bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutralization of Delta variant with sera of Covishield vaccinees and COVID-19 recovered vaccinated individuals
Authors: Sapkal Gajanan N. , Yadav Pragya D. , Sahay Rima R. , Deshpande Gururaj , Gupta Nivedita , Nyayanit Dimpal A , Patil Deepak Y. , Kumar Sanjay , Abraham Priya , Panda Samiran , Bhargava Balram 
Published: July 2021

AbstractThe recent emergence of B.1.617 lineage has created grave public health problem in India. The lineage further mutated to generate sub-lineages B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.617.3. Apparently, the Delta variant has slowly dominated the other variants including B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.617.3. With this, World Health Organization has described this sub-lineage as variant of concern. The high transmissibility associated with Delta variant has led to second wave of pandemic in India which affected millions of people. Besides this, variant of concerns has been reported to show lower neutralization to several approved vaccines. This has led to breakthrough infections after completion of vaccination regimen. There is limited information available on the duration of protective immune response post-infection, vaccination or breakthrough infection with SARS-CoV-2. In this study, we have evaluated immune response in sera of the Covishield vaccinated individuals belonging to category: I. one dose vaccinated, II. two doses vaccinated, III. COVID-19 recovered plus one dose vaccinated, IV. COVID-19 recovered plus two doses vaccinated and V. breakthrough COVID-19 cases. The findings of the study demonstrated that the breakthrough cases and the COVID-19 recovered individuals with one or two dose of vaccine had relatively higher protection against Delta variant in comparison to the participants who were administered either one or two doses of Covishield™. Prior vaccination results in less severe disease against subsequent infection provide evidence that both humoral and cellular immune response play an important role in protection.
Knowledge-based antibody repertoire simulation, a novel allele detection tool evaluation and application
Authors: Yang Xiujia , Zhu Yan , Zeng Huikun , Chen Sen , Guan Junjie , Wang Qilong , Lan Chunhong , Sun Deqiang , Yu Xueqing , Zhang Zhenhai 
Published: July 2021

AbstractDetailed knowledge of the diverse immunoglobulin germline genes is critical for the study of humoral immunity. Hundreds of alleles have been discovered by analyzing antibody repertoire sequencing (Rep-seq or Ig-seq) data via multiple novel allele detection tools (NADTs). However, the performance of these NADTs through antibody sequences with intrinsic somatic hypermutations (SHMs) is unclear. Here, we developed a tool to simulate repertoires by integrating the full spectrum features of an antibody repertoire such as germline gene usage, junctional modification, position-specific SHM and clonal expansion based on 2152 high-quality datasets. We then systematically evaluated these NADTs using both simulated and genuine Ig-seq datasets. Finally, we applied these NADTs to 687 Ig-seq datasets and identified 43 novel alleles using defined criteria. Twenty-five alleles were validated through findings of other sources. In addition to the novel alleles detected, our simulation tool, the results of our comparison, and the streamline of this process may benefit further humoral immunity studies via Ig-seq.
Tetrapod diversity facets in jeopardy during the Anthropocene
Authors: Tordoni Enrico , Toussaint Aurèle , Pärtel Meelis , Nogues-Bravo David , Theodoridis Spyros , Carmona Carlos Pérez 
Published: July 2021

AbstractHuman activities have eroded biodiversity, yet the varying influence of past versus recent impacts across the distinct facets of biodiversity is still poorly understood. Weighting taxonomic information by phylogenetic and functional diversity in a novel multifaceted index (μ-Diversity) across more than 17,000 tetrapod species, we show the geography of multifaceted tetrapod diversity, and the role of climate stability and water-energy dynamics coupled with the timing of inception of agriculture in explaining broad-scale patterns of tetrapod diversity. In particular, the varying geography of the timing of agriculture expansion since the Neolithic affected μ-Diversity at least as much as recent human impacts, especially in birds, mammals, and reptiles, suggesting that human imprints may have shaped tetrapod diversity for millennia through legacy effects of past land use modifications. The long-lasting effect of humans will only accelerate, as the most diverse areas for μ-Diversity (tropical Africa, South East Asia and Central and South America) are disproportionally exposed to both future climate and land-use change.
Strategies for the site-specific decoration of DNA origami nanostructures with functionally intact proteins
Authors: Hellmeier Joschka , Platzer René , Mühlgrabner Vanessa , Schneider Magdalena C. , Kurz Elke , Schütz Gerhard J. , Huppa Johannes B. , Sevcsik Eva 
Published: July 2021

AbstractDNA origami structures provide flexible scaffolds for the organization of single biomolecules with nanometer precision. While they find increasing use for a variety of biological applications, the functionalization with proteins at defined stoichiometry, high yield, and under preservation of protein function remains challenging. In this study, we applied single molecule fluorescence microscopy in combination with a cell biological functional assay to systematically evaluate different strategies for the site-specific decoration of DNA origami structures, focusing on efficiency, stoichiometry and protein functionality. Using an activating ligand of the T-cell receptor (TCR) as protein of interest, we found that two commonly used methodologies underperformed with regard to stoichiometry and protein functionality. While strategies employing tetravalent wildtype streptavidin for coupling of a biotinylated TCR-ligand yielded mixed populations of DNA origami structures featuring up to 3 proteins, the use of divalent (dSAv) or DNA-conjugated monovalent streptavidin (mSAv) allowed for site-specific attachment of a single biotinylated TCR-ligand. The most straightforward decoration strategy, via covalent DNA conjugation, resulted in a 3-fold decrease in ligand potency, likely due to charge-mediated impairment of protein function. Replacing DNA with charge-neutral PNA in a ligand conjugate emerged as the coupling strategy with the best overall performance in our study, as it produced the highest yield with no multivalent DNA origami structures and fully retained protein functionality. With our study we aim to provide guidelines for the stoichiometrically defined, site-specific functionalization of DNA origami structures with proteins of choice serving a wide range of biological applications.
Improved Metabolite Prediction Using Microbiome Data-Based Elastic Net Models
Authors: Xie Jialiu , Cho Hunyong , Lin Bridget M. , Pillai Malvika , Heimisdottir Lara H. , Bandyopadhyay Dipankar , Zou Fei , Roach Jeffrey , Divaris Kimon , Wu Di 
Published: July 2021

AbstractMicrobiome data are becoming increasingly available in large health cohorts yet metabolomics data are still scant. While many studies generate microbiome data, they lack matched metabolomics data or have considerable missing proportions of metabolites. Since metabolomics is key to understanding microbial and general biological activities, the possibility of imputing individual metabolites or inferring metabolomics pathways from microbial taxonomy or metagenomics is intriguing. Importantly, current metabolomics profiling methods such as the HMP Unified Metabolic Analysis Network (HUMAnN) have unknown accuracy and are limited in their ability to predict individual metabolites. To address this gap, we developed a novel metabolite prediction method, and we present its application and evaluation in an oral microbiome study. We developed ENVIM based on the Elastic Net Model (ENM) to predict metabolites using micorbiome data. ENVIM introduces an extra step to ENM to consider variable importance scores and thus achieve better prediction power. We investigate the metabolite prediction performance of ENVIM using metagenomic and metatranscriptomic data in a supragingival biofilm multi-omics dataset of 297 children ages 3-5 who were participants of a community-based study of early childhood oral health (ZOE 2.0) in North Carolina, United States. We further validate ENVIM in two additional publicly available multi-omics datasets generated from studies of gut health and vagina health. We select gene-family sets based on variable importance scores and modify the existing ENM strategy used in the MelonnPan prediction software to accommodate the unique features of microbiome and metabolome data. We evaluate metagenomic and metatranscriptomic predictors and compare the prediction performance of ENVIM to the standard ENM employed in MelonnPan. The newly-developed ENVIM method showed superior metabolite predictive accuracy than MelonnPan using metatranscriptomics data only, metagenomics data only, or both of these two. Both methods perform better prediction using gut or vagina microbiome data than using oral microbiome data for the samples’ corresponding metabolites. The top predictable compounds have been reported in all these three datasets from three different body sites. Enrichment of prediction some contributing species has been detected.
Physics-based inverse design of cholesterol attracting transmembrane helices reveals a paradoxical role of hydrophobic length
Authors: Methorst Jeroen , Verwei Nino , Hoffmann Christian , Chodnicki Paweł , Sansevrino Roberto , Wang Han , van Hilten Niek , Aschmann Dennis , Kros Alexander , Andreas Loren , Czub Jacek , Milovanovic Dragomir , Risselada Herre Jelger 
Published: July 2021

The occurrence of linear cholesterol-recognition motifs in alpha-helical transmembrane domains has long been debated. Here, we demonstrate the ability of a genetic algorithm guided by coarse-grained molecular dynamics simulations—a method coined evolutionary molecular dynamics (Evo-MD)—to directly resolve the sequence which maximally attracts cholesterol for single-pass alpha-helical transmembrane domains (TMDs). We illustrate that the evolutionary landscape of cholesterol attraction in membrane proteins is characterized by a sharp, well-defined global optimum. Surprisingly, this optimal solution features an unusual short, slender hydrophobic block surrounded by three successive lysines. Owing to the membrane thickening effect of cholesterol, cholesterol-enriched ordered phases favor TMDs characterized by a long rather than a too short hydrophobic length (a negative hydrophobic mismatch). However, this short hydrophobic pattern evidently offers a pronounced net advantage for the attraction of free cholesterol in both coarse-grained and atomistic simulations. We illustrate that optimal cholesterol attraction is in fact based on the superposition of two distinct structural features: (i) slenderness and (ii) hydrophobic mismatch. In addition, we explore the evolutionary occurrence and feasibility of the two features by analyzing existing databases of membrane proteins and through the direct expression of analogous short hydrophobic sequences in live cell assays. The puzzling sequence variability of proposed linear cholesterol-recognition motifs is indicative of a sub-optimal membrane-mediated attraction of cholesterol which markedly differs from ligand binding based on shape compatibility.Significance StatementOur work demonstrates how a synergy between evolutionary algorithms and high-throughput coarse-grained molecular dynamics can yield fundamentally new insights into the evolutionary fingerprints of protein-mediated lipid sorting. We illustrate that the evolutionary landscape of cholesterol attraction in isolated transmembrane domains is characterized by a well-defined global optimum. In contrast, sub-optimal attraction of cholesterol is associated with a diverse solution space and features a high sequence variability despite acting on the same unique molecule. The contrasting physicochemical nature of the resolved attraction optimum suggests that cholesterol attraction via linear motifs does not pose a dominant pressure on the evolution of transmembrane proteins.
Hypervariable-Locus Melting Typing (HLMT): a novel, fast and inexpensive sequencing-free approach to pathogen typing based on High Resolution Melting (HRM) analysis
Authors: Perini Matteo , Piazza Aurora , Panelli Simona , Papaleo Stella , Alvaro Alessandro , Vailati Francesca , Corbella Marta , Saluzzo Francesca , Gona Floriana , Castelli Daniele , Farina Claudio , Marone Piero , Cirillo Daniela Maria , Cavallero Annalisa , Zuccotti Gian Vincenzo , Comandatore Francesco 
Published: July 2021

AbstractObjectivesSubspecies pathogen typing is a pivotal tool to detect the emergence of high-risk clones in hospital settings and to limit their spreading among patients. Unfortunately, the most used subspecies typing methods (i.e. Pulsed-field Gel Electrophoresis - PFGE, Multi-Locus Sequence Typing - MLST and Whole Genome Sequencing - WGS) are too expensive and time consuming to be suitable for real-time surveillance. Here we present Hypervariable-Locus Melting Typing (HLMT), a novel subspecies typing approach based on High Resolution Melting (HRM) analysis, which allows pathogen typing in a few hours and with ∼5 euros per sample.MethodsHLMT types the strains by clustering them using melting temperatures (HLMT-clustering) and/or by assigning them to Melting Types (MTs) on the basis of a reference dataset (HLMT-assignment). We applied HLMT (clustering and typing) to 134 Klebsiella pneumoniae strains collected during outbreaks or surveillance programs in four hospitals. Then, we compared HLMT typing results to PFGE, MLST and WGS.ResultsHLMT-clustering distinguishes most of the K. pneumoniae high-risk clones with a sensitivity comparable to PFGE and MLST. It also drawed surveillance epidemiological curves comparable to those obtained by MLST, PFGE and WGS typing. Furthermore, the results obtained by HLMT-assignment were coherent to MLST for 96% of the typed strains with a Jaccard index of 0.912.ConclusionsHLMT is a fast and scalable method for pathogen typing, suitable for real-time hospital microbiological surveillance. HLMT is also inexpensive and thus it is applicable to infection control programs in low-middle income countries.
Programmable Cleavage of Double-stranded DNA by Combined Action of Argonaute CbAgo from Clostridium butyricum and Nuclease Deficient RecBC Helicase from E.coli
Authors: Vaiskunaite Rita , Vainauskas Jogirdas , Morris Janna , Potapov Vladimir , Bitinaite Jurate 
Published: July 2021

ABSTRACTProkaryotic Argonautes (pAgos) use small nucleic acids as specificity guides to cleave single-stranded DNA at complementary sequences. DNA targeting function of pAgos creates attractive opportunities for DNA manipulations that require programmable DNA cleavage. Discovery of mesophilic Argonautes active at physiological temperature places pAgos closer to their possible application for genome editing as a simpler alternative to CRISPR/Cas nucleases. Currently, the use of mesophilic pAgos as programmable DNA endonucleases is hampered by their poor action on double-stranded DNA (dsDNA), mainly due to their inability to invade the DNA duplex. The present study demonstrates that efficient in vitro cleavage of double-stranded DNA by mesophilic Argonaute CbAgo from Clostridium butyricum can be activated via the DNA strand unwinding activity of nuclease deficient mutant of RecBC DNA helicase from Escherichia coli (referred to as RecBexo-C). Properties of CbAgo and characteristics of simultaneous cleavage of complementary DNA strands in concurrence with DNA strand unwinding by RecBexo-C were thoroughly explored using 0.3-25 kb DNA substrates. When combined with RecBexo-C helicase, CbAgo was capable of cleaving target sequences located 11-12.5 kb from the ends of linear dsDNA at 37ºC. Our study demonstrates that CbAgo with RecBexo-C can be programmed to generate dsDNA fragments flanked with custom-designed single-stranded overhangs suitable for ligation with compatible DNA fragments. At present, the combination of CbAgo and RecBexo-C represents the most efficient mesophilic DNA-guided DNA-cleaving programmable endonuclease for use in diagnostic and synthetic biology methods that require sequence-specific nicking/cleavage of dsDNA at any desired location.
Fungal community composition along a gradient of permafrost thaw
Authors: Kluge Mariana , Wurzbacher Christian , Wauthy Maxime , Clemmensen Karina Engelbrecht , Hawkes Jeffrey , Einarsdottir Karolina , Stenlid Jan , Peura Sari 
Published: July 2021

AbstractThermokarst activity at permafrost sites releases considerable amount of ancient carbon to the atmosphere. A large part of this carbon is released via thermokarst ponds, and fungi could be an important organismal group enabling its recycling. However, our knowledge about aquatic fungi growing in thermokarstic systems is extremely limited. In this study, we collected samples from five permafrost sites distributed across circumpolar Arctic and representing a gradient of permafrost integrity. Samples were taken from the ponds surface water, the detritus and the sediment at the bottom of the ponds. These samples were extracted for total DNA, which was then amplified using primers targeting the fungal ITS2 region of the ribosomal genes. These amplicons were sequenced using PacBio technology. Surface water samples were also collected to analyze the chemical conditions in the ponds, including nutrient status and the quality and quantity of dissolved organic carbon. This dataset gives a unique overview of the impact of the thawing permafrost on fungal communities and their potential role on carbon recycling.
PEPSDI: Scalable and flexible inference framework for stochastic dynamic single-cell models
Authors: Persson Sebastian , Welkenhuysen Niek , Shashkova Sviatlana , Wiqvist Samuel , Reith Patrick , Schmidt Gregor W. , Picchini Umberto , Cvijovic Marija 
Published: July 2021

AbstractMathematical modelling is an invaluable tool to describe dynamic cellular processes and to rationalise cell-to-cell variability within the population. This requires statistical methods to infer unknown model parameters from dynamic, multi-individual data accounting for heterogeneity caused by both intrinsic and extrinsic noise. Here we present PEPSDI, a scalable and flexible framework for Bayesian inference in state-space mixed-effects stochastic dynamic single-cell models. Unlike previous frameworks, PEPSDI imposes a few modelling assumptions when inferring unknown model parameters from time-lapse data. Specifically, it can infer model parameters when intrinsic noise is modelled by either exact or approximate stochastic simulators, and when extrinsic noise is modelled by either time-varying, or time-constant parameters that vary between cells. This allowed us to identify hexokinase activity as a source of extrinsic noise, and to deduce that sugar availability dictates cell-to-cell variability in the budding yeastSaccharomyces cerevisiaeSNF1 nutrient sensing pathway.
miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells
Authors: Tanaka Pedro Paranhos , Oliveira Ernna Hérida , Vieira-Machado Mayara Cristina , Duarte Max Jordan , Assis Amanda Freire , Bombonato-Prado Karina Fittipaldi , Passos Geraldo Aleixo 
Published: July 2021

AbstractBackgroundThe autoimmune regulator (Aire) gene is critical for the appropriate establishment of central immune tolerance. As one of the main controllers of promiscuous gene expression in the thymus, Aire promotes the expression of thousands of downstream tissue-restricted antigen (TRA) genes, cell adhesion genes and transcription factor genes in medullary thymic epithelial cells (mTECs). Despite the increasing knowledge about the role of Aire as an upstream transcriptional controller, little is known about the mechanisms by which this gene could be regulated.ResultsHere, we assessed the posttranscriptional control of Aire by miRNAs. The in silico miRNA-mRNA interaction analysis predicted thermodynamically stable hybridization between the 3′ UTR of Aire mRNA and miR-155, which was confirmed to occur within the cellular milieu through a luciferase reporter assay. This finding enabled us to hypothesize that miR-155 might play a role as an intracellular posttranscriptional regulator of Aire mRNA. To test this hypothesis, we transfected a murine mTEC cell line with a miR-155 mimic in vitro, which reduced the mRNA and protein levels of Aire. Moreover, large-scale transcriptome analysis showed the modulation of 311 downstream mRNAs, which included 58 TRA mRNAs. Moreover, miR-155 mimic-transfected cells exhibited a decrease in their chemotaxis property compared with control thymocytes.ConclusionOverall, the results indicate that miR-155 may posttranscriptionally control Aire mRNA as well as a crucial process by which mTECs allow migration of thymocytes through chemotaxis.
Fungal effector SIB1 of Colletotrichum orbiculare has unique structural features and can suppress plant immunity in Nicotiana benthamiana
Authors: Zhang Ru , Isozumi Noriyoshi , Mori Masashi , Okuta Ryuta , Singkaravanit-Ogawa Suthitar , Imamura Tomohiro , Gan Pamela , Shirasu Ken , Ohki Shinya , Takano Yoshitaka 
Published: July 2021

AbstractFunctional screening of effector candidates using a transient expression assay in Nicotiana benthamiana identified two virulence-related effectors, named SIB1 and SIB2 (Suppression of Immunity in N. benthamiana), of an anthracnose fungus Colletotrichum orbiculare, which infects both cucurbits and N. benthamiana. Agrobacterium-mediated transient expression of SIB1 or SIB2 increased the susceptibility of N. benthamiana to C. orbiculare, which suggested these effectors can suppress immune responses in N. benthamiana. The presence of SIB1 and SIB2 homologs was found to be limited to the genus Colletotrichum. SIB1 suppressed both the generation of reactive oxygen species (ROS) triggered by the bacterial pathogen-associated molecular pattern (PAMP), flg22, and the cell death response triggered by the Phytophthora infestans INF1 elicitin in N. benthamiana. We determined the NMR-based structure of SIB1 to obtain its structural insights. The three-dimensional structure of SIB1 comprises five β-strands, each containing three disulfide bonds. The overall conformation was found to be a cylindrical shape, such as the well-known antiparallel β-barrel structure. However, the β-strands were found to display a unique topology, one pair of these β-strands formed a parallel β-sheet. These results suggest that the effector SIB1 present in Colletotrichum fungi has unique structural features and can suppress PAMP-triggered immunity (PTI) in N. benthamiana.
Co-deletion of ATAD1 with PTEN primes cells for BIM-mediated apoptosis
Authors: Winter Jacob M. , Fresenius Heidi L. , Keys Heather R. , Cunningham Corey N. , Ryan Jeremy , Sirohi Deepika , Berg Jordan A. , Tripp Sheryl R. , Barta Paige , Agarwal Neeraj , Letai Anthony , Sabatini David M. , Wohlever Matthew L. , Rutter Jared 
Published: July 2021

AbstractPTEN is a potent tumor suppressor gene that is frequently mutated or deleted in human cancers. Such deletions often include portions of the 10q23 locus beyond the bounds of PTEN itself, in many cases resulting in the disruption of additional genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic BIM protein from mitochondria to inactivate it. Cells lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which increase BIM and trigger apoptosis. Thus, we demonstrate that mitochondrial protein quality control interfaces with cell death in a clinically actionable manner.