bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of STING due to COPI-deficiency
Authors: Steiner Annemarie , Schaale Katja Hrovat , Prigione Ignazia , De Nardo Dominic , Dagley Laura F. , Yu Chien-Hsiung , Laohamonthonkul Pawat , Harapas Cassandra R. , Gantier Michael P. , Gattorno Marco , Volpi Stefano , Davidson Sophia , Masters Seth L. 
Published: July 2020

AbstractCOPA syndrome is caused by loss-of-function mutations in the COP-α subunit of coatomer protein complex I (COPI), which participates in retrograde vesicular trafficking of proteins from the Golgi to the endoplasmic reticulum (ER). Disease manifests early in life with arthritis, lung pathology, kidney dysfunction and systemic inflammation associated with NF-κB activation and type I interferon (IFNαβ) production. Here, we generatedin vitromodels for COPA syndrome and interrogated inflammatory signalling pathways via a range of biochemical and molecular biological techniques. Results were confirmed with cell lines in which mutant COPA was overexpressed and with COPA syndrome patient PBMCs. We identified Stimulator of Interferon Genes (STING), as a driver of inflammation in COPA syndrome. Furthermore, we found that genetic deletion of COPG1, another COPI subunit protein, induced NF-κB and type I IFN pathways similar to COPA-deficiency. Finally, we demonstrate thatin vitro, inflammation due to COPA syndrome mutations was ameliorated by treatment with the small molecule STING inhibitor H-151. Therefore, inflammation induced by deletion of COPI subunits in general suggests a link between retrograde trafficking and STING regulation, and this innate immune sensor represents a novel therapeutic target in COPA syndrome.
Exceptional aggregation propensity of amino acids in polyglutamine amino-acid-homopolymer
Authors: Mishra Rahul , Thakur Ashwani K. 
Published: July 2020

AbstractSimilar aggregation and β-sheet propensity of amino acids in globular proteins and amyloids, suggests comparable principles of their formation. Here we show that during the process of aggregation into amyloid-like fibers, these rules are not the same in an amino-acid-homopolymer (AAHP) polyglutamine (PolyGln). An aggregation kinetic analysis on nine-point mutants of a forty-six long PolyGln peptide was carried in physiological conditions. At the dynamic equilibrium state of aggregation, critical-concentration derived free-energy differences, signifying aggregation propensity of incorporated amino acids were obtained. None of the obtained propensities correlated with existing conventional aggregation and β-sheet propensities of the amino acids in proteins and amyloids. Further, the differential aggregation behavior of all the peptides only correlated with van der Waals volume of the incorporated amino acid and not with any other physicochemical characteristic of amino acids. The new rules obtained from PolyGln AAHP provide an opportunity to explore physiological relevance of a mutation within AAHP in human proteome. Additionally, this study opens up new avenues for protein model design exploring folding and aggregation behavior of other amino-acid-homopolymer (AAHP) existing in the human proteome.SignificanceMutational analysis within PolyGln sequences adds to the knowledge of unique aggregation propensities of amino acids within PolyGln AAHP. This study highlights the importance of van der Waals volume in dictating stability-instability of an aggregation fold and in turn aggregation kinetics and thermodynamic stability of aggregates. The analysis signifies the role of Gln-Gln interlocking system within PolyGln folding motif and extent of disruption caused by van der Waals volume of an amino acid. The results can be taken as a starting point to evaluate the possible impact of amino acid insertions in PolyGln stretches of other proteins. It also opens opportunities to study the structural and functional relationship of other AAHPS for their unique folding and aggregation behavior. Learning outcome can be utilized as a bottom–up approach to design amyloid biomaterial with different strengths for biomedical applications.
Thalamic inputs determine functionally distinct gamma bands in mouse primary visual cortex
Authors: Meneghetti Nicolò , Cerri Chiara , Tantillo Elena , Vannini Eleonora , Caleo Matteo , Mazzoni Alberto 
Published: July 2020

AbstractGamma band is known to be involved in the encoding of visual features in the primary visual cortex (V1). Recent results in rodents V1 highlighted the presence, within a broad gamma band (BB) increasing with contrast, of a narrow gamma band (NB) peaking at ∼60 Hz suppressed by contrast and enhanced by luminance. However, the processing of visual information by the two channels still lacks a proper characterization. Here, by combining experimental analysis and modeling, we prove that the two bands are sensitive to specific thalamic inputs associated with complementary contrast ranges. We recorded local field potentials from V1 of awake mice during the presentation of gratings and observed that NB power progressively decreased from low to intermediate levels of contrast. Conversely, BB power was insensitive to low levels of contrast but it progressively increased going from intermediate to high levels of contrast. Moreover, BB response was stronger immediately after contrast reversal, while the opposite held for NB. All the aforementioned dynamics were accurately reproduced by a recurrent excitatory-inhibitory leaky integrate-and-fire network, mimicking layer IV of mouse V1, provided that the sustained and periodic component of the thalamic input were modulated over complementary contrast ranges. These results shed new light on the origin and function of the two V1 gamma bands. In addition, here we propose a simple and effective model of response to visual contrast that might help in reconstructing network dysfunction underlying pathological alterations of visual information processing.Significance StatementGamma band is a ubiquitous hallmark of cortical processing of sensory stimuli. Experimental evidence shows that in the mouse visual cortex two types of gamma activity are differentially modulated by contrast: a narrow band (NB), that seems to be rodent specific, and a standard broad band (BB), observed also in other animal models.We found that narrow band correlates and broad band anticorrelates with visual contrast in two complementary contrast ranges (low and high respectively). Moreover, BB displayed an earlier response than NB. A thalamocortical spiking neuron network model reproduced the aforementioned results, suggesting they might be due to the presence of two complementary but distinct components of the thalamic input into visual cortical circuitry.
Pili allow dominant marine cyanobacteria to avoid sinking and evade predation
Authors: del Mar Aguilo-Ferretjans Maria , Bosch Rafael , Puxty Richard J. , Latva Mira , Zadjelovic Vinko , Chhun Audam , Sousoni Despoina , Polin Marco , Scanlan David J. , Christie-Oleza Joseph A. 
Published: July 2020

ABSTRACTHow oligotrophic marine cyanobacteria position themselves in the water column is currently unknown. The current paradigm is that these organisms avoid sinking due to their reduced size and passive drift within currents. Here, we show that one in four picocyanobacteria encode a type IV pilus which allows these organisms to increase drag and remain suspended at optimal positions in the water column, as well as evade predation by grazers. The evolution of this sophisticated floatation mechanism in these purely planktonic streamlined microorganisms has profound implications for our current understanding of microbial distribution in the oceans, predator-prey interactions and, ultimately, will influence future models of carbon flux dynamics in the oceans.
A viral guide RNA delivery system for CRISPR-based transcriptional activation and heritable targeted DNA demethylation inArabidopsis thaliana
Authors: Ghoshal Basudev , Vong Brandon , Picard Colette L. , Suhua Feng , Tam Janet May , Jacobsen Steven E. 
Published: July 2020

AbstractPlant RNA viruses are used as delivery vectors for their high level of accumulation and efficient spread during virus multiplication and movement. Utilizing this concept, several viral-based guide RNA delivery platforms for CRISPR-Cas9 genome editing have been developed. The CRISPR-Cas9 system has also been adapted for epigenome editing. While systems have been developed for CRISPR-Cas9 based gene activation or site-specific DNA demethylation, viral delivery of guide RNAs remains to be developed for these purposes. To address this gap we have developed a tobacco rattle virus (TRV)-based single guide RNA delivery system for epigenome editing inArabidopsis thaliana. Because tRNA-like sequences have been shown to facilitate the cell-to-cell movement of RNAs in plants, we used the tRNA-guide RNA expression system to express guide RNAs from the viral genome to promote heritable epigenome editing. We demonstrate that the tRNA-gRNA system with TRV can be used for both transcriptional activation and targeted DNA demethylation in Arabidopsis. We achieved up to ~8% heritability of the induced demethylation phenotype in the progeny of virus inoculated plants. We did not detect the virus in the next generation, indicating effective clearance of the virus from plant tissues. Thus, TRV delivery, combined with a specific tRNA-gRNA architecture, provides for fast and effective epigenome editing.Author summaryThe discovery of CRISPR-CAS9 and its non-catalytic variants have provided enormous capacity for crop improvement and basic research by modifying the genome and the epigenome. The standard methods for delivering genome and epigenome editing reagents to plants consist of generating stable transgenic lines through tissue culture processes, which have several drawbacks including the need for plant regeneration and crossing. To overcome some of these challenges, plant virus-based platforms are being developed for genome editing. Although viruses have a limited cargo capacity, limiting the use of viruses to encode entire editing systems, guide RNAs have been successfully delivered to transgenic CAS9 expressing plants for genome editing. However, the use of viruses for CRISPR-based epigenome editing and transcriptional activation have not yet been explored. In this study we show that viral delivery of guide RNAs using a modified tobacco rattle virus can be used for transcriptional activation and heritable epigenome editing. This study advances the use of plant RNA viruses as delivery agents for epigenome editing.
Screening and testing for a suitable untransfected cell line for SARS-CoV-2 studies
Authors: Pommerenke Claudia , Rand Ulfert , Uphoff Cord C. , Nagel Stefan , Zaborski Margarete , Hauer Vivian , Kaufmann Maren , Meyer Corinna , Denkmann Sabine A. , Riese Peggy , Eschke Kathrin , Kim Yeonsu , Safranko Zeljka Macak , Kurolt Ivan-Christian , Markotic Alemka , Brunotte Linda , Ludwig Stephan , Cicin-Sain Luka , Steenpaß Laura 
Published: July 2020

AbstractAt present, the novel pandemic coronavirus SARS-CoV-2 is a major global threat to human health and hence demands united research activities at different levels. Finding appropriate cell systems for drug screening and testing molecular interactions of the virus with the host cell is mandatory for drug development and understanding the mechanisms of viral entry and replication. For this, we selected human cell lines represented in the Cancer Cell Line Encyclopedia (CCLE) based on RNA-seq data determined transcript levels of ACE2 and TMPRSS2, two membrane proteins that have been identified to aid SARS-CoV-2 entry into the host cell. mRNA and protein expression of these host factors were verified via RQ-PCR and western blot. We then tested permissiveness of these cell lines towards SARS-CoV-2 infection, cytopathic effect, and viral replication finding limited correlation between receptor expression and infectability. One of the candidate cancer cell lines, the human colon cancer cell line CL-14, tested positive for SARS-CoV-2 infection. Our data argue that SARS-CoV-2 in vitro infection models need careful selection and validation since ACE2/TMPRSS2 receptor expression on its own does not guarantee permissiveness to the virus.Author summaryIn the midst of the pandemic outbreak of corona-virus SARS-CoV-2 therapeutics for disease treatment are still to be tested and the virus-host-interactions are to be elucidated. Drug testing and viral studies are commonly conducted with genetically manipulated cells. In order to find a cell model system without genetic modification we screened human cell lines for two proteins known to facilitate entry of SARS-CoV-2. We confirmed and quantified permissiveness of current cell line infection models, but dismissed a number of receptor-positive cell lines that did not support viral replication. Importantly, ACE2/TMPRSS2 co-expression seems to be necessary for viral entry but is not sufficient to predict permissiveness of various cancer cell lines. Moreover, the expression of specific splice variants and the absence of missense mutations of the host factors might hint on successful infection and virus replication of the cell lines.
Gradual Compaction of the Central Spindle Decreases its Dynamicity as Revealed in PRC1 and EB1 Gene-Edited Human Cells
Authors: Asthana Jayant , Cade Nicholas I. , Normanno Davide , Lim Wei Ming , Surrey Thomas 
Published: July 2020

ABSTRACTDuring mitosis the spindle undergoes morphological and dynamic changes. It reorganizes at the onset of anaphase when the antiparallel bundler PRC1 accumulates and recruits central spindle proteins to the midzone. Little is known about how the dynamic properties of the central spindle change during its morphological changes in human cells. Using gene editing, we generated human cells that express from their endogenous locus fluorescent PRC1 and EB1 to quantify their native spindle distribution and binding/unbinding turnover. EB1 plus end tracking revealed a general slowdown of microtubule growth, while PRC1, similar to its yeast orthologue Ase1, binds increasingly strongly to compacting antiparallel microtubule overlaps. KIF4A and CLASP1 bind more dynamically to the central spindle, but also show slowing down turnover. These results show that the central spindle gradually becomes more stable during mitosis, in agreement with a recent ‘bundling, sliding and compaction’ model of antiparallel midzone bundle formation in the central spindle during late mitosis.
Benchmarking Orthogroup Inference Accuracy: Revisiting Orthobench
Authors: Emms D.M. , Kelly S. 
Published: July 2020

AbstractOrthobench is the standard benchmark to assess the accuracy of orthogroup inference methods. It contains 70 expert curated reference orthogroups (RefOGs) that span the Bilateria and cover a range of different challenges for orthogroup inference. Here we leveraged improvements in tree inference algorithms and computational resources to re-interrogate these RefOGs and carry out an extensive phylogenetic delineation of their composition. This phylogenetic revision altered the membership of 31 of the 70 RefOGs, with 24 subject to extensive revision and a further 7 that required minor changes. We further used these revised and updated RefOGs to provide an assessment of the orthogroup inference accuracy of widely used orthogroup inference methods. Finally, we provide an open-source benchmarking suite to support the future development and use of the Orthobench benchmark.Significance statementOrthogroup inference forms the foundation of comparative genomic analysis. Benchmarks to evaluate performance are essential to enable these methods to be compared and stimulate further method development. Here we present an update to the orthobench benchmark database and provide a comparative performance evaluation of commonly used orthogroup inference methods.
Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer
Authors: Madsen Ralitsa R. , Rueda Oscar M. , Robin Xavier , Caldas Carlos , Semple Robert K. , Vanhaesebroeck Bart 
Published: July 2020

ABSTRACTA PI3Kα-selective inhibitor has recently been approved for use in breast tumours harbouring mutations inPIK3CA, the gene encoding PI3Kα. Preclinical studies have suggested that the PI3K/AKT/mTORC1 signalling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. No direct evidence for such a correlation has been demonstrated to date in human tumours. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumour samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K signalling scores and stemness scores. Unexpectedly, stratification of tumours according toPIK3CAgenotype revealed a “biphasic” relationship of mutantPIK3CAallele dosage with these scores. Relative to tumour samples withoutPIK3CAmutations, the presence of a single copy of a hotspotPIK3CAvariant was associated with lower PI3K signalling and stemness scores, whereas tumours with multiple copies ofPIK3CAhotspot mutations showed higher PI3K signalling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygousPIK3CAH1047Rexpression. Collectively, our analysis provides evidence for a signalling strength-dependent PI3K-stemness relationship in human breast cancer, which may aid future patient stratification for PI3K-targeted therapies.
Excitation-contraction coupling and its relation to synaptic dysfunction in Drosophila
Authors: Ormerod Kiel G. , Scibelli Anthony E. , Littleton J. Troy 
Published: July 2020

AbstractThe Drosophila neuromuscular system is widely used to characterize synaptic development and function. However, little is known about how specific synaptic deficits alter neuromuscular transduction and muscle contractility that ultimately dictate behavioural output. Here we develop a system for detailed characterization of excitation-contraction coupling at Drosophila larval NMJs and demonstrate how specific synaptic and neuronal manipulations disrupt muscle contractility. Muscle contraction force increases with motoneuron stimulation frequency and duration, showing considerable plasticity between 5-40 Hz, while saturating above 50 Hz. Temperature is negatively correlated with muscle performance and enhanced at lower temperatures. A screen for modulators of muscle contractility led to the identification and characterization of the molecular and cellular pathway by which a specific FMRFa peptide, TPAEDFMRFa, increases muscle performance. These findings indicateDrosophilaNMJs provide a robust system to relate synaptic dysfunction to alterations in excitation-contraction coupling.
Crash simulation of fuselage section in the rebound process and the secondary-impact process
Authors: Jin Zibo , Li Daochun , Xiang Jinwu 
Published: July 2020

Purpose
This paper aims to investigate the rebound process and the secondary-impact process of the fuselage section that occurs in the actual crash events.

Design/methodology/approach
A full-scale three-dimensional finite element model of the fuselage section was developed to carry out the dynamic simulations. The rebound process was simulated by removing the impact surface at a certain point, while the secondary-impact process was simulated by striking the impact surface against the fuselage bottom after the first impact.

Findings
For the rebound process, the fuselage structure restores deformation due to the springback of the fuselage bottom, and it results in structural vibration of the fuselage section. For the secondary-impact process, the fuselage deformation is similar with that of the single impact process, indicating that the intermittent impact loading has little influence on the overall deformation of the fuselage section. The strut failure is the determining factor to the acceleration responses for both the rebound process and the secondary-impact process.

Practical implications
The rebound process and the secondary-impact process, which is difficult to study by experiments, was investigated by finite element simulations. The structure deformations and acceleration responses were obtained, and they can provide guidance for the crashworthy design of fuselage structures.

Originality/value
This research first investigated the rebound process and the secondary-impact process of the fuselage section. The absence of the ground load and the secondary-impact was simulated by controlling the impact surface, which is a new simulating method and has not been used in the previous research.
Deregulation, technical efficiency and production risk in rice farming: evidence from Zhejiang Province, China
Authors: Wang Juanli , Etienne Xiaoli , Ma Yongxi 
Published: July 2020

PurposeThe purpose of this paper is to evaluate the technical efficiency and production risk in China's rice production and examine the effect of factor market reform on these two agricultural performance metrics.Design/methodology/approachUsing an unbalanced farm-level panel data with 2,193 observations on 329 rice farms from 2004 to 2016, the authors estimate a translog stochastic production frontier model that accounts for both technical inefficiency and production risk. A one-step procedure through the maximum likelihood method that combines the stochastic production frontier, technical inefficiency and production risk functions is used to circumvent the bias problem often found in the conventional two-step model.FindingsEstimation results show that both land and labor market reforms significantly improved the level of technical efficiency over the years, although the effect of land market deregulation is of a much higher magnitude compared to the latter. The land market reform, however, has also increased the risk of production. The authors further find that a higher proportion of hired labor in total labor cost helps lower production risk, while also acting to decrease technical efficiency. Additionally, agricultural subsidies not only increased the output variability but also lowered technical efficiencyOriginality/valueFirst, the authors evaluate the effect of market deregulation on technical efficiency and production risk under a stochastic frontier framework that simultaneously accounts for both production performance metrics, which is important from a statistical point of view. Further, the authors exploit both cross-sectional and time-series variations in a panel setting to more accurately estimate the technical inefficiency scores and production risk for individual farmers, and investigate how the exogenous land and labor market reforms influence these two production performance measures in China's rice farming. This is the first study in the literature to analyze these questions under a panel framework.