bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant
Authors: Hajnik Renee L. , Plante Jessica A. , Liang Yuejin , Alameh Mohamad-Gabriel , Tang Jinyi , Zhong Chaojie , Adam Awadalkareem , Scharton Dionna , Rafael Grace H. , Liu Yang , Hazell Nicholas C. , Sun Jiaren , Soong Lynn , Shi Pei-Yong , Wang Tian , Sun Jie , Weissman Drew , Weaver Scott C. , Plante Kenneth S. , Hu Haitao 
Published: December 2021

AbstractEmergence of SARS-CoV-2 variants of concern (VOC), including the highly transmissible delta strain, has posed challenges to current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified mRNA vaccine that expresses the more conserved viral nucleoprotein (mRNA-N). We show that mRNA-N alone was able to induce a modest but significant control of SARS-CoV-2 in mice and hamsters. Critically, by combining mRNA-N with the clinically approved S-expressing mRNA vaccine (mRNA-S-2P), we found that combinatorial mRNA vaccination (mRNA-S+N) led to markedly enhanced protection against the SARS-CoV-2 delta variant compared to mRNA-S. In a hamster model, we demonstrated that while mRNA-S alone elicited significant control of the delta strain in the lungs (∼45-fold reduction in viral loads compared to un-vaccinated control), its effectiveness in the upper respiratory tract was weak, whereas combinatorial mRNA-S+N vaccination induced markedly more robust control of the delta variant infection in the lungs (∼450-fold reduction) as well as in the upper respiratory tract (∼20-fold reduction). Immune analyses indicated that induction of N-specific immunity as well as augmented S-specific T-cell response and neutralizing antibody activity were collectively associated the enhanced protection against SARS-CoV-2 delta strain by combinatorial mRNA vaccination. These findings suggest that the combined effects of protection in the lungs and upper respiratory tract could both reduce the risk of severe disease as well as of infection and transmission.
Prior selfing occur in larger flowers in a mixed mating species with delayed selfing
Authors: Masuda Kana , Ushimaru Atushi 
Published: December 2021

AbstractTheory predicts that prior self-pollination (prior selfing) should not evolve in mixed mating species that enable delayed selfing. In this study, we test the hypotheais that prior selfing has evolved under severe pollinator limitation in the mixed mating species Commelina communis which can reproduce via delayed selfing. The hypothesis predicts that prior selfing occurs more frequently in populations with very low pollinator availability and/or in smaller flowers which receive infrequent visitations. We tested the predictions by comparing the degree of prior selfing among ten populations experiencing various levels of pollinator limitation and by examining a relationship between individual flower size and the occurrence of prior selfing. Populations with higher pollinator availability had higher prior selfing rate. Moreover, prior selfing occurs more frequently in larger flowers. These findings were totally opposite patterns of the predictions and the previous findings. We proposed new hypotheses that prior selfing has been maintained by the presence of reproductive interference from the congener and/or propotency in C. communis to explain our unexpected findings. We should verify potential effects of reproductive interference and propotency in future to elucidate the mystery of prior selfing in this mixed mating species with delayed selfing.
Simultaneous analysis of antigen-specific B and T cells after SARS-CoV-2 infection and vaccination
Authors: Newell Krista L. , Waldran Mitchell J. , Thomas Stephen J. , Endy Timothy P. , Waickman Adam T. 
Published: December 2021

AbstractConventional methods for quantifying and phenotyping antigen-specific lymphocytes can rapidly deplete irreplaceable specimens. This is due to the fact that antigen-specific T and B cells have historically been analyzed in independent assays each requiring millions of cells. A technique that facilitates the simultaneous detection of antigen-specific T and B cells would allow for more thorough immune profiling with significantly reduced sample requirements. To this end, we developed the B And T cell Tandem Lymphocyte Evaluation (BATTLE) assay, which allows for the simultaneous identification of SARS-CoV-2 Spike reactive T and B cells using an optimized Activation Induced Marker (AIM) T cell assay and dual-color B cell antigen probes. Using this assay, we demonstrate that antigen-specific B and T cell subsets can be identified simultaneously using conventional flow cytometry platforms and provide insight into the differential effects of mRNA vaccination on B and T cell populations following natural SARS-CoV-2 infection.
Investigating the conformational dynamics of Zika virus NS4B protein
Authors: Bhardwaj Taniya , Kumar Prateek , Giri Rajanish 
Published: December 2021

AbstractZika virus (ZIKV) NS4B protein is a membranotropic protein having multifunctional roles such as evasion of host-immune system, and induction of host membrane rearrangement for viral genome replication and processing of polyprotein. Despite its versatile functioning, its topology and dynamics are not entirely understood. Presently, there is no NMR or X-ray crystallography-based structure available for any flaviviral NS4B protein. Therefore, in this study, we have investigated the structural dynamics of Zika Virus NS4B protein through 3D structure models using molecular dynamics (MD) simulations approach and experiments. Subsequently, we employed a reductionist approach to understand the dynamics of ZIKV NS4B protein. For this, we studied its N-terminal (residues 1-38), C-terminal (residues 194-251), and cytosolic (residues 131-169) regions in isolation. Further, we have performed experiments to prove the maximum dynamics in its cytosolic region. Using a combination of computational tools and circular dichroism (CD) spectroscopy, we validate the cytosolic region as an intrinsically disordered protein region (IDR). The microsecond-long all atoms molecular dynamics and replica-exchange MD simulations complement the experimental observations. We have also analysed its behaviour under the influence of differently charged liposomes and macromolecular crowding agents which may have significance on its overall dynamics. Lastly, we have proposed a ZIKV NS4B protein model illustrating its putative topology consisting of various membrane-spanning and non-membranous regions.HighlightsMicrosecond simulations of NS4B N-terminus and cytosolic regions exposed their dynamic nature.C-terminal region remains intact in presence lipid bilayer during 1 μs simulations.Spectroscopic results also reveal the cytosolic region as an intrinsically disordered region.Cytosolic region exhibits gain-of-structure property under helix inducing solvents.
DeepRank-GNN: A Graph Neural Network Framework to Learn Patterns in Protein-Protein Interfaces
Authors: Réau M. , Renaud N. , Xue L. C. , Bonvin A. M. J. J. 
Published: December 2021

AbstractGaining structural insights into the protein-protein interactome is essential to understand biological phenomena and extract knowledge for rational drug design or protein engineering. We have previously developed DeepRank, a deep-learning framework to facilitate pattern learning from protein-protein interfaces using Convolutional Neural Network (CNN) approaches. However, CNN is not rotation invariant and data augmentation is required to desensitize the network to the input data orientation which dramatically impairs the computation performance. Representing protein-protein complexes as atomic- or residue-scale rotation invariant graphs instead enables using graph neural networks (GNN) approaches, bypassing those limitations.We have developed DeepRank-GNN, a framework that converts protein-protein interfaces from PDB 3D coordinates files into graphs that are further provided to a pre-defined or user-defined GNN architecture to learn problem-specific interaction patterns. DeepRank-GNN is designed to be highly modularizable, easily customized, and is wrapped into a user-friendly python3 package. Here, we showcase DeepRank-GNN’s performance for scoring docking models using a dedicated graph interaction neural network (GINet). We show that this graph-based model performs better than DeepRank, DOVE and HADDOCK scores and competes with iScore on the CAPRI score set. We show a significant gain in speed and storage requirement using DeepRank-GNN as compared to DeepRank.DeepRank-GNN is freely available fromhttps://github.com/DeepRank/DeepRank-GNN.Contacta.m.j.j.bonvin@uu.nl
Deciphering the genetic links between NAFLD and co-occurring conditions using a liver gene regulatory network
Authors: Gokuladhas Sreemol , Schierding William , Fadason Tayaza , Choi Murim , O’Sullivan Justin M. 
Published: December 2021

AbstractBackground & AimsNon-alcoholic fatty liver disease (NAFLD) is a multi-system metabolic disease that co-occurs with various hepatic and extra-hepatic diseases. The phenotypic manifestation of NAFLD is primarily observed in the liver. Therefore, identifying liver-specific gene regulatory interactions between variants associated with NAFLD and multimorbid conditions may help to improve our understanding of underlying shared aetiology.MethodsHere, we constructed a liver-specific gene regulatory network (LGRN) consisting of genome-wide spatially constrained expression quantitative trait loci (eQTLs) and their target genes. The LGRN was used to identify regulatory interactions involving NAFLD-associated genetic modifiers and their inter-relationships to other complex traits.Results and ConclusionsWe demonstrate that MBOAT7 and IL32, which are associated with NAFLD progression, are regulated by spatially constrained eQTLs that are enriched for an association with liver enzyme levels. MBOAT7 transcript levels are also linked to eQTLs associated with cirrhosis, and other traits that commonly co-occur with NAFLD. In addition, genes that encode interacting partners of NAFLD-candidate genes within the liver-specific protein-protein interaction network were affected by eQTLs enriched for phenotypes relevant to NAFLD (e.g. IgG glycosylation patterns, OSA). Furthermore, we identified distinct gene regulatory networks formed by the NAFLD-associated eQTLs in normal versus diseased liver, consistent with the context-specificity of the eQTLs effects. Interestingly, genes targeted by NAFLD-associated eQTLs within the LGRN were also affected by eQTLs associated with NAFLD-related traits (e.g. obesity and body fat percentage). Overall, the genetic links identified between these traits expand our understanding of shared regulatory mechanisms underlying NAFLD multimorbidities.
Protein Organization with Manifold Exploration and Spectral Clustering
Authors: Dubourg-Felonneau Geoffroy , Shams Shahab , Akiva Eyal , Lee Lawrence 
Published: December 2021

AbstractWe present a method to provide a biologically meaningful representation of the space of protein sequences. While billions of protein sequences are available, organizing this vast amount of information into functional categories is daunting, time-consuming and incomplete. We present our unsupervised approach that combines Transformer protein language models, UMAP graphs, and spectral clustering to create meaningful clusters in the protein spaces. To demonstrate the meaningfulness of the clusters, we show that they preserve most of the signal present in a dataset of manually curated enzyme protein families.
The polyanionic drug suramin neutralizes histones and prevents endotheliopathy
Authors: Villalba Nuria , Sackheim Adrian M. , Lawson Michael A. , Haines Laurel , Chen Yen-Lin , Sonkusare Swapnil K. , Ma Yong-Tao , Li Jianing , Majumdar Dev , Bouchard Beth A. , Boyson Jonathan E. , Poynter Matthew E. , Nelson Mark T. , Freeman Kalev 
Published: December 2021

AbstractDrugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but may cause secondary, deleterious effects such as excessive bleeding. Here, we demonstrate that suramin—a widely available polyanionic drug—completely neutralizes the toxic effects of histones. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sub-lethal doses of histones in vivo. Suramin also prevented lung edema, intra-alveolar hemorrhage and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.Significance StatementPathologic levels of circulating histones cause acute endotheliopathy, characterized by widespread disruption of critical endothelial functions and thromboinflammation. We discovered that suramin binds histones and prevents histone-induced endothelial dysfunction, thrombin generation, lung injury, and death. Histone binding is a novel mechanism of action for suramin, considered among the safest and most effective drugs by the World Health Organization. These results support the use of suramin for protection of blood vessels in conditions exacerbated by circulating histones including trauma and sepsis.
Quantitative Action Spectroscopy Reveals ARPE-19 Sensitivity to Long-Wave Ultraviolet Radiation at 350 nm and 380 nm
Authors: Anderson Graham , McLeod Andrew , Bagnaninchi Pierre , Dhillon Baljean 
Published: December 2021

AbstractThe role of ultraviolet radiation (UVR) exposure in the pathology of age-related macular degeneration (AMD) has been debated for decades with epidemiological evidence failing to find a clear consensus for or against it playing a role. A key reason for this is a lack of foundational research into the response of living retinal tissue to UVR in regard to AMD-specific parameters of tissue function. We therefore explored the response of cultured retinal pigmented epithelium (RPE), the loss of which heralds advanced AMD, to specific wavelengths of UVR across the UV-B and UV-A bands found in natural sunlight.Using a bespoke in vitro UVR exposure apparatus coupled with bandpass filters we exposed the immortalised RPE cell line, ARPE-19, to 10nm bands of UVR between 290 and 405nm. Physical cell dynamics were assessed during exposure in cells cultured upon specialist electrode culture plates which allow for continuous, non-invasive electrostatic interrogation of key cell parameters during exposure such as monolayer coverage and tight-junction integrity. UVR exposures were also utilised to quantify wavelength-specific effects using a rapid cell viability assay and a phenotypic profiling assay which was leveraged to simultaneously quantify intracellular reactive oxygen species (ROS), nuclear morphology, mitochondrial stress, epithelial integrity and cell viability as part of a phenotypic profiling approach to quantifying the effects of UVR.Electrical impedance assessment revealed unforeseen detrimental effects of UV-A, beginning at 350nm, alongside previously demonstrated UV-B impacts. Cell viability analysis also highlighted increased effects at 350nm as well as 380nm. Effects at 350nm were further substantiated by high content image analysis which highlighted increased mitochondrial dysfunction and oxidative stress.We conclude that ARPE-19 cells exhibit a previously uncharacterised sensitivity to UV-A radiation, specifically at 350nm and somewhat less at 380nm. If upheld in vivo, such sensitivity will have impacts upon geoepidemiological risk scoring of AMD.
No support for a meiosis suppressor inDaphnia pulex: Comparison of linkage maps reveals normal recombination in males of obligate parthenogenetic lineages
Authors: Molinier Cécile , Lenormand Thomas , Haag Christoph R. 
Published: December 2021

AbstractIt is often assumed that obligate parthenogenesis (OP) evolves by a disruption of meiosis and recombination. One emblematic example that appears to support this view is the crustaceanDaphnia pulex. Here, by constructing high-density linkage maps, we estimate genome-wide recombination rates in males that are occasionally produced by OP lineages, as well as in males and females of cyclical parthenogenetic (CP) lineages. The results show no significant differences in recombination rates and patterns between CP and OP males nor between CP male and CP females. The observation that recombination is not suppressed in OP males invalidates the hypothesis of a general meiosis suppressor responsible for OP. Rather, our findings suggest that inD. pulex, as in other species where OP evolves from CP ancestors, the CP to OP transition evolves through a re-use of the parthenogenesis pathways already present in CP and through their extension to the entire life cycle, at least in females. In addition to the implications for the evolution of OP, the genetic maps produced by this study constitute an important genomic resource for the model speciesDaphnia.
Fission of megamitochondria into multiple smaller well-defined mitochondria in the ageing zebrafish retina
Authors: Burgoyne Thomas , Toms Maria , Way Chris , Tracey-White Dhani , Futter Clare E. , Moosajee Mariya 
Published: December 2021

AbstractMitochondria are essential adenosine triphosphate (ATP)-generating cellular organelles. In the retina, they are highly numerous in the photoreceptors and retinal pigment epithelium (RPE) due to their high energetic requirements. Fission and fusion of the mitochondria within these cells allow them to adapt to changing demands over the lifespan of the organism. Using transmission electron microscopy, we examined the mitochondrial ultrastructure of zebrafish photoreceptors and RPE from 5 days post fertilisation (dpf) through to late adulthood (3 years). Notably, mitochondria in the youngest animals were large and irregular shaped with a loose cristae architecture, but by 8 dpf they had reduced in size and expanded in number with more defined cristae. When investigating temporal gene expression of several mitochondrial-related markers, they indicated fission as the dominant mechanism contributing to these changes observed over time. This is likely to be due to continued mitochondrial stress resulting from the oxidative environment of the retina and prolonged light exposure. We have characterised retinal mitochondrial ageing in a key vertebrate model organism, that provides a basis for future studies of retinal diseases that are linked to mitochondrial dysfunction.
Photosynthesis and antioxidant metabolism modulate the low-temperature resistance of seed germination in maize
Authors: Meng Aiju , Wen Daxing , Zhang Chunqing 
Published: December 2021

AbstractSpring maize is usually subjected to low-temperature stress during seed germination, which retards seedling growth even if under a suitable temperature. However, the mechanism underlying maize seed germination under low-temperature stress modulating seedling growth after being transferred to normal temperature is still ambiguous. In this study, we used two maize inbred lines with different low-temperature resistance (SM and RM) to investigate the mechanism. The results showed that the SM line had higher lipid peroxidation and lower total antioxidant capacity and germination percentage than the RM line under low-temperature stress, which indicated that the SM line was more vulnerable to low-temperature stress. Further transcriptome analysis revealed that seed germination under low-temperature stress caused down-regulation of photosynthesis related gene ontology (GO) terms in two lines. Moreover, the SM line displayed down-regulation of ribosome and superoxide dismutase (SOD) related genes, whereas genes involved in SOD and vitamin B6 were up-regulated in the RM line. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that photosynthesis and antioxidant metabolism related pathways played important roles in seed germination in response to low-temperature stress, and the photosynthetic system displayed a higher damage degree in the SM line. Both qRT-PCR and physiological characteristics experiments showed similar results with transcriptome data. Taken together, we propose a model for maize seed germination in response to low-temperature stress.One sentence summaryDamage degree of photosynthesis and total antioxidant capacity (especially SOD activity) determine diverse low-temperature resistance among maize inbred lines at the germination stage.
Noncanonical structural requirements of neurofibromin SUMOylation reveal a folding-deficiency of several pathogenic mutants
Authors: Bergoug Mohammed , Mosrin Christine , Godin Fabienne , Doudeau Michel , Sosic Iva , Suskiewicz Marcin , Vallée Béatrice , Bénédetti Hélène 
Published: December 2021

ABSTRACTNeurofibromin (Nf1) is a large multidomain protein encoded by the tumour-suppressor gene NF1. NF1 is mutated in a frequently occurring genetic disease, neurofibromatosis type I, and in various cancers. The best described function of Nf1 is its Ras-GTPase activity, carried out by its GAP-related domain (GRD). SecPH, another structurally well-characterized domain of Nf1, is immediately adjacent to the GRD and interacts with lipids and proteins, thus connecting Nf1 to diverse signalling pathways. Here, we demonstrate, for the first time, that Nf1 and SecPH are substrates of the SUMO pathway. We identified a well-defined SUMOylation profile of SecPH and a main SUMOylation event on Lys1731 that appears to play a role in Ras-GAP activity. Our data allowed us to characterize a new set of pathogenic Nf1 missense mutants that exhibits a disrupted SUMOylation profile that may correlate with their unfolding. Accordingly, Lys1731 SUMOylation is mediated by a noncanonical structural motif, therefore allowing a read-out of SecPH conformation and folding status.
A conserved viral amphipathic helix governs the replication site-specific membrane association
Authors: Sathanantham Preethi , Zhao Wenhao , He Guijuan , Murray Austin , Fenech Emma , Diaz Arturo , Schuldiner Maya , Wang Xiaofeng 
Published: December 2021

AbstractPositive-strand RNA viruses assemble their viral replication complexes (VRCs) on specific host organelle membranes, yet it is unclear how viral replication proteins recognize and what motifs or domains in viral replication proteins determine their localizations. We show here that an amphipathic helix, helix B in replication protein 1a of brome mosaic virus (BMV), is necessary for 1a’s localization to the nuclear endoplasmic reticulum (ER) membrane where BMV assembles its VRCs. Helix B is also sufficient to target soluble proteins to the nuclear ER membrane in yeast and plant cells. We further show that an equivalent helix in several plant- and human-infecting viruses of the alphavirus-like superfamily targets fluorescent proteins to the organelle membranes where they form their VRCs, including ER, vacuole, and Golgi membranes. Our work reveals a conserved helix that governs the localization of VRCs among a group of viruses and points to a possible target for developing broad-spectrum antiviral strategies.