bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of action of rigosertib does not involve tubulin binding
Authors: Baker Stacey J. , Cosenza Stephen C. , Athuluri-Divakar Saikrishna , Reddy M.V. Ramana , Vasquez-Del Carpio Rodrigo , Jain Rinku , Aggarwal Aneel K , Reddy E. Premkumar 
Published: December 2019

SUMMARYRigosertib is a novel benzyl styryl sulfone that inhibits the growth of a wide variety of human tumor cellsin vitroandin vivoand is currently in Phase III clinical trials. We recently provided structural and biochemical evidence to show that rigosertib acts as a RAS-mimetic by binding to Ras Binding Domains (RBDs) of the RAF and PI3K family proteins and disrupts their binding to RAS. In a recent study, Jost et al (2017) attributed the mechanism of action of rigosertib to microtubule-binding. In these studies, rigosertib was obtained from a commercial vendor. We have been unable to replicate the reported results with clinical grade rigosertib, and hence compared the purity of clinical grade and commercially sourced rigosertib. We find that the commercially sourced rigosertib contains approximately 5% ON01500, a potent inhibitor of tubulin polymerization. Clinical grade rigosertib, which is free of this impurity, does not exhibit tubulin binding activity.In vivo, cell lines that express mutant β-tubulin (TUBBL240F) were also reported to be resistant to the effects of rigosertib. However, our studies showed that both wild-type and TUBBL240F-expressing cells failed to proliferate in the presence of rigosertib at concentrations that are lethal to wild-type cells. Morphologically, we find that rigosertib, at lethal concentrations, induced a senescence-like phenotype in the small percentage of both wild-type and TUBBL240F-expressing cells that survive in the presence of rigosertib. Our results suggest that TUBBL240F expressing cells are more prone to undergo senescence in the presence of rigosertib as well as BI2536, an unrelated ATP-competitive pan-PLK inhibitor. The appearance of these senescent cells could be incorrectly scored as resistant cells in flow cytometric assays using short term cultures.
WITHDRAWN: Oligomerization of the antimalarial drug targetPfATP4 is essential for parasite survival
Authors: Ramanathan Aarti A. , Morrisey Joanne M. , Daly Thomas M. , Bergman Lawrence W. , Mather Michael W. , Vaidya Akhil B. 
Published: December 2019

Withdrawal StatementThe authors have withdrawn their manuscript owing to further investigations on PfATP4 that have revealed that the main conclusion of the preprint that PfATP4 forms oligomers is incorrect. Initial cryogenic electron microscopy observations showed a large detergent belt that surrounds monomers of PfATP4, which could have affected migration of the molecule on blue-native polyacrylamide gels. This gave an incorrect impression of the molecule to be in a dimeric or oligomeric state. Authors regret this error in interpreting the data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Integration of system phenotypes in microbiome networks to identify candidate synthetic communities: a study of the grafted tomato rhizobiome
Authors: Poudel Ravin , Jumpponen Ari , Kennelly Megan M. , Rivard Cary , Gomez-Montano Lorena , Garrett Karen A. 
Published: December 2019

ABSTRACTUnderstanding factors influencing microbial interactions, and designing methods to identify key taxa, are complex challenges for achieving microbiome-based agriculture. Here we study how grafting and the choice of rootstock influence root-associated fungal communities in a grafted tomato system. We studied three tomato rootstocks (BHN589, RST-04-106 and Maxifort) grafted to a BHN589 scion and profiled the fungal communities in the endosphere and rhizosphere by sequencing the Internal Transcribed Spacer (ITS2). The data provided evidence for a rootstock effect (explaining ~2% of the total captured variation, p < 0.01) on the fungal community. Moreover, the most productive rootstock, Maxifort, supported greater fungal species richness than the other rootstocks or controls. We then constructed a phenotype-OTU network analysis (PhONA) using an integrated machine learning and network analysis approach based on sequence-based fungal Operational Taxonomic Units (OTUs) and associated tomato yield data. PhONA provides a graphical framework to select a testable and manageable number of OTUs to support microbiome-enhanced agriculture. We identified differentially abundant OTUs specific to each rootstock in both endosphere and rhizosphere compartments. Subsequent analyses using PhONA identified OTUs that were directly associated with tomato fruit yield, and others that were indirectly linked to yield through their links to these OTUs. Fungal OTUs that are directly or indirectly linked with tomato yield may represent candidates for synthetic communities to be explored in agricultural systems.IMPORTANCEThe realized benefits of microbiome analyses for plant health and disease management are often limited by the lack of methods to select manageable and testable synthetic microbiomes. We evaluated the composition and diversity of root-associated fungal communities from grafted tomatoes. We then constructed a phenotype-OTU network analysis (PhONA) using these linear and network models. By incorporating yield data in the network, PhONA identified OTUs that were directly predictive of tomato yield, and others that were indirectly linked to yield through their links to these OTUs. Follow-up functional studies of taxa associated with effective rootstocks, identified using approaches like PhONA, could support the design of synthetic fungal communities for microbiome-based crop production and disease management. The PhONA framework is flexible for incorporation of other phenotypic data and the underlying models can readily be generalized to accommodate other microbiome or other ‘omics data.
mtDNA-based reconstructions of change in effective population sizes of Holarctic birds do not agree with their reconstructed range sizes based on paleoclimates
Authors: Miller Eleanor F. , Green Rhys E. , Balmford Andrew , Beyer Robert , Somveille Marius , Leonardi Michela , Amos William , Manica Andrea 
Published: December 2019

AbstractDuring the Quaternary, large climate oscillations had profound impacts on the distribution, demography and diversity of species globally. Birds offer a special opportunity for studying these impacts because surveys of geographical distributions, publicly-available genetic sequence data, and the existence of species with adaptations to life in structurally different habitats, permit large-scale comparative analyses. We use Bayesian Skyline Plot (BSP) analysis of mitochondrial DNA to reconstruct profiles depicting how effective population size (Ne) may have changed over time, focussing on variation in the effect of the last deglaciation among 102 Holarctic species. Only 3 species showed a decline inNesince the Last Glacial Maximum (LGM) and 7 showed no sizeable change, whilst 92 profiles revealed an increase inNe. Using bioclimatic Species Distribution Models (SDMs), we also estimated changes in species potential range extent since the LGM. Whilst most modelled ranges also increased, we found no correlation across species between the magnitude of change in range size and change inNe. The lack of correlation between SDM and BSP reconstructions could not be reconciled even when range shifts were considered. We suggest the lack of agreement between these measures might be linked to changes in population densities which can be independent of range changes. We caution that interpreting either SDM or BSPs independently is problematic and potentially misleading. Additionally, we found thatNeof wetland species tended to increase later than species from terrestrial habitats, possibly reflecting a delayed increase in the extent of this habitat type after the LGM.
YBEY is an essential biogenesis factor for mitochondrial ribosomes
Authors: Summer Sabrina , Smirnova Anna , Gabriele Alessandro , Toth Ursula , Mandela Fasemore , Förstner Konrad U. , Kuhn Lauriane , Chicher Johana , Hammann Philippe , Mitulović Goran , Entelis Nina , Tarassov Ivan , Rossmanith Walter , Smirnov Alexandre 
Published: December 2019

ABSTRACTRibosome biogenesis requires numerous trans-acting factors, some of which are deeply conserved. In Bacteria, the endoribonuclease YbeY is believed to be involved in 16S rRNA 3’-end processing and its loss was associated with ribosomal abnormalities. In Eukarya, YBEY appears to generally localize to mitochondria (or chloroplasts). Here we show that the deletion of human YBEY results in a severe respiratory deficiency and morphologically abnormal mitochondria as an apparent consequence of impaired mitochondrial translation. Reduced stability of 12S rRNA and the deficiency of several proteins of the small ribosomal subunit inYBEYknockout cells pointed towards a defect in mitochondrial ribosome biogenesis. The specific interaction of mitoribosomal protein uS11m with YBEY suggests that the latter recruits uS11m to the nascent small subunit in its late assembly stage. This scenario shows similarities with final stages of cytosolic ribosome biogenesis, and may represent a late checkpoint before the mitoribosome engages in translation.
Polyandry is extremely rare in the firefly squid,Watasenia scintillans
Authors: Sato Noriyosi , Tsuda Sei-Ichiro , Alam Nur E , Sasanami Tomohiro , Iwata Yoko , Kusama Satoshi , Inamura Osamu , Yoshida Masa-aki , Hirohashi Noritaka 
Published: December 2019

AbstractAlthough polygamy has versatile benefits for both sexes, many species favor monogamy for reasons with the clarity or unclarity. In cephalopods, all species are regarded to be polygamous, which could be attributed to their common life-history traits. Contrary to this prediction, we show empirical evidence for monogamy in the firefly squid,Watasenia scintillans. The peak spawning season comes after male disappearance owning to long-reserved spermatangia deposited by male at exact locations (bilateral pouches under neck collar) on female with a symmetric distribution. Such a non-random placement of spermatangia prompted us to hypothesize that females engage in lifetime monoandry. Hence we assigned genotypes of female-stored spermatangia and offspring. We found that in 94.7 % females, the spermatangia were delivered from a single male and all embryos in the same egg string sired by sperm from stored spermatangia. Throughout the season, relative testes mass was much smaller inW. scintillansthan all other cephalopods previously examined. The mean number of male-stored spermatophores was approximately 30, the equivalent to 2.5 mates. Our demographic and morphometrical data agree with the prediction that monogyny is favored when potential mates are scarce such as absence of female remating. Together, these results suggest the likelihood of mutual monogamy.
A comprehensive study of Phospholipid fatty acid rearrangements in the early onset of the metabolic syndrome: correlations to organ dysfunction
Authors: Bacle Amélie , Kadri Linette , Khoury Spiro , Ferru-Clément Romain , Faivre Jean-François , Cognard Christian , Bescond Jocelyn , Krzesiak Amandine , Contzler Hugo , Delpech Nathalie , Colas Jenny , Vandebrouck Clarisse , Sébille Stéphane , Ferreira Thierry 
Published: December 2019

AbstractThe balance within phospholipids (PL) between Saturated Fatty Acids (SFA) and mono- or poly-Unsaturated Fatty Acids (UFA), is known to regulate the biophysical properties of cellular membranes. As a consequence, perturbating this balance alters crucial cellular processes in many cell types, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spreading of the Western-diet, which is specifically enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome, known as the Metabolic Syndrome (MetS), which is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis. However, no clear correlations between diet-induced fatty acid redistribution within cellular PL, the severity/chronology of the symptoms associated to MetS and the function of the targeted organs, particularly in the early onset of the disease, have been established. In an attempt to fill this gap, we analyzed in the present study PL remodeling in rats exposed during 15 weeks to a High Fat/High Fructose diet (HFHF) in several organs, including known MetS targets. We show that fatty acids from the diet can distribute within PL in a very selective way, with PhosphatidylCholine being the preferred sink for this distribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the exception of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs.
Recent hybridization and allopolyploidy reprogrammedSpartinamicroRNA expression under xenobiotic induced stress
Authors: Cavé-Radet Armand , Salmon Armel , Tran Van Canh Loup , Moyle Richard L. , Pretorius Lara-Simone , Lima O. , Ainouche Malika L. , El Amrani Abdelhak 
Published: December 2019

AbstractXenobiotic detoxification is a common trait of all living organisms, necessary for developmental plasticity and stress tolerance. The gene set involved in this biological process is dubbed the xenome (i.e.involved in drug metabolism in mammals, degradation of allelochemicals and environmental pollutants by bacteria and plant communities). Recently, we found that allopolyploidy increased tolerance to xenobiotics (phenanthrene) inSpartina. To decipher the molecular mechanisms underlying this process, we examined how interspecific hybridization and genome doubling impact miRNAs expression under xenobiotic induced stress. In this work we used a deep sequencing approach, and analyzed the parental speciesS. alternifloraandS. maritima, their F1 hybridS. x townsendiiand the allopolyploidS. anglicaunder phenanthrene exposure. We found that hybridization and genome doubling reprogrammed a myriad of miRNAs under phenanthrene-induced stress. Hence, to identify the master miRNAs involved in phenanthrene tolerance, we performed experimental functional validation of phenanthrene-responsive Spar-miRNAs using Arabidopsis T-DNA mutant lines inserted in homologous MIR genes, 39 knock out T-DNAArabidopsismutants, tagged in the most conserved miRNAs genes in vascular plants were screened. Development of MIR159 and MIR156 mutants was significantly affected under phenanthrene-induced stress. Subsequently, we performedin plantaexperimental validation to confirm the interaction between these miRNAs and their targets. These analyses suggest that MIR159 and MIR156 regulatory modules were targeted to induce the xenome relaxation and impact developmental plasticity responses in phylogenetically distant species under xenobiotic-induced stress.Graphical abstract
BZIP Transcription Factors Modulate DNA Supercoiling Transitions
Authors: Hörberg Johanna , Reymer Anna 
Published: December 2019

ABSTRACTTorsional stress on DNA, introduced by molecular motors, constitutes an important regulatory mechanism of transcriptional control. Torsional stress can modulate specific binding of transcription factors to DNA and introduce local conformational changes that facilitate the opening of promoters and nucleosome remodeling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total helical twist of a DNA fragment, we addressed the impact of torsional stress on DNA complexation with a human BZIP transcription factor, MafB. We gradually over- and underwind DNA alone and in complex with MafB by 5° per dinucleotide step, monitoring the evolution of the protein-DNA contacts at different degrees of torsional strain. Our computations show that MafB changes the DNA sequence-specific response to torsional stress. The dinucleotide steps that are susceptible to absorb most of the torsional stress become more torsionally rigid, as they are involved in the protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stress-induced DNA deformation, but mostly maintains the specific contacts with DNA. This results in a significant asymmetric increase of free energy of DNA twisting transitions, relative to free DNA, where overtwisting is more energetically unfavorable. Our data suggest that MafB could act as a torsional stress insulator, modulating the propagation of torsional stress along the chromatin fiber, which might promote cooperative binding of other transcription factors.
Regional glia-related metabolite levels are higher at older age and scale negatively with visuo-spatial working memory: A cross-sectional proton MR spectroscopy study at 7 tesla on normal cognitive ageing
Authors: Lind Anna , Boraxbekk Carl-Johan , Petersen Esben Thade , Paulson Olaf Bjarne , Siebner Hartwig Roman , Marsman Anouk 
Published: December 2019

AbstractProton MR spectroscopy (1H-MRS) has been used to assess regional neurochemical brain changes during normal ageing, but results have varied. Exploiting the increased sensitivity at ultra-high field strength, we performed 1H-MRS in 60 healthy volunteers to asses age-related differences in neuron- and glia-related metabolite levels and their relation to cognitive ageing. Gender was balanced and participants were assigned to a younger, middle and older group according to their age, ranging from 18 to 79 years. They underwent 1H-MRS of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus and thalamus and performed a visuo-spatial working memory task outside the scanner. Multivariate ANCOVA revealed a significant overall effect of age group on metabolite levels in all brain regions of interest. Considering specific metabolites, elevated levels of glia-related metabolites in older age groups were observed in all brain regions. For the neuron-related metabolites, differences among age groups were only observed in two regions. We found higher levels of total N-acetyl aspartate in hippocampus for the older than the middle group, and lower levels of glutamate in DLPFC in the older than the younger group. Working memory performance correlated negatively with levels of glia-related metabolites for total creatine and total choline in ACC and myo-inositol in hippocampus and thalamus, but not with neuron-related metabolites. Together, the results show that age effects on glia-related metabolites scale with cognitive ageing in multiple brain regions. We conclude that 1H-MRS-derived glia-related markers may be of value in longitudinal studies of brain ageing.Significance statementNeurochemical ageing is an integral component of age-related cognitive decline. Proton MR spectroscopy (1H-MRS) studies of in vivo neurochemical changes across the lifespan have, however, yielded inconclusive results. Due to the higher spectral resolution and sensitivity, 7 tesla 1H-MRS has potential to improve consistency of the results. Here we apply this technique to demonstrate that glia-related metabolites are elevated in older age in anterior cingulate cortex, hippocampus and thalamus with a novel link to cognitive ageing of visuo-spatial working memory. This study is the first to investigate normal ageing in these brain regions using 7 tesla 1H-MRS and the results indicate that glia-related metabolites could be of value in longitudinal studies of cognitive ageing.
Thousands of missing variants in the UK BioBank are recoverable by genome realignment
Authors: Jia Tongqiu , Munson Brenton , Allen Hana Lango , Ideker Trey , Majithia Amit R. 
Published: December 2019

AbstractThe UK Biobank is an unprecedented resource for human disease research. In March 2019, 49,997 exomes were made publicly available to investigators. Here we note that thousands of variant calls are unexpectedly absent from the current dataset, with 641 genes showing zero variation. We show that the reason for this was an erroneous read alignment to the GRCh38 reference. The missing variants can be recovered by modifying read alignment parameters to correctly handle the expanded set of contigs available in the human genome reference.
Detection of active Granzyme A in NK92 cells with fluorescent activity-based probe
Authors: Kołt Sonia , Janiszewski Tomasz , Kaiserman Dion , Modrzycka Sylwia , Snipas Scott J. , Salvesen Guy , Drąg Marcin , Bird Phillip I. , Kasperkiewicz Paulina 
Published: December 2019

AbstractCytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) kill compromised cells to defend against tumor and viral infections. Both effector cell types use multiple strategies to induce target cell death including Fas/CD95 activation; and the release of perforin and a group of lymphocyte granule serine proteases called granzymes. Granzymes have relatively broad and overlapping substrate specificities and may hydrolyze a wide range of peptidic epitopes; it is therefore challenging to identify their natural and synthetic substrates and to distinguish their localization and functions. Here, we present a specific and potent substrate, an inhibitor, and an activity-based probe of Granzyme A (GrA) that can be used to follow functional GrA in cells.
Continuous, multidimensional coding of 3D complex tactile stimuli by primary sensory neurons of the vibrissal system
Authors: Bush Nicholas E. , Solla Sara A. , Hartmann Mitra J. Z. 
Published: December 2019

AbstractTo reveal the full representational capabilities of sensory neurons, it is essential to observe their responses to complex stimuli. In the rodent vibrissal system, mechanical information at the whisker base drives responses of primary sensory neurons in the trigeminal ganglion (Vg). Studies of how Vg neurons encode stimulus properties are typically limited to 2D analyses and restricted stimulus sets. Here we record from Vg neurons during 3D stimulation while quantifying the complete 3D whisker shape and mechanics. Results show that individual Vg neurons simultaneously represent multiple mechanical features of the stimulus, do not preferentially encode principal components of the stimuli, and represent continuous and tiled variations of all available mechanical information. As a population, the neurons span a continuum of rapid and slow adaptation properties; a binary distinction between these adaptation classes is oversimplified. These results contrast with proposed codes in which Vg neurons segregate into functional classes.
tRNA fragments (tRFs) populations analysis in mutants affecting tRNAs processing and tRNA methylation
Authors: Molla-Herman Anahi , Angelova Margarita , Carré Clément , Antoniewski Christophe , Huynh Jean-René 
Published: December 2019

AbstracttRNA fragments (tRFs) are a class of small non-coding RNAs (sncRNAs) derived from tRNAs. tRFs are highly abundant in many cell types including stem cells and cancer cells, and are found in all domains of life. Beyond translation control, tRFs have several functions ranging from transposon silencing to cell proliferation control. However, the analysis of tRFs presents specific challenges and their biogenesis is not well understood. They are very heterogeneous and highly modified by numerous post-transcriptional modifications. Here we describe a bioinformatic pipeline to study tRFs populations and shed light onto tRNA fragments biogenesis. Indeed, we used small RNAs Illumina sequencing datasets extracted from wild type and mutant Drosophila ovaries affecting two different highly conserved steps of tRNA biogenesis: 5’pre-tRNA processing (RNase-P subunit Rpp30) and tRNA 2’-O-methylation (CG7009 and CG5220). Using our pipeline, we show how defects in tRNA biogenesis affect nuclear and mitochondrial tRFs populations and other small non-coding RNAs biogenesis, such as small nucleolar RNAs (snoRNAs). This tRF analysis workflow will advance the current understanding of tRFs biogenesis, which is crucial to better comprehend tRFs roles and their implication in human pathology.