bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models
Authors: Bixler Sandra L. , Stefan Christopher P. , Jay Alexandra , Rossi Franco , Ricks Keersten M. , Shoemaker Charles J. , Moreau Alicia M. , Zeng Xiankun , Hooper Jay W. , Dyer David , Frick Ondraya , Koehler Jeffrey W. , Kearney Brian , DiPinto Nina , Liu Jun , Tostenson Samantha , Clements Tamara L. , Smith Jeffrey M. , Johnson Joshua A. , Berrier Kerry , Esham Heather , Delp Korey L. , Coyne Susan R. , Bloomfield Holly , Kuehnert Paul , Akers Kristen , Gibson Kathleen , Minogue Timothy D. , Nalca Aysegul , Pitt Margaret L. M. 
Published: April 2021

AbstractThe emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.
Multidimensional natal isotopic niches reflect migratory patterns in birds
Authors: Franzoi A. , Larsen S. , Franceschi P. , Hobson K.A. , Pedrini P. , Camin F. , Bontempo L. 
Published: April 2021

AbstractNaturally occurring stable isotope ratios in animal tissues allow estimation of species trophic position and ecological niche. Measuring multiple isotopes of migratory species along flyway bottlenecks offers the opportunity to sample multiple populations and species whose tissues carry information at continental scales.We measuredδ2H,δ18O,δ13C,δ15N in juvenile feathers of 21 bird species captured at a migratory bottleneck in the Italian Alps.We examined if trends in individual isotopes reflected known migratory strategies and whether dietary (δ13C-δ15N) and spatially-explicit breeding origin (δ2H-δ18O) niche breadth (NB) differed among long-distance trans-Saharan (TS), short-distance (IP) and irruptive (IR) intra-Palearctic migrants, and whether they correlated with reported populations long-term trends.In both TS and IP groups, speciesδ2H declined with capture date, indicating that northern populations reached the stopover site later in the season, following a Type-I migration strategy. Values ofδ2H indicated that breeding range of TS migrants extended farther north than IP and IR migrants. The breeding season was longer for IP migrants whoseδ13C andδ15N values declined and increased, respectively, with time of capture.Average species dietary NB did not differ among migratory groups, but TS migrants displayed wider breeding origin niches, suggesting that long-distant migration is linked to broader ecological niches. Isotope origin NB well reflected species geographic range extent, while dietary NB did not correlate with literature accounts of species’ diet. We found no relationship between species breeding NB and population trends in Europe, implying that conditions in the wintering grounds could be more important for the long-term persistence of species.We demonstrate that isotopic measurements of passerines migrating through a bottleneck represents a unique opportunity to investigate large-scale life-history phenomena relevant to conservation.
AzuCR RNA modulates carbon metabolism as a dual-function RNA inEscherichia coli
Authors: Raina Medha , Aoyama Jordan J. , Bhatt Shantanu , Paul Brian J. , Storz Gisela 
Published: April 2021

AbstractBacteria have evolved small RNAs (sRNAs) to regulate numerous biological processes and stress responses. While sRNAs generally are considered to be “noncoding”, a few have been found to also encode a small protein. Here we describe one such dual-function RNA that modulates carbon utilization inEscherichia coli. The 164 nucleotide RNA was previously shown to encode a 28 amino acid protein (denoted AzuC). We discovered the membrane-associated AzuC protein interacts with GlpD, the aerobic glycerol-3-phosphate dehydrogenase, leading to increased GlpD activity. Overexpression of the RNA encoding AzuC results in a growth defect in glycerol and galactose medium. The defect in galactose medium was still observed for a stop codon mutant derivative, suggesting a potential regulatory role for the RNA. Consistent with this observation, we found thatcadAandgalEare repressed by base pairing with the RNA (denoted AzuCR). Interestingly, translation of AzuC interferes with the observed repression ofcadAandgalEby AzuCR and base pairing interferes with AzuC translation, demonstrating that the translation and base pairing functions compete.
Neonatal neuronal WWOX gene therapy rescuesWwoxnull phenotypes
Authors: Repudi Srinivasarao , Kustanovich Irina , Abu-Swai Sara , Stern Shani , Aqeilan Rami I. 
Published: April 2021

AbstractWW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations inWWOXcause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murineWwoxrecapitulates phenotypes ofWwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murineWwoxor humanWWOXcDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery inWwoxnull mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality ofWwox-null mice. These findings provide a proof-of-concept forWWOXgene therapy as a promising approach to curing children with WOREE and SCAR12.
OCT4 interprets and enhances nucleosome flexibility
Authors: MacCarthy Caitlin M. , Huertas Jan , Ortmeier Claudia , vom Bruch Hermann , Reinke Deike , Sander Astrid , Bergbrede Tim , Schöler Hans R. , Cojocaru Vlad 
Published: April 2021

AbstractPioneer transcription factors are proteins that induce cellular identity transitions by binding to inaccessible regions of DNA in nuclear chromatin. They contribute to chromatin opening and recruit other factors to regulatory DNA elements. The structural features and dynamics modulating their interaction with nucleosomes are still unresolved. From a combination of experiments and molecular simulations, we reveal here how the pioneer factor and master regulator of pluripotency, Oct4, interprets and enhances nucleosome structural flexibility. The magnitude of Oct4’s impact on nucleosome dynamics depends on the binding site position and the mobility of the unstructured tails of nucleosomal histone proteins. Oct4 propagates and stabilizes open nucleosome conformations by specific sequence recognition and nonspecific DNA exploration. Our findings provide a structural basis for the versatility of transcription factors in engaging with nucleosomes and have implications for understanding how pioneer factors induce chromatin dynamics.
H2A ubiquitination is essential for Polycomb Repressive Complex 1-mediated gene regulation in Marchantia polymorpha
Authors: Liu Shujing , Trejo-Arellano Minerva S. , Qiu Yichun , Eklund D. Magnus , Köhler Claudia , Hennig Lars 
Published: April 2021

AbstractPolycomb repressive complex 1 (PRC1) and PRC2 are chromatin regulators maintaining transcriptional repression. The deposition of H3 lysine 27 tri-methylation (H3K27me3) by PRC2 is known to be required for transcriptional repression, whereas the contribution of H2A ubiquitination (H2Aub) in the Polycomb repressive system remains unclear in plants. We directly tested the requirement of H2Aub for gene regulation in Marchantia polymorpha by generating point mutations in H2A that prevent ubiquitination by PRC1. These mutants show reduced H3K27me3 levels on the same target sites as mutants defective in PRC1 subunits MpBMI1 and the homolog MpBMI1L, revealing that PRC1-catalyzed H2Aub is essential for Polycomb system function. Furthermore, by comparing transcriptome data between mutants in MpH2A and MpBMI1/1L, we demonstrate that H2Aub contributes to the PRC1-mediated transcriptional level of genes and transposable elements. Together, our data demonstrate that H2Aub plays a direct role in H3K27me3 deposition and is required for PRC1-mediated transcriptional changes in both genic and intergenic regions in Marchantia.
A positive correlation between GC content and growth temperature in prokaryotes
Authors: Hu En-Ze , Lan Xin-Ran , Liu Zhi-Ling , Gao Jie , Niu Deng-Ke 
Published: April 2021

AbstractBackgroundGC pairs are generally more stable than AT pairs; GC-rich genomes were proposed to be more adapted to high temperatures than AT-rich genomes. Previous studies consistently showed positive correlations between growth temperature and the GC contents of structural RNA genes. However, for the whole genome sequences and the silent sites of the codons in protein-coding genes, the relationship between GC content and growth temperature is in a long-lasting debate.ResultsWith a dataset much larger than previous studies (681 bacteria and 155 archaea with completely assembled genomes), our phylogenetic comparative analyses showed positive correlations between optimal growth temperature (Topt) and GC content both in bacterial and archaeal structural RNA genes and in bacterial whole genome sequences, chromosomal sequences, plasmid sequences, core genes, and accessory genes. However, in the 155 archaea, we did not observe a significant positive correlation of Topt with whole-genome GC content (GCw) or GC content at four-fold degenerate sites. We randomly drew 155 samples from the 681 bacteria for 1000 rounds. In most cases (> 95%), the positive correlations between Topt and genomic GC contents became statistically nonsignificant (P > 0.05). This result suggested that the small sample sizes might account for the lack of positive correlations between growth temperature and genomic GC content in the 155 archaea and the bacterial samples of previous studies. Comparing the GC content among four categories (psychrophiles/psychrotrophiles, mesophiles, thermophiles, and hyperthermophiles) also revealed a positive correlation between GCw and growth temperature in bacteria. By including the GCw of incompletely assembled genomes, we expanded the sample size of archaea to 303. Positive correlations between GCw and Topt appear especially after excluding the halophilic archaea whose GC contents might be are strongly shaped by intense UV radiation.ConclusionsThis study explains the previous contradictory observations and ends a long debate. Prokaryotes growing in high temperatures have higher GC contents. Thermal adaptation is one possible explanation for the positive association. Meanwhile, we propose that the elevated efficiency of DNA repair in response to heat mutagenesis might have the by-product of increasing GC content like that happens in intracellular symbionts and marine bacterioplankton.
Influenca: a gamified assessment of value-based decision-making for longitudinal studies
Authors: Neuser Monja P. , Kräutlein Franziska , Kühnel Anne , Teckentrup Vanessa , Svaldi Jennifer , Kroemer Nils B. 
Published: April 2021

AbstractReinforcement learning is a core facet of motivation and alterations have been associated with various mental disorders. To build better models of individual learning, repeated measurement of value-based decision-making is crucial. However, the focus on lab-based assessment of reward learning has limited the number of measurements and the test-retest reliability of many decision-related parameters is therefore unknown. Here, we developed an open-source cross-platform applicationInfluencathat provides a novel reward learning task complemented by ecological momentary assessment (EMA) for repeated assessment over weeks. In this task, players have to identify the most effective medication by selecting the best option after integrating offered points with changing probabilities (according to random Gaussian walks). Participants can complete up to 31 levels with 150 trials each. To encourage replay on their preferred device, in-game screens provide feedback on the progress. Using an initial validation sample of 127 players (2904 runs), we found that reinforcement learning parameters such as the learning rate and reward sensitivity show low to medium intra-class correlations (ICC: 0.22-0.52), indicating substantial within- and between-subject variance. Notably, state items showed comparable ICCs as reinforcement learning parameters. To conclude, our innovative and openly customizable app framework provides a gamified task that optimizes repeated assessments of reward learning to better quantify intra- and inter-individual differences in value-based decision-making over time.
Activation of proneuronal transcription factorAscl1in maternal liver ensures a healthy pregnancy
Authors: Lee Joonyong , Garcia Veronica , Nambiar Shashank M. , Jiang Huaizhou , Dai Guoli 
Published: April 2021

AbstractBackground & AimsMaternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice.MethodsTo investigate whether and howAscl1plays a pregnancy-dependent role, we deleted theAscl1gene specifically in maternal hepatocytes from mid-gestation until term.ResultsAs a result, we identified multipleAscl1-dependent phenotypes. Maternal livers lackingAscl1exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepaticAscl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient forAscl1exhibited robust activation ofinsulin-like growth factor 2expression, which may contribute to theAscl1-dependent phenotypes widespread in maternal and uteroplacental compartments.ConclusionIn summary, we demonstrate that maternal liver, via activatingAscl1expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies revealAscl1as a novel and critical regulator of the physiology of pregnancy.SynopsisHow the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression ofAscl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring.Graphical Abstract
A synthetic protein as efficient multitarget regulator against complement over-activation
Authors: Ruiz-Molina Natalia , Parsons Juliana , Müller Madeleine , Hoernstein Sebastian N.W , Bohlender Lennard L. , Pumple Steffen , Zipfel Peter F. , Häffner Karsten , Reski Ralf , Decker Eva L. 
Published: April 2021

AbstractThe complement system constitutes the innate defense against pathogens. Its dysregulation leads to diseases and is a critical determinant in many viral infections, e.g.COVID-19. Factor H (FH) is the main regulator of the alternative pathway of complement activation and could be a therapy to restore homeostasis. However, recombinant FH is not available. Engineered FH versions may present alternative therapeutics. Here, we designed a synthetic protein, MFHR13, as a multitarget complement regulator. It combines the dimerization and C5-regulatory domains of human FH-related protein 1 (FHR1) with the C3-regulatory and cell surface recognition domains of human FH. MFHR13 includes the FH variant I62, which we characterized to induce improved C3b binding and cofactor activity compared to the variant V62. After comparative protein structure modelling, we introduced the SCR FH13, which includes anN-glycosylation site for higher protein stability. In summary, the fusion protein MFHR13 comprises SCRs FHR11-2:FH1-4:FH13:FH19-20. It shows an enhanced heparin binding and protects sheep erythrocytes from complement attack exhibiting 26 and 4-fold the regulatory activity of eculizumab and human FH, respectively. Furthermore, it also blocks the terminal pathway of complement activation and we demonstrate that MFHR13 and FHR1 bind to all proteins forming the membrane attack complex, which contributes to the mechanistic understanding of FHR1. We consider MFHR13 a promising candidate as a therapeutic for complement-associated diseases.
Genetic resistance to stripe rust infection of the wheat ear is controlled by genes controlling foliar resistance and flowering time
Authors: Bouvet Laura , Percival-Alwyn Lawrence , Berry Simon , Fenwick Paul , Holdgate Sarah , Mackay Ian J. , Cockram James 
Published: April 2021

AbstractYellow rust (YR), or stripe rust, is a fungal infection of wheat (Triticum aestivumL.) caused by the pathogenPuccinia striiformisWestend f. sp.tritici(Pst). While much research has focused on YR infection of wheat leaves, we are not aware of reports investigating the genetic control of YR resistance in other wheat structures, such as the ears. Here we use an eight-founder population to undertake genetic analysis of glume YR infection in wheat ears. Five quantitative trait loci (QTL) were identified, each explaining between ~3-7% of the phenotypic variation. Of these, three (QYrg.niab-2D.2, QYrg.niab-4D.1andQYrg.niab-5A.1) co-located with QTL for leaf YR resistance previously identified in the same population, with evidence suggestingQYrg.niab-5A.1may correspond to the adult plant resistance locusYr34which originates fromT. monococcumssp.monococcumand that resistance atQYrg.niab-2D.2may be conferred by chromosomal introgression from a wheat relative. Additional leaf YR resistance QTL previously identified in the population were not detected as controlling glume resistance, with the remaining two glume YR QTL linked to genetic loci controlling flowering time. The first of these,QYrg.niab-2D.1, mapped to the major flowering time locusPhotoperiod-D1(Ppd-D1), with the early-flowering allele from the MAGIC founder Soissons conferring reduced glume YR resistance. The second,QYrg.niab-4A.1, was identified in one trial only, and was located close to a flowering time QTL. This indicates earlier flowering results in increased glume YR susceptibility, likely due to exposure of tissues during environmental conditions more favourable forPstinfection. Collectively, our results provide first insights into the genetic control of YR resistance in glumes, controlled by subsets of QTL for leaf YR resistance and flowering time. This work provides specific genetic targets for the control of YR resistance in both the leaves and the glumes, and may be especially relevant inPst-proneagricultural environments where earlier flowering is favoured.Core ideasPuccinia striiformisWestend f. sp.tritici(Pst) causes yellow rust (YR) in wheat leaves and ears.We present the first reports for the genetic control of YR on the wheat ear.Ear YR infection is controlled by subsets of QTL controlling leaf resistance and flowering time.The findings are relevant to wheat breeding forPst-prone environments.
A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice
Authors: Martinez David R. , Schaefer Alexandra , Gobeil Sophie , Li Dapeng , De la Cruz Gabriela , Parks Robert , Lu Xiaozhi , Barr Maggie , Manne Kartik , Mansouri Katayoun , Edwards Robert J. , Yount Boyd , Anasti Kara , Montgomery Stephanie A. , Shen Shaunna , Zhou Tongqing , Kwong Peter D. , Graham Barney S. , Mascola John R. , Montefiori David. C. , Alam Munir , Sempowski Gregory D. , Wiehe Kevin , Saunders Kevin O. , Acharya Priyamvada , Haynes Barton F. , Baric Ralph S. 
Published: April 2021

AbstractSARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.