bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammasome activation in infected macrophages drives COVID-19 pathology
Authors: Sefik Esen , Qu Rihao , Junqueira Caroline , Kaffe Eleanna , Mirza Haris , Zhao Jun , Brewer J. Richard , Han Ailin , Steach Holly R. , Israelow Benjamin , Blackburn Holly N. , Velazquez Sofia , Chen Y. Grace , Halene Stephanie , Iwasaki Akiko , Meffre Eric , Nussenzweig Michel , Lieberman Judy , Wilen Craig B. , Kluger Yuval , Flavell Richard A. 
Published: September 2021

AbstractSevere COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system1-20. Blocking either viral replication with Remdesivir21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.
SIN-like pathway kinases regulate the end of mitosis in the methylotrophic yeast Ogataea polymorpha
Authors: Jiangyan Shen , Takegawa Kaoru , Pereira Gislene , Maekawa Hiromi 
Published: September 2021

AbstractThe Mitotic exit network (MEN) is a conserved signalling pathway essential for termination of mitosis in the budding yeast Saccharomyces cerevisiae. All MEN components are highly conserved in the methylotrophic budding yeast Ogataea polymorpha, except for Cdc15 kinase. Amongst O. polymorpha protein kinases that have some similarity to ScCdc15, only two had no other obvious homologues in S. cerevisiae and these were named OpHCD1 and OpHCD2 for homologue candidate of ScCdc15. A search in other yeast species revealed that OpHcd2 has an armadillo type fold in the C-terminal region as found in SpCdc7 kinases of the fission yeast Schizosaccharomyces pombe, which are homologues of ScCdc15; while OpHcd1 is homologous to SpSid1 kinase, a component of the Septation Initiation Network (SIN) of S. pombe not present in the MEN. Since the deletion of either OpHCD1 or OpHCD2 resulted in lethality under standard growth conditions, conditional mutants were constructed by introducing an ATP analog sensitive mutation. For OpHCD2, we constructed and used new genetic tools for O. polymorpha that combined the Tet promoter and the improved auxin-degron systems. Conditional mutants for OpHCD1 and OpHCD2 exhibited significant delay in late anaphase and defective cell separation, suggesting that both genes have roles in mitotic exit and cytokinesis. These results suggest a SIN-like signalling pathway regulates termination of mitosis in O. polymorpha and that the loss of Sid1/Hcd1 kinase in the MEN occurred relatively recently during the evolution of budding yeast.
Fast and cost-effective age estimation in Bengal tiger and Asiatic lion: applicability of cementum analysis method
Authors: Vipin  , Sharma Chandra P , Sharma Vinita , Goyal Surendra P , Gupta Sandeep K 
Published: September 2021

AbstractAge estimation methods, through cementum analysis, for wild animals are rarely developed in Southeast Asian Countries. In the present study, we describe the applicability of the cementum analysis technique for developing a fast (±19 hours) and cost-effective age estimation method for Bengal tiger (Panthera tigris tigris) and Asiatic lion (Panthera leo persica) using incisor tooth. The I2and I3incisor teeth from the right mandible of a tiger and I2and I3from the left maxilla of a lion were used in the study. The longitudinal sections of the tooth were made using a low cost hand grinding technique on sand papers followed by decalcification and staining with hematoxylin. The cementum layers were counted under the microscope at 100X or 200X magnifications. Two cementum layers were observed in each of the I2and I3incisor tooth of tiger and six cementum layers were observed in each of the I2and I3incisor teeth of lion. The permanent incisors in tiger and lion erupt between 12-14 months; hence, we added 1 year to the counted number of cementum layers to estimate the final age of tiger and lion incisors. The absolute age of tiger and lion incisors was estimated to be of 2+1 years and 6+1 years, respectively. The same number of cementum layers in both incisors respective to the tiger and lion were observed. Therefore, we suggest (i) undertake the blind test and (ii) collect incisor teeth from naturally died or killed individuals for strengthening the database on the age of the wild population. This optimized method may be suitable for many carnivore species, applicable in wildlife forensic studies and can be used by researchers with minimum expertise, time, and funds requirements throughout the world.
The Synechocystis ORF slr0201 product is involved in succinate dehydrogenase-mediated cyclic electron transfer around PSI
Authors: Xiong Fusheng , Yang Yang , Fu Xiyuan 
Published: September 2021

AbstractThe Synechocystis sp. PCC 6803 open reading frame (ORF) slr0201 was originally annotated as heterodisulfide reductase B subunit (HdrB). The slr0201 encodes a 301-amino acid hypothetical protein with the predicted amino acid sequence significantly homologous to not only the HdrB from methanogenic bacteria, but also some novel succinate dehydrogenase C subunit (SdhC) found in Archaea and Campylobacter. Genetic manipulation via knocking-out approach created a Δslr0201 mutant showing a ΔsdhB-like phenotype that was characterized by impaired succinate-dependent DCPIP reduction activities, reduced SDH-mediated respiratory electron transports, lower cellular contents of succinate and fumarate, slower KCN-induced increases in Chl fluorescence yield in the dark, and weak state 2/strong state 1 transitions, being indicative of a more oxidized PQ pool. In addition, slower re-reductions of the photosystem (PS) I reaction center P700 upon light-off were also monitored in the Δslr0201, indicating functional involvements of Slr0201 in cyclic electron transfer around PSI. Both photoautptrophical and photomixotrophical growth rates of the Δslr0201 strain resembled to those of the wild type, but substantial growth deteriorations occurred when arginine (∼25 mM) or other two urea-cycle relevant amino acids (citrulline and ornithine) were added, which were attributed to generations and accumulations of certain hazardous metabolites. Based on the ΔsdhB-resembling phenotype, in conjunction with its high sequence similarities to some archaeal SdhC, we proposed that the slr0201 encodes a SDH function-relevant protein and is most likely the SdhC, a membrane anchoring subunit, which, while being genetically distinct from those in traditional bacterial SDH, belongs to the C subunit of novel archaeal SDH.
Growing Glycans in Rosetta: Accuratede novoglycan modeling, density fitting, and rational sequon design
Authors: Adolf-Bryfogle Jared , Labonte Jason W. , Kraft John C. , Shapovalov Maxim , Raemisch Sebastian , Lütteke Thomas , DiMaio Frank , Bahl Christopher D. , Pallesen Jesper , King Neil P. , Gray Jeffrey J. , Kulp Daniel W. , Schief William R. 
Published: September 2021

AbstractCarbohydrates and glycoproteins modulate key biological functions. Computational approaches inform function to aid in carbohydrate structure prediction, structure determination, and design. However, experimental structure determination of sugar polymers is notoriously difficult as glycans can sample a wide range of low energy conformations, thus limiting the study of glycan-mediated molecular interactions. In this work, we expanded theRosettaCarbohydrateframework, developed and benchmarked effective tools for glycan modeling and design, and extended the Rosetta software suite to better aid in structural analysis and benchmarking tasks through the SimpleMetrics framework. We developed a glycan-modeling algorithm,GlycanTreeModeler, that computationally builds glycans layer-by-layer, using adaptive kernel density estimates (KDE) of common glycan conformations derived from data in the Protein Data Bank (PDB) and from quantum mechanics (QM) calculations. After a rigorous optimization of kinematic and energetic considerations to improve near-native sampling enrichment and decoy discrimination,GlycanTreeModelerwas benchmarked on a test set of diverse glycan structures, or “trees”. Structures predicted byGlycanTreeModeleragreed with native structures at high accuracy for bothde novomodeling and experimental density-guided building.GlycanTreeModeleralgorithms and associated tools were employed to designde novoglycan trees into a protein nanoparticle vaccine that are able to direct the immune response by shielding regions of the scaffold from antibody recognition. This work will inform glycoprotein model prediction, aid in both X-ray and electron microscopy density solutions and refinement, and help lead the way towards a new era of computational glycobiology.
Integration of a radiofrequency coil and commercial field camera for ultra-high-field MRI
Authors: Gilbert Kyle M. , Dubovan Paul , Gati Joseph S. , Menon Ravi S. , Baron Corey A. 
Published: September 2021

ABSTRACTPurposeTo develop an RF coil with an integrated commercial field camera for ultra-high field (7 T) neuroimaging. The RF coil will operate within a head-only gradient coil and be subject to the corresponding design constraints. The RF coil can thereafter be used for subject-specific correction of k-space trajectories—notably in gradient-sensitive sequences such as single-shot spiral imaging.MethodsThe transmit and receive performance was evaluated before and after the integration of field probes, while field probes were evaluated when in an optimal configuration external to the coil and after their integration. Diffusion-weighted EPI and single-shot spiral acquisitions were employed to evaluate the efficacy of correcting higher order field perturbations and the consequent effect on image quality.ResultsField probes had a negligible effect on RF-coil performance, including the transmit efficiency, transmit uniformity, and mean SNR over the brain. Modest reductions in field-probe signal lifetimes were observed, caused primarily by non-idealities in the gradient and shim fields of the head-only gradient coil at the probe positions. The field monitoring system could correct up to second-order field perturbations in single-shot spiral imaging.ConclusionThe integrated RF coil and field camera was capable of concurrent field monitoring within a 7T head-only scanner and facilitated the subsequent correction of k-space trajectories during spiral imaging.
Feature-reweighted representational similarity analysis: A method for improving the fit between computational models, brains, and behavior
Authors: Kaniuth Philipp , Hebart Martin N. 
Published: September 2021

AbstractRepresentational Similarity Analysis (RSA) has emerged as a popular method for relating representational spaces from human brain activity, behavioral data, and computational models. RSA is based on the comparison of representational (dis-)similarity matrices (RDM or RSM), which characterize the pairwise (dis-)similarities of all conditions across all features (e.g. fMRI voxels or units of a model). However, classical RSA treats each feature as equally important. This ‘equal weights’ assumption contrasts with the flexibility of multivariate decoding, which reweights individual features for predicting a target variable. As a consequence, classical RSA may lead researchers to underestimate the correspondence between a model and a brain region and, in case of model comparison, may lead them to select an inferior model. The aim of this work is twofold: First, we sought to broadly test feature-reweighted RSA (FR-RSA) applied to computational models and reveal the extent to which reweighting model features improves RSM correspondence and affects model selection. Previous work suggested that reweighting can improve model selection in RSA but it has remained unclear to what extent these results generalize across datasets and data modalities. To draw more general conclusions, we utilized a range of publicly available datasets and three popular deep neural networks (DNNs). Second, we propose voxel-reweighted RSA, a novel use case of FR-RSA that reweights fMRI voxels, mirroring the rationale of multivariate decoding of optimally combining voxel activity patterns. We found that reweighting individual model units markedly improved the fit between model RSMs and target RSMs derived from several fMRI and behavioral datasets and affected model selection, highlighting the importance of considering FR-RSA. For voxel-reweighted RSA, improvements in RSM correspondence were even more pronounced, demonstrating the utility of this novel approach. We additionally show that classical noise ceilings can be exceeded when FR-RSA is applied and propose an updated approach for their computation. Taken together, our results broadly validate the use of FR-RSA for improving the fit between computational models, brain, and behavioral data, possibly allowing us to better adjudicate between competing computational models. Further, our results suggest that FR-RSA applied to brain measurement channels could become an important new method to assess the correspondence between representational spaces.
The BNT162b2 mRNA vaccine induces polyfunctional T cell responses with features of longevity
Authors: Guerrera Gisella , Picozza Mario , D’Orso Silvia , Placido Roberta , Pirronello Marta , Verdiani Alice , Termine Andrea , Fabrizio Carlo , Giannessi Flavia , Sambucci Manolo , Balice Maria Pia , Caltagirone Carlo , Salvia Antonino , Rossini Angelo , Battistini Luca , Borsellino Giovanna 
Published: September 2021

AbstractVaccination against SARS-CoV-2 infection has shown to be effective in preventing hospitalization for severe COVID-19. However, multiple reports of break-through infections and of waning antibody titers have raised concerns on the durability of the vaccine, and current discussions on vaccination strategies are centered on evaluating the opportunity of a third dose administration. Here, we monitored T cell responses to the Spike protein of SARS-CoV-2 in 71 healthy donors vaccinated with the Pfizer–BioNTech mRNA vaccine (BNT162b2) for up to 6 months after vaccination. We find that vaccination induces the development of a sustained anti-viral memory T cell response which includes both the CD4+ and the CD8+ lymphocyte subsets. These lymphocytes display markers of polyfunctionality, are fit for interaction with cognate cells, show features of memory stemness, and survive in significant numbers the physiological contraction of the immune response. Collectively, this data shows that vaccination with BNT162b2 elicits an immunologically competent and potentially long-lived SARS-CoV-2-specific T cell population. Understanding the immune responses to BNT162b2 provides insights on the immunological basis of the clinical efficacy of the current vaccination campaign and may instruct future vaccination strategies.
Pre-mRNA Splicing Factor U2AF2 Recognizes Distinct Conformations of Nucleotide Variants at the Center of the pre-mRNA Splice Site Signal
Authors: Glasser Eliezra , Maji Debanjana , Biancon Giulia , Keedakkatt Puthenpeedikakkal Anees Mohammed , Cavender Chapin E. , Tebaldi Toma , Pulvino Mary J. , Jenkins Jermaine L. , Mathews David H. , Halene Stephanie , Kielkopf Clara L. 
Published: September 2021

ABSTRACTThe essential pre-mRNA splicing factor U2AF2 (also called U2AF65) identifies polypyrimidine (Py) tract signals of nascent transcripts, despite length and sequence variations. Previous studies have shown that the U2AF2 RNA recognition motifs (RRM1 and RRM2) preferentially bind uridine-rich RNAs. Nonetheless, the specificity of the RRM1/RRM2 interface for the central Py tract nucleotide has yet to be investigated. We addressed this question by determining crystal structures of U2AF2 bound to a cytidine, guanosine, or adenosine at the central position of the Py tract, and compared U2AF2-bound uridine structures. Local movements of the RNA site accommodated the different nucleotides, whereas the polypeptide backbone remained similar among the structures. Accordingly, molecular dynamics simulations revealed flexible conformations of the central, U2AF2-bound nucleotide. The RNA binding affinities and splicing efficiencies of structure-guided mutants demonstrated that U2AF2 tolerates nucleotide substitutions at the central position of the Py tract. Moreover, enhanced crosslinking and immunoprecipitation of endogenous U2AF2 in human erythroleukemia cells showed uridine-sensitive binding sites with lower sequence conservation at the central nucleotide positions of otherwise uridine-rich, U2AF2-bound splice sites. Altogether, these results highlight the importance of RNA flexibility for protein recognition and take a step towards relating splice site motifs to pre-mRNA splicing efficiencies.
Multiple metals influence distinct properties of the Arabidopsis circadian clock
Authors: Hargreaves Jessica K. , Oakenfull Rachael J. , Davis Amanda M. , Pullen Freya , Knight Marina I. , Pitchford Jon W. , Davis Seth J. 
Published: September 2021

AbstractCircadian rhythms coordinate endogenous events with external signals, and are essential to biological function. When environmental contaminants affect these rhythms, the organism may experience fitness consequences such as reduced growth or increased susceptibility to pathogens. In their natural environment plants may be exposed to a wide range of industrial and agricultural pollutants. Here, we investigate how the addition of various metal salts to the environment can impact plant-circadian rhythms, via the promoter:luciferase system. The consequences of these environmental changes were found to be varied and complex. Therefore, in addition to Fourier-based analyses, we apply novel wavelet-based spectral hypothesis testing and clustering methodologies to organize and understand the data. We are able to classify broad sets of responses to environmental contaminants, including pollutants which increase, or decrease, the period, or which induce a lack of precision or disrupt any meaningful periodicity. The methods are general, and may be applied to discover common responses and hidden structures within a wide range of biological time series data.
Optogenetic control of NOTCH1 signalling
Authors: Kałafut Joanna , Czapiński Jakub , Przybyszewska-Podstawka Alicja , Czerwonka Arkadiusz , Sahlgren Cecilia , Rivero-Müller Adolfo 
Published: September 2021

AbstractThe Notch signalling pathway is a crucial regulator of cell differentiation as well as tissue organisation. Dysregulation of Notch signalling has been linked to the pathogenesis of different diseases. Notch plays a key role in breast cancer progression by controlling the interaction between the tumour cells and the microenvironment as well as by increasing cell motility and invasion. NOTCH1 is a mechanosensitive receptor, where mechanical force is required to activate the proteolytic cleavage and release of the Notch intracellular domain (NICD). Here, we circumvent this step by regulating Notch activity by light. To achieve this, we have engineered a membrane-bound optogenetic NOTCH1 receptor (optoNotch) to control the activation of NOTCH1 intracellular domain (N1ICD) and its downstream transcriptional activities. Using optoNotch we confirm that NOTCH1 activation increases cell proliferation in MCF7 and MDA-MB-468 breast cancer cells in 2D and spheroid 3D cultures. OptoNotch allows fine-tuning ligand-independent regulation of N1ICD to understand the spatiotemporal complexity of Notch signalling.
Large-scale mapping of positional changes of hypoxia-responsive genes upon activation
Authors: Nakayama Koh , Shachar Sigal , Finn Elizabeth H. , Sato Hiroyuki , Hirakawa Akihiro , Misteli Tom 
Published: September 2021

AbstractChromosome structure and nuclear organization are important factors in the regulation of gene expression. Transcription of a gene is influenced by local and global chromosome features such as condensation status and histone modifications. The relationship between the position of a gene in the cell nucleus and its activity is less clear. Here, we used high-throughput imaging to perform a large-scale analysis of the spatial location of a set of nearly 100 hypoxia-inducible genes to determine whether their location within the nucleus is correlated with their activity state upon stimulation. Radial distance analysis demonstrated that the majority of HIF- and CREB-inducible hypoxia responsive genes are located in the intermediate region of the nucleus. Radial position of numerous responsive genes changed upon hypoxic treatment. Analysis of the relative distances amongst a subset of HIF target gene groups revealed that some gene pairs also altered their relative location to each other upon hypoxic treatment, suggesting higher order chromatin rearrangements. While these changes in location occurred in response to hypoxic activation of the target genes, they did not correlate with the extent of their activation. These results suggest that induction of the hypoxia-responsive gene expression program is accompanied by spatial alterations of the genome, but that radial and relative gene positions are not directly related to gene activity.
Nanopore sequencing methods detect cell-free DNA associated with MRD and CNS infiltration in pediatric Acute Lymphoblastic Leukemia
Authors: Sampathi Shilpa , Chernyavskaya Yelena , Haney Meghan G. , Moore L. Henry , Snyder Isabel A. , Cox Anna H. , Fuller Brittany L. , Taylor Tamara J. , Badgett Tom C. , Blackburn Jessica S. 
Published: September 2021

AbstractAcute Lymphoblastic Leukemia (ALL) patients that are positive for minimal residual disease (MRD) after therapy or have leukemic infiltration into the central nervous system (CNS) are considered high risk and receive intensive chemotherapy regimens. Current methods to diagnose MRD and CNS infiltration rely on detecting leukemic cells in patient samples using pathology, flow cytometry, or next-generation sequencing. However, leukemic blasts may persist in the patient but not be physically present in bone marrow biopsy or biofluid sample, leading to inaccurate or delayed patient diagnosis. We have developed a nanopore sequencing workflow to detect B-ALL-associated cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) samples. Quantitation of B-cell specific VDJ recombination events in cfDNA samples defined B-ALL clonal heterogeneity. This workflow allowed us to track the response of individual B-ALL clones throughout treatment. Detection of cfDNA also predicted the clinical diagnosis of MRD and CNS disease. Importantly, we identified patients diagnosed as CNS negative who had low B-cell derived cell-free DNA levels in their CSF sample that correlated with B-cell clones present in the bone marrow. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient even when blasts are not in the biofluid sample. Nanopore analysis of cell-free DNA is a simple, rapid, and inexpensive assay that can serve as a valuable complement to traditional clinical diagnostic approaches for ALL.Abstract Figure