bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic response to divergent selection for flowering times reveals convergence and key players of the underlying gene regulatory network
Authors: Tenaillon Maud I. , Seddiki Khawla , Mollion Maeva , Guilloux Martine Le , Marchadier Elodie , Ressayre Adrienne , Dillmann Christine 
Published: November 2018

ABSTRACTArtificial selection experiments are designed to investigate phenotypic evolution of complex traits and its genetic basis. Here we focused on flowering time, a trait of key importance for plant adaptation and life-cycle shifts. We undertook divergent selection experiments from two maize inbred lines. After 13 generations of selection, we obtained a time-lag of roughly two weeks between Early- and Late-populations. We used this material to characterize the genome-wide transcriptomic response to selection in the shoot apical meristem before, during and after floral transition in field conditions during two consecutive years. We validated the reliability of performing RNA-sequencing in uncontrolled conditions. We found that roughly half of maize genes were expressed in the shoot apical meristem, 59.3% of which were differentially expressed. We detected a majority of genes with differential expression between inbreds and across meristem status, and retrieved a subset of 2,451 genes involved in the response to selection. Among these, we found a significant enrichment for genes with known function in maize flowering time. Furthermore, they were more often shared between inbreds than expected by chance, suggesting convergence of gene expression. We discuss new insights into the expression pattern of key players of the underlying gene regulatory network including theZea maysgenesCENTRORADIALIS(ZCN8),RELATED TO AP2.7(RAP2.7),MADS4(ZMM4),KNOTTED1(KN1),GIBBERELLIN2-OXIDASE1(GA2ox1), as well as alternative scenarios for genetic convergence.
Fractional Deletion Of Compound Kushen Injection, A Natural Compound Mixture, Indicates Cytokine Signaling Pathways Are Critical For Its Perturbation Of The Cell Cycle
Authors: Aung TN , Nourmohammadi S , Qu Z , Harata-Lee Y , Cui J , Shen HY , Yool AJ , Pukala T , Hong Du , Kortschak RD , Adelson DL 
Published: November 2018

AbstractWe have used computational and experimental biology approaches to identify candidate mechanisms of action of a traditional Chinese medicine. Compound Kushen Injection (CKI), in a breast cancer cell line in which CKI causes apoptosis. Because CKI is a complex mixture of plant secondary metabolites, we used a high-performance liquid chromatography (HPLC) fractionation and reconstitution approach to define chemical fractions required for CKI to induce apoptosis in MDA-MB-231 cells. Our initial fractionation separated major from minor compounds, and showed that the major compounds accounted for little of the activity of CKI. By systematically perturbing the major compounds in CKI we found that removal of no single major compound could alter the effect of CKI on cell viability and apoptosis. However, simultaneous removal of two major compounds identified oxymatrine and oxysophocarpine as critical compounds with respect to CKI activity. We then used RNA sequencing and transcriptome analysis to correlate compound removal with gene expression and phenotype data. We determined that many compounds in CKI are required for its effectiveness in triggering apoptosis but that significant modulation of its activity is conferred by a small number of compounds. In conclusion, CKI may be typical of many plant based extracts that contain many compounds in that no single compound is responsible for all of the bioactivity of the mixture and that many compounds interact in a complex fashion to influence a network containing many targets.
A curative combination therapy for lymphomas achieves high fractional cell killing through low cross-resistance and drug additivity but not synergy
Authors: Palmer Adam C , Chidley Christopher , Sorger Peter K 
Published: November 2018

SUMMARYCurative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction; together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50-year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.
The Time Course of Ineffective Sham Blinding During 1mA tDCS
Authors: Greinacher Robert , Buhôt Larissa , Möller Lisa , Learmonth Gemma 
Published: November 2018

AbstractBackgroundStudies using transcranial direct current stimulation (tDCS) typically compare the effects of an active (10-30min) relative to a shorter sham (placebo) protocol. Both active and sham tDCS are presumed to be perceptually identical on the scalp, and thus represent an effective method of delivering double-blinded experimental designs. However, participants often show above-chance accuracy when asked which condition involved active/sham retrospectively.Objective/HypothesisWe aimed to assess the time course of sham-blinding during active and sham tDCS. We predicted that 1) Participants will be aware that the current is switched on for a longer duration in the active versus the sham protocol, 2) Active anodal tDCS will reduce reaction times more effectively than sham.Methods32 adults were tested in a pre-registered, double-blinded, within-subjects design. A forced-choice reaction time task was undertaken before, during and after active (10min 1mA) and sham (20s 1mA) tDCS. The anode was placed over the left primary motor cortex (C3) to target the right hand, and the cathode on the right forehead. Two probe questions were asked every 30s: “Is the stimulation on? “and “How sure are you?”.ResultsDistinct periods of non-overlapping confidence intervals were identified between the active and sham conditions, totalling 5min (57.1% of the total difference in stimulation time). These began immediately after sham ramp-down and lasted until the active protocol had ended. Active tDCS had no effect on reaction times compared to sham (ΔRT active vs sham p>0.38 in all blocks).ConclusionsWe show a failure of placebo control during low-intensity tDCS.
TAPBPR mediates peptide dissociation from MHC class I using a leucine lever
Authors: Ilca F. Tudor , Neerincx Andreas , Hermann Clemens , Marcu Ana , Stevanovic Stefan , Deane Janet E , Boyle Louise H 
Published: November 2018

AbstractTapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.Impact StatementThis work demonstrates for the first time that the K22-D35 loop of TAPBPR is the essential region for mediating peptide exchange and peptide selection on major histocompatibility complex class I molecules.
The invisibility cloak: Chitin binding protein ofVerticillium nonalfalfaedisguises fungus from plant chitinases
Authors: Volk Helena , Marton Kristina , Flajšman Marko , Radišek Sebastjan , Hein Ingo , Podlipnik Črtomir , Javornik Branka , Berne Sabina 
Published: November 2018

AbstractDuring fungal infections, plant cells secrete chitinases that digest chitin in the fungal cell walls. The recognition of released chitin oligomers via lysin motif (LysM)-containing immune receptors results in the activation of defence signalling pathways. We report here thatVerticillium nonalfalfae, a hemibiotrophic xylem-invading fungus, prevents this recognition process by secreting a CBM18 (carbohydrate binding motif 18)-chitin binding protein, VnaChtBP, which is transcriptionally activated specifically during the parasitic life stages. VnaChtBP is encoded by theVna8.213gene which is highly conserved within the species, suggesting high evolutionary stability and importance for the fungal lifestyle. In a pathogenicity assay, however,Vna8.213knockout mutants exhibit wilting symptoms similar to the wild type fungus, suggesting thatVna8.213activity is functionally redundant during fungal infection of hop. In binding assay, recombinant VnaChtBP binds chitin and chitin oligomersin vitrowith submicromolar affinity and protects fungal hyphae from degradation by plant chitinases. Using a yeast-two-hybrid assay, homology modelling and molecular docking, we demonstrated that VnaChtBP forms dimers in the absence of ligands and that this interaction is stabilized by the binding of chitin hexamers with a similar preference in the two binding sites. Our data suggest that, in addition to chitin binding LysM (CBM50) and Avr4 (CBM14) fungal effectors, structurally unrelated CBM18 effectors have convergently evolved to prevent hydrolysis of the fungal cell wall against plant chitinases.
A comparison of Alberta’s Infant Motor Scale and Brazelton Neonatal Behavior Assessment Scale
Authors: Perera Priyantha , Godamunne Pavithra , Nandasena Sumal , Tipre Meghan , Wimalasiri Udaya , Reader Mark , Beddage Thulani , Smith Tamika , Kasturiratne Anuradhani , Sathiakumar Nalini , Wickremasinghe Rajitha 
Published: November 2018

AbstractBackground and aimsThe Neonatal Behavior Assessment Scale (NBAS) was introduced by Brazelton is a useful tool to assess neurodevelopment in newborn in research setting. However, it is complex, time-consuming and requires specialized training for administration and is therefore difficult tool to use in routine clinical settings. The Alberta Infant Motor Scale (AIMS) is a simple tool to assess of motor maturation of a child up to 18 months and can be administered with minimal training for the health care professionals. The study goal of this study was to evaluate the reliability and validity of the AIMS in comparison with the NBAS in assessing motor maturity at birth.MethodsWe administered the AIMS and NBAS to a total of 66 newborn babies delivered in three obstetric units at the Colombo North Teaching Hospital in Ragama, Sri Lanka. The subjects were selected from a sample of 545 newborn babies in an ongoing birth-cohort study evaluating effects of prenatal exposure to biomass smoke and infant neurodevelopment. Trained research assistants administered first the NBAS, followed by the AIMS one-hour later. Univariate and bivariate statistics were used to compare the two scales.ResultsIrrespective of maturity, sex, birth weight or socio-demographic characteristics, all babies had scored on the 75th percentile in the AIMS. In the NBAS, there was a significant variation in the Brazelton motor score scaled to 100. Low birth weight babies showed a narrower variation in the NABS score. None of the scales indicated a motor deficit in any of the children.ConclusionNBAS identifies subtle differences in motor maturity of full term babies that the AIMS fails to detect
Using transcriptome sequencing and pooled exome capture to study local adaptation in the giga-genome ofPinus cembra
Authors: Rellstab Christian , Dauphin Benjamin , Zoller Stefan , Brodbeck Sabine , Gugerli Felix 
Published: November 2018

AbstractDespite decreasing sequencing costs, whole-genome sequencing for population-based genome scans for selection is still prohibitively expensive for organisms with large genomes. Moreover, the repetitive nature of large genomes often represents a challenge in bioinformatic and downstream analyses. Here we use in-depth transcriptome sequencing to design probes for exome capture in Swiss stone pine (Pinus cembra), a conifer with an estimated genome size of 29.3 Gbp and no reference genome available. We successfully applied around 55,000 self-designed probes, targeting 25,000 contigs, to DNA pools of seven populations from the Swiss Alps and identified > 140,000 SNPs in around 13,000 contigs. The probes performed equally well in pools of the closely related speciesPinus sibirica; in both species, more than 70% of the targeted contigs were sequenced at a depth ≥ 40x, i.e. the number of haplotypes in the pool. However, a thorough analysis of individually sequencedP. cembrasamples indicated that a majority of the contigs (63%) represented multi-copy genes. We therefore removed paralogous contigs based on heterozygote excess and deviation from allele balance. Without putatively paralogous contigs, allele frequencies of population pools represented accurate estimates of individually determined allele frequencies. Using population genetic and landscape genomic methods, we show that inferences of neutral and adaptive genetic variation may be biased when not accounting for such multi-copy genes. Future studies should therefore put more emphasis on identifying paralogous loci, which will be facilitated by the establishment of additional high-quality reference genomes.
An updated phylogeny of theAlphaproteobacteriareveals that the parasiticRickettsialesandHolosporaleshave independent origins
Authors: Muñoz-Gómez Sergio A. , Hess Sebastian , Burger Gertraud , Franz Lang B. , Susko Edward , Slamovits Claudio H. , Roger Andrew J. 
Published: November 2018

ABSTRACTTheAlphaproteobacteriais an extraordinarily diverse and ancient group of bacteria. Previous attempts to infer its deep phylogeny have been plagued with methodological artefacts. To overcome this, we analyzed a dataset of 200 single-copy and conserved genes and employed diverse strategies to reduce compositional artefacts. Such strategies include using novel dataset-specific profile mixture models and recoding schemes, and removing sites, genes and taxa that are compositionally biased. We show that theRickettsialesandHolosporales(both groups of intracellular parasites of eukaryotes) are not sisters to each other, but instead, theHolosporaleshas a derived position within theRhodospirillales. Furthermore, we find that theRhodospirillalesmight be paraphyletic and that theGeminicoccaceaecould be sister to all ancestrally free-living alphaproteobacteria. Our robust phylogeny will serve as a framework for future studies that aim to place mitochondria, and novel environmental diversity, within theAlphaproteobacteria.
OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome
Authors: Xu Ranjie , Brawner Andrew T , Li Shenglan , Liu JingJing , Kim Hyosung , Xue Haipeng , Pang Zhiping P. , Kim Woo-Yang , Hart Ronald P. , Liu Ying , Jiang Peng 
Published: November 2018

SUMMARYDown syndrome (DS) is a common neurodevelopmental disorder, and cognitive defects in DS patients may arise form imbalances in excitatory and inhibitory neurotransmission. Understanding the mechanisms underlying such imbalances may provide opportunities for therapeutic intervention. Here, we show that human induced pluripotent stem cells (hiPSCs) derived from DS patients overproduce OLIG2+ventral forebrain neural progenitors. As a result, DS hiPSC-derived cerebral organoids excessively produce specific subclasses of GABAergic interneurons and cause impaired recognition memory in neuronal chimeric mice. Increased OLIG2 expression in DS cells directly upregulates interneuron lineage-determining transcription factors. shRNA-mediated knockdown ofOLIG2largely reverses abnormal gene expression in early-stage DS neural progenitors, reduces interneuron production in DS organoids and chimeric mouse brains, and improves behavioral deficits in DS chimeric mice. Thus, altered OLIG2 expression may underlie neurodevelopmental abnormalities and cognitive defects in DS patients.
Pan-cancer analysis on microRNA-mediated gene activation
Authors: Tan Hua , Huang Shan , Zhang Zhigang , Qian Xiaohua , Sun Peiqing , Zhou Xiaobo 
Published: November 2018

ABSTRACTWhile microRNAs (miRNAs) were widely considered to repress target genes at mRNA and/or protein levels, emerging evidence from in vitro experiments has shown that miRNAs can also activate gene expression in particular contexts. However, this counterintuitive observation has rarely been reported or interpreted in in vivo conditions. We systematically explored the positive correlation between miRNA and gene expressions and its potential implications in tumorigenesis, based on 8375 patient samples across 31 major human cancers from The Cancer Genome Atlas (TCGA). Results indicated that positive miRNA-gene correlations are surprisingly prevalent and consistent across cancer types, and show distinct patterns than negative correlations. The top-ranked positive correlations are significantly involved in the immune cell differentiation and cell membrane signaling related processes, and display strong power in stratifying patients in terms of survival rate, demonstrating their promising clinical relevance. Although intragenic miRNAs generally tend to co-express with their host genes, a substantial portion of miRNAs shows no obvious correlation with their host gene due to non-conservation. A miRNA can upregulate a gene by inhibiting its upstream suppressor, or shares transcription factors with that gene, both leading to positive correlation. The miRNA/gene sites associated with the top-ranked positive correlations are more likely to form super-enhancers compared to randomly chosen pairs, suggesting a potential epigenetics mechanism underlying the upregulation. Wet-lab experiments revealed that positive correlations partially remain in the in vitro condition. Our study provides the field with new perspectives on the critical role of miRNA in gene regulation and novel insights regarding the complex mechanisms underlying miRNA functions, and reveals the clinical significance of the potential positive regulation of gene expression by miRNA.
Physiological and transcriptomic analysis of yellow leaf coloration inPopulus deltoidesMarsh
Authors: Zhang Shuzhen , Wu Xiaolu , Cui Jie , Zhang Fan , Wan Xueqin , Liu Qinglin , Zhong Yu , Lin Tiantian 
Published: November 2018

AbstractAs important deciduous tree,Populus deltoidesMarsh possesses a high ornamental value for its leaves remaining yellow during the non-dormant period. However, little is known about the regulatory mechanism of leaf coloration inPopulus deltoidesMarsh. Thus, we analyzed physiological and transcriptional differences of yellow leaves (mutant) and green leaves (wild-type) ofPopulus deltoidesMarsh. Physiological experiments showed that the contents of chlorophyll (Chl) and carotenoid are lower in mutant, the flavonoid content is not differed significantly between mutant and wild-type. Transcriptomic sequencing was further used to identify 153 differentially expressed genes (DEGs). Functional classifications based on Gene Ontology enrichment and Genomes enrichment analysis indicated that the DEGs were involved in Chl biosynthesis and flavonoid biosynthesis pathway. Among these, geranylgeranyl diphosphate (CHLP) genes associated with Chl biosynthesis showed down-regulation, while chlorophyllase (CLH) genes associated with Chl degradation were up-regulated in yellow leaves. The expression levels of these genes were further confirmed using quantitative real-time PCR (RT-qPCR). Furthermore, the measurement of the main precursors of Chl confirmed that CHLP is vital enzymes for the yellow leaf color phenotype. Consequently, the formation of yellow leaf color is due to disruption of Chl synthesis and catabolism rather than flavonoid content. These results contribute to our understanding of mechanisms and regulation of leaf color variation in poplar at the transcriptional level.
Transmission of mechanical information by purinergic signaling
Authors: Mikolajewicz N. , Sehayek S. , Wiseman P. W. , Komarova S. V. 
Published: November 2018

1AbstractThe human skeleton constantly interacts and adapts to the physical world. We have previously reported that physiologically-relevant mechanical forces lead to small, repairable membrane injuries in bone-forming osteoblasts, resulting in the release of ATP and stimulation of purinergic (P2) calcium responses in neighbouring cells. The goal of this study was to develop a theoretical model describing injury-related ATP and ADP release, extracellular diffusion and degradation, and purinergic responses in neighboring cells. The model was validated using experimental data obtained by measuring intracellular free calcium ([Ca2+]i) elevations following mechanical stimulation of a single osteoblast. The validated single-cell injury model was then scaled to a tissue-level injury to investigate how purinergic responses communicate information about injuries with varying geometries. We found that total ATP released, peak extracellular ATP concentration and the ADP-mediated signaling component contributed complementary information regarding the mechanical stimulation event. The total amount of ATP released governed the maximal distance from the injury at which purinergic responses were stimulated, as well as the overall number of responders. The peak ATP concentration reflected the severity of an individual cell injury and determined signal propagation velocity and temporal synchrony of responses. Peak ATP concentrations also discriminated between minor and severe injuries that led to the release of similar total amounts of ATP due to differences in injury repair dynamics. The third component was ADP-mediated signaling which became relevant only in larger tissue-level injuries, and it conveyed information about the distance to the injury site and its geometry. Taken together, this study identified specific features of extracellular ATP/ADP spatiotemporal signals that encode the severity of the mechanical stimulus, the distance from the stimulus, as well as the mechano-resilient status of the tissue.