bluuebunny/crossref_metadata_2025_split huggingface dataset:
ciRS-7 exonic sequence is embedded in a long non-coding RNA locus
Authors: Barrett Steven P. , Parker Kevin R. , Horn Caroline , Mata Miguel , Salzman Julia 
Published: July 2017

AbstractciRS-7 is an intensely studied, highly expressed and conserved circRNA. Essentially nothing is known about its biogenesis, including the location of its promoter. A prevailing assumption has been that ciRS-7 is an exceptional circRNA because it is transcribed from a locus lacking any mature linear RNA transcripts of the same sense. Our interest in the biogenesis of ciRS-7 led us to develop an algorithm to define its promoter. This approach predicted that the human ciRS-7 promoter coincides with that of the long non-coding RNA, LINC00632. We validated this prediction using multiple orthogonal experimental assays. We also used computational approaches and experimental validation to establish that ciRS-7 exonic sequence is embedded in linear transcripts that are flanked by cryptic exons in both human and mouse. Together, this experimental and computational evidence generate a new view of regulation in this locus: (a) ciRS-7 is like other circRNAs, as it is spliced into linear transcripts; (b) expression of ciRS-7 is primarily determined by the chromatin state of LINC00632 promoters; (c) transcription and splicing factors sufficient for ciRS-7 biogenesis are expressed in cells that lack detectable ciRS-7 expression. These findings have significant implications for the study of the regulation and function of ciRS-7, and the analytic framework we developed to jointly analyze RNA-seq and ChlP-seq data reveal the potential for genome-wide discovery of important biological regulation missed in current reference annotations.Author SummarycircRNAs were recently discovered to be a significant product of ‘host’ gene expression programs but little is known about their transcriptional regulation. Here, we have studied the expression of a well-known circRNA named ciRS-7. ciRS-7 has an unusual function for a circRNA; it is believed to be a miRNA sponge. Previously, ciRS-7 was thought to be transcribed from a locus lacking any mature linear isoforms, unlike all other circular RNAs known to be expressed in human cells. However, we have found this to be false; using a combination of bioinformatic and experimental genetic approaches, in both human and mouse, we discovered that linear transcripts containing the ciRS-7 exonic sequence, linking it to upstream genes. This suggests the potential for additional functional roles of this important locus and provides critical information to begin study on the biogenesis of ciRS-7.
Chemical Gating of the Mechanosensitive Piezo1 Channel by Asymmetric Binding of its Agonist Yoda1
Authors: Lacroix Jerome J. , Botello-Smith Wesley M. , Luo Yun 
Published: July 2017

AbstractPiezo proteins are homotrimeric ion channels that play major roles in normal and pathological mechanotransduction signaling in mammalian organisms. Their pharmacological control hence represents a potential therapeutic avenue. Yoda1, a Piezo1-selective small molecule agonist, is the only known selective Piezo modulator. How Yoda1 selectively interacts with Piezo1 and opens its pore is unknown. Here, by engineering and characterizing chimeras, we identified a minimal region responsible for Yoda1 binding. This region is located at the interface between the pore and the putative mechanosensory domains in each subunit. By characterizing hybrid channels containing Yoda1-insensitive and Yoda1-sensitive monomers, we demonstrate that the presence of only one Yoda1-sensitive Piezo1 subunit is sufficient for chemical activation, implicating that the asymmetric binding of Yoda1 to a single subunit enables channel opening. These findings shed light onto the gating mechanisms of Piezo channels and will pave the way for the rationale design of new Piezo channels modulators.
Suppression of Transposable Elements in Leukemic Stem Cells
Authors: Colombo Anthony R. , Zubair Asif , Thiagarajan Devi , Nuzhdin Sergey , Triche Timothy J. , Ramsingh Giridharan 
Published: July 2017

AbstractGenomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing ‘viral mimicry’, causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.
Restoration of Eastern oyster populations with positive density dependence
Authors: Moore Jacob L , Puckett Brandon , Schreiber Sebastian J 
Published: July 2017

ABSTRACTPositive density dependence can create a threshold of population states below which extinction of the population occurs. The existence of this threshold, which can often be a complex, multi-dimensional surface, rather than a single point, is of particular importance in degraded populations for which there is a desire for successful restoration. Here, we incorporated positive density dependence into a closed, size- and age-structured integral projection model parameterized with empirical data from an Eastern oyster,Crassostrea virginica, population in Pamlico Sound, North Carolina. To understand the properties of the threshold surface, and implications for restoration, we introduced a general method based on a linearization of the threshold surface at its unique, unstable equilibrium. We estimated the number of oysters of a particular age (i.e. stock enhancement), or the surface area of hard substrate required (i.e. habitat enhancement), to move a population from an extinction trajectory to a persistent trajectory. The location of the threshold surface was strongly affected by changes in the amount of local larval retention. Traditional stock enhancement with oysters less than a year old (i.e. spat) required three times as many oysters relative to stock enhancement with oysters between ages three and seven, while the success of habitat enhancement depended upon the initial size distribution of the population. The methodology described here demonstrates the importance of considering positive density dependence in oyster populations, and also provides insights into effective management and restoration strategies when dealing with a high dimensional threshold separating extinction and persistence.
Accurate detection of complex structural variations using single molecule sequencing
Authors: Sedlazeck Fritz J. , Rescheneder Philipp , Smolka Moritz , Fang Han , Nattestad Maria , Haeseler Arndt von , Schatz Michael C. 
Published: July 2017

AbstractStructural variations (SVs) are the largest source of genetic variation, but remain poorly understood because of limited genomics technology. Single molecule long read sequencing from Pacific Biosciences and Oxford Nanopore has the potential to dramatically advance the field, although their high error rates challenge existing methods. Addressing this need, we introduce open-source methods for long read alignment (NGMLR,https://github.com/philres/ngmlr) and SV identification (Sniffles,https://github.com/fritzsedlazeck/Sniffles) that enable unprecedented SV sensitivity and precision, including within repeat-rich regions and of complex nested events that can have significant impact on human disorders. Examining several datasets, including healthy and cancerous human genomes, we discover thousands of novel variants using long reads and categorize systematic errors in short-read approaches. NGMLR and Sniffles are further able to automatically filter false events and operate on low amounts of coverage to address the cost factor that has hindered the application of long reads in clinical and research settings.
An MM and QM Study of Biomimetic Catalysis of Diels-Adler Reactions Using Cyclodextrins
Authors: Chen Wei , Sun Lipeng , Tang Zhiye , Chang Chia-en A. 
Published: July 2017

AbstractWe performed computational research to investigate the mechanism by which cyclodextrins (CDs) catalyze Diels-Alder reactions between 9-anthracenemethanol and N-cyclohexylmaleimide. Hydrogen bonds (Hbonds) between N-cyclohexylmaleimide and the hydroxyl groups of cyclodextrins were suggested to play an important role in the catalysis.However, our free energy calculations and molecular dynamics simulations showed that these Hbonds are not stable, and quantum mechanics calculations suggested that the reaction is not promoted by these Hbonds. The binding of 9-anthracenemethanol and N-cyclohexylmaleimide to cyclodextrins was the key to the catalysis. Cyclodextrins act as a container to hold the two reactants in the cavity, pre-organizes them for the reactions, and thus reduces the entropy penalty to the activation free energy. Dimethyl-β-CD was a better catalyst for this specific reaction than β-CD because of its stronger van der Waals interaction with the pre-organized reactants and better performance in reducing the activation energy. This computational work sheds light on the mechanism of the catalytic reaction by cyclodextrins and introduces new perspectives of supramolecular catalysis.
Revealing mechanisms of infectious disease transmission through empirical contact networks
Authors: Sah Pratha , Otterstatter Michael , Leu Stephan T. , Leviyang Sivan , Bansal Shweta 
Published: July 2017

AbstractThe spread of pathogens fundamentally depends on the underlying contacts between individuals. Modeling infectious disease dynamics through contact networks is sometimes challenging, however, due to a limited understanding of pathogen transmission routes and infectivity. We developed a novel tool, INoDS (Identifying Network models of infectious Disease Spread) that estimates the predictive power of empirical contact networks to explain observed patterns of infectious disease spread. We show that our method is robust to partially sampled contact networks, incomplete disease information, and enables hypothesis testing on transmission mechanisms. We demonstrate the applicability of our method in two host-pathogen systems:Crithidia bombiin bumble bee colonies and Salmonella in wild Australian sleepy lizard populations. The performance of INoDS in synthetic and complex empirical systems highlights its role in identifying transmission pathways of novel or neglected pathogens, as an alternative approach to laboratory transmission experiments, and overcoming common data-collection constraints.
A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery
Authors: Chen Wei , Tang Zhiye , Cholko Tim , Chang Chia-en A. 
Published: July 2017

AbstractThe activities of CDK8 with partner Cyclin C (CycC) are a common feature of many diseases, especially cancers. Here we report the study of dynamic behaviors and energy profiles of 13 CDK8/CycC systems, including the DMG-in and DMG-out conformations as well as 5 type I ligands and 5 type II ligands, with all-atom unbiased molecular dynamics (MD) simulations. We observed numerous regional motions within CDK8, which move in concert to form five major protein motions. The motion of the activation loop doesn’t appear to influence the binding of both types of ligands. Type I ligands remarkably reduce the motion of the C-terminal tail through the strong cation-π interaction between the ligands and ARG356, and type II ligands stabilize the αC helix by forming stable hydrogen bonds with GLU66. The MD calculations also confirmed the importance of CycC to the stability of the CDK8 system as well as the ligand binding. The MMPB/SA results show that van der Waals interaction is the main driving force for the binding of both types of ligands, but electrostatic energy and entropy penalty plays important roles in the binding of type II ligands. The volume analysis results indicate that the induced fitting theory applies in the binding of type I ligands. These results would help to improve the affinities of the existing ligands. Our MD work is complementary to crystal structures and may have implications in the development of new CDK8 inhibitors as well as in the field of drug discovery.
Transient states and barriers from molecular simulations and milestoning theory: kinetics in ligand-protein recognition and compound design
Authors: Tang Zhiye , Chen Si-Han , Chang Chia-en A. 
Published: July 2017

AbstractThis study applies a novel computational strategy to investigate molecular recognition and binding kinetics using five pyrazolourea ligands dissociating from cyclin-dependent kinase 8 with cyclin C (CDK8/CycC) as an example. The computed free energy barriers guide designing compounds using the transient conformations unavailable in experiments. The intermediates and their free energy profile during ligand association and discussion processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. We used metadynamics and a pathway search method to sample pathways and applied combined reduced dimensionality, molecular dynamics (MD) simulations and milestoning theory to construct the free energy profile and estimate the residence time. The binding free energy and the trend of binding kinetics agreed with experiments. We explain the why of the barriers and the kinetics and use the information to assist ligand design. Guided by a barrier of a ligand passing an αC helix and activation loop, we introduced one hydroxyl group to parent compounds to design our ligands with increased residence time and validated our prediction by experiments. This work provides a novel and robust approach to investigate dissociation kinetics of large and flexible systems for understanding unbinding mechanisms and designing new small molecule drugs with desired binding kinetics.Significance StatementThe transient conformations during ligand binding/unbinding control non-covalent binding kinetics. However, the transient structures and their free energy landscape of flexible ligand-protein systems are unavailable in experiments and challenging to model. Due to lack of understanding in binding kinetics, even scientists know that kinetic properties can be important in drug development, calculations using the intermediate states to design ligands with preferred binding kinetics are absent. We overcome these challenges and compute ligand-protein unbinding free energy profile using a novel method with molecular dynamics simulations, reduced dimensionality, and milestoning theory to deepen our understanding in molecular recognition. We also designed compounds based on the computed free energy barriers and experimentally validated that our designed compound can increase residence time.
Genetics of vaccination-related narcolepsy
Authors: Ollila Hanna M. , Wennerstrom Annika , Partinen Markku , Mignot Emmanuel , Saarela Janna , Kirjavainen Turkka , Hublin Christer , Schneider Logan D. , Himanen Sari-Leena , Saarenpää-heikkilä Outi , Saavalainen Paivi , Tienari Pentti J. , Vaarala Outi , Perola Markus 
Published: July 2017

AbstractNarcolepsy type 1 is a severe hypersomnia affecting 1/3000 individuals. It is caused by a loss of neurons producing hypocretin/orexin in the hypothalamus. In 2009/2010, an immunization campaign directed towards the new pandemic H1N1 Influenza-A strain was launched and increased risk of narcolepsy reported in Northern European countries following vaccination with Pandemrix®, an adjuvanted H1N1 vaccine resulting in ~250 vaccination-related cases in Finland alone. Using whole genome sequencing data of 2000 controls, exome sequencing data of 5000 controls and HumanCoreExome chip genotypes of 81 cases with vaccination-related narcolepsy and 2796 controls, we, built a multilocus genetic risk score with established narcolepsy risk variants. We also analyzed, whether novel risk variants would explain vaccine-related narcolepsy. We found that previously discovered risk variants had strong predictive power (accuracy of 73% and P<2.2*10−16; and ROC curve AUC 0.88) in vaccine-related narcolepsy cases with only 4.9% of cases being assigned to the low risk category. Our findings indicate genetic predisposition to vaccine-triggered narcolepsy, with the possibility of identifying 95% of people at risk.
Identification of disease resistance genes from a Chinese wild 1 grapevine (Vitis davidii) by analysing grape transcriptomes and transgenic Arabidopsis plants
Authors: Zhang Ying , Yao Jia-Long , Feng Hu , Jiang Jianfu , Fan Xiucai , Sun Haisheng , Jia Yun-Fei , Zhu Yanyan , Wang Ran , Liu Chonghuai 
Published: July 2017

HighlightTranscription profiles showed that 20 candidate genes were obviously co-expressed at 12 hpi in 30Vitis davidii.VdWRKY53 trancription factor enhanced the resisitance in grapevine and Arabidopsis.AbstractThe molecular mechanisms underlying disease tolerance in grapevines remain uncharacterized, even though there are substantial differences in the resistance of grapevine species to fungal and bacterial diseases. In this study, we identified genes and genetic networks involved in disease resistance in grapevines by comparing the transcriptomes of a strongly resistant clone of Chinese wild grapevine (Vitis davidiicv. Ciputao 941,DAC) and a susceptible clone of European grapevine (Vitis viniferacv. Manicure Finger,VIM) before and after infection with white rot disease (Coniella diplodiella). Disease resistance-related genes were triggered inDACapproximately 12 hours post infection (hpi) withC. diplodiella. Twenty candidate resistant genes were co-expressed inDAC. One of these candidate genes,VdWRKY53(GenBank accessionKY124243), was over-expressed in transgenicArabidopsis thalianaplants and was found to provide these plants with enhanced resistance toC. diplodiella,Pseudomonas syringaepvtomatoPDC3000, andGolovinomyces cichoracearum. This result indicates thatVdWRKY53may be involved in nonspecific resistance via interaction with fungal and oomycete elicitor signals and the activation of defence gene expression. These results provide potential gene targets for molecular breeding to develop resistant grape cultivars.
Insulin Does Not AugmentIn VitroTumor Growth Under A Hyperglycemia-Mimicking Milieu And In A Calorie Restriction-Resembling Manner
Authors: Liao Tao , Li Xiao-Hui , Chen Yan-Ping , Tan Li-Li , Zhang Ji-Da , Huang Xin-An , Xu Qin , Huang Sui-Qing , Li Chang-Qing , Zeng Qing-Ping 
Published: July 2017

AbstractBackgroundWhether insulin enhances or represses tumor cell proliferation remains debating and inconclusive although epidemiological data indicated insulin use raises a risk of cancer incidence in patients with diabetes mellitus (DM).Methodology/Principle FindingsWe cultured rat pituitary adenoma cells in a high-glucose medium to simulate hyperglycemia occurring in DM patients. Upon incubation with or without insulin, repressed tumor cell proliferation and downregulated tumor marker expression occur accompanying with mitigated oxidative stress and compromised apoptosis. Mechanistically, insulin resistance-abrogated glucose uptake was suggested to create an intracellular low-glucose milieu, leading to cellular starvation resembling calorie restriction (CR). While downregulation of insulin-like growth factor 1 (IGF-1) occurring in CR was validated, oncogene downregulation and tumor suppressor gene upregulation seen in CR was also replicated byNOS2knockdown.Conclusions/SignificanceCellular starvation can exert CR-like anti-tumor effects regardless of insulin presence or absence.
PhaMers identifies novel bacteriophage sequences from thermophilic hot springs
Authors: Deaton Jonathan , Yu Feiqiao Brian , Quake Stephen R. 
Published: July 2017

AbstractMetagenomic sequencing approaches have become popular for the purpose of dissecting environmental microbial diversity, leading to the characterization of novel microbial lineages. In addition of bacterial and fungal genomes, metagenomic analysis can also reveal genomes of viruses that infect microbial cells. Because of their small genome size and limited knowledge of phage diversity, discovering novel phage sequences from metagenomic data is often challenging. Here we describe PhaMers (Phagek-Mers). a phage identification tool that uses supervised learning to classify metagenomic contigs as phage or non-phage on the basis of tetranucleotide frequencies. a technique that does not depend on existing gene annotations. PhaMers compares the tetranucleotide frequencies of metagenomic contigs to phage and bacteria references from online databases. resulting in assignments of lower level phage taxonomy based on sequence similarity. Using PhaMers. we identified 103 novel phage sequences from hot spring samples of Yellowstone National Park based on data generated from a microfluidic-based minimetagenomic approach. We analyzed assembled contigs over 5 kbp in length using PhaMers and compared the results with those generated by VirSorter, a publicly available phage identification and annotation package. We analyzed the performance of phage genome prediction and taxonomic classification using PhaMers. and presented putative hosts and taxa for some of the novel phage sequences. Finally. mini-metagenomic occurrence profiles of phage and prokaryotic genomes were used to verify putative hosts.
Parallel loss of symbiosis genes in relatives of nitrogen-fixing non-legumeParasponia
Authors: van Velzen Robin , Holmer Rens , Bu Fengjiao , Rutten Luuk , van Zeijl Arjan , Liu Wei , Santuari Luca , Cao Qingqin , Sharma Trupti , Shen Defeng , Roswanjaya Yuda P. , Wardhani Titis A.K. , Kalhor Maryam Seifi , Jansen Joëlle , van den Hoogen D. Johan , Güngör Berivan , Hartog Marijke , Hontelez Jan , Verver Jan , Yang Wei-Cai , Schijlen Elio , Repin Rimi , Schilthuizen Menno , Schranz M. Eric , Heidstra Renze , Miyata Kana , Fedorova Elena , Kohlen Wouter , Bisseling Ton , Smit Sandra , Geurts Rene 
Published: July 2017

AbstractRhizobium nitrogen-fixing nodules are a well-known trait of legumes, but nodules also occur in other plant lineages either with rhizobium or the actinomyceteFrankiaas microsymbiont. The widely accepted hypothesis is that nodulation evolved independently multiple times, with only a few losses. However, insight in the evolutionary trajectory of nodulation is lacking. We conducted comparative studies usingParasponia(Cannabaceae), the only non-legume able to establish nitrogen fixing nodules with rhizobium. This revealed thatParasponiaand legumes utilize a large set of orthologous symbiosis genes. Comparing genomes ofParasponiaand its non-nodulating relativeTremadid not reveal specific gene duplications that could explain a recent gain of nodulation inParasponia. Rather,Tremaand other non-nodulating species in the Order Rosales show evidence of pseudogenization or loss of key symbiosis genes. This demonstrates that these species have lost the potential to nodulate. This finding challenges a long-standing hypothesis on evolution of nitrogen-fixing symbioses, and has profound implications for translational approaches aimed at engineering nitrogen-fixing nodules in crop plants.