bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis C Virus Drugs Simeprevir and Grazoprevir Synergize with Remdesivir to Suppress SARS-CoV-2 Replication in Cell Culture
Authors: Bafna Khushboo , White Kris , Harish Balasubramanian , Rosales Romel , Ramelot Theresa A. , Acton Thomas B. , Moreno Elena , Kehrer Thomas , Miorin Lisa , Royer Catherine A. , García-Sastre Adolfo , Krug Robert M. , Montelione Gaetano T. 
Published: December 2020

SummaryEffective control of COVID-19 requires antivirals directed against SARS-CoV-2 virus. Here we assess ten available HCV protease inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS- CoV-2 Mproand HCV NS3/4A proteases, and virtual docking experiments show that all ten HCV drugs can potentially bind into the Mprobinding cleft. Seven of these HCV drugs inhibit SARS-CoV-2 Mproprotease activity, while four dock well into the PLprosubstrate binding cleft and inhibit PLproprotease activity. These same seven HCV drugs inhibit SARS-CoV-2 virus replication in Vero and/or human cells, demonstrating that HCV drugs that inhibit Mpro, or both Mproand PLpro, suppress virus replication. Two HCV drugs, simeprevir and grazoprevir synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, thereby increasing remdesivir inhibitory activity as much as 10-fold.HighlightsSeveral HCV protease inhibitors are predicted to inhibit SARS-CoV-2 Mproand PLpro.Seven HCV drugs inhibit Mproenzyme activity, four HCV drugs inhibit PLpro.Seven HCV drugs inhibit SARS-CoV-2 replication in Vero and/or human cells.HCV drugs simeprevir and grazoprevir synergize with remdesivir to inhibit SARS- CoV-2.eTOC blurbBafna, White and colleagues report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 Mproand/or PLproproteases and SARS-CoV-2 replication in cell culture. Two drugs, simeprevir and grazoprevir, synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir antiviral activity as much as 10-fold.Abstract Figure
A GPCR negative feedback loop underlies efficient coding of external stimuli
Authors: Ruach Rotem , Yellinek Shai , Itskovits Eyal , Zaslaver Alon 
Published: December 2020

AbstractEfficient navigation based on chemical cues is an essential feature shared by all animals. These cues may be encountered in complex spatio-temporal patterns and with orders of magnitude varying intensities. Nevertheless, sensory neurons accurately extract the relevant information from such perplexing signals. Here, we show how a single sensory neuron inC. elegansworms can cell-autonomously encode complex stimulus patterns composed of instantaneous sharp changes and of slowly-changing continuous gradients. This encoding relies on a simple negative feedback in the GPCR signaling pathway in which TAX-6/Calcineurin plays a key role in mediating the feedback inhibition. Crucially, this negative feedback pathway supports several important coding features that underlie an efficient navigation strategy, including exact adaptation and adaptation to the magnitude of the gradient’s first derivative. A simple mathematical model accurately captured the fine neural dynamics of both wt andtax-6mutant animals, further highlighting how the calcium-dependent activity of TAX-6/Calcineurin dictates GPCR inhibition and response dynamics. As GPCRs are ubiquitously expressed in all sensory neurons, this mechanism may be a universal solution for efficient cell-autonomous coding of external stimuli.
Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity
Authors: Doyle Daniel Z. , Lam Mandy M. , Qalieh Adel , Qalieh Yaman , Sorel Alice , Funk Owen H. , Kwan Kenneth Y. 
Published: December 2020

AbstractLoss-of-function mutations in chromatin remodeler geneARID1Aare a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterizeArid1afunction during cortical development and find unexpectedly selective roles forArid1ain subplate neurons. Subplate neurons (SPNs), strategically positioned at the interface of cortical grey and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pan-cortical deletion ofArid1aleads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. SparseArid1adeletion, however, does not autonomously misroute callosal axons, implicating non-cell autonomousArid1afunctions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by corticalArid1adeletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression followingArid1adeletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate-thalamocortical axon co-fasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically testArid1asufficiency in subplate, we generate a cortical plate deletion ofArid1athat spares SPNs. In this model, subplateArid1aexpression is sufficient for subplate-thalamocortical axon co-fasciculation and extracellular matrix assembly. Consistent with these wiring functions, subplateArid1asufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus,Arid1ais a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.SignificanceThe cognitive, perceptive, and motor capabilities of the mammalian cerebral cortex depend on assembly of circuit connectivity during development. Subplate neurons, strategically located at the junction of grey and white matter, orchestrate the wiring of cortical circuits. Using a new approach to study gene necessity and sufficiency in subplate neurons, we uncover an essential role for chromatin remodelerArid1ain subplate neuron gene expression and axon guidance functions. Cortical deletion ofArid1adisrupts subplate-dependent formation of corpus callosum, targeting of thalamocortical axons, and development of sensory maps. Together, our study identifiesArid1aas a central regulator of subplate-dependent axon pathfinding, establishes subplate function as essential to callosum development, and highlights non-cell autonomous mechanisms in neural circuit formation and disorders thereof.
Microbe-seq: high-throughput, single-microbe genomics with strain resolution, applied to a human gut microbiome
Authors: Zheng Wenshan , Zhao Shijie , Yin Yehang , Zhang Huidan , Needham David M. , Evans Ethan D. , Dai Chengzhen L. , Lu Peter J. , Alm Eric J. , Weitz David A. 
Published: December 2020

AbstractWe presentMicrobe-seq, a high-throughput single-microbe method that yields strain-resolved genomes from complex microbial communities. We encapsulate individual microbes into droplets with microfluidics and liberate their DNA, which we amplify, tag with droplet-specific barcodes, and sequence. We useMicrobe-seqto explore the human gut microbiome; we collect stool samples from a single individual, sequence over 20,000 microbes, and reconstruct nearly-complete genomes of almost 100 bacterial species, including several with multiple subspecies strains. We use these genomes to probe genomic signatures of microbial interactions: we reconstruct the horizontal gene transfer (HGT) network within the individual and observe far greater exchange within the same bacterial phylum than between different phyla. We probe bacteria-virus interactions; unexpectedly, we identify a significantin vivoassociation between crAssphage, an abundant bacteriophage, and a single strain ofBacteroides vulgatus. Microbe-seqcontributes high-throughput culture-free capabilities to investigate genomic blueprints of complex microbial communities with single-microbe resolution.
Primary restriction of S-RNase cytotoxicity by a stepwise ubiquitination and degradation pathway inPetunia hybrida
Authors: Zhao Hong , Song Yanzhai , Li Junhui , Zhang Yue , Huang Huaqiu , Li Qun , Zhang Yu’e , Xue Yongbiao 
Published: December 2020

ABSTRACTIn self-incompatible Solanaceous species, the pistil S-RNase acts as cytotoxin to inhibit self-pollination but is polyubiquitinated by the pollen-specific non-selfS-locus F-box (SLF) proteins and subsequently degraded by the ubiquitin-proteasome system (UPS), allowing cross-pollination. However, it remains unclear how S-RNase is restricted by the UPS. Here, we first show thatPetunia hybrida(Ph) S3-RNase is largely ubiquitinated by K48-linked polyubiquitin chains at three regions, R I, II and III. R I is ubiquitinated in unpollinated, self- and cross-pollinated pistils, indicating its occurrence prior to PhS3-RNase uptake into pollen tubes, whereas R II and III are exclusively ubiquitinated in cross-pollinated pistils. Second, removal of R II ubiquitination resulted in significantly reduced seed sets from cross-pollination and that of R I and III in less extents, indicating their increased cytotoxicity. In consistent, the mutated R II of PhS3-RNase resulted in marked reduction of its degradation, whereas that of R I and III in less reductions. Taken together, our results demonstrate that PhS3-RNase R II functions as a major ubiquitination region for its destruction and R I and III as minor ones, revealing that its cytotoxicity is primarily restricted by a stepwise UPS mechanism for cross-pollination inP. hybrida.ONE SENTENCE SUMMARYBiochemical and transgenic analyses reveal thatPetunia hybridaS3-RNase cytotoxicity is largely restricted by a stepwise ubiquitination and degradation pathway during cross-pollination.
Transcriptional responses to arbuscular mycorrhizal symbiosis development are conserved in the early divergentMarchantia paleacea
Authors: Sgroi Mara , Paszkowski Uta 
Published: December 2020

AbstractArbuscular mycorrhizal symbiosis (AMS) arose in land plants more than 400 million years ago, perhaps acting as a major contributor to plant terrestrialization. The ability to engage in AMS is evolutionarily conserved across most clades of extant land plants, including early diverging bryophytes. Despite its broad taxonomic distribution, little is known about the molecular components that underpin AMS in early diverging land plants as the mechanisms regulating the symbiosis were primarily characterized in angiosperms. Several AMS associated genes were recently shown to be conserved in liverworts and hornworts, but evidence of them being associated with symbiosis in bryophytes is scarce. In this study, we characterised the dynamic response of the liverwortMarchantia paleaceatoRhizophagus irregulariscolonization by time-resolved transcriptomics across progressive stages of symbiosis development. Gene orthology inference and comparative analysis of theM. paleaceatranscriptional profile with a well characterised legume model -Medicago truncatula- revealed a deep conservation of transcriptional responses to AMS across distantly related species. We identified evolutionarily conserved patterns of expression of genes required for pre-symbiotic signalling, intracellular colonization and symbiotic nutrient exchange. Our study demonstrates that the genetic machinery regulating key aspects of symbiosis in plant hosts is largely conserved and coregulated across distantly related land plants. If bryophytes are confirmed to be monophyletic, our analysis provides novel insights on the first molecular pathways associated with symbiosis at the dawn of plant colonization of land.Significance StatementArbuscular mycorrhizal symbiosis (AMS) between plants and soil fungi was proposed as one of the key adaptations enabling land colonization by plants. The symbiosis is widespread across most extant plant clades, including early-diverging bryophytes, suggesting that it evolved before the last common ancestor of land plants. Recent phylogenetic analyses uncovered that genes regulating AMS in angiosperms are present in the genomes of bryophytes. Our work shows that a set of these genes are transcriptionally induced during AMS in liverworts. Based on the conservation of their transcriptional profiles across land plants, we propose that these genes acquired an AMS-associated function before the last common ancestor of land plants.
Expression of macromolecular organic nitrogen degrading enzymes identifies potential mediators of soil organic N availability to an annual grass
Authors: Sieradzki Ella T. , Nuccio Erin E. , Pett-Ridge Jennifer , Firestone Mary K. 
Published: December 2020

AbstractNitrogen (N) commonly limits terrestrial plant growth partly because most soil-N is present as macromolecular organic compounds and not directly available to plants. Soil microbes degrade these large N-containing substrates to gradually release plant-available inorganic-N throughout the growing season, potentially meeting plant demand. Knowing which microbes are responsible for release of organic N, as well as their spatiotemporal patterns of activity, can enable microbial management strategies that increase plant access to soil-N and reduce dependency on fertilizer-N. We used time-resolved metatranscriptomes to follow taxonomy-resolved differential expression of N-depolymerizing enzymes.Taxonomic groups show adaptations based on extracellular proteases to specialized habitats in soil characterized by presence (Betaproteobacteria) or absence (Thaumarcheota) of live roots and root detritus (Deltaproteobacteria and Fungi). A similar increase of eukaryotic chitinases near root detritus hints at predation of fungi. Others demonstrate temporal patterns such as increasing expression over time, implying increased competitiveness with substrate depletion (Chloroflexi). Phylotypes from the same genus can have different potential benefits to the plant based on protease expression (e.g., Janthinobacterium), which should be considered when designing bioaugmentation. We identify one Janthinobacterium phylotype and two Burkholderiales that may be candidates for bioaugmentation near young roots and a Rhizobacter which could benefit mature roots.
Maladaptive oxidative stress cascade drives type I interferon hyperactivity in TNF activated macrophages promoting necrosis in murine tuberculosis granulomas
Authors: Brownhill Eric , Yabaji Shivraj M. , Zhernovkov Vadim , Rukhlenko Oleksii S. , Seidel Kerstin , Bhattacharya Bidisha , Chatterjee Sujoy , Chen Hui A. , Crossland Nicholas , Bishai William , Kholodenko Boris N. , Gimelbrant Alexander , Kobzik Lester , Kramnik Igor 
Published: December 2020

ABSTRACTTuberculosis remains a critical infectious disease world-wide. The development of novel therapeutic strategies requires greater understanding of host factors that contribute to disease susceptibility. A major unknown in TB pathogenesis is the mechanism of necrosis in TB granulomas that leads to the massive lung tissue damage and cavity formation necessary for the pathogen transmission. In humans, TB progression has been linked to hyperactivity of type I IFN (IFN-I) pathway, the primary cause of which remains elusive.We studied the mechanistic drivers of pulmonary TB progression using a unique model B6J.C3-Sst1C3HeB/FejKrmn mice that develop human-like necrotic TB granulomas and IFN-I hyperactivity. We established that IFNβ super-induction occurred in the susceptible macrophages in response to continuous TNF stimulation in the context of a dysregulated antioxidant defense. We observed that unresolving oxidative stress amplified the induction of IFNβ through JNK activation and induced the Integrated Stress Response via PKR activation as a compensatory pathway. Subsequently, PKR amplifies IFNβ upregulation, forming a positive feedback loop, maintaining the hyperinflammatory state in susceptible macrophages and leading to mitochondrial dysfunction. Thus, within the inflammatory milieu, a cell-intrinsic mechanism of chronic regulatory dysfunction and unresolved stress gradually weakens the macrophage and ultimately promotes the necrotization of TB granulomas. The aberrant macrophage response to TNF can be prevented by an iron chelator and inhibitor of lipid peroxidation, ferrostatin-1. Moreover, ferrostatin treatment increased macrophage survival and boosted bacterial control in the TNF-stimulated macrophages infected with virulent Mtb. These findings identify targets for host-directed therapeutics to interrupt necrotization in TB granulomas.
Genome-wide identification and comparative analysis ofDofgene family inBrassica napus
Authors: Lohani Neeta , Babaei Saeid , Singh Mohan B. , Bhalla Prem L. 
Published: December 2020

AbstractDOF, DNA binding with one finger proteins are plant-specific transcription factors shown to play roles in diverse plant functions. However, a—little is known about DOF protein repertoire of the allopolyploid crop,Brassica napus. Here, we report genome-wide identification and systematic analysis of theDoftranscription factor family in this important oilseed crop. We identified 117Brassica napusDof genes (BnaDofs). So far, this is the largest number ofDofgenes reported in a single eudicot species. Based on phylogenetic analysis,BnaDofswere classified into nine groups (A, B1, B2. C1, C2.1, C2.2, C3, D1, D2). Most members belonging to a particular group displayed conserved gene structural organisation and similar protein motifs distribution. Chromosomal localisation analysis highlighted the uneven distribution ofBnaDofsacross all chromosomes. Evolutionary analysis exemplified that the divergence ofBrassicagenus from Arabidopsis, the whole genome triplication event, and the hybridisation ofB. oleraceaandB. rapato formB. napus, followed by gene loss and rearrangements, led to the expansion and divergence of Dof TF gene family inB. napus. Functional annotation of BnaDof proteins, cis-element analysis of their promoters suggested potential roles in organ development, the transition from vegetative to the reproductive stage, light responsiveness, phytohormone responsiveness as well as abiotic stress responses. Furthermore, the transcriptomic analysis highlighted the preferential tissue-specific expression patters ofBnaDofsand their role in response to various abiotic stress. Overall, this study provides a comprehensive understanding of the molecular structure, evolution, and potential functional roles ofDofgenes in plant development and abiotic stress response.
Longest Order Conserved Exemplar Subsequences
Authors: Zhang Shu , Pu Lianrong , Yang Runmin , Wang Luli , Zhu Daming , Jiang Haitao 
Published: December 2020

AbstractWe propose a new problem whose input data are two linear genomes together with two indexed gene subsequences of them, which asks to find a longest common exemplar subsequence of the two given genomes with a subsequence identical to the given indexed gene subsequences. We present an algorithm for this problem such that the algorithm is allowed to take diminishing time and space to solve the problem by setting the indexed genes with an incremental number. Although an incremental number of indexed genes were selected, the algorithm was verified definite to reach a solution whose length insistently comes very close to a real longest common exemplar subsequence of the two given genomes.Aiming at 23 human/gorilla chromosome pairs, the algorithm was examined for use in questing for longest common exemplar subsequences whose basic units are annotated genes as well as pseudo genes, namely consecutive DNA subsequences. By contrasting the pseudo gene common exemplar subsequences the algorithm had reached for the human chromosomes 7 and 16 and their gorilla homologues with those annotated genes in the human and gorilla chromosomes, we found more than 1 000 and 500 pseudo genes in the human chromosomes 7 and 16 that occur in the same order as they are in the gorilla chromosomes 7 and 16 and, do not overlap with any annotated gene.Author summaryThere is a benefit of the algorithm: It can reach a long enough common exemplar subsequence of two linear genomes in as fast a speed as one requires even if the given genomes would be equipped with too many duplicated genes, which can be done by setting incremental number of indexed genes. We developed a Java software based on the algorithm, that has been available for download onhttps://github.com/ShuZhang-sdu/LCES.Only in need to set the indexed gene sequences as null, was it verified successful for our algorithm to obtain the longest common exemplar subsequences of the annotated gene summary pairs extracted from 23 human/gorilla chromosome pairs.In convenience for researchers to find new motifs or conserved genes, we devoted for the algorithm to quest pseudo gene (i.e. consecutive DNA subsequences) summary pairs of the 23 human/gorilla chromosome pairs for solutions. There are 20 pseudo gene summary pairs whose longest common exemplar subsequences have been found by the algorithm with null indexed gene sequences. The other 3 pseudo gene summary pairs were verified solvable for the algorithm to reach their longest common exemplar subsequences that have to admit subsequences identical to given indexed gene subsequences. There were informed to exist 2 353 and 1 148 pseudo genes in the gorilla chromosome 7 and 16 that occur in the same order as they are in the human chromosome 7 and 16 and, do not overlap with any annotated gene. These pseudo genes should be significant for annotating the human or gorilla genome.
The statistical challenge of finding spontaneous changes in functional connectivity in high-dimensional fMRI data
Authors: Vidaurre Diego 
Published: December 2020

AbstractAn important question in neuroscience is whether or not we can interpret spontaneous variations in the pattern of correlation between brain areas, which we refer to as functional connectivity or FC, as an index of dynamic neuronal communication in fMRI. That is, can we measure time-varying FC reliably? And, if so, can FC reflect information transfer between brain regions at relatively fast-time scales? Answering these questions in practice requires dealing with the statistical challenge of having high-dimensional data and a comparatively lower number of time points or volumes. A common strategy is to use PCA to reduce the dimensionality of the data, and then apply some model, such as the hidden Markov model (HMM) or a Bayesian mixture of distributions, to find a set of distinct FC patterns or states. The distinct spatial properties of these FC states together with the time-resolved switching between them offer a flexible description of time-varying FC. In this work, we show that in this context PCA can suffer from systematic biases and loss of sensitivity for the purposes of finding time-varying FC. To get around these issues, we propose a novel variety of the HMM, the HMM-PCA, where the states are themselves PCA decompositions. Since PCA is based on the data covariance, the state-specific PCA decompositions reflect distinct patterns of FC. We show, theoretically and empirically, that fusing dimensionality reduction and time-varying FC estimation in one single step can avoid these problems and outperform alternative approaches, eventually facilitating the quantification of transient communication in the brain.Author summaryWe show that PCA, although widely used in practice, can introduce important biases and loss of sensitivity in the estimation of time-varying functional connectivity on high-dimensional fMRI data. We discuss these limitations and propose a new method that, by performing dimensionality reduction and time-varying functional connectivity estimation in one single step, can effectively overcome these limitations.