bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broad Dengue Neutralization in Mosquitoes Expressing an Engineered Antibody
Authors: Buchman Anna , Gamez Stephanie , Li Ming , Antoshechkin Igor , Lee Shin-Hang , Wang Shin-Wei , Chen Chun-Hong , Klein Melissa J. , Duchemin Jean-Bernard , Crowe James E. , Paradkar Prasad N. , Akbari Omar S. 
Published: May 2019

AbstractWith dengue virus (DENV) becoming endemic in tropical and subtropical regions worldwide, there is a pressing global demand for effective strategies to control the mosquitoes that spread this disease. Recent advances in genetic engineering technologies have made it possible to create mosquitoes with reduced vector competence, limiting their ability to acquire and transmit pathogens. Here we describe the development of Aedes aegypti mosquitoes synthetically engineered to impede vector competence to DENV. These mosquitoes express a gene encoding an engineered single-chain variable fragment derived from a broadly neutralizing DENV human monoclonal antibody and have significantly reduced viral infection, dissemination, and transmission rates for all four major antigenically distinct DENV serotypes. Importantly, this is the first engineered approach that targets all DENV serotypes, which is crucial for effective disease suppression. These results provide a compelling route for developing effective genetic-based DENV control strategies, which could be extended to curtail other arboviruses.Significance StatementHere we describe the development of Ae. aegypti mosquitoes synthetically engineered to impede vector competence to multiple serotypes of DENV. Given the global significance of DENV, these mosquitoes may be used to curtail Dengue transmission by this potent vector.
Characterization of core bacterial species in theDaphnia magnamicrobiota using shotgun metagenomics
Authors: Cooper Reilly O. , Cressler Clayton E. 
Published: May 2019

AbstractBackgroundThe keystone zooplanktonDaphnia magnahas recently been used as a model system for understanding host-microbiota interactions. However, the bacterial species present and functions associated with their genomes are not well understood. In order to understand potential functions of these species, we combined 16S rRNA sequencing and shotgun metagenomics to characterize the whole-organism microbiota ofDaphnia magna.ResultsFive metagenome-assembled genomes (MAGs) were assembled from theDaphnia magnamicrobiota. Phylogenetic placement of these MAGs indicated that two belong to theLimnohabitansgenus, one toPolaromonas, one toPedobacter, and one unclassifiable below the Burkholderiaceae family. Average nucleotide identity of these MAGs to their closest sequenced relative was <95%, suggesting these may be new species in known genera. 16S rRNA community profiling shows that theDaphnia magnamicrobiota is distinct from its culture environment. Genes involved in host colonization and immune system evasion were detected across the MAGs. Some metabolic pathways were specific to some MAGs, including sulfur oxidation, nitrate reduction, and flagellar assembly. Threonine and arginine exporters were encoded by theLimnohabitansand Burkholderiaceae MAGs, and pathways for key vitamin biosynthesis and export were identified across MAGs.ConclusionsIn this study, we characterize five metagenome-assembled bacterial genomes within theDaphnia magnamicrobiota. Our examination of functions associated with these genomes shows a diversity of nutrient acquisition and metabolism pathways present that may benefit the host, as well as genomic signatures of host association and immune system evasion.
A putative microcin amplifies Shiga toxin 2a production ofEscherichia coliO157:H7
Authors: Figler Hillary M. , Xiaoli Lingzi , Banerjee Kakolie , Hoffmann Maria , Yao Kuan , Dudley Edward G. 
Published: May 2019

AbstractEscherichia coliO157:H7 is a foodborne pathogen, implicated in various multi-state outbreaks. It encodes Shiga toxin on a prophage, and Shiga toxin production is linked to phage induction. AnE. colistrain, designated 0.1229, was identified that amplified Stx2a production when co-cultured withE. coliO157:H7 strain PA2. Growth of PA2 in 0.1229 cell-free supernatants had a similar effect, even when supernatants were heated to 100°C for 10 min, but not after treatment with Proteinase K. The secreted molecule was shown to use TolC for export and the TonB system for import. The genes sufficient for production of this molecule were localized to a 5.2 kb region of a 12.8 kb plasmid. This region was annotated, identifying hypothetical proteins, a predicted ABC transporter, and a cupin superfamily protein. These genes were identified and shown to be functional in two otherE. colistrains, and bioinformatic analyses identified related gene clusters in similar and distinct bacterial species. These data collectively suggestE. coli0.1229 and otherE. coliproduce a microcin that induces the SOS response in target bacteria. Besides adding to the limited number of microcins known to be produced byE. coli, this study provides an additional mechanism by whichstx2aexpression is increased in response to the gut microflora.ImportanceHow the gut microflora influences the progression of bacterial infections is only beginning to be understood. Antibiotics are counter-indicated forE. coliO157:H7 infections, and therefore treatment options are limited. An increased understanding of how the gut microflora directs O157:H7 virulence gene expression may lead to additional treatment options. This work identifiedE. colithat enhance the production of Shiga toxin by O157:H7, through the secretion of a proposed microcin. This work demonstrates another mechanism by which non-O157E. colistrains may increase Shiga toxin production, and adds to our understanding of microcins, a group of antimicrobials that are less well understood than colicins.
PIN-LIKES coordinate brassinosteroid signalling with nuclear auxin input in Arabidopsis thaliana
Authors: Sun Lin , Feraru Elena , Feraru Mugurel I. , Wabnik Krzysztof , Kleine-Vehn Jürgen 
Published: May 2019

AbstractAuxin and brassinosteroids (BR) are crucial growth regulators and display overlapping functions during plant development. Here, we reveal an alternative phytohormone crosstalk mechanism, revealing that brassinosteroid signaling controls nuclear abundance of auxin. We performed a forward genetic screen for imperial pils (imp) mutants that enhance the overexpression phenotypes of PIN-LIKES (PILS) putative intracellular auxin transport facilitator. Here we report that the imp1 mutant is defective in the brassinosteroid-receptor BRI1. Our data reveals that BR signaling transcriptionally and posttranslationally represses accumulation of PILS proteins at the endoplasmic reticulum, thereby increasing nuclear abundance and signaling of auxin. We demonstrate that this alternative phytohormonal crosstalk mechanism integrates BR signaling into auxin-dependent organ growth rates and likely has widespread importance for plant development.
Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging
Authors: Barbu Miruna C. , Spiliopoulou Athina , Colombo Marco , McKeigue Paul , Clarke Toni-Kim , Howard David M. , Adams Mark J. , Shen Xueyi , Lawrie Stephen M. , McIntosh Andrew M. , Whalley Heather C. 
Published: May 2019

AbstractBackgroundExpression quantitative trait loci (eQTL) are genetic variants associated with gene expression. Using genome-wide genotype data, it is now possible to impute gene expression using eQTL mapping efforts. This approach can be used to analyse previously unexplored relationships between gene expression and heritablein vivomeasures of human brain structural connectivity.MethodsUsing large-scale eQTL mapping studies, we computed 6,457 gene expression scores (eQTL scores) using genome-wide genotype data in UK Biobank, where each score represents a genetic proxy measure of gene expression. These scores were then tested for associations with two diffusion tensor imaging measures, fractional anisotropy (NFA=14,518) and mean diffusivity (NMD=14,485), representing white matter structural integrity.ResultsWe found FDR-corrected significant associations between 8 eQTL scores and structural connectivity phenotypes, including global and regional measures (βabsoluteFA=0.0339-0.0453; MD=0.0308-0.0381) and individual tracts (βabsoluteFA=0.0320-0.0561; MD=0.0295-0.0480). The loci within these eQTL scores have been reported to regulate expression of genes involved in various brain-related processes and disorders, such as neurite outgrowth and Parkinson’s disease (DCAKD,SLC35A4,SEC14L4,SRA1,NMT1,CPNE1,PLEKHM1,UBE3C).DiscussionOur findings indicate that eQTL scores are associated with measures ofin vivobrain connectivity and provide novel information not previously found by conventional genome-wide association studies. Although the role of expression of these genes regarding white matter microstructural integrity is not yet clear, these findings suggest it may be possible, in future, to map potential trait- and disease-associated eQTL toin vivobrain connectivity and better understand the mechanisms of psychiatric disorders and brain traits, and their associated imaging findings.
Protein level variability determines phenotypic heterogeneity in proteotoxic stress response
Authors: Guilbert Marie , Anquez François , Pruvost Alexandra , Thommen Quentin , Courtade Emmanuel 
Published: May 2019

AbstractCell-to-cell variability in stress response is a bottleneck for the construction of accurate and predictive models that could guide clinical diagnosis and treatment of diseases as for instance cancers. Indeed such phenotypic heterogeneity can lead to fractional killing and persistence of a subpopulation of cells resistant to a given treatment. The heat shock response network plays a major role in protecting the proteome against several types of injuries. We combine high-throughput measurements and mathematical modeling to unveil the molecular origin of the phenotypic variability in the heat shock response network. Although the mean response coincides with known biochemical measurements, we found a surprisingly broad diversity in single cell dynamics with a continuum of response amplitudes and temporal shapes for several stimuli strengths. We theoretically predict that the broad phenotypic heterogeneity is due to network ultrasensitivity together with variations in the expression level of chaperons controlled by heat shock factor 1. We experimentally confirm this prediction by mapping the response amplitude to concentrations chaperons and heat shock factor 1 expression level.
Detecting and controlling dye effects in single-virus fusion experiments
Authors: Rawle R. J. , Giraldo A. M. Villamil , Boxer S. G. , Kasson P. M. 
Published: May 2019

AbstractFluorescent dye-dequenching assays provide a powerful and versatile means to monitor membrane fusion events. They have been used in bulk assays, for measuring single events in live cells, and for detailed analysis of fusion kinetics for liposomal, viral, and cellular fusion processes; however, the dyes used also have the potential to perturb membrane fusion. Here, using single-virus measurements of influenza membrane fusion, we show that fluorescent membrane probes can alter both the efficiency and the kinetics of lipid mixing in a dye- and illumination-dependent manner. R18, a dye that is commonly used to monitor lipid mixing between membranes, is particularly prone to these effects, while Texas Red is somewhat less sensitive. R18 further undergoes photoconjugation to viral proteins in an illumination-dependent manner that correlates with its inactivation of viral fusion. These results demonstrate how fluorescent probes can perturb measurements of biological activity and provide both data and a method for determining minimally perturbative measurement conditions.Statement of SignificanceFluorescent dyes are powerful tools for labeling membranes and tracking subcellular objects, and fluorescence dequenching has further been used as a sensitive assay for membrane fusion. Here we show how incorporation of membrane dyes can perturb membrane fusion by influenza virus in a light-dependent manner. We provide a strategy to mitigate this by minimizing dye and light exposure. Finally, we show how in some cases these effects can be due to covalent reaction of some dyes with viral proteins upon illumination. These phenomena may be general and should be carefully controlled for in experiments using such labels.
Functionalized microcarriers improve T cell manufacturing by facilitating migratory memory T cell production and increasing CD4/CD8 ratio
Authors: Dwarshuis Nathan J. , Song Hannah W. , Patel Anokhi , Kotanchek Theresa , Roy Krishnendu 
Published: May 2019

AbstractAdoptive cell therapies (ACT) using chimeric antigen receptor (CAR) T cells have shown promise in treating cancer, but manufacturing large numbers of high quality cells remains challenging. Critically, current T cell expansion technologies only partially recapitulate thein vivomicroenvironment found in the human lymph nodes. In these organs, T cells expand at high cell density with autocrine/paracrine signaling, as well as signals from the extracellular matrix (ECM). Here we describe a T cell expansion system using degradable gelatin microcarriers functionalized with anti-CD3 and anti-CD28 monoclonal antibodies (mAbs), which address several of these shortcomings. We show that using this system, we can achieve approximately 2-fold greater expansion compared to functionalized magnetic beads, the current industry standard. Furthermore, carriers generated higher numbers of CCR7+CD62L+ migratory, central memory T cells and CD4+ T cells across multiple donors. Both these phenotypes have emerged as important for establishing durable and effective responses in patients receiving T cell immunotherapies. We further demonstrate that carriers can achieve greater memory cell yield compared to beads across a range of IL2 concentrations from 20 U/mL to 100 U/mL. These differences were greater at lower IL2 concentrations, indicating that the carriers are more efficient. We optimized this system using a design of experiments (DOE) approach and found that the carrier concentration affects the memory cell yield in a quadratic manner, where high or low concentrations are detrimental to memory formation. Finally, we show that carriers do not hinder CAR transduction and can maintain the CD4 and memory phenotype advantages in CAR-transduced T cells.
A molecular mechanism for the procentriole recruitment of Ana2
Authors: McLamarrah Tiffany A. , Speed Sarah K. , Buster Daniel W. , Fagerstrom Carey J. , Galletta Brian J. , Rusan Nasser M. , Rogers Gregory C. 
Published: May 2019

AbstractCentriole duplication begins with the assembly of a pre-procentriole at a single site on a mother centriole and proceeds with the hierarchical recruitment of a conserved set of proteins, including Polo-like kinase 4 (Plk4)/ZYG-1, Ana2/SAS-5/STIL, and the cartwheel protein Sas6. During assembly, Ana2/STIL stimulates Plk4 kinase activity, and in turn, Ana2/STIL’s C-terminus is phosphorylated, allowing it to bind and recruit Sas6. The assembly steps immediately preceding Sas6-loading appear clear, but the mechanism underlying the upstream pre-procentriole recruitment of Ana2/STIL is not. In contrast to proposed models of Ana2/STIL recruitment, we recently showed that Drosophila Ana2 targets procentrioles independent of Plk4-binding. Instead, Ana2 recruitment requires Plk4 phosphorylation of Ana2’s N-terminus, but the mechanism explaining this process is unknown. Here, we show that the amyloid-like domain of Sas4, a centriole surface protein, binds Plk4 and Ana2, and facilitates phosphorylation of Ana2’s N-terminus which increases Ana2’s affinity for Sas4. Consequently, Ana2 accumulates at the procentriole to induce daughter centriole assembly.
Agency plans are inadequate to conserve US endangered species under climate change
Authors: Delach Aimee , Caldas Astrid , Edson Kiel , Krehbiel Robb , Murray Sarah , Theoharides Katie , Vorhees Lauren , Malcom Jacob W. , Salvo Mark , Miller Jennifer R. B. 
Published: May 2019

AbstractDespite widespread evidence of climate change as a threat to biodiversity, it is unclear whether government policies and agencies are adequately addressing this threat to species1–4. We evaluate species sensitivity, a component of climate change vulnerability, and whether climate change is discussed as a threat in planning for climate-related management action in official documents from 1973-2018 for all 459 US animals listed as endangered under the Endangered Species Act. We find that 99.8% of species are sensitive to one or more of eight sensitivity factors, but agencies consider climate change as a threat to only 64% of species and plan management actions for only 18% of species. Agencies are more likely to plan actions for species sensitive to more factors, but such planning has declined since 2016. Results highlight the gap between climate change sensitivity and the attention from agencies charged with conserving endangered species.
Nuclear lamin B is crucial to the nuclear envelope integrity and extracellular trap release in neutrophils
Authors: Li Yubin , Werth Victoria P. , Mall Moritz , Liu Ming-Lin 
Published: May 2019

AbstractIt’s not clear how nuclear envelope (NE) is ruptured for chromatin externalization during NETosis. The membrane rupture during neutrophil NET release was described as a membrane lysis process, this notion, however, has been questioned. Here, we found that lamin B, the structural NE component, was involved in NETosis. Unexpectedly, lamin B was not fragmented by destructive proteolysis, but rather disassembled into its intact full-length molecule, in NETotic cells with ruptured NE. In the mechanistic study, our experiments demonstrated that cytosolic PKCα translocated to the nucleus, where it serves as a NETotic lamin kinase to induce lamin B phosphorylation, following by lamina disassembly and NE rupture. To determine causality, we found that decreasing lamin B phosphorylation, by PKCα inhibition or genetic deletion, or mutation at the PKCα consensus phosphorylation sites of lamin B, attenuated extracellular trap formation. Importantly, strengthening NE by lamin B overexpression attenuated neutrophil NETosisin vivoand alleviated exhibition of NET-associated inflammatory cytokines in UVB irradiated skin of lamin B transgenic mice. These findings advance our understanding of NETosis process and elucidate a cellular mechanism that PKCα-mediated lamin B phosphorylation drives nuclear envelope rupture for NET release in neutrophils.Graphical Abstract
PHLPP1 Counter-regulates STAT1-mediated Inflammatory Signaling
Authors: Cohen-Katsenelson Ksenya , Stender Joshua D. , Kawashima Agnieszka T. , Lordén Gema , Uchiyama Satoshi , Nizet Victor , Glass Christopher K. , Newton Alexandra C. 
Published: May 2019

ABSTRACTInflammation is an essential aspect of innate immunity but also contributes to diverse human diseases. Although much is known about the kinases that control inflammatory signaling, less is known about the opposing phosphatases. Here we report that deletion of the gene encoding PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) protects mice from lethal lipopolysaccharide (LPS) challenge and liveEscherichia coliinfection. Investigation of PHLPP1 function in macrophages reveals that it controls the magnitude and duration of inflammatory signaling by dephosphorylating the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce the expression of target genes involved in innate immunity and cytokine signaling. This previously undescribed function of PHLPP1 depends on a bipartite nuclear localization signal in its unique N-terminal extension. Our data support a model in which nuclear PHLPP1 dephosphorylates STAT1 to control the magnitude and duration of inflammatory signaling in macrophages.HIGHLIGHTSPHLPP1 controls the transcription of genes involved in inflammatory signalingPHLPP1 dephosphorylates STAT1 on Ser727 to reduce its transcriptional activityPHLPP1 has a nuclear localization signal and a nuclear exclusion signalLoss of PHLPP1 protects mice from sepsis-induced death
Large increases in emissions of methane and nitrous oxide from eutrophication in Lake Erie
Authors: Fernandez Julianne M. , Townsend-Small Amy , Zastepa Arthur , Watson Susan B. , Brandes Jay A. 
Published: May 2019

AbstractEutrophication is linked to greenhouse gas emissions from inland waters. Phytoplankton blooms in Lake Erie, one of Earth’s largest lakes, have increased with nutrient runoff linked to climate warming, although greenhouse gas emissions from this or other large eutrophic lakes are not well characterized. We measured greenhouse gases around Lake Erie in all four seasons and found that CH4and N2O emissions have increased 10 times or more with re-eutrophication, especially during and after phytoplankton blooms. Lake Erie is a positive source of CH4throughout the entire year and around the entire lake, with the highest emissions in spring and summer near the mouth of the Maumee River. While Lake Erie is an overall N2O source, it is an N2O sink in winter throughout the lake and in some locations during large phytoplankton blooms. We estimate that Lake Erie emits ~6300 metric tons of CH4-C yr−1(± 19%) and ~600 metric tons N2O-N yr−1(± 37%): almost 500,000 metric tons CO2-eq yr−1total. These results highlight the gravity of eutrophication-related increases in large lake GHG emissions: an overlooked, but potentially major feedback to global climate change.