural equation modeling (CFA–SEM).FindingsThe research instrument and the proposed model were fit. However, health belief was not proven to have a significant impact on attitude. The perceived behavioral control (PBC) also did not significantly affect repurchase intention.Research limitations/implicationsFuture research that utilizes TPB should incorporate emotional belief as part of the attitude variable.Practical implicationsIn the designing and marketing process, managers of herbal teas companies should consider the health benefits of their products and the feeling of joy it might incite.Originality/valueThe TPB was initially constructed from three variables: subjective norm, attitude and perceived behavioral control (PBC). Unlike previous research, this study considered cognitive and emotional beliefs as the factors that affected attitude.
Investigating consumers' behavioral intentions toward suboptimal produce: an extended theory of planned behavior – a cross-cultural study
Authors: Adel Ahmed M. , Dai Xin , Roshdy Rana S. 
Published: June 2021

PurposeThis study extends the theory of planned behavior (TPB) through the inclusion of motivating variables for suboptimal produce preference (i.e. environmental concern, food waste awareness, and familiarity), and demotivating variables (i.e. health consciousness and risk perception) to investigate behavioral intentions toward suboptimal produce.Design/methodology/approachA quantitative research methodology using the online survey technique is employed to collect cross-cultural data from respondents from China (n = 430) and Egypt (n = 441). Structural equation modeling (SEM) via SmartPLS v.3.2.9 is used to analyze data.FindingsThe proposed extended TPB model could enhance predicting consumers' behavioral intentions toward suboptimal produce except for “environmental concern” since it has been found that environmental concern has a nonsignificant effect on consumers' attitudes and behavioral intentions toward suboptimal produce in both countries. The results also reveal that the proposed extended TPB constructs could predict 79.9% of intentions to purchase suboptimal produce and 65.3% of the variance in intentions to recommend such produce for others.Originality/valueThis study is one of the few attempts that investigates the suboptimal food consumption based on a theoretical lens by extending the TPB model. Previous studies on suboptimal food do not pay attention to the demotivating variables such as health consciousness and risk perception, and thus, this thesis represents the first effort that sheds light on such variables. Moreover, prior investigation on such issues in Egypt and China as a cross-cultural research has not existed.