bluuebunny/crossref_metadata_2025_split huggingface dataset:
T-cell activation is modulated by the 3D mechanical microenvironment
Authors: Majedi Fatemeh S. , Hasani-Sadrabadi Mohammad Mahdi , Thauland Timothy J. , Li Song , Bouchard Louis-S. , Butte Manish J. 
Published: March 2019

AbstractT cells recognize mechanical forces through a variety of cellular pathways, including mechanical triggering of the T-cell receptor (TCR) and mechanical triggering of the integrin LFA-1. We show here that T cells can recognize forces arising from the rigidity of the microenvironment. We fabricated 3D hydrogels with mechanical stiffness tuned to 4 kPa and 40 kPa and specially engineered be microporous independent of stiffness. We cultured T cells and antigen presenting cells within the matrices and studied activation by flow cytometry and live imaging. We found there was an augmentation of T-cell activation in the context of mechanically stiffer 3D material as compared to the softer material. In contrast, proliferation, activation markers, and migration were all diminished in T cells cultured in the softer material. These results show that T cells can sense their mechanical environment and amplify responses in the context of mechanical stiffness.
Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress
Authors: Chakraborty Debapriya , Felzen Vanessa , Hiebel Christof , Stürner Elisabeth , Perumal Natarajan , Manicam Caroline , Sehn Elisabeth , Grus Franz , Wolfrum Uwe , Behl Christian 
Published: March 2019

AbstractOxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator ofBAG3-mediated selective macroautophagyand highly relevant for the clearance of aggregated proteins in cells was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over a key part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.
Elimination of Egfr-Overexpressing Cancer Cells by CD32 Chimeric Receptor T Cells in Combination with Cetuximab or Panitumumab
Authors: Caratelli Sara , Arriga Roberto , Sconocchia Tommaso , Ottaviani Alessio , Lanzilli Giulia , Pastore Donatella , Cenciarelli Carlo , Venditti Adriano , Del Principe Maria Ilaria , Lauro Davide , Landoni Elisa , Du Hongwei , Savoldo Barbara , Ferrone Soldano , Dotti Gianpietro , Sconocchia Giuseppe 
Published: March 2019

ABSTRACTCetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). While the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects a poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on NK cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32) to a similar extent. Here, we have compared the ability of T cells, engineered with a novel low-affinity CD32131R-chimeric receptor (CR), and those engineered with the low-affinity CD16158F–CR T cells in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. Following T cell transduction, the percentage of CD32131R-CR T cells was (74±10) significantly higher than that of CD16158F-CR T cells (46±15). Only CD32131R-CR T cells bound panitumumab. CD32131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+cells, in a reverse ADCC assayin vitro. Cross-linking of CD32131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and secretion of IFN gamma (IFNγ) and tumor necrosis factor alpha (TNFα). Neither cetuximab nor panitumumab induced Fcγ-CR T anti-tumor activity against KRAS-mutated HCT116, non-small-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. ADCC of Fcγ-CR T cells was significantly associated with the over-expression of EGFR on ECCs. In conclusion, CD32131R-CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR.Article categoryTumor Immunology and MicroenvironmentNovelty and ImpactMonoclonal antibody-redirected Fcγ-CR T cell immunotherapy represents a promising approach in the fight against cancer. Here, we expand the application of this methodology to TNBC overexpressing the EGFR utilizing a novel CD32A131R-CR in combination with anti-EGFR mAbs. Our study supports the use of CD32A131R-CR T cells combined with panitumumab or cetuximab for targeting TNBC cells overexpressing the EGFR. Our results may be utilized as a platform for the rational design of therapies targeting TNBC overexpressing EGFR.
ROS accumulation and associated cell death mediates susceptibility to Alternaria brassicae in Arabidopsis accessions
Authors: Mandal Sayanti , Rajarammohan Sivasubramanian , Kaur Jagreet 
Published: March 2019

AbstractAlternaria brassicae is a necrotrophic fungal pathogen capable of infecting most of the agriculturally important Brassica species. The mechanisms underlying invasion of A. brassicae and host responses are unknown. In the present study, we exploited the natural variation in Arabidopsis to understand the molecular and cellular mechanisms underlying resistance to A. brassicae. Using a subset of resistant (Ei-2, Ull2-3, Lz-0, and Cvi-0) and susceptible (Gre-0, Est-1, and Zdr1) accessions, we show that the susceptibility to A. brassicae is associated with higher ROS accumulation and cell death. Susceptibility to A. brassicae was reduced in the rboh (D, E and F) mutants that are incapable of producing ROS, suggesting that RBOH D, E and F may act as negative regulators of defence against this pathogen. Additionally, our data also supports the hypothesis that the Jasmonic acid (JA), Ethylene (ET) and Abscisic acid (ABA) signalling pathways positively contribute to resistance against necrotrophic pathogens. In summary, these results reveal the central role of ROS and cell death in the pathogenesis of A. brassicae and expand our understanding of plant-necrotroph interactions.
Labour sharing promotes coexistence in atrazine degrading bacterial communities
Authors: Billet Loren , Devers Marion , Rouard Nadine , Martin-Laurent Fabrice , Spor Aymé 
Published: March 2019

SUMMARYMicrobial communities exert a pivotal role in the biodegradation of xenobiotics including pesticides1. In the case of atrazine, multiple studies have shown that its degradation involved a consortia rather than a single species2,3,4,5, but little is known about how interdependency between the species composing the consortium is set up. The Black Queen Hypothesis (BQH) formalized theoretically the conditions leading to the evolution of dependency between species6: members of the community called ‘helpers’ provide publicly common goods obtained from the costly degradation of a compound, while others called ‘beneficiaries’ take advantage of the public goods, but lose access to the primary resource through adaptive degrading gene loss. Here, we test whether liquid media supplemented with the herbicide atrazine could support coexistence of bacterial species through BQH mechanisms. We observed the establishment of dependencies between species through atrazine degrading gene loss. Labour sharing between members of the consortium led to coexistence of multiple species on a single resource and improved atrazine degradation potential. Until now, pesticide degradation has not been approached from an evolutionary perspective under the BQH framework. We provide here an evolutionary explanation that might invite researchers to consider microbial consortia, rather than single isolated species, as an optimal strategy for isolation of xenobiotics degraders. Also, we anticipate that future research should focus on the bioaugmentation with stabilized and tightly structured microbial degrading consortia as an effective solution forin situbioremediation of sites polluted with recalcitrant compounds.
Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1
Authors: Tricaud Nicolas , Gautier Benoit , Van Hameren Gerben , Berthelot Jade , Gonzalez Sergio , Chrast Roman 
Published: March 2019

AbstractThe maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.
Insight into the genetic aetiology of retinal detachment by combining small clinical and large population-based datasets
Authors: Boutin Thibaud S. , Charteris David G. , Chandra Aman , Campbell Susan , Hayward Caroline , Campbell Archie ,   UK Biobank Eye & Vision Consortium, Nandakumar Priyanka , Hinds David ,   23andMe Research Team, Mitry Danny , Vitart Veronique 
Published: March 2019

AbstractIdiopathic retinal detachment is a serious common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. Genetic correlations between retinal detachment and high myopia or cataract operation were high, respectively 0.46 (SE=0.08) and 0.44 (SE=0.07), in the UK Biobank dataset and in line with known epidemiological associations. Meta-analysis of genome-wide association studies using UK Biobank retinal detachment cases (N=3977) and two cohorts, each comprising ∼1000 rhegmatogenous retinal detachment patients, uncovered 11 genome-wide significant association signals, near or withinZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1andLOXL1.Replication in the 23andMe dataset, where retinal detachment is self-reported by participants, firmly establishes association at six lociFAT3, COL22A1, TYR, BMP3, ZC3H11BandPLCE1.The former two seem to particularly impact on retinal detachment, the latter three shed light on shared aetiologies with cataract, myopia and glaucoma.Author SummaryRetinal detachments are common conditions that may lead to permanent severe sight reduction or blindness; they are a major cause of emergency eye surgery. The most common type of retinal detachment follows a break in the retina and is thought to be in part genetically determined but little is known about the contributing individual genetic risk variants. The condition prevalence increases with age and with common eye conditions such as myopia, cataract or glaucoma. We showed that the retinal detachment cases derived from self-report or hospitalisation records in the large UK Biobank dataset show very similar characteristics to samples of carefully clinically evaluated retinal detachment with break cases and therefore could be used to perform genetic analysis of the condition. Association studies require large sample of cases and by pooling Biobank and clinical cases, this study identifies 11 novel significant associations, six of which were further replicated in an independent population-based dataset (23andMe). Two of the replicated findings seem to specifically underline retinal detachment risk while three others highlight shared genetic risk with myopia, cataract and/or glaucoma, paving the way to better understanding of these conditions and of their overlap.
DNA methylation, microRNA expression profiles and their relationships with transcriptome in grass-fed and grain-fed Angus Cattle rumen tissue
Authors: Li Yaokun , Carrillo José A. , Ding Yi , He Yanghua , Zhao Chunping , Liu Jianan , Zan Linsen , Song Jiuzhou 
Published: March 2019

AbstractRumen is a critical organ for supplying nutrients for the growth and production of bovine, which might function differently under grass-fed and grain-fed regimens considering the association of gene expression, DNA methylation, and microRNA expression. The objective of this study was to explore the potential mechanism influencing rumen function of grass-fed and grain-fed animals. Methylated DNA binding domain sequencing (MBD-Seq) and microRNA-Seq were respectively utilized to detect the DNA methylation and microRNA expression in rumen tissue of grass-fed and grain-fed Angus cattle. Integration analysis revealed that the expression of the differentially expressed genes ADAMTS3 and ENPP3 was correlated with the methylation abundance of the corresponding DMRs inside these two genes, and these two genes were reported to be respectively involved in biosynthesis and regulation of glycosyltransferase activity; the differentially expressed microRNA bta-mir-122 was predicted to possibly target the differentially expressed genes OCLN and RBM47, potentially affecting the rumen function; the microRNA bta-mir-655 was exclusively detected in grain-fed group; its targets were involved in the significantly enriched insulin and TGF-beta signaling pathways, which might worked together to regulate the function of rumen, resulting in different characteristics between grass-fed and grain-fed cattle. Collectively, our results provided insights into understanding the mechanisms determining rumen function and unraveled the biological basis underlying the economic traits to improve the productivity of animals.
Reconstruction and Analysis of aKluyveromyces marxianusGenome-scale Metabolic Model
Authors: Marcišauskas Simonas , Ji Boyang , Nielsen Jens 
Published: March 2019

AbstractBackgroundKluyveromyces marxianusis a thermotolerant yeast with multiple biotechnological potentials for industrial applications, which can metabolize a broad range of carbon sources, including less conventional sugars like lactose, xylose, arabinose and inulin. These phenotypic traits are sustained even up to 45°C, what makes it a relevant candidate for industrial biotechnology applications, such as ethanol production. It is therefore of much interest to get more insight into the metabolism of this yeast. Recent studies suggested, that thermotolerance is achieved by reducing the number of growth-determining proteins or suppressing oxidative phosphorylation. Here we aimed to find related factors contributing to the thermotolerance ofK. marxianus.ResultsHere, we reported the first genome-scale metabolic model ofKluyveromyces marxianus, iSM996, using a publicly availableKluyveromyces lactismodel as template. The model was manually curated and refined to include missing species-specific metabolic capabilities. The iSM996 model includes 1913 reactions, associated with 996 genes and 1531 metabolites. It performed well to predict the carbon source utilization and growth rates under different growth conditions. Moreover, the model was coupled with transcriptomics data and used to perform simulations at various growth temperatures.ConclusionsK. marxianusiSM996 represents a well-annotated metabolic model of thermotolerant yeast, which provide new insight into theoretical metabolic profiles at different temperatures ofK. marxianus. This could accelerate the integrative analysis of multi-omics data, leading to model-driven strain design and improvement.
A Systematic Evaluation of Single Cell RNA-Seq Analysis Pipelines
Authors: Vieth Beate , Parekh Swati , Ziegenhain Christoph , Enard Wolfgang , Hellmann Ines 
Published: March 2019

AbstractThe recent rapid spread of single cell RNA sequencing (scRNA-seq) methods has created a large variety of experimental and computational pipelines for which best practices have not been established, yet. Here, we use simulations based on five scRNA-seq library protocols in combination with nine realistic differential expression (DE) setups to systematically evaluate three mapping, four imputation, seven normalisation and four differential expression testing approaches resulting in ∼ 3,000 pipelines, allowing us to also assess interactions among pipeline steps. We find that choices of normalisation and library preparation protocols have the biggest impact on scRNA-seq analyses. Specifically, we find that library preparation determines the ability to detect symmetric expression differences, while normalisation dominates pipeline performance in asymmetric DE-setups. Finally, we illustrate the importance of informed choices by showing that a good scRNA-seq pipeline can have the same impact on detecting a biological signal as quadrupling the sample size.
Power relations and the accounting system in the Archbishop’s Seminary of Siena (1666-1690)
Authors: Magliacani Michela , Di Pietra Roberto 
Published: March 2019

Purpose
Accounting can affect and determine power relations. Previous studies have emphasized how accounting has been used by “central” powers; less is known from the perspective of “local” power and its capacity to resist and protect its interests. The purpose of this paper is to investigate the relationship between the Archbishop’s Seminary of Siena (ASS) (local) and Roman ecclesiastic institutions (central). This study contributes to filling the existing gap in the literature regarding how accounting could be used as a tool for deception in local/central power relations.

Design/methodology/approach
The research methodology is based on a case study and archival research. The ASS case study was analyzed through its archive, made up for the most part of accounting books. As to the approach adopted, the authors used the Foucault framework to observe power relations in order to identify possible ways in which accounting can be employed as a factor of deception.

Findings
Power relations between the ASS and Roman ecclesiastic institutions were maintained through a system of reporting that limited the influence of the ecclesiastical power of Rome over the Seminary’s administration and control. The relationship thus runs contrary to the findings in previous studies. The accounting system was managed as a factor of deception in favor of local interests and the limitation of central ecclesiastic power.

Research limitations/implications
This study contributes to enhancing the existing literature on governmentality, proposing a different perspective in which power relations are based on the use of accounting. The Foucaldian approach demonstrates its validity, even though the power relations under consideration have the unusual feature of occurring within the context of religious institutions.

Originality/value
This study on the ASS has allowed the identification of two relevant points: the local/central dichotomy is consistent with the logic of power relations as theorized by Foucault, even in cases where it highlights the role of a local power in limiting the flow of information to a central one; and the ASS accounting system was used as a factor of deception.
Piston-electric propulsion system as reliable alternative for classic and nonconventional piston engine configurations
Authors: Dziugiel Bartosz 
Published: March 2019

PurposeThe purpose of this paper is to define reliability requirements to be imposed on electric engines to assure similar or higher value of mean time between failures (MTBF) for mixed piston-electric propulsion configurations when compared to classic and unconventional piston engine configurations.Design/methodology/approachReliability estimation was done using mathematical model of safety of light aircraft commercial operations. The model was developed on the basis of Federal Aviation Administration and National Transport Safety Board data. The analysis was conducted for numerous piston and electric configurations. It allowed comparison of selected solutions and definition of relation between electric engine MTBF and MTBF calculated for entire mixed piston-electric propulsion system.FindingsIt was found that, from reliability point of view, mixed piston-electric engine propulsion is attractive alternative for classic single- and twin-piston configuration. It would allow to at least doubling of MTBF for propulsion without increase of operational cost.Practical implicationsRationale behind exploiting electric propulsion in aviation is provided. Relation between electric engine reliability and entire propulsion reliability was identified and defined. Minimum requirements concerning MTBF value for electric engine application in aviation was assessed. Conclusions from this study can be used for definition of requirements for new aircraft and by the regulatory authorities.Originality/valueOriginality consists in use of real accident statistics included in mathematical model of safety for assessment of MTBF for various classic and novel piston and piston-electric engine configurations of light aircraft. Output from the study can be exploited by the industry.