bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad-spectrum antivirals of protoporphyrins inhibit the entry of highly pathogenic emerging viruses
Authors: Lu Shengsheng , Pan Xiaoyan , Chen Daiwei , Xie Xi , Wu Yan , Shang Weijuan , Jiang Xiaming , Sun Yuan , Fan Sheng , He Jian 
Published: May 2020

AbstractSevere emerging and re-emerging viral infections such as Lassa fever, Avian influenza (AI), and COVID-19 caused by SARS-CoV-2 urgently call for new strategies for the development of broad-spectrum antivirals targeting conserved components in the virus life cycle. Viral lipids are essential components, and viral-cell membrane fusion is the required entry step for most unrelated enveloped viruses. In this paper, we identified a porphyrin derivative of protoporphyrin IX (PPIX) that showed broad antiviral activitiesin vitroagainst a panel of enveloped pathogenic viruses including Lassa virus (LASV), Machupo virus (MACV), and SARS-CoV-2 as well as various subtypes of influenza A viral strains with IC50values ranging from 0.91±0.25 μM to 1.88±0.34 μM. A mechanistic study using influenza A/Puerto Rico/8/34 (H1N1) as a testing strain showed thatPPIXinhibits the infection in the early stage of virus entry through biophysically interacting with the hydrophobic lipids of enveloped virions, thereby inhibiting the formation of the negative curvature required for fusion and blocking the entry of enveloped viruses into host cells. In addition, the preliminary antiviral activities ofPPIXwere further assessed by testing mice infected with the influenza A/Puerto Rico/8/34 (H1N1) virus. The results showed that compared with the control group without drug treatment, the survival rate and mean survival time of the mice treated withPPIXwere apparently prolonged. These data encourage us to conduct further investigations usingPPIXas a lead compound for the rational design of lipid-targeting antivirals for the treatment of infection with enveloped viruses.
MSCs Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma
Authors: Chastkofsky Michael , Pituch Katarzyna C. , Katagi Hiroaki , Ilut Liliana , Xiao Ting , Han Yu , Sonabend Adam M. , Curiel David T. , Bonner Erin R. , Nazarian Javad , Horbinski Craig , James Charles D. , Saratsis Amanda M. , Hashizume Rintaro , Lesniak Maciej S. , Balyasnikova Irina V. 
Published: May 2020

AbstractDiffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiation therapy is the standard of care treatment for DIPG, but offers only transient relief of symptoms for DIPG patients without providing significant survival benefit. Oncolytic virotherapy (OV) is an anticancer treatment that has been investigated for treating various types of brain tumors. Here, we have explored the use of mesenchymal stem cells (MSC) for OV delivery and evaluated treatment efficacy using preclinical models of DIPG. Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins that are important for OV entry, and that MSCs loaded with OV disseminate within and release OV throughout the tumor in mice bearing DIPG brainstem xenografts. When combining administration of OV-loaded MSCs with radiotherapy, mice bearing brainstem DIPG xenografts experience a significant survival benefit, relative to that conferred by either therapy alone (p<0.0001). Our results support further preclinical investigation of cell-based OV therapy with radiation for potential translation in treating DIPG patients.
Emergence and organization of adult brain function throughout child development
Authors: Yates Tristan S. , Ellis Cameron T. , Turk-Browne Nicholas B. 
Published: May 2020

AbstractAdult cognitive neuroscience has guided the study of human brain development by identifying regions associated with cognitive functions at maturity. The activity, connectivity, and structure of a region can be compared across ages to characterize the developmental trajectory of the corresponding function. However, observed developmental differences may not only reflect the maturation of the function but also its organization across the brain. That is, a function may be mature in children but supported by different brain regions and thus underestimated by focusing on adult regions. To test these possibilities, we investigated the presence, maturity, and localization of adult functions in children using probabilistic shared response modeling, a machine learning approach for functional alignment. After learning a lower-dimensional feature space from fMRI activity as adults watched a movie, we translated these shared features into the anatomical brain space of children 3–12 years old. To evaluate functional maturity, we correlated this reconstructed activity with the children’s actual fMRI activity as they watched the same movie. We found reliable correlations throughout cortex, even in the youngest children. The strength of the correlation in the precuneus, inferior frontal gyrus, and lateral occipital cortex increased over development and predicted chronological age. These age-related changes were driven by three types of developmental trajectories across distinct features of adult function: emergence from absence to presence, consistency in anatomical expression, and reorganization from one anatomical region to another. This data-driven approach to studying brain-wide function during naturalistic perception provides an abstract description of cognitive development throughout childhood.Significance StatementWhen watching a movie, your brain processes many types of information—plotlines, characters, locations, etc. A child watching this movie receives the same input, but some of their cognitive abilities (e.g., motion detection) are more developed than others (e.g., emotional reasoning). Beyond anatomical differences, when does the child brain begin tofunctionlike an adult brain? We used a data-driven approach to extract different aspects of brain activity from adults while they watched a movie during fMRI. We then predicted what the brain activity of a child would look like if they had processed the movie the same way. Comparing this prediction with actual brain activity from children allowed us to track the development of human brain function.
Bypass of DNA Interstrand crosslinks by a Rev1-DNA polymerase ζ complex
Authors: Bezalel-Buch Rachel , Cheun Young K. , Roy Upasana , Schärer Orlando D. , Burgers Peter M. 
Published: May 2020

AbstractDNA polymerase ζ (Pol ζ) and Rev1 are essential for the repair of DNA interstrand crosslink (ICL) damage. We have used yeast DNA polymerases η, ζ, and Rev1 to study translesion synthesis (TLS) past a nitrogen mustard-based ICL with an 8-atom linker between the crosslinked bases. The Rev1-Pol ζ complex was most efficient in complete bypass synthesis, by 2-3 fold, compared to Pol ζ alone or Pol η. Rev1 protein, but not its catalytic activity, was required for efficient TLS. A dCMP residue was faithfully inserted across the ICL-G by Pol η, Pol ζ, and Rev1-Pol ζ. Rev1-Pol ζ, and particularly Pol ζ alone showed a tendency to stall before the ICL, whereas Pol η stalled just after insertion across the ICL. The stalling of Pol η directly past the ICL is attributed to its autoinhibitory activity, caused by elongation of the short ICL-unhooked oligonucleotide (a six-mer in our study) by Pol η providing a barrier to further elongation of the correct primer. No stalling by Rev1-Pol ζ directly past the ICL was observed, suggesting that the proposed function of Pol ζ as an extender DNA polymerase is also required for ICL repair.
Prolonged impacts of past agriculture and overgrazing on soil fungal communities in restored forests
Authors: Tatsumi Shinichi , Matsuoka Shunsuke , Fujii Saori , Makoto Kobayashi , Osono Takashi , Isbell Forest , Mori Akira S. 
Published: May 2020

AbstractSoil fungi can help improve ecosystem restoration, yet our understanding of how they reassemble in degraded land is limited. Here, we studied fungal community structure using DNA metabarcoding in reforested sites following agricultural abandonment and overgrazing. Two treatments, namely ‘reforestation using different numbers of tree species’ and ‘deer exclusion,’ have been applied for multiple decades in the study sites. We found that local fungal richness (alpha diversity) and total fungal richness (gamma diversity) were 1.9–2.9 and 1.3–1.9 times greater, respectively, in reforested stands than in natural forests. These results were regardless of the number of tree species planted in the reforested stands. Conversely, reforested stands had a spatially homogenized community structure with relatively lower degrees of compositional dissimilarity among sites within each stand (beta diversity). These findings were attributable to lower environmental heterogeneity, stronger dispersal limitation, and a comparatively shorter time since the onset of community assembly in reforested stands. Deer exclosures had no detectable effect on fungal community structure. Overall, the agricultural legacy in fungal community structure appears to have persisted for decades, even under proactive restoration of aboveground vegetation. Direct human intervention belowground may therefore be necessary for the recovery of soil biota once altered.
Impacts of the Samarco tailing dam collapse on metals and arsenic concentration in freshwater fish muscle from Doce River, southeastern Brazil
Authors: Ferreira Frederico Fernandes , Freitas Mariella Bontempo Duca de , Szinwelski Neucir , Vicente Natállia , Medeiros Laila Carine Campos , Gonçalves Reynaud Schaefer Carlos Ernesto , Dergam Jorge Abdala , Sperber Carlos Frankl 
Published: May 2020

AbstractOn November 2015, Samarco tailings dam in Mariana MG, Brazil, collapsed, releasing 62 million tons of tailings that advanced through 668 km of the Doce River and adjacent floodplain. Although being the worst environmental disaster in Brazil, little is known about consequences to aquatic biota. Here we evaluate the effects of the tailings mudflow on metal and arsenic concentration in fish and how concentration correlates with water and fish characteristics. We quantified semitotal amounts of Ag, Al, As, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb and Zn in fish muscle tissue using ICP-MS in 255 individuals (34 species) sampled in unaffected and affected along the Doce River basin. Arsenic and Hg were higher in fish from affected sites, likely due to turbulent mixing of previously sedimented material by the giant tailings wave. Silver and Zn concentrations were higher in unaffected sites. Arsenic concentration inGeophagus brasiliensisdecreased with increasing fish weight. Copper and Zn decreased with increasing fish weight considering the whole assembly of fish. The tailings mudflow increased water conductivity and conductivity increased Al concentration in fish, so we expected a larger Al concentration in fishes from affected sites. However, the observed Al concentration in fishes from affected sites was lower than expected by water conductivity. Thus, the tailings mudflow reduced Al uptake or accumulation in fishes. Mercury decreased with increasing water conductivity in both unaffected and affected sites considering all species and inG. brasiliensisalone. Despite the relatively low concentration range of metals and As found in fish, fishes from sites affected by the iron ore tailings mudflow showed higher As and Hg concentration, compared to fishes from unaffected sites. The higher As and Hg in affected sites require further detailed monitoring to ensure safeguards of human health by fishing activity along the Doce River.
Polishing Copy Number Variant Calls on Exome Sequencing Data via Deep Learning
Authors: Özden Furkan , Alkan Can , Çiçek A. Ercüment 
Published: May 2020

AbstractAccurate and efficient detection of copy number variants (CNVs) is of critical importance due to their significant association with complex genetic diseases. Although algorithms that use whole genome sequencing (WGS) data provide stable results with mostly-valid statistical assumptions, copy number detection on whole exome sequencing (WES) data shows comparatively lower accuracy. This is unfortunate as WES data is cost efficient, compact and is relatively ubiquitous. The bottleneck is primarily due to non-contiguous nature of the targeted capture: biases in targeted genomic hybridization, GC content, targeting probes, and sample batching during sequencing. Here, we present a novel deep learning model,DECoNT, which uses the matched WES and WGS data and learns to correct the copy number variations reported by any off-the-shelf WES-based germline CNV caller. We train DECoNT on the 1000 Genomes Project data, and we show that we can efficiently triple the duplication call precision and double the deletion call precision of the state-of-the-art algorithms. We also show that our model consistently improves the performance independent from (i) sequencing technology, (ii) exome capture kit and (iii) CNV caller. Using DECoNT as a universal exome CNV call polisher has the potential to improve the reliability of germline CNV detection on WES data sets.
Diel Oscillations of Particulate Metabolites Reflect Synchronized Microbial Activity in the North Pacific Subtropical Gyre
Authors: Boysen Angela K. , Carlson Laura T. , Durham Bryndan P. , Groussman Ryan D. , Aylward Frank O. , Ribalet François , Heal Katherine R. , DeLong Edward F. , Armbrust E. Virginia , Ingalls Anitra E. 
Published: May 2020

AbstractLight is the primary input of energy into the sunlit ocean, driving daily oscillations in metabolism of primary producers. The consequences of this solar forcing have implications for the whole microbial community, yetin situmeasurements of metabolites, direct products of cellular activity, over the diel cycle are scarce. We evaluated community-level biochemical consequences of diel oscillations in the North Pacific Subtropical Gyre by quantifying 79 metabolites in particulate organic matter in surface waters every four hours over eight days. Total particulate metabolite concentration peaked at dusk, even when normalized to biomass estimates. The concentrations of 70% of individual metabolites exhibited 24-hour periodicity. Despite the diverse organisms that use them, primary metabolites involved in anabolic processes and redox maintenance had significant 24-hour periodicity. Osmolytes exhibited the largest diel oscillations, implying rapid turnover and metabolic roles beyond cell turgor maintenance. Metatranscriptome analysis revealed the taxa involved in production and consumption of some metabolites, including the osmolyte trehalose. This compound displayed the largest diel oscillations in abundance and was likely produced by the nitrogen-fixing cyanobacteriumCrocosphaerafor energy storage. These findings demonstrate that paired measurements of particulate metabolites and transcripts resolve strategies microbes use to manage daily energy and redox oscillations.
The role of high cholesterol in age-related COVID19 lethality
Authors: Wang Hao , Yuan Zixuan , Pavel Mahmud Arif , Jablonski Sonia Mediouni , Jablonski Joseph , Hobson Robert , Valente Susana , Reddy Chakravarthy B. , Hansen Scott B. 
Published: May 2020

ABSTRACTCoronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the entry of pseudotyped SARS-CoV-2 and the infectivity of the virion. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol shows almost twice the total number of endocytic entry points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the endocytic entry site where SARS-CoV-2 presumably docks to efficiently exploit entry into the cell. Furthermore, in cells producing virus, cholesterol optimally positions furin for priming SARS-CoV-2, producing a more infectious virion with improved binding to the ACE2 receptor. In vivo, age and high fat diet induces cholesterol loading by up to 40% and trafficking of ACE2 to endocytic entry sites in lung tissue from mice. We propose a component of COVID19 severity based on tissue cholesterol level and the sensitivity of ACE2 and furin to cholesterol. Molecules that reduce cholesterol or disrupt ACE2 localization with viral entry points or furin localization in the producer cells, may reduce the severity of COVID19 in obese patients.
Deep profiling of protease substrate specificity enabled by dual random and scanned human proteome substrate phage libraries
Authors: Zhou Jie , Li Shantao , Leung Kevin K. , O’Donovan Brian , Zou James Y. , DeRisi Joseph L. , Wells James A. 
Published: May 2020

AbstractProteolysis is a major post-translational regulator of biology both inside and outside of cells. Broad identification of optimal cleavage sites and natural substrates of proteases is critical for drug discovery and to understand protease biology. Here we present a method that employs two genetically encoded substrate phage display libraries coupled with next generation sequencing (SPD-NGS) that allows up to 10,000-fold deeper sequence coverage of the typical 6 to 8 residue protease cleavage sites compared to state-of-the-art synthetic peptide libraries or proteomics. We applied SPD-NGS to two classes of proteases, the intracellular caspases 2, 3, 6, 7 and 8, and the ectodomains of the membrane sheddases, ADAMs 10 and 17. The first library (Lib 10AA) was used to determine substrate cleavage motifs. Lib 10AA contains a highly diverse randomized 10-mer substrate peptide sequences (109unique members) that was displayed mono-valently on filamentous phage and bound to magnetic beads via an N-terminal biotin. The protease was allowed to cleave the SPD beads, and the released phage subjected to up to three total rounds of positive selection followed by next generation sequencing (NGS). This allowed us to identify from 104to 105unique cleavage sites over a 1000-fold dynamic range of NGS counts (ranging from 3-4000), and produced consensus and optimal cleavage motifs based positional sequencing scoring matrices that closely matched synthetic peptide data. A second SPD-NGS library (Lib hP) was constructed that allowed us to identify candidate human proteome sequences. Lib hP displayed virtually the entire human proteome tiled in contiguous 49AA sequences with 25AA overlaps (nearly 1 million members). After three rounds of positive selection we identified up to 104natural linear cut sites depending on the protease and captured most of the examples previously identified by proteomics (ranging from 30 to 1500) and predicted 10 to 100-fold more. Structural bioinformatics was used to facilitate the identification of candidate natural protein substrates. SPD-NGS is rapid, reproducible, simple to perform and analyze, inexpensive, renewable, with unprecedented depth of coverage for substrate sequences. SPD-NGS is an important tool for protease biologists interested protease specificity for specific assays and inhibitors and to facilitate identification of natural protein substrates.
What doesn’t kill you makes you stronger: detoxification ability as an honest sexually selected signal
Authors: González-Santoyo Isaac , González-Tokman Daniel , Tapia-Rodríguez Miguel , Córdoba-Aguilar Alex 
Published: May 2020

AbstractSexual selection maintains colourful signals that increase sexual attractiveness and dominance. Some sexually selected, colourful signals are pigments synthesized from ingested amino acids. The underlying metabolic pathways for these pigments often release toxic byproducts that can reduce individual survival. However, rather than discarding these otherwise harmful byproducts, animals may use them by integrating them into sexually selected traits. We tested this idea using males of the damselflyHetaerina americana, which bear a red-pigmented wing spot that is sexually selected through male-male competition for mating territories. First, by using chromatography and confocal microscopy, we determined that the red wing spots are generated by ommochrome pigments derived from tryptophan metabolism. Second, we injected a group of males with the toxic precursor of these ommochromes, 3-hydroxy-kynurenine (3-Hk), confirming the toxicity of this compound in adult males. Finally, by using spectrophotometry and confocal microscopy, we showed that adult males injected with a LC50of 3-Hk had more ommochromes in their wing spots than controls but similar survival, suggesting that the deposition of ommochrome pigment in the wing detoxifies the tryptophan metabolism process. Thus, we report for the first time that sexually selected pigmented signals involve the biochemical treatment of excreted compounds that could otherwise have lethal effects, a hypothesis we call “detoxifying ability signalling”. Our results provide new insights about the origin and maintenance of sexual signals, elucidating a mechanism for the evolution of honest indicators of quality that could have arisen due to natural selection.
The winning methods for predicting cellular position in the DREAM single cell transcriptomics challenge
Authors: Pham Vu VH , Li Xiaomei , Truong Buu , Nguyen Thin , Liu Lin , Li Jiuyong , Le Thuc D 
Published: May 2020

AbstractMotivationPredicting cell locations is important since with the understanding of cell locations, we may estimate the function of cells and their integration with the spatial environment. Thus, the DREAM Challenge on Single Cell Transcriptomics required participants to predict the locations of single cells in the Drosophila embryo using single cell transcriptomic data.ResultsWe have developed over 50 pipelines by combining different ways of pre-processing the RNA-seq data, selecting the genes, predicting the cell locations, and validating predicted cell locations, resulting in the winning methods for two out of three sub-challenges in the competition. In this paper, we present anRpackage,SCTCwhatateam, which includes all the methods we developed and theShinyweb-application to facilitate the research on single cell spatial reconstruction. All the data and the example use cases are available in the Supplementary material.AvailabilityThe scripts of the package are available athttps://github.com/thanhbuu04/SCTCwhatateamand theShinyapplication is available athttps://github.com/pvvhoang/SCTCwhatateam-ShinyAppContactThuc.Le@unisa.edu.auSupplementary informationSupplementary data are available atBriefings in Bioinformaticsonline.