bluuebunny/crossref_metadata_2025_split huggingface dataset:
The landscape of selection in 551 Esophageal Adenocarcinomas defines genomic biomarkers for the clinic
Authors: Frankell AM , Jammula S , Li X , Contino G , Killcoyne S , Abbas S , Perner J , Bower L , Devonshire G , Ococks E , Grehan N , Mok J , O’Donovan M , MacRae S , Eldridge M , Tavare S , Fitzgerald RC ,   the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
Published: April 2018

AbstractEsophageal Adenocarcinoma (EAC) is a poor prognosis cancer type with rapidly rising incidence. Our understanding of genetic events which drive EAC development is limited and there are few molecular biomarkers for prognostication or therapeutics. We have accumulated a cohort of 551 genomically characterised EACs (73% WGS and 27% WES) with clinical annotation and matched RNA-seq. Using a variety of driver gene detection methods, we discover 77 EAC driver genes (73% novel) and 21 non-coding driver elements (95% novel), and describe mutation and CNV types with specific functional impact. We identify a mean of 4.4 driver events per case derived from both copy number events and mutations. We compare driver mutation rates to the exome-wide mutational excess calculated using Non-synonymous vs Synonymous mutation rates (dNdS). We observe mutual exclusivity or co-occurrence of events within and between a number of EAC pathways (GATA factors, Core Cell cycle genes, TP53 regulators and the SWI/SNF complex) suggestive of important functional relationships. These driver variants correlate with tumour differentiation, sex and prognosis. Poor prognostic indicators (SMAD4, GATA4) are verified in independent cohorts with significant predictive value. Over 50% of EACs contain sensitising events for CDK4/6 inhibitors which are highly correlated with clinically relevant sensitivity in a panel EAC cell lines and organoids.
Ephemeral states in protein folding under force captured with a novel magnetic tweezers design
Authors: Tapia-Rojo Rafael , Eckels Edward C. , Fernandez Julio M. 
Published: April 2018

AbstractMagnetic tape heads are ubiquitously used to read and record on magnetic tapes in technologies as diverse as old VHS tapes, modern hard drive disks, or magnetic bands on credit cards. Their design highlights the ability to convert electric signals into fluctuations of the magnetic field at very high frequencies, which is essential for the high density storage demanded nowadays. Here, we twist this conventional use of tape heads to implement one in a new magnetic tweezers design, which offers the unique capability of changing the force with a bandwidth of ~ 10 kHz. We calibrate our instrument by developing an analytical expression that predicts the magnetic force acting on a superparamagnetic bead based on the Karlqvist approximation of the magnetic field created by a tape head. This theory is validated by measuring the force dependence of protein L unfolding/folding step sizes, and the folding properties of the R3 talin domain. We demonstrate the potential of our instrument by carrying out millisecond-long quenches to capture the formation of the ephemeral molten globule state in protein L, which has never been observed before. Our instrument provides for the first time the capability of interrogating individual molecules under fast-changing forces with a control and resolution below a fraction of a pN, opening a range of novel force spectroscopy protocols to study protein dynamics under force.
Investigating the effect of Target of Rapamycin kinase inhibition on theChlamydomonas reinhardtiiphosphoproteome: from known homologs to new targets
Authors: Werth Emily G. , McConnell Evan W. , Couso Inmaculada , Perrine Zoee , Crespo Jose L. , Umen James G. , Hicks Leslie M. 
Published: April 2018

SummaryTarget of Rapamycin (TOR) kinase is a conserved regulator of cell growth whose activity is modulated in response to nutrients, energy and stress. Key proteins involved in the pathway are conserved in the model photosynthetic microalgaChlamydomonas reinhardtii, but the substrates of TOR kinase and downstream signaling network have not been elucidated. Our study provides a new resource for investigating the phosphorylation networks governed by the TOR kinase pathway in Chlamydomonas.We used quantitative phosphoproteomics to investigate the effects of inhibiting Chlamydomonas TOR kinase on dynamic protein phosphorylation. Wild-type and AZD-insensitive Chlamydomonas strains were treated with TOR-specific chemical inhibitors (rapamycin, AZD8055 and Torin1), after which differentially affected phosphosites were identified.Our quantitative phosphoproteomic dataset comprised 2,547 unique phosphosites from 1,432 different proteins. Inhibition of TOR kinase caused significant quantitative changes in phosphorylation at 258 phosphosites, from 219 unique phosphopeptides.Our results include Chlamydomonas homologs of TOR signaling-related proteins, including a site on RPS6 with a decrease in phosphorylation. Additionally, phosphosites on proteins involved in translation and carotenoid biosynthesis were identified. Follow-up experiments guided by these phosphoproteomic findings in lycopene beta/epsilon cyclase showed that carotenoid levels are affected by TORC1 inhibition and carotenoid production is under TOR control in algae.
A European whitefish linkage map and its implications for understanding genome-wide synteny between salmonids following whole genome duplication
Authors: De-Kayne Rishi , Feulner Philine G.D. 
Published: April 2018

AbstractGenomic datasets continue to increase in size and ease of production for a wider selection of species including non-model organisms. For many of these species highly contiguous and well-annotated genomes are unavailable due to their prohibitive complexity and cost. As a result, a common starting point for genomic work in non-model species is the production of a linkage map, which involves the grouping and relative ordering of genetic markers along the genome. Dense linkage maps facilitate the analysis of genomic data in a variety of ways, from broad scale observations regarding genome structure e.g. chromosome number and type or sex-related structural differences, to fine scale patterns e.g. recombination rate variation and co-localisation of differentiated regions. Here we present both a sex-averaged and sex-specific linkage maps forCoregonus sp. “Albock”containing 5395 single nucleotide polymorphism (SNP) loci across 40 linkage groups to facilitate future investigation into the genomic basis of whitefish adaptation and speciation. The map was produced using restriction-site associated digestion (RAD) sequencing data from two wild-caught parents and 156 F1 offspring in Lep-MAP3. We discuss the differences between our sex-avagerated and sex-specific maps and identify synteny betweenC. sp. “Albock”linkage groups and the Atlantic salmon (Salmo salar) genome. Our synteny analysis confirms that many patterns of homology observed between Atlantic salmon andOncorhynchusandSalvelinusspecies are also shared by members of the Coregoninae subfamily.
A consistent picture of TRPV1 activation emerges from molecular simulations and experiments
Authors: Kasimova Marina A. , Yazici Aysenur Torun , Yudin Yevgen , Granata Daniele , Klein Michael L. , Rohacs Tibor , Carnevale Vincenzo 
Published: April 2018

ABSTRACTAlthough the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes occurring in the pore domain and resulting in ionic conduction have not been identified yet. Here, we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves the rotation of a conserved asparagine in S6 from the S4-S5 linker toward the pore. This rotation is correlated with the dehydration of four peripheral cavities located between S6 and the S4-S5 linker and the hydration of the pore. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, analyze newly available structures and re-examine previously reported water accessibility and mutagenesis experiments. Overall, we provide several independent lines of evidence that corroborate our hypothesis. Finally, we show that the proposed molecular mechanism is compatible with the currently existing idea that in TRPV1 the selectivity filter acts as a secondary gate.
Identification of midbrain neurons essential for vocal communication
Authors: Tschida Katherine , Michael Valerie , Han Bao-Xia , Zhao Shengli , Sakurai Katsuyasu , Mooney Richard , Wang Fan 
Published: April 2018

AbstractVocalizations are an essential medium for communication and courtship in numerous mammalian species ranging from mice to humans. In mammals, the midbrain PAG serves as an obligatory node in a vocalization-related network that spans the forebrain and brainstem1–3, as bilateral lesions of the PAG result in mutism2–5. Despite the PAG’s importance for vocal production, the identity, function, and connectivity of PAG neurons involved in vocalization has remained elusive, in part because the PAG is a functionally and anatomically heterogeneous structure that serves myriad roles including nociception, defensive behaviors, and autonomic regulation6–9. Here we used a viral genetic “tagging” method10,11 to identify a distinct subset of PAG neurons in the male mouse that are selectively activated during the production of ultrasonic vocalizations (USVs) elicited by female cues. Silencing these PAG-USV neurons rendered males mute without affecting their other courtship behaviors and also impaired their ability to attract female mice in a social choice assay. Activating these neurons using chemogenetic or optogenetic methods strongly elevated USV production, even in the absence of female cues. Notably, the timing of individual USVs was entrained to the expiratory phase of breathing but not to the pattern of optogenetic stimulation, suggesting that PAG-USV neural activity initiates and sets the duration of vocal bouts and recruits downstream premotor circuits that precisely pattern vocal output. Consistent with this idea, we found that PAG-USV neurons extend axons into pontine and medullary regions that are speculated to contain premotor central pattern generators important for vocalization3,12,13. These experiments establish the identity of the PAG neurons selectively required for USV production in mice, map their efferent connections, and demonstrate the communicative salience of male USVs in promoting female social affiliation.
Site-specific transgenesis of theD. melanogasterY-chromosome using CRISPR/Cas9
Authors: Buchman Anna , Akbari Omar S. 
Published: April 2018

AbstractDespite the importance of Y-chromosomes in evolution and sex determination, their heterochromatic, repeat-rich nature makes them difficult to sequence and genetically manipulate, and therefore they generally remain poorly understood. For example, theD. melanogasterY-chromosome, one of the best understood, is widely heterochromatic and composed mainly of highly repetitive sequences, with only a handful of expressed genes scattered throughout its length. Efforts to insert transgenes on this chromosome have thus far relied on either random insertion of transposons (sometimes harboring ‘landing sites’ for subsequent integrations) with limited success or on chromosomal translocations, thereby limiting the types of Y-chromosome related questions that could be explored. Here we describe a versatile approach to site-specifically insert transgenes on the Y-chromosome inD. melanogastervia CRISPR/Cas9-mediated HDR. We demonstrate the ability to insert, and detect expression from, fluorescently marked transgenic transgenes at two specific locations on the Y-chromosome, and we utilize these marked Y-chromosomes to detect and quantify rare chromosomal nondisjunction effects. Finally, we discuss how this Y-docking technique could be adapted to other insects to aid in the development of genetic control technologies for the management of insect disease vectors and pests.
Clairvoyante: a multi-task convolutional deep neural network for variant calling in Single Molecule Sequencing
Authors: Luo Ruibang , Sedlazeck Fritz J. , Lam Tak-Wah , Schatz Michael C. 
Published: April 2018

AbstractThe accurate identification of DNA sequence variants is an important, but challenging task in genomics. It is particularly difficult for single molecule sequencing, which has a per-nucleotide error rate of ~5%-15%. Meeting this demand, we developed Clairvoyante, a multi-task five-layer convolutional neural network model for predicting variant type (SNP or indel), zygosity, alternative allele and indel length from aligned reads. For the well-characterized NA12878 human sample, Clairvoyante achieved 99.73%, 97.68% and 95.36% precision on known variants, and 98.65%, 92.57%, 87.26% F1-score for whole-genome analysis, using Illumina, PacBio, and Oxford Nanopore data, respectively. Training on a second human sample shows Clairvoyante is sample agnostic and finds variants in less than two hours on a standard server. Furthermore, we identified 3,135 variants that are missed using Illumina but supported independently by both PacBio and Oxford Nanopore reads. Clairvoyante is available open-source (https://github.com/aquaskyline/Clairvoyante), with modules to train, utilize and visualize the model.
Illuminating microbial metabolic activities in the dark deep ocean with metaproteomics
Authors: Xie Zhang-Xian , Zhang Shu-Feng , Zhang Hao , Kong Ling-Fen , Lin Lin , Wang Da-Zhi 
Published: April 2018

AbstractThe deep ocean is the largest habitat on earth and holds diverse microbial life forms. Significant advances have been made in microbial diversity and their genomic potential in the deep ocean, however, little is known about microbial metabolic activity that is crucial to regulate the bathypelagic carbon sequestration. Here, we characterized proteomes covering large particulate (>0.7 μm), small particulate (0.2-0.7 μm) and dissolved (10 kDa-0.2 μm) fractions collected at a depth of 3000 m in the South China Sea. The Rhodospirillales, SAR324, SAR11, Nitrosinae/Tectomicrobia were the major contributors in the particulate fraction whereas Alteromonadales and viruses dominated the dissolved counterpart. Frequent detection of transcription or translation proteins in the particulate fractions indicated active metabolism of SAR324, Archaea, SAR11, and possible viable surface microbes, e.g. Prochlorococcus. Transporters for diverse substrates were the most abundant functional groups, and numerous spectra of formate dehydrogenases and glycine betaine transporters unveiled the importance of methylated compounds for the survival of deep-sea microbes. Notably, abundant non-viral proteins, especially transporters and cytoplasmic proteins, were detected in the dissolved fraction, indicating their potential roles in nutrient scavenging and the stress response. Our size-based proteomic study implied the holistic microbial activity mostly acting on the labile dissolved organic matter as well as the potential activities of surface microbes and dissolved non-viral proteins in the deep ocean.ImportanceThe deep ocean produces one third of the biological CO2 in the ocean. However, little is known about metabolic activity of the bathypelagic microbial community which is crucial for understanding the biogeochemical cycling of organic matter, especially the formation of bulk refractory dissolved organic matter (DOM), one of the largest reservoirs of reduced carbon on Earth. This study provided the protein evidence firstly including both particulate and dissolved fractions to comprehensively decipher the active microbes and metabolic processes involved in the DOM recycling in the deep ocean. Our data supported the hypothesis of the carbon and energy supply from the labile DOM after the solution of sinking particles to the bathypelagic microbial community.
Introducing ribosomal tandem repeat barcoding for fungi
Authors: Wurzbacher Christian , Larsson Ellen , Bengtsson-Palme Johan , den Wyngaert Silke Van , Svantesson Sten , Kristiansson Erik , Kagami Maiko , Henrik Nilsson R. 
Published: April 2018

AbstractSequence analysis of the various ribosomal genetic markers is the dominant molecular method for identification and description of fungi. However, there is little agreement on what ribosomal markers should be used, and research groups utilize different markers depending on what fungal groups are targeted. New environmental fungal lineages known only from DNA data reveal significant gaps in the coverage of the fungal kingdom both in terms of taxonomy and marker coverage in the reference sequence databases. In order to integrate references covering all of the ribosomal markers, we present three sets of general primers that allow the amplification of the complete ribosomal operon from the ribosomal tandem repeats. The primers cover all ribosomal markers (ETS, SSU, ITS1, 5.8S, ITS2, LSU, and IGS) from the 5’ end of the ribosomal operon all the way to the 3’ end. We coupled these primers successfully with third generation sequencing (PacBio and Nanopore sequencing) to showcase our approach on authentic fungal herbarium specimens. In particular, we were able to generate high-quality reference data with Nanopore sequencing in a high-throughput manner, showing that the generation of reference data can be achieved on a regular desktop computer without the need for a large-scale sequencing facility. The quality of the Nanopore generated sequences was 99.85 %, which is comparable with the 99.78 % accuracy described for Sanger sequencing. With this work, we hope to stimulate the generation of a new comprehensive standard of ribosomal reference data with the ultimate aim to close the huge gaps in our reference datasets.
Buffering gene expression noise by microRNA based feedforward regulation
Authors: Bokes Pavol , Hojcka Michal , Singh Abhyudai 
Published: April 2018

AbstractCells use various regulatory motifs, including feedforward loops, to control the intrinsic noise that arises in gene expression at low copy numbers. Here we study one such system, which is broadly inspired by the interaction between an mRNA molecule and an antagonistic microRNA molecule encoded by the same gene. The two reaction species are synchronously produced, individually degraded, and the second species (microRNA) exerts an antagonistic pressure on the first species (mRNA). Using linear-noise approximation, we show that the noise in the first species, which we quantify by the Fano factor, is sub-Poissonian, and exhibits a nonmonotonic response both to the species lifetime ratio and to the strength of the antagonistic interaction. Additionally, we use the Chemical Reaction Network Theory to prove that the first species distribution is Poissonian if the first species is much more stable than the second. Finally, we identify a special parametric regime, supporting a broad range of behaviour, in which the distribution can be analytically described in terms of the confluent hypergeometric limit function. We verify our analysis against large-scale kinetic Monte Carlo simulations. Our results indicate that, subject to specific physiological constraints, optimal parameter values can be found within the mRNA-microRNA motif that can benefit the cell by lowering the gene-expression noise.
Sexual maturation and embryonic development in octopus: use of energy and antioxidant defence mechanisms usingOctopus mimusas a model
Authors: Olivares Alberto , Rodríguez-Fuentes Gabriela , Mascaró Maite , Sánchez Ariadna , Ortega Karen , Caamal-Monsreal Claudia , Tremblay Nelly , Rosas Carlos 
Published: April 2018

AbstractSexual maturation and reproduction influence the status of a number of physiological processes and consequently the ecology and behaviour of cephalopods. UsingOctopus mimusas model species, the present study examined the changes in biochemical composition that take place during gonadal maturation of octopus females and its consequences in embryo and hatchlings characteristics, including energetic metabolites, digestive enzymes and antioxidant defence mechanisms. A total of 32Octopus mimusadult females were sampled during ovarian maturation; biochemical composition (metabolites and digestive enzymes) of digestive gland (DG) and ovaries (only metabolites) were followed during physiological and functional maturation. Levels of protein (Prot), triacyl glycerol (TG), cholesterol (Chol), glucose (Glu) and glycogen (Gly) were evaluated. The activity of alkaline and acidic enzymes also was measured in DG. Simultaneously, groups of eggs coming from mature females were sampled along development, and metabolites (Prot, TG, Glu, Gly, TG, Chol), digestive enzymes activity (Lipases, alkaline and acidic), antioxidant defence mechanisms and radical oxygen species (ROS) were evaluated. This study shows that ovarium is a site for reserve of some nutrients for reproduction. Presumably, TG where stored at the beginning of the maturation processes followed by Chol, both at the same time were energetically supported by Glu, derived from Gly following gluconeogenic pathways. Nutrients and enzymes (metabolic, digestive and REDOX system) where maintained without significant changes and in a low activity during organogenesis. Our findings suggest that activity was not energetically costly; in contrast, during the embryo growth there was mobilization of nutrients and activation of the metabolic and digestive enzymes. Increments in consumption of yolk and glycogen, and reduction in molecules associated with oxidative stress allowed paralarvae to hatch with the antioxidant defence mechanisms ready to support ROS production.
Classification of the gifted natural product producerStreptomyces roseofacienssp. nov. by polyphasic taxonomy
Authors: van der Aart Lizah T. , Nouinoui Imen , Kloosterman Alexander , Ingual José Mariano , Willemse Joost , Goodfellow Michael , van Wezel Gilles P. 
Published: April 2018

ABSTRACTA novel verticillate strain of streptomycetes,Streptomycesstrain MBT76T, was isolated from the QinLing mountains, which harbours more than 40 biosynthetic gene clusters for natural products. Here we present full taxonomic classification of strain MBT76T, and show that it has chemotaxonomic, genomic and morphological properties consistent with its classification in the genusStreptomyces. Strain MBT76Tis part of the cluster of Streptoverticillates, a group within the genusStreptomycesthat has characteristic whorl-forming spores produced in chains along the lateral wall of the hyphae. Multi-locus sequence analysis based on five housekeeping gene alleles showed that MBT76Tis closely related toStreptomyces hiroshimensis. Average Nucleotide Identification (ANI) and Genome to Genome Distance Calculation (GGDC) of the genomes of strain MBT76TandS. hiroshimensisseparated them into distinct species. Strain MBT76Trepresents a novel species of the genusStreptomycesfor which we propose the nameStreptomyces roseofacienssp. nov. The type strain is MBT76T(=NCCB 100637T=DSM 106196T). The whole genome of MBT76Thas 7974 predicted open reading frames and a total genome size of 8.64 Mb. Further genomic analysis showed that verticillate streptomycetes lack the sporulation genessgE, and our data suggest that this is a useful genetic marker for the spore-chain morphology of the verticillates.