bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene-centric intra- and inter-clade recombination in a context ofEsche-richia colisubpopulations
Authors: Kang Yu , Shi Xing , Yuan Lina , Chu Yanan , Chen Fei , He Zilong , Gao Zhancheng , Jia Xinmiao , Lin Qiang , Ma Qin , Wang Jian , Fu Rongrong , Wu Jiayan , Xiao Jingfa , Hu Songnian , Yu Jun 
Published: April 2017

ABSTRACTRecombination is one of the most important mechanisms of prokaryotic species evolution but its exact roles are still in debate. Here we try to infer genome-wide recombination events within a species uti-lizing a dataset of 104 complete genomes ofEscherichia colifrom diverse origins, among which 45 from world-wide animal-hosts are in-house sequenced using SMRT (single-molecular real time) technology.Two major clades are identified based on evidences of ecological and physiological characteristics, as well as distinct genomic features implying scarce inter-clade genetic exchange. By comparing the synteny of identical fragments genome-widely searched for each genome pair, we achieve a fine-scale map of re-combination within the population. The recombination is rather extensive within clade, which is able to break linkages between genes but does not interrupt core genome framework and primary metabolic port-folios possibly due to natural selection for physiological compatibility and ecological fitness. Meanwhile,the recombination between clades declines drastically as the phylogenetic distance increases, generally 10-fold reduced than those of the intra-clade, which establishes genetic barrier between clades. These empirical data of recombination suggest its critical role in the early stage of speciation, where recombina-tion rate differs according to phylogentic distance. The extensive intra-clade recombination coheres sister strains into a quasi-sexual group and optimizes genes or alleles to streamline physiological activities,whereas shapely declined inter-clade recombination split the population into clades adaptive to divergent ecological niches.Significance StatementRoles of recombination in species evolution have been debated for decades due to difficulties in inferring recombination events during the early stage of speciation, especially when recombination is always complicated by frequent gene transfer events of bacterial genomes. Based on 104 high-quality completeE. coligenomes, we infer gene-centric dynamics of recombination in the formation of twoE. coliclades or subpopulations, and recombination is found to be rather intensive in a within-clade fashion, which forces them to be quasi-sexual. The recombination events can be mapped among individual genomes in the context of genes and their variations; decreased between-clade and increased intra-claderecombination engender a genetic barrier that further encourages clade-specific secondary metabolic portfolios for better environmental adaptation. Recombination is thus a major force that accelerates bacterial evolution to fit ecological diversity.
RNA-seq 2G: online analysis of differential gene expression with comprehensive options of statistical methods
Authors: Zhang Zhe , Zhang Yuanchao , Evans Perry , Chinwalla Asif , Taylor Deanne 
Published: April 2017

ABSTRACTRNA-seq has become the most prevalent technology for measuring genome-wide gene expression, but the best practices for processing and analysing RNA-seq data are still an open question. Many statistical methods have been developed to identify genes differentially expressed between sample groups from RNA-seq data. These methods differ by their data distribution assumptions, choice of statistical test, and computational resource requirements. Over 25 methods of differential expression detection were validated and made available through a user-friendly web portal, RNA-seq 2G. All methods are suitable for analysing differential gene expression between two groups of samples. They commonly use a read count matrix derived from RNA-seq data as input and statistically compare groups for each gene. The web portal uses a Shiny app front-end and is hosted by a cloud-based server provided by Amazon Web Service. The comparison of methods showed that the data distribution assumption is the major determinant of differences between methods. Most methods are more likely to find that longer genes are differentially expressed, which substantially impacts downstream gene set-level analysis. Combining results from multiple methods can potentially diminish this bias. RNA-seq 2G makes the analysis of RNA-seq data more accessible and efficient, and is freely available athttp://rnaseq2g.awsomics.org.
Brainwide mapping of endogenous serotonergic transmission via chemogenetic-fMRI
Authors: Giorgi Andrea , Migliarini Sara , Gritti Marta , Galbusera Alberto , Maddaloni Giacomo , De Luca Maria Antonietta , Tonini Raffaella , Gozzi Alessandro , Pasqualetti Massimo 
Published: April 2017

ABSTRACTSerotonergic transmission affects behaviours and neuro-physiological functions via the orchestrated recruitment of distributed neural systems. It is however unclear whether serotonin’s modulatory effect entails a global regulation of brainwide neural activity, or is relayed and encoded by a set of primary functional substrates. Here we combine DREADD-based chemogenetics and mouse fMRI, an approach we term “chemo-fMRI”, to causally probe the brainwide substrates modulated by phasic serotonergic activity. We describe the generation of a conditional knock-in mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that chemogenetic stimulation of the serotonin system does not affect global brain activity, but results in region-specific activation of a set of primary target regions encompassing parieto-cortical, hippocampal, and midbrain structures, as well as ventro-striatal components of the mesolimbic reward systems. Many of the activated regions also exhibit increased c-Fos immunostaining upon chemogenetic stimulation in freely-behaving mice, corroborating a neural origin for the observed functional signals. These results identify a set of regional substrates that act as primary functional targets of endogenous serotonergic stimulation, and establish causation between phasic activation of serotonergic neurons and regional fMRI signals. They further highlight a functional cross-talk between serotonin and mesolimbic dopamine systems hence providing a novel framework for understanding serotonin dependent functions and interpreting data obtained from human fMRI studies of serotonin modulating agents.
Inflated false negative rates undermine reproducibility in task-based fMRI
Authors: Lohmann G. , Stelzer J. , Müller K. , Lacosse E. , Buschmann T. , Kumar V.J. , Grodd W. , Scheffler K. 
Published: April 2017

AbstractReproducibility is generally regarded as a hallmark of scientific validity. It can be undermined by two very different factors, namely inflated false positive rates or inflated false negative rates. Here we investigate the role of the second factor, i.e. the degree to which true effects are not detected reliably. The availability of large public databases and also supercomputing allows us to tackle this problem quantitatively. Specifically, we estimated the reproducibility in task-based fMRI data over different samples randomly drawn from a large cohort of subjects obtained from the Human Connectome Project. We use the full cohort as a standard of reference to approximate true positive effects, and compute the fraction of those effects that was detected reliably using standard software packages at various smaller sample sizes. We found that with standard sample sizes this fraction was less than 25 percent. We conclude that inflated false negative rates are a major factor that undermine reproducibility. We introduce a new statistical inference algorithm based on a novel test statistic and show that it improves reproducibility without inflating false positive rates.
Concurrent tACS-fMRI reveals causal influence of power synchronized neural activity on resting state fMRI connectivity
Authors: Bächinger Marc , Zerbi Valerio , Moisa Marius , Polania Rafael , Liu Quanying , Mantini Dante , Ruff Christian , Wenderoth Nicole 
Published: April 2017

AbstractResting state fMRI (rs-fMRI) is commonly used to study the brain’s intrinsic neural coupling, which reveals specific spatiotemporal patterns in the form of resting state networks (RSN). It has been hypothesized that slow rs-fMRI oscillations (<0.1 Hz) are driven by underlying electrophysiological rhythms that typically occur at much faster timescales (>5 Hz); however, causal evidence for this relationship is currently lacking. Here we measured rs-fMRI in humans while applying transcranial alternating current stimulation (tACS) to entrain brain rhythms in left and right sensorimotor cortices.The two driving tACS signals were tailored to the individual’s alpha rhythm (8-12 Hz) and fluctuated in amplitude according to a 1 Hz power envelope. We entrained the left versus right hemisphere in accordance to two different coupling modes where either alpha oscillations were synchronized between hemispheres (phase-synchronized tACS) or the slower oscillating power envelopes (power-synchronized tACS).Power-synchronized tACS significantly increased rs-fMRI connectivity within the stimulated RSN compared to phase-synchronized or no tACS. This effect outlasted the stimulation period and tended to be more effective in individuals who exhibited a naturally weak interhemispheric coupling. Using this novel approach, our data provide causal evidence that synchronized power fluctuations contribute to the formation of fMRI-based RSNs. Moreover, our findings demonstrate that the brain’s intrinsic coupling at rest can be selectively modulated by choosing appropriate tACS signals, which could lead to new interventions for patients with altered rs-fMRI connectivity.Significance StatementResting state fMRI has become an important tool to estimate brain connectivity. However, relatively little is known about how slow hemodynamic oscillations measured with fMRI relate to electrophysiological processes.It was suggested that slowly fluctuating power envelopes of electrophysiological signals synchronize across brain areas and that the topography of this activity is spatially correlated to resting state networks derived from rs-fMRI. Here we take a novel approach to address this problem and establish a causal link between the power fluctuations of electrophysiological signals and rs-fMRI via a new neuromodulation paradigm, which exploits these power-synchronization mechanisms.These novel mechanistic insights bridge different scientific domains and are of broad interest to researchers in the fields of Medical Imaging, Neuroscience, Physiology and Psychology.
karyoploteR: an R/Bioconductor package to plot customizable linear genomes displaying arbitrary data
Authors: Gel Bernat , Serra Eduard 
Published: April 2017

AbstractMotivationData visualization is a crucial tool for data exploration, analysis and interpretation. For the visualization of genomic data there lacks a tool to create customizable non-circular plots of whole genomes from any species.ResultsWe have developed karyoploteR, an R/Bioconductor package to create linear chromosomal representations of any genome with genomic annotations and experimental data plotted along them. Plot creation process is inspired in R base graphics, with a main function creating karyoplots with no data and multiple additional functions, including custom functions written by the end-user, adding data and other graphical elements. This approach allows the creation of highly customizable plots from arbitrary data with complete freedom on data positioning and representation.AvailabilitykaryoploteR is released under Artistic-2.0 License. Source code and documentation are freely available through Bioconductor (http://www.bioconductor.org/packages/karyoploteR)Contactbgel@igtp.cat
The date palm (Phoenix dactyliferaL.) in Siwa oasis (Egypt): How ethnographic, morphometric, and genetic analyses together explain the local agrobiodiversity
Authors: Battesti Vincent , Gros-Balthazard Muriel , Ogéron Clémence , Ivorra Sarah , Terral Jean-Frédéric , Newton Claire 
Published: April 2017

AbstractThe agrobiodiversity of the Siwa oasis (in Egypt), located at the crossroads of ancient Trans-Saharan routes, is evaluated in this article focusing on the date palm (Phoenix dactyliferaL.), the oasis “ecosystem engineer”. This assessment confronts different ontologies: diversity as expressed and maintained by the folk categorization system of the Siwa inhabitants (through the results of an ethnographical analysis) and diversity described by genetic sciences and a morphometric tool based on the size and geometry of the seeds. This work is also an opportunity to evaluate this tool intended for archaeobotany. Beyond a simple instrumentalization of one discipline by another, this study offers a space of mutual enrichment: on the relative importance of the feral and cultivated date palms, the local relevance of the concept of “cultivar” and the confirmation of the existence of “ethnovarieties”.
Loss and gain of function experiments implicate TMEM18 as a mediator of the strong association between genetic variants at human Chromosome 2p25.3 and obesity
Authors: Larder Rachel , Michelle Sim M. F. , Gulati Pawan , Antrobus Robin , Loraine Tung Y.C. , Rimmington Debra , Ayuso Eduard , Polex-Wolf Joseph , Lam Brian Y.H. , Dias Cristina , Logan Darren W. , Virtue Sam , Bosch Fatima , Yeo Giles S.H. , Saudek Vladimir , O’Rahilly Stephen , Coll Anthony P. 
Published: April 2017

AbstractAn intergenic region of human Chromosome 2 (2p25.3) harbours genetic variants which are among those most strongly and reproducibly associated with obesity. The molecular mechanisms mediating these effects remain entirely unknown. The gene closest to these variants isTMEM18, encoding a transmembrane protein localised to the nuclear membrane. The expression ofTmem18within the murine hypothalamic paraventricular nucleus was altered by changes in nutritional state, with no significant change seen in three other closest genes. Germline loss ofTmem18in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression ofTmem18in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We confirmed the nuclear membrane localisation of TMEM18 but provide new evidence that it is has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis thatTMEM18itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.
A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data
Authors: Bertl Johanna , Guo Qianyun , Juul Malene , Besenbacher Søren , Muhlig Nielsen Morten , Hornshøj Henrik , Skou Pedersen Jakob , Hobolth Asger 
Published: April 2017

AbstractBackgroundDetailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration.ResultsTo take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures.ConclusionWe find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.
Replication Fork Slowing and Stalling are Distinct, Checkpoint-Independent Consequences of Replicating Damaged DNA
Authors: Iyer Divya Ramalingam , Rhind Nicholas 
Published: April 2017

AbstractIn response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions, we have analyzed the checkpoint in the fission yeastSchizosaccharomyces pombeusing a single-molecule DNA combing assay, which allows us to unambiguously separate the contribution of origin and fork regulation towards replication slowing, and allows us to investigate the behavior of individual forks. Moreover, we have interrogated the role of forks interacting with individual sites of damage by using three damaging agents—MMS, 4NQO and bleomycin—that cause similar levels of replication slowing with very different frequency of DNA lesions. We find that the checkpoint slows replication by inhibiting origin firing, but not by decreasing fork rates. However, the checkpoint appears to facilitate replication of damaged templates, allowing forks to more quickly pass lesions. Finally, using a novel analytic approach, we rigorously identify fork stalling events in our combing data and show that they play a previously unappreciated role in shaping replication kinetics in response to DNA damage.Author SummaryFaithful duplication of the genome is essential for genetic stability of organisms and species. To ensure faithful duplication, cells must be able to replicate damaged DNA. To do so, they employ checkpoints that regulate replication in response to DNA damage. However, the mechanisms by which checkpoints regulate DNA replication forks, the macromolecular machines that contain the helicases and polymerases required to unwind and copy the parental DNA, is unknown. We have used DNA combing, a single-molecule technique that allows us to monitor the progression of individual replication forks, to characterize the response of fission yeast replication forks to DNA damage that blocks the replicative polymerases. We find that forks pass most lesions with only a brief pause and that this lesion bypass is checkpoint independent. However, at a low frequency, forks stall at lesions, and that the checkpoint is required to prevent these stalls from accumulating single-stranded DNA. Our results suggest that the major role of the checkpoint is not to regulate the interaction of replication forks with DNA damage,per se, but to mitigate the consequences of fork stalling when forks are unable to successfully navigate DNA damage on their own.
Hypocretin underlies the evolution of sleep loss in the Mexican cavefish
Authors: Jaggard James B. , Stahl Bethany A. , Lloyd Evan , Prober David A. , Duboue Erik R. , Keene Alex C. 
Published: April 2017

AbstractThe duration of sleep varies dramatically between species, yet little is known about genetic bases or evolutionary factors driving this variation in behavior. The Mexican cavefish,Astyanax mexicanus, exists as surface populations that inhabit rivers, and multiple independently derived cave populations with convergent evolution on sleep loss. The number of Hypocretin/Orexin (HCRT)-positive hypothalamic neurons is increased significantly in cavefish, and HCRT is upregulated at both the transcript and protein levels. Pharmacological or genetic inhibition of HCRT signaling increases sleep duration in cavefish without affecting sleep in surface fish, suggesting enhanced HCRT signaling underlies sleep loss in cavefish. Ablation of the lateral line or starvation, manipulations that selectively promote sleep in cavefish, inhibithcrtexpression in cavefish while having little effect in surface fish. These findings provide the first evidence of genetic and neuronal changes that contribute to the evolution of sleep loss, and support a conserved role for HCRT in sleep regulation.
Exhaustive capture of biological variation in RNA-seq data through k-mer decomposition
Authors: Audoux Jérôme , Philippe Nicolas , Chikhi Rayan , Salson Mikaël , Gallopin Mélina , Gabriel Marc , Le Coz Jérémy , Commes Thérèse , Gautheret Daniel 
Published: April 2017

AbstractEach individual cell produces its own set of transcripts, which is the combined result of genetic variation, transcription regulation and post-transcriptional processing. Due to this combinatorial nature, obtaining the exhaustive set of full-length transcripts for a given species is a never-ending endeavor. Yet, each RNA deep sequencing experiment produces a variety of transcripts that depart from the reference transcriptome and should be properly identified. To address this challenge, we introduce a k-mer-based software protocol for capturing local RNA variation from a set of standard RNA-seq libraries, independently of a reference genome or transcriptome. Our software, called DE-kupl, analyzes k-mer contents and detects k-mers with differential abundance directly from the raw data files, prior to assembly or mapping. This enables to retrieve the virtually complete set of unannotated variation lying in an RNA-seq dataset. This variation is subsequently assigned to biological events such as differential lincRNAs, antisense RNAs, splice and polyadenylation variants, introns, expressed repeats, and SNV-harboring or exogenous RNA. We applied DE-kupl to public RNA-seq datasets, including an Epythelial-Mensenchymal Transition model and different human tissues. DE-kupl identified abundant novel events and showed excellent reproducibility when applied to independent deep sequencing experiments. DE-kupl is a new paradigm for analyzing differential RNA-seq data with no preconception on target events, which can also provide fresh insights into existing RNA-seq repositories.