bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA splicing programs define tissue compartments and cell types at single cell resolution
Authors: Olivieri Julia Eve , Dehghannasiri Roozbeh , Wang Peter , Jang SoRi , de Morree Antoine , Tan Serena Y. , Ming Jingsi , Wu Angela Ruohao , Consortium Tabula Sapiens , Quake Stephen R. , Krasnow Mark A. , Salzman Julia 
Published: May 2021

AbstractMore than 95% of human genes are alternatively spliced. Yet, the extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach that is agnostic to transcript annotation, to detect cell-type-specific regulated splicing in > 110K carefully annotated single cells from 12 human tissues. Using 10x data for discovery, 9.1% of genes with computable SpliZ scores are cell-type specifically spliced. These results are validated with RNA FISH, single cell PCR, and in high throughput with Smart-seq2. Regulated splicing is found in ubiquitously expressed genes such as actin light chain subunitMYL6and ribosomal proteinRPS24, which has an epithelial-specific microexon. 13% of the statistically most variable splice sites in cell-type specifically regulated genes are also most variable in mouse lemur or mouse. SpliZ analysis further reveals 170 genes with regulated splicing during sperm development using, 10 of which are conserved in mouse and mouse lemur. The statistical properties of the SpliZ allow model-based identification of subpopulations within otherwise indistinguishable cells based on gene expression, illustrated by subpopulations of classical monocytes with stereotyped splicing, including an un-annotated exon, inSAT1, a Diamine acetyltransferase. Together, this unsupervised and annotation-free analysis of differential splicing in ultra high throughput droplet-based sequencing of human cells across multiple organs establishes splicing is regulated cell-type-specifically independent of gene expression.
The ASC inflammasome adapter controls the extent of peripheral protein aggregate deposition in inflammation-associated amyloidosis
Authors: Losa Marco , Emmenegger Marc , De Rossi Pierre , Schürch Patrick M , Serdiuk Tetiana , Pengo Niccolò , Capron Danaëlle , Bieli Dimitri , Rupp Niels J , Carta Manfredi C , Frontzek Karl J , Lysenko Veronika , Reimann Regina R , Lakkaraju Asvin KK , Nuvolone Mario , Westermark Gunilla T , Nilsson K. Peter R. , Polymenidou Magdalini , Theocharides Alexandre P. A. , Hornemann Simone , Picotti Paola , Aguzzi Adriano 
Published: May 2021

AbstractASC-containing inflammasomes form specks, extracellular aggregates which enhance the aggregation of Aβ amyloid in Alzheimer’s disease. This raises the question whether ASC participates to additional aggregation proteinopathies. Here we show that ASC controls the extent of inflammation-associated AA amyloidosis, a systemic disease caused by the aggregation of the acute-phase reactant serum amyloid A (SAA). Using superresolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis. Purified recombinant ASC specks accelerated SAA fibril formationin vitro. Mass spectrometry after limited proteolysis showed that ASC interacts with SAA via its pyrin domain. In a murine model of inflammation-associated AA amyloidosis, splenic AA amyloid load was conspicuously decreased inPycardtm1Vmd/tm1Vmdmice which lack ASC. This reduction was not a consequence of enhanced amyloid phagocytosis, as SAA stimulation increased phagocytic activity inPycard+/+, but not inPycard-/-macrophages. Treatment with anti-ASC antibodies decreased the amyloid loads in wild-type mice suffering from AA amyloidosis. The prevalence of natural anti-ASC IgG (-logEC50≥ 2) in 19,334 hospital patients was <0.01%, suggesting that anti-ASC antibody treatment modalities would not be confounded by natural autoimmunity. Higher anti-ASC titers did not correlate with any specific disease, suggesting that anti-ASC immunotherapy may be well-tolerated. These findings expand the role played by ASC to extraneural proteinopathies of humans and experimental animals and suggest that anti-ASC immunotherapy may contribute to resolving such diseases.
Structural and evolutionary analysis unveil functional adaptations in the promiscuous behavior of serum albumins
Authors: Rueda Ana Julia Velez , Benítez Guillermo Ignacio , Sommese Leandro Matías , Ardanaz Sebastián M. , Borucki Estefanía L. , Palopoli Nicolas , Iglesias Luis E , Parisi Gustavo 
Published: May 2021

AbstractPromiscuous activities have been related to the capacity to catalyze reactions different from those a protein has evolved to sustain. From this evolutionary perspective, we rethought the serum albumins promiscuous behavior. We found that the cross aldol condensation of acetone and p-formylbenzonitrile is a promiscuous reaction conserved in humans and other mammals. Structural and evolutionary analysis indicates that the involved residues could have evolved for a still unknown biological function. Our results could contribute to better characterize the serum albumin family and raise questions about the evolution of protein promiscuity and function.
Seroepidemiological survey on pigs and cattle for novel K88 (F4)-like colonization factor detected in human enterotoxigenicEscherichia coli
Authors: Tanimoto Yoshihiko , Inoue Miyoko , Komatsu Kana , Odani Atsuyuki , Wada Takayuki , Kage-Nakadai Eriko , Nishikawa Yoshikazu 
Published: May 2021

AbstractEnterotoxigenicEscherichia coli(ETEC) strains that express various fimbrial or nonfimbrial colonization factors and enterotoxins are critical causes of diarrheal diseases. Human ETEC serotype O169:H41 (O169) has been a representative of epidemic ETEC worldwide; the organism shows massive adherence to HEp-2 cells similar to enteroaggregativeE. coli. Previously, we determined the complete sequence of the unstable virulence plasmid, pEntYN10. The plasmid included a unique set of genes encoding a novel colonization factor (CF) resembling K88 (F4) of porcine ETEC, in addition to CS6, a well-known representative CF of human ETEC, and another novel CF similar to CS8 (CFA/III) of human ETEC. To determine whether the K88-like CF (after this, K88O169) allows the organisms to infect domestic animals like the original K88-harboring strains that can cause diarrhea in piglets, samples were tested for antibodies against recombinant proteins of possible paralogous adhesins, FaeG1 and FaeG2, from K88O169and the FaeG of typical K88 (F4). The seroepidemiological study using recombinant antigens (two paralogs FaeG1 and FaeG2 from K88O169) showed reactivity of porcine (18.0%) and bovine (17.1%) sera to K88O169FaeG1 and/or FaeG2 antigens on indirect ELISA tests. These results suggest thatE. coliwith K88O169adhesin can infect various hosts, including pigs and cattle. This is the first report of domestic animals having antibodies to K88O169of human ETEC. Although human ETEC had been thought to be distinguished from those of domestic animals based on colonization factors, zoonotic strains may conceal themselves among human ETEC organisms. The concept of One Health should be adopted to intervene in ETEC infections among animals and humans.
Ventilation-induced epithelial injury drives biological onset of lung traumain vitroand is mitigated with anti-inflammatory therapeutics
Authors: Nof Eliram , Artzy-Schnirman Arbel , Bhardwaj Saurabh , Sabatan Hadas , Waisman Dan , Hochwald Ori , Gruber Maayan , Borenstein-Levin Liron , Sznitman Josué 
Published: May 2021

AbstractMortality rates among patients suffering from acute respiratory failure remain perplexingly high despite maintenance of blood homeostasis. Thebiotraumahypothesis advances that mechanical forces from invasive ventilation trigger immunological factors that spread systemically. Yet, how these forces elicit an immune response remains unclear. Here we show that flow-induced stresses under mechanical ventilation can injure the bronchial epithelium of ventilatedin vitroupper airway models and directly modulate inflammatory cytokine secretion associated with pulmonary injury. We identify site-specific susceptibility to epithelial erosion in airways from jet-flow impaction and measure an increase in cell apoptosis and modulated secretions of cytokines IL-6, 8 and 10. We find that prophylactic pharmacological treatment with anti-inflammatory therapeutics reduces apoptosis and pro-inflammatory signaling during ventilation. Our 3Din vitroairway platform points to a previously overlooked origin of lung injury and showcases translational opportunities in preclinical pulmonary research towards protective therapies and improved protocols for patient care.
Phenomics data processing: A plot-level model for repeated measurements to extract the timing of key stages and quantities at defined time points
Authors: Roth Lukas , Rodríguez-Álvarez María Xosé , van Eeuwijk Fred , Piepho Hans-Peter , Hund Andreas 
Published: May 2021

AbstractDecision-making in breeding increasingly depends on the ability to capture and predict crop responses to changing environmental factors. Advances in crop modeling as well as high-throughput field phenotyping (HTFP) hold promise to provide such insights. Processing HTFP data is an interdisciplinary task that requires broad knowledge on experimental design, measurement techniques, feature extraction, dynamic trait modeling, and prediction of genotypic values using statistical models. To get an overview of sources of variation in HTFP, we develop a general plot-level model for repeated measurements. Based on this model, we propose a seamless step-wise procedure that allows for carry on of estimated means and variances from stage to stage. The process builds on the extraction of three intermediate trait categories; (1) timing of key stages, (2) quantities at defined time points or periods, and (3) dose-response curves. In a first stage, these intermediate traits are extracted from low-level traits’ time series (e.g., canopy height) using P-splines and the quarter of maximum elongation rate method (QMER), as well as final height percentiles. In a second and third stage, extracted traits are further processed using a stage-wise linear mixed model analysis. Using a wheat canopy growth simulation to generate canopy height time series, we demonstrate the suitability of the stage-wise process for traits of the first two above-mentioned categories. Results indicate that, for the first stage, the P-spline/QMER method was more robust than the percentile method. In the subsequent two-stage linear mixed model processing, weighting the second and third stage with error variance estimates from the previous stages improved the root mean squared error. We conclude that processing phenomics data in stages represents a feasible approach if estimated means and variances are carried forward from one processing stage to the next. P-splines in combination with the QMER method are suitable tools to extract timing of key stages and quantities at defined time points from HTFP data.HighlightsGeneral plot-level model for repeated high-throughput field phenotyping measurementsExtraction of three main intermediate trait categories for dynamic modelingSeamless processing approach that integrates temporal and spatial modelingPhenomics data processing cheatsheet
Fine-scale spatial genetic structure across the species range reflects recent colonization of high elevation habitats in silver fir (Abies albaMill.)
Authors: Major Enikő I. , Höhn Mária , Avanzi Camilla , Fady Bruno , Heer Katrin , Opgenoorth Lars , Piotti Andrea , Popescu Flaviu , Postolache Dragos , Vendramin Giovanni G. , Csilléry Katalin 
Published: May 2021

AbstractVariation in genetic diversity across species ranges has long been recognized as highly informative for assessing populations’ resilience and adaptive potential. The spatial distribution of genetic diversity, referred to as fine-scale spatial genetic structure (FSGS), also carries information about recent demographic changes, yet it has rarely been connected to range scale processes. We studied eight silver fir (Abies albaMill.)population pairs (sites), growing at high and low elevations, representative of the main genetic lineages of the species. A total of 1368 adult trees and 540 seedlings were genotyped using 137 and 116 single nucleotide polymorphisms (SNPs), respectively. Sites revealed a clear east-west isolation-by-distance pattern consistent with the post-glacial colonization history of the species. Genetic differentiation among sites (FCT=0.148) was an order of magnitude greater than between elevations within sites (FSC=0.031), nevertheless high elevation populations consistently exhibited a stronger FSGS. Structural equation modeling revealed that elevation and, to a lesser extent, post-glacial colonization history, but not climatic and habitat variables, were the best predictors of FGSG across populations. These results may suggest that high elevation habitats have been colonized more recently across the species range. Additionally, paternity analysis revealed a high reproductive skew among adults and a stronger FSGS in seedlings than in adults, suggesting that FSGS may conserve the signature of demographic changes for several generations. Our results emphasize that spatial patterns of genetic diversity within populations provide complementary information about demographic history and could be used for defining conservation priorities.
Aminoglycoside antibiotics inhibit phage infection by blocking an early step of the phage infection cycle
Authors: Kever Larissa , Hardy Aël , Luthe Tom , Hünnefeld Max , Gätgens Cornelia , Milke Lars , Wiechert Johanna , Wittmann Johannes , Moraru Cristina , Marienhagen Jan , Frunzke Julia 
Published: May 2021

AbstractIn response to viral predation, bacteria have evolved a wide range of defense mechanisms, which rely mostly on proteins acting at the cellular level. Here, we show that aminoglycosides, a well-known class of antibiotics produced byStreptomyces, are potent inhibitors of phage infection in widely divergent bacterial hosts. We demonstrate that aminoglycosides block an early step of the viral life cycle, prior to genome replication. Phage inhibition was also achieved using supernatants from natural aminoglycoside producers, hinting at a broad physiological significance of the antiviral properties of aminoglycosides. Strikingly, we show that acetylation of the aminoglycoside antibiotic apramycin abolishes its antibacterial effect, but retains its antiviral properties. Altogether, this study expands the knowledge of potential aminoglycoside functions in bacterial communities suggesting that aminoglycosides are not only used by their producers as toxic molecules against their bacterial competitors, but could also provide protection against the threat of phage predation at the community level.
Immunoinformatics approach for a novel multi-epitope vaccine construct against spike protein of human coronaviruses
Authors: Kumar Avinash , Rathi Ekta , Kini Suvarna G 
Published: May 2021

AbstractSpike (S) proteins are an attractive target as it mediates the binding of the SARS-CoV-2 to the host through ACE-2 receptors. We hypothesize that the screening of S protein sequences of all the HCoVs would result in the identification of potential multi-epitope vaccine candidates capable of conferring immunity against various HCoVs. In the present study, several machine learning-basedin-silicotools were employed to design a broad-spectrum multi-epitope vaccine candidate against S protein of human coronaviruses. To the best of our knowledge, it is one of the first study, where multiple B-cell epitopes and T-cell epitopes (CTL and HTL) were predicted from the S protein sequences of all seven known HCoVs and linked together with an adjuvant to construct a potential broad-spectrum vaccine candidate. Secondary and tertiary structures were predicted, validated and the refined 3D-model was docked with an immune receptor. The vaccine candidate was evaluated for antigenicity, allergenicity, solubility, and its ability to achieve high-level expression in bacterial hosts. Finally, the immune simulation was carried out to evaluate the immune response after three vaccine doses. The designed vaccine is antigenic (with or without the adjuvant), non-allergenic, binds well with TLR-3 receptor and might elicit a diverse and strong immune response.
N-glycosylation of CD24 mediates cell motility but inhibits cell proliferation in colorectal cancer
Authors: Hakami Zaki , Raposo Teresa , Alsulaiman Abdullah , Dalleywater William , Otifi Hassan , Horobin Charlotte , Garrie Karin , Ilyas Mohammad 
Published: May 2021

AbstractCD24 confers features of stemness and enhances cell motility in colorectal cancer. It contains numerousO-glycosylation sites but just two putativeN-glycosylation sites. The study aimed to mutateN-glycosylation as it thought to be important in mediating many glycoproteins’ function.Site-directed mutagenesis performed to mutateN-glycosylation sites by converting asparagine residues to glutamine. Each site was mutated individually (CD24N36Qand CD24N52Q) and in combination (CD24N[36,52]Q) and were overexpressed in HCT116 and SW480 cell lines. The effect of the mutant CD24 on cell viability, cell motility and induction of downstream targets was compared to wild-type CD24 and empty vector control (EVC).Overexpression of the individually mutated clones increased cell motility compared to EVC but was significantly less than that induced by CD24WT. Overexpression of the double mutant clone resulted in near-complete abrogation of cell motility induction. Unexpectedly, the expression of mutant clones (single and double) increased cell viability. Analysis of downstream targets and F-actin staining demonstrated reduced induction of known CD24 targets by mutant vectors and reduced epithelial-mesenchymal transition.In conclusion, eachN-glycosylation site on CD24 contributes partially to induce motility by CD24, and these are additive. Loss of theN-glycosylation results in an unexpected gain of proliferative function.HighlightsCD24 is a heavily glycosylated molecule that contains two N-glycosylation sites, and these contribute to the activation of downstream targets and induction of cell motilityEach N-glycosylation site contributes partially, and their effects appear to be additiveThe N-glycosylation sites may exert an inhibitory effect on cell proliferationMuch of the CD24 activity is mediated through post-transcriptional effects
Ventral Intermediate Nucleus structural connectivity-derived segmentation: anatomical reliability and variability
Authors: Bertino Salvatore , Basile Gianpaolo Antonio , Bramanti Alessia , Ciurleo Rossella , Tisano Adriana , Anastasi Giuseppe Pio , Milardi Demetrio , Cacciola Alberto 
Published: May 2021

AbstractThe Ventral intermediate nucleus (Vim) of thalamus is the most targeted structure for the treatment of drug-refractory tremors. Since methodological differences across existing studies are remarkable and no gold-standard pipeline is available, in this study, we tested different parcellation pipelines for tractography-derived putative Vim identification.Thalamic parcellation was performed on a high quality, multi-shell dataset and a downsampled, clinical-like dataset using two different diffusion signal modeling techniques and two different voxel classification criteria, thus implementing a total of four parcellation pipelines. The most reliable pipeline in terms of inter-subject variability has been picked and parcels putatively corresponding to motor thalamic nuclei have been selected by calculating similarity with a histology-based mask of Vim. Then, spatial relations with optimal stimulation points for the treatment of essential tremor have been quantified. Finally, effect of data quality and parcellation pipelines on a volumetric index of connectivity clusters has been assessed.We found that the pipeline characterized by higher-order signal modeling and threshold-based voxel classification criteria was the most reliable in terms of inter-subject reliability regardless data quality. The maps putatively corresponding to Vim were those derived by precentral- and dentate nucleus-thalamic connectivity. However, tractography-derived functional targets showed remarkable differences in shape and sizes when compared to a ground truth model based on histochemical staining on seriate sections of human brain. Thalamic voxels connected to contralateral dentate nucleus resulted to be the closest to literature-derived stimulation points for essential tremor but at the same time showing the most remarkable inter-subject variability. Finally, the volume of connectivity parcels resulted to be significantly influenced by data quality and parcellation pipelines. Hence, caution is warranted when performing thalamic connectivity-based segmentation for stereotacting targeting.
Protective pan-ebolavirus combination therapy by two multifunctional human antibodies
Authors: Gilchuk Pavlo , Murin Charles D. , Cross Robert W. , Ilinykh Philipp A. , Huang Kai , Kuzmina Natalia , Borisevich Viktoriya , Agans Krystle N. , Geisbert Joan B. , Carnahan Robert H. , Nargi Rachel S. , Sutton Rachel E , Suryadevara Naveenchandra , Zost Seth J. , Bombardi Robin G. , Bukreyev Alexander , Geisbert Thomas W. , Ward Andrew B. , Crowe James E. 
Published: May 2021

AbstractEbolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies rEBOV-515 and rEBOV-442 that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity and resisted viral escape, and they were optimized for their Fc-mediated effector function activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.
The effects of cognitive load on query reformulation: mental demand, temporal demand and frustration
Authors: Na Kyoungsik 
Published: May 2021

PurposeThis study explores the effects of cognitive load on the propensity to reformulate queries during information seeking on the web.Design/methodology/approachThis study employs an experimental design to analyze the effect of manipulations of cognitive load on the propensity for query reformulation between experimental and control groups. In total, three affective components that contribute to cognitive load were manipulated: mental demand, temporal demand and frustration.FindingsA significant difference in the propensity of query reformulation behavior was found between searchers exposed to cognitive load manipulations and searchers who were not exposed. Those exposed to cognitive load manipulations made half as many search query reformulations as searchers not exposed. Furthermore, the National Aeronautical and Space Administration Task Load Index (NASA-TLX) cognitive load scores of searchers who were exposed to the three cognitive load manipulations were higher than those of searchers who were not exposed indicating that the manipulation was effective. Query reformulation behavior did not differ across task types.Originality/valueThe findings suggest that a dual-task method and NASA-TLX assessment serve as good indicators of cognitive load. Because the findings show that cognitive load hinders a searcher's interaction with information search tools, this study provides empirical support for reducing cognitive load when designing information systems or user interfaces.