bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intimate genetic relationships and fungicide resistance in multiple strains of human pathogenic fungus Aspergillus fumigatus isolated from a plant bulb
Authors: Takahashi Hiroki , Oiki Sayoko , Kusuya Yoko , Urayama Syun-ichi , Hagiwara Daisuke 
Published: May 2021

SummaryFungal infections are increasingly dangerous because of environmentally-dispersed resistance to antifungal drugs. Azoles are commonly used antifungal drugs, but they are also used as fungicides in agriculture, which may enable enrichment of azole-resistant strains of the human pathogen Aspergillus fumigatus in the environment. Understanding of environmental dissemination and enrichment of genetic variation associated with azole resistance in A. fumigatus is required to suppress resistant strains. Here, we focused on eight strains of azole-resistant A. fumigatus isolated from a single tulip bulb for sale in Japan. This set includes strains with TR34/L98H/T289A/I364V/G448S and TR46/Y121F/T289A/S363P/I364V/G448S mutations in the cyp51A gene, which showed higher tolerance to several azoles than strains harboring TR46/Y121F/T289A mutation. The strains were typed by microsatellite typing, single nucleotide polymorphism profiles, and mitochondrial and nuclear genome analyses. The strains grouped differently using each typing method, suggesting historical genetic recombination among the strains. Our data also revealed that some strains isolated from the tulip bulb showed tolerance to other classes of fungicide, such as QoI and carbendazim, followed by related amino acid alterations in the target proteins. Considering spatial-temporal factors, plant bulbs are an excellent environmental niche for fungal strains to encounter partners, and to obtain and spread resistance-associated mutations.
Psychological factors underpinning vaccine willingness in Israel, Japan and Hungary
Authors: Goodwin Robin , Ben-Ezra Menachem , Takahashi Masahito , Luu Lan-Anh Nguyen , Borsfay Krisztina , Kovács Mónika , Hou Wai-Kai , Hamama-Raz Yaira , Levin Yafit 
Published: May 2021

AbstractThe rapid international spread of the SARS-CoV-2 virus 19 led to unprecedented attempts to develop and administer an effective vaccine. However, there is considerable vaccine hesitancy in some countries. We investigated willingness to vaccinate in three nations with historically different levels of vaccine willingness and attitudes: Israel, Japan and Hungary. Employing an ecological-systems approach we analysed associations between demographic factors and health status, individual cognitions, normative pressures, trust in government, belief in COVID-19 myths and willingness to be vaccinated, using data from three nationally representative samples (Israel, N=1011 (Jan 2021); Japan, N= 997 (Feb 2021); Hungary, N=1131 (Apr 2021)). In Israel 74% indicated a willingness to vaccinate, but only 51% in Japan and 31% in Hungary. Multigroup regression analyses indicated greater vaccine willingness amongst those who perceived benefits to vaccination, anticipated regret if not vaccinated and trusted the government. Multi-group latent class analysis of ten COVID-19 (mis)beliefs identified three classes of myths, with concerns about the alteration of DNA (Israel), allergies (Hungary) and catching COVID-19 from the vaccine (Japan) specific to vaccine willingness for each culture. Intervention campaigns should focus on increasing trust and addressing culturally specific myths while emphasising the individual and social group benefits of vaccination.
A Promising Chemical Series of Positive Allosteric Modulators of the μ-Opioid Receptor that Enhance the Antinociceptive Efficacy of Opioids but not their Adverse Effects
Authors: Pryce Kerri D. , Kang Hye Jin , Sakloth Farhana , Liu Yongfeng , Khan Susan , Toth Katalin , Kapoor Abhijeet , Nicolais Andrew , Che Tao , Qin Lihuai , Bertherat Feodora , Kaniskan H. Ümit , Jin Jian , Cameron Michael D. , Roth Bryan L. , Zachariou Venetia , Filizola Marta 
Published: May 2021

ABSTRACTPositive allosteric modulators (PAMs) of the µ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.
Reprogrammed tracrRNAs enable repurposing RNAs as crRNAs and detecting RNAs
Authors: Liu Yang , Pinto Filipe , Wan Xinyi , Peng Shuguang , Li Mengxi , Xie Zhen , French Christopher E. , Wang Baojun 
Published: May 2021

AbstractIn type II CRISPR systems, the guide RNA (gRNA) consists of a CRISPR RNA (crRNA) and a hybridized trans-acting CRISPR RNA (tracrRNA) which interacts directly with Cas9 and is essential to its guided DNA targeting function. Though tracrRNAs are diverse in sequences and structures across type II CRISPR systems, the programmability of crRNA-tracrRNA hybridization for particular Cas9 has not been studied adequately. Here, we revealed the high programmability of crRNA-tracrRNA hybridization for Streptococcus pyogenes Cas9. By reprogramming the crRNA-tracrRNA hybridized sequence, reprogrammed tracrRNAs can repurpose various RNAs as crRNAs to trigger CRISPR function. We showed that the engineered crRNA-tracrRNA pairs enable design of orthogonal cellular computing devices and hijacking of endogenous RNAs as crRNAs. We next designed novel RNA sensors that can monitor the transcriptional activity of specific genes on the host genome and detect SARS-CoV-2 RNA in vitro. The engineering potential of crRNA-tracrRNA interaction has therefore redefined the capabilities of CRISPR/Cas9 system.
CellMap: Characterizing the types and composition of iPSC-derived cells from RNA-seq data
Authors: Ouyang Zhengyu , Bourgeois Nathanael , Lyashenko Eugenia , Cundiff Paige , Cullen Patrick F. , Challa Ravi , Li Kejie , Zhang Xinmin , Casey Fergal , Engle Sandi , Zhang Baohong , Zavodszky Maria I. 
Published: May 2021

AbstractInduced pluripotent stem cell (iPSC) derived cell types are increasingly employed as in vitro model systems for drug discovery. For these studies to be meaningful, it is important to understand the reproducibility of the iPSC-derived cultures and their similarity to equivalent endogenous cell types. Single-cell and single-nucleus RNA sequencing (RNA-seq) are useful to gain such understanding, but they are expensive and time consuming, while bulk RNA-seq data can be generated quicker and at lower cost. In silico cell type decomposition is an efficient, inexpensive, and convenient alternative that can leverage bulk RNA-seq to derive more fine-grained information about these cultures. We developed CellMap, a computational tool that derives cell type profiles from publicly available single-cell and single-nucleus datasets to infer cell types in bulk RNA-seq data from iPSC-derived cell lines.
Effect of water temperature on the behavior ofNeptunea cumingiiand the histology, immune enzyme activity, and transcriptome of its gills and kidneys
Authors: Zhang Dandan , Dong Xiaoyu , Zhu Jianye , Yang Jiacheng , Tian Ying , Wang Luo , Mao Junxia , Wang Xubo , Chang Yaqing , Hao Zhenlin 
Published: May 2021

AbstractThe behavior of the marine snailNeptunea cumingiicultured at different temperatures (0, 4, 8, 12, 16 (control), 20, 24, and 28°C) and the histology, immune enzyme activity, and transcriptome of its gills and kidneys were studied using ecological and molecular methods. At 0°C, most of the snails shrank in size and did not eat during the first 6 h. At 28°C, snails also did not eat, death began to occur at 24 h. when the temperature was 8 °C and 12 °C, there was no significant difference in the mean feed intake ofN. cumingii(P>0.05). And it was higher than the average conch intake under other temperature conditions. However, the histology of the gills and kidneys differed among test temperatures. At 0°C, the morphology of the gill pieces was difficult to judge. At 24°C, edema was present in the small gills, and at 28°C the small gills were severely deformed, the distance between the gill capillaries and the surrounding area was enlarged, and the gill tissue was severely damaged. Temperature increase or decrease from 16°C caused the columnar cells of the kidney to become shorter and more numerous. The total antioxidant capacity (T-AOC), catalase (CAT) and superoxide dismutase activities (SOD) of the gill and kidney differed significantly among the temperature conditions (p < 0.05). Transcriptome results showed that temperature change resulted in up-regulation of 2339 genes and down-regulation of 2058 genes in the gills, and in up-regulation of 2300 genes and down-regulation of 2060 genes in the kidneys ofN. cumingii. Furthermore, the DEGs were subject to GO and KEGG enrichment analysis, and which showed that most of the DEGs in gill were involved in protein folding, defolding, translation, ribosome, and most of the DEGs in kidney were involved in DNA recombination, nuclear euchromatin, RNA-directed DNA polymerase activity. Finally, the results from this study show thatN. cumingiiprefers the temperature range was 8 to 16, temperature increase or decrease from that range, many aspects ofN. cumingiibiology could be significantly affected.
Nucleocapsid mutation R203K/G204R increases the infectivity, fitness and virulence of SARS-CoV-2
Authors: Wu Haibo , Xing Na , Meng Kaiwen , Fu Beibei , Xue Weiwei , Dong Pan , Xiao Yang , Liu Gexin , Luo Haitao , Zhu Wenzhuang , Lin Xiaoyuan , Meng Geng , Zhu Zhenglin 
Published: May 2021

AbstractIn addition to the mutations on the spike protein (S), co-occurring mutations on nucleocapsid (N) protein are also emerging in SARS-CoV-2 world widely. Mutations R203K/G204R on N, carried by high transmissibility SARS-CoV-2 lineages including B.1.1.7 and P.1, has a rapid spread in the pandemic during the past year. In this study, we performed comprehensive population genomic analyses and virology experiment concerning on the evolution, causation and virology consequence of R203K/G204R mutations. The global incidence frequency (IF) of 203K/204R has rose up from nearly zero to 76% to date with a shrinking from August to November in 2020 but bounced later. Our results show that the emergence of B.1.1.7 is associated with the second growth of R203K/G204R mutants. We identified positive selection evidences that support the adaptiveness of 203K/204R variants. The R203K/G204R mutant virus was created and compared with the native virus. The virus competition experiments show that 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly in relation to the ribonucleocapsid (RNP) assemble during the virus replication. Moreover, the 203K/204R virus increased the infectivity in a human lung cell line and induced an enhanced damage to blood vessel of infected hamsters’ lungs. In consistence, we observed a positive association between the increased severity of COVID-19 and the IF of 203K/204R from in silicon analysis of global clinical and epidemic data. In combination with the informatics and virology experiment, our work suggested the contribution of 203K/204R to the increased transmission and virulence of the SARS-CoV-2. In addition to mutations on the S protein, the mutations on the N protein are also important to virus spread during the pandemic.
Extremely potent Human Monoclonal Antibodies for the Prophylaxis and Therapy of Tetanus
Authors: Pirazzini Marco , Grinzato Alessandro , Corti Davide , Barbieri Sonia , Leka Oneda , Vallese Francesca , Tonellato Marika , Silacci-Fregni Chiara , Piccoli Luca , Kandiah Eaazhisai , Schiavo Giampietro , Zanotti Giuseppe , Lanzavecchia Antonio , Montecucco Cesare 
Published: May 2021

ABSTRACTHuman monoclonal antibodies were used here to study the mechanism of neuron intoxication by tetanus neurotoxin protein toxins and as a safe preventive and therapeutic substitute of hyperimmune sera. By screening memory B cells of immune donors, we selected two monoclonal antibodies specific for tetanus neurotoxin with exceptionally high neutralizing activities, which have been extensively characterized both structurally and functionally. We found that these antibodies interfere with the binding and translocation of the neurotoxin into neurons by interacting with two epitopes, whose definition pinpoints crucial events in the cellular pathogenesis of tetanus. Some mechanistic aspects of tetanus neurotoxin intoxication were revealed, explaining at the same time, the unprecedented neutralization ability of these antibodies. Importantly, these antibodies are exceptionally efficient in preventing experimental tetanus when injected in mice long before the neurotoxin. Moreover, their Fab derivatives neutralize tetanus neurotoxin in post-exposure experiments, suggesting their potential therapeutic use upon intrathecal injection. As such, these human monoclonal antibodies, as well as their Fab derivatives, meet all requirements for being considered for prophylaxis and therapy of human tetanus and are ready for clinical trials.
Temporary prey storage along swarm columns of army ants: an adaptive strategy for successful raiding?
Authors: de Lima Hilário Póvoas , Teseo Serafino , Castro de Lima Raquel Leite , Ferreira-Châline Ronara Souza , Châline Nicolas 
Published: May 2021

AbstractWhile pillaging the brood of other ant colonies, Eciton army ants accumulate prey in piles, or caches, along their foraging trails. Widely documented, these structures have historically been considered as byproducts of heavy traffic or aborted relocations of the ants’ temporary nest, or bivouac. However, we recently observed that caches of the hook-jawed army ant, Eciton hamatum, appeared independently from heavy traffic or bivouac relocations. In addition, the flow of prey through caches varied based on the quantity of prey items workers transported. As this suggested a potential adaptive function, we developed agent-based simulations to compare raids of caching and non-caching virtual army ants. We found that caches increased the amount of prey that relatively low numbers of raiders were able to retrieve. However, this advantage became less conspicuous - and generally disappeared - as the number of raiders increased. Based on these results, we hypothesize that caches maximize the amount of prey that limited amounts of raiders can retrieve, especially as prey colonies coordinately evacuate their brood. In principle, caches also allow workers to safely collect multiple prey items and efficiently transport them to the bivouac. Further field observations are needed to test this and other hypotheses emerging from our study.
SCARF1-induced efferocytosis plays an immunomodulatory role in humans, and autoantibodies targeting SCARF1 are produced in patients with systemic lupus erythematosus
Authors: Jorge April M. , Lao Taotao , Kim Rachel , Licciardi Samantha , ElKhoury Joseph , Luster Andrew , Means Terry K. , Ramirez-Ortiz Zaida G. 
Published: May 2021

AbstractDeficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerancein humans, and that dysregulation of this processcouldcontribute to SLE. Here, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+dendritic cells (DCs) initiates an interleukin-10 (IL-10) anti-inflammatory response mediated by the phosphorylation of signal transducer and activator of transcription 1 (STAT1). Unexpectedly, there was no significant difference in SCARF1 expression in SLE patient samples compared to healthy donor samples. However, we detected anti-SCARF1 autoantibodies in 26% of SLE patients, which was associated with dsDNA antibody positivity. Furthermore, our data shows a direct correlation of the levels of anti-SCARF1 in the serum and defects in the removal of ACs. Depletion of immunoglobulin restores efferocytosis in SLE serum, suggesting that defects in the removal of ACs is partially mediated by SCARF1 pathogenic autoantibodies. Our data demonstrate that human SCARF1 is an AC receptor in DCs and plays a role in maintaining tolerance and homeostasis.
Selection for cell yield does not reduce overflow metabolism in E. coli
Authors: Rabbers Iraes , Gottstein Willi , Feist Adam , Teusink Bas , Bruggeman Frank J. , Bachmann Herwig 
Published: May 2021

AbstractOverflow metabolism is ubiquitous in nature, and it is often considered inefficient because it leads to a relatively low biomass yield per consumed carbon. This metabolic strategy has been described as advantageous because it supports high growth rates during nutrient competition.Here we experimentally evolved bacteria without nutrient competition by repeatedly growing and mixing millions of parallel batch cultures of E. coli. Each culture originated from a water-in-oil emulsion droplet seeded with a single cell. Unexpectedly we found that overflow metabolism (acetate production) did not change. Instead the numerical cell yield during the consumption of the accumulated acetate increased as a consequence of a reduction in cell size. Our experiments and a mathematical model show that fast growth and overflow metabolism followed by the consumption of the overflow metabolite, leads to a higher numerical cell yield and therefore a higher fitness compared to full respiration of the substrate. This provides an evolutionary scenario where overflow metabolism can be favourable even in the absence of nutrient competition.
Nonsense-mediated mRNA decay utilizes complementary mechanisms to suppress mRNA and protein accumulation
Authors: Udy Dylan B. , Bradley Robert K. 
Published: May 2021

ABSTRACTNonsense-mediated mRNA decay (NMD) is an essential, highly conserved quality control pathway that detects and degrades mRNAs containing premature termination codons (PTCs). Although the essentiality of NMD is frequently ascribed to its prevention of truncated protein accumulation, the extent to which NMD actually suppresses proteins encoded by NMD-sensitive transcripts is less well-understood than NMD-mediated suppression of mRNA. Here, we describe a reporter system that permits accurate quantification of both mRNA and protein levels via stable integration of paired reporters encoding NMD-sensitive and NMD-insensitive transcripts into the AAVS1 safe harbor loci in human cells. We use this system to demonstrate that NMD suppresses proteins encoded by NMD-sensitive transcripts by up to ∼8-fold more than the mRNA itself. Our data indicate that NMD limits the accumulation of proteins encoded by NMD substrates by mechanisms beyond mRNA degradation, such that even when NMD-sensitive mRNAs escape destruction, their encoded proteins are still effectively suppressed.
An approach to gene-based testing accounting for dependence of tests among nearby genes
Authors: Yurko Ronald , Roeder Kathryn , Devlin Bernie , G’Sell Max 
Published: May 2021

AbstractIn genome-wide association studies (GWAS), it has become commonplace to test millions of SNPs for phenotypic association. Gene-based testing can improve power to detect weak signal by reducing multiple testing and pooling signal strength. While such tests account for linkage disequilibrium (LD) structure of SNP alleles within each gene, current approaches do not capture LD of SNPs falling in different nearby genes, which can induce correlation of gene-based test statistics. We introduce an algorithm to account for this correlation. When a gene’s test statistic is independent of others, it is assessed separately; when test statistics for nearby genes are strongly correlated, their SNPs are agglomerated and tested as a locus. To provide insight into SNPs and genes driving association within loci, we develop an interactive visualization tool to explore localized signal. We demonstrate our approach in the context of weakly powered GWAS for autism spectrum disorder, which is contrasted to more highly powered GWAS for schizophrenia and educational attainment. To increase power for these analyses, especially those for autism, we use adaptive p-value thresholding (AdaPT), guided by high-dimensional metadata modeled with gradient boosted trees, highlighting when and how it can be most useful. Notably our workflow is based on summary statistics.
Distance-based Reconstruction of Protein Quaternary Structures from Inter-Chain Contacts
Authors: Soltanikazemi Elham , Quadir Farhan , Roy Raj S. , Cheng Jianlin 
Published: May 2021

AbstractPredicting the quaternary structure of a protein complex is an important and challenging problem. Inter-chain residue-residue contact prediction can provide useful information to guide the ab initio reconstruction of quaternary structures of protein complexes. However, few methods have been developed to build quaternary structures from predicted inter-chain contacts. Here, we introduce a new gradient descent optimization algorithm (GD) to build quaternary structures of protein dimers utilizing inter-chain contacts as distance restraints. We evaluate GD on several datasets of homodimers and heterodimers using true or predicted contacts. GD consistently performs better than a simulated annealing method and a Markov Chain Monte Carlo simulation method. Using true inter-chain contacts as input, GD can reconstruct high-quality structural models for homodimers and heterodimers with average TM-score ranging from 0.92 to 0.99 and average interface root mean square distance (I-RMSD) from 0.72 Å to 1.64 Å. On a dataset of 115 homodimers, using predicted inter-chain contacts as input, the average TM-score of the structural models built by GD is 0.76. For 46% of the homodimers, high-quality structural models with TM-score >= 0.9 are reconstructed from predicted contacts. There is a strong correlation between the quality of the reconstructed models and the precision and recall of predicted contacts. If the precision or recall of predicted contacts is >20%, GD can reconstruct good models for most homodimers, indicating only a moderate precision or recall of inter-chain contact prediction is needed to build good structural models for most homodimers. Moreover, the accuracy of reconstructed models positively correlates with the contact density in dimers and depends on the initial model and the probability threshold of selecting predicted contacts for the distance-based structure optimization.