bluuebunny/crossref_metadata_2025_split huggingface dataset:
Herpes Simplex Virus Co-Infection Facilitates Rolling Circle Replication of the Adeno-Associated Virus Genome
Authors: Meier Anita F. , Tobler Kurt , Leisi Remo , Lkharrazi Anouk , Ros Carlos , Fraefel Cornel 
Published: December 2020

ABSTRACTAdeno-associated virus (AAV) genome replication only occurs in the presence of a co-infecting helper virus such as adenovirus type 5 (AdV5) or herpes simplex virus type 1 (HSV-1). AdV5-supported replication of the AAV genome has been described to occur in a strand-displacement rolling hairpin replication (RHR) mechanism initiated at the AAV 3’ inverted terminal repeat (ITR) end. It has been assumed that the same mechanism applies to HSV-1-supported AAV genome replication. Using nanopore sequencing as a novel, high-throughput approach to study viral genome replication we demonstrate the formation of double-stranded head-to-tail concatemers of AAV genomes in the presence of HSV-1, thus providing evidence for an unequivocal rolling circle replication (RCR) mechanism. This stands in contrast to the textbook model of AAV genome replication when HSV-1 is the helper virus.SIGNIFICANCEEfficient adeno-associated virus (AAV) replication requires the presence of helper factors, which can be provided by co-infecting helper viruses such as adenoviruses or herpesviruses. AAV replication has been described to occur as a rolling hairpin replication mechanism. However, we show that during a herpes simplex virus type 1 (HSV-1) supported replication, AAV rolling circle-like replication intermediates are formed. Thus, this study stands in contrast to the textbook model of AAV genome replication. Additionally, we introduce nanopore sequencing as a novel, high-throughput approach to study viral genome replication in unprecedented detail.
Drosophila glue protects from predation
Authors: Borne Flora , Prigent Stéphane R. , Molet Mathieu , Courtier-Orgogozo Virginie 
Published: December 2020

AbstractAnimals can be permanently attached to a substrate in terrestrial environments at certain stages of their development. Pupa adhesion has evolved multiple times in insects and is thought to maintain the animal in a place where it is not detectable by predators. Here, we investigate whether pupa adhesion in Drosophila can also protect the animal by preventing potential predators from detaching the pupa. We measured the adhesion of Drosophila species sampled from the same area and found that pupa adhesion varies among species, which can be explained by different glue production strategies. Then, we compared attached and manually detached pupae in both field and laboratory assays to investigate the role of pupa adhesion to prevent predation. First, we found that attached pupae remain on site 30 % more than detached pupae in the field after three days, probably because they are less predated. Second, we observed that attached pupae are less efficiently predated by ants in the laboratory: they are not carried back to the ant nest and more ants are needed to consume them onsite. Our results show that pupa adhesion can prevent the animal from being taken away by predators and is crucial for Drosophila fly survival.
Time Perception through the Processing of Verb Tenses: An ERP study regarding Mental Time Travel
Authors: Papageorgiou Charalabos , Giannopoulos Anastasios E. , Fokas Athanasios S. , Thompson Paul M. , Kapsalis Nikolaos C. , Papageorgiou Panos , Stachtea Xanthi , Capsalis Christos N. 
Published: December 2020

ABSTRACTHumans are equipped with the so-called Mental Time Travel (MTT) ability, which allows them to consciously construct and elaborate past or future scenes. The mechanisms underlying MTT remain elusive. This study focused on the late positive potential (LPP) and alpha oscillations, considering that LPP covaries with the temporal continuity whereas the alpha oscillations index the temporal organization of perception. To that end, subjects were asked to focus on performing two mental functions engaging working memory, which involved mental self-projection into either the present-past (PP) border or the present-future (PF) border. To evaluate underlying mechanisms, the evoked frontal late positive potentials (LPP) as well as their cortical sources were analyzed via the standardized low-resolution brain electromagnetic tomography (sLORETA) technique. The LPP amplitudes - in the left lateral prefrontal areas that were elicited during PF tasks - were significantly higher than those associated with PP, whereas opposite patterns were observed in the central and right prefrontal areas. Crucially, the LPP activations of both the PP and PF self-projections overlapped with the brain’s default mode network and related interacting areas. Finally, we found enhanced alpha-related activation with respect to PP in comparison to PF, predominantly over the right hemisphere central brain regions (specifically, the precentral gyrus). These findings confirm that the two types of self-projection, as reflected by the frontally-distributed LPP, share common cortical resources that recruit different brain regions in a balanced way. This balanced distribution of brain activation might signify that biological time tends to behave in a homeostatic way.
Identification of key genes and associated pathways in neuroendocrine tumors through bioinformatics analysis and predictions of small drug molecules
Authors: Devarbhavi Praveenkumar , Vastrad Basavaraj , Tengli Anandkumar , Vastrad Chanabasayya , Kotturshetti Iranna 
Published: December 2020

AbstractNeuroendocrine tumor (NET) is one of malignant cancer and is identified with high morbidity and mortality rates around the world. With indigent clinical outcomes, potential biomarkers for diagnosis, prognosis and drug target are crucial to explore. The aim of this study is to examine the gene expression module of NET and to identify potential diagnostic and prognostic biomarkers as well as to find out new drug target. The differentially expressed genes (DEGs) identified from GSE65286 dataset was used for pathway enrichment analyses and gene ontology (GO) enrichment analyses and protein - protein interaction (PPI) analysis and module analysis. Moreover, miRNAs and transcription factors (TFs) that regulated the up and down regulated genes were predicted. Furthermore, validation of hub genes was performed. Finally, molecular docking studies were performed. DEGs were identified, including 453 down regulated and 459 up regulated genes. Pathway and GO enrichment analysis revealed that DEGs were enriched in sucrose degradation, creatine biosynthesis, anion transport and modulation of chemical synaptic transmission. Important hub genes and target genes were identified through PPI network, modules, target gene - miRNA network and target gene - TF network. Finally, survival analyses, receiver operating characteristic (ROC) curve and RT-PCR validated the significant difference of ATP1A1, LGALS3, LDHA, SYK, VDR, OBSL1, KRT40, WWOX, NINL and PPP2R2B between metastatic NET and normal controls. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying NET and provide candidate targets for future research.
Multiplexed experimental strategies for fragment library screening using SPR biosensors
Authors: FitzGerald Edward A. , Vagrys Darius , Opassi Giulia , Klein Hanna F. , Hamilton David J. , Boronat Pierre , Cederfelt Daniela , Talibov Vladimir O. , Abramsson Mia , Moberg Anna , Lindgren Maria T. , Holmgren Claes , Dobritzsch Doreen , Davis Ben , O’Brien Peter , Wijtmans Maikel , van Muijlwijk-Koezen Jacqueline E. , Hubbard Roderick E. , de Esch Iwan J.P , Danielson U. Helena 
Published: December 2020

AbstractSurface plasmon resonance biosensor technology (SPR) is ideally suited for fragment-based lead discovery. However, generally suitable experimental procedures or detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are lacking. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. By adopting a multiplexed strategy, the range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded. We here illustrate innovative strategies using five challenging targets and variants thereof. Two libraries of 90 and 1056 fragments were screened using two different flow-based SPR biosensor systems, allowing different experimental approaches. Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted.
Neoantigen driven B cell and CD4+T follicular helper cell collaboration promotes robust anti-tumor CD8+T cell responses
Authors: Cui Can , Wang Jiawei , Chen Ping-Min , Connolly Kelli A. , Damo Martina , Fagerberg Eric , Chen Shuting , Eisenbarth Stephanie C. , Zhao Hongyu , Craft Joseph , Joshi Nikhil S. 
Published: December 2020

AbstractCD4+T follicular helper (TFH) cells provide help to B cells, which is critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To investigate further, we developed an LUAD model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells were necessary for tumor control, as were effector CD8+T cells. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens. Thus, tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+T cells by facilitating interactions with tumor-specific B cells.Abstract Figure
SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation
Authors: Thorne Lucy G , Reuschl Ann-Kathrin , Zuliani-Alvarez Lorena , Whelan Matthew V.X. , Noursadeghi Mahdad , Jolly Clare , Towers Greg J 
Published: December 2020

SummarySARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through activation of cytoplasmic RNA-ensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing, or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19.HighlightsSARS-CoV-2 activates RNA sensors and consequent inflammatory responses in lung epithelial cellsEpithelial RNA sensing responses drive pro-inflammatory macrophage activationExogenous inflammatory stimuli exacerbate responses to SARS-CoV-2 in both eplithelial cells and macrophagesImmunomodulators inhibit RNA sensing responses and consequent macrophage inflammationGraphical Abstract
A cognitive state transformation model for task-general and task-specific subsystems of the brain connectome
Authors: Yoo Kwangsun , Rosenberg Monica D , Kwon Young Hye , Scheinost Dustin , Constable R Todd , Chun Marvin M 
Published: December 2020

AbstractThe human brain flexibly controls different cognitive behaviors, such as memory and attention, to satisfy contextual demands. Much progress has been made to reveal task-induced modulations in the whole-brain functional connectome, but we still lack a way to model changes in the brain’s functional organization. Here, we present a novel connectome-to-connectome (C2C) state transformation framework that enables us to model the brain’s functional reorganization in response to specific task goals. Using functional magnetic resonance imaging data from the Human Connectome Project, we demonstrate that the C2C model accurately generates an individual’s task-specific connectomes from their task-free connectome with a high degree of specificity across seven different cognitive states. Moreover, the C2C model amplifies behaviorally relevant individual differences in the task-free connectome, thereby improving behavioral predictions. Finally, the C2C model reveals how the connectome reorganizes between cognitive states. Previous studies have reported that task-induced modulation of the brain connectome is domain-specific as well as domain-general, but did not specify how brain systems reconfigure to specific cognitive states. Our observations support the existence of reliable state-specific systems in the brain and indicate that we can quantitatively describe patterns of brain reorganization, common across individuals, in a computational model.
Identification of COVID-19-relevant transcriptional regulatory networks and associated kinases as potential therapeutic targets
Authors: Su Chen , Rousseau Simon , Emad Amin 
Published: December 2020

ABSTRACTIdentification of transcriptional regulatory mechanisms and signaling networks involved in the response of host to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, we combined a series of recently developed computational tools to identify transcriptional regulatory networks involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus. In addition, using network-guided analyses, we identified signaling pathways that are associated with these networks and kinases that may regulate them. The results identified classical antiviral response pathways including Interferon response factors (IRFs), interferons (IFNs), and JAK-STAT signaling as key elements upregulated by SARS-CoV-2 in comparison to mock-treated cells. In addition, comparing SARS-Cov-2 infection of airway epithelial cells to other respiratory viruses identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory networks identified herein reflect a combination of experimentally validated hits and novel pathways supporting the computational pipeline to quickly narrow down promising avenue of investigations when facing an emerging and novel disease such as COVID-19.
Diffusion of metabolites across gap junctions mediates metabolic coordination of β-islet cells
Authors: Rao Vishnu P. , Rizzo Megan A. 
Published: December 2020

AbstractLoss of oscillatory insulin secretion is an early marker of type II diabetes. In an individual beta-cell, insulin secretion is triggered by glucose metabolism, which leads to membrane depolarization and calcium influx. Islet β-cells display coordinated secretion; however, it is unclear how the heterogeneous population of insulin-secreting beta cells coordinate their response to glucose. The mechanisms underlying both electrical and calcium synchronicity are well explored. Even so, the mechanism governing metabolic coordination is unclear given key glycolytic enzymes’ heterogeneous expression. To understand how islet cells coordinate their metabolic activity, a microfluidic applicator delivered glucose stimulation to spatially defined areas of isolated mouse islets. We measured metabolic responses using NADH/NADPH (or NAD(P)H) autofluorescence and calcium changes using Fluo-4 fluorescence. Glucose stimulated a rise in NAD(P)H even in islet areas unexposed to the treatment, suggesting metabolic coordination. A gap junction inhibitor blocked the coordinated NAD(P)H rise in the low-glucose areas. Additionally, metabolic communication did not occur in immortalized β-cell clusters known to lack gap junctions, demonstrating their importance for metabolic coupling. Metabolic communication also preceded glucose-stimulated rises in intracellular calcium. Further, pharmacological blockade of calcium influx did not disrupt NAD(P)H rises in untreated regions. These data suggest that metabolic coordination between islet beta-cells relies on gap-junctional activity and precedes synchronous electrical and calcium activity.
Massive colonization of protein-coding exons by selfish genetic elements inParameciumgermline genomes
Authors: Sellis Diamantis , Guérin Frédéric , Arnaiz Olivier , Pett Walker , Lerat Emmanuelle , Boggetto Nicole , Krenek Sascha , Berendonk Thomas , Couloux Arnaud , Aury Jean-Marc , Labadie Karine , Malinsky Sophie , Bhullar Simran , Meyer Eric , Sperling Linda , Duret Laurent , Duharcourt Sandra 
Published: December 2020

AbstractCiliates are unicellular eukaryotes with both a germline genome and a somatic genome in the same cytoplasm. The somatic macronucleus (MAC), responsible for gene expression, is not sexually transmitted but develops from a copy of the germline micronucleus (MIC) at each sexual generation. In the MIC genome ofParamecium tetraurelia, genes are interrupted by tens of thousands of unique intervening sequences, called Internal Eliminated Sequences (IESs), that have to be precisely excised during the development of the new MAC to restore functional genes. To understand the evolutionary origin of this peculiar genomic architecture, we sequenced the MIC genomes of nineParameciumspecies (from ∼100 Mb inP. aureliaspecies to > 1.5 Gb inP. caudatum). We detected several waves of IES gains, both in ancestral and in more recent lineages. While the vast majority of IESs are single-copy in present-day genomes, we identified several families of mobile IESs, including non-autonomous elements acquired via horizontal transfer, that generated tens to thousands of new copies. These observations provide the first direct evidence that transposable elements can account for the massive proliferation of IESs inParamecium. The comparison of IESs of different evolutionary ages indicates that, over time, IESs shorten and diverge rapidly in sequence while they acquire features that allow them to be more efficiently excised. We nevertheless identified rare cases of IESs that are under strong purifying selection across theaureliaclade. The cases examined contain or overlap cellular genes that are inactivated by excision during development, suggesting conserved regulatory mechanisms. Similar to the evolution of introns in eukaryotes, the evolution ofParameciumIESs highlights the major role played by selfish genetic elements in shaping the complexity of genome architecture and gene expression.
MaPPeRTrac: A Massively Parallel, Portable, and Reproducible Tractography Pipeline
Authors:   A collaboration between the U.S. Department of Energy and TRACK-TBI, Moon Joseph , Bremer Peer-Timo , Mukherjee Pratik , Markowitz Amy J. , Palacios Eva M. , Cai Lanya T. , Rodriguez Alexis , Xiao Yukai , Manley Geoffrey T. , Madduri Ravi K. 
Published: December 2020

AbstractLarge-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational cost. We developed MaPPeRTrac, a probabilistic tractography pipeline that simplifies and vastly accelerates this process on a wide range of high performance computing (HPC) environments. It fully automates the entire tractography pipeline, from management of raw MRI machine data to edge density imaging (EDI) of the structural connectome. Dependencies are containerized withDockerorSingularityand de-coupled from code to enable rapid proto-typing and modification. Data artifacts are strictly organized with theBrain Imaging Data Structure(BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using theParslparallel programming frame-work, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so that it may accelerate brain connectome research for a broader user community.
Genome evolution in a putatively asexual wasp
Authors: Tvedte Eric S. , Ward Austin C. , Trendle Benjamin , Forbes Andrew A. , Logsdon John M. 
Published: December 2020

AbstractAsexual lineages are destined for extinction—a result predicted by theory and revealed in practice. Short-term benefits of asexuality are eventually outstripped by their fitness costs: losses of sex and recombination are together expected to reduce efficacy of selection, increase mutation load, and thus, lower fitness. We characterized genomic patterns of accumulating mutations inDiachasma muliebre, a parasitic wasp that has apparently lost sex, an inference supported by many decades of field collections of 1000s of individuals in which only females were found. The split betweenD. muliebreand its closest sexual relative,Diachasma ferrugineum, is quite recent, allowing us to observe initial events in the evolution of this putative asexual species. First, we find a faster rate of molecular evolution across theD. muliebregenome. In addition, we observed a marked excess of replacement nucleotide substitutions in orthologous genes in the putatively asexualD. muliebrewhen compared toD. ferrugineum. This pattern directly indicates genome-wide relaxed selection in this young, putatively asexual species, the resulting mutational load from which is expected to ultimately lead to extinction. However, these genomic effects occur in the presence of genomic recombination initially detected by a previous study and also supported by analyses of genome-wide substitution rates within codons. In addition, following completion of the genome sequence and its analysis, we discovered twoD. muliebremales, suggesting the possibility of rare sex in this species. Haplodiploid animals, including the sexual ancestors ofD. muliebre, bear small genetic loads, likely making their initial transitions to asexuality relatively benign. Paradoxically, an elevated rate of mutation accumulation resulting from asexuality, when accompanied by retention of recombination and/or rare sex, could actually be beneficial: we hypothesize that the novel variation introduced by mutation along with limited shuffling of genes may facilitate initial adaptation and extend persistence of such lineages.