bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atom Identifiers Generated by a Graph Coloring Method Enable Compound Harmonization Across Metabolic Databases
Authors: Jin Huan , Mitchell Joshua M. , Moseley Hunter N.B. 
Published: June 2020

AbstractMetabolic flux analysis requires both a reliable metabolic model and metabolic profiles in characterizing metabolic reprogramming. Advances in analytic methodologies enable production of high-quality metabolomics datasets capturing isotopic flux. However, useful metabolic models can be difficult to derive due to the lack of relatively complete atom-resolved metabolic networks for a variety of organisms, including human. Here, we developed a graph coloring method that creates unique identifiers for each atom in a compound facilitating construction of an atom-resolved metabolic network. What is more, this method is guaranteed to generate the same identifier for symmetric atoms, enabling automatic identification of possible additional mappings caused by molecular symmetry. Furthermore, a compound coloring identifier derived from the corresponding atom coloring identifiers can be used for compound harmonization across various metabolic network databases, which is an essential first step in network integration. With the compound coloring identifiers, 8865 correspondences between KEGG and MetaCyc compounds are detected, with 5451 of them confirmed by other identifiers provided by the two databases. In addition, we found that the Enzyme Commission numbers (EC) of reactions can be used to validate possible correspondence pairs, with 1848 unconfirmed pairs validated by commonality in reaction ECs. Moreover, we were able to detect various issues and errors with compound representation in KEGG and MetaCyc databases by compound coloring identifiers, demonstrating the usefulness of this methodology for database curation.
A harmonised systems-wide re-analysis of greenhouse gas emissions from sunflower oil production
Authors: Alcock Thomas D , Salt David E , Ramsden Stephen J 
Published: June 2020

AbstractSunflower (Helianthus annuusL.) is the largest source of vegetable oil in Europe and the fourth largest globally. Intensive cultivation and post-harvest steps contribute to global food-systems’ greenhouse gas (GHG) emissions. However, variation between production systems and reporting disparity have resulted in discordance in previous emissions estimates. To assess systems-wide GHG implications of meeting increasing edible oil demand using sunflower, we performed a unified re-analysis of primary life cycle inventory data, representing 995 farms in 11 countries, from a saturating search of published literature. Total GHG emissions varied from 1.1 to 4.2 kg CO2-equivalent per kg oil across systems, 62% of which originated from cultivation. Major emissions sources included diesel- and fertiliser-use, with irrigation electricity contributing most to between-systems variation. Our harmonised, cross-study re-analysis not only enabled robust comparisons and identification of mitigation opportunities across sunflower oil production systems, but also lays the groundwork for comparisons between alternative oil crops.
Tamoxifen reduces inflammatory infiltration of neutrophils in the airways
Authors: Mansilla Agustín , Soto Jaime , Henríquez Claudio , Philp Amber , Mall Marcus A. , Sarmiento José , Flores Carlos A. 
Published: June 2020

ABSTRACTTamoxifen is a drug of choice for treatment of breast cancer but it has also been reported to bear anti-inflammatory activity. Previously, we have observed that tamoxifen treatment successfully reduced inflammation in horses affected by equine asthma syndrome. More notorious, tamoxifen was effective at reducing the infiltration of neutrophils in the inflamed airways by a mechanism that increases efferocytosis, allowing the resolution of inflammation. Due to the emerging increase in patients with chronic inflammatory lung diseases, there is an urgent need for therapies that help reduce airway inflammation. Thus we tested the effect of tamoxifen on airway neutrophil infiltration by using three different mouse models for acute and chronic inflammation of the lung. We found that the drug was able to produce a significant reduction in neutrophils in all scenarios. Ussing chamber experiments demonstrated that tamoxifen has no effect on fluid secretion and absorption, discarding a possible reduction in mucociliary clearance due to the known ion-channel blocking effects of tamoxifen. Since this drug has been largely used in human medicine, tamoxifen might be a “low hanging fruit” for a novel anti-inflammatory therapy for airway diseases characterized by neutrophilic inflammation.
Exploring the complexity of soybean (Glycine max) transcriptional regulation using global gene co-expression networks
Authors: Almeida-Silva Fabricio , Moharana Kanhu C. , Machado Fabricio B. , Venancio Thiago M. 
Published: June 2020

ABSTRACTSoybean (Glycine max(L.) Merr.) is one of the most important crops worldwide, constituting a major source of protein and edible oil. Gene co-expression networks (GCN) have been extensively used to study transcriptional regulation and evolution of genes and genomes. Here, we report a soybean GCN using 1,284 publicly available RNA-Seq samples from 15 distinct tissues. We found modules that are differentially regulated in specific tissues, comprising processes such as photosynthesis, gluconeogenesis, lignin metabolism, and response to biotic stress. We identified transcription factors among intramodular hubs, which probably integrate different pathways and shape the transcriptional landscape in different conditions. The top hubs for each module tend to encode proteins with critical roles, such as succinate dehydrogenase and RNA polymerase subunits. Importantly, gene essentiality was strongly correlated with degree centrality and essential hubs enriched in genes involved in nucleic acids metabolism and regulation of cell replication. By using a using a guilt-by-association approach, we predicted functions for 93 of 106 hubs without functional description in soybean. Most of the duplicated genes had different transcriptional profiles, supporting their functional divergence, although paralogs originating from whole-genome duplications (WGD) are more often preserved in the same module than those from other mechanisms. Together, our results highlight the importance of GCN analysis in unraveling key functional aspects of the soybean genome, in particular those associated with hub genes and WGD events.
Histo-morphological development of the digestive tract of larval hybrid Malaysian mahseer (Barbonymus gonionotus♀ ×Tor tambroides ♂)
Authors: Kamarudin Mohd Salleh , Ismail Muhammad Azfar , Syukri Fadhil , Latif Kamil 
Published: June 2020

AbstractNew carp hybrids are being developed for the aquaculture industry to support rising seafood demands. The present study was carried out to observe the changes in digestive tract, histology and functional capabilities of the new hybrid carp larvae for a better understanding of its digestive capability and the prediction of its best weaning time to a compound diet. A tubal digestive tract was elongated to the anus and buccal cavity by 3 DAH that coincided with the mouth opening and the start of exogenous feeding. A functional stomach was observed at 7 DAH with the relative gut index (RGI) of 10.7 ± 0.06. A layer of supranuclear protein was observed with lipoprotein at the outer layer of the digestive tract at 7 DAH. The morpho-histological results of this study indicated that hybrid Malaysian mahseer larvae should be able to digest, ingest and absorb an artificial diet beginning from 7 DAH. At this stage, the hybrid larvae could be gradually or perhaps totally weaned to an artificial diet of a suitable particle size.
Contribution of larvae developing on corn and dry beans to the adult population of western bean cutworm in Michigan
Authors: Bunn Dakota C. , de Oliveira Eduardo Dias , Springborn Frederick , Gonzalez-Meler Miquel A. , Miller Nicholas 
Published: June 2020

AbstractThe western bean cutworm,Striacosta albicosta(Smith) (Lepidoptera: Noctuidae), is historically a pest of both corn (Zea maysL.) and dry beans (Phaseolussp L.) in the western Great Plains. However, it has recently undergone an eastward range expansion establishing itself across the Corn Belt in twenty-five states and four Canadian provinces. To mitigate the effects of infestation in Michigan, foliar insecticides are used in dry beans whereas management of the pest in corn relies more heavily on the use of Bt-expressing hybrids. In this study stable carbon isotope analysis was used to determine what crop adult moths developed on as larvae with analysis showing that very few of the adult moths developed on dry beans. These results suggest that beans and corn are not suitable as co-refuges and that mainly adults which developed on corn are contributing to the next generation of western bean cutworm in Michigan.
Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity
Authors: Babolmorad Ghazal , Latif Asna , Pollock Niall M. , Domingo Ivan K. , Delyea Cole , Rieger Aja M. , Allison W. Ted , Bhavsar Amit P. 
Published: June 2020

AbstractToll-like receptor 4 (TLR4) is famous for recognizing the bacterial endotoxin lipopolysaccharide (LPS) as its canonical ligand. TLR4 is also activated by other classes of agonist including some Group 9/10 transition metals. Roles for these non-canonical ligands in pathobiology mostly remain obscure, though TLR4 interactions with metals can mediate immune hypersensitivity reactions. In this work, we tested whether TLR4 can be activated by the Group 10 transition metal, platinum. We demonstrated that in the presence of TLR4, platinum activates pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. Platinum is the active moiety in cisplatin, a very potent and invaluable chemotherapeutic used to treat solid tumors in childhood cancer patients. Unfortunately, cisplatin use is limited due to an adverse effect of permanent hearing loss (cisplatin-induced ototoxicity, CIO). Herein, we demonstrated that cisplatin also activates TLR4, prompting the hypothesis that TLR4 mediates aspects of CIO. Cisplatin activation of TLR4 was independent of the TLR4 co-receptors CD14 and MD-2, which is consistent with TLR4 signaling elicited by transition metals. We found that TLR4 is required for cisplatin-induced inflammatory, oxidative and apoptotic responses in an ear outer hair cell line and for hair cell damagein vivo. Thus, TLR4 is a promising therapeutic target to mitigate CIO. We additionally identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicityin vitro. Further work is warranted towards inhibiting TLR4 as a route to mitigating this adverse outcome of childhood cancer treatment.Significance StatementThis work identifies platinum, and its derivative cisplatin, as new agonists for TLR4. TLR4 contributes to cisplatin-induced hair cell deathin vitroandin vivo. Genetic and small molecule inhibition of TLR4 identify this receptor as a druggable therapeutic target with promise to curtail cisplatin-induced ototoxicity, a devastating side-effect of an otherwise invaluable chemotherapeutic tool.
Learning retention mechanisms and evolutionary parameters of duplicate genes from their expression data
Authors: DeGiorgio Michael , Assis Raquel 
Published: June 2020

AbstractLearning about the roles that duplicate genes play in the origins of novel phenotypes requires an understanding of how their functions evolve. To date, only one method—CDROM—has been developed with this goal in mind. In particular, CDROM employs gene expression distances as proxies for functional divergence, and then classifies the evolutionary mechanisms retaining duplicate genes from comparisons of these distances in a decision tree framework. However,CDROMdoes not account for stochastic shifts in gene expression or leverage advances in contemporary statistical learning for performing classification, nor is it capable of predicting the underlying parameters of duplicate gene evolution. Thus, here we developCLOUD, a multi-layer neural network built upon a model of gene expression evolution that can both classify duplicate gene retention mechanisms and predict their underlying evolutionary parameters. We show that not only is theCLOUDclassifier substantially more powerful and accurate thanCDROM, but that it also yields accurate parameter predictions, enabling a better understanding of the specific forces driving the evolution and long-term retention of duplicate genes. Further, application of theCLOUDclassifier and predictor to empirical data fromDrosophilarecapitulates many previous findings about gene duplication in this lineage, showing that new functions often emerge rapidly and asymmetrically in younger duplicate gene copies, and that functional divergence is driven by strong natural selection. Hence,CLOUDrepresents the best available method for classifying retention mechanisms and predicting evolutionary parameters of duplicate genes, thereby also highlighting the utility of incorporating sophisticated statistical learning techniques to address long-standing questions about evolution after gene duplication.
A mutation in theDrosophila melanogaster evestripe 2 minimal enhancer is buffered by flanking sequences
Authors: Lopez-Rivera Francheska , Foster Olivia K. , Vincent Ben J. , Pym Edward C. G. , Bragdon Meghan D. J. , Estrada Javier , DePace Angela H. , Wunderlich Zeba 
Published: June 2020

AbstractEnhancers are DNA sequences composed of transcription factor binding sites that drive complex patterns of gene expression in space and time. Until recently, studying enhancers in their genomic context was technically challenging. Therefore, minimal enhancers, the shortest pieces of DNA that can drive an expression pattern that resembles a gene’s endogenous pattern, are often used to study features of enhancer function. However, evidence suggests that some enhancers require sequences outside the minimal enhancer to maintain function under environmental perturbations. We hypothesized that these additional sequences also prevent misexpression caused by a transcription factor binding site mutation within a minimal enhancer. Using theDrosophila melanogaster even-skippedstripe 2 enhancer as a case study, we tested the effect of a Giant binding site mutation (gt-2) on the expression patterns driven by minimal and extended enhancer reporter constructs. We found that, in contrast to the misexpression caused by the gt-2 binding site mutation in the minimal enhancer, the same gt-2 binding site mutation in the extended enhancer did not have an effect on expression. The buffering of expression levels, but not expression pattern, is partially explained by an additional Giant binding site outside the minimal enhancer. Mutating the gt-2 binding site in the endogenous locus had no significant effect on stripe 2 expression. Our results indicate that rules derived from mutating enhancer reporter constructs may not represent what occurs in the endogenous context.
EBSeq: improving mixing computations for multi-group differential expression analysis
Authors: Ma Xiuyu , Kendziorski Christina , Newton Michael A. 
Published: June 2020

ABSTRACTEBSeqis a Bioconductor package designed to calculate empirical-Bayesian inference summaries from sequence-based gene-expression (RNA-Seq) data. It produces gene or isoform-specific scores that measure various patterns of differential expression among a set of sample groups, and is most commonly deployed to measure differential expression between two groups. Its use of local posterior probabilities from a fitted mixture model provides the data analyst a direct way to score the false discovery rate of any reported list of genes, and it is one of the only tools that can address local false discovery rates when analyzing multiple sample groups. Contemporary applications have increasing numbers of sample groups, and the algorithms deployed inEBSeqare neither space nor time efficient in this important case. We describe a version update utilizing code improvements and novel pruning and clustering algorithms in order to reduce the complexity of mixture computations. The algorithms are supported by a theoretical analysis and tested empirically on a variety of benchmark and synthetic data sets.
FREQUENT GENE CONVERSION IN HUMAN EMBRYOS INDUCED BY DOUBLE STRAND BREAKS
Authors: Liang Dan , Gutierrez Nuria Marti , Chen Tailai , Lee Yeonmi , Park Sang-Wook , Ma Hong , Koski Amy , Ahmed Riffat , Darby Hayley , Li Ying , Dyken Crystal Van , Mikhalchenko Aleksei , Gonmanee Thanasup , Hayama Tomonari , Zhao Han , Wu Keliang , Zhang Jingye , Hou Zhenzhen , Park Jumi , Kim Chong-Jai , Gong Jianhui , Yuan Yilin , Gu Ying , Shen Yue , Olson Susan B. , Yang Hui , Battaglia David , O’Leary Thomas , Krieg Sacha A. , Lee David M. , Wu Diana H. , Duell P. Barton , Kaul Sanjiv , Kim Jin-Soo , Heitner Stephen B. , Kang Eunju , Chen Zi-Jiang , Amato Paula , Mitalipov Shoukhrat 
Published: June 2020

AbstractApplications of genome editing ultimately depend on DNA repair triggered by targeted double-strand breaks (DSBs). However, repair mechanisms in human cells remain poorly understood and vary across different cell types. Here we report that DSBs selectively induced on a mutant allele in heterozygous human embryos are repaired by gene conversion using an intact wildtype homolog as a template in up to 40% of targeted embryos. We also show that targeting of homozygous loci facilitates an interplay of non-homologous end joining (NHEJ) and gene conversion and results in embryos which carry identical indel mutations on both loci. Additionally, conversion tracks may expand bidirectionally well beyond the target region leading to an extensive loss of heterozygosity (LOH). Our study demonstrates that gene conversion and NHEJ are two major DNA DSB repair mechanisms in preimplantation human embryos. While gene conversion could be applicable for gene correction, extensive LOH presents a serious safety concern.
Glyphosate used to control invasivePhragmites australisin standing water poses little risk to aquatic biota
Authors: Robichaud C.D. , Rooney R.C. 
Published: June 2020

AbstractWhen an invasive wetland grass degrades a Ramsar wetland and Important Bird Area, decisive management action is called for. To limit the extent and spread of EuropeanPhragmites australis, the Ontario government began the first, large-scale application of glyphosate (Roundup Custom®) over standing water to control an invasive species in Canadian history. Between 2016 and 2018, over 1000 ha of marsh were treated. To assess the risk this herbicide presented to aquatic biota, we measured the concentration of glyphosate, its primary breakdown product aminomethylphosphonic acid (AMPA), and the alcohol ethoxylate-based adjuvant Aquasurf® in water and sediments in areas of the highest exposure risk and up to 150 m into adjacent bays. We never detected glyphosate or AMPA at concentrations exceeding thresholds of toxicological concern. The maximum observed concentration of glyphosate in water was 0.320 ppm, occurring within 24 hr of application. The maximum glyphosate concentration in sediment was 0.250 ppm, occurring within 30 days of application. AMPA was detectable in water and sediment, indicating microbial breakdown of glyphosate in the marsh, but at low concentrations (maxwater= 0.025 ppm, maxsed= 0.012 ppm). The maximum distance from the point of application at which glyphosate was detected in the water was 100 m, vs. 0 m for AMPA. Concentrations in water returned to pre-treatment levels (<DL) within 20-30 days of application. In sediment, glyphosate residue persisted above detection limits (>0.005 ppm) for over one year but less than two years. Concentrations of alcohol ethoxylates were variable in space and time, following a pattern that could not be attributed to Aquasurf® application. The direct, over-water application of Roundup Custom® with Aquasurf® to control invasiveP. australisdoes not pose a toxicological risk to aquatic biota.HighlightsGlyphosate-based herbicide was applied directly to >1000 ha of marsh to control invasiveP. australisGlyphosate and AMPA did not reach levels of toxicological concern for aquatic biotaAquasurf® exceedances were observed but could not be attributed toP. australiscontrol activityGlyphosate, AMPA, and Aquasurf® dispersed no more than 100 m from the point of applicationGlyphosate, AMPA and Aquasurf® in water returned to baseline levels within 30 days of applicationGlyphosate, AMPA and Aquasurf® in sediment returned to baseline levels within 2 years
Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics
Authors: Watkins Laura C. , DeGrado William F. , Voth Gregory A. 
Published: June 2020

ABSTRACTPrevalent resistance to inhibitors that target the influenza A M2 proton channel has necessitated a continued drug design effort, supported by a sustained study of the mechanism of channel function and inhibition. Recent high-resolution X-ray crystal structures present the first opportunity to see how the adamantyl-amine class of inhibitors bind to M2 and disrupt and interact with the channel’s water network, providing insight into the critical properties that enable their effective inhibition in wildtype M2. In this work, we test the hypothesis that these drugs act primarily as mechanism-based inhibitors by comparing hydrated excess proton stabilization during proton transport in M2 with the interactions revealed in the crystal structures, using the Multiscale Reactive Molecular Dynamics (MS-RMD) methodology. MS-RMD, unlike classical molecular dynamics, models the hydrated proton (hydronium-like cation) as a dynamic excess charge defect and allows bonds to break and form, capturing the intricate interactions between the hydrated excess proton, protein atoms, and water. Through this, we show that the ammonium group of the inhibitors is effectively positioned to take advantage of the channel’s natural ability to stabilize an excess protonic charge and is thus acting as a hydronium-mimic. Additionally, we show that the channel is especially stable in the drug binding region, highlighting the importance of this property for binding the adamantane group. Finally, we characterize an additional hinge point near Val27, which dynamically responds to charge and inhibitor binding. Altogether, this work further illuminates a dynamic understanding of the mechanism of drug inhibition in M2, grounded in the fundamental properties that enable the channel to transport and stabilize excess protons, with critical implications for future drug design efforts.TOC Graphic